CLINICAL INVESTIGATION PLAN

Transcription

HEPAR-trial
CCMO NL25956.041.08
METC 08-450
CLINICAL INVESTIGATION PLAN
Radioactive holmium microspheres for the treatment of patients with
non-resectable liver metastases of mixed origin; a single center,
interventional, non-randomized, open label, safety study.
Authors:
B.A. Zonnenberg, MD PhD
M.A.A.J. van den Bosch, MD PhD
T.B. Bosma, CRC trainee
W. Bult, Reg. Ph.
M.G.E.H. Lam, MD PhD
J.F.W. Nijsen, PhD
A.D. van het Schip, PhD
M.A.D. Vente, DVM PhD
T.C. de Wit, PhD
Final version:
28
Date:
April 29, 2011
© University Medical Center Utrecht
Final version 28, 29-04-2011
Page 1 of 45
HEPAR-trial
CCMO NL25956.041.08
METC 08-450
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Principal
investigator
B.A. Zonnenberg, medical oncologist
UMC Utrecht
Department of Internal Medicine
Division of Internal Medicine and
Dermatology
E 02.222
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 56680, #1154
Investigators
M.A.A.J. van den Bosch, interventional
1
radiologist
2
W.P.Th.M. Mali, interventional radiologist
3
M.G.E.H. Lam, nuclear medicine physician
4
I.H.M. Borel Rinkes, oncological surgeon
UMC Utrecht
P.O. Box 85500
NL-3508 GA UTRECHT
Division of Radiology, Radiotherapy
and Nuclear Medicine:
1
Department of Radiology
E 01.132
Tel.: +31 88 75 6689
2
Department of Radiology
E 01.132
Tel.: +31 88 75 6689, #1070
3
Department of Nuclear Medicine
E 02.222
Tel.: +31 88 75 57779, #3705
Division of Surgical Specialisms:
Department of Surgery
G 04.228
Tel.: +31 88 75 58072, #1219
4
Production
manager
J.F.W Nijsen, assistant professor
UMC Utrecht
Department of Radiology and Nuclear
Medicine
and Nuclear Medicine
E 02.222
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 56676
Sponsor
M. Hendriks, medical manager
UMC Utrecht
E 01.335
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 56689
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HEPAR-trial
CCMO NL25956.041.08
METC 08-450
Independent
physician
Dr. G.D. Valk, internist-endocrinologist
UMC Utrecht
Department of Endocrinology
Dermatology
C 02.222
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 56304
Study
Coordinator
T.B. Bosma, trainee Clinical Research
Coordinator
UMC Utrecht
Trial bureau Radiology, Radiotherapy
E 02.222
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 51321, #1081
Laboratory
sites
J. den Hartog, manager laboratory
UMC Utrecht
Department Laboratory of Clinical
Chemistry and Haematology
Division of Laboratory and Pharmacy
G03.550
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 58669
Tel. secr.: +31 88 75 57604 / 57612,
#4351
Pharmacy
W. Meulenhoff, pharmacist
UMC Utrecht
Department Pharmacy
Division of Laboratory and Pharmacy
D.00.218
P.O. Box 85500
NL-3508 GA UTRECHT
Tel.: +31 88 75 56089, #1004
Monitor
K. Groot, Clinical Research Associate
Julius Clinical Research B.V.
J.F. Kennedylaan 101
NL-3981 GB BUNNIK
Tel.: +31 30 656 91 25
Mob.: +31 6 3805 99 72
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HEPAR-trial
CCMO NL25956.041.08
METC 08-450
PROTOCOL SIGNATURE SHEET
Name
Signature
Date
Head of Division
M. Hendriks, Medical Manager,
Division Radiology, Radiotherapy
Principal Investigator
B.A. Zonnenberg, medical
oncologist
Department of Internal Medicine
Dermatology
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HEPAR-trial
CCMO NL25956.041.08
METC 08-450
TABLE OF CONTENTS
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE....................................... 2
PROTOCOL SIGNATURE SHEET........................................................................................ 4
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS................................................ 8
SUMMARY...........................................................................................................................10
1.
INTRODUCTION AND RATIONALE.............................................................................12
2.
OBJECTIVES ...............................................................................................................14
3.
STUDY DESIGN...........................................................................................................14
4.
STUDY POPULATION .................................................................................................16
4.1
Inclusion criteria ....................................................................................................16
4.2
Exclusion criteria...................................................................................................16
5.
TREATMENT OF PATIENTS........................................................................................18
5.1
Schedule of procedures ........................................................................................18
5.2
Study procedures..................................................................................................19
5.2.1
Screening......................................................................................................19
5.2.2
Visit 1 (week 0)..............................................................................................19
5.2.3
Visit 2 (week 1-2)...........................................................................................20
5.2.4
Visit 3 (week 2-3)...........................................................................................21
5.2.5
Visit 4-7 (week 3-6) .......................................................................................21
5.2.6
Visit 8 (week 7)..............................................................................................21
5.2.7
Visit 9-13 (week 8-12) ...................................................................................21
5.2.8
Visit 14 (week 13; final visit) ..........................................................................22
5.3
Holmium content ...................................................................................................22
5.4
Laboratory examinations.......................................................................................22
5.5
Radiation exposure rate ........................................................................................22
5.6
Use of co-medication ............................................................................................22
5.7
Escape medication................................................................................................23
6.
INVESTIGATIONAL MEDICAL DEVICE.......................................................................24
6.1
Name and description of investigational medical product ......................................24
6.2
Animal studies.......................................................................................................24
6.3
Clinical studies ......................................................................................................24
6.4
Summary of known and potential risks and benefits..............................................24
6.4.1
Potential risks................................................................................................24
6.4.2
Potential benefits...........................................................................................24
6.5
Dose .....................................................................................................................25
6.6
Accountability of radioactive device.......................................................................26
7.
SAFETY PROFILE .......................................................................................................28
7.1
General.................................................................................................................28
7.1.1
Fatigue ..........................................................................................................28
7.1.2
Fever.............................................................................................................28
7.1.3
Abdominal pain .............................................................................................28
7.1.4
Gastrointestinal toxicity .................................................................................28
7.1.5
Tumor Lysis Syndrome..................................................................................28
7.1.6
Radiation hepatitis.........................................................................................28
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7.1.7
Veno oclussive disease .................................................................................29
7.1.8
Carcinoid crisis..............................................................................................29
7.2
Technique related .................................................................................................29
7.2.1
Peptic Ulceration ...........................................................................................29
7.2.2
Pancreatitis ...................................................................................................29
7.2.3
Radiation Pneumonitis ..................................................................................29
7.2.4
Radiation induced cholecystitis......................................................................29
7.2.5
Aneurysma Spurium/Haematoma..................................................................30
7.2.6
Infection/inflammation of the arterial puncture wound....................................30
7.2.7
Iatrogenic arterial dissection..........................................................................30
7.2.8
Contrast induced renal insufficiency ..............................................................30
8.
METHODS....................................................................................................................31
8.1
Study endpoints ....................................................................................................31
8.1.1
Primary study endpoint..................................................................................31
8.1.2
Secondary study endpoints ...........................................................................31
8.2
Withdrawal of individual patients ...........................................................................31
8.2.1
Replacement of withdrawn patients...............................................................32
8.3
Premature termination of the study .......................................................................32
8.3.1
Definition of Radiation Dose Limiting Toxicity (RDLT) ...................................32
8.3.2
Determination of MTRD.................................................................................32
8.4
Independent Data Monitoring Committee (IDMC)..................................................32
9.
SAFETY REPORTING .................................................................................................34
9.1
Section 10 WMO event .........................................................................................34
9.2
Adverse events and adverse device effects ..........................................................34
9.3
Serious adverse events.........................................................................................34
9.4
Suspected unexpected serious adverse reactions (SUSAR) .................................34
9.5
Documentation......................................................................................................35
9.5.1
Intensity.........................................................................................................35
9.5.2
Treatment relationship...................................................................................35
9.6
Follow-up of adverse events .................................................................................36
10.
STATISTICAL ANALYSIS.........................................................................................37
11.
ETHICALCONSIDERATIONS...................................................................................37
11.1 Regulation statement ............................................................................................37
11.1.1
Obligations of the investigator .......................................................................37
11.2 Recruitment and consent ......................................................................................37
11.2.1
Consent.........................................................................................................37
11.3 Benefits and risks assessment, group relatedness................................................38
11.3.1
Benefits .........................................................................................................38
11.3.2
Risks .............................................................................................................38
11.4 Confidentiality .......................................................................................................38
11.5 Financing ..............................................................................................................38
11.6 Compensation for injury ........................................................................................38
11.7 Incentives..............................................................................................................38
12.
ADMINISTRATIVE ASPECTS AND PUBLICATION .................................................39
12.1 Case Report Forms...............................................................................................39
12.1.1
Completing CRF’s .........................................................................................39
12.1.2
Corrections to CRF’s .....................................................................................39
12.2 Source document verification ................................................................................39
12.3 Monitoring .............................................................................................................40
12.4 Amendments.........................................................................................................40
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HEPAR-trial
12.5
12.6
12.7
12.8
13.
CCMO NL25956.041.08
METC 08-450
Annual progress report..........................................................................................40
Annual safety report ..............................................................................................40
End of study report................................................................................................41
Publication policy ..................................................................................................41
REFERENCE LIST ...................................................................................................42
Appendices
Appendix I
Appendix II
Appendix III
Appendix IV
Appendix V
Appendix VI
Appendix VII
Appendix VIII
Appendix IX
Appendix X
Declaration of Helsinki
CTCAE v3.0
WHO Performance status
RECIST-criteria
Laboratory parameters, normal values
CBO-directive “Richtlijn Voorzorgsmaatregelen bij jodiumhoudende
contrastmiddelen”, page 23-26
EORTC questionnaire QLQ-C30 with colorectal liver metastases module
QLQ-LMC21
Patient Information
Informed Consent Form
Summary preclinical investigations
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CCMO NL25956.041.08
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
166
HoPLLA-MS
5-FU/LV
90
Y-MS
µg
µmol
ABR
AE
ALT
ANC
AST
AR
CA
CBO
CCMO
CRF
CRP
CT
CTCAE
CV
DSMB
e.g.
ECG
EORTC
EU
EudraCT
FAS
GBq
GCP
GMP
Gy
h
HCC
IB
IC
ICH
IDMC
IEC
IMDD
IU
i.v.
keV
kg
km
L
LDH
MBq
METC
holmium-166 loaded poly(L-lactic acid) microspheres
5-fluorouracil in combination with leucovorin
yttrium-90 microspheres
microgram
micromole
ABR form (General Assessment and Registration form) is the application form that
is required for submission to the accredited Ethics Committee (in Dutch: ABR =
Algemene Beoordeling en Registratie)
Adverse Event
alanine aminotransferase
absolute neutrophil count
aspartate aminotransferase
Adverse Reaction
Competent Authority
Quality institute for Healthcare
Central Committee on Research Involving Human Subjects
Case Record Form
C-reactive protein
Computed Tomography
Common Terminology Criteria for Adverse Events
Curriculum Vitae
Data Safety Monitoring Board
exemlpi gratia
Electrocardiogram
European Organization for Research and Treatment of Cancer
European Union
European drug regulatory affairs Clinical Trials
Full Analysis Set
Giga Becquerel
Good Clinical Practice
Good Manufacturing Practice
Gray
hour(s)
hepatocellular carcinoma
Investigator’s Brochure
Informed Consent
International Conference on Harmonization
Independent Data Monitoring Committee
Independent Ethics Committee
Investigational Medical Device Dossier
International Units
intravenous
kilo electron volt
kilogram
kilometer
liter
Lactate dehydrogenase
Mega Becquerel
Medical research ethics committee (MREC) (in Dutch: Medisch Ethische
ToetsingsCommissie (METC))
Page 8 of 45
HEPAR-trial
MeV
mg
ml
MRI
MTRD
NCI
NSAIDs
NYHA
PPS
PET
PI
PT
PTC
PTT
QOL
RDLT
RECIST
RID
ROI
SAE
SDV
SGOT
SGPT
SOP
SPC
SPECT
SVC
Sponsor
SUSAR
t
Tc-MAA
TLS
ULN
UMC
VEGF
Vx2
Wbp
WHO
WMO
CCMO NL25956.041.08
METC 08-450
mega electron volt
Milligram
Millilitre
Magnetic Resonance Imaging
Maximum Tolerated Radiation Dose
National Cancer Institute
Non-Steroidal Anti-Inflammatory Drugs
New York Heart Association
Per Protocol Set
Positron Emission Tomography
Principal Investigator
prothrombin time
Protocol
partial thromboplastin time
Quality of Life
Radiation Dose Limiting Toxicity
Response Evaluation Criteria in Solid Tumors
Reactor Institute Delft
Region of Interest
Serious Adverse Event
source data verification
Serum glutamate oxaloacetate transaminase
serum glutamate pyruvate transaminase
Standard Operating Procedure
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst)
Single Photon Emission Computed Tomography
Superior vena cava
The sponsor is the party that commissions the organisation or performance of the
research, for example a pharmaceutical
company, academic hospital, scientific organisation or investigator. A party that
provides funding for a study but does not commission it is not regarded as the
sponsor, but referred to as a subsidising party.
Suspected Unexpected Serious Adverse Reaction
time
Technetrium macroaggregates
Tumor Lysis Syndrome
Upper Limit of Normal
University Medical Center (in Dutch: Universitair Medisch Centrum)
Vascular Endothelial Growth Factor
virus induced papilloma in rabbits liver
Personal Data Protection Act (in Dutch: Wet bescherming persoonsgevens)
World Health Organization
Medical Research Involving Human Subjects Act (in Dutch: Wet Medischwetenschappelijk Onderzoek met mensen
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HEPAR-trial
CCMO NL25956.041.08
METC 08-450
SUMMARY
Acronym
Rationale
Objective
Study design
Study population
Intervention
Study endpoints
Duration of treatment
Methodology
Number of study centers
Adverse events
Inclusion period
Holmium Embolization Particles for Arterial
RadioTherapy – HEPAR-trial
A significant need for new treatment options for
dominant liver metastases is recognized, because
survival of patients with unresectable liver disease is
poor. The preclinical phase of studies with
166
Ho-PLLA-MS has been successfully completed and
now clinical studies for evaluation of safety and
efficacy are warranted.
Primary objective:
To establish the safety and toxicity profile of treatment
with 166Ho-PLLA-MS.
Secondary objectives:
• To evaluate tumor response.
• To evaluate biodistribution.
• To evaluate performance status.
• To evaluate Quality of Life (QOL).
• To compare Tc-MAA-scan with
166
Ho-PLLA-MS safety dose scan.
Interventional, treatment, non-randomized, open label
uncontrolled, safety study.
15 to 24 patients, male and female aged 18 years and
over with dominant liver metastases. All histologies
are acceptable, provided no standard therapeutic
options are available, such as chemotherapy and
surgery.
166
Ho-PLLA-MS will be administered via a catheter
during angiography.
Primary endpoint:
Safety and toxicity profile of treatment with
166
Ho-PLLA-MS.
Secondary endpoints:
• Tumor response.
• Biodistribution.
• Performance status.
• Quality of Life.
• Comparison of Tc-MAA-scan and
166
Ho-PLLA-MS safety dose scan.
The study consists of a screening period of
approximately 2 weeks followed by a treatment period
of approximately 14 weeks.
Cohorts of 3 successive patients will be treated with 4
dose levels of 166Ho-PLLA-MS. If a RDLT occurs the
cohort will be increased to 6 patients. If at least 2
patients out of 6 have a RDLT, then the MTRD is
reached.
Single Center (UMC Utrecht).
All adverse events will be recorded throughout the
study.
May 2009 – November 2010.
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Analysis
Interim analysis will be performed after every 3
patients. Full analysis will be performed after the last
patient’s last visit. The primary endpoint will be
evaluated in FAS. The secondary endpoints will be
evaluated in FAS and PPS.
Manufacturers of the medical device 165Ho-PLLA-MS are manufactured by the radionuclide
pharmacy of the UMC Utrecht, The Netherlands.
165
Ho-PLLA-MS are neutron activated by the Reactor
Instituut Delft, The Netherlands.
166
Ho-PLLA-MS are prepared by the radionuclide
pharmacy of the UMC Utrecht, The Netherlands.
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HEPAR-trial
1.
CCMO NL25956.041.08
METC 08-450
INTRODUCTION AND RATIONALE
Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma) is the sixth most
common cancer, worldwide. The incidence rate is over 600,000 new cases each year and
the mortality rate is almost as high. Five-year survival rates are only 3-5% because the
majority of patients is not eligible for surgical resection (partial hepatectomy or orthotopic
liver transplantation) [1, 2]. Systemic chemotherapy has proven ineffective in HCC. However,
the recently introduced sorafenib, an oral multikinase inhibitor, offers a survival benefit of
several months [3].
The liver is also the most common site of metastatic spread. As many as 50% of all patients
with a primary malignancy will in due course develop hepatic metastases. Metastases
confined to the liver most commonly, but not exclusively, occurs from colorectal carcinoma,
of which the incidence is very high as well [4]. Each year worldwide approximately one
million people develop cancer of the large bowel (colorectal carcinoma) [1]. The primary
tumor is in general resectable but unfortunately in 25% of cases the cancer will have spread
to the liver at the time of diagnosis whereas in due time more than 50% of patients will
develop hepatic metastases [5, 6]. Subtotal hepatic resection is the treatment of choice, yet
only 20-30% of patients are eligible for surgical resection of the liver metastases [7]. If
resection is performed with curative intent a 33% 5-year survival is reported [8].
For several decades, standard first-line chemotherapy for colorectal cancer has consisted of
5-fluorouracil in combination with leucovorin (5-FU/LV). Nowadays, oxaliplatin or irinotecan is
added to 5-FU/LV which has improved median survival from 12 to 20 months [9, 10].
Typically, long-term survival for patients with unresectable metastatic disease remains less
than 5% [6]. The use of anti-angiogenic drugs has further improved the prognosis of these
patients. The Vascular Endothelial Growth Factor (VEGF) antibody bevacizumab is now
considered standard treatment with 5-FU and oxaliplatin containing combinations. Median
survival is now considered to be about two years with this triple combination [11-13]
Therefore, a significant need for new treatment options is recognized. One novel treatment
modality is yttrium-90 radioembolization which consists of injecting beta-particle emitting
yttrium-90 loaded (glass or resin) microspheres into the hepatic artery using a catheter. The
clinical results of this form of internal radiation therapy are promising [14, 15]. It has been
reported in literature that the administration of yttrium-90 microspheres (90Y-MS) along with
chemotherapy (5-FU/LV) more than doubled survival with no difference in quality of life
compared to chemotherapy alone [16]. It is not known if this is also the case with the use of
the triple regimen (bevacizumab, oxaliplatin and 5-FU).
Although 90Y-MS therapy is evermore used and considered a safe and effective treatment
option for patients with liver dominant disease, these microspheres have a major drawback:
following administration the actual biodistribution cannot be accurately visualized [17]. For
this reason, holmium-166 loaded poly(L-lactic acid) microspheres (166Ho-PLLA-MS) have
been developed [18, 19] at the Department of Radiology and Nuclear Medicine of the
University Medical Center (UMC) Utrecht. Like yttrium-90, holmium-166 emits high-energy
beta particles that can eradicate tumors but they also emit gamma radiation which allows for
nuclear imaging. Visualization of the microspheres is possible. This is very useful for several
reasons. Prior to administration of the therapeutic dose a small scout dose of 166Ho-PLLA-MS
can be instilled to predict the distribution of the therapeutic dose. Also, quantitative analysis
of the nuclear scans would allow assessment of the radiation dose delivered on both the
tumor(s) and the normal liver (dosimetry) [20]. In addition, since holmium is highly
paramagnetic it can be visualized using magnetic resonance imaging (MRI). Quantitative
analysis of these MRI scans is possible as well and especially useful for medium- and longterm monitoring of the intrahepatic behavior of the microspheres [21, 22].
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The pharmaceutical quality of the 166Ho-PLLA-MS has been thoroughly investigated and
proven to be satisfactory [23-25]. Several animal studies have been conducted to investigate
the intrahepatic distribution (ratio tumor:normal liver), the toxicity profile/biocompatibility of
the 166Ho-PLLA-MS, safety of the administration procedure, and efficacy of these particles. A
non-survival biodistribution study in rats was performed in which it was demonstrated that the
166
Ho-PLLA-MS deposition was restricted to the liver and that in the tumorous tissue the
radioactivity concentration was six times higher than in the non-target tissue [26]. To
demonstrate that 166Ho-PLLA-MS injected into the hepatic artery have a tumoricidal effect, an
efficacy study in Vx2 carcinoma bearing rabbits was performed. In all animals that were
treated with 166Ho-PLLA-MS tumor growth was arrested and necrosis set in [27]. In a rat
study, in order to show that 166Ho-PLLA-MS are biocompatible, rods composed of (decayed)
166
Ho-PLLA-MS were implanted into the liver and the animals were terminated between 3
days and 18 months post implantation during which time no biochemical or clinical side
effects were observed [28]. Finally, an extensive toxicity study in healthy pigs was conducted
[29]. Five animals were administered (non-radioactive) 165Ho-PLLA-MS and in 13 animals
(radioactive) 166Ho-PLLA-MS were instilled into the hepatic artery. The animals were injected
with 166Ho-PLLA-MS in amounts of radioactivity corresponding with very high absorbed liver
doses. Just very mild side effects were seen: slight and transitory inappetence and
somnolence, which may well have been associated with the anesthetic and analgesic agents
that had been given and not necessarily with the microsphere ‘treatment’. A very important
adverse event (AE) which had occurred in two animals (166Ho-PLLA-MS) was inadvertent
deposition of 166Ho-PLLA-MS into the so-called gastroduodenal artery with consequent
radioembolization of the gastric wall. To avoid this type of complication, in analogy to what is
already customary in yttrium-90 therapy, selected vessels in patients will be occluded by
coiling prior to administration of 166Ho-PLLA-MS [30, 31].
The preclinical phase has been successfully completed and now clinical studies for
evaluation of safety and efficacy are warranted.
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HEPAR-trial
2.
CCMO NL25956.041.08
METC 08-450
OBJECTIVES
In this safety study a new device will be investigated, namely radioactive holmium
microspheres for microbrachytherapy for the treatment of liver malignancies. In a group of 15
to 24 patients, treated with increasing amounts of radioactive microspheres, the device will
be investigated on safety.
Primary objective:
• To establish the safety and toxicity profile of treatment with 166Ho-PLLA-MS.
Secondary objectives:
• To evaluate tumor response.
• To evaluate biodistribution.
• To evaluate performance status.
• To evaluate Quality of Life (QOL).
• To compare Tc-MAA-scan with 166Ho-PLLA-MS safety dose scan
3.
STUDY DESIGN
Study type
Study design
Study start date
Estimated study completion date
Interventional
Treatment, safety study, non-randomized, open label,
medical device*
May 2009
November 2010
This single centre study will be conducted in a minimum of 15 and a maximum of 24 patients
with liver metastases for whom no standard surgical or chemotherapeutic options will be
available. A standard dose escalation protocol with four cohorts will be used. Consecutive
patients will be treated in cohorts of 3 with identical amounts of 600 mg microspheres, where
the last cohort will consist of at least 6 patients. The first three cohorts will be extended when
toxicity is observed ( see 8.3.2). The specific activity will be increased by adapting irradiation
time in the nuclear reactor. The first cohort will be treated with a dose of 1.3 GBq/kg (liver
weight). The second cohort will be treated with a dose of 2.5 GBq/kg (liver weight). The third
cohort will be treated with a dose of 3.8 GBq/kg (liver weight) and the fourth cohort will be
treated with a dose of 5.0 GBq/kg (liver weight). See for dose calculation chapter 6.5.
* Regarding the method of administration (through a catheter inside the hepatic artery), invivo characteristics (no release of radionuclide) and mechanism of action (local irradiation
of the tumor) 166Ho-PLLA-MS is comparable to the two 90Y-MS products, either resin based
(SIR-Spheres) or glass based (TheraSphere), which are currently applied clinically and are
commercially available. The main difference and therefore main expected improvement
compared to the 90Y-MS is in the use of the radionuclide 166Ho to irradiate the tumor. In
contrast to 90Y, 166Ho can be visualised both by SPECT and MRI, which is important to
accurately detect biodistribution and perform dosimetric calculations. The shorter half-life of
166
Ho (26.8 h vs. 64.2 h for 90Y) also is an advantage, since high doserates on the tumor
can be achieved.
Both commercially available 90Y-MS products are approved by the FDA and EMEA as a
medical device. According to the FDA ((http://www.fda.gov/cdrh/devadvice/312.html) a
medical device is defined as:
"an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or
other similar or related article, including a component part, or accessory which is:
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recognized in the official National Formulary, or the United States Pharmacopoeia, or any
supplement to them, intended for use in the diagnosis of disease or other conditions, or in
the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
intended to affect the structure or any function of the body of man or other animals, and
which does not achieve any of it's primary intended purposes through chemical action
within or on the body of man or other animals and which is not dependent upon being
metabolized for the achievement of any of its primary intended purposes."
This definition provides a clear distinction between a medical device and other FDA
regulated products such as drugs. If the primary intended use of the product is
achieved through chemical action or by being metabolized by the body, the product
is usually a drug.
According to this definition and by analogy with the 90Y-MS we consider the 166Ho-PLLAMS as a medical device. The Dutch medicine evaluation board (College ter Beoordeling
van Geneesmiddelen) has discussed this issue (13 July 2007) and concluded that the
microspheres are to be considered as a medical device (see IMDD Appendix 1).
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HEPAR-trial
4.
CCMO NL25956.041.08
METC 08-450
STUDY POPULATION
The study will include patients with dominant liver metastases. All histologies are acceptable,
provided no standard therapeutic options are available, such as chemotherapy and surgery.
4.1
Inclusion criteria
Patients meeting the following criteria may enter the study:
1.
Patients must have given written informed consent.
2.
Female or male aged 18 years and over.
3.
Confirmed histological diagnosis of metastatic malignancy with dominant liver
metastases without standard therapeutic options for treatment including
chemotherapy or surgery. Dominant liver metastases are defined (according to the
Response Evaluation Criteria in Solid Tumors (RECIST) methodology, see
Appendix IV) as the diameter of all metastases in the liver must be more than 200%
of the sum of the diameters of all soft tissue lesions outside the liver.
4.
Life expectancy of 12 weeks or longer.
5.
World Health Organisation (WHO) Performance status 0-2 (see Appendix III).
6.
One or more measurable lesions at least 10 mm in the longest diameter by spiral
Computed Tomography (CT) scan (5 mm slice thickness) according to the RECIST
criteria.
7.
Negative pregnancy test for women of childbearing potential.
4.2
Exclusion criteria
Patients meeting any of the following criteria cannot enter the study:
1.
Brain metastases or spinal cord compression, unless irradiated at least 4 weeks
prior to the date of the experimental treatment and stable without steroid treatment
for at least 1 week.
2.
Radiation therapy within the last 4 weeks before the start of study therapy.
3.
The last dose of prior chemotherapy has been received less than 4 weeks prior the
start of study therapy.
4.
Major surgery within 4 weeks, or incompletely healed surgical incision before
starting study therapy.
5.
Any unresolved toxicity greater than National Cancer Institute (NCI), Common
Terminology Criteria for Adverse Events (CTCAE version 3.0, see Appendix II)
grade 2 from previous anti-cancer therapy.
6.
Serum bilirubin > 1.5 x Upper Limit of Normal (ULN).
7.
Serum creatinine > 185 µmol/L.
8.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline
phosphatase (ALP) > 5 x ULN.
9.
Leukocytes < 4.0 109/l and/or platelet count < 150 109/l.
10. Significant cardiac event (e.g. myocardial infarction, superior vena cava (SVC)
syndrome, New York Heart Association (NYHA) classification of heart disease ≥2
within 3 months before entry, or presence of cardiac disease that in the opinion of
the Investigator increases the risk of ventricular arrhythmia.
11. Pregnancy or breast feeding (women of child-bearing potential).
12. Comorbidity with a grave prognosis (estimated survival <3 months) and/or worse
then the basic disease for which the patients will be included in the study.
13. Patients with abnormalities of the bile ducts (such as stents) with a increased
chance of infections of the bile ducts.
14. Patients suffering from diseases with a increased chance of liver toxicity, such as
primary biliairy cirrhosis or xeroderma pigmentosum.
15. Patients suffering from psychic disorders that make a comprehensive judgement
impossible, such as psychosis, hallucinations and/or depression.
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16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
CCMO NL25956.041.08
METC 08-450
Patients who are declared incompetent.
Previous enrolment in the present study or previous treatment with
radioembolization.
Treated with an investigational agent within 42 days prior to starting study
treatment.
Female patients who are not using an acceptable method of contraception (oral
contraceptives, barrier methods, approved contraceptive implant, long-term
injectable contraception, intrauterine device or tubal ligation) OR are less than 1
year postmenopausal or surgically sterile during their participation in this study
(from the time they sign the consent form) to prevent pregnancy.
Male patients who are not surgically sterile or do not use an acceptable method of
contraception during their participation in this study (from the time they sign the
consent form) to prevent pregnancy in a partner.
Evidence of portal hypertension, splenomegaly or ascites.
Body weight over 150 kg.
Active hepatitis (B and/or C).
Liver weight > 3 kg (determined by software using CT data).
Allergy for i.v. contrast used (Visipaque®).
MRI contra-indications: severe claustrophobia, metal shrapnel, implanted
pacemaker and/or neurostimulators.
Patients who have arterial variations that will not allow whole liver treatment.
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5.
TREATMENT OF PATIENTS
5.1
Schedule of procedures
Procedures
Screening
Informed consent
X
In-/exclusion
X
Demographic data
X
Medical/surgical and
medication history
Physical exam, vital
signs and WHO
performance status
Treatment and follow-up period
W0
W1
W2
W3
W4
X
X
X
X
W5
W6
W7
W8
W9
X
X
X
X
X
W10
W11
W12
W13
X
X
X
X
X
X
Pregnancy test
(urine)
X
X
X
X
EORTC
Questionnaire
X
X
X
CT scan
X
X
X
MRI scan
X
PET scan*
X
X4
Angiography
X
Pre-safety dose of
Tc-99m-MAA
X
Safety dose of
X
X
X
X
X
X
X
166
Ho-PLLA-MS
Therapeutic dose of
166
Ho-PLLA-MS
X
Ho-excretion (blood
samples + 48 h urine)
X
X1
Scintigraphy
Radiation exposure
rate
X2
X3
X
ECG
X
Laboratory
examination type A**
X
X
X
Laboratory
examination type B**
X
X
X
X
X
Laboratory
examination type C**
Monitoring of (S)AE’s
+ concomitant med.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
* Positron Emission Tomography (PET) will only be performed in FDG-avid tumors.
** Laboratory examination type A (blood), B (blood) and C (blood and urine) see table 2: Laboratory parameters for safety.
1.
Tc-99m-MAA scintigraphy
2.
Safety scintigraphy
3.
Post treatment scintigraphy
4.
Non-contrast enhanced MRI of a limited duration
Table 1: Schedule of study procedures
Page 18 of 45
X
X
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Laboratory
examination
Type A
(blood)
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Parameters
Hematology
Coagulation
profile
Serum
chemistry
Type B
(blood)
Hematology
Serum
chemistry
Type C
(blood and urine)
Holmium
content
Leukocytes, erythrocytes, hemoglobin (Hb), hematocrit (HCT),
mean corpuscular volume (MCV), mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration (MCHC),
differential leukocyte count (neutrophils, lymphocytes, monocytes,
eosinophils, basophils) and platelet count.
Reagent-independent prothrombin ratio PT/PTT. If PT and/or PTT
are out of range, Thrombin time (TT) will be automatically
measured. Activated partial thromboplastin time (APTT).
Creatinine, total bilirubin, alkaline phosphatase, SGPT/ALT,
SGOT/AST, γGT, glucose, chloride, calcium, potassium, sodium,
total protein, albumin, bicarbonate, urea, magnesium, phosphorus,
ammonia, LDH, CRP and relevant tumor markers.
Total: 10 ml
Leukocytes, erythrocytes, hemoglobin (Hb), hematocrit (HCT),
mean corpuscular volume (MCV), mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration (MCHC),
differential leukocyte count (neutrophils, lymphocytes, monocytes,
eosinophils, basophils) and platelet count.
Creatinine, total bilirubin, alkaline phosphatase, SGPT/ALT,
SGOT/AST, γGT, glucose, albumin, ammonia, LDH and CRP.
Total: 4 ml
Holmium content.
Total blood: 4.5 ml
Table 2: Laboratory parameters for safety.
5.2
Study procedures
5.2.1
Screening
The screening visit will take place at the outpatient clinic within 14 days prior to the fist
angiography. During this visit the following procedures must be documented and reviewed as
a part of the screening process:
• Informed Consent.
• Inclusion and exclusion criteria.
• Demographic data.
• Medical and surgical history.
• Previous and ongoing medications (within the last 3 months).
• Physical examination including height and weight.
• Vital signs, including blood pressure (after at least 3 minutes sitting), pulse and
temperature.
• WHO performance assessment.
• CT, MRI and Positron Emission Tomography (PET) scan (scans should be
performed within 2 weeks prior to the first angiography). Positron Emission
Tomography (PET) will only be performed in FDG-avid tumors.
• ECG.
• Laboratory examination type A (blood).
5.2.2
Visit 1 (week 0)
Patients will be hospitalized on the evening before the day of angiography. They will be
discharged approximately 24 hours after the intervention unless complications will occur.
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During this visit the following procedures must be documented and reviewed as a part of the
study:
• Physical examination and vital signs (blood pressure, pulse and temperature).
• Pregnancy test for women of childbearing age.
• Concomitant medication.
• Monitoring of occurrence of (serious) adverse events.
• Laboratory examination type A (blood).
On day 0 the patient is subjected to an angiography of the upper abdominal vessels. At least
the celiac trunk and upper mesenteric artery are visualised. Followed by coiling of relevant
(aberrant) vessels, especially branches of the celiac axis supplying the organs. This
procedure will be performed by a skilled and trained interventional radiologist*. The catheter
is introduced using the Seldinger technique. Prior to the procedure the patient is offered a
tranquilizer. Premedication consists of proton pump inhibitors (pantoprazol 1 dd 40 mg),
starting at the day of the intervention. Proton pump inhibitors are prescribed to the patients to
be used until the end of the follow up.
* The attending intervention-radiologist, after finishing his residency in Radiology, stayed for
an additional 2 year training in interventional radiology at Stanford University Medical
Center (USA) and AMC Amsterdam. In the USA he was for the first time exposed to Y90
radioembolization. He performed additional supervised radioembolizations in the University
Hospital in Gent. Currently, he performs these radioembolizations on a routine basis in the
UMC Utrecht.
After successful angiography and coiling of relevant vasculature a dose of Tc-99m-MAA will
be administered. The patient is subjected to scintigraphy to determine the distribution. Both
planar imaging of the thorax and abdomen will be performed, as well as Single Photon
Emission Computed Tomography (SPECT) of abdomen. Images will be evaluated
qualitatively and quantitatively. Excessive extrahepatic deposition of activity is a contraindication for administration of the therapeutic dose. ROI (region of interest) analysis will be
used to calculate lung shunting. Lung shunting should not exceed 20% of the dose Tc-99mMAA. If the amount of lung shunting can not be reduced using standard radiological
interventional techniques to decrease lung shunting under 20%, the patient will not be
eligible to receive a safety and therapeutic dose of 166Ho-PLLA-MS.
5.2.3
Visit 2 (week 1-2)
The second intervention takes place around 1 week after the first intervention but no longer
than 2 weeks after. Patients will be hospitalized on the evening before the day of treatment.
They will be discharged approximately 48 hours after the intervention unless complications
will occur. During this visit the following procedures must be documented and reviewed as a
part of the study:
• Collecting of 48 hours urine for holmium content.
• Laboratory examination type A and C (blood and urine).
• Radiation exposure rate.
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Prior to the procedure the patient is offered a tranquilizer. An experienced interventional
radiologist will administer the safety dose of 166Ho-PLLA-MS through a catheter inside the
hepatic artery at the position as planned during the first intervention. In order to detect
inadvertent administration to the lungs or other (upper abdominal organs) a scintigraphy will
be performed after administration of the safety dose of 166HoPLLA-MS to assess the
distribution. Both planar imaging of the thorax and abdomen will be performed, as well as
SPECT of the abdomen. When the amount of lung shunting does not exceed 20% of the
safety dose of 166HoPLLA-MS, the therapeutic dose of 166HoPLLA-MS will be administered.
In order to obtain detailed information on the distribution of the 166Ho-PLLA-MS an MRI will
be performed both after the safety dose and the therapeutic dose. The MRI after the safety
dose will be a non-contrast enhanced MRI of limited duration.
The amount of radioactivity administered to the patient is determined by the study protocol
(see chapter 6.5). An experienced nuclear physician will assist the radiologist during
administration.
5.2.4
Visit 3 (week 2-3)
This visit will take place at the outpatient clinic. During this visit the following procedures
must be documented and reviewed as a part of the study:
• Laboratory examination type B (blood).
• A post treatment scintigraphy (scan will be acquired when the administered dose
will have decayed to approximately 500 MBq, which will take around 4 days,
depending on the administered dose).
• A MRI will also be performed.
5.2.5
Visit 4-7 (week 3-6)
These visits will take place at the outpatient clinic. During these visits the following
procedures must be documented and reviewed as a part of the study:
• Laboratory examination type B (blood).
5.2.6
Visit 8 (week 7)
• CT and PET scan.
5.2.7
Visit 9-13 (week 8-12)
These visits will take place at the outpatient clinic. During these visits the following
procedures must be documented and reviewed as a part of the study:
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•
•
•
•
•
5.2.8
CCMO NL25956.041.08
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Physical examination and vital signs (blood pressure, pulse and temperature).
WHO performance assessment.
Concomitant medication.
Monitoring of occurrence of (serious) adverse events.
Laboratory examination type B (blood).
Visit 14 (week 13; final visit)
• CT, MRI and PET scan.
5.3
Holmium content
Pooled urine samples will be collected in week 1 from 0-3 hours, 3-6 hours, 6-24 hours and
24-48 hours following 166Ho-PLLA-MS administration. In week 7 and week 13 pooled 24
hours urine will be collected (Laboratory examination type C, see tables 1 and 2). The date
and time of the start and the end of the collection period, the volume and whether the
collection was complete or not, will be noted in the Case Record Form (CRF). Measurement
of holmium content in urine and blood will be performed. The data and the time of
measurement and the results will be reported in the CRF.
During the hospitalization in week 1 (at t = 0, 3, 6, 24 and 48 hours following 166Ho-PLLA-MS
administration) and the outpatient clinic visits in week 7 and week 13 blood will be drawn for
measuring the holmium content in the blood.
5.4
Laboratory examinations
Blood samples for safety parameters will be taken using an indwelling canula or by single
vein puncture. During the follow-up visits with the investigator, blood samples for safety
parameters will be drawn by a research nurse and delivered to the Laboratory of Clinical
Chemistry and Haematology (see table 2).
5.5
Radiation exposure rate
During the hospitalization in week 1 the radiation exposure rate will be measured at t = 0, 3,
6, 24 and 48 hours from 1 meter distance (see table 1).
5.6
Use of co-medication
All patients that are eligible for the experimental treatment will receive proton pump inhibitors
(pantoprazol 1 dd 40 mg) starting the day before the catheterisation, which will be continued
until the end of the follow-up.
During the vascular intervention the patient will receive heparin (1000 IU/ml in saline, up to
2500 IU), to avoid the formation of thromboembolism during the intervention.
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The vascular intervention will be performed under x-ray guidance. To be able to visualise the
blood vessels during the procedure, a non-ionogenic x-ray contrast agent (jodixanol,
Visipaque®) will be administered to the patient.
Should women of childbearing age require microsphere therapy, non-pregnancy needs to be
ascertained prior to treatment. Therefore, proper contraceptive measures should be used,
such as the birth control pill.
5.7
Escape medication
Patients will receive oral analgesics (paracetamol up to 4000 mg/24h) for relief of fever and
pain after the administration of microspheres. To reduce nausea and vomiting, patients will
receive anti-emetics (ondansetron up to 3 dd 8 mg) during the first 24 hours after
administration of microspheres. In the case of persisting nausea, metoclopramide (up to 300
mg/24h) will be used. Patients suffering from diarrhoea will receive loperamide (up to 16
mg/24h).
The vascular contrast agent jodixanol (Visipaque®) can cause renal insufficiency in poorly
hydrated patients. Therefore, all patients will be hydrated according to the CBO-directive.
This consists of 1.5 l NaCl 0.9% prior and post angiography.
Inadvertent shunting of microspheres to organs such as the lungs, stomach and gall bladder
is associated with serious side effects. To reduce toxicity of the radioactive microspheres in
this case, amifostine (Ethyol® , up to 200 mg i.v./m2 for 7 days) can be administered.
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6.
INVESTIGATIONAL MEDICAL DEVICE
6.1
Name and description of investigational medical product
CCMO NL25956.041.08
METC 08-450
The device under investigation comprises radioactive particles dedicated for treatment of
hepatic malignancies. The particles, called microspheres, contain the radionuclide holmium166, which emits gamma rays (81 keV) and high-energy (1.8 MeV) beta particles. The beta
particles are responsible for the therapeutic effect of the device, the gamma ray can be used
for nuclear imaging purposes.
Liver metastases are preferably supplied by the hepatic artery. This selective vascularisation
allows the use of the hepatic artery for selective administration to the metastases without
compromising hepatic flow by the portal vein. The microspheres are locally administered by
means of selective catheterisation of the hepatic artery by a trained intervention radiologist.
6.2
Animal studies
Several animal studies have been performed with 166Ho-PLLA-MS. These studies were
aimed to get insight into the toxic effect, the method/technique of administration, efficacy,
safety and in vivo stability of the microspheres. The studies have been performed on rats,
rabbits, and pigs. The animal studies showed promising and positive results. An overview
and summary of the animal studies performed is given in Appendix X and the Investigational
Medical Device Dossier (IMDD, page 14, 18 and Appendix 6).
6.3
Clinical studies
This study will be the first clinical study to be performed with this medical device.
166
Ho-PLLA-MS and 90Y-MS are applied in a similar fashion (administration into the hepatic
artery using a catheter) and can therefore be compared. A description of comparative studies
is given in the IMDD (page 16 and 17).
6.4
Summary of known and potential risks and benefits
6.4.1
Potential risks
Based on the literature on 90Y-MS and animal studies on 166Ho-PLLA-MS, it is expected that,
if the 166Ho-PLLA-MS are administered correctly, the risk of complications is low. However, it
has been described in the literature that, due to excessive radiation doses delivered to the
liver parenchyma, “radiation hepatitis” is known to occur [16, 32]. This veno-occlusive
disease can usually be managed by steroid treatment but in some cases will result in
fulminant liver failure. However, the incidence of this complication is very low. There is also
the risk of known side effects (see chapter 7).
6.4.2
Potential benefits
The data and information provided in the IMDD demonstrates that the 166Ho-PLLA-MS are
suitable for therapy due to their radiotherapeutic and safety properties (see IMDD chapter
2.1.2 and chapter 4.4). The radioactive therapeutic dosage can be adjusted per patient
based on liver weight (see IMDD chapter 5.2).
In short, the use of radioactive microspheres administered intra-arterially as radionuclide
therapy for liver malignancies can overcome disadvantages of external beam radiation,
which is limited by the radiosensitivity of healthy liver tissue. Microspheres have the potential
to provide treatment to previously untreatable patients. The preclinical data of 166Ho-PLLAMS presented in this dossier provide a rational basis for further clinical investigations.
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6.5
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Dose
The amount of 166Ho radioactivity (A) that must be administered to a patient to deliver the
desired absorbed liver dose can be calculated according to the following formula [29]:
AHo166 (MBq)/LW (kg) = Liver Dose (Gy)/15.87 x 10 -3(J/MBq) = Liver Dose (Gy) x 63 (MBq/J)
where LW is the liver weight of the patient which may be determined using CT, MRI or
ultrasound scans.
The calculated dose is based on the assumption that all administered activity will be equally
distributed over the whole liver. This is not a realistic assumption but a rather conservative
and safe approach. Using this approach, only mild adverse events were encountered in
healthy pigs treated with calculated whole liver doses up to 150 Gy [29]. The administered
activity will show heterogeneous distribution over the liver enabling regeneration of relatively
spared liver tissue. In this study 4 dose levels were chosen (calculated whole liver doses of
20 Gy, 40 Gy, 60 Gy and 80 Gy). This allows for a conservative approach while delivering
therapeutic doses to all patients at the same time.
In the matrix “Dose (Gy) and activity (MBq) relation of holmium-166 treatment” examples of
amounts of activity for typical liver weights are given for the four investigated cohorts: 1.3
GBq/kg (liver weight), 2.5 GBq/kg (liver weight), 3.8 GBq/kg (liver weight) and 5.0 GBq/kg
(liver weight). A maximum of 15.1 GBq will be given to the maximum treated liver weight
(inclusive the tumour tissue) of 3 kg. The amounts of 166Ho radioactivity are calculated with
the above described formula.
Dose (Gy) and activity (MBq) relation of holmium-166 treatment
Liver dose (Gy)
10
20
30
40
50
60
70
80
1
A (MBq)
630
1260
1890
2520
3150
3780
4410
5040
1.5
A (MBq)
945
1890
2835
3780
4725
5670
6615
7560
LW (kg)
2
A (MBq)
1260
2520
3780
5040
6300
7560
8820
10080
2.5
A (MBq)
1575
3150
4725
6300
7875
9450
11025
12600
3
A (MBq)
1890
3780
5670
7560
9450
11340
13230
15120
4 dose cohorts: 1.3 GBq/kg; 2.5 GBq/kg (40 Gy); 3.8 GBq/kg (60Gy) and 5.0 GBq/kg (80Gy)
Matrix 1: Dose (Gy) and activity (MBq) relation of holmium-166 treatment
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6.6
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Accountability of radioactive device
The following flowchart demonstrates the route from preparation to disposition of the
radioactive device 166Ho-PLLA-MS.
1.
2.
3.
Preparation of
165
Ho-PLLA-MS
Neutron activation
of 165Ho-PLLA-MS
(Radionuclide
pharmacy)
(RID Delft)
6.
5.
Preparation of
Ho-PLLA-MS for
patient administration
166
(Radionuclide
pharmacy)
4.
Disposition of
radioactivity
Measurement of
radioactivity left in
administration materials
(Radionuclide
pharmacy)
(Radionuclide
pharmacy)
Administration of
Ho-PLLA-MS to
patient
166
(Interventional suite
Radiology dept.)
Figure 1: 166Ho-PLLA-MS flowchart, route from preparation to disposition.
Step 1
–
Preparation of 165Ho-PLLA-MS is carried out in the Good Manufacturing Practice
(GMP) facility (room E.02.4.11) of the radionuclide pharmacy of the UMC
Utrecht. After passing quality control, batches of 165Ho-PLLA-MS are stored in
the radionuclide pharmacy at room temperature in room E.02.422 in a vacuum
dessicator.
Before neutron activation patient dose vials are given a unique identification
number with a permanent marker that is resistant to neutron irradiation. A
complete description of the preparation, labelling and release of 165Ho-PLLA-MS
is given in the IMDD (page 9-11, Appendix 2 and 3, PTC-01 and PTC-02).
Step 2
–
Neutron activation is carried out in the Reactor Instituut Delft (RID). A complete
description of neutron activation is given in the IMDD (page 12, Appendix 4 and
7 and PTC-04).
Step 3
–
Preparation of 166Ho-PLLA-MS for patient administration is carried out in the
GMP facility (room E.02.4.11) of the radionuclide pharmacy of the UMC Utrecht.
A complete description of the preparation of 166Ho-PLLA-MS is given in the
IMDD (Appendix 4, PTC-01 and PTC-05).
Step 4
–
Administration of 166Ho-PLLA-MS to the patient is carried out in the
interventional suite of the Radiology department. A complete description of the
method of administration of 166Ho-PLLA-MS is given in the IMDD (page 19).
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Step 5
–
Measurement of radioactivity left in the administration materials is carried out in
the GMP facility (room E.02.4.11) of the radionuclide pharmacy of the UMC
Utrecht. Measurement is performed to calculate the net activity administered to
the patient.
Step 6
–
Disposition of radioactivity is carried out in room E.00.2.19. A complete
description of the disposition of radioactivity is given in the IMDD (PTC.300.02).
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7.
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SAFETY PROFILE
The following effects are expected based on literature on treatment with 90Y-MS [14, 33-36].
A similar safety profile is expected for 166Ho-PLLA-MS. The safety profile is divided in general
and technique related effects.
7.1
General
When the patient is treated with the proper technique, without excessive radiation to any
organ, the common adverse events after receiving radioactive microspheres are fever,
abdominal pain, nausea, vomiting, diarrhoea and fatigue. An abnormality of liver function
tests is likely to occur. This may be up to grade 3 or 4 (CTCAE vs 3) in the case of
AST/SGOT, ALT/SGPT, γGT, ALP and LDH, without direct clinical relevance. In general
these effects are transient [31].
7.1.1
Fatigue
Fatigue is often observed in patients. In general it does not exceed grade 2.
7.1.2
Fever
Fever can be observed immediately after the embolization (post-embolization syndrome) or
later in the follow-up. This can last for one week. The occurrence of fever later in the followup may be caused by the development of hepatic abscesses.
7.1.3
Abdominal pain
Right upper quadrant abdominal pain is frequently observed in patients undergoing radioembolization, but easily managed by outpatient medication.
7.1.4
Gastrointestinal toxicity
Nausea, vomiting, or both may be controlled with anti-emetic therapy. Ondansetron (up to 3
dd 8 mg) is recommended the first 24 hours after the administration. Subsequently,
metoclopramide (up to 300 mg/24h) can be prescribed. Diarrhoea should be treated with
adequate doses of loperamide (up to 16 mg/24h).
7.1.5
Tumor Lysis Syndrome
A major complication but very rare complication is a Tumor Lysis Syndrome (TLS). This is
caused by rapid necrosis of the tumor. Laboratory tests show a high serum LDH, high uric
acid, high serum potassium, high phosphate and low serum calcium. In patients with solid
tumors this side effect is extremely rare. Supportive care including fluids is recommended.
7.1.6
Radiation hepatitis
The frequency of radiation hepatitis is very uncommon in radioembolization due to the
inhomogeneous distribution that may be anticipated. There is no specific therapy for this
particular side effect. In case hepatic insufficiency occurs only the use of high doses of
lactulose and, if appropriate, assessing brain pressure and relieving increased brain pressure
might be beneficial. Hepatic insufficiency may occur in < 1% of all treated patients.
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7.1.7
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Veno oclussive disease
Veno occlusive disease (VOD) may occur by radiation damage to the portal veins. This is
caused by activation of the coagulation system probably by enodothelial damage.
Anticoagulants such as low molecular heparin (Fraxiparin in therapeutic dosages) have been
shown to be beneficial.
7.1.8
Carcinoid crisis
In cases patients with neuroendocrine tumours receive this experimental treatment the
release of neuroendocrine factors may give rise to the so called ‘carcinoid syndrome’. This
consists of high blood pressure , flushing and diarrhoea. This syndrome can be prevented to
some extent with octreotide (300 µg i.v./24h).
7.2
Technique related
The following effects are directly related to inadvertent deposition of the microspheres in
organs other than the liver, and should therefore be classified as technique related:
In case significant amounts of the dose of the 166Ho-PLLA-MS are deposited outside the liver
the potential toxicity may be decreased by starting treatment with the radiation scavenger
amifostine (up to 200 mg i.v./m2 for 7 days). It is imperative to start this treatment as soon as
possible.
7.2.1
Peptic Ulceration
A peptic ulcer may occur in < 10% of all treated patients. The development of acute peptic
ulceration is suggested by the symptoms of ulcer disease and diagnosed by endoscopy. If
this were to occur the patient should be treated using best standard practice, including pain
relief, gastric acid blocking drugs and intravenous fluids (pantoprazol i.v. up to 80 mg).
Treatment is the same as for any cause of peptic ulceration.
7.2.2
Pancreatitis
Pancreatitis may occur in 1% of all treated patients. The post treatment nuclear scan will
determine if the microspheres have lodged in the pancreas or other organs, but additional
tests such as serum amylase are also indicated if pancreatitis is suspected. If this were to
occur the patient should be treated using best standard practice, including pain relief, and
intravenous fluids (pantoprazol i.v. up to 80 mg).
7.2.3
Radiation Pneumonitis
High levels of implanted radiation and/or excessive shunting to the lung may lead to radiation
pneumonitis. This may be suspected if patients develop a non-productive cough several days
or weeks after the implantation of the microspheres and is diagnosed by chest X-ray.
Patients should be treated with systemic corticosteroids (1 mg/kg/day) and supportive care
until the condition has subsided.
7.2.4
Radiation induced cholecystitis
A rare complication is a radiation induced cholecystitis, which may occur in 1-2 % of all
treated patients. This side effect can be expected a few weeks after the intervention.
Complaints are local pain in the liver area, sometimes colicky in nature, elevated bilirubin
values and an increased CRP. Treatment may consist of a cholecystectomy.
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7.2.5
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Aneurysma Spurium/Haematoma
As a complication of arterial catheterization in the groin a false aneurysm may develop within
a few days after the procedure. This can be suspected because of local pain and a swelling
in the groin. It can be visualized by ultrasound. If this aneurysm is becoming very large and
threatens or causes skin necrosis, or is expanding rapidly as it may be infected, surgical
management should be performed. In most cases ultrasound-guided compression will be
effective. Ultrasound-guided injection of bovine thrombin is also very successful [37]. In rare
cases, pseudoaneurysms less than 2 cm can be managed conservatively and monitored by
serial imaging to confirm spontaneous resolution. In case a hematoma is diagnosed this will
resolve spontaneously.
7.2.6
Infection/inflammation of the arterial puncture wound
As a complication of arterial catheterization in the groin an infection/inflammation of the
arterial puncture wound may develop. Adequate antibacterial treatment will be provided to
resolve this.
7.2.7
Iatrogenic arterial dissection
If a dissection of an (abdominal) artery is suspected, this can be managed in general by
medical treatment (such as lowering of the blood pressure). But if the dissection ruptures,
immediate surgery should be performed. Depending on the size of the lesion and the
affected vessel an embolization may be performed.
7.2.8
Contrast induced renal insufficiency
Although the frequency of contrast-induced renal insufficiency has decreased by the use of
non-ionogenic contrast, care should be taken to hydrate the patient adequately. Particularly
in patients with an impaired food intake and or diabetes mellitus this will require also
adequate hydration (> 2 l of fluid/24 h) prior to both angiographic procedures. If renal
insuffiency develops, patients will complain about asthenia, vomiting may occur and edeme
can be observed. The diagnosis is made by laboratory testing. Rehydration is generally
sufficient. Care should be taken to prevent hyperkalemia to avoid cardiac rhythm
abnormalities. To prevent nefrotoxicity, patients will be pre- and posthydrated according to
the CBO-directive “Richtlijn Voorzorgsmaatregelen bij jodiumhoudende contrastmiddelen”,
page 23-26 (see Appendix VI).
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8.
METHODS
8.1
Study endpoints
8.1.1
Primary study endpoint
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To establish the safety and toxicity profile of treatment with 166Ho-PLLA-MS. This profile will
be established using CTCAE (incl. SAE) methodology (CTCAE vs 3). The profile will be used
to determine the Maximum Tolerated Radiation Dose (MTRD, see chapter 8.3.2).
8.1.2
•
•
•
•
•
8.2
Secondary study endpoints
To evaluate tumor response: CT of the liver will be used to quantify tumor response in
time according to Response Criteria in Solid Tumor (RECIST) guidelines. Tumor size
will be assessed on the porto-venous phase of the dynamic contrast-enhanced CTimages. At fixed intervals in time (6 and 12 weeks after treatment), the largest liver
lesions are selected, to a maximum of five, and the maximum diameter in axial plane
is measured. The sum of the maximum diameter of the lesions is recorded.
Complete Response (CR): disappearance of all lesions, confirmed at 6 weeks
Partial Response (PR): ≥ 30% decrease in the sum of the longest diameters
of target lesions, with the baseline measurements taken as reference,
confirmed at 6 weeks
Stable Disease (SD): <30% decrease and <20% increase
Progressive Disease (PD): ≥20% increase in the sum of the longest diameters
of target lesions, with the baseline measurements taken as reference or
appearance of new lesions
To assess changes in tumor viability a PET-scan will be performed. Antitumoral effect
will also be assessed by relevant tumor markers (e.g. CEA for colorectal carcinoma,
AFP for hepatoma and Chromogranine A for neuroendocrine tumors) responses.
Tumor marker changes will be expressed as a percentage of the pre-treatment
values.
To evaluate biodistribution using CT, quantitative SPECT and MRI, blood analysis
and urinalysis.
To evaluate performance status using WHO performance status criteria.
To evaluate QOL using EORTC questionnaire QLQ-C30 with colorectal liver
metastases module QLQ-LMC21 (see Appendix VII).
To compare Tc-MAA-scan with 166Ho-PLLA-MS safety dose scan using hepatic
scintigraphy, both planar and SPECT.
Withdrawal of individual patients
Patients can leave the study at any time for any reason if they wish to do so without any
consequences for treatment or care. The investigator can decide to withdraw a patient from
the study for urgent medical reasons.
Patients may be withdrawn from the study if:
• A serious adverse event occurs.
Patients will be withdrawn from the study if:
• The investigator considers it in the best interest of the patient that he/she be
withdrawn.
• The patient withdraws consent.
• The patient is unable to comply with the protocol procedures
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The date and reason for withdrawal must be recorded. If the patient withdraws consent after
the therapeutic dose of 166Ho-PLLA-MS has been administered, the patient will be advised to
agree to follow-up safety investigations. In case of a serious adverse event a follow-up visit
will be arranged by the investigator.
8.2.1
Replacement of withdrawn patients
All patients registered in the study will be accounted for. Patients who do not receive the active
compound will be replaced by another patient at the same dose level, in order to allow at least
adequate assessment of the toxicity of 3 patients in a particular dose group. All patients that
received the experimental treatment will be available for the toxicity assessment, regardless if
they completed the 12 weeks of follow-up. If patients did not complete the full 12 weeks of
follow-up, they will be replaced.
8.3
Premature termination of the study
8.3.1
Definition of Radiation Dose Limiting Toxicity (RDLT)
Any of the following events which are considered possibly or probably related to the
administration of 166Ho-PLLA-MS will be considered a RDLT during the 12 weeks follow-up
period:
•
•
•
•
•
•
Grade 3-4 neutropenic infection (ANC < 1.0 x 109/L) with fever > 38.3°C,
Grade 4 neutropenia lasting > 7 days,
Grade 4 thrombocytopenia (platelet count < 25.0 x109/L),
Grade 3 thrombocytopenia lasting for > 7 days,
Any other grade 3 or 4 toxicity (excluding expected AST/SGOT, ALT/SGPT, γGT, ALP
and LDH elevation, elevated bilirubin and lymphocytopenia) possibly related to study
device, using NCI CTCAE v3.0.
Any life threatening event possibly related to the study device.
Disease progression will not be considered to be RDLT.
8.3.2
Determination of MTRD
If no RDLT is observed, the next cohort of 3 patients will be treated at the next radiation dose
level. If 1 patient with RDLT is observed in a particular cohort, it will be extended to
maximally 6 patients. If 2 or more patients in a particular cohort suffer from RDLT, the study
will be terminated because the endpoint e.g. the MTRD is reached. The dose level prior to
the toxic radiation dose will become the recommended dose for efficacy studies (the MTRD).
If an event is classified as grade 3 or 4 administration technique related, the patient will be
replaced. If administration related RDLT occurs in 2 out of 6 consecutive patients (33%), the
study will be suspended. This will be reported to the METC.
8.4
Independent Data Monitoring Committee (IDMC)
An IDMC is established. The IDMC is an external independent group including the following
members:
•
•
Dr. J.M.H. de Klerk, Meander Medical Center Amersfoort; a nuclear physician with
specific experience in radionuclide therapy and dosimetry.
Dr. O.M. van Delden, Academisch Medisch Centrum Amsterdam; a interventionradiologist with specific experience in oncological patients and embolization therapy.
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•
•
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Dr. B. Oldenburg, Universitair Medisch Centrum Utrecht; a gastro-enterologist with
specific experience in oncological patients with liver metastases.
Prof. Dr. K.C.B. Roes, Universitair Medisch Centrum Utrecht; a biostatistician.
The members have no conflict of interest with the sponsor because they are not involved in
the study, nor are they receiving funds.
The IDMC will perform a safety review after every three patients. The IDMC will receive
reports on a regular basis on all SAEs reported for this trial. The IDMC will work according to
Standard Operating Procedures (SOPs). Recruitment will not be interrupted unless otherwise
requested by the Chairman of the IDMC.
The responsibilities of the IDMC include:
• minimize the exposure of patients to an unsafe therapy or dose
• make recommendations for changes in study processes where appropriate
• advise on the need for dose adjustments because of safety issues
• endorse continuation of the study
• inform the METC in case of unexpected toxicity and/or when the well being of the
subjects is jeopardized
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9.
SAFETY REPORTING
9.1
Section 10 WMO event
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In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
patients and the reviewing accredited METC if anything occurs, on the basis of which it
appears that the disadvantages of participation may be significantly greater than was
foreseen in the research proposal. The study will be suspended pending further review by
the METC, except insofar as suspension would jeopardise the patients’ health. The
investigator will take care that all patients are kept informed.
9.2
Adverse events and adverse device effects
Adverse events are defined as any undesirable experience occurring to a patient during a
clinical trial, whether or not considered related to the investigational medical device. All
adverse events reported spontaneously by the patient or observed by the investigator or his
staff will be recorded. An adverse device effect occurs when there is a causal relationship
between the device and an adverse event.
9.3
Serious adverse events
A serious adverse event is any untoward medical occurrence or effect that at any dose
results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
- results in persistent or significant disability or incapacity;
- is a congenital anomaly or birth defect;
- is a new event of the trial likely to affect the safety of the patients, such as an
unexpected outcome of an adverse reaction, lack of efficacy of a medical device
used for the treatment of a life threatening disease, major safety finding from a
newly completed animal study, etc.
All SAEs will be reported to the accredited METC that approved the protocol, according to
the requirements of that METC.
9.4
Suspected unexpected serious adverse reactions (SUSAR)
Adverse reactions are all untoward and unintended responses to an investigational product
related to any dose administered. Unexpected adverse reactions are adverse reactions, of
which the nature, or severity, is not consistent with the applicable product information.
The sponsor will report expedited the following SUSARs to the METC:
− SUSARs that have arisen in the clinical trial that was assessed by the METC;
− SUSARs that have arisen in other clinical trial of the same sponsor and with the
same medical product, and that could have consequences for the safety of the
patients involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted
once every half year to the METC. This line-listing provides an overview of all SUSARs from
the study medicine, accompanied by a brief report highlighting the main points of concern.
The sponsor will report expedited all SUSARs to the competent authority, the Medicine
Evaluation Board and the competent authorities in other Member States.
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The expedited reporting will occur not later than 15 days after the sponsor has first
knowledge of the adverse reactions. For fatal or life threatening cases the term will be
maximal 7 days for a preliminary report with another 8 days for completion of the report.
9.5
Documentation
Attention is to be paid to the occurrence of AEs at all stages of the examination. Thus, the
patient should be closely observed by the investigator both during and after the treatment.
The recording phase for AEs will start with the first study drug administration and will end the
last day of the follow-up period. AEs related to hematological or renal toxicity which are still
present at the end of the follow-up period will be followed up until complete resolution as
assessed by the investigator. Any adverse events have to be documented in detail as
indicated on the CRF. The following information is required:
• The date and time of onset of any AEs
• The duration (the entire duration of an event or symptom, calculated from date of
onset and date of end)
• The maximum intensity (mild, moderate or severe; for definitions, see below).
• The drug relationship of the AE to the investigational product (for definitions, see
below)
• Any study drug action taken and any other action taken by the investigator to
resolve the adverse events (entered in free text)
• The outcome of the adverse event (recovered completely, recovered with residual
effects, continuing).
• An assessment of the seriousness of the event will be made by the investigator.
9.5.1
Intensity
Toxicities listed in the NCI CTCAE v3.0 are graded on a scale of 0 to 4. If a specific adverse
event is not included in the toxicity scale, the investigator is to classify its intensity according
to the following definitions:
Intensity
Mild
Definition
The patient is aware of signs or symptoms, but they are easily tolerated.
Usually does not require additional therapy or discontinuation of study
treatment.
Moderate
The signs and symptoms are sufficient to restrict, but do not prevent
usual activity; possibly requires additional therapy but usually does not
require discontinuation of study treatment.
Severe
The patient is unable to perform usual activities and usually requires
discontinuation of study treatment.
Table 3: Intensity grading of AE’s not described in NCI CTCAE v3.0
9.5.2
Treatment relationship
The investigator will be asked whether an AE is related to the administration of 166Ho-PLLAMS, or whether he is not capable to define a clear relationship to the study device. The
investigator will also be asked whether an AE is related to inadvertent deposition of the
microspheres in organs other than the liver, and should therefore be classified as technique
related.
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Categories
None
Unlikely
Possible
Probable
Definite
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Definition
The time course between administration of 166Ho-PLLA-MS and
occurrence or worsening of the adverse event rules out a causal
relationship
and/or
another cause is confirmed and no indication of involvement of 166HoPLLA-MS in the occurrence/worsening of the adverse event exists.
The time course between administration of 166Ho-PLLA-MS and
occurrence or worsening of the adverse event makes a causal
relationship unlikely
and/or
the known effects of 166Ho-PLLA-MS or of the substance class provide no
indication of involvement in occurrence/worsening of the adverse event
and another cause adequately explaining the adverse event is known
and/or
regarding the occurrence/worsening of the adverse event a plausible
causal chain may be deduced from the known effects of 166Ho-PLLA-MS
or the substance class, but another cause is much more probable
and/or
another cause is confirmed and involvement of 166Ho-PLLA-MS in the
occurrence/worsening of the adverse event is unlikely.
Regarding the occurrence/worsening of the adverse event, a plausible
causal chain may be deduced from the pharmacological properties of
166
Ho-PLLA-MS or the substance class, but another cause just as likely
to be involved is also known
or
although the physical properties of 166Ho-PLLA-MS or the substance
class provide no indication of involvement in the occurrence/worsening of
the adverse event, no other cause gives adequate explanation
The physical properties of 166Ho-PLLA-MS or of the substance class
and/or
the course of the adverse event after dechallenge and, if applicable, after
rechallenge
and/or
specific tests suggest involvement of 166Ho-PLLA-MS in the
occurrence/worsening of the adverse event, although another cause
cannot be ruled out.
The physical properties of 166Ho-PLLA-MS or of the substance class
and
the course of the adverse event after dechallenge and, if applicable, after
rechallenge
and
specific tests indicate involvement of 166Ho-PLLA-MS in the
occurrence/worsening of the adverse event and no indication of other
causes exists.
The available information is not sufficient for causality assessment.
Unclassified [only
used for SAE]
Table 4: categories of treatment relationship of AE’s
9.6
Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable situation has been
reached. Depending on the event, follow up may require additional tests or medical
procedures as indicated, and/or referral to the general physician or a medical specialist.
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10.
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STATISTICAL ANALYSIS
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be
calculated for each quantitative variable; frequency counts by category will be made for each
qualitative variable. Interim analysis will be performed after every 3 patients. Inclusion of
patients in the next cohort will be performed if the IDMC has scrutinized the toxicity data and
gave permission to proceed.
Two sets of study data will be evaluated: the primary endpoint will be evaluated in the Full
Analysis Set (FAS). The FAS is defined as the set of data generated from the included
patients who received at least the safety dose. The secondary endpoints will be evaluated in
both FAS and Per Protocol Set (PPS). The PPS is defined as the set of data generated from
the included patients who complied with the protocol.
11.
ETHICALCONSIDERATIONS
11.1
Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki (version
9.10.2004) (see Appendix I) and in accordance with the Medical Research Involving Human
Patients Act (WMO), the requirements of International Conference on Harmonization - Good
Clinical Practice (ICH-GCP) and this protocol. The protocol is submitted to the Independent
Ethics Committee (IEC) and to the Radiation Protection Committee of the UMC Utrecht. The
study will not start until written approval of the IEC of the UMC Utrecht has been received by
the investigator.
11.1.1
Obligations of the investigator
An updated copy of the curriculum vitae of each investigator and co-investigator will be
provided to the ethics committee. For the purpose of ensuring compliance with GCP and
regulatory guidelines, Health Authorities may conduct a site audit or an inspection. By
signing this protocol the investigator agrees to allow regulatory agencies to have direct
access to the study records for review.
11.2
Recruitment and consent
Patients with liver metastases will be referred, after analysis for surgical metastasectomy, by the
department of Surgery to the Principal Investigator (PI). The PI will inform every patient and
obtain their informed consent.
11.2.1
Consent
Before enrollment into the study the PI will inform every patient, verbally and in writing
(Appendix VIII) about the nature of the study, its purpose, procedures, expected duration and
the benefits and risks involved in study participation. Each patient will be given the opportunity
to ask questions and will be informed about the right to withdraw from the study at any time
without prejudice. Patients must be given adequate opportunity (at least 48 hours) to read the
information and enquire about details of the study before consent is given. Patients will have to
voluntary sign and date a written informed consent statement before participation (Appendix IX).
The informed consent statement will be signed and dated by the PI, or by a person delegated
with this responsibility by the PI. The patient will receive a copy of the signed consent
statement. This will include use of the acquired data for regulatory approval and product
information.
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11.3
Benefits and risks assessment, group relatedness
11.3.1
Benefits
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It is anticipated that treatment with radioactive microspheres will reduce tumor size and will
improve quality of life as known from literature from yttrium-90 [38-40]. It is anticipated that
the gamma emission of the radioactive Holmium will improve the safety of the procedure.
Also the difference in specific activity of 166Ho-PLLA-MS compared to the currently available
yttrium-90 may improve therapeutic results.
Participation in this study may possibly produce useful scientific data for the future. Regular
medical check-ups during the study can be seen as an additional benefit. The number of
visits (15) is comparable to a standard chemotherapy protocol. However, the scheduling is
different.
There are 10 more visits in comparison to treatment with 90Y-MS, which is a regular in the
UMC Utrecht since the beginning of 2009. The treatment with 90Y-MS is considered the
standard treatment in Europe.
11.3.2
Risks
Apart from the angiographic procedures and device related toxicity as described in chapter 7,
standard radiological and nuclear procedures are also used that may have their inherent side
effects. For the frequent blood sampling an indwelling cannula may be used and this may be
accompanied by mild bruising and also, in rare cases, by transient inflammation of the vessel
wall. After initial irritation, the presence of an indwelling cannula is usually painless and
hardly noticeable. The same applies to single vein punctures for blood sampling. When
needed, the use of a urethral catheter may also cause infection.
The total amount of blood withdrawn during the study will be up to 100 ml (normal blood
donation: 500 ml).
11.4
Confidentiality
All persons involved in the study agree to keep confidential any information pertaining to the
patient’s identity which becomes known to them in the course of the study.
11.5
Financing
This academic study is investigator driven; the investigators are employed solely by the UMC
Utrecht, a conflict of interest will not arise.
11.6
Compensation for injury
Injury directly related to participation in this study will be covered by the existing insurance of
the UMC Utrecht. Investigators and appropriate staff will be indemnified by the UMC Utrecht
for liability for study induced injury.
11.7
Incentives
The patients will receive compensation for travelling expenses; € 0.28/km and a ticket for
free parking.
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12.
ADMINISTRATIVE ASPECTS AND PUBLICATION
12.1
Case Report Forms
CRF’s will be provided by the UMC Utrecht. The CRF will be completed by the Clinical
Research Coordinator and Research Nurse.
12.1.1
Completing CRF’s
It is the responsibility of each investigator to ensure that the CRF’s are legible, correct and
complete. All relevant questions must be answered and no empty data blocks should exist.
However, in a situation where it is unavoidable that data cannot be entered, this should be
indicated in the CRF by entering the following in the relevant field:
ND
NK
NA
-
not done
not known
not available (i.e. test done but result not available) or not applicable
The signature at the end of each CRF by the principal investigator, investigator or authorized
co-investigator will serve as confirmation that the information recorded is complete, accurate
and has not been falsified.
12.1.2
Corrections to CRF’s
Errors, changes and/or additions entered on original CRF’s must be corrected by drawn in a
single line through the incorrect entry and writing the new entry as close to the original as
possible so as to leave the correct entry legible. If necessary the reason for the change must be
given. The correction must be initialed and dated by the authorized person making the change.
12.2
Source document verification
For the purpose of this study, the ‘source documents’ are defined as the patient’s hospital
medical records, clinician note’s, laboratory print outs, digital and hard copies of imaging,
memos, electronic data, etc. The Clinical Research Coordinator will require direct access to the
source documents in order to verify CRF entries.
As an absolute minimum, the source documents must include:
• A record that the patient has participated in a clinical trial, by study title, protocol
number, patient identification code and date of entry in the study (e.g. by signed
Informed Consent Form).
• Evidence that the patient satisfied all inclusion and exclusion criteria.
• A record of the doses and dates of administration of the investigational drugs
• A record of the safety parameters
• A record of the uptake and excretion data
• A record of concomitant medications
• Hard copies of relevant imaging
• A record of all adverse events.
Entries in the patient’s source documents must be signed and dated according to usual hospital
procedure. After completion of the study the completed patient files will be stored in the hospital
archives and maintained for a minimum of 15 years.
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12.3
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Monitoring
On-site monitoring (by UMC Utrecht: Division Julius Centrum) will be applied in order to
assure the quality and validity of the research data. Monitors will perform source data
verification (SDV) on the research data by comparing the data entered into the CRF with the
available source documentation in the regular patient records.
A complete check will be performed on
•
•
•
•
•
•
Informed Consent Forms (availability and correctness)
Verification of existence and identity of the participant
In- & Exclusion criteria
Reporting and follow-up of AEs / SAEs / SARs / SUSARs
Primary and Secondary Endpoints
166
Ho-PLLA-MS accountability
In addition to the complete check on the above mentioned items, a random sample of the
other research data will be checked.
The random sample will be selected from the completed CRFs prior to a monitoring visit.
Over the course of the study, the random sample will be spread to include;
• >50% of the participants at least once
• all types of visits at least once
If the quality of the data in the random sample is insufficient, the monitor will inform the
principal investigator and additional monitoring will be applied. A monitoring report will be
made after each visit and kept in the Study Master File.
12.4
Amendments
Amendments are changes made to the clinical investigation plan after a favourable opinion
by the METC of the UMC Utrecht has been obtained. All amendments will be notified to the
METC that gave the favourable opinion.
12.5
Annual progress report
The sponsor/investigator will submit a summary of the progress of the trial to the METC once
a year. Information will be provided on the date of inclusion of the first patient, numbers of
patients included and numbers of patients that have completed the trial, serious adverse
events/ serious adverse reactions, other problems, and amendments.
12.6
Annual safety report
The annual safety report may be combined with the annual progress report.
In addition to the expedited reporting of SUSARs, the principal investigator will submit, once
a year throughout the clinical trial, a safety report to the METC, competent authority,
Medicine Evaluation Board and competent authorities of the concerned Member States.
This safety report consists of:
• a list of all suspected (unexpected or expected) serious adverse reactions, along with
an aggregated summary table of all reported serious adverse reactions, ordered by
organ system, per study;
• a report concerning the safety of the patients, consisting of a complete safety analysis
and an evaluation of the balance between the efficacy and the harmfulness of the
medicine under investigation.
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12.7
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End of study report
The investigator will notify the METC of the end of the study within a period of 8 weeks. The
end of the study is defined as the last patient’s last visit.
In case the study is ended prematurely, the investigator will notify the METC, including the
reasons for the premature termination.
Within one year after the end of the study, the investigator/sponsor will submit a final study
report with the results of the study, including any publications/abstracts of the study, to the
accredited METC.
12.8
Publication policy
Any publication of the study results will be considered as a collaborative effort between the
investigators and appropriate personnel. Authorship shall be determined by mutual consent.
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