In February 2013, GlaxoSmithKline (GSK)

Transcription

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical
transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK
Clinical Study Register.
The following guiding principles have been applied to the disclosure:
 Information will be excluded in order to protect the privacy of patients and all named
persons associated with the study
 Patient data listings will be completely removed* to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the GSK
Clinical Study Register.
 Aggregate data will be included; with any direct reference to individual patients excluded
*Complete removal of patient data listings may mean that page numbers are no longer consecutively
numbered
CONFIDENTIAL
CONFIDENTIAL
TheGlaxoSmithKline
GlaxoSmithKline
of companies
The
groupgroup
of companies
ZM2008/00140/00
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LOV111821
Division: World Wide Development
Retention Category: GRS019
Information Type: Condensed Clinical Study Report
Title:
A Second Open-Label Extension of a Double-Blind, Parallel,
Phase IV Study to Assess the Efficacy and Safety of Adjunctive
OMACOR® Therapy in Hypertriglyceridemic Subjects Treated
with Antara
Phase:
IV
Compound Number:
GSK2212836
Effective Date:
23-FEB-2009
Description: This was a 24-month, open-label extension study to an 8-week doubleblind study (Study LOV111859/OM5) followed by an 8-week, open-label extension
study (LOV111860/OM5X). Study LOV111859/OM5 was conducted to evaluate
whether combination therapy with OMACOR® (Product name has been changed to
LOVAZA®; omega-3-acid ethyl esters) and Antara (fenofibrate) would result in a greater
reduction in serum triglyceride levels in hypertriglyceridemic subjects than treatment
with fenofibrate alone.
Subject: OMACOR, LOVAZA, GSK2212836, omega-3-acid ethyl esters,
hypertriglyceridemia
Authors:
Indication Studied: Very high triglycerides in those receiving fenofibrate therapy
Initiation Date:
15Mar2006
Completion Date:
NA
Early Termination Date:
07May2008
Date of Report:
23Feb2009
Sponsor Signatory:
(and Medical Officer)
BSc (Hons), MRCP (UK)
CVM Medicines Development Centre
GlaxoSmithKline
The study protocol, any amendments, the informed consent, and any other information
that required pre-approval were reviewed and approved by a national, regional, or
investigational centre ethics committee or institutional review board. This study was
performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard
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Operating Procedures for all processes involved, including the archiving of essential
documents. Written informed consent was obtained from each subject prior to the
performance of any study-specific procedures. Case report forms were provided for each
subject's data to be recorded.
Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
Page
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
1. TITLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
2. INVESTIGATOR(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
3. STUDY CENTER(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
4. PUBLICATION(S) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
5. STUDY PERIOD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
6. PHASE OF DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
7. OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
8. METHODOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
9. NUMBER OF SUBJECTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
10. DIAGNOSIS AND CRITERIA FOR INCLUSION . . . . . . . . . . . . . . . . . . . .
8
11. TREATMENT AND ADMINISTRATION . . . . . . . . . . . . . . . . . . . . . . . . . .
9
12. CRITERIA FOR EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
13. STATISTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
14. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.1. Demography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.2. Efficacy Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14.3. Safety Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
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12
15
15. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
16. DATE OF REPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
14 TABLES, FIGURES, AND GRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
16.2 PATIENT DATA LISTINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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LIST OF TABLES
Page
Table 1 Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2 Demography (Safety Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 3 Serum Triglycerides (MITT Population1) . . . . . . . . . . . . . . . . . . . . . .
Table 4 Difference Between % Change from Baseline to End of Study
OM5X and Study OM5XX in Serum Triglycerides by Additional
Lipid-Lowering Agent Status (MITT Population) . . . . . . . . . . . . . . . . . . . .
Table 5 Secondary Efficacy/Outcome Variables (MITT Population) . . . . . . . .
Table 6 Number of Subjects Retained by Month/Visit . . . . . . . . . . . . . . . . . . .
Table 7 Most Frequent (>3%) Treatment-Emergent Adverse Events (Safety
Population) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 8 Treatment-Emergent Serious Adverse Events (Safety Population) . .
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Abbreviations
AE
ALT
ANOVA
Apo
Apo A-1
Apo B
AST
BMI
CK
CRF
d
DHA
dL
DVT
ECG
EPA
ER
g
GSK
HDL-C
ICH
IEC
IRB
IV
kg
LDL-C
LOCF
m2
mg
MITT
Mm Hg
Non-HDL-C
SAE
SD
TC
TED
TG
TX
U/L
VLDL-C
WBC
Adverse Event
Alanine aminotransferase
Analysis of variance
Apolipoprotein
Apolipoprotein A-1
Apolipoprotein B
Aspartate aminotransferase
Body mass index
Creatine kinase
Case Report Form
day
docosahexaenoic acid
deciliter
Deep vein thrombosis
electrocardiogram
eicosapentaenoic acid
Emergency room
gram
GlaxoSmithKline
High-density lipoprotein cholesterol
International Conference on Harmonisation
Independent Ethics Committee
Institutional Review Board
intravenous
kilogram
Low-density lipoprotein cholesterol
Last observation carried forward
meter squared
milligram
Modified Intent-to-Treat
millimeters mercury
Non-high-density lipoprotein cholesterol
Serious adverse event
Standard deviation
Total cholesterol
Thromboembolitic disease
triglyceride
treatment
Units per liter
Very low-density lipoprotein cholesterol
White blood cell
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Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the
GlaxoSmithKline group of companies
LOVAZA
OMACOR
Antara
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1.
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TITLE
A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to Assess
the Efficacy and Safety of Adjunctive OMACOR®1 Therapy in Hypertriglyceridemic
Subjects Treated with Antara™2
1
OMACOR® was approved in the U.S. in November 2004. The U.S. ownership was previously held by
Reliant Pharmaceuticals Inc. until December 2007 when Reliant was acquired by GlaxoSmithKline.
Furthermore, during the course of this study, the brand name OMACOR® was changed to LOVAZA®.
However, to maintain continuity in the documentation of study OM5XX, the name OMACOR® is the
brand name being used in this clinical study report.
2
GSK are aware that Antara is now a Registered Trademark; however the protocol denoted Antara as a
Trademark.
2.
INVESTIGATOR(S)
This was a large multi-center study.
3.
STUDY CENTER(S)
There were 32 sites in the United States; subjects were enrolled at 25 sites.
4.
PUBLICATION(S)
None at the time of this report.
5.
STUDY PERIOD
15Mar2006 to 01May2008
Study OM5XX was terminated early due to the lack of substantial incremental change in
the primary endpoint lipid values in the original study (Study OM5) and the first
extension (Study OM5X) in subjects receiving the combination of Antara and
OMACOR®.
6.
PHASE OF DEVELOPMENT
IV
7.
OBJECTIVES
The primary objective of this 24-month open-label extension was to assess the continued
efficacy of adjunctive OMACOR® (omega-3-acid ethyl esters) therapy in
hypertriglyceridemic subjects treated with Antara (fenofibrate) in lowering serum
triglyceride (TG) levels.
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The secondary objectives were to evaluate the continued safety of OMACOR® + Antara
during a 24-month open-label extension of the previous 8-week open-label extension
(Study LOV111860/OM5X, referred to hereafter as Study OM5X) to the original 8-week
double-blind study (Study LOV111859/OM5, referred to hereafter as Study OM5), and to
assess the effects of OMACOR® + Antara on other lipids and markers for cardiovascular
risk.
8.
METHODOLOGY
Study LOV111821/OM5XX (referred to hereafter as Study OM5XX) utilized an openlabel design with 7 clinical visits. Visit 1XX in the current study coincided with Visit 4X
of the previous 8-week, open-label study (Study OM5X). All subjects who completed
Study OM5X were to receive open-label Antara (fenofibrate) 130 mg/d plus open-label
OMACOR® 4 g/d for up to an additional 24 months.
9.
NUMBER OF SUBJECTS
One hundred six subjects completed Study OM5X and were eligible for enrollment in
OM5XX. Thirteen declined to participate in Study OM5XX. Table 1 outlines overall
subject disposition for those who entered Study OM5XX.
Table 1
Subject Disposition
Entered Study OM5XX, N
Ongoing in Study as of Month 12 Visit
Completers of 24 month Visit
Modified Intent-to-Treat (MITT) Population1
Safety Population2
Total Number Subjects Withdrawn, N (%)
Withdrawn due to Adverse Events, n (%)
Withdrawn due to Lack of Efficacy, n (%)
Withdrawn for Other Reasons, n (%)
Sponsor Termination, n (%)
93 (100%)
59 (63.4%)
9 (9.7%)
89 (95.7%)
89 (95.7%)
84 (90.3)
2 (2.2)
0
20 (21.5)
62 (66.7)
Data Source: Table 14.1.1, Table 14.1.1a
1. Subjects who have a baseline assessment in Study OM5 and at least one on-therapy Study OM5XX efficacy
assessment.
2. Subjects who received a dose of study medication and returned for at least one safety assessment after
enrollment in Study OM5XX.
10.
DIAGNOSIS AND CRITERIA FOR INCLUSION
Subjects were men and women who had successfully completed the previous open-label
extension study (OM5X) and had met all inclusion and exclusion criteria for the original
double-blind study (OM5) and throughout Study OM5X, or who had a renewed waiver of
a previously approved protocol deviation. The main eligibility criteria for Study OM5
were that subjects be 18 to79 years of age (inclusive) at screening, with fasting serum TG
levels ≥500 mg/dL and <1300 mg/dL (average of Weeks -2 and -1) and BMI ≥ 25 kg/m2
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and ≤43 kg/m2. Subjects enrolled directly from the end of Study OM5X into Study
OM5XX.
11.
TREATMENT AND ADMINISTRATION
Participants received open-label OMACOR® (omega-3-acid ethyl esters;
eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]), orally at a dose of 4 g/d
each evening in 4 capsules (1 g/capsule) and open-label Antara (fenofibrate)
130mg/capsule for up to an additional 24 months.
At the investigator’s discretion, subjects could receive additional lipid-lowering agents at
the end of Study OM5X or anytime throughout the current study to ensure that subjects
received standard of care. Acceptable agents were statins and/or ezetimibe (simvastatin
was suggested in the protocol). The addition of any such agent was considered in the
analysis of the data; see Section 13 for details.
12.
CRITERIA FOR EVALUATION
Primary Outcome/Efficacy Variable. The primary efficacy endpoint was the
difference between the within-group mean percent change from baseline in serum TG
level observed at the end of Study OM5X (average of Weeks 14 and 16 in Study OM5X
minus average of Weeks -2, -1 and 0 in Study OM5) and the mean percent change from
baseline observed at the end of Study OM5XX (endpoint of last observation carried
forward [LOCF] in Study OM5XX minus average of Weeks -2, -1 and 0 in Study OM5).
Secondary Outcome/Efficacy Variable(s). The secondary efficacy endpoints were
serum total cholesterol (TC), very low density lipoprotein-cholesterol (VLDL-C), low
density lipoprotein-cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C),
non-HDL-C, the ratio of TC to HDL-C, apolipoprotein (apo) A-I, and apo B in all
subjects as described for the primary efficacy variable, except that the Study OM5
baseline values for the both apo A-I and apo B were defined as the averages of Weeks -1
and 0 instead of Weeks -2, -1, and 0.
Safety assessments included adverse events, vital signs, hematology and clinical
chemistry laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase
[AST], creatine kinase [CK], fasting glucose, creatinine, total bilirubin, alkaline
phospahatase, sodium, potassium, bicarbonate, blood urea nitrogen, chloride), and
urinalysis.
13.
STATISTICAL METHODS
All qualifying subjects who completed Study OM5X were eligible to enroll in extension
Study OM5XX; therefore, no power calculation was used to determine the sample size
required to demonstrate significant differences in the outcome analyses for
Study OM5XX.
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Efficacy data were analyzed and summarized for the Modified Intent-to-Treat (MITT)
population. The MITT population was defined as subjects who have a baseline
assessment in Study OM5 and at least one on-therapy Study OM5XX efficacy
assessment.
Safety data were analyzed and summarized for the Safety population. The Safety
population was defined as all subjects who received a dose of study medication and
returned for at least 1 safety assessment after enrollment in Study OM5XX. Given that
no appreciable differences were noted between treatment groups (subjects who received
active drug during the Study OM5 double-blind phase versus subjects who received
placebo during the Study OM5 double-blind phase) in the Study OM5 and Study OM5X
analyses, subjects’ data were summarized and analyzed as one pooled group. Those
subjects who received additional lipid-lowering agents were included in the outcome
analyses by applying the method of LOCF to the lipid data measured at the last available
visit before the start of any add-on lipid-lowering medication. All tests of significance,
unless otherwise stated, were performed at a significance level of alpha=0.05, two-sided.
Unless otherwise noted, continuous variables were summarized descriptively using
number of subjects (n), mean, standard deviation (SD), median, minimum, and
maximum, and categorical variables were summarized descriptively using the frequency
counts and the percentage of subjects in each category.
A repeated measures analysis of variance (ANOVA) model was generated to compare
within-group mean percent change from baseline in TG observed at the end of Study
OM5X (average of Weeks 14 and 16 in Study OM5X minus average of Weeks -2, -1 and
0 in Study OM5) and the mean percent change from baseline observed at the end of
Study OM5XX (endpoint of LOCF in Study OM5XX minus average of Weeks -2, -1 and
0 in Study OM5). If the normality assumption was rejected, then the data were ranked
and ANOVA was run on the rank transformed data (ie Kruskal-Wallis ANOVA), and the
medians were presented as the measure of central tendency in lieu of the means.
As a result of early termination of the study by the Sponsor, only 9 of the 93 subjects
(9.7%) enrolled had completed the full 24-month treatment period. However, at 12
months, there were 59 completed subjects and evaluable data were available for 58
subjects. An ad hoc analysis of the primary efficacy variable was therefore performed for
the 58 subjects in the MITT population who had data through Month 12.
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14.
SUMMARY
14.1.
Demography
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Demographic characteristics are summarized in Table 2.
Table 2
Demography (Safety Population)
All Subjects1 (N=89)
Median Values
20:69
52.4 (27-71, 9.99)
Females: Males
Mean Age, years (range, SD)
Race and Ethnicity2
White, n (%)
Hispanic or Latino
American Indian or Alaska Native
Asian
Black or African American
BMI, mean kg/m2 (range, SD)
82 (92.1)
2 (2.2 %)
1 (1.1 %)
3 (3.4 %)
2 (2.2 %)
32.4 (23.6-44.7, 4.59)
Data Source: Table 14.1.2
enrollment in Study OM5XX.
2. Subjects may have reported more than one race and ethnicity
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14.2.
Efficacy Results
Primary Efficacy Results. The differences in median percent change from baseline
triglyceride concentration between the initial (OM5X) and current extension (OM5XX)
studies were not statistically significantly different (Table 3). Results were similar for
subjects who received additional lipid-lowering agents and those who did not (Table 4).
Table 3
Serum Triglycerides (MITT Population1)
OM5 Baseline2
OM5X End-of-Tx3
OM5XX End-of-Tx
% Change from OM5 Baseline to OM5X
End-of-Tx
% Change from OM5 Baseline to OM5XX
Month 124
% Change from OM5 Baseline to OM5XX
End-of-Tx5
Difference Between OM5X and OM5XX %
Changes
P-value6
Completers of
12-month Visit
(N=58)7
716.5
262.8
226.5
-59.8
Final Visit
(LOCF)
(N=89)
700.0
261.0
247.0
-60.6
Median, %
-70.5
N/A
Median, %
N/A
-62.0
Median, %
-6.2
-2.6
>0.999 (r)
0.9999
Median, mg/dL
Median, mg/dL
Median, mg/dL
Median, %
Data Source: Table 14.2.1.1, Table 14.2.1.1a
assessment.
2. Study OM5 Baseline = Average of Week -2, Week -1, Week -1 Repeat Lab (if applicable) and Week 0.
3. Study OM5X End-of-Treatment (End–of-Tx) = Average of Week 14 and Week 16 (if 1 of the 2 measurements was
missing, then only the 1 non-missing value was used).
4. 12-month Study OM5XX End-of-Tx data available for the 58 subjects who completed the Month-12 visit (including
clinical lab evaluation).
5. Final Study OM5XX End-of-Tx = last Study OM5XX available visit data.
6. P value is from repeated measures ANOVA with baseline as covariate; (r) indicates that data were ranked prior to
performing ANOVA.
7. Subjects who had completed Study OM5X and had completed Study OM5XX visits up to and including Month 12.
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Table 4
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Difference Between % Change from Baseline to End of Study OM5X
and Study OM5XX in Serum Triglycerides by Additional LipidLowering Agent Status (MITT Population)
All Subjects2
N
Median, %
Min, Max, %
95% Confidence Interval, %
P-value1
89
-2.6
-70.3, 149.1
(-2.8, 9.4)
0.9999
Received
Additional LipidLowering Agents
60
-1.1
-70.3, 149.1
(-2.1,15.1)
0.9999
Did Not Receive
Additional LipidLowering Agents
29
-3.6
-39.4, 40.7
(-9.1, 2.7)
0.9999
Data Source: Table 14.2.1.2. Confidence interval based on t distribution.
1. From repeated measures ANOVA.
assessment.
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Secondary Efficacy Results are summarized in Table 5.
Table 5
Secondary Efficacy/Outcome Variables (MITT Population)
Median Values
Total Cholesterol
OM5 Baseline1
OM5XX End-of-Treatment (Tx)1
% Change from OM5 Baseline to OM5XX End-of-Tx
VLDL-C (calculated)
OM5 Baseline1
OM5XX End-of-Tx1
LDL-C (direct)
LOV111859/OM5 Baseline1
OM5XX End-of-Tx1
HDL-C
OM5XX End-of-Tx1
Non-HDL-C
OM5XX End-of-Tx1
TC/HDL-C ratio
OM5XX End-of-Tx1
Apo A-I
OM5XX End-of-Treatment1
Apo B
OM5 Baseline1
OM5XX End-of-Tx1
mg/dL
mg/dL
%
251.0
207.0
-13.2
mg/dL
mg/dL
%
119.3
51.5
-54.6
mg/dL
mg/dL
%
87.3
115.0
37.5
mg/dL
mg/dL
%
38.5
32.5
-11.1
mg/dL
mg/dL
%
212.0
175.0
-13.3
%
6.7
6.5
0.0
mg/dL
mg/dL
%
121.5
127.0
2.9
mg/dL
mg/dL
%
118.0
109.0
-7.3
Data Source: Table 14.2.2.1, Table 14.2.2.2
1. Study OM5 Baseline = Average of Weeks -2, Week -1, Week -1 Repeat Lab (if applicable) and Week 0,
Study OM5XX End-of-Treatment = last OM5XX available visit data.
assessment.
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14.3.
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Safety Results
Exposure to study medication. Exposure data were not formally analyzed. Ninetythree subjects entered the current trial after completing 8 weeks of double-blind (OM5)
and 8 weeks of open-label treatment (OM5X); 9 subjects completed the 24 months of
open-label therapy (Table 6).
Table 6
Number of Subjects Retained by Month/Visit
Visit
Month 0
Month 4
Month 8
Month 12
Month 16
Month 20
Month 24
Total n (%)
93
85 (91.4)
78 (83.9)
59 (63.4)
42 (45.2)
21 (22.6)
9 (9.7)
Data source: Table 14.1.1b
Adverse Events. For subjects who had an ongoing AE at their final study visit, a follow
up AE CRF page was collected to document resolution or stabilization of the AE. A total
of 69 subjects (77.5%) experienced at least one treatment-emergent adverse event (AE).
The most common AEs were upper respiratory tract infection (16.9%), influenza (6.7%),
and hypertension (6.7%) (Table 7).
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Table 7
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Most Frequent (>3%) Treatment-Emergent Adverse Events (Safety
Population)
n (%)
69 (77.5%)
15 (16.9%)
6 (6.7%)
6 (6.7%)
5 (5.6%)
5 (5.6%)2
5 (5.6%)
5 (5.6%)
4 (4.5%)
3 (3.4%)
3 (3.4%)
3 (3.4%)
3 (3.4%)
3 (3.4%)
3 (3.4%)
3 (3.4%)
Subjects with any AE(s)
Upper respiratory tract infection
Influenza
Hypertension
Back pain
Diabetes mellitus
Nausea
Sinusitis
Skin laceration
Abdominal Pain
Arthralgia
Diarrhea
Gastroenteritis
Shoulder pain
Weight decreased
Anxiety
Percentages are calculated as 100 x n/N.
1. Subjects who had completed Study OM5X and had at least 1 safety assessment after enrollment in Study
OM5XX
2. Includes diabetes mellitus or non-insulin-dependent diabetes mellitus
Deaths. There were no deaths reported in this study.
Serious Adverse Events. Subjects who experienced an SAE during the study were
followed for 30 days after the completion of the study, or until the SAE has resolved.
Four treatment-emergent serious AEs (SAEs) were reported by the investigator (Table 8).
None of these SAEs were considered by the investigator to be possibly related or related
to study treatment and all resolved.
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Table 8
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Treatment-Emergent Serious Adverse Events (Safety Population)
n (%) [n= possibly/related to
OMACOR®]
4 (4.5%)
1 (1.1%) [0]
1 (1.1%) [0]
1 (1.1%) [0]
1 (1.1%) [0]
Subjects with any SAE1, n (%)
Acute myocardial infarction
Elevated liver function tests
L2-3 herniated lumbar disk
R lower extremity cellulitis
1. If a subject experienced the same event more than once, the first occurrence is tabulated. Percentages are
calculated as 100 x n/N.
enrollment in Study OM5XX..
Withdrawal due to AEs: Two subjects were withdrawn from OM5XX due to AEs. A
brief description follows.
•
•
NOTE:
The subject was not withdrawn from the
study for the AE. Study drug was restarted and the subject continued in the study until
the study was terminated by sponsor (refer to Listing 16.2.1.1).
Vital sign data were not tabulated. Six (6.7%) subjects had treatment-emergent
hypertension reported as AEs; none of these events were considered to be related to study
medication. One (1.1%) subject had bradycardia reported as a treatment-emergent AE;
the investigator considered the AE unlikely to be related to study medication. None of
these events were considered by the investigator to be serious and none of these subjects
had study medication discontinued due to these events.
Laboratory assessments. Only ALT, AST, CK, and glucose data were summarized (see
Table 14.4.1). Adverse events associated with these selected serum chemistry
assessments are summarized in the following paragraphs. No adverse events were
reported for any of the other serum chemistry parameters (creatinine, total bilirubin,
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sodium, potassium, bicarbonate, blood urea nitrogen, chloride), hematology parameters
or urinalysis.
One subject had “liver function test abnormal” reported as an SAE; the event was
considered unlikely to be related to study medication. One additional subject had
increased ALT and increased AST reported as AEs; neither of these AEs was considered
to be related to study medication. Neither subject had study medication discontinued due
to these events.
Five subjects had diabetes mellitus or non-insulin-dependent diabetes mellitus reported as
treatment-emergent AEs. In two subjects it was considered not related and 3 subjects it
was considered unlikely to be related to study medication. A sixth subject had “blood
glucose increased” and another had hyperglycemia reported as AEs; in both cases, the AE
was considered to be possibly related to study medication. None of these subjects had
study medication discontinued due to these events.
15.
CONCLUSIONS
Study OM5XX extended OMACOR® and Antara concomitant therapy for subjects with
very-high baseline TG (500 mg/dL to 1300 mg/dL) for up to an additional 24 months
after an 8-week extension (Study OM5X) of an 8-week double-blind, placebo-controlled
study (Study OM5). In this series of studies, the magnitude of triglyceride-lowering
effect with concomitant OMACOR® and Antara therapy (as measured by percentage
change from baseline) appeared to plateau at 8 to 16 weeks after initiation of therapy
(with median reductions from baseline ranging from 59% to 61% during Study OM5 and
Study OM5X), and were sustained over a period 12 - 24 months (with overall median
reductions from baseline ranging from 62% to 71%).
Reductions from baseline for other lipid variables (e.g., non-HDL-C, VLDL-C, and TC)
showed similar sustained effects over the extended combined therapy period when
compared to the 8 and 16-week results from the prior OM5 and OM5X studies.
Similarly, the increase from baseline LDL-C observed over the 2-year extended period,
was consistent with that observed in the short-term OM5 and OM5X studies. Increases
in LDL-C levels are a well known effect of treatment of hypertriglyceridemia with either
fibrates or omega-3 fatty acids [Bays, 2008], and is reported in the approved labeling for
OMACOR® and Antara for those with very high triglycerides
[Antara Package Insert, 2007; LOVAZA Package Insert, 2008]. The observed increase in
LDL-C in the OMACOR® group was more than offset by the larger decline in calculated
VLDL-C, resulting in a lower non-HDL-C and thus a net reduction in cholesterol carried
by potentially atherogenic particles [Garg, 1990; Robinson 2009].
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Four non-fatal SAEs were reported during the Study OM5XX study period. All of these
events resolved, and none was considered by the investigator to be related to study
medication. No new safety signals were detected with extended use of concomitant
OMACOR® and Antara, and the combination was generally safe and well-tolerated.
16.
DATE OF REPORT
23 February 2009
REFERENCES
Antara (Fenofibrate) Oscient Pharmaceuticals Corporation. Waltham, MA. Product
Information. 2008.
Bays HE, Tighe AP, Sadovsky R, Davidson MH. Prescription omega-3 fatty acids and
their lipid effects: physiologic mechanisms of action and clinical implications. Expert
Review of Cardiovascular Therapy. 2008;6:391-409.
Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care.
1990:13(2):153-169.
LOVAZA (Omega-3-acid ethyl esters) GlaxoSmithKline. Triangle Research Park, NC,
Product Information. 2008.
Robinson JG, Wang S, Smith BJ. Meta-analysis of the relationship between non-highdensity lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll
Cardiol 2009;53:316-22.
CASE NARRATIVES
There may be minor discrepancies in the details of the SAEs included in the clinical
narratives compared with the safety tabulations. This is because the data comes from two
different databases (i.e., locked clinical trials database and dynamic SAE database) and
has been collected at different points in time. However, all key data points are
reconciled. It is considered that these minor differences do not change the overall clinical
significance or understanding of the SAE.
This section contained data from each individual patient, rather than in aggregate. They have been excluded to
protect patient privacy. Anonymized data from each patient may be made available subject to an approved
research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical
Study Register.
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14 Tables, Figures and Graphs
Page
14.1 Demographic Data Summary Figures and Tables . . . . . . . . . . . . . . . . .
Table 14.1.1 Subject Disposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 14.1.1a Subject Disposition as of Month 12 Visit . . . . . . . . . . . . . .
Table 14.1.1b Subject Retention by Month/Visit . . . . . . . . . . . . . . . . . . . .
Table 14.1.2 Demographic Characteristics - Safety Population . . . . . . . .
25
26
27
28
29
14.2 Efficacy Data Summary Figures and Tables . . . . . . . . . . . . . . . . . . . . . .
Table 14.2.1.1 Primary Efficacy Analyses: Lipid Measurements - MITT
Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 14.2.1.1a Primary Efficacy Analyses up to Month 12: Lipid
Measurements - MITT Population . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 14.2.1.2 Primary Efficacy Analyses: Lipid Measurements, By
Lipid-Lowering Agent Groups - MITT Population . . . . . . . . . . . . . . . .
Table 14.2.2.1 Secondary Efficacy Summary: Selected Serum Lipid
Table 14.2.2.1a Secondary Efficacy Summary Up to Month 12:
Selected Serum Lipid Measurements -MITT Population . . . . . . . . . .
Table 14.2.2.2 Secondary Efficacy Summary: Apolipoproteins
Table 14.2.3.1 Tertiary Efficacy Summary: Selected VAP and Lp-PLA2
31
14.3 Safety Data Summary Figures and Tables . . . . . . . . . . . . . . . . . . . . . . .
Table 14.3.1 Occurrence of OM5XX Treatment-Emergent Adverse
Events by System Organ Class andPreferred Term - Safety
Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 14.3.2 Occurence of OM5XX Serious Treatment-Emergent
Adverse Event by Relationship to Lovaza -safety Population . . . . . .
105
14.4 Laboratory Data Summary Figures and Tables . . . . . . . . . . . . . . . . . . .
Table 14.4.1 Selected Serum Chemistry Panel - Safety Population . . . .
Table 14.4.1a Selected Serum Chemistry Panel up to Month 12 Safety Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
115
116
24
32
36
39
40
60
81
87
106
114
128
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14.1 Demographic Data Summary Figures and Tables
25
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Table 14.1.1 Subject Disposition
2 (2.2 %)
2 (2.2 %)
0 (0.0 %)
4 (4.3 %)
7 (7.5 %)
7 (7.5 %)
62 (66.7 %)
0 (0.0 %)
CONFIDENTIAL
26
Enrolled
Completed Study
Discontinued Study
Modified Intent-to-Treat (MITT) Population [1]
Safety Population [2]
Discontinued due to:
Adverse Event or Serious Adverse Event
Noncompliance with Protocol
Pregnancy
Laboratory abnormality
Withdrew consent
Lost to Follow-up
Sponsor Study Termination
Other
Total
(N=93)
n(%)
93(100.0 %)
9 (9.7 %)
84 (90.3 %)
89 (95.7 %)
89 (95.7 %)
Reference: Listing 16.2.1.1: Overall Subject Disposition.
[1] Subjects who have an OM5 baseline and at least one on-therapy OM5XX assessment.
[2] Subjects who received a dose of study medication and returned for at least one safety assessment.
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Table 14.1.1a Subject Disposition as of Month 12 Visit
1 (1.1 %)
1 (1.1 %)
0 (0.0 %)
4 (4.3 %)
5 (5.4 %)
5 (5.4 %)
18 (19.4 %)
0 (0.0 %)
CONFIDENTIAL
27
Enrolled
Ongoing in Study as of Month 12 Visit
Discontinued Study before Month 12 Visit
Modified Intent-to-Treat (MITT) Population [1]
Safety Population [2]
Discontinued due to:
Adverse Event or Serious Adverse Event
Noncompliance with Protocol
Pregnancy
Laboratory abnormality
Withdrew consent
Lost to Follow-up
Sponsor Study Termination
Other
Total
(N=93)
n(%)
93(100.0 %)
59 (63.4 %)
34 (36.6 %)
89 (95.7 %)
89 (95.7 %)
[1] Subjects who have an OM5 baseline and at least one on-therapy OM5XX assessment.
[2] Subjects who received a dose of study medication and returned for at least one safety assessment.
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Table 14.1.1b Subject Retention by Month/Visit
28
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Month/Visit
Month 0
Month 4
Month 8
Month 12
Month 16
Month 20
Month 24
Total
(N=93)
n(%)
93(100.0 %)
85 (91.4 %)
78 (83.9 %)
59 (63.4 %)
42 (45.2 %)
21 (22.6 %)
9 (9.7 %)
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Table 14.1.2 Demographic Characteristics - Safety Population
Age (years)
N
Mean(Std)
Median
Min, Max
89
52.4(9.99)
54.0
27.0, 71.0
Race and Ethnicity (n (%))
Hispanic or Latino
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
2 (2.2 %)
1 (1.1 %)
3 (3.4 %)
2 (2.2 %)
0 (0.0 %)
82 (92.1 %)
Weight(kg)
N
Mean(Std)
Median
Min, Max
89
97.3(15.63)
96.7
66.7, 130.9
Characteristic
Gender (n (%))
29
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Reference: Listing 16.2.2.1: Subject Demographics and Informed Consent.
Subjects may have reported more than one race and ethnicity.
[2]Subjects who had completed the previous OM5X open-label extension (8 weeks) study and have at least one safety assessment after enrollment into study OM5XX.
CONFIDENTIAL
Male
Female
All
Subjects[2]
(N=89)
69 (77.5 %)
20 (22.5 %)
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Table 14.1.2 Demographic Characteristics - Safety Population
Characteristic
Height(cm)
BMI (kg/m^2)
N
Mean(Std)
Median
Min, Max
89
32.4(4.59)
32.6
23.6, 44.7
30
Reference: Listing 16.2.2.1: Subject Demographics and Informed Consent.
Subjects may have reported more than one race and ethnicity.
CONFIDENTIAL
N
Mean(Std)
Median
Min, Max
All
Subjects[2]
(N=89)
89
173.3(8.80)
173.5
149.9, 191.0
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14.2 Efficacy Data Summary Figures and Tables
31
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Table 14.2.1.1 Primary Efficacy Analyses: Lipid Measurements - MITT Population
Visit
Triglycerides (mg/dL)
Month 0
Month 4
32
Month 12
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Reference: Listing 16.2.3.1: Lipid Profile
[1] P-value from repeated measures ANOVA.
[2] OM5 Baseline = Average of Week -2, Week -1, Week -1 Repeat Lab (if applicable) and Week 0
OM5X End-of-Treatment = Average of Week 14 and Week 16 (if one of the two measurements is missing,
then only the one non-missing value was used)
OM5XX End-of-Treatment = last OM5XX available visit data
[3]Subjects who had completed the previous OM5X open-label extension (8 weeks) study and have at least one on-therapy OM5XX assessment
CONFIDENTIAL
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[3]
(N=89)
89
301.2(151.39)
263.0
94.0, 926.0
85
324.3(249.72)
254.0
89.0, 1737.0
77
316.5(421.43)
241.0
75.0, 3721.0
58
277.9(185.37)
226.5
80.0, 1034.0
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Visit
Month 16
Month 20
OM5 Baseline [2]
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33
Month 24
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[3]
(N=89)
42
344.3(439.71)
252.0
82.0, 2866.0
21
289.8(160.63)
249.0
122.0, 828.0
9
365.2(372.04)
212.0
76.0, 1295.0
89
751.8(235.83)
700.0
407.3, 1637.5
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Visit
OM5X End-of-Treatment [2]
-58.2(20.72)
-60.6
-85.3, 55.9
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-444.4(249.56)
-403.3
-1374.5, 536.5
89
CONFIDENTIAL
34
N
Mean(Std)
Median
Min, Max
OM5XX End-of-Treatment [2]
N
Mean(Std)
Median
Min, Max
Change from OM5 Baseline to OM5X N
End-of-Treatment
Mean(Std)
Median
Min, Max
Percent Change from OM5 Baseline N
to OM5X End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[3]
(N=89)
89
307.5(184.98)
261.0
107.0, 1496.5
89
335.6(269.78)
247.0
65.0, 1737.0
89
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Visit
Change from OM5 Baseline to
OM5XX End-of-Treatment
35
Difference Between OM5X and
OM5XX Percent Changes
Mean(Std)
Median
Min, Max
N
-416.3(302.16)
-423.0
-1432.5, 778.3
89
Mean(Std)
Median
Min, Max
N
-54.9(32.33)
-62.0
-88.9, 115.0
89
Mean(Std)
Median
Min, Max
P-Value [1]
3.3(29.01)
-2.6
-70.3, 149.1
0.9999
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CONFIDENTIAL
Percent Change from OM5 Baseline
to OM5XX End-of-Treatment
N
All Subjects[3]
(N=89)
89
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Table 14.2.1.1a Primary Efficacy Analyses up to Month 12: Lipid Measurements - MITT Population
Visit
Month 0
Month 4
36
Month 12
CONFIDENTIAL
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[1]
(N=58)
58
310.6(150.31)
290.5
94.0, 926.0
58
316.7(210.06)
254.5
89.0, 999.0
57
339.9(484.29)
243.0
75.0, 3721.0
58
277.9(185.37)
226.5
80.0, 1034.0
[1] Subjects who had completed the previous OM5X open-label extension (8 weeks) study and have completed OM5XX Visits up to month 12.
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OM5X End-of-Treatment = Average of Week 14 and Week 16 (if one of the two measurements is missing, then only the one non-missing value was used)
[3] P-value is from repeated measures ANOVA with baseline as covariate. (r) indicates that data were ranked prior to performing ANOVA.
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Visit
OM5 Baseline [2]
37
Mean(Std)
Median
Min, Max
Percent Change from OM5 Baseline to OM5X End-of- N
Treatment
Mean(Std)
Median
Min, Max
-437.2(248.23)
-405.6
-1078.3, 536.5
58
-57.0(22.34)
-59.8
-85.3, 55.9
CONFIDENTIAL
Change from OM5 Baseline to OM5X End-ofTreatment
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
All Subjects[1]
(N=58)
58
759.9(224.65)
716.5
407.3, 1369.3
58
322.8(204.66)
262.8
112.5, 1496.5
58
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Visit
Change from OM5 Baseline to OM5XX Month 12
Visit
N
-482.0(239.44)
-433.9
-1153.3, 74.0
58
-63.0(22.14)
-70.5
-86.4, 7.7
58
-6.0(17.85)
-6.2
-61.6, 33.0
>0.999 (r)
CONFIDENTIAL
38
Mean(Std)
Median
Min, Max
Percent Change from OM5 Baseline to OM5XX Month N
12 Visit
Mean(Std)
Median
Min, Max
Difference Between OM5X and OM5XX Percent
N
Changes
Mean(Std)
Median
Min, Max
P-Value [3]
All Subjects[1]
(N=58)
58
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Table 14.2.1.2 Primary Efficacy Analyses: Lipid Measurements, By Lipid-Lowering Agent Groups - MITT Population
Overall
39
Did Not Receive Lipid-Lowering Agents
6.5(33.32)
-1.1
-70.3, 149.1
(-2.1, 15.1)
0.9999
29
-3.2(15.50)
-3.6
-39.4, 40.7
(-9.1, 2.7)
0.9999
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Confidence interval based on the t-distribution.
3.3(29.01)
-2.6
-70.3, 149.1
(-2.8, 9.4)
0.9999
60
CONFIDENTIAL
Received Lipid-Lowering Agents
Difference Between Percent Change from OM5 Baseline to
N
OM5X End-of-Treatment and Percent Change from OM5 Baseline
Mean(Std)
Median
Min, Max
95% Confidence Interval
P-Value [1]
N
Mean(Std)
Median
Min, Max
P-Value [1]
N
Mean(Std)
Median
Min, Max
P-Value [1]
All Subjects[2]
(N=89)
89
1
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Table 14.2.2.1 Secondary Efficacy Summary: Selected Serum Lipid Measurements - MITT Population
Visit
Total Cholesterol (Total-C) (mg/dL)
Month 0
Month 4
40
Month 12
Month 16
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[1] OM5 Baseline = Average of Week -2, Week -1 and Week 0
CONFIDENTIAL
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
232.9(55.32)
224.0
134.0, 507.0
85
218.7(49.23)
211.0
126.0, 381.0
77
211.2(49.25)
202.0
133.0, 371.0
58
202.1(47.43)
194.0
129.0, 358.0
42
211.0(55.37)
205.5
121.0, 352.0
2
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Visit
Month 20
Month 24
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CONFIDENTIAL
41
OM5 Baseline [1]
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
21
203.5(39.21)
201.0
127.0, 277.0
9
195.9(53.24)
182.0
121.0, 307.0
89
255.4(54.89)
251.0
170.0, 430.7
89
234.2(53.07)
225.0
141.0, 510.0
89
219.2(56.78)
207.0
121.0, 381.0
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-21.3(43.46)
-18.2
-205.2, 98.3
89
-7.2(14.70)
-6.7
-47.6, 25.3
89
-36.2(49.68)
-30.7
-172.7, 51.3
89
-13.2(17.24)
-13.2
-55.1, 20.1
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All Subjects[2]
(N=89)
89
CONFIDENTIAL
42
Visit
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
5
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Visit
(lab-direct VLDL-C) (mg/dL)
Month 0
43
Month 8
Month 12
Month 16
50.0(15.91)
49.0
19.0, 80.0
65
44.5(14.79)
43.0
18.0, 77.0
65
44.9(17.18)
41.0
15.0, 76.0
47
40.7(15.74)
39.0
16.0, 78.0
35
45.6(17.06)
46.0
16.0, 79.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
75
7
GlaxoSmithKline
08/01/2008
Page 7 of 32
Visit
Month 20
44
OM5 Baseline [1]
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
48.5(17.35)
48.0
24.0, 75.0
7
42.9(21.48)
41.0
15.0, 79.0
12
61.0(10.04)
61.0
48.5, 79.0
79
49.0(14.45)
48.0
21.5, 79.5
CONFIDENTIAL
Month 24
N
All Subjects[2]
(N=89)
18
8
GlaxoSmithKline
08/01/2008
Page 8 of 32
Visit
(calcld VLDL-C) (mg/dL)
Month 0
45
Month 8
Month 12
Month 16
56.1(27.91)
52.0
9.0, 179.0
84
52.0(25.96)
50.5
7.0, 157.0
75
46.1(23.21)
43.0
9.0, 146.0
58
50.6(27.19)
46.0
9.0, 120.0
41
50.6(25.15)
47.0
14.0, 140.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
87
10
GlaxoSmithKline
08/01/2008
Page 10 of 32
Visit
Month 20
46
OM5 Baseline [1]
49.3(24.73)
47.0
21.0, 126.0
8
43.6(24.37)
35.5
13.0, 84.0
89
121.4(32.73)
119.3
63.0, 218.3
89
55.8(27.91)
46.5
18.5, 189.5
88
58.0(32.49)
51.5
9.0, 157.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 24
N
All Subjects[2]
(N=89)
21
12
GlaxoSmithKline
08/01/2008
Page 12 of 32
-65.4(32.57)
-65.9
-160.5, 13.2
88
-53.5(20.16)
-58.3
-82.2, 14.9
88
-63.1(35.06)
-60.9
-163.3, 13.3
88
-51.7(23.79)
-54.6
-88.4, 10.5
ZM2008/00140/00
LOV111821
All Subjects[2]
(N=89)
88
CONFIDENTIAL
47
Visit
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
13
GlaxoSmithKline
08/01/2008
Page 13 of 32
Visit
Low-density lipoprotein Cholesterol
(LDL-C) (mg/dL)
Month 0
48
Month 8
Month 12
Month 16
140.4(47.04)
134.0
35.0, 316.0
85
127.9(41.72)
124.0
40.0, 245.0
77
125.9(37.95)
119.0
22.0, 217.0
58
117.3(37.33)
114.5
37.0, 248.0
42
122.2(47.19)
115.5
27.0, 272.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
15
GlaxoSmithKline
08/01/2008
Page 15 of 32
Visit
(LDL-C) (mg/dL)
Month 20
49
OM5 Baseline [1]
118.7(26.69)
120.0
73.0, 164.0
9
101.7(22.23)
102.0
62.0, 131.0
89
94.2(36.49)
87.3
37.7, 207.7
89
141.3(44.34)
135.0
37.0, 309.0
89
123.1(41.60)
115.0
37.0, 272.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 24
N
All Subjects[2]
(N=89)
21
17
GlaxoSmithKline
08/01/2008
Page 17 of 32
(LDL-C) (mg/dL)
47.1(32.30)
42.7
-35.2, 132.2
89
58.1(39.80)
52.8
-24.8, 147.7
89
28.9(38.97)
30.3
-85.3, 144.7
89
40.3(45.64)
37.5
-49.0, 159.7
ZM2008/00140/00
LOV111821
All Subjects[2]
(N=89)
89
CONFIDENTIAL
50
Visit
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
18
GlaxoSmithKline
08/01/2008
Page 18 of 32
Visit
(HDL-C) (mg/dL)
Month 0
51
Month 8
Month 12
Month 16
36.9(10.58)
35.0
10.0, 82.0
84
36.3(9.53)
37.0
11.0, 58.0
76
36.1(11.43)
34.0
10.0, 81.0
58
34.3(9.59)
33.0
12.0, 57.0
41
33.7(9.04)
33.0
15.0, 60.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
20
GlaxoSmithKline
08/01/2008
Page 20 of 32
Visit
(HDL-C) (mg/dL)
Month 20
52
OM5 Baseline [1]
35.5(10.08)
35.0
20.0, 61.0
8
36.4(9.55)
35.5
27.0, 57.0
89
38.3(8.83)
38.5
12.7, 70.7
89
37.1(9.98)
36.0
10.5, 76.0
88
34.9(10.29)
32.5
15.0, 73.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 24
N
All Subjects[2]
(N=89)
21
22
GlaxoSmithKline
08/01/2008
Page 22 of 32
(HDL-C) (mg/dL)
-1.1(6.44)
-0.9
-20.2, 23.0
88
-2.5(16.02)
-3.0
-62.9, 44.1
88
-3.3(8.20)
-4.0
-19.7, 22.3
88
-6.7(27.92)
-11.1
-47.2, 175.6
ZM2008/00140/00
LOV111821
All Subjects[2]
(N=89)
88
CONFIDENTIAL
53
Visit
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
23
GlaxoSmithKline
08/01/2008
Page 23 of 32
Visit
Non-High-Density Lipoprotein Cholesterol Month 0
(Non-HDL-C) (mg/dL)
54
Month 8
Month 12
Month 16
196.0(55.51)
188.0
109.0, 495.0
84
180.4(45.18)
178.5
80.0, 310.0
76
173.0(46.79)
168.5
100.0, 306.0
58
167.8(47.03)
159.0
89.0, 307.0
41
174.4(53.43)
171.0
85.0, 309.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
25
GlaxoSmithKline
08/01/2008
Page 25 of 32
Visit
(Non-HDL-C) (mg/dL)
55
OM5 Baseline [1]
168.0(38.45)
168.0
102.0, 245.0
8
145.6(35.45)
145.5
92.0, 215.0
89
215.9(49.84)
212.0
134.5, 380.7
89
197.0(53.44)
189.0
114.5, 498.5
88
182.2(53.29)
175.0
88.0, 321.0
ZM2008/00140/00
LOV111821
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
CONFIDENTIAL
Month 24
N
All Subjects[2]
(N=89)
21
27
GlaxoSmithKline
08/01/2008
Page 27 of 32
-18.9(41.86)
-14.9
-185.0, 117.8
88
-7.8(16.56)
-7.2
-51.4, 30.9
88
-33.1(48.78)
-26.4
-169.3, 45.3
88
-14.2(19.91)
-13.3
-64.8, 20.1
ZM2008/00140/00
LOV111821
All Subjects[2]
(N=89)
88
CONFIDENTIAL
56
Visit
Non-High-Density Lipoprotein Cholesterol Change from OM5 Baseline to OM5X N
(Non-HDL-C) (mg/dL)
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
28
GlaxoSmithKline
08/01/2008
Page 28 of 32
Visit
Ratio of Total to HDL Cholesterol
Month 0
Month 4
Month 12
Month 16
ZM2008/00140/00
LOV111821
CONFIDENTIAL
57
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
7.0(4.42)
6.0
3.0, 42.0
84
6.6(3.10)
6.0
3.0, 26.0
76
6.4(2.64)
6.0
2.0, 16.0
58
6.4(2.42)
6.0
3.0, 16.0
41
6.6(2.68)
6.0
3.0, 15.0
30
GlaxoSmithKline
08/01/2008
Page 30 of 32
Visit
Month 20
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
58
OM5 Baseline [1]
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
21
6.3(2.15)
6.0
4.0, 13.0
8
5.1(1.25)
5.0
3.0, 7.0
89
6.9(2.07)
6.7
3.7, 21.7
89
7.0(4.61)
6.0
3.0, 44.5
88
6.7(2.25)
6.5
3.0, 13.0
32
GlaxoSmithKline
08/01/2008
Page 32 of 32
0.1(3.59)
-0.3
-3.7, 31.2
88
-1.4(31.30)
-4.8
-45.2, 234.6
88
-0.2(2.61)
0.0
-15.7, 5.0
88
-0.8(29.51)
0.0
-72.4, 74.6
ZM2008/00140/00
LOV111821
All Subjects[2]
(N=89)
88
CONFIDENTIAL
59
Visit
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
1
GlaxoSmithKline
08/01/2008
Page 1 of 21
Table 14.2.2.1a Secondary Efficacy Summary Up to Month 12: Selected Serum Lipid Measurements - MITT Population
Visit
Month 0
Month 4
60
Month 12
ZM2008/00140/00
LOV111821
OM5XX End-of-Treatment = last OM5XX available visit data by Month 12
CONFIDENTIAL
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
232.9(55.32)
224.0
134.0, 507.0
85
218.7(49.23)
211.0
126.0, 381.0
77
211.2(49.25)
202.0
133.0, 371.0
58
202.1(47.43)
194.0
129.0, 358.0
2
GlaxoSmithKline
08/01/2008
Page 2 of 21
Visit
OM5 Baseline [1]
-21.3(43.46)
-18.2
-205.2, 98.3
ZM2008/00140/00
LOV111821
CONFIDENTIAL
61
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
255.4(54.89)
251.0
170.0, 430.7
89
234.2(53.07)
225.0
141.0, 510.0
89
215.6(53.44)
207.0
129.0, 381.0
89
3
GlaxoSmithKline
08/01/2008
Page 3 of 21
Visit
62
Mean(Std)
Median
Min, Max
N
-7.2(14.70)
-6.7
-47.6, 25.3
89
Mean(Std)
Median
Min, Max
N
-39.8(47.89)
-33.0
-186.7, 42.0
89
Mean(Std)
Median
Min, Max
-14.5(16.69)
-13.9
-52.2, 17.3
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
4
GlaxoSmithKline
08/01/2008
Page 4 of 21
Visit
Month 0
63
Month 8
Month 12
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
50.0(15.91)
49.0
19.0, 80.0
65
44.5(14.79)
43.0
18.0, 77.0
65
44.9(17.18)
41.0
15.0, 76.0
47
40.7(15.74)
39.0
16.0, 78.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
75
5
GlaxoSmithKline
08/01/2008
Page 5 of 21
Visit
OM5 Baseline [1]
N
-22.9(7.39)
-22.8
-32.0, -12.5
ZM2008/00140/00
LOV111821
61.0(10.04)
61.0
48.5, 79.0
79
49.0(14.45)
48.0
21.5, 79.5
8
31.3(15.12)
25.5
16.0, 59.0
8
CONFIDENTIAL
64
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
12
6
GlaxoSmithKline
08/01/2008
Page 6 of 21
Visit
65
Mean(Std)
Median
Min, Max
N
-39.3(12.07)
-36.0
-58.3, -25.3
8
Mean(Std)
Median
Min, Max
N
-27.1(12.47)
-32.0
-39.0, -2.0
8
Mean(Std)
Median
Min, Max
-47.2(21.70)
-53.5
-68.0, -3.3
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
8
7
GlaxoSmithKline
08/01/2008
Page 7 of 21
Visit
Month 0
66
Month 8
Month 12
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
56.1(27.91)
52.0
9.0, 179.0
84
52.0(25.96)
50.5
7.0, 157.0
75
46.1(23.21)
43.0
9.0, 146.0
58
50.6(27.19)
46.0
9.0, 120.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
87
8
GlaxoSmithKline
08/01/2008
Page 8 of 21
Visit
OM5 Baseline [1]
N
-65.4(32.57)
-65.9
-160.5, 13.2
ZM2008/00140/00
LOV111821
121.4(32.73)
119.3
63.0, 218.3
89
55.8(27.91)
46.5
18.5, 189.5
88
56.9(31.41)
50.0
9.0, 157.0
88
CONFIDENTIAL
67
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
9
GlaxoSmithKline
08/01/2008
Page 9 of 21
Visit
68
Mean(Std)
Median
Min, Max
N
-53.5(20.16)
-58.3
-82.2, 14.9
88
Mean(Std)
Median
Min, Max
N
-64.2(37.62)
-60.0
-173.3, 11.0
88
Mean(Std)
Median
Min, Max
-51.9(24.64)
-56.9
-91.6, 12.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
88
10
GlaxoSmithKline
08/01/2008
Page 10 of 21
Visit
(LDL-C) (mg/dL)
Month 0
69
Month 8
Month 12
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
140.4(47.04)
134.0
35.0, 316.0
85
127.9(41.72)
124.0
40.0, 245.0
77
125.9(37.95)
119.0
22.0, 217.0
58
117.3(37.33)
114.5
37.0, 248.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
11
GlaxoSmithKline
08/01/2008
Page 11 of 21
(LDL-C) (mg/dL)
Visit
OM5 Baseline [1]
N
47.1(32.30)
42.7
-35.2, 132.2
ZM2008/00140/00
LOV111821
94.2(36.49)
87.3
37.7, 207.7
89
141.3(44.34)
135.0
37.0, 309.0
89
121.6(38.17)
118.0
37.0, 248.0
89
CONFIDENTIAL
70
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
12
GlaxoSmithKline
08/01/2008
Page 12 of 21
(LDL-C) (mg/dL)
Visit
71
Mean(Std)
Median
Min, Max
N
58.1(39.80)
52.8
-24.8, 147.7
89
Mean(Std)
Median
Min, Max
N
27.4(35.34)
26.3
-49.3, 144.7
89
Mean(Std)
Median
Min, Max
39.3(47.74)
30.3
-32.8, 209.8
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
13
GlaxoSmithKline
08/01/2008
Page 13 of 21
Visit
(HDL-C) (mg/dL)
Month 0
72
Month 8
Month 12
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
36.9(10.58)
35.0
10.0, 82.0
84
36.3(9.53)
37.0
11.0, 58.0
76
36.1(11.43)
34.0
10.0, 81.0
58
34.3(9.59)
33.0
12.0, 57.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
14
GlaxoSmithKline
08/01/2008
Page 14 of 21
(HDL-C) (mg/dL)
Visit
OM5 Baseline [1]
N
-1.1(6.44)
-0.9
-20.2, 23.0
ZM2008/00140/00
LOV111821
38.3(8.83)
38.5
12.7, 70.7
89
37.1(9.98)
36.0
10.5, 76.0
88
34.8(10.42)
33.0
12.0, 73.0
88
CONFIDENTIAL
73
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
15
GlaxoSmithKline
08/01/2008
Page 15 of 21
(HDL-C) (mg/dL)
Visit
74
Mean(Std)
Median
Min, Max
N
-2.5(16.02)
-3.0
-62.9, 44.1
88
Mean(Std)
Median
Min, Max
N
-3.4(8.28)
-3.6
-19.7, 22.3
88
Mean(Std)
Median
Min, Max
-7.3(28.20)
-10.9
-56.7, 175.6
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
88
16
GlaxoSmithKline
08/01/2008
Page 16 of 21
Visit
(Non-HDL-C) (mg/dL)
75
Month 8
Month 12
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
196.0(55.51)
188.0
109.0, 495.0
84
180.4(45.18)
178.5
80.0, 310.0
76
173.0(46.79)
168.5
100.0, 306.0
58
167.8(47.03)
159.0
89.0, 307.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
89
17
GlaxoSmithKline
08/01/2008
Page 17 of 21
Visit
Non-High-Density Lipoprotein Cholesterol OM5 Baseline [1]
(Non-HDL-C) (mg/dL)
N
-18.9(41.86)
-14.9
-185.0, 117.8
ZM2008/00140/00
LOV111821
215.9(49.84)
212.0
134.5, 380.7
89
197.0(53.44)
189.0
114.5, 498.5
88
179.0(50.07)
172.5
89.0, 307.0
88
CONFIDENTIAL
76
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
18
GlaxoSmithKline
08/01/2008
Page 18 of 21
Visit
Non-High-Density Lipoprotein Cholesterol Percent Change from OM5 Baseline
(Non-HDL-C) (mg/dL)
77
Mean(Std)
Median
Min, Max
N
-7.8(16.56)
-7.2
-51.4, 30.9
88
Mean(Std)
Median
Min, Max
N
-36.3(47.15)
-29.7
-179.7, 45.3
88
Mean(Std)
Median
Min, Max
-15.6(19.44)
-13.5
-57.6, 21.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
88
19
GlaxoSmithKline
08/01/2008
Page 19 of 21
Visit
Month 0
Month 4
Month 12
ZM2008/00140/00
LOV111821
CONFIDENTIAL
78
Month 8
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
7.0(4.42)
6.0
3.0, 42.0
84
6.6(3.10)
6.0
3.0, 26.0
76
6.4(2.64)
6.0
2.0, 16.0
58
6.4(2.42)
6.0
3.0, 16.0
20
GlaxoSmithKline
08/01/2008
Page 20 of 21
Visit
OM5 Baseline [1]
0.1(3.59)
-0.3
-3.7, 31.2
ZM2008/00140/00
LOV111821
CONFIDENTIAL
79
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
6.9(2.07)
6.7
3.7, 21.7
89
7.0(4.61)
6.0
3.0, 44.5
88
6.7(2.33)
7.0
3.0, 16.0
88
21
GlaxoSmithKline
08/01/2008
Page 21 of 21
Visit
80
Mean(Std)
Median
Min, Max
N
-1.4(31.30)
-4.8
-45.2, 234.6
88
Mean(Std)
Median
Min, Max
N
-0.3(2.64)
-0.2
-15.7, 6.3
88
Mean(Std)
Median
Min, Max
-1.6(29.94)
-1.8
-72.4, 85.7
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
88
1
GlaxoSmithKline
08/22/2008
Page 1 of 6
Table 14.2.2.2 Secondary Efficacy Summary: Apolipoproteins Measurements - MITT Population
Visit
Apolipoprotein A-I (Apo A-I) (mg/dL)
Month 0
Month 4
81
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
87
125.8(29.81)
126.0
27.0, 210.0
81
127.0(28.39)
126.0
44.0, 199.0
59
128.8(25.58)
127.0
69.0, 184.0
8
121.6(18.21)
124.0
91.0, 150.0
2
GlaxoSmithKline
08/22/2008
Page 2 of 6
Visit
OM5 Baseline [1]
1.2(16.77)
2.0
-58.0, 44.5
ZM2008/00140/00
LOV111821
CONFIDENTIAL
82
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
123.5(25.99)
121.5
45.5, 236.5
89
124.7(28.11)
122.0
26.5, 219.0
89
129.5(24.61)
127.0
86.0, 243.0
89
3
GlaxoSmithKline
08/22/2008
Page 3 of 6
Visit
83
Mean(Std)
Median
Min, Max
N
1.3(14.45)
1.7
-68.6, 34.4
89
Mean(Std)
Median
Min, Max
N
6.0(18.09)
4.0
-27.5, 81.5
89
Mean(Std)
Median
Min, Max
7.1(22.94)
2.9
-20.4, 179.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
4
GlaxoSmithKline
08/22/2008
Page 4 of 6
Visit
Apolipoprotein B (mg/dL)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
84
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
87
121.9(32.19)
117.0
74.0, 260.0
81
114.0(29.93)
109.0
53.0, 220.0
59
108.4(28.89)
102.0
66.0, 199.0
8
104.5(37.09)
98.5
71.0, 191.0
5
GlaxoSmithKline
08/22/2008
Page 5 of 6
Visit
OM5 Baseline [1]
-0.7(22.93)
0.0
-59.0, 61.5
ZM2008/00140/00
LOV111821
CONFIDENTIAL
85
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
123.1(28.26)
118.0
58.0, 212.5
89
122.4(30.36)
120.0
74.5, 274.0
89
113.9(31.57)
109.0
48.0, 220.0
89
6
GlaxoSmithKline
08/22/2008
Page 6 of 6
Visit
86
Mean(Std)
Median
Min, Max
N
0.8(17.82)
0.0
-39.9, 47.6
89
Mean(Std)
Median
Min, Max
N
-9.3(28.16)
-6.5
-87.0, 49.5
89
Mean(Std)
Median
Min, Max
-6.1(20.82)
-7.3
-59.3, 35.4
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
1
GlaxoSmithKline
08/01/2008
Page 1 of 18
Table 14.2.3.1 Tertiary Efficacy Summary: Selected VAP and Lp-PLA2 Measurements - MITT Population
Visit
VLDL 1+2 (large) and VLDL 3 (small)
(direct) (mg/dL)
Month 0
Month 4
Month 24
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
38.8(12.42)
37.0
19.0, 79.0
82
37.6(16.20)
35.0
16.0, 120.0
58
34.3(13.32)
32.5
17.0, 75.0
8
37.8(29.13)
26.5
16.0, 106.0
CONFIDENTIAL
87
Month 12
N
All Subjects[2]
(N=89)
87
2
GlaxoSmithKline
08/01/2008
Page 2 of 18
(direct) (mg/dL)
Visit
OM5 Baseline [1]
N
-24.7(17.22)
-22.5
-64.0, 17.0
ZM2008/00140/00
LOV111821
64.1(20.81)
63.5
28.0, 113.0
87
38.8(12.42)
37.0
19.0, 79.0
89
38.2(19.35)
34.0
14.0, 120.0
86
CONFIDENTIAL
88
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
88
3
GlaxoSmithKline
08/01/2008
Page 3 of 18
(direct) (mg/dL)
Visit
89
Mean(Std)
Median
Min, Max
N
-35.2(20.89)
-39.6
-68.1, 42.1
88
Mean(Std)
Median
Min, Max
N
-25.9(21.09)
-24.5
-86.0, 29.0
88
Mean(Std)
Median
Min, Max
-38.2(25.04)
-40.8
-78.9, 37.7
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
86
4
GlaxoSmithKline
08/01/2008
Page 4 of 18
Visit
LDL 1+2 (Large) and LDL 3+4 (Small)
(mg/dL)
Month 0
90
Month 12
Month 24
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
116.9(41.33)
115.8
26.3, 265.0
82
107.2(36.58)
104.4
28.6, 209.6
58
105.5(33.41)
104.3
28.6, 209.6
8
88.8(23.26)
90.7
55.7, 126.2
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
87
5
GlaxoSmithKline
08/01/2008
Page 5 of 18
(mg/dL)
Visit
OM5 Baseline [1]
N
48.1(33.14)
45.7
-53.5, 122.3
ZM2008/00140/00
LOV111821
68.8(35.42)
62.2
20.3, 168.5
87
116.9(41.33)
115.8
26.3, 265.0
89
108.7(37.32)
106.1
25.8, 239.6
86
CONFIDENTIAL
91
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
88
6
GlaxoSmithKline
08/01/2008
Page 6 of 18
(mg/dL)
Visit
92
Mean(Std)
Median
Min, Max
N
97.1(86.13)
80.4
-34.7, 447.7
88
Mean(Std)
Median
Min, Max
N
39.1(36.65)
41.0
-71.6, 148.1
88
Mean(Std)
Median
Min, Max
88.0(92.49)
58.2
-56.2, 423.2
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
86
7
GlaxoSmithKline
08/01/2008
Page 7 of 18
Visit
HDL2 (large) and HDL3 (small) (mg/dL)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
93
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
87
35.0(9.17)
34.0
14.0, 76.0
82
34.7(8.41)
34.5
13.0, 57.0
58
35.2(8.80)
34.0
20.0, 58.0
8
34.8(10.66)
33.5
22.0, 57.0
8
GlaxoSmithKline
08/01/2008
Page 8 of 18
Visit
OM5 Baseline [1]
0.1(6.01)
1.0
-13.0, 20.0
ZM2008/00140/00
LOV111821
CONFIDENTIAL
94
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
88
35.0(7.30)
34.0
15.0, 58.0
87
35.0(9.17)
34.0
14.0, 76.0
89
36.5(10.23)
35.0
21.0, 84.0
86
9
GlaxoSmithKline
08/01/2008
Page 9 of 18
Visit
95
Mean(Std)
Median
Min, Max
N
0.7(16.98)
3.0
-38.5, 44.0
88
Mean(Std)
Median
Min, Max
N
1.6(7.74)
1.0
-14.0, 28.0
88
Mean(Std)
Median
Min, Max
5.7(24.87)
2.8
-35.0, 133.3
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
86
10
GlaxoSmithKline
08/01/2008
Page 10 of 18
Visit
Intermediate-density lipoprotein (IDL)
(mg/dL)
Month 0
96
Month 12
Month 24
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
22.1(9.53)
21.0
6.0, 58.0
82
19.6(8.41)
18.5
3.0, 48.0
58
19.5(12.97)
17.5
3.0, 90.0
8
15.1(7.41)
16.0
5.0, 29.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
87
11
GlaxoSmithKline
08/01/2008
Page 11 of 18
(mg/dL)
Visit
OM5 Baseline [1]
N
1.5(10.30)
2.0
-23.0, 34.0
ZM2008/00140/00
LOV111821
20.8(10.29)
18.5
5.0, 50.0
87
22.1(9.53)
21.0
6.0, 58.0
89
20.1(11.07)
19.0
1.0, 59.0
86
CONFIDENTIAL
97
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
88
12
GlaxoSmithKline
08/01/2008
Page 12 of 18
(mg/dL)
Visit
98
Mean(Std)
Median
Min, Max
N
24.1(71.49)
12.9
-71.4, 420.0
88
Mean(Std)
Median
Min, Max
N
-0.8(11.09)
0.0
-35.0, 25.0
88
Mean(Std)
Median
Min, Max
11.0(77.86)
0.0
-90.9, 500.0
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
86
13
GlaxoSmithKline
08/01/2008
Page 13 of 18
Visit
Lipoprotein (a) [Lp(a)] (mg/dL)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
99
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
87
6.0(5.15)
4.0
0.0, 24.0
82
6.6(5.68)
4.0
0.0, 26.0
58
6.1(5.58)
4.5
0.0, 29.0
8
8.3(9.29)
5.5
3.0, 31.0
14
GlaxoSmithKline
08/01/2008
Page 14 of 18
Visit
OM5 Baseline [1]
-9.5(9.80)
-7.5
-44.0, 9.0
ZM2008/00140/00
LOV111821
CONFIDENTIAL
100
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
88
15.5(9.05)
16.0
1.0, 44.0
87
6.0(5.15)
4.0
0.0, 24.0
89
6.9(7.06)
4.0
0.0, 35.0
86
15
GlaxoSmithKline
08/01/2008
Page 15 of 18
Visit
101
Mean(Std)
Median
Min, Max
N
-45.6(62.35)
-66.7
-100.0, 300.0
88
Mean(Std)
Median
Min, Max
N
-8.5(10.07)
-7.5
-41.0, 22.0
88
Mean(Std)
Median
Min, Max
-33.7(86.12)
-55.1
-100.0, 400.0
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
86
16
GlaxoSmithKline
08/01/2008
Page 16 of 18
Visit
Lipoprotein Associated Phospholipase A2
(Lp-PLA2) (ng/mL)
Month 0
102
Month 12
Month 24
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
ZM2008/00140/00
LOV111821
257.8(81.08)
225.5
141.0, 560.0
81
239.5(64.09)
230.0
125.0, 461.0
59
219.4(57.84)
206.0
120.0, 357.0
6
206.0(65.78)
187.5
130.0, 311.0
CONFIDENTIAL
Month 4
N
All Subjects[2]
(N=89)
86
17
GlaxoSmithKline
08/01/2008
Page 17 of 18
(Lp-PLA2) (ng/mL)
Visit
OM5 Baseline [1]
N
-65.8(94.10)
-47.0
-387.0, 139.0
ZM2008/00140/00
LOV111821
325.5(84.89)
321.0
163.0, 566.0
86
257.8(81.08)
225.5
141.0, 560.0
87
227.4(62.29)
218.0
88.0, 380.0
84
CONFIDENTIAL
103
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
18
GlaxoSmithKline
08/01/2008
Page 18 of 18
(Lp-PLA2) (ng/mL)
Visit
104
Mean(Std)
Median
Min, Max
N
-17.3(24.48)
-19.4
-68.4, 56.5
87
Mean(Std)
Median
Min, Max
N
-97.1(78.09)
-96.0
-264.0, 115.0
87
Mean(Std)
Median
Min, Max
-27.4(20.76)
-29.9
-65.2, 43.4
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
84
CONFIDENTIAL
14.3 Safety Data Summary Figures and Tables
105
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Page 1 of 8
Table 14.3.1 Occurrence of OM5XX Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term - Safety Population
ZM2008/00140/00
LOV111821
Reference: Listing 16.2.4.1: Adverse Events
Percentages are calculated as n/N
CONFIDENTIAL
106
All
Subjects[1]
(N=89)
System Organ Class
Preferred Term
Subjects with one or more adverse events (n(%))
69 (77.5 %)
Cardiac disorders
Any
3 (3.4 %)
Atrial flutter
1 (1.1 %)
Bradycardia
1 (1.1 %)
Cardiomyopathy
1 (1.1 %)
Congenital, familial and genetic disorders
Any
1 (1.1 %)
Mixed hyperlipidaemia
1 (1.1 %)
Ear and labyrinth disorders
Any
3 (3.4 %)
Ear congestion
2 (2.2 %)
Eustachian tube dysfunction
1 (1.1 %)
Endocrine disorders
Any
5 (5.6 %)
Diabetes mellitus
2 (2.2 %)
Diabetes mellitus non-insulin-dependent 3 (3.4 %)
Gastrointestinal disorders
Any
25 (28.1 %)
Abdominal pain
3 (3.4 %)
Abdominal pain upper
1 (1.1 %)
Abdominal tenderness
1 (1.1 %)
Constipation
2 (2.2 %)
Diarrhoea
3 (3.4 %)
Dyspepsia
1 (1.1 %)
2
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CONFIDENTIAL
107
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Gastrointestinal disorders
Gastritis
1 (1.1 %)
Gastrooesophageal reflux disease 2 (2.2 %)
Hiatus hernia
1 (1.1 %)
Nausea
5 (5.6 %)
Tooth impacted
1 (1.1 %)
Umbilical hernia
2 (2.2 %)
Vomiting
2 (2.2 %)
General disorders and administration site conditions Any
6 (6.7 %)
Asthenia
1 (1.1 %)
Chest discomfort
1 (1.1 %)
Cyst
1 (1.1 %)
Fatigue
1 (1.1 %)
Pain
1 (1.1 %)
Pyrexia
1 (1.1 %)
Hepatobiliary disorders
Any
2 (2.2 %)
Hepatic cyst
1 (1.1 %)
Hepatic steatosis
1 (1.1 %)
Immune system disorders
Any
2 (2.2 %)
Dermatitis contact
2 (2.2 %)
Infections and infestations
Any
48 (53.9 %)
3
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CONFIDENTIAL
108
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Infections and infestations
Body tinea
1 (1.1 %)
Bronchitis
2 (2.2 %)
Cellulitis
1 (1.1 %)
Dental caries
1 (1.1 %)
Diverticulitis
1 (1.1 %)
Fungal infection
1 (1.1 %)
Gastroenteritis
3 (3.4 %)
Gastroenteritis viral
2 (2.2 %)
Influenza
6 (6.7 %)
Labyrinthitis
1 (1.1 %)
Nasopharyngitis
2 (2.2 %)
Oral infection
1 (1.1 %)
Paronychia
1 (1.1 %)
Pharyngitis streptococcal
1 (1.1 %)
Respiratory tract infection
1 (1.1 %)
Sinusitis
5 (5.6 %)
Tooth abscess
1 (1.1 %)
Upper respiratory tract infection 15 (16.9 %)
Urinary tract infection
2 (2.2 %)
Injury, poisoning and procedural complications Any
15 (16.9 %)
4
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CONFIDENTIAL
109
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Injury, poisoning and procedural complications Arthropod bite
1 (1.1 %)
Back injury
1 (1.1 %)
Incision site complication
1 (1.1 %)
Joint sprain
2 (2.2 %)
Meniscus lesion
2 (2.2 %)
Procedural pain
1 (1.1 %)
Rib fracture
2 (2.2 %)
Skin laceration
4 (4.5 %)
Wrist fracture
1 (1.1 %)
Investigations
Any
13 (14.6 %)
Alanine aminotransferase increased
1 (1.1 %)
Aspartate aminotransferase increased 1 (1.1 %)
Blood glucose increased
1 (1.1 %)
Blood triglycerides increased
2 (2.2 %)
Electrocardiogram abnormal
1 (1.1 %)
Liver function test abnormal
1 (1.1 %)
Low density lipoprotein increased
1 (1.1 %)
Weight decreased
3 (3.4 %)
Weight increased
2 (2.2 %)
Metabolism and nutrition disorders
Any
5 (5.6 %)
5
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CONFIDENTIAL
110
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Metabolism and nutrition disorders
Dehydration
1 (1.1 %)
Dyslipidaemia
1 (1.1 %)
Hyperglycaemia
1 (1.1 %)
Hypertriglyceridaemia
1 (1.1 %)
Lactose intolerance
1 (1.1 %)
Musculoskeletal and connective tissue disorders Any
29 (32.6 %)
Arthralgia
3 (3.4 %)
Arthritis
1 (1.1 %)
Back pain
5 (5.6 %)
Exostosis
1 (1.1 %)
Flank pain
1 (1.1 %)
Intervertebral disc protrusion 2 (2.2 %)
Muscle spasms
2 (2.2 %)
Musculoskeletal chest pain
1 (1.1 %)
Musculoskeletal stiffness
1 (1.1 %)
Myalgia
1 (1.1 %)
Osteoarthritis
2 (2.2 %)
Pain in extremity
2 (2.2 %)
Plantar fasciitis
1 (1.1 %)
Rotator cuff syndrome
2 (2.2 %)
6
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CONFIDENTIAL
111
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Musculoskeletal and connective tissue disorders Shoulder pain
3 (3.4 %)
Tendonitis
1 (1.1 %)
Nervous system disorders
Any
14 (15.7 %)
Carpal tunnel syndrome 1 (1.1 %)
Dizziness
2 (2.2 %)
Headache
1 (1.1 %)
Hypoaesthesia
1 (1.1 %)
Insomnia
1 (1.1 %)
Migraine
2 (2.2 %)
Neuropathy peripheral 1 (1.1 %)
Paraesthesia
2 (2.2 %)
Radiculopathy
1 (1.1 %)
Syncope
1 (1.1 %)
Syncope vasovagal
1 (1.1 %)
Psychiatric disorders
Any
6 (6.7 %)
Anxiety
3 (3.4 %)
Depression
2 (2.2 %)
Stress
1 (1.1 %)
Renal and urinary disorders
Any
2 (2.2 %)
Hypertonic bladder
1 (1.1 %)
7
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CONFIDENTIAL
112
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Renal and urinary disorders
Pollakiuria
1 (1.1 %)
Reproductive system and breast disorders
Any
9 (10.1 %)
Atrophic vulvovaginitis
1 (1.1 %)
Benign prostatic hyperplasia 1 (1.1 %)
Epididymitis
2 (2.2 %)
Erectile dysfunction
1 (1.1 %)
Menometrorrhagia
1 (1.1 %)
Ovarian adhesion
1 (1.1 %)
Prostatitis
2 (2.2 %)
Respiratory, thoracic and mediastinal disorders Any
11 (12.4 %)
Asthma
1 (1.1 %)
Bronchospasm
1 (1.1 %)
Cough
2 (2.2 %)
Dyspnoea
1 (1.1 %)
Pharyngolaryngeal pain
1 (1.1 %)
Respiratory tract congestion 1 (1.1 %)
Rhinitis allergic
2 (2.2 %)
Sinus congestion
1 (1.1 %)
Sleep apnoea syndrome
1 (1.1 %)
Skin and subcutaneous tissue disorders
Any
5 (5.6 %)
8
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Page 8 of 8
CONFIDENTIAL
113
All
Subjects[1]
System Organ Class
Preferred Term
(N=89)
Skin and subcutaneous tissue disorders Dermatitis contact 2 (2.2 %)
Rash
1 (1.1 %)
Rash generalised 1 (1.1 %)
Urticaria
1 (1.1 %)
Vascular disorders
Any
7 (7.9 %)
Hot flush
1 (1.1 %)
Hypertension
6 (6.7 %)
ZM2008/00140/00
LOV111821
1
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08/01/2008
Page 1 of 1
Table 14.3.2 Occurrence of OM5XX Serious Treatment-Emergent Adverse Events
by Relationship to Lovaza - Safety Population
Reference: Listing 16.2.4.2: Serious Adverse Events
[1] If a subject experiences the same event more than once, the first occurrence is tabulated
CONFIDENTIAL
114
Serious Adverse Event
Relationship to Lovaza
Any Serious Treatment-Emergent Adverse Event [1] (n(%)) Any
ACUTE MYOCARDIAL INFARCTION
Any
Not Related
ELEVATED LIVER FUNCTION
Any
Unlikely
L2-3 HERNIATED LUMBAR DISK
Any
Not Related
R LOWER EXTREMITY CELLULITUS
Any
Not Related
All
Subjects[2]
(N=89)
4 (4.5 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
1 (1.1 %)
ZM2008/00140/00
LOV111821
CONFIDENTIAL
14.4 Laboratory Data Summary Figures and Tables
115
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1
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08/01/2008
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Table 14.4.1 Selected Serum Chemistry Panel - Safety Population
Visit
Alanine Aminotransferase (ALT) (U/L)
Month 0
Month 4
116
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
47.3(25.62)
43.0
14.0, 149.0
84
47.7(25.00)
41.0
13.0, 131.0
58
51.5(30.08)
42.5
13.0, 188.0
9
64.0(31.53)
64.0
28.0, 119.0
2
GlaxoSmithKline
08/01/2008
Page 2 of 12
Visit
OM5 Baseline [1]
CONFIDENTIAL
117
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
42.1(21.18)
38.0
13.0, 115.0
89
47.3(25.62)
43.0
14.0, 149.0
89
53.3(30.38)
47.0
12.0, 151.0
89
5.2(19.81)
3.0
-57.0, 80.0
ZM2008/00140/00
LOV111821
3
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08/01/2008
Page 3 of 12
Visit
118
Mean(Std)
Median
Min, Max
N
18.4(50.08)
7.7
-57.7, 268.4
89
Mean(Std)
Median
Min, Max
N
11.2(24.01)
7.0
-45.0, 114.0
89
Mean(Std)
Median
Min, Max
32.2(60.98)
19.0
-50.6, 308.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
4
GlaxoSmithKline
08/01/2008
Page 4 of 12
Visit
Aspartate Aminotransferase (AST) (U/L)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
119
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
33.8(16.12)
30.0
14.0, 123.0
84
34.4(19.74)
29.0
16.0, 159.0
58
34.7(15.64)
29.0
16.0, 86.0
9
40.8(18.14)
34.0
20.0, 78.0
5
GlaxoSmithKline
08/01/2008
Page 5 of 12
Visit
OM5 Baseline [1]
CONFIDENTIAL
120
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
31.2(17.22)
28.0
15.0, 165.0
89
33.8(16.12)
30.0
14.0, 123.0
89
38.1(28.06)
31.0
16.0, 214.0
89
2.6(11.05)
1.0
-42.0, 36.0
ZM2008/00140/00
LOV111821
6
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08/01/2008
Page 6 of 12
Visit
121
Mean(Std)
Median
Min, Max
N
12.0(30.59)
4.3
-50.8, 113.0
89
Mean(Std)
Median
Min, Max
N
7.0(22.58)
2.0
-32.0, 179.0
89
Mean(Std)
Median
Min, Max
24.0(66.67)
8.0
-49.2, 511.4
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
7
GlaxoSmithKline
08/01/2008
Page 7 of 12
Visit
Creatine Kinase (CK) (U/L)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
122
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
148.0(111.36)
116.0
30.0, 700.0
84
133.5(72.43)
116.5
34.0, 370.0
58
143.5(75.95)
132.5
32.0, 399.0
9
178.3(81.93)
145.0
102.0, 338.0
8
GlaxoSmithKline
08/01/2008
Page 8 of 12
Visit
OM5 Baseline [1]
CONFIDENTIAL
123
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
145.7(91.80)
121.0
38.0, 584.0
89
148.0(111.36)
116.0
30.0, 700.0
89
161.0(159.78)
124.0
29.0, 1306.0
89
2.3(66.13)
-6.0
-178.0, 297.0
ZM2008/00140/00
LOV111821
9
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08/01/2008
Page 9 of 12
Visit
124
Mean(Std)
Median
Min, Max
N
3.3(37.45)
-4.7
-63.9, 149.6
89
Mean(Std)
Median
Min, Max
N
15.3(119.24)
1.0
-166.0, 722.0
89
Mean(Std)
Median
Min, Max
13.1(69.84)
0.6
-69.7, 528.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
10
GlaxoSmithKline
08/01/2008
Page 10 of 12
Visit
Glucose (mg/dL)
Month 0
Month 4
Month 24
ZM2008/00140/00
LOV111821
CONFIDENTIAL
125
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
112.1(28.99)
105.0
70.0, 245.0
84
118.6(34.03)
107.0
78.0, 254.0
58
124.5(36.64)
110.5
84.0, 283.0
9
141.3(45.05)
116.0
103.0, 212.0
11
GlaxoSmithKline
08/01/2008
Page 11 of 12
Glucose (mg/dL)
Visit
OM5 Baseline [1]
CONFIDENTIAL
126
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=89)
89
109.4(21.03)
103.0
79.0, 165.0
89
112.1(28.99)
105.0
70.0, 245.0
89
122.2(41.71)
107.0
77.0, 323.0
89
2.7(17.13)
1.0
-42.0, 89.0
ZM2008/00140/00
LOV111821
12
GlaxoSmithKline
08/01/2008
Page 12 of 12
Glucose (mg/dL)
Visit
127
Mean(Std)
Median
Min, Max
N
2.2(13.07)
0.9
-29.3, 57.1
89
Mean(Std)
Median
Min, Max
N
12.8(32.41)
4.0
-72.0, 167.0
89
Mean(Std)
Median
Min, Max
11.1(25.32)
3.6
-43.9, 107.1
ZM2008/00140/00
LOV111821
CONFIDENTIAL
N
All Subjects[2]
(N=89)
89
1
GlaxoSmithKline
09/05/2008
Page 1 of 12
Table 14.4.1a Selected Serum Chemistry Panel up to Month 12 - Safety Population
Visit
Month 0
Month 4
128
OM5 Baseline [1]
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
46.5(22.42)
45.0
14.0, 104.0
57
50.8(25.97)
43.0
13.0, 131.0
58
51.5(30.08)
42.5
13.0, 188.0
58
41.6(17.37)
41.0
13.0, 89.0
ZM2008/00140/00
LOV111821
2
GlaxoSmithKline
09/05/2008
Page 2 of 12
Visit
15.8(43.07)
9.2
-57.7, 160.0
58
9.9(26.10)
6.0
-52.0, 141.0
ZM2008/00140/00
LOV111821
4.9(17.89)
4.0
-41.0, 64.0
58
CONFIDENTIAL
129
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
OM5XX Month 12 Visit
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
46.5(22.42)
45.0
14.0, 104.0
58
3
GlaxoSmithKline
09/05/2008
Page 3 of 12
Visit
to OM5XX Month 12 Visit
N
Mean(Std)
Median
Min, Max
29.1(60.90)
15.4
-62.7, 300.0
CONFIDENTIAL
130
All Subjects[2]
(N=58)
58
ZM2008/00140/00
LOV111821
4
GlaxoSmithKline
09/05/2008
Page 4 of 12
Visit
Month 0
Month 4
131
OM5 Baseline [1]
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
32.9(12.90)
30.5
14.0, 82.0
57
34.5(15.55)
30.0
16.0, 87.0
58
34.7(15.64)
29.0
16.0, 86.0
58
29.4(9.02)
28.0
15.0, 64.0
ZM2008/00140/00
LOV111821
5
GlaxoSmithKline
09/05/2008
Page 5 of 12
Visit
13.3(30.14)
7.9
-37.0, 113.0
58
5.3(12.85)
1.5
-12.0, 45.0
ZM2008/00140/00
LOV111821
3.5(9.07)
2.0
-17.0, 29.0
58
CONFIDENTIAL
132
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
32.9(12.90)
30.5
14.0, 82.0
58
6
GlaxoSmithKline
09/05/2008
Page 6 of 12
Visit
N
Mean(Std)
Median
Min, Max
19.7(43.38)
4.9
-28.2, 200.0
CONFIDENTIAL
133
All Subjects[2]
(N=58)
58
ZM2008/00140/00
LOV111821
7
GlaxoSmithKline
09/05/2008
Page 7 of 12
Visit
Month 0
Month 4
134
OM5 Baseline [1]
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
145.9(97.03)
118.0
30.0, 621.0
57
136.4(71.01)
118.0
34.0, 365.0
58
143.5(75.95)
132.5
32.0, 399.0
58
146.1(83.23)
125.5
47.0, 459.0
ZM2008/00140/00
LOV111821
8
GlaxoSmithKline
09/05/2008
Page 8 of 12
Visit
1.9(33.16)
-2.3
-63.9, 149.6
58
-2.6(53.84)
1.0
-173.0, 156.0
ZM2008/00140/00
LOV111821
-0.2(63.95)
-2.5
-178.0, 297.0
58
CONFIDENTIAL
135
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
145.9(97.03)
118.0
30.0, 621.0
58
9
GlaxoSmithKline
09/05/2008
Page 9 of 12
Visit
N
Mean(Std)
Median
Min, Max
2.9(33.12)
1.1
-58.7, 100.0
CONFIDENTIAL
136
All Subjects[2]
(N=58)
58
ZM2008/00140/00
LOV111821
10
GlaxoSmithKline
09/05/2008
Page 10 of 12
Visit
Glucose (mg/dL)
Month 0
Month 4
137
OM5 Baseline [1]
CONFIDENTIAL
Month 12
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
116.5(31.59)
106.0
85.0, 245.0
57
122.3(35.26)
108.0
86.0, 254.0
58
124.5(36.64)
110.5
84.0, 283.0
58
112.5(22.32)
104.5
89.0, 165.0
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11
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Page 11 of 12
Glucose (mg/dL)
Visit
3.3(14.04)
0.5
-26.9, 57.1
58
12.0(27.82)
6.0
-40.0, 127.0
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4.0(19.42)
0.5
-42.0, 89.0
58
CONFIDENTIAL
138
N
Mean(Std)
Median
Min, Max
End-of-Treatment
Mean(Std)
Median
Min, Max
Mean(Std)
Median
Min, Max
N
Mean(Std)
Median
Min, Max
All Subjects[2]
(N=58)
58
116.5(31.59)
106.0
85.0, 245.0
58
12
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Glucose (mg/dL)
Visit
N
Mean(Std)
Median
Min, Max
10.8(22.09)
4.9
-26.3, 81.4
CONFIDENTIAL
139
All Subjects[2]
(N=58)
58
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Patient Data Listings
Page
16.2.1 Overall subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
140
Listing 16.2.1.1 Overall Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . .
141
16.2.2 Demographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Listing 16.2.2.1 Subject Demographics and Informed Consent . . . . . . . .
149
150
16.2.3 Individual Efficacy Response Data . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16.2.3.1 Serum Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Listing 16.2.3.1 Lipid Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
155
155
156
16.2.4 Adverse Event Listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16.2.4.1 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Listing 16.2.4.1 Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16.2.4.2 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Listing 16.2.4.2 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . .
16.2.4.3 Adverse Event Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Listing 16.2.4.3 Adverse Event Follow-Up . . . . . . . . . . . . . . . . . . . . .
483
483
484
526
527
528
529
140
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
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A SECOND OPEN-LABEL EXTENSION OF A DOUBLE-BLIND, PARALLEL,
PHASE IV STUDY TO ASSESS THE EFFICACY AND SAFETY OF ADJUNCTIVE
OMACOR® THERAPY IN HYPERTRIGLYCERIDEMIC SUBJECTS TREATED
WITH ANTARA™
Protocol Number: OM5XX
Document Dates
Original Protocol: 27 January 2006
Administrative Change #1: 31 May 2007
Administrative Change #2: 25 April 2008
GlaxoSmithKline
2301 Renaissance Blvd
King of Prussia, PA 19406
Subsidiary of GlaxoSmithKline
CONFIDENTIAL
GlaxoSmithKline
Protocol OM5XX
Administrative Change #2, 25 April 2008
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CONFIDENTIAL
SUMMARY OF ADMINISTRATIVE CHANGES
The following table is a summary of changes to the Original Protocol and Administrative
Changes #1 and #2. The present document is entitled “Administrative Change #2” and
incorporates only Administrative Change #2 revisions itemized in the table.
Rationale
Change
Reliant to
GlaxoSmith
Kline
Rationale
Change in
Medical
Monitor and
Radiant
Development
Contact
Rationale
Change in
Medical
Monitor
Section/
Location
All
applicable
Section/
Location
5.3.4
Section/
Location
5.3.4
Change in
Radiant
Development
Contact
5.3.4
Rationale
Section/
Location
5.3.7
Change in
reporting
pregnancies
Original Protocol and
Administrative Change #1
Reliant Pharmaceuticals Inc.
Original Protocol
MD
515 N. State Street, Suite 2700
Radiant Development
Ph:
Fax:
MD
Medical Director
Radiant Development
Ph:
Fax:
MD
Medical Director
Radiant Development
Ph:
Fax:
Original Protocol
The investigator will immediately
notify the Medical Monitor about
the pregnancy and complete a
pregnancy report form.
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GlaxoSmithKline
MD
Radiant Development
Ph:
Fax:
MD
Director, Cardiovascular MDC
GlaxoSmithKline
Ph:
Fax:
Email:
Clinical Trial Associate
Radiant Development
Ph:
Fax:
The investigator will immediately
notify Radiant Development about the
pregnancy and complete a pregnancy
report form.
2
CONFIDENTIAL
Rationale
Delete text
referencing
the name of
the Medical
Monitor
Section/
Location
3.5.1
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Original Protocol
If a subject has a TG level >1000
mg/dL at any point during the
treatment period, an alert will be
sent out to the investigator. The
investigator will have the option of
repeating the test, and with input
from the Medical Monitor (Dr.
will decide how
to proceed with the subject.
If a subject has a TG level >1000
mg/dL at any point during the treatment
period, an alert will be sent out to the
investigator and Medical Monitor. The
investigator will have the option of
repeating the test, and with input from
the Medical Monitor, will decide how
to proceed with the subject.
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INVESTIGATOR SIGNATURE SHEET
A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to
Assess the Efficacy and Safety of Adjunctive Omacor® Therapy in
Hypertriglyceridemic Subjects Treated with Antara™
By my signature below, I attest that I have read, understood, and agree to abide by all
conditions, instructions, and restrictions contained in this protocol administrative change
(including appendices). I will not initiate this study without approval from the appropriate
Institutional Review Board (IRB) and I understand that any changes in the protocol must
be approved in writing by the Sponsor and the IRB before they can be implemented,
except where necessary to eliminate immediate hazards to the subject.
Approval Signatures:
Investigator:
Signature
Date
Name
Name of Facility
Address
City, State, Zip code
Phone Number
Fax Number
Email Address
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CONFIDENTIAL
SPONSOR SIGNATURE SHEET
A Second Open-Label Extension of a Double~Blind, Parallel, Phase IV Study to
Assess the Efficacy and Safety of Adjunctive Omacor® Therapy in
By my signature below, I approve of this protocol administrative change.
25 I}.,,J of
Sponsor Company:
Dr.
BSc (Hons), MRCP (UK)
Vice President
Cardiovascular Clinical Research
CVMMDC
GlaxoSmithKline
Phone
Email
GlaxoSmithKline
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TABLE OF CONTENTS
Page
SUMMARY OF ADMINISTRATIVE CHANGES........................................................... 2
INVESTIGATOR SIGNATURE SHEET .......................................................................... 4
SPONSOR SIGNATURE SHEET ..................................................................................... 5
LIST OF ABBREVIATIONS............................................................................................. 8
PROTOCOL SYNOPSIS.................................................................................................... 9
1.0 BACKGROUND/RATIONALE ............................................................................. 12
2.0 OBJECTIVES .......................................................................................................... 13
3.0 STUDY MATERIALS AND PROCEDURES........................................................ 14
3.1 Flow Chart ............................................................................................................ 14
3.2 Study Design......................................................................................................... 16
3.3 Study Sample ........................................................................................................ 16
3.3.1 Inclusion Criteria ............................................................................................ 16
3.3.2 Exclusion Criteria ........................................................................................... 16
3.4 Study Drug ............................................................................................................ 17
3.4.1 Description...................................................................................................... 17
3.4.2 Labeling .......................................................................................................... 17
3.4.3 Storage and Dispensing................................................................................... 17
3.4.4 Blinding........................................................................................................... 18
3.5 Clinical Measurements.......................................................................................... 18
3.5.1 Laboratory Measurements .............................................................................. 18
3.5.2 Apolipoprotein and Specialty Testing ............................................................ 19
3.5.3 Blood Pressure Assessment ............................................................................ 19
3.5.4 Anthropometrics ............................................................................................. 19
3.6 Dietary Measurements .......................................................................................... 20
3.7 Procedures at Each Clinic Visit ............................................................................ 20
3.7.1 End of OM5X Open-Label Treatment (Visit 1XX, Month 0; same day as Visit
4X of study OM5X, Week 16).................................................................................. 20
3.7.2 Treatment (Visit 2XX, Month 4) .................................................................... 20
3.7.3 Treatment (Visit 3XX, Month 8) .................................................................... 21
3.7.4 Treatment (Visit 4XX, Month 12) .................................................................. 21
3.7.8 Early Termination Procedures ........................................................................ 23
3.8 Assessment of Outcomes ...................................................................................... 24
3.8.1 Primary Outcome Analysis ............................................................................. 24
3.8.2 Main Hypothesis ............................................................................................. 24
3.8.3 Secondary Outcome Analyses ........................................................................ 24
3.8.4 Tertiary Outcome Analyses ............................................................................ 25
3.9 Safety Assessment ................................................................................................ 25
4.0 DATA ANALYSIS AND STATISTICAL METHODS ......................................... 26
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4.1 Sample Size........................................................................................................... 26
4.2 Statistical Analyses ............................................................................................... 26
4.2.1 Baseline........................................................................................................... 27
4.2.2 Outcome Analyses .......................................................................................... 27
4.2.3 Safety Analyses............................................................................................... 27
4.2.4 Dietary Analyses............................................................................................. 27
4.2.5 Missing or Incomplete Data............................................................................ 28
5.0 STUDY MONITORING ......................................................................................... 28
5.1 Concomitant Medication and Treatment .............................................................. 28
5.2 Compliance Monitoring ........................................................................................ 28
5.3 Adverse Event Monitoring.................................................................................... 28
5.3.1 Grading and Severity ...................................................................................... 29
5.3.2 Relationship .................................................................................................... 29
5.3.3 Serious Adverse Event Definition/Qualification ............................................ 31
5.3.4 Serious Adverse Event Reporting Instructions ............................................... 31
5.3.5 CRF Recording of Adverse Events................................................................. 32
5.3.6 Serious Adverse Event Follow-Up ................................................................. 32
5.3.7 Pregnancy........................................................................................................ 33
6.0 CONDUCT OF THE STUDY ................................................................................. 33
6.1 Ethics and Regulatory Considerations .................................................................. 33
6.2 Institutional Review Board ................................................................................... 34
6.3 Informed Consent and Protected Health Information........................................... 34
6.4 Subject Confidentiality ......................................................................................... 34
6.5 Withdrawal of Subjects from the Study................................................................ 35
7.0 ADMINISTRATIVE MATTERS............................................................................ 35
7.1 Changes to the Protocol ........................................................................................ 35
7.2 Protocol Deviations and Violations ...................................................................... 35
7.3 Case Report Forms................................................................................................ 36
7.4 Clinical Monitoring............................................................................................... 36
7.5 Auditing Procedures.............................................................................................. 37
7.6 Record Retention .................................................................................................. 38
7.7 Termination of Study ............................................................................................ 38
7.8 Final Report/Publications...................................................................................... 38
8.0 STUDY MEDICATION.......................................................................................... 39
9.0 DISCLOSURE......................................................................................................... 39
10.0 REFERENCES ........................................................................................................ 40
APPENDIX 1: EXCLUSIONARY MEDICATIONS ..................................................... 41
APPENDIX 2: INVESTIGATION OF INCREASES IN TESTS OF
LIVER FUNCTION AND CREATINE KINASE ........................................................... 44
APPENDIX 3: THERAPEUTIC LIFESTYLE CHANGES DIET ................................. 46
APPENDIX 4: EATING PATTERN ASSESSMENT TOOL......................................... 47
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LIST OF ABBREVIATIONS
AE
ANOVA
Apo A-I
Apo B
Apo C-III
CK (CPK)
CRF
DHA
EPA
EPAT
FDA
g/d
HbA1c
HDL-C
hs-CRP
HOMA
ICH
IRB
ITT
LDL-C
LOCF
Lp(a)
Lp-PLA2
mg/dL
MPO
NCEP
PP
RLP-C
SAE
SAS
SOC
TG
TLC
Total-C
VAP
VLDL-C
Adverse event
Apolipoprotein A-I
Apolipoprotein B
Apolipoprotein C-III
Creatine (Phospho)Kinase
Case report form
Docosahexaenoic acid
Eicosapentaenoic acid
Eating Pattern Assessment Tool
Food and Drug Administration
Grams per day
Glycosylated hemoglobin
High sensitivity C-reactive protein
Homeostatic model assessment
International Conference on Harmonization
Intent-to-treat
Lipoprotein(a)
Lipoprotein-associated phospholipase A2
Milligrams per deciliter
Myeloperoxidase
National Cholesterol Education Program
Per protocol
Remnant lipoprotein cholesterol
Statistical Analysis Software
Standard-of-care
Triglycerides
Therapeutic Lifestyle Changes
Total cholesterol
Vertical Auto-Profile Method
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PROTOCOL SYNOPSIS
PROTOCOL TITLE: A Second Open-Label Extension of a Double-Blind, Parallel,
Phase IV Study to Assess the Efficacy and Safety of Adjunctive Omacor® Therapy in
TEST PRODUCTS:
• Omacor® (Omega-3-acid ethyl esters; eicosapentaenoic acid [EPA] +
docosahexaenoic acid [DHA]) administered as four 1-g capsules/d
• Antara™ (fenofibrate) 130 mg capsules, administered as one capsule/d
OBJECTIVES:
Primary: The primary objective of this 24-month extension is to assess the continued
efficacy of adjunctive Omacor® therapy in hypertriglyceridemic subjects treated with
Antara™ for lowering triglyceride (TG) levels.
Secondary:
• To evaluate the continued safety of Antara™ plus Omacor® during a 24-month
open-label extension of the previous 8-week open-label extension (OM5X) to
Protocol OM5.
• To assess the effects of Antara™ plus Omacor® on other lipids and markers for
cardiovascular risk.
SUBJECT POPULATION: Subjects must have completed the previous OM5X openlabel extension (8-weeks), and must have met all inclusion/criteria for the OM5 study or
have a renewed waiver of a previously approved protocol deviation in either the OM5X
or OM5 study. A sample size of 150 randomized subjects is planned for study OM5 and
all willing and eligible subjects will enroll in OM5XX.
STUDY DESIGN: This trial will utilize an open-label design with seven clinic visits.
Visit 1XX in study OM5XX coincides with Visit 4X of the previous OM5X 8-week
open-label study. All subjects who completed the previous OM5X study will receive
open-label Antara™ 130 mg/d plus open-label Omacor® 4 g/d for a 24-month extended
treatment period. At the Investigator’s discretion, subjects may receive additional lipidlowering agents at the end of OM5X or at anytime throughout the OM5XX study to
insure subjects receive standard-of-care (SOC). Acceptable agents are statins and/or
ezetimibe (simvastatin is suggested); see Exclusion Criteria and Safety sections
(including Section 3.9), and Excluded Medications in Appendix 1 .
OUTCOME MEASUREMENTS:
Primary Efficacy Endpoint:
The primary endpoint will be the difference between the within-group mean percent
change (from baseline) in TG level observed at the end of OM5X (average of Weeks 14
and 16 minus average of Week -2, -1 and 0 in OM5) and the mean percent change (from
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baseline) observed at the end of OM5XX (Month 24 minus average of Week -2, -1 and 0
in OM5).
For those subjects who receive additional lipid lowering agents, the method of last
observation carried forward (LOCF) will be applied to the lipid data measured at the last
available visit before the initiation of the additional agents. Subjects who receive
additional lipid-lowering agents will also be analyzed as a separate group from those who
do not.
Secondary Efficacy Endpoints:
• Total cholesterol (total-C), very low-density lipoprotein cholesterol (VLDL-C),
LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, the totalC:HDL-C ratio, and apolipoproteins A-I and B in all subjects will be evaluated as
described for TG above.
• Additional time points may also be analyzed for the all of the above lipid
variables.
Subjects who received additional lipid-lowering agents will be analyzed as described
above.
For apolipoproteins, baseline in the OM5 double blind will be defined as the average of
Weeks -1 and 0.
Tertiary Efficacy Endpoints:
The group mean percent changes in the variables below will be evaluated as for the lipid
variables above:
¾ Apo C-III and remnant lipoprotein cholesterol (RLP-C)
¾ Analysis by the Vertical Auto-Profile method (VAP™) of lipid
subfraction cholesterol carried by:
VLDL1+2 (large) and VLDL3 (small)
LDL1+2 (large) and LDL3+4 (small)
HDL2 (large) and HDL3 (small)
Lipoprotein (a) [Lp(a)]
¾ Body weight
¾ Waist Circumference
¾ Blood pressure
¾ HOMA insulin resistance in subjects not taking hypoglycemic medication
¾ High sensitivity C-reactive protein (hs-CRP)
¾ Lipoprotein-associated phospholipase A2 (Lp-PLA2)
¾ Myeloperoxidase (MPO)
¾ Fatty acid profile (total fatty acids, EPA, DHA, and arachidonic acid)
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Except for blood pressure, all tertiary variables will have the OM5 baseline defined as
Week 0. Blood pressure will have the OM5 baseline as defined above for TG and the
lipid variables.
Subjects who receive additional lipid-lowering agents will be analyzed as described
above.
SAFETY MEASUREMENTS: Safety assessments will include vital signs and adverse
events (AEs) recorded at each clinic visit and changes from screening/baseline of OM5,
OM5X and OM5XX to the end of the open-label 24-month treatment extension in
clinical laboratory measurements.
STATISTICAL ANALYSES: Baseline characteristics for the start of OM5 and
OM5XX trials will be presented including demographic, anthropometric, blood pressure,
and lipid values will be presented with standard descriptive statistics. Parametric and
non-parametric analyses (analysis of variance, chi-square tests, or other techniques, as
appropriate) will be used, where appropriate, to compare responses of the pooled group
over time.
For pooled analyses of efficacy variables for all subjects, within-group responses will be
assessed using repeated measures ANOVA. The initial models will include terms for
baseline value, time, center, and time by center interaction. The models will be reduced in
a stepwise manner until only significant factors, or time, remain. Data may be ranked
prior to running these analyses if the distribution for any variable does not approximate a
normal curve. Within-group differences in the assessments described above in the Safety
Measurements section will also be assessed using repeated measures ANOVA.
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BACKGROUND/RATIONALE
Elevated TG concentration is an independent risk factor for coronary heart disease
(Ginsberg 2001). Incidence rates of major coronary events in the Munster Heart Study
increased from 4.4% in persons with TG levels < 200 mg/dL to 9.3% among individuals
with TG levels 200-399 mg/dL, and 13.2% in persons with TG levels 400-799 mg/dL
(Assmann 1996).
Statins, nicotinic acid, and fibrates have demonstrated efficacy for improving atherogenic
dyslipidemia, reducing coronary heart disease events, and slowing or reversing the
progression of coronary atherosclerosis. Statins are the most commonly used lipidaltering drugs. Although statins produce significant reductions in LDL-C levels, fibrates
and nicotinic acid are more effective agents for lowering TG levels (Stein 1998). Fibrates
significantly reduce fasting TG concentration (20-50%) and postprandial TG
concentration and increase HDL-C concentration (10-35%). In addition, alterations in
LDL structure (a shift toward larger, more buoyant LDL particles) and changes in various
hemostatic and inflammatory markers contribute to the cardioprotective effect of fibrate
therapy.
Fenofibrate is a fibrate prodrug that is hydrolyzed immediately upon absorption to its
principal active form. Antara™, fenofibrate microgranules, will be examined in the
present study. This formulation of fenofibrate overcomes the typically poor
bioavailability of fenofibrate by virtue of its micronized formulation.
Another group of effective TG-reducing agents is omega-3 fatty acids. Marine-based
omega-3 fatty acids (EPA and DHA) are generally more effective for lowering TG levels
than plant-based (alpha-linolenic acid) products. An examination of 65 clinical trials
indicated that supplementation with ~3-4 g/d of EPA+DHA lowered TG levels 25-30%
vs. controls (Harris 1997a). Changes in TG concentration were also accompanied by mild
increases in LDL-C (5-10%) and HDL-C (1-3%) levels (Harris 1997a). The ability of
omega-3 fatty acids to lower TG concentration seems to be most pronounced in persons
with hypertriglyceridemia (34% decrease in hypertriglyceridemic subjects vs. 25% in
normotriglyceridemic subjects) (Harris 1997a, Ginsberg 2001).
Omacor®, omega-3-acid ethyl esters, is an omega-3 fatty acid concentrate. Unlike many
other marine oil products, Omacor® contains ≥ 90% omega-3 fatty acids, providing 3.4
g/d of EPA+DHA in 4 g of oil and no heavy metal or other contamination. Omacor® has
demonstrated efficacy in reducing elevated TG concentrations (Harris 1997b,
Durrington 2001, Bhatnagar 2003, Calabresi 2004).
In the present extension study, the long-term (24-month) efficacy and safety of the
Antara™ and Omacor® co-administration will be examined in persons with baseline TG
concentrations ≥ 500 mg/dL and < 1300 mg/dL and BMI ≥ 25 kg/m2 and ≤ 43 kg/m2.
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Both drugs are hypotriglyceridemic agents that act by increasing fatty acid catabolism
and decreasing TG synthesis and secretion by the liver.
2.0
OBJECTIVES
The primary objective of this 24-month extension is to assess the continued efficacy of
adjunctive Omacor® therapy in hypertriglyceridemic subjects treated with Antara™ for
lowering triglyceride TG levels.
Secondary objectives of this study are to evaluate the continued safety of Antara™ plus
Omacor® during a 24-month open-label extension of the previous 8-week open-label
extension (OM5X) to Protocol OM5, and to assess the effects of Antara™ plus Omacor®
on other lipids and markers for cardiovascular risk.
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3.0
STUDY MATERIALS AND PROCEDURES
3.1
Flow Chart
End of OM5X
Treatment
OM5XX Treatment
1XX1
2XX
3XX
4XX
5XX
6XX
7XX
0
4
8
12
16
20
24
X
X
X
X
X
X
T
X
X
X
X
X
X
Waist Circumference
T
X
X
X
X
X
X
Serum Chemistry
T
X
Hematology
T
X
Urinalysis
T
X
Fasting Lipid Profile
T
X
hs-CRP
T
X
X
X
Fasting Insulin5
T
X
X
X
Apo AI and Apo B
T
X
X
X
Specialty Labs6
T
X
X
X
T
X
X
X
T
X
X
X
Visit
Month
Informed Consent
X
2
Clinical Assessments
T
Corrected/Updated Medical History3
X
Vital Signs
4
7
Fatty Acid Profile
Store Serum and Plasma Samples8
9
X
X
X
X
X
X
Serum Pregnancy Test
T
In-Clinic Urine Pregnancy Test9
X
T
Dietary Reinforcement10
X
X
X
X
X
X
Dispense/Redispense Study Drug
X
X
X
X
X
X
Collect Study Drug/Assess Compliance
T
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
“T” denotes a procedure performed for the previous OM5X open-label study that does not need to be
duplicated for the OM5XX study and for which data will be transcribed to OM5XX case report forms.
Footnotes appear on the following page.
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Footnotes:
1
Visit 1XX in study OM5XX should coincide with Visit 4X of the previous OM5X double-blind
study. A lab kit will not be utilized for Visit 1XX.
2
Clinical assessments include body weight, concomitant medication use, study drug tolerability,
and AEs.
3
The corrected medical history from OM5X will be transcribed to case report forms for OM5XX
and updated with any adverse events or other medical findings that occurred during study OM5X.
All clinically significant or ongoing adverse events from OM5X will be considered part of a
subject’s medical history for OM5XX.
4
Heart rate and blood pressure will be measured.
5
Fasting insulin level for HOMA assessment will be measured only in subjects who are nondiabetic, defined as those not taking any hypoglycemic medications.
6
Specialty labs will include Apo C-III, RLP-C, MPO, Lp-PLA2, and lipid subfraction cholesterol
by VAP™.
7
Fatty acid profile will include total fatty acids, EPA, DHA, and arachidonic acid.
8
Serum and plasma will be stored for possible future non-genetic analyses of risk markers for
cardiovascular disease, such as inflammatory markers (interleukin-1, interleukin-6, tumor
necrosis factor-alpha, intracellular adhesion molecule, and vascular cell adhesion molecule) and
apo A5.
9
Pregnancy tests will be performed at the clinic for all women <56 years of age.
10
Subjects will receive reinforcement of the National Cholesterol Education Program (NCEP)
TLC diet at each clinic visit.
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3.2
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Study Design
This Phase IV study will utilize an open-label design with seven clinic visits. OM5X
Visit 4X (Week 16) of the previous, open-label extension study is Visit 1XX of the
OM5XX study, at which subjects will provide written informed consent. There will
be six treatment visits (Visits 2XX–7XX). Visit months are utilized for the present
study and are numbered 0, 4, 8, 12, 16, 20 and 24.
At the Investigator’s discretion, subjects who require additional LDL-C and/or nonHDL-C lowering may receive statins and/or ezetimibe at the end of OM5X, or at
anytime during OM5XX to insure SOC (simvastatin is suggested). For all agents, the
Investigator will follow all safety procedures outlined in this protocol (see Exclusion
Criteria and Safety sections, including Section 3.9, and Excluded Medications in
Appendix 1).
Eligibility for entry into this study was based on the inclusion/exclusion criteria
described in Sections 3.4.1 and 3.4.2 of the double-blind OM5 protocol.
3.3
Study Sample
3.3.1
Inclusion Criteria
1. Must have met all inclusion/criteria for the OM5 study or have a
renewed waiver of a previously approved protocol deviation in either the
OM5X or OM5 study.
2. Must have completed the previous open-label OM5X extension to Week
16.
3. Must provide written informed consent on or before Visit 4X of the
previous open-label extension study (i.e., Visit 1XX of the present
study).
3.3.2
Exclusion Criteria
1. Study drug compliance <50% in OM5X.
2. Any ongoing severe or serious adverse event from OM5X, or any AE
probably or definitely related to the study medication, unless approved
by the Medical Monitor or Sponsor.
3. Medications excluded from OM5 and OM5X that continued to be
excluded in OM5XX are as follows and are described in Appendix 1:
a. Lipid-lowering ingredient/supplements (including marine oil
based omega-3 fatty acids, and niacin or its analogues at
doses >400 mg/d).
b. Lipid-lowering medications not provided for study OM5XX
(including statins, bile acid sequestrants, cholesterol
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absorption inhibitors, and fibrates), except statins and/or
ezetimibe provided at the Investigator’s discretion.
c. Weight loss drugs.
d. Phenytoin, cyclosporine, or warfarin.
4. Individual has a condition the investigator believes would interfere
with the evaluation of the subject or put the subject at undue risk.
3.4
Study Drug
3.4.1
Description
Study drugs will be supplied by GlaxoSmithKline.
At each visit, subjects will receive a 4-month supply of drug in 4 bottles with 30
Antara™ 130 mg capsules per bottle plus 4 bottles with 120 Omacor® 1g
capsules per bottle (omega-3-acid ethyl esters, 4 g/d). An additional fifth bottle
of each will be supplied as extra to use as needed. Dosing instructions will be
printed on each bottle. Subjects will be instructed to take Antara™ (1 capsule)
and Omacor® (4 capsules) in the evening.
All bottles will be returned to the clinic at each visit in order to assess
compliance with use of Antara™ capsules and Omacor® capsules.
3.4.2
Labeling
Bottles will be affixed with a single panel label containing the protocol number,
investigative drug legend, storage conditions, dosage instructions, name and
address of manufacturer. Each subjects randomization number and initials
should be written onto the label.
3.4.3
Storage and Dispensing
Study drugs will be stored at room temperature (77°F) under the responsibility
of the investigator or delegated staff until dispensed. Excursions between 5986° F are permitted. After being dispensed, drugs will be stored at room
temperature. It is the investigator’s responsibility to maintain a log of study
drugs allocated and returned. The investigator will only dispense the medication
to authorized persons and to subjects in the trial. At the end of the trial, the
investigator will return all remaining study drugs to GlaxoSmithKline or a
designated representative.
Drug supplies are to be used only in accordance with this protocol and under
supervision of the Principal Investigator. All records must be available for
inspection by Radiant Development and are subject to Food and Drug
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Administration (FDA) inspection at any time. Copies of the records will be
provided to Radiant Development at the conclusion of the study. A written
explanation will be required for any missing drugs.
3.4.4
Blinding
Both Antara™ and Omacor® will be administered in an open-label fashion.
3.5
Clinical Measurements
3.5.1
Laboratory Measurements
Mayo Central Laboratory for Clinical Trials, Rochester, Minnesota will perform
all clinical laboratory measurements and specialty tests with the exception of
lipid subfraction cholesterol by VAP™. The procedures for these measurements
will be described in detail in a laboratory manual developed by the central
laboratory. The timing of these measurements is charted in Section 3.1.
The following will be performed as a part of the serum chemistry panel:
creatinine, fasting glucose, total bilirubin, alkaline phosphatase, alanine
transaminase, aspartate transaminase, sodium, potassium, bicarbonate, creatine
phosphokinase, blood urea nitrogen, and chloride.
The following will be performed as a part of the hematology analysis:
hemoglobin, hematocrit, erythrocytes, mean corpuscular volume, mean
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and
white blood cell count.
The following will be performed as a part of the urinalysis: appearance, glucose,
ketones (qualitative), hemoglobin (qualitative), protein, nitrite, bilirubin, specific
gravity, pH, urobilinogen, and microscopic examination.
Serum pregnancy tests will be performed on all women <56 years of age.
Fasting (>10 hrs) serum lipids (total-C, VLDL-C, LDL-C, HDL-C, Total-C:
HDL-C ratio, non-HDL-C, and TG) will be analyzed according to the
Standardization Program of the Center for Disease Control and Prevention and
the National Heart, Lung and Blood Institute.
If a subject has a TG level >1000 mg/dL at any point during the treatment
period, an alert will be sent out to the investigator and Medical Monitor. The
investigator will have the option of repeating the test, and with input from the
Medical Monitor, will decide how to proceed with the subject.
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Hs-CRP and fatty acid profile (including total fatty acids, EPA, DHA, and
arachidonic acid) will also be measured.
Fasting insulin will be measured in subjects who are non-diabetic, defined as
those not taking any hypoglycemic medications. HOMA insulin resistance
calculations will be performed for these patients using fasting glucose and
fasting insulin levels according to the formula described by Wallace (2004).
3.5.2
Apolipoprotein and Specialty Testing
Laboratory tests including Apo A-I, Apo B, Apo C-III, RLP-C, MPO, and LpPLA2 will be analyzed by Mayo Central Laboratory for Clinical Trials,
Rochester, Minnesota. Lipid subfraction cholesterol by the VAP™ method will
be analyzed by Atherotech, Inc., Birmingham, Alabama. The timing of these
measurements is charted in Section 3.1.
3.5.3
Blood Pressure Assessment
Resting blood pressure and pulse will be measured at all clinic visits. Blood
pressure will be obtained after the subject has been sitting for 5 minutes.
Subjects must refrain from smoking cigarettes or ingesting caffeine during the
30 minutes preceding the measurement. Systolic and diastolic pressure will be
measured using a calibrated instrument. Two measurements will be taken, each
separated by 2 minutes. The average of these measurements will be recorded,
unless they differ by >5 mm Hg. In this case, an additional reading will be
obtained and all three readings will be averaged. Pulse rate will be taken
manually from the radial pulse.
3.5.4
Anthropometrics
Anthropometrics will include weight (without shoes) and waist circumference
measurements at each visit. Measurement of waist circumference will be
performed according to guidelines established by the National Heart, Lung, and
Blood Institute (NHLBI 2000) using a non-stretch anthropometric tape. To
ensure accuracy and reliability, the anatomical site of the waist measurement
will be carefully determined as explained below. A constant pressure will be
applied to the tape so there is no indentation of the skin. Two measurements will
be taken and averaged. If these differ by >0.5 cm, a third measurement will be
taken and the outlying value discarded (i.e., the closest two measurements will
be averaged and reported if a 3rd measurement is necessary).
Subjects should stand straight with weight equally distributed over both legs and
breathe normally. The iliac crest will be palpated and a mark made on the skin
with a felt-tip pen. The waist is then measured on a horizontal plane at the level
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of the iliac crest. The measuring tape should be snug, but not compressing the
skin. The measurement should be made at the end of a normal expiration.
3.6
Dietary Measurements
Dietary instructions regarding the NCEP TLC diet (Appendix 3) will be reinforced at
each clinic visit.
The EPAT (Appendix 4) will be used to assess general dietary intake at Visit 4XX
(Month 12) and Visit 7XX (Month 24).
3.7
Procedures at Each Clinic Visit
3.7.1 End of OM5X Open-Label Treatment (Visit 1XX, Month 0; same
day as Visit 4X of study OM5X, Week 16)
•
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•
•
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•
3.7.2
•
•
Written informed consent
Transcribe corrected medical history from Visit 1X of OM5X and update
Transcribe concomitant medication use from Visit 4X of OM5X
Transcribe study drug tolerability and AEs from Visit 4X of OM5X
Transcribe body weight (without shoes) and waist circumference from
Visit 4X of OM5X
Transcribe standardized measurement of vital signs from Visit 4X of
OM5X
The following data will come from OM5X and do not need to be
repeated:
o Serum chemistry, hematology, and urinalysis
o Fasting lipid profile
o hs-CRP
o Fasting insulin (only in subjects not taking hypoglycemic
medication)
o Apo AI and Apo B
o Specialty labs
o Fatty acid profile
o Serum pregnancy test (for women <56 years of age)
In-clinic urine pregnancy test (for women <56 years of age)
Transcribe EPAT from Visit 4X of OM5X
Reinforcement of dietary counseling
Transcribe compliance information from Visit 4X of OM5X
Dispense study drugs
Treatment (Visit 2XX, Month 4)
Concomitant medication use
Study drug tolerability and AEs
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•
•
•
•
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•
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3.7.3
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3.7.4
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Body weight (without shoes)
Waist circumference
Vital signs
Serum chemistry
hs-CRP
Fasting insulin (only in subjects not taking hypoglycemic medication)
Apo AI and Apo B
Specialty labs
Fatty acid profile
Fasting lipid profile
Store serum and plasma samples
Collect study drugs
Redispense study drugs
Study drug compliance
Waist circumference
Vital signs
Collect study drug
Waist circumference
Vital signs
Serum chemistry
hs-CRP
Apo AI and Apo B
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•
•
•
•
•
•
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3.7.5
•
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•
•
•
•
•
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3.7.6
•
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3.7.7
•
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Specialty labs
Fatty acid profile
EPAT
Collect study drug
Waist circumference
Vital signs
Collect study drug
Waist circumference
Vital signs
Collect study drug
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•
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Waist circumference
Vital signs
Serum chemistry
Hematology
Urinalysis
hs-CRP
Apo AI and Apo B
Specialty labs
Fatty acid profile
Serum pregnancy test (for women <56 years of age)
EPAT
Collect study drug
Early Termination Procedures
The term "Early Termination" refers to a subject’s non-completion of a study
whether by his or her own choice or due to discontinuation of the study by the
Sponsor.
In the absence of a medical contraindication or significant protocol violation,
every effort will be made by the Principal Investigator to keep the subject in the
study. Should the subject decide to withdraw, an attempt will be made to
conduct an early termination visit, which will include all procedures normally
done at Visit 7XX, Month 24.
The primary reason for a subject withdrawing prematurely should be selected
from the following standard categories:
Adverse Event - events that in the judgment of the Principal Investigator for the
best interest of the subject require discontinuation of study medication (includes
all categories of drug relatedness; Not Related, Unlikely, Possibly, Probably,
and Definitely).
Death - death of the subject, whether study related or not.
Withdrawal of Consent - subject desires to withdraw from further participation
in the study in the absence of a medical need to withdraw determined by the
Principal Investigator, or the subject did not return for one or more follow-up
visit(s) following dispensing of test drug. The reason was unknown.
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Protocol Violation - the subject's findings or conduct failed to meet the protocol
entry criteria or failed to adhere to the protocol requirements. The violation
necessitated premature termination from the study.
Other - causes of premature termination from the study other than the above,
such as theft or loss of study drugs, termination of study by Sponsor, etc.
3.8
Assessment of Outcomes
3.8.1
Primary Outcome Analysis
The primary endpoint will be the difference between the within-group mean
percent change (from baseline) in TG level observed at the end of OM5X
(average of Weeks 14 and 16 minus average of Week -2, -1 and 0 in OM5) and
the mean percent change (from baseline) observed at the end of OM5XX
(Month 24 minus average of Week -2, -1 and 0 in OM5).
In order to include those subjects who received additional lipid lowering agents,
the method of last observation carried forward (LOCF) will be applied to the
lipid data measured at the last available visit before the start of the additional
agent(s). Subjects who receive additional lipid-lowering agents will also be
analyzed as a separate group from those who do not.
3.8.2
Main Hypothesis
The null hypothesis is:
H0: There will be no significant within-group difference between the mean
percent change (from baseline) observed at the end of OM5X (average of Weeks
14 and 16) and the mean percent change (from baseline) observed at the end of
OM5XX (Month 24)).
3.8.3
Secondary Outcome Analyses
The secondary endpoints will include the within-group mean percent change in
total cholesterol (total-C), VLDL-C, LDL-C, HDL-C, non-HDL-C, the totalC:HDL-C ratio, and apo A-I and B in all subjects will be evaluated as described
for TG above.
Additional time points may be analyzed for all of the above lipid variables.
For apolipoproteins, baseline in the OM5 double blind will be defined as the
average of Weeks -1 and 0.
Subjects who receive additional lipid-lowering agents will be analyzed as
described above.
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Tertiary Outcome Analyses
The tertiary outcome analyses are the within-group (all subjects) mean percent
changes from baseline for the following variables (and analyzed as described for
TG above):
Apo C-III
RLP-C
VAP analysis of cholesterol carried by VLDL1+2 (large) and
VLDL3 (small)
VAP analysis of cholesterol carried by LDL1+2 (large) and LDL3+4
(small)
VAP analysis of cholesterol carried by HDL2 (large) and HDL3
(small)
VAP analysis of cholesterol carried by intermediate-density
lipoprotein (IDL)
VAP analysis of cholesterol carried by Lp(a)
Body weight
Waist circumference
Blood pressure
HOMA insulin resistance (only in patients not taking
hypoglycemic medication)
Hs-CRP
Lp-PLA2
MPO
Fatty acid profile (total fatty acids, EPA, DHA, and arachidonic
acid)
There is a possibility that subjects who switch from placebo to Omacor upon
entry into OM5X (“switchers”) will show a differential triglyceride response
compared to subjects who were initially randomized to Omacor treatment (“nonswitchers”. If this is the case, then the "switcher" and "non-switcher" groups will
not be pooled and responses for these two subsets of the OM5XX study sample
will be analyzed separately.
Subjects who receive additional lipid-lowering agents will be analyzed as
described above.
3.9
Safety Assessment
Safety and tolerability will be assessed by monitoring treatment-emergent AEs at
each visit (Visits 1XX-7XX). Laboratory test results will be analyzed at Visits 1XX
and 7XX (serum chemistry at at Visits 1XX, 2XX, 4XX and 7XX). A serum
pregnancy test will be conducted at Visits 1XX and 7XX. Body weight, waist
circumference and vital signs will be measured at each clinic visit.
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To insure SOC, if a statin (simvastatin is suggested) is used for any subject requiring
additional lipid lowering, liver function and creatine phosphokinase testing will be
performed as specified in the package insert for that statin. Tolerability to the “addon” statin should be assessed according to procedures outlined in Appendix 2.
In all cases when the Investigator prescribes an additional lipid-lowering agent, the
Investigator must follow the general safety warnings and precautions provided in the
package insert of the specified mediation.
Any additional laboratory assessments required per SOC precautions should be
conducted at an unscheduled study visit and be performed by the study central
laboratory.
4.0
DATA ANALYSIS AND STATISTICAL METHODS
4.1
Sample Size
All qualifying subjects who completed open-label OM5X will be given the option to
enroll in the extension study OM5XX. One hundred and fifty subjects are planned to
be randomized in study OM5, OM5X, and enrolled into OM5XX. No power
calculation was used to determine the sample size required for OM5XX to
demonstrate any significant differences in outcome analyses.
4.2
Statistical Analyses
A complete statistical analysis plan will be formalized prior to database lock. All
statistical analyses will be completed using Statistical Analyses Software (SAS®)
programs.
The safety population will include all subjects who receive a dose of study
medication and return to the clinic for at least one safety assessment after enrollment
into study OM5XX. The intent-to-treat (ITT) population will comprise data for all
subjects who are enrolled in this extension study. In addition, the per protocol (PP)
population will be identified as a subset of the ITT population, in which subjects will
be excluded for the following reasons:
•
•
Violations of inclusion or exclusion criteria that could influence the evaluation
of response.
Non-compliance by the subject, including, but not limited to:
• missing appointments,
• less than 80% compliance with study drug consumption, or
• use of prohibited drugs or any products thought to alter the primary
outcome variable during the study (see Appendix 1)
• Dropout after enrollment, without providing at least one post-enrollment
efficacy sample.
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Exclusion from the per protocol population of study OM5X.
Baseline
Baseline demographic, anthropometric, blood pressure, and lipid values will be
presented with general descriptive statistics.
4.2.2
Outcome Analyses
The primary response measurement will compare the within-group mean percent
change from baseline (average of Weeks -2,-1 and 0 of the OM5 double blind
study) to the end of the OM5X study (average of Weeks 14 and 16) with the
mean percent change from baseline at the end-of-treatment (Month 24) of study
OM5XXin TG level. A repeated measures ANOVA model will be generated to
compare mean percent TG changes within the group. If necessary,
transformations will be applied prior to running ANOVA in order to improve
kurtosis and/or skew or a non-parametric alternative test (e.g., Kruskal-Wallis)
will be employed. The initial models will include terms for baseline value, time,
center, and time by center interaction. The models will be reduced in a stepwise
manner until only significant factors, or time, remain. Data may be ranked prior
to running these analyses if the distribution for any variable does not
approximate a normal curve.
Note that subjects who receive additional lipid-lowering agents will be included
in the outcome analyses by implementing LOCF on the last available visit
before the start of any add-on medication. These subjects will also be analyzed
separately from subjects who do not receive additional agents.
4.2.3
Safety Analyses
The safety assessments will be based on the safety population and will include
vital signs and adverse events (AEs) recorded at each clinic visit and changes
from baseline/screening of double-blind study OM5, and from the end of the
OM5X extension (Visit 4X) to the end of OM5XX open-label treatment in
clinical laboratory measurements. Within-group differences in safety measures
will be assessed by repeated measures ANOVA.
4.2.4
Dietary Analyses
Dietary instructions regarding the NCEP TLC diet (Appendix 3) will be
reinforced at each clinic visit. The EPAT (Appendix 4) will be used to assess
general dietary intake at Visit 4XX (Month 12) and Visit 7XX (Month 24).
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Missing or Incomplete Data
For the ITT analysis, the method of last observation carried forward (LOCF)
will be utilized, including those subjects receiving additional lipid-lowering
agents as described above. For missing data, the previous non-baseline value
will be carried forward for each subsequent visit with missing data (if agreed
upon by the Sponsor and Radiant Development prior to database lock).
Incomplete data from subjects who withdrew early from Study OM5XX will be
included in the ITT analysis utilizing LOCF. Only measured values will be
utilized for the PP analysis (unless a decision to include them on a case-by-case
basis is made by the Sponsor and Radiant Development prior to database lock).
In the event that only one on-treatment lipid variable measurement is available,
that variable will be used rather than the average of two measurements.
5.0
STUDY MONITORING
5.1
Concomitant Medication and Treatment
All concomitant medications used during the study will be reported to the study
personnel for assessment and recorded in the subject’s case report form (CRF)
record.
Administration of the medications described in the “Exclusion Criteria” section and
Appendix 1 is not allowed during this study, except for statins and/or ezetimibe
prescribed at the Investigator’s discretion. If a subject requires these medications,
that subject may not enter the study. If the medication can be safely withdrawn or an
appropriate substitution can be made, the subject may enter the study provided the
change is completed within the time restrictions described in the exclusion criteria.
5.2
Compliance Monitoring
Compliance with study drug consumption will be evaluated by subject interview and
the counting of unused study drugs (Antara™, Omacor®) returned to the clinic at
Visits 2XX–7XX. Compliance will be recorded as a percent of scheduled intakes of
Antara™ and Omacor® consumed. Non-compliance will be defined as consumption
of <80% of the scheduled intakes of Antara™ and Omacor®. Approval from the
Medical Monitor will be required for a subject to continue in the study if his/her
Antara™ or Omacor® compliance drops below 50%.
5.3
Adverse Event Monitoring
An AE is defined as: any untoward medical occurrence in a subject or clinical
investigation following written informed consent from the subject which does not
necessarily have a causal relationship with this treatment. An AE can be any
unfavorable or unintended sign (including an abnormal finding), symptom, or
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disease temporally associated with the use of a medicinal (investigational) product,
whether or not related to the medicinal (investigational) product.
This includes any occurrence that is new in onset or aggravated in severity or
frequency from the baseline condition, or abnormal results of diagnostic procedures
(including laboratory test abnormalities). Events that occur with comparable
frequency and severity to the subject’s baseline condition should not be considered
AEs. Events should be considered AEs if they:
•
•
•
•
result in discontinuation from the study,
require treatment or any other therapeutic intervention,
require further diagnostic evaluation (excluding a repetition of the same
procedure to confirm the abnormality),
are associated with clinical signs or symptoms judged by the investigator to
have a significant clinical impact.
Elective hospitalizations planned prior to a subject providing informed consent (e.g.,
elective cosmetic procedures) are not AEs.
5.3.1
Grading and Severity
The investigator will evaluate all AEs as to their severity, and record the
outcome and action taken on the AE CRF. AEs will be graded as:
Mild:
Awareness of symptoms but easily tolerated
Moderate: Discomfort enough to interfere with but not prevent daily activity
Severe: Unable to perform usual activity
5.3.2
Relationship
The investigator will also judge the likelihood that the AE was related to the
study drug and document this on the appropriate CRF as:
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NOT RELATED
This category applies to those adverse experiences which, after careful consideration,
are clearly and incontrovertibly due to extraneous causes (disease, environment, etc.)
UNLIKELY
(must have one)
In general, this category can be considered applicable to those experiences that after
careful medical consideration at the time they are evaluated, are judged to be
unrelated to the test drug. An adverse experience may be considered unlikely related
if or when:
1) It does not follow a reasonable temporal sequence from administration of the test
drug.
2) It could readily have been produced by the subject's clinical state, environmental
or toxic factors, or other modes of therapy administered to the subject.
3) It does not follow a known pattern of response to the test drug.
4) It does not reappear or worsen when the drug is re-administered.
POSSIBLY
(must have two)
This category applies to those adverse experiences for which, after careful medical
consideration at the time they are evaluated, a connection with the test drug
administration appears unlikely but cannot be ruled out with certainly. An adverse
experience may be considered possibly related if or when:
1) It follows a reasonable temporal sequence from administration of the drug.
2) It could not readily have been produced by the patient's clinical state,
environmental or toxic factors, or other therapy administered to the patient.
3) It follows a known pattern of response to the test drug.
PROBABLY
(must have three)
This category applies to those adverse experiences that, after careful medical
consideration at the time they are evaluated, are felt with a high degree of certainty to
be related to the test drug. An adverse experience may be considered probably related
if and when:
2) It could not be reasonably explained by the known characteristics of the patient's
clinical state, environmental or toxic factors, or other modes of therapy
administered to the patient.
3) It disappears or decreases on cessation or reduction in dose. There are important
exceptions when an adverse event does not disappear upon discontinuation of the
drug, yet drug-relatedness clearly exists (e.g., bone marrow depression, fixed drug
eruptions, tardive dyskinesia).
DEFINITELY
(must have all)
This category applies to those adverse experiences which, the investigator feels are
incontrovertibly related to the test drug. An adverse experience may be assigned an
attribution of definitely related if or when:
2) It could not be reasonably explained by the known characteristics of the subject's
clinical state, environmental or toxic factors, or other modes of therapy
administered to the subject.
3) It disappears or decreases on cessation or reduction in dose and recurs with reexposure to drug. (Note: this is not to be construed as requiring re-exposure of
the subject, however, a category of definitely related can only be used when a
recurrence is observed).
Appropriate therapeutic action and follow-up measures will be performed by the
investigator in accordance with good medical practice. These actions and
measures will continue until the condition is resolved and/or the etiology is
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identified. In the event of a serious adverse event (SAE), the subject may be
dropped from the study if the investigator deems it necessary.
5.3.3
Serious Adverse Event Definition/Qualification
A SAE is defined as an AE that results in any of the following outcomes:
•
Death (note that death is the outcome of a SAE and the cause of death
should be listed as the AE)
Life-threatening event
In-patient hospitalization or prolongation of existing hospitalization
A persistent or significant disability/incapacity
Congenital anomaly or birth defect
Any other important medical event that may not result in death, be lifethreatening, or require hospitalization, may be considered a SAE when,
based upon appropriate medical judgment, the event may jeopardize the
subject and may require medical or surgical intervention to prevent one
of the outcomes listed above. Examples of such medical events include
allergic bronchospasm requiring intensive treatment in an emergency
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug
abuse.
•
•
•
•
•
5.3.4
Serious Adverse Event Reporting Instructions
If in the opinion of a study physician the event meets the criteria of a SAE the
following procedures will be followed:
•
The investigator will report the SAE by telephone immediately upon
becoming aware of the event, directly to Radiant Development and fax
the SAE report, AE CRF page, and any other applicable information to
Radiant Development within 24 hours of reporting the event. Radiant
Development’s contact will be:
Clinical Trial Associate
Radiant Development
Chicago, IL 60610
Tel:
Fax:
Email:
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The Medical Monitor will be:
MD
Director, Cardiovascular MDC
GlaxoSmithKline
Ph:
Fax:
Email:
•
•
•
•
5.3.5
The Principal Investigator will also notify the IRB of the event within
the time frame specified under the IRB Standard Operating
Procedures after becoming aware of the SAE. An initial report
followed promptly by a complete report will be forwarded to the IRB, or
in accordance with site IRB policy.
The subject will be observed and monitored carefully until the condition
stabilizes and/or resolves or its cause is identified or is otherwise
determined by the Medical Monitor and Principal Investigator. Follow-up
information relating to a SAE must be submitted to Radiant Development
by telephone, fax, or overnight courier as soon as additional data related
to the event are available.
If a subject is hospitalized or hospitalization is prolonged due to the SAE,
the hospital discharge summary will be obtained if possible when it
becomes available.
If a death occurs and an autopsy is performed, a copy of the autopsy
report will be obtained if possible when it becomes available. All efforts
must be undertaken to obtain follow-up information promptly.
CRF Recording of Adverse Events
All AEs will be recorded on the AE CRF page. All SAEs that occur during the
clinical trial must be reported to Radiant Development as described above
within 24 hours of becoming aware of the event using the SAE form. Subjects
who experience an SAE during the study will be followed for 30 days after the
completion of the study, or until the SAE has resolved. For subjects who have an
ongoing AE at their final study visit, a follow up AE CRF page will be collected
to document resolution or stabilization of the AE.
5.3.6
Serious Adverse Event Follow-Up
For all SAEs occurring during the study or within 30 days of the last
administration of study drug, the investigator must submit follow-up reports to
Radiant Development regarding the subject’s subsequent course. All SAEs that
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are ongoing at the end of the study or upon discontinuation of the subject’s
participation must be followed until resolution or stabilization.
5.3.7
Pregnancy
Omega-3-acid ethyl esters were not mutagenic or clastogenic with or without
metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella
typhimurium and Eschericia coli or in the chromosomal aberration assay in
Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl
esters were negative in the in vivo mouse micronucleus assay. In a rat fertility
study, with oral gavage dosages of 100, 600, 2000 mg/kg/d, males were treated
for 10 weeks prior to mating and females were treated for 2 weeks prior to and
throughout mating, gestation and lactation. No adverse effect on fertility was
observed at 2000 mg/kg/d (5 times human systemic exposure following an oral
dose of 4 g/d based on a body surface area comparison).
The safety of Omacor® and Antara™ during pregnancy has not been established,
and therefore should not be used by pregnant women. Consequently, women of
childbearing potential will be required to use appropriate contraceptive methods
to avoid pregnancy.
Female subjects <56 years of age will undergo serum and urine pregnancy tests
during the study. Pregnant or lactating women will be excluded from the study.
Should a female subject become pregnant at any time during the study, the
investigator will be required to follow the subject through the pregnancy term
and report to Radiant Development the course of the pregnancy including
perinatal and neonatal outcome.
Although pregnancy is not a SAE all pregnancies occurring during this
study will be reported within 24 hours of notification. The investigator will
immediately notify Radiant Development about the pregnancy and complete a
pregnancy report form.
Note: Regarding pregnancy, if simvastatin or any prescribed “add-on”
medication is used, the Investigator must follow the precautions and safety
warnings provided in the package insert for the specified medication.
6.0
CONDUCT OF THE STUDY
6.1
Ethics and Regulatory Considerations
This study will be conducted according to Good Clinical Practice Guidelines, the
Declaration of Helsinki (2000), and US 21 CFR. Signed written informed consent for
the study will be obtained from all subjects before protocol-specific procedures are
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carried out. Subjects will be informed of their right to withdraw from the study at
any time.
6.2
The Principal Investigator will ensure that an appropriately constituted IRB, in
compliance with the requirements of 21 CFR 56, reviews and approves the clinical
study. Before the study is started, the Principal Investigator will forward copies of
the protocol and consent form for this study to the IRB for review and approval. The
IRB must be informed of all subsequent protocol amendments and of serious and
unexpected AEs occurring during the study that are likely to affect the safety of the
subjects or the conduct of the trial. In addition, the Principal Investigator will
immediately forward copies of all correspondence with the IRB to Radiant
Development. IRB approval must refer to the study by exact protocol title and
number, identify the documents reviewed, and state the date of review.
6.3
Informed Consent and Protected Health Information
The study will be explained verbally as well as on the informed consent document.
Each subject will be given ample opportunity to inquire about details of the study
and to read and understand the consent form before signing it.
Consent must be documented by dated signature of the subject. Each subject’s signed
informed consent document must be kept on file by the Principal Investigator for
possible inspection by regulatory authorities or by the Sponsor. The subject should
receive a copy of the written informed consent document once he/she has signed.
GlaxoSmithKline recognizes the importance of protecting the privacy of subject
data. Therefore, for study sites within the US, the Informed Consent Form will
incorporate, or be accompanied by, a separate document incorporating Health
Insurance Portability and Accountability Act compliant wording, by which subjects
authorize the use and disclosure of their Protected Health Information by the
investigator and by those persons who need that information for the purposes of this
study.
A subject may not be admitted to the study unless informed consent of the subject (or
his/her legally authorized representative) has been obtained.
6.4
Subject Confidentiality
The Principal Investigator is responsible for ensuring that subjects’ anonymity will
be maintained. CRFs or other documents will identify subjects by initials, number, or
code, and not by name. The Principal Investigator will keep a subject enrollment log
showing codes, names, and addresses. All documents showing the subjects’ identity
will be kept in strict confidence by the Principal Investigator. However, the Principal
Investigator agrees that the Sponsor, its employees or agents, the IRB, as well as
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representatives of the FDA, will have the right to audit and review pertinent medical
records relating to this clinical trial and that the subjects will provide written
informed consent to this effect.
6.5
Withdrawal of Subjects from the Study
Subjects may be removed from the study for any of the following reasons:
• a subject requests discontinuation;
• the Principal Investigator initiates removal for medical or compliance reasons;
• occurrence of any AE or condition that could, in the Principal Investigator’s
opinion, interfere with the evaluation of the treatment effect or put the subject
at undue risk.
It is understood by all concerned that an excessive rate of withdrawals can render the
study uninterpretable; therefore, unnecessary withdrawal of subjects should be
avoided. Should a subject decide to withdraw, all efforts will be made to complete
and report observations as thoroughly as possible. In the event that a subject is
withdrawn from the study, the reason for the withdrawal will be documented in the
CRF. Prior to a subject’s withdrawal from the study, an attempt will be made to
conduct an early termination visit, which will include all procedures normally done
at Visit 7XX, Month 24.
7.0
ADMINISTRATIVE MATTERS
All references to Radiant Development in this section include all designees e.g., Contract
Research Organizations or Consultants acting on behalf of Radiant Development.
7.1
Changes to the Protocol
All changes to the protocol must be documented by amendments to the protocol
signed by the Sponsor and the Principal Investigator. If the amendment represents a
substantial change to the protocol, the amended protocol and a revised informed
consent form will be submitted for approval to the IRB. A copy of the approval will
be provided to Radiant Development. Where the local IRB regulations regarding
protocol amendments differ from this policy, the local regulations will apply.
The above-mentioned requirements do not preclude any immediate action from
being taken in the interests of subjects' safety.
7.2
Protocol Deviations and Violations
Any protocol deviation from the inclusion/exclusion criteria requires an approved
waiver from the Medical Monitor or designee prior to enrollment in order to enroll
that subject into the study. A deviation also occurs in any situation that significantly
affects subject safety or the ability to evaluate the efficacy of the study drug during
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the study (e.g., a significant window violation, drug accountability <50%). The site
should accurately document the deviation and approval in the source document and
complete the protocol deviation CRF. Deviations that could significantly influence
subject safety will be reported to the IRB.
A protocol violation occurs when a subject breaches or disobeys any part of the
protocol without prior notification to and approval by the Medical Monitor or
Sponsor. In this instance, the site should accurately document the deviation in the
source document and complete the protocol deviation CRF. Violations that could
significantly influence subject safety will be reported to the IRB.
7.3
Case Report Forms
Each evaluation recorded in the CRF will be performed at the time specified in the
protocol. All CRFs will be printed on three-part NCR paper. The monitor will collect
the top two copies of the CRF page. The investigator will retain one copy in the
subject’s CRF binder.
Data collected in the CRF will be documented in an anonymous fashion (i.e., the
subject will be identified only by a study number and their initials). Should the
identity of the subject become necessary for safety or regulatory reasons,
confidentiality by both the Sponsor and the investigator will be maintained.
All information required by the protocol should be documented in the source records
and provided in the CRF. An explanation must be given for any omissions. All CRFs
must be completed and made available as soon as possible after the subject’s visit, in
order that the monitor may verify the validity and completeness of the data on the
CRFs and permit prompt transmission of the data. The investigator should review
and sign (as required) all CRFs for completeness, accuracy, and legibility before the
monitor reviews and collects the data.
The investigator must agree to complete and maintain source documents for each
subject participating in the study.
All information on the CRFs must be traceable back to the source documents. The
source documents should contain all demographic and medical information,
including laboratory data, electrocardiograms, etc. The subject’s file should also
indicate that he/she is participating in the clinical study, referencing the study
number and the study medication.
7.4
Clinical Monitoring
An initiation meeting will be conducted by Radiant Development or an approved
representative. At this meeting the protocol, CRFs, and pertinent aspects of the Code
of Federal Regulations will be reviewed with the investigator and all study staff.
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Frequent monitoring visits will be conducted during the study. The investigator will
make a reasonable amount of time available to the monitor on reasonable notice to
assist with monitoring of the CRFs.
At each visit the monitor will review CRFs and source documents to ensure that all
items have been completed and that the data provided are accurate and obtained in
the manner specified in the protocol. The subjects' clinical records will be reviewed
to confirm that:
•
•
•
•
•
•
the data are consistent with the physician's clinical source records;
the background clinical and laboratory data and concomitant medications are
documented in the CRFs;
there is an accurate account of the dosage and schedule of administration of
concomitant medications;
the dosage and schedule of administration of the study drug conform to the
protocol;
information (e.g. AEs) has been recorded in the appropriate place in the case
report form;
the study drug is being stored correctly, and an accurate record of its
dispensing to the subjects, is being maintained.
Incorrect, inappropriate, or illegible entries onto the CRFs will be returned to the
investigator for correction.
No data disclosing the identity of subjects will leave the study center. Radiant
Development and any designees will maintain confidentiality of all subject records.
Completed CRFs will be collected by Radiant Development as soon as the monitor
has verified the data. A copy of the CRFs will remain in the possession of the
investigator. The investigator must ensure that the CRFs and other study
documentation are stored in a secure location.
During the course of the study, the responsible Radiant Development staff will be
available to discuss any matters relating to the conduct of the study.
7.5
Auditing Procedures
In addition to the monitoring visits outlined above, an investigational site may
undergo a quality assurance audit. Radiant Development representatives or a
regulatory agency such as the FDA or European Medicines Evaluations Agency may
conduct the audit. If a regulatory agency requests an audit of the study site, the
investigator is required to inform the Sponsor and Radiant Development
immediately.
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7.6
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Record Retention
All study documentation generated in connection with this study will be retained for
at least five years after the last approval of a marketing application in an
International Conference on Harmonization (ICH)-region and until there are no
pending or contemplated marketing applications in an ICH-region or at least 5 years
have elapsed since the formal discontinuation of clinical development of the
investigational product. These documents should be retained for a longer period,
however, if required by the applicable regulatory requirements or by an agreement
with the Sponsor. It is the responsibility of the Sponsor to inform the
investigator/Institution as to when these documents no longer need be retained. The
study documents include IRB approvals for the study protocol and all amendments,
all source documents and laboratory records, CRF copies, signed subject informed
consent forms, FDA form 1572, and any other pertinent study document. The
investigator agrees to supply Radiant Development with a written confirmation that
these procedures are in place and will be adhered to.
7.7
Termination of Study
The Sponsor and the Principal Investigator reserve the right to terminate the study at
any time. In terminating the study, the Sponsor and the Principal Investigator will
assure that adequate consideration is given to the protection of each subject’s
interest.
7.8
Final Report/Publications
Any formal presentation or publication of data collected as a direct or indirect result
of this trial will be considered as a joint publication by the investigator(s) and the
Sponsor. In the case of multicenter studies, it is mandatory that the first publication
be made based on the totality of data obtained from all centers, analyzed as stipulated
in the protocol. The resulting publication will name Principal Investigators according
to the policy of the chosen journal. Where it is not permitted for all Principal
Investigators to be included as authors, the publication will name all Principal
Investigators within the publication.
Individual investigators may publish data arising from their own subjects. The
investigator will provide the Sponsor with copies of written publications (including
abstracts and posters) at least 30 days in advance of submission. This review is to
permit the Sponsor to review the communication for accuracy (thus avoiding
potential discrepancies with submissions to regulatory authorities), to verify that
confidential information is not inadvertently divulged, to allow adequate input or
supplementary information that may not have been available to the investigator, and
to allow establishment of co-authorship.
Investigators participating in multicenter studies must agree not to engage in
presentations based on data gathered individually or by a subgroup of centers before
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publication of the first main publication, unless this has been agreed otherwise by all
other Investigators and the Sponsor. However, in the event that no publication of the
overall results has been submitted 18 months after approval of the Clinical Study
Report, Investigators may publish results of one or more center’s subjects to the
same review as outlined above. The Sponsor will circulate proposed multi-center
publications to all Principal Investigators for review. Review by Principal
Investigators must be completed in 30 days.
8.0
STUDY MEDICATION
All study medications will be supplied to the Principal Investigator. Drug supplies must
be kept in an appropriate, secure area (see Section 3.5.3) and maintained under the
storage conditions specified in the protocol.
The Principal Investigator will oversee that an accurate record regarding the shipment
and dispensing of the test drug is maintained, using a drug accountability log. An
accurate drug disposition record will be kept specifying the date and amount dispensed to
each subject and any supplies either destroyed or returned to the Sponsor. This inventory
record must be available for inspection by and is subject to regulatory inspection at any
time. Copies of this record will be provided to the Sponsor by the investigator at the
conclusion of the study.
Drug supplies are to be used only in accordance with this protocol and under the
supervision of the investigator. The investigator agrees not to destroy any labels, empty
bottles, or unused drug supply.
At the conclusion of the study, and, if appropriate, during the course of the study, the
investigator will ship all used and unused drug containers, labels, and a copy of a
completed drug and code label disposition form to the Sponsor.
9.0
DISCLOSURE
By conducting this study, the investigator agrees that all information provided will be
maintained by the investigator and his/her staff in strict confidence. Such information
may be communicated to the Scientific Committee and/or Institutional Review
Board/Ethics Committee under a similar, appropriate understanding of the confidential
nature of the information. Study documents provided (protocols, Investigators' brochures,
CRFs and other material) will be stored appropriately to ensure their confidentiality. It is
understood that the confidential information provided to the investigator will not be
disclosed to others without written authorization, except to the extent necessary to obtain
informed consent from those subjects who are eligible and choose to participate in the
study. Such information will not be provided to potential subjects or subjects by
telephone or to any other individual.
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10.0 REFERENCES
Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated
lipoprotein (a) are risk factors for major coronary events in middle-aged men. Am J
Cardiol 1996;77:1179-1184.
Bhatnagar D, Durrington PN. Omega-3 fatty acids: their role in the prevention and
treatment of atherosclerosis related risk factors and complications. Int J Clin Pract
2003;57:305-314.
Calabresi L, Villa B, Canavesi M, Sirtori CR, James RW, Bernini F, Franceschini G. An
omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein
2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia.
Metabolism 2004;53:153-158.
Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M.
An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased
triglycerides in simvastatin treated patients with coronary heart disease and persisting
hypertriglyceridemia. Heart 2001;85:544-548.
Ginsberg HN. Hypertriglyceridemia: new insights and new approaches to pharmacologic
therapy. Am J Cardiol 2001; 87:1174-1180.
Harris WS. Omega-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr
1997a;65suppl:1645S-1654S.
Harris WS. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc
Risk 1997b;4:385-391.
National Institutes of Health. Third Report of the National Cholesterol Education
Program Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III). NIH Publication 01-3670, 2000.
Accessed online at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm
Stein EA, Lane M, Laskarzewski P. Comparison of statin in hypertriglyceridemia. Am J
Cardiol 1998;81:66B-69B.
Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care
2004;27:1487-1495.
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APPENDIX 1: EXCLUSIONARY MEDICATIONS
This list is not intended to be comprehensive.
CLASS OF DRUG
Weight-loss drugs
GENERIC/BRAND NAME
Excluded throughout OM5XX
Benzphetamine HCl (Didrex)
Diethylpropion HCl (Tenuate)
Orlistat (Xenical)
Phendimetrazine tartrate (Bontril)
Phentermine (Adipex)
Phentermine resin (Ionamin)
Sibutramine (Meridia)
Over-the-counter weight-loss medications/products
Lipid-altering
ingredients/supplements
Marine oil based omega-3 fatty acid supplements
Niacin/nicotinic acid-containing vitamins and supplements
with >400 mg niacin/nicotinic acid
Lipid-altering
medications not provided
for study use, except
statins and/or ezetimibe
provided at the
Investigator’s discretion
Atorvastatin calcium (Lipitor
Cholestyramine (Prevalite)
Clofibrate (Atromid-S)
Colesevelam HCl (WelChol)
Colestipol HCl (Colestid)
Ezetimibe (Zetia)
Fenofibrate (Tricor)
Fluvastatin (Lescol)
Gemfibrozil (Lopid)
Lovastatin (Advicor, Mevacor)
Niacin/nicotinic acid
Pravastatin sodium (Pravachol)
Rosuvastatin Calcium (Crestor)
Simvastatin (Vytorin, Zocor)
Antiepileptics
Phenytoin (Dilantin)
Immunosuppressants
Cyclosporine (Neoral, Sandimmune)
Cardiovascular
medications
Warfarin (Coumadin)
Androgens
Use of the following is acceptable during the study, but
may lead to exclusion from the per protocol population:
Fluoxymesterone (Halotestin)
Methyltestosterone (Testred)
Oxandrolone (Oxandrin)
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CLASS OF DRUG
GENERIC/BRAND NAME
Testosterone (Androderm, AndroGel, Testoderm)
Testosterone cypionate (Virilon)
Testosterone enanthate (Delatestryl)
Retinoids
Isotretinoin (Accutane, Roaccutane)
Corticosteroids
Oral or systemic use of:
Betamethasone
Budesonide
Cortisone
Dexamethasone
Hydrocortisone
Methylprednisolone
Prednisolone
Prednisone
Triamcinolone
Systemic use of:
Fludrocortisone acetate (Florinef)
Topical (inhaled, intranasal or dermal) use of more than 1500
mcg daily of any corticosteroid
Unstable Use of the Following Excluded
Lipid-altering
Dietary fiber supplements (including >2 teaspoons Metamucil
ingredients/supplements
or psyllium-containing supplement per day)
Sterol/stanol products
Red rice yeast supplements
Garlic supplements
Soy isoflavone supplements
Flaxseed oil
Thyroid hormones
Levothyroxine (Levo-T, Levothroid, Levoxyl
Synthroid)
Liothyronine (Cytomel, Triostat)
Liotrix (Thyrolar)
Thyroglobulin
Thyroid (Armour Thyroid, Thyrar, Thyroid Strong, Westhroid)
Hypertension
medications
Alpha-adrenergic agonists
Alpha-adrenergic blockers
Angiotensin-converting enzyme inhibitors
Angiotensin II receptor blockers
Beta-adrenergic blockers
Calcium channel blockers
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CLASS OF DRUG
GENERIC/BRAND NAME
Central alpha-adrenergic blockers
Diuretics
Ganglionic blockers
Vasodilators
Hypoglycemic
medications
Acarbose (Prandase, Precose)
Acetohexamide (Dymelor)
Chlorpropamide (Diabinese)
Diazoxide (Proglycem)
Glimepiride (Amaryl)
Glipizide (Glucotrol)
Glipizide + Metformin (Metaglip)
Glucagon
Glucovance (Glyburide + Metformin)
Glyburide (DiaBeta, Micronase)
Insulin
Metformin (Glucophage, Glucophage XR)
Miglitol (Glycet)
Nateglinide (Starlix)
Pioglitazone (Actos)
Repaglinide (Prandin)
Rosiglitazone (Avandia)
Rosiglitazone + Metformin (Avandamet)
Tolazamide (Tolinase)
Tolbutamide (Orinase)
Estrogens
esterified estrogens (Climestrone, Estratab, Menorest, NeoEstrone)
estradiol (Alora, Climara, CombiPatch, Cypionate,
Delestrogen, Estinyl, FemPatch, Gynogen, Depogen, Dioval,
Duragen, Estraderm, Esta-L, Estrace)
conjugated estrogens (Premarin)
estrone (Aquest, Femogen Forte, Estronol, Kestrone-5, Theelin
Aqueous)
Progestins
crinone
progestacert
progesterones
progestogens (norethindrone acetate, levonorgestrel,
norgestamate,
desogestrel, medroxyprogesterone acetate)
all other hormones, hormone replacement therapies
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APPENDIX 2:
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INVESTIGATION OF INCREASES IN TESTS OF LIVER
FUNCTION AND CREATINE KINASE
AST/ALT/BILIRUBIN:
All increases in transaminases (AST and/or ALT) or bilirubin that show either of the
following increases will be investigated:
a) an increase to > 3 x ULN AND an increase of at least 30% above baseline
OR
b) an increase to > 2 x ULN AND an increase of at least 70% above the baseline
AST/ALT/ALKALINE PHOSPHATASE:
An increase in Alkaline Phosphatase to > 2 x ULN AND an increase in one or more of
the following:
a) ALT; b) AST; or, c) bilirubin > ULN will be investigated
PROCEED AS FOLLOWS:
•
•
The subject should remain on study drug pending a repeat lab test, unless results
are of concern to the Principal Investigator. If this is the case, the patient should
be discussed with the Medical Monitor immediately.
Contact subject immediately for:
o Repeat lab tests via the central lab
o Interview subject with regard to other factors relating to risk of
hepatotoxicity
o Examine subject for physical signs of hepatotoxicity
If the abnormality is NOT confirmed by the repeat tests:
o The test will be subsequently repeated only according to the intervals
required by the protocol.
o An adverse event form will be completed only if the Principal Investigator
considers it appropriate.
If the abnormality IS confirmed by the repeat tests:
o A serious adverse event form must be completed immediately
o Contact the medical monitor who may request additional tests be
performed (i.e., clotting screens, viral serology and imaging studies)
o Contact subject to discontinue study drug(s) and return to clinic
o Repeat tests until they have returned to baseline or a diagnosis has been
confirmed. The interval of follow up will be agreed upon between the
Principal Investigator and the Medical Monitor.
o If a diagnosis of hepatotoxicity secondary to factors not related to study
treatment is determined, contact the Medical Monitor and discontinue the
subject from study.
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CK ELEVATIONS:
Increases in creatine kinase (CK) > 10 x ULN will be investigated.
PROCEED AS FOLLOWS:
•
Contact subject immediately and schedule a repeat CK, plus serum creatinine and
urinalysis via central lab
•
Contact subject immediately for:
o Repeat CK plus serum creatinine and urinalysis via the central lab
o Interview subject with regard to other factors relating to muscle pain or
weakness and any predisposing factors such as unusual physical activity,
heavy alcohol intake, viral illness, or new concomitant medications.
o Examine subject for muscle tenderness, weakness, and/or rash.
If the elevation of > 10 x ULN is confirmed by the repeat evaluation:
• Document the Adverse Event.
• Discontinue subject from study treatment and will return for follow-up in 4 to 10
days, or sooner if symptoms of myopathy appear or worsen or urine turns dark in
color.
• These steps will be repeated at subsequent study visits until CK levels return to
normal or an alternative diagnosis has been reached.
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APPENDIX 3: THERAPEUTIC LIFESTYLE CHANGES DIET
The guidelines developed by the National Cholesterol Education Program’s (NCEP)
Third Expert Panel on the Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults recommends a multifaceted lifestyle approach to reduce the risk of
coronary heart disease (NIH Publication 01-3670,2000,
http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm). The recommended ranges
of intake for specific dietary components are listed in the table below.
Nutrient Composition of the Therapeutic Lifestyle Changes Diet
Nutrient
Recommended Intake
Total Fat
25-35% of total calories
Saturated Fatty Acids
<7% of total calories
Monounsaturated Fatty Acids
Up to 20% of total calories
Polyunsaturated Fatty Acids
Up to 10% of total calories
Carbohydrates
50-60% of total calories
Fiber
20-30 grams per day
Protein
Approx. 15% of total calories
Cholesterol
Total Calories
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Protocol OM5XX
<200 mg per day
Balance energy intake and expenditure to maintain
desirable body weight/prevent weight gain
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APPENDIX 4: EATING PATTERN ASSESSMENT TOOL
This section contained Clinical Outcome Assessment data collection questionnaires or
indices, which are protected by copyright laws and therefore have been excluded.
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Statistical Analysis Plan
Sponsor:
GlaxoSmithKline
Protocol Number:
OM5XX version 2.2
Protocol Date:
27 January 2006
Protocol Title:
A SECOND OPEN-LABEL EXTENSION OF A DOUBLE-BLIND, PARALLEL, PHASE
IV STUDY TO ASSESS THE EFFICACY AND SAFETY OF ADJUNCTIVE
OMACOR® THERAPY IN HYPERTRIGLYCERIDEMIC SUBJECTS TREATED WITH
ANTARA™
SAP Version:
Final
SAP Date:
June 4, 2008
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Table of Contents
LIST OF ABBREVIATIONS AND ACRONYMS.................................................................................................................... 4
1.
PROTOCOL OVERVIEW ............................................................................................................................. 6
1.1.
Study Objectives ........................................................................................................................................................ 6
1.2.
Trial Design and Visit Structure .............................................................................................................................. 6
1.3.
Study Treatment ....................................................................................................................................................... 7
1.4.
Study Population ....................................................................................................................................................... 7
1.5.
Size of Trial Sample .................................................................................................................................................. 7
1.6.
Randomization Methods ........................................................................................................................................... 8
1.7.
Procedures for Unblinding ....................................................................................................................................... 8
2.
EFFICACY PARAMETERS .......................................................................................................................... 8
2.1.
Primary Efficacy Parameter .................................................................................................................................... 8
2.2.
Secondary Efficacy Parameters ............................................................................................................................... 8
2.3.
Tertiary Efficacy Parameters ................................................................................................................................... 8
3.
SAFETY PARAMETERS............................................................................................................................... 8
3.1.
Adverse Events .......................................................................................................................................................... 8
3.2.
Serum Chemistry ...................................................................................................................................................... 9
4.
ANALYSIS POPULATIONS ......................................................................................................................... 9
4.1.
Safety Population ...................................................................................................................................................... 9
4.2.
Intent-to-Treat Population ....................................................................................................................................... 9
5.
STATISTICAL METHODOLOGY .............................................................................................................. 9
5.1.
Statistical and Analytical Issues ............................................................................................................................... 9
5.1.1.
Statistical Methods ................................................................................................................................................. 9
5.1.2.
Baseline and End-of-Treatment Definitions ......................................................................................................... 10
5.1.3.
Repeated Laboratory Measurements .................................................................................................................... 10
5.1.4.
Computed Variables ............................................................................................................................................. 10
5.1.5.
Handling of Dropouts and Missing Data .............................................................................................................. 11
Pooling of Centers ................................................................................................................................................ 11
5.1.6.
5.2.
Subject Characteristics ........................................................................................................................................... 11
5.2.1.
Subject Disposition .............................................................................................................................................. 11
5.2.2.
Discontinuations and Deviations .......................................................................................................................... 11
5.2.3.
Demographic Characteristics................................................................................................................................ 11
5.3.
Efficacy Analyses..................................................................................................................................................... 12
5.3.1.
Primary Efficacy Analysis.................................................................................................................................... 12
5.3.2.
Secondary Efficacy Analyses ............................................................................................................................... 12
5.3.3.
Tertiary Efficacy Analyses ................................................................................................................................... 13
5.4.
Safety Analyses ........................................................................................................................................................ 13
5.4.1.
Adverse Events ..................................................................................................................................................... 13
5.4.2.
Serum Chemistry .................................................................................................................................................. 13
6.
TABLES , LISTINGS & FIGURES............................................................................................................. 14
6.1.
Tables ....................................................................................................................................................................... 14
6.2.
Listings ..................................................................................................................................................................... 14
6.3.
Figures ...................................................................................................................................................................... 14
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LIST OF ABBREVIATIONS AND ACRONYMS
AE
ALT
ANOVA
Apo A-I
Apo B
Apo C-III
AST
bpm
BMI
BUN
CPK
CRF
cm
dL
DHA
EPAT
EPA
FDA
g
g/d
HbA1c
HDL-C
HOMA-IR
hs-CRP
ICH
IDL
IRB
ITT
Kcal
kg
L
LDL-C
LOCF
Lp-PLA2
Lp(a)
m
max
MCH
MCHC
MCV
mg
mg/dL
min
MITT
mm Hg
mmol
MPO
ng
nm
NCEP
NMR
Non-HDL-C
Adverse event
Alanine aminotransferase
Apolipoprotein A-I
Apolipoprotein B
Apolipoprotein C-III
Aspartate aminotransferase
Beats per minute
Body mass index
Blood urea nitrogen
Creatine phosphokinase
Case report form
Centimeter
Deciliter
Docosahexaenoic acid
Eicosapentaenoic acid
Food and Drug Administration
Grams
Grams per day
Glycosylated hemoglobin
Homeostatic model assessment for insulin resistance
High sensitivity C-reactive protein
International Conference on Harmonization
Intermediate-density lipoprotein
Intent-to-treat
Kilocalorie
Kilogram
Liter
Lipoprotein associated phospholipase A2
Lipoprotein(a)
Meters
Maximum
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Mean corpuscular volume
Milligrams
Milligrams per deciliter
Minimum
Modified intent-to-treat
Millimeters of mercury
Millimole
Myeloperoxidase
Nanograms
Nanometers
National Cholesterol Education Program
Nuclear magnetic resonance
Non high-density lipoprotein cholesterol
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NDS-R
PP
RLP-C
SAE
SAS
SD
SOC
Std
TG
TLC
Total-C
umol
uIU
VAP™
VLDL-C
P
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Nutrition Data System for Research
Per protocol
Remnant-like particle cholesterol
Statistical Analysis Software
Standard Deviation
System Organ Class
Standard deviation
Triglycerides
Therapeutic Lifestyle Changes
Total cholesterol
Micromole
Micro-International Unit
Vertical Auto-Profile
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1. PROTOCOL OVERVIEW
This study will examine the long-term (24-month) efficacy and safety of the Antara and Omacor® coadministration in persons with baseline TG concentrations t 500 mg/dL and < 1300 mg/dL and BMI t 25
kg/m2 and d 43 kg/m2. Both drugs are hypotriglyceridemic agents that act by increasing fatty acid
catabolism and decreasing TG synthesis and secretion by the liver.
Since the study was terminated, a condensed clinical study report will be written for this study; therefore,
summaries and analyses described in this analysis plan correspond to those summaries needed for a
condensed study report.
In August of 2007 Reliant Pharmaceuticals, Inc. changed the trade name of Omacor® (omega-3-acid ethyl
esters) to Lovaza® (omega-3-acid ethyl esters). Reliant Pharmaceuticals, Inc. took this step at the request
of the FDA and in response to a limited number of reports of prescribing and dispensing errors due to
similarity in trade name between the company’s Omacor® capsules and Xanodyne Pharmaceuticals’
Amicar® (aminocaproic acid). The name change was intended to minimize the potential for such errors in
the future. All displays will use Lovaza when referring to treatment groups.
1.1. Study Objectives
Primary:
The primary objective of this 24-month extension is to assess the continued efficacy of adjunctive
Omacor® therapy in hypertriglyceridemic subjects treated with Antara™ for lowering triglyceride TG
levels.
Secondary:
Secondary objectives of this study are to evaluate the continued safety of Antara™ plus Omacor® during
a 24-month open-label extension of the previous 8-week open-label extension (OM5X) to Protocol OM5,
and to assess the effects of Antara™ plus Omacor® on other lipids and markers for cardiovascular risk.
1.2. Trial Design and Visit Structure
This Phase IV study will utilize an open-label design with seven clinic visits. OM5X Visit 4X (Week 16)
of the previous, open-label extension study is Visit 1XX of the OM5XX study, at which subjects will
provide written informed consent. There will be six treatment visits (Visits 2XX–7XX). Visit months are
utilized for the present study and are numbered 0, 4, 8, 12, 16, 20 and 24.
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Below is a summary of visits across all studies OM5, OM5X and OM5XX.
Study
OM5
OM5
OM5
OM5
OM5
OM5
OM5
OM5 – OM5X
OM5X
OM5X
OM5X – OM5XX
OM5XX
OM5XX
OM5XX
OM5XX
OM5XX
OM5XX
Visit
1
2
3
4
5
6
7
8 = 1X
2X
3X
4X = 1XX
2XX
3XX
4XX
5XX
6XX
7XX
Description
Week -6
Week -2
Week -1
Week 0
Week 2
Week 4
Week 6
Week 8
Week 12
Week 14
Week 16 = Month 0 in OM5XX
Month 4 in OM5XX
Month 8 in OM5XX
Month 12 in OM5XX
Month 16 in OM5XX
Month 20 in OM5XX
Month 24 in OM5XX
At the Investigator’s discretion, subjects who require additional LDL-C and/or non-HDL-C lowering may
receive statins and/or ezetimibe at the end of OM5X, or at anytime during OM5XX to insure subjects
receive standard-of-care (simvastatin is suggested). For all agents, the Investigator will follow all safety
procedures outlined in the protocol (see Exclusion Criteria and Safety protocol sections, including Section
3.9, and Excluded Medications in Appendix 1).
1.3. Study Treatment
At each visit, subjects will receive a 4-month supply of drug in 4 bottles with 30 Antara 130 mg
capsules per bottle plus 4 bottles with 120 Omacor 1g capsules per bottle (omega-3-acid ethyl esters, 4
g/d). An additional fifth bottle of each will be supplied as extra to use as needed. Dosing instructions will
be printed on each bottle. Subjects will be instructed to take Antara (1 capsule) and Omacor® (4
capsules) in the evening.
1.4. Study Population
Subjects must have completed the previous OM5X open-label extension (8-weeks), and must have met all
inclusion/criteria for the OM5 study or have a renewed waiver of a previously approved protocol
deviation in either the OM5X or OM5 study.
1.5. Size of Trial Sample
All qualifying subjects who completed open-label OM5X will be given the option to enroll in the
extension study OM5XX. One hundred and fifty subjects are planned to be randomized in study OM5,
enrolled into OM5X, and then enrolled into OM5XX. No power calculation was used to determine the
sample size required for OM5XX to demonstrate any significant differences in outcome analyses.
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1.6. Randomization Methods
As an extension study of OM5, all subjects will receive Omacor® (omega-3-acid ethyl esters, 4 g/d, 4
capsules/day) administered concomitantly with Antara 130 mg/d (1 capsule/day).
1.7. Procedures for Unblinding
Both Antara and Omacor® will be administered in an open-label fashion.
2. EFFICACY PARAMETERS
2.1. Primary Efficacy Parameter
The primary efficacy parameter will be the difference between the within-group mean percent change
from baseline in TG level observed at the end of OM5X (average of Weeks 14 and 16 in OM5X minus
average of Week -2, -1 and 0 in OM5) and the mean percent change from baseline observed at the end of
OM5XX (endpoint or LOCF in OM5XX minus average of Week -2, -1 and 0 in OM5).
2.2. Secondary Efficacy Parameters
The following serum lipid parameters will be summarized:
x Total cholesterol (Total-C) (mg/dL)
x Very low-density lipoprotein cholesterol (VLDL-C) (mg/dL)
x Low-density lipoprotein cholesterol (LDL-C) (mg/dL)
x High-density lipoprotein cholesterol (HDL-C) (mg/dL)
x Non-high-density lipoprotein cholesterol (Non-HDL-C) (mg/dL)
x Ratio of total cholesterol to HDL cholesterol
The following apolipoproteins will be summarized:
x Apolipoprotein A-I (Apo A-I) (mg/dL)
x Apolipoprotein B (Apo B) (mg/dL)
2.3. Tertiary Efficacy Parameters
The following tertiary efficacy parameters will be summarized:
x Analysis by the Vertical Auto-Profile method (VAP™) of lipid subfraction cholesterol carried by:
o VLDL 1+2 (large) and VLDL 3 (small)
o LDL 1+2 (large) and LDL 3+4 (small)
o HDL 2 (large) and HDL 3 (small)
o Intermediate-density lipoprotein (IDL)
o Lipoprotein (a) [Lp(a)]
x Lipoprotein-associated phospholipase A2 (Lp-PLA2)
3. SAFETY PARAMETERS
3.1. Adverse Events
Adverse events (AEs) and serious AEs will be summarized.
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3.2. Serum Chemistry
The following selected serum chemistry parameters will be summarized:
x Alanine aminotransferase (ALT) (U/L)
x Aspartate aminotransferase (AST) (U/L)
x Creatine phosphokinase (CPK) (U/L)
x Fasting glucose (mg/dL)
4. ANALYSIS POPULATIONS
4.1. Safety Population
The safety population will include all subjects who receive a dose of study medication and return to the
clinic for at least one safety assessment after enrollment into study OM5XX.
4.2. Intent-to-Treat Population
The intent-to-treat (ITT) population will comprise data for all subjects who are enrolled in this extension
study. A modified ITT population will be used for efficacy summaries. To be included in the MITT
population, subjects must have an OM5 baseline and at least one on-therapy OM5XX assessment.
5. STATISTICAL METHODOLOGY
5.1. Statistical and Analytical Issues
Subjects will be summarized and analyzed as one treatment group given that no appreciable differences
were noted between treatment groups (i.e., switchers and non-switchers) in the OM5 and OM5X analyses
consistent with Section 3.8.4 of the protocol.
5.1.1. Statistical Methods
All statistical analyses will be the responsibility of Radiant Development. Statistical programming and
analyses will be performed using SAS (SAS Institute, Cary, NC) 1 Version 8.2 or higher. All tests of
significance, unless otherwise stated, will be performed at a significance level of alpha=0.05, two-sided.
Unless otherwise noted, continuous variables will be summarized descriptively using number of subjects
(n), mean, standard deviation (Std), median, minimum, and maximum, and categorical variables will be
summarized descriptively using the frequency counts and the percentage of subjects in each category.
Safety data will be analyzed and summarized for the Safety population.
Efficacy analyzed and summarized for the MITT population.
1
SAS System for Windows, Version 8.2, SAS Institute, Inc., Cary, N.C., 2001
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5.1.2. Baseline and End-of-Treatment Definitions
Parameter
Lipid Profile
Apolipoprotein:
Apo A1 and ApoB
Lipid Subfraction by
VAP™
Serum Chemistry
Baseline of the
OM5 double-blind
treatment
Average of Weeks 2,-1, Repeat (if
applicable) and 0
Average of Weeks 1 and 0*
Week 0
End of OM5 doubleblind treatment
End of OM5X openlabel treatment
Average of Weeks 6 and
8*
Average of Weeks 14
and 16*
Average of Weeks 6 and
8*
Week 8
Average of Weeks 14
and 16*
Week 16
Week 0
Week 8
Week 16
P
End of OM5XX
open-label
treatment
Last OM5XX
available visit
Last OM5XX
available visit
Last OM5XX
available visit
Last OM5XX
available visit
*If one of the two measurements is missing, then only the one non-missing value will be used.
5.1.3. Repeated Laboratory Measurements
The investigator has the option of repeating laboratory tests. Only the originally scheduled test result will
be used for tabulations.
5.1.4. Computed Variables
The following variables will be computed programmatically using SAS.
Baseline Value = Baseline as defined in study OM5
Percent Change from Baseline =100*(Final Value– Baseline Value)/Baseline Value
Non-HDL-C = Total-C – HDL-C
Total-C: HDL-C = Total-C / HDL-C
Analysis by VAP™ method of Lipid Subfraction cholesterol for the following parameters will be
calculated as:
VLDL 1+2 (large) = Total VLDL – VLDL 3
LDL 1+2 (large) = LDL 1 + LDL 2
LDL 3+4 (small) = LDL 3 + LDL 4
LDL 1+2 (large) and LDL 3+4 (small) = LDL 1 + LDL 2 + LDL 3 + LDL 4
HDL 2 (large) and HDL 3 (small) = HDL 2 + HDL 3
Height (cm) = Height (in)*2.54
Weight (kg) = Weight (lb) /2.2
BMI = Weight (kg) / [Height (m)]2 where Height (m) = Height (cm)/100
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5.1.5. Handling of Dropouts and Missing Data
For the MITT analysis, the method of last observation carried forward (LOCF) will be utilized for
analyses. The value of the last non-baseline OM5XX visit (any visit post-enrollment) will be carried
forward to the subsequent visit(s), if missing. For summaries by visit, only subjects with available data at
that visit will be tabulated.
For those subjects who receive additional lipid lowering agents, the method of last observation carried
forward (LOCF) will be applied to the lipid data measured at the last available visit before the initiation of
the additional agents.
For the serum chemistry parameters, the method of last observation carried forward (LOCF) will be
applied only for the endpoint of OM5XX
5.1.6. Pooling of Centers
All investigative centers will follow the same detailed investigative plan and are intended to be similar
with respect to the number of subjects. Additionally, a central laboratory will be utilized for all laboratory
results, thus center effect is not expected to be a factor in the endpoint outcomes and data from all centers
will be pooled. Sensitivity analyses were thoroughly explored in the OM5X study and no differences
were observed; therefore, center effects will not be assessed in the OM5XX analyses.
5.2. Subject Characteristics
5.2.1. Subject Disposition
The disposition of subjects will be summarized. The number and percent of subjects in the Safety and
MITT populations will be presented.
The number of subjects will be presented for following groups:
x Enrolled Subjects: Subjects who were enrolled.
x Completed Subjects: Enrolled subjects who successfully complete the study.
x Discontinued Subjects: Enrolled subjects who do not successfully complete the study, including
subjects who were prematurely terminated due to study termination.
5.2.2. Discontinuations and Deviations
The number of subjects who discontinue the study will be tabulated by reason for discontinuation. The
summary should include the number and percentage of subjects who were prematurely terminated due to
sponsor’s termination of the study.
The percent incidence rate of discontinuation will be computed as:
100*number of subjects discontinued per reason/total number of subjects
5.2.3. Demographic Characteristics
Descriptive statistics will be provided for the following demographic variables collected at the OM5
screening and/or baseline visits:
x Gender (male, female)
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x
x
x
x
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Age (years)
Race and ethnicity (Hispanic or Latino, American Indian or Alaska Native, Asian, Black or
African American, Native Hawaiian or Other Pacific Islander, or White)
Height (cm)
Weight (kg)
BMI (kg/m2)
5.3. Efficacy Analyses
5.3.1. Primary Efficacy Analysis
Descriptive statistics of the primary efficacy parameter will be presented for the following:
x baseline (average of weeks -2, -1 and 0) of OM5 double-blind treatment
x end of OM5X open-label treatment (average of weeks 14 and 16)
x end of OM5XX open-label treatment (endpoint or LOCF)
x each OM5XX study visit (including only data available at each visit, i.e., no LOCF)
x change and percentage change from the baseline of OM5 double-blind treatment to the end of
OM5X open-label treatment
OM5XX open-label treatment
A repeated measures ANOVA model will be generated to compare within-group mean percent change
from baseline in TG observed at the end of OM5X (average of Weeks 14 and 16 in OM5X minus average
of Week -2, -1 and 0 in OM5) and the mean percent change from baseline observed at the end of OM5XX
(endpoint or LOCF in OM5XX minus average of Week -2, -1 and 0 in OM5). If necessary,
transformations will be applied prior to running ANOVA in order to improve kurtosis and/or skew or a
non-parametric alternative test (e.g., Kruskal-Wallis) will be employed. The initial models will include
terms for baseline value and time. The models will be reduced in a stepwise manner until only significant
factors or time remains. Data may be ranked prior to running these analyses if the distribution for any
variable does not approximate a normal curve.
Note that subjects who receive additional lipid-lowering agents will be included in the outcome analyses
by implementing LOCF on the last available visit before the start of any add-on medication. These
subjects will also be analyzed separately from subjects who do not receive additional agents if the number
of subjects is greater than 10% and less than 50% of the total population.
5.3.2. Secondary Efficacy Analyses
All secondary efficacy parameters will be summarized descriptively for the following:
x baseline of OM5 double-blind treatment (average of weeks -1 and 0 for Apo A-1 and Apo B;
average of weeks -2, -1 and 0 for all other parameters)
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change and percentage change from the baseline of OM5 double-blind treatment to the end of
Only summaries will be provided for secondary efficacy parameters.
5.3.3. Tertiary Efficacy Analyses
Selected tertiary parameters (specified in Section 2.3) will be summarized descriptively for the following:
x baseline of OM5 double-blind treatment (average of weeks -2, -1 and 0)
Only summaries will be provided for tertiary efficacy parameters.
5.4. Safety Analyses
5.4.1. Adverse Events
Adverse events (AEs) will be coded using the MedDRA dictionary (version 9 or higher). The occurrence
of treatment-emergent AEs will be presented by system organ class (SOC) and preferred term. If a
subject experiences the same event more than once, the first occurrence will be tabulated. A tabulation of
serious AEs will also be provided.
5.4.2. Serum Chemistry
Select serum chemistry clinical laboratory parameters (as specified in Section 3.2) will be summarized
descriptively for the following:
x baseline of OM5 double-blind treatment
x each OM5XX visit (including only data available at each visit, i.e., no LOCF)
x change from the baseline of OM5 double-blind treatment to the end of OM5X open-label
treatment
x change from the baseline of OM5 double-blind treatment to the end of OM5XX open-label
treatment
A listing of serum chemistry parameters will not be provided.
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6. TABLES, LISTINGS & FIGURES
6.1. Tables
Table 14.1.1 Subject Disposition
Table 14.1.2 Demographic Characteristics – Safety Population
Table 14.2.1.1 Primary Efficacy Analyses: Lipid Measurements – MITT Population
Table 14.2.1.2 Primary Efficacy Analyses: Lipid Measurements, By Lipid-Lowering Agent Groups – MITT
Population
Table 14.2.2.1 Secondary Efficacy Summary: Serum Lipid Measurements – MITT Population
Table 14.2.2.2 Secondary Efficacy Summary: Apolipoproteins Measurements – MITT Population
Table 14.2.3.1 Selected Tertiary Efficacy Parameter Summary – MITT Population
Table 14.3.1 Occurrence of OM5XX Treatment-Emergent Adverse Events by System Organ Class and Preferred
Term – Safety Population
Table 14.3.2 Occurrence of OM5XX Serious Adverse Events by System Organ Class and Preferred Term – Safety
Population
Table 14.4.1 Selected Serum Chemistry Parameters – Safety Population
6.2. Listings
Listing 16.2.1.1 Overall Subject Disposition
Listing 16.2.2.1 Subject Demographics and Informed Consent
Listing 16.2.3.1 Lipid Profile
Listing 16.2.4.1 Adverse Events
Listing 16.2.4.2 Serious Adverse Events
Listing 16.2.4.3 Adverse Event Follow-Up
6.3. Figures
Figure 14.2.1.1 Mean TG level by visit and LOCF– MITT Population
(PROGRAMMER NOTE: This graph will include mean TG for OM5 baseline, end of OM5X, each OM5XX visit,
and endpoint/LOCF of OM5XX)
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Attachment 1
PLANNED TABLES
The following table shells will be produced for the safety and modified intent-to-treat as appropriate.
Table 14.1.1 Subject Disposition ............................................................................................................................................................................................................ 2
Table 14.1.2 Demographic Characteristics – Safety Population............................................................................................................................................................. 3
Table 14.2.1.1 Primary Efficacy Analyses: Lipid Measurements – MITT Population........................................................................................................................... 4
Table 14.2.1.2 Primary Efficacy Analyses: Lipid Measurements, By Lipid-Lowering Agent Groups – MITT Population................................................................... 7
Table 14.2.2.1 Secondary Efficacy Summary: Selected Serum Lipid Measurements – MITT Population ............................................................................................ 8
Table 14.2.2.2 Secondary Efficacy Summary: Apolipoproteins Measurements – MITT Population................................................................................................... 10
Table 14.3.1 Occurrence of OM5XX Treatment-Emergent Adverse Events by System Organ Class and Preferred Term – Safety Population ................................. 12
Table 14.4.1 Selected Serum Chemistry Panel – Safety Population..................................................................................................................................................... 13
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Statistical Analysis Plan Final – Attachment 1
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June 4, 2008
Attachment 2:
PLANNED LISTINGS
The following listings will be generated.
Listing 16.2.1.1 Overall Subject Disposition ...................................................................................................................................................................................................2
Listing 16.2.2.1 Subjects Demographics and Informed Consent .....................................................................................................................................................................3
Listing 16.2.3.1 Lipid Profile ...........................................................................................................................................................................................................................4
Listing 16.2.4.1 Adverse Events.......................................................................................................................................................................................................................5
Listing 16.2.4.2 Serious Adverse Events..........................................................................................................................................................................................................6
Listing 16.2.4.3 Adverse Event Follow-Up......................................................................................................................................................................................................9
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List of IEC’s or IRB’s
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MD, Chairperson, Medical Consultant
PhD, Chairperson
Chairperson
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This section contained Principal Investigator’s Curriculum Vitae and has been excluded to
protect Principal Investigator privacy.
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Information and Consent Form
GlaxoSmithKline
OM5XX
INFORMATION AND CONSENT FORM
Study Title:
A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to
Assess the Efficacy and Safety of Adjunctive Lovaza™ (formerly known as
Omacor™) Therapy in Hypertriglyceridemic Subjects Treated with Antara™
Protocol #:
OM5XX
Sponsor:
Reliant Pharmaceuticals, Inc.
Study Doctor:
XXX-XXX-XXXX
Telephone Number: XXX XXX XXXX
After Office Hours: XXX-XXX-XXXX
The study doctor wants to know if you would like to be part of a research study. This form
describes the study in order to help you decide if you want to participate. This form will tell you
what you will have to do during the study and the risks and benefits of the study.
Please ask the study doctor or study staff about anything in this form that you have questions
about or do not understand. You should discuss your participation with anyone you choose in
order to better understand this study and your options. Do not sign this form unless you are
satisfied with the answers to your questions and decide that you want to be part of this study.
Being in this study does not replace your regular medical care.
WHAT IS THIS STUDY ABOUT?
You have hypertriglyceridemia (elevated triglyceride levels in your blood), and you have
completed Reliant Pharmaceuticals, Inc. studies OM5 and OM5X. Researchers want to
continue studying if a drug called Omacor®, in combination with a drug called Antara™ and a
change in diet, can help people with hypertriglyceridemia. G
This 2-year extension study will test an investigational use of Omacor and Antara. An
“investigational use” is a use that is being tested and is not approved in the United States by the
U.S. Food and Drug Administration (FDA). The FDA has approved Omacor for use in adults to
treat severe hypertriglyceridemia (high triglyceride levels above 500 mg/dL). The FDA has also
approved Antara to treat hypertriglyceridemia. The FDA has not approved the use of Omacor in
combination with Antara.
You do not have to be in this study to get Antara or Omacor.
The study doctor will give Antara and Omacor to people in this study to see if the combination is
safe and can help them. Everyone in this study will get Antara and Omacor and continue on the
same diet.
It is planned that about 150 people with hypertriglyceridemia who are 18 to 79 years old will be
in this study. All participants will get Antara and Omacor for 2 years.
Initials __________ Date __________
Version 2, dated 05/02/08
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IS THERE ANYTHING ELSE I CAN DO FOR MY HYPERTRIGLYCERIDEMIA?
You do not have to be in this study to get help for your hypertriglyceridemia. The study doctor
will talk to you about other things you can do for hypertriglyceridemia. Some other things you
can do are:
•
•
Get counseling for diet and lifestyle.
Take medications such as statins, niacin, or fibrates.
WHO IS PAYING FOR THIS STUDY?
A company called GlaxoSmithKline, the sponsor of the study, is paying for this study to happen.
GlaxoSmithKline is also paying the study doctor to do this study.
WILL IT COST ANYTHING TO BE IN THIS STUDY?
While you are in the study, you still need to get regular medical care. You (and/or your health
care payer) will still have to pay for the costs of your regular medical care that are not a part of
this study.
You do not have to pay for study drugs, study visits, or tests that are part of the study. To find
out more about costs, you can ask the study doctor or study staff.
You may have to pay the costs of diagnosing and treating a condition or injury that you or others
think is a direct result of your being in the study. This could happen if:
•
•
the sponsor and/or the study doctor do not think the condition or injury is a direct result
of your being in the study
you have not followed the directions the study doctor or study staff gave you about the
study
HOW DO I KNOW IF I CAN BE IN THE STUDY?
You may be in this study if you have successfully completed Reliant Pharmaceuticals, Inc. study
OM5X to Week 16 and have met all of the entry requirements for this study (OM5XX).
You may not be in this study if you continue to take some of the restricted medications from the
OM5 and OM5X studies. The study doctor or study staff will tell you more about this.
HOW LONG WILL I BE IN THE STUDY?
If you decide to be in this study and the study doctor says you can be in the study, your
participation will last about 2 years. You will have to come to the study center about 7 times
during the study. The study staff will tell you when to come in for your study visits. You should
ask the study staff how long your visits will last.
Initials __________ Date __________
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WHAT WILL HAPPEN DURING THIS STUDY?
If you qualify to be in the study and agree to participate by signing this consent form, the study
doctor will have you continue to follow a low-saturated fat diet for the entire study (2 years).
The study doctor will give you capsules to swallow every day for 2 years. You will take 1
capsule of Antara and 4 capsules of Omacor in the evening for 2 years.
This study does not involve anyone taking placebo (capsules that look like active drug but have
no active ingredient). Everyone in this study will take Omacor and Antara, and everyone will
take the same dose:
•
Omacor 4 grams per day + Antara 130 milligrams per day
You are the only one who should take the study drugs. You should make sure that no one else
takes them.
While you are in the study, you must:
•
•
•
•
Follow the instructions you are given.
Come to the study center for all visits with the study doctor.
Tell the study doctor or study staff about any changes in your health.
Tell the study doctor or study staff if you want to stop being in the study at any time.
What happens when I come for study visits?
Before you can start the study, the study doctor or study staff will talk to you about the study.
Then you have to sign this form before the study doctor or study staff can do any study
procedures.
After you sign this form, the study doctor or study staff will do the things listed below when you
come in for study visits. If you would like more information about which tests and procedures
will be done at each study visit, ask the study doctor or study staff.
•
•
•
•
•
•
•
•
Health and Medication Questions: Ask you to answer questions about your health,
your medical history, and the medications you are currently taking.
Weight: See how much you weigh.
Waist Circumference: Measure your waist.
Blood Pressure, Pulse: Check your blood pressure by putting a band around your
arm. This will squeeze your arm for about a minute. Check your pulse.
Blood Tests: Take some blood to do laboratory tests. The study doctor will ask you to
fast (eat and drink nothing except water) for 10 hours before study visits during which
you will give blood samples. Some of your blood will be stored for possible future tests
of risk markers for cardiovascular disease, such as inflammation or blood flow. No
genetic testing will be done with these stored samples.
Urine Tests: Take a urine sample to do laboratory tests.
Pregnancy Tests: If you are a woman under 56 years of age, you will have blood and
urine pregnancy tests. You will be told if the test results are positive. The results of the
test must be negative in order to participate in the study.
Questionnaires: Ask you to complete questionnaires about your health and diet.
Initials __________ Date __________
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•
•
Diet Counseling: Tell you what to eat and drink during the study.
Study Drugs: Give you a supply of study drugs and tell you how to take them. Ask you
to bring back all unused study drugs to each visit.
Some of the study procedures might be done as part of your regular medical care even if you do
not take part in this research study. The study doctor or a member of the study staff can answer
any questions you may have about the procedures that are not part of your standard care.
After the study is over, you should talk to the study doctor about your future treatment for
hypertriglyceridemia.
Ask the study doctor for the estimated recovery time of your participation in this study.
WILL BEING IN THIS STUDY HELP ME?
The study drugs may reduce your triglyceride levels, but there is no guarantee that participating
in this study will help you. Your hypertriglyceridemia might not improve or might get worse while
you are in this study. Information from this study may help develop new treatments for people in
the future.
ARE THERE RISKS TO ME IF I AM IN THIS STUDY?
What can happen if I take Antara?
Some people who have taken Antara had the following side effects:
•
•
•
•
•
•
•
abdominal pain
back pain
headache
nausea
constipation
increased cough and/or cold-like symptoms
elevated liver function tests, indicating possible liver problems. The study doctor will
check your liver function test results during the study.
What can happen if I take Omacor?
Some people who have taken Omacor had the following side effects:
•
•
•
•
•
•
belching (burping)
nausea
vomiting
bloating
diarrhea
constipation
Initials __________ Date __________
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Could I have an allergic reaction?
Sometimes people have allergic reactions to drugs. A severe allergic reaction could be lifethreatening. Some things that happen during an allergic reaction are:
•
•
•
•
•
•
•
a rash
having a hard time breathing
wheezing when you breathe
sudden drop in blood pressure
swelling around the mouth, throat, or eyes
fast pulse
sweating
Please get medical help and notify the study doctor or study staff if you experience any of these
or any other side effects during the study.
If I stop taking my regular medication, what are the risks?
If you stopped your regular medication to be in study OM5 or OM5X and you are still off the
medication during this study, your hypertriglyceridemia symptoms might come back or get
worse. Please tell the study doctor or study staff right away if you have any problems with your
health.
Could I have any other problems with my health if I do this research study?
It is possible that problems and side effects of Omacor and Antara that nobody knows about
could happen to you, which include your hypertriglyceridemia getting worse or even death. If
the study doctor learns any new information about Omacor or Antara that might change your
mind about continuing in the study, the study doctor or study staff will tell you about it.
It is possible that taking Omacor or Antara with your regular medications or supplements may
change how Omacor, Antara, your regular medications, or your regular supplements work. It is
very important that you tell the study doctor about all medications or supplements you are taking
during the study.
What are the risks of giving blood for this study?
Fasting before the study visits could cause dizziness, headaches, stomach discomfort, or
fainting.
The study doctor or study staff will take your blood by sticking a needle in your arm. Some
problems you might have from this are:
•
•
•
•
•
It may hurt.
You may get a bruise.
You may feel dizzy.
You might faint.
You might get an infection at the place where the needle went into your arm.
Initials __________ Date __________
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You will give about 15 tablespoons of blood during the study.
Are there risks to me if I am pregnant during the study?
If you are a woman, you cannot be in this study if you are:
•
•
•
pregnant
planning to become pregnant during the study
nursing a child
If a woman is pregnant or nursing a child while taking Omacor and Antara, there may be risks to
the unborn baby or nursing child. Nobody knows what these risks are right now. Some drugs
cause women to have their babies prematurely (early) or to have babies with birth defects.
The study doctor will require women under 56 years old who join the study to have pregnancy
tests during the study. A pregnancy test does not keep you from becoming pregnant.
If you are able to have children, the study doctor will discuss appropriate birth control options
with you. Use of cyclic hormonal contraceptives is not allowed in this study. The study doctor
or study staff can review alternate methods of birth control with you. Some methods of birth
control will not work when you are taking certain drugs.
If you think that you have become pregnant during the study, you must tell the study doctor
immediately. If you become pregnant, you will be removed from the study, and the study doctor
may track the pregnancy and report the outcome to the sponsor and
(IRB).
WILL I GET PAID?
You will get $XXX if you finish the whole study. If you do not finish the whole study, you will get
$XXX for each study visit you finish. The study doctor or study staff can tell you more about
when you will get paid.
WHAT IF I GET HURT OR SICK WHILE I AM IN THE STUDY?
If you get hurt or sick as a direct result of being in this study, the sponsor will pay the costs of
reasonable medical treatment that is not covered by your medical or hospital insurance or by
third party or governmental programs providing such coverage. If you have not followed the
study doctor’s instructions about the study, the sponsor may not pay these expenses. Be aware
that your health plan might not cover the costs of study-related injuries or illnesses.
No other form of compensation is routinely available other than what is listed in this consent
form. You will not lose any legal rights as a research participant by signing this consent form.
For more information, please contact the study doctor or a member of the study staff.
If you believe that you have a physical injury or illness as a result of your participation in this
research study, you should contact the study doctor immediately at the phone number listed on
page 1 of this consent form.
Initials __________ Date __________
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DO I HAVE TO BE IN THIS STUDY?
Your decision to be in this study is voluntary. You do not have to be in the study if you don’t
want to, and you can change your mind at any time. There will be no penalty to you, and you
won’t lose any benefits except for benefits having to do with the study. Your regular medical
care at this study center will not change if you decide not to be in the study.
The study doctor or sponsor can remove you from the study at any time, even if you want to
stay in the study. This could happen if:
•
•
•
The study doctor believes it is best for you to stop being in the study.
You do not follow directions about the study.
The sponsor stops the study for any reason.
If you want to stop being in the study, tell the study doctor or study staff and return all unused
study drug and study materials. If you stop being in the study early, the study doctor or study
staff may ask you some questions about being in the study. To help your removal from the
study happen safely, you may be asked to participate in more tests.
WHO CAN I TALK TO ABOUT THE STUDY?
You can ask questions about the study any time. You can call the study doctor at any time.
You should call the study doctor if you have questions about the study procedures, study costs
(if any), study payment (if any), or if you get hurt or sick during the study.
Study Doctor:
XXX-XXX-XXXX
Telephone Number: XXX-XXX-XXXX
After Office Hours:
XXX-XXX-XXXX
(IRB) reviewed this study.
is a
group of people who review research studies to protect the rights and welfare of research
participants and is not affiliated with the study doctor or the sponsor. If you have questions
about what it means to be in a research study or about your rights as a research participant, you
can call
or visit the
website at
is located in
Office hours are 8:00 AM to 5:00 PM Pacific Time, Monday through Friday.
Ask to speak with a Research Participant Liaison at
(toll free).
____________________________________________________________
WHO WILL USE AND SHARE INFORMATION ABOUT MY BEING IN
THIS STUDY?
This section explains who will use and share your study-related health
information if you agree to be in this study. If you do not sign this form, you
cannot be in the study.
Initials __________ Date __________
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During the study, the study doctor and study staff will use, collect, and
record health information about you (your “records”). Your records include
any information about you that the study doctor needs to do the study,
including information from the tests described above. Your records also
will include other identifying information about you, such as your name and
address.
If you sign this form:
• You allow the study doctor and study staff to use your records to
carry out this study.
• You allow the study doctor to share your records with the sponsor,
GlaxoSmithKline; people who work with or for the sponsor; and other
researchers involved in this study. These people will use your
records to review the study and to check the safety and results of the
study.
• You allow the study doctor or sponsor to use some facts about your
being in this study in books, magazines, journals, and scientific
meetings. If this happens, no one will use your name.
• You allow the study doctor to share all of your records and this signed
consent form with government agencies, including the U.S. Food and
Drug Administration (FDA) and other government agencies in the
U.S. and other countries. The study doctor may also share your
records with regulatory agencies, like
(IRB). These agencies may use your records to check
the study information, how researchers are doing the study,
participants’ safety, and the results of the study.
• You allow the study doctor to share your records with your health
care payer to resolve your claim if you are hurt because of being in
this study. If this happens, the study doctor or the sponsor may share
your records with their insurance carriers to resolve your insurance
claim, and the study doctor may also request medical records from
your other health care providers to learn more about your condition.
There are national and state laws that make the study doctor protect the
privacy of your records. However, you do not have a guarantee of absolute
privacy because of the need to share your information. After the study
doctor shares your records with the sponsor and others, the laws may no
Initials __________ Date __________
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longer protect the privacy of your records. The sponsor or others may
share your records with other people who do not have to protect the privacy
of your records.
If you would like to know how the sponsor will protect the privacy of your
records, ask the study doctor how to get this information.
You have the right to see and copy your records. However, if you sign this
form, you might not be able to see or copy some of your records until after
all participants finish the study.
You can cancel this consent to use and share your records at any time. If
you want to cancel your consent, you must write a letter to the study doctor.
If you cancel your consent:
• You will not be able to be in the study.
• The study doctor will not be able to use or share your records unless
it is necessary to protect the integrity of the study.
This consent to use and share your records expires in 50 years.
You will receive a signed copy of this form for your records.
Indicate your agreement to the use and sharing of your records by
checking the box below and signing:
I agree to the use and sharing of my records related to this study as
described above.
Signature of Participant
Date
Initials __________ Date __________
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DO YOU WANT TO BE IN THIS STUDY?
I have read this form, and I have been able to ask questions about this study. The study doctor
or study staff has talked with me about this study. I voluntarily agree to take part in this study.
By signing this form, I have not given up any of my legal rights as a research participant. I will
receive a signed copy of this consent form for my records.
Printed Name of Participant
Signature of Participant
Date
I attest that the participant named above had enough time to consider this information, had an
opportunity to ask questions, and voluntarily agreed to be in this study.
Printed Name of Person Explaining Consent
Signature of Person Explaining Consent
Date
I attest that I or my representative discussed this study with the participant named above.
Signature of Principal Investigator or Sub-Investigator
Initials __________ Date __________
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Documentation of Inter-Laboratory Standardization Methods and Quality Assurance
Procedures
1
Reliant Pharmaceuticals / OM5XX
CHEMISTRY
ANALYTE
Sodium
Potassium
Glucose
Alkaline phosphatase
2
Creatinine
Chloride
Bicarbonate (CO2)
BUN
Creatine kinase (CK)
ALT (SGPT)
Female, Male
Female, Male
Female, Male
Female, 18-23 years
Female, 24-45 years
Female, 46-50 years
Female, 51-55 years
Female, 56-60 years
Female, 61-65 years
Female, ≥66 years
Male, 18 years
Male, ≥19 years
Female, Male
Female, Male
Female
Male
Female, Male
135 - 145
3.6 – 4.8
70 - 100
52 – 144
37 – 98
39 – 100
41 – 108
46 – 118
50 – 130
55 – 142
52 – 222
45 – 115
12-31
0.1 – 1.0
0.7 – 1.2
0.9 – 1.4
100 – 108
Female, Male
22 – 29
Female
Male
Female
Male
Female
Male
6 – 21
8 – 24
38 – 176
52 – 336
9 – 29
10 – 45
CRITICAL VALUES
LOW
HIGH
UNITS
(≤)
(≥)
mmol/L
2.5
6.0
mmol/L
40
401
mg/dL
INCLUSION
EXCLUSION
U/L
CONFIDENTIAL
AST (SGOT)
Total bilirubin
REFERENCE RANGE
U/L
mg/dL
10.0
mg/dL
mmol/L
mmol/L
mg/dL
U/L
U/L
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URINALYSIS
ANALYTE
Female, Male
Female, Male
Female, Male
Female, Male
Female, Male
Female, Male
Female, Male
Female, Male
Female, Male
CRITICAL VALUES
LOW
HIGH
UNITS
(≤)
(≥)
g/dL
3
Negative
Negative
Negative
Negative
Negative
Negative
1.001-1.030
N/A
Normal
Not reported (neg) or
WBC
Female, Male
1-3
Not reported (neg) or
RBC
Female, Male
Occ.<1
Hyaline casts
Female, Male
Any number
NOTE: All other members of the microscopic examination are abnormal in any amount.
INCLUSION
EXCLUSION
CONFIDENTIAL
Glucose
Ketones
Hemoglobin
Protein
Nitrite
Bilirubin
Specific Gravity
pH
Urobilinogen
REFERENCE RANGE
/hpf
/hpf
/lpf
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LIPID PANEL
ANALYTE
Cholesterol
Triglyceride
HDL Cholesterol
VLDL Cholesterol
Female, Male
No range established
CRITICAL VALUES
LOW
HIGH
UNITS
(≤)
(≥)
INCLUSION
EXCLUSION
mg/dL
mg/dL
mg/dL
CONFIDENTIAL
4
LDL Cholesterol, direct
measure
REFERENCE RANGES BASED ON
NATIONAL CHOLESTEROL EDUCATION
PROGRAM (NCEP) GUIDELINES
Desirable
<200
Borderline high
200-239
High
≥240
Normal
<150
Borderline high
150-199
i h
High
200 – 499
Very high
≥500
Low
<40
Normal
40 – 60
Desirable
>60
Optimal
<100
Low risk
100-129
Borderline high
130-159
High
160-189
Very high
≥ 190
mg/dL
mg/dL
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MISCELLANEOUS
ANALYTE
Pregnancy
hsCRP
Apolipoprotein A-1
Apolipoprotein B
Female
Low risk
Average risk
High Risk
Acute inflammation
Female
Male
Female
Negative
<1.0
1.0-3.0
>3.0
>10.0
98-210
88-180
44-148
Male
Female, Male
5
55-151
1.4 - 14
14 – 100
30 - 250
520 - 1490
7.3 – 16.8
EPA
DHA
Female, Male
Arachidonic Acid
Total Fatty Acids
CRITICAL VALUES
LOW
HIGH
UNITS
(≤)
(≥)
INCLUSION
EXCLUSION
INCLUSION
EXCLUSION
mg/L
mg/dL
mg/dL
CONFIDENTIAL
Insulin
Fatty Acid Profile:
REFERENCE RANGE
uIU/mL
umol/L
umol/L
umol/L
mmol/L
SPECIALTY LABS
ANALYTE
Female, Male
Female, Male
Female, Male
No range established
27.3 - 559
< 7.5
Female
93 - 472
Male
134 - 480
CRITICAL VALUES
LOW
HIGH
UNITS
(≤)
(≥)
mg/dL
ng/mL
mg/dL
ng/mL
Ver. April 2, 2007
ZM2008/00140/00
LOV111821
Apolipoprotein CIII
MPO
RLP-C
Lipoprotein Associated
Phospholipase A2 (PLAC)
(Lp-PLA2)
REFERENCE RANGE
ANALYTE
Total LDL-Cholesterol - Direct
Total HDL-Cholesterol - Direct
Total VLDL-Cholesterol - Direct
Sum Total Cholesterol
Triglycerides - Direct
6
IDL Cholesterol
Real-LDL Cholesterol
Sum total LDL-C
Real-LDL Size Pattern
INCLUSION
EXCLUSION
< 130 mg/dL
≥ 40 mg/dL
< 30 mg/dL
< 200 mg/dL
< 150 mg/dL
< 160 mg/dL
< 10 mg/dL
< 20 mg/dL
< 100 mg/dL
< 130 mg/dL
A
Female: > 15 mg/dL
Male: > 10 mg/dL
Female: > 25 mg/dL
Male: > 30 mg/dL
ZM2008/00140/00
LOV111821
HDL-2
(Large, Buoyant; most protective)
HDL-3
(Small, Dense; least protective)
VLDL-3 (Small Remnant)
CRITICAL
VALUES
CONFIDENTIAL
Total Non-HDL Cholesterol (LDL
+ VLDL)
Lp(a) Cholesterol
ALL REFERENCE RANGES
APPLY TO BOTH FEMALE AND
MALE
≥ 18 YRS.
< 10 mg/dL
Ver. April 2, 2007
Sponsor Test Name Order Code
Methodology
Antibody to human Apo B is added to a diluted aliquot of plasma or serum. The increase in light
Apolipo A1 and B
80318
scatter resulting from the antigen-antibody reaction is measured and is a function of the
concentration of Apo B. A multi-point standard curve is used for calculation of Apo B concentrations
from the light scattering values.
Antibody to human Apo AI is added to a diluted aliquot of plasma or serum. The increase in light
scatter resulting from the antigen-antibody reaction is measured and is a function of the
concentration of Apo AI. A multi-point standard curve is used for calculation of Apo AI
concentrations from the light scattering values.
80317
460461
200204
CRP
124005
Colorimetric
The Roche E170 CKMB method is a sandwich electrochemilumin-escence immunoassay which
employs two monoclonal antibodies. CKMB in the sample reacts with both a biotinylated
monoclonal CKMB-specific antibody and a monoclonal CKMB-specific antibody labeled with a
ruthenium complex to form a sandwich complex. Streptavidin-coated microparticles are added and
the mixture is aspirated into the measuring cell where the microparticles are magnetically captured
onto the surface of the electrode. Application of a voltage to the electrode induces a
chemiluminescent emission which is then measured.
The quantitative determination of hs-CRP is achieved by a latex particle-enhanced
immunoturbidimetric assay on a Hitachi 912 automated analyzer, using reagents from Diasorin.
Latex particles coated with antihuman CRP antibodies aggregate in the presence of serum CRP,
forming immune complexes. The immune complexes cause increased turbidity (measured at 572
nm), which is proportional to the concentration of CRP in the serum. The sample hs-CRP
concentration is determined by comparison to hs-CRP standards of known concentration.
Direct LDL
CONFIDENTIAL
7
Apolipo CIII
Chemistry
CK-MB reflex
9342
ZM2008/00140/00
LOV111821
Separation of LDLs from very low density lipoprotein (VLDL) and high density lipoprotein (HDL) by
ultracentrifugation and selective precipitation; quantitation of cholesterol by usual colorimetry.
(Trinder P: Determination of glucose in blood using glucose oxidase with an alternative oxygen
acceptor. Ann Clin Biochem 1969;6:24-27)
Sponsor Test Name Order Code
Methodology
Quantitation of fatty acids of specific chain lengths is performed as follows: a 2-step, acid-base
Fatty Acid Profile
82042
hydrolysis is followed by hexane extraction and derivatization with pentafluorobenzyl bromide.
Separation and detection are accomplished by capillary gas chromatography
electron-capture negative ion-mass spectrometry . Quantitation is based on analysis in the selected
ion-monitoring mode by using 13 stable isotope-labeled internal standards.
15800
15800
440008
Hemoglobin A1C
124055
N/A
N/A
The Coulter LH750 instrument provides a white cell count, red cell count, and platelet count using
impedance counting. Automated differentials are performed on the instrument using VCS
technology, which combines volume, conductivity and light-scatter measurement of individual cells
to provide a 3 dimensional plot of cell populations and sub-populations (Coulter Systems Reference
Guide,Beckman-Coulter Corporation Miami, FL, 2001).
8
HbA1c determination is performed on the Roche Modular System and is based on turbidimetric
immunoinhibition (TINIA) using a hemolyzed whole blood sample. HbA1c antibodies in the reagent
react specifically with glycated hemoglobin in the sample and form soluble antigen-antibody
complexes. Since the specific HbA1c antibody-binding site is present only once on the HbA1c
molecule, no aggregates can form. Polyhaptens in the R2 Working Solution then bind the excess
antibodies and the resulting agglutinated complex is measured turbidimetrically. Therefore, the
amount of HbA1c in the sample is inversely proportional to the amount of turbidity
formed.
110001
Lipid Profile
460380
The instrument used is a Beckman Cooulter DxI 800. The Beckman Coulter insulin assay is a
simultaneous "sandwich" assay, which uses an anti-insulin mouse monoclonal antibody labeled with
alkaline phosphatase and paramagnetic particles coated with a second mouse monoclonal antiinsulin antibody. A "sandwich" is formed by the 2 monoclonal antibodies binding to different
antigenic sites on the insulin in the patient
specimen. After separation in a magnetic field, all materials not bound to the solid phase are
washed away. A chemiluminescent substrate is added to the reaction vessel and light generated by
the reaction is measured with a luminometer. The proton production is directly proportional to the
concentration of insulin in the specimen and is determined by means of a stored, multi-point
calibration curve.
Enzymatic Colorimetric & Friedewald Equation
ZM2008/00140/00
LOV111821
Insulin
CONFIDENTIAL
FF1
FF2
Hematology
Sponsor Test Name
Lp-PLA2
MPO
Pregnancy
RLP-C
Storage Apo A5
Storage ICAM
Storage IL-1 beta
Storage IL-6
Storage TNF-alpha
Storage VCAM
Urinalysis
Order Code
81043
440017
200011
91355
15802
15802
15802
15802
15802
15802
450000
Methodology
Bioassay (BA)
Enzyme-Linked Immunosorbent Assay (ELISA)
Immunoenzymatic Assay
Immunoaffinity isolation of remnant lipoproteins followed by enzymic cholesterol determination
N/A
N/A
N/A
N/A
N/A
N/A
VAP subclasses
209004
A microscopic examination is performed on urine sediments by conventional microscopy or by
automation using the IRIS 900UDx. Determination of which method to use is made by visual
inspection. If the has an acceptable appearance and the amount is adequate, the urine is analyzed
on the IRIS 900UDx. All remaining urines have a manual microscopic is performed on the sediment.
N/A
CONFIDENTIAL
9
Reagent strip chemistries (protein, glucose, specific gravity, pH, ketones, bilirubin, hemoglobin,
nitrite, urobilinogen, leukocyte esterase) are determined by the Boehringer Mannheim/Hitachi
CHEMSTRIP Super UA Automated Urine Analyzer (SUA), which uses reflectance photometry to
analyze the color and light reflected from reagent pads on the strips. (Chemstrip IRIStrips
900Udx Urine Test Strips package insert. Roche Diagnostics Corporation. Indianapolis, IN 46256
7/2003)
ZM2008/00140/00
LOV111821
CONFIDENTIAL
ZM2008/00140/00
LOV111821
Listing of Patients receiving test drug(s)/Investigational Product(s) from Specific Batches
1
CONFIDENTIAL
Omacor 120 ct batch number: 348690
Antara 30 ct batch number: 5EE0078
2
ZM2008/00140/00
LOV111821
This section contained data from each individual patient, rather than in aggregate. They have
been excluded to protect patient privacy. Anonymized data from each patient may be made
available subject to an approved research proposal. For further information please see the
Patient Level Data section of the GSK Clinical Study Register.
1

In February 2013, GlaxoSmithKline (GSK)

Transcription

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