P1110 LoA 3 Training (14 June 2016 IMPAACT Annual Meeting)

IMPAACT P1110
A Phase I Trial to Evaluate the
Safety and Pharmacokinetics of
RAL in HIV-1 Exposed Neonates
at High Risk of Acquiring HIV-1
Infection
Diana Clarke, Chair
Mark Mirochnick, Vice-Chair
Yvonne Bryson, Vice-Chair
P1110 Protocol Team
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Diana Clarke
Mark Mirochnick
Yvonne Bryson
Ed Acosta
Betsy Smith
Rohan Hazra
Kat Calabrese
Bobbie Graham
Stephanie Popson
Patty Anthony
Rohan Hazra
Brenda Homony
Oswald Dadson
Terry Fenton
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Stephen Spector
Mae Cababasay
Jiajia Wang
Deborah Persaud
Michelle Wildman
Hedy Teppler
Anne Chain
Larissa Wenning
Brenda Harmony
RoseAnn Murray
Diane Costello
Katie Myers
P1110 Study Design and
Eligibility Criteria Overview
IMPAACT P1110
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Study Design: Phase I, open label, noncomparative dose-finding study for RAL oral
granules for suspension
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Sample Size: 32 evaluable infants (projected
50 mother-infant pairs)
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Population: HIV-1 exposed full-term neonates
(aged < 48 hours) assessed as high risk of
acquiring HIV-1 infection
Maternal Inclusion Criteria
 Documented
maternal HIV infection
 Mother is at high risk of transmitting HIV to
infant as evidenced by any of the following:
Has not received any antiretroviral therapy
during current pregnancy prior to onset of labor
and delivery (intrapartum ARVs are allowed)
2) HIV RNA > 1000 copies/mL within 4 weeks (28
days) prior to delivery
3) Receipt of ARV for < 4 weeks (28 days) before
delivery
1)
Maternal Inclusion Criteria
 Mother
is at high risk of transmitting HIV to
infant as evidenced by any of the following
(cont.):
On ARVs for ≥ 4 weeks but has not taken any
ARV for > 7 days prior to delivery
5) Mother has known documented multi-class drug
resistant virus to at least one class of ARV
drugs (to more than one class of ARV drugs).
(sub-bullet #5 changed with LoA #3)
4) Maternal written informed consent for study
participation
4)
Maternal Exclusion Criteria
1)
Known maternal-fetal blood group
incompatibility as evidenced by the
presence of an unexpected clinically
significant maternal red cell antibody that is
known to be capable of causing hemolytic
disease of the fetus/newborn
2)
Up to 6 mothers only: Mother receiving RAL
as part of her cART regimen after delivery
and intending to breastfeed her infant
(Cohort 1 only)
Infant Inclusion Criteria
1)
HIV-1 exposed full-term neonates aged ≤48
hours. Infant may have received up to 48
hours of standard of care ARV prophylaxis
before enrollment
2)
Infant gestational age at birth at least 37 weeks
3)
No known severe congenital malformation or
other medical condition not compatible with life
or that would interfere with study participation
or interpretation, as judged by the examining
clinician
Infant Inclusion Criteria (cont.)
4)
Birth weight ≥ 2 kg
5)
Able to take oral medications
Parent or legal guardian able and willing to
provide signed informed consent
6)
Infant Exclusion Criteria
1)
Infant with bilirubin exceeding the
American Academy of Pediatrics
guidelines for phototherapy, using the
infant’s gestational age and risk factors
2)
Clinical evidence of renal disease such as
edema, ascites, or encephalopathy
3)
Receipt of disallowed medications phenytoin, phenobarbital, rifampin
Cohort 1 Status
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Cohort 1: 2 single doses with first dose
administered within 48 hours of birth and second
dose at 7 to 10 days of life
 PK sampling done following each dose
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Cohort 1 is closed to accrual with n=16
Cohort 2 Status
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Cohort 2: Daily dosing starting within 48 hours
of birth and continued for 6 weeks in addition to
standard of care PMTCT
 PK sampling (specified in LoA #2)
 RAL-unexposed sub-group is open to accrual
with n=25
Within 48 hours – Day 7
of life (Week 1 of life)
RALunexposed
infants
RAL-exposed
infants
RAL 1.5 mg/kg oral
granules for suspension
daily (refer to Table A in
Appendix III).
Days 8 – 28 of life
(Weeks 2-4 of life)
Days 29 – 42 of life
(Weeks 5-6 of life)
RAL 3 mg/kg oral
granules for suspension
twice daily (refer to
Table C in Appendix III).
RAL 6 mg/kg oral
granules for suspension
twice daily (refer to
Table E in Appendix III).
To be further specified by an amendment once the data are available from the
Cohort 1, RAL-exposed group.
P1110 Version 1.0
Protocol Documents
Letter of Amendment #3, dated 18 May 2016
Letter of Amendment #2, dated 30 June 2015
Clarification Memorandum #4, dated 8 May 2015
Clarification Memorandum #3, dated 15 January 2015
Clarification Memorandum #2, dated 16 September 2014
Letter of Amendment #1, dated 22 April 2014
Clarification Memorandum #1, dated 01 April 2014
Protocol Version 1.0, dated 10 December 2012
P1110, Version 1: CM’s and LOA’s
 CM
#1 and CM #2: Clarified maternal HIV
testing and multi-class drug resistance
 LOA
#1: Allowed enrollment of up to 6 RALexposed infants into cohort 1
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RAL-exposed infants to receive lower initial dose
but same second dose as RAL-naïve infants
Initial dose: 1.5 mg/kg; Second dose 3 mg/kg
 CM
#3: Clarified dosing of RAL-naïve infants
P1110, Version 1: CM’s and LOA’s
 CM
#4: Cohort 1 RAL-naïve arm closed (n=10)
with open slots for additional RAL-exposed
 LOA
#2: Opened Cohort 2 (daily dosing) to
RAL-naïve infants
 LOA
#3…
LoA #3 Modifications
Summary of Changes
LoA #3 Modifications
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Section 4.12, sub-bullet 5, Maternal Inclusion
criterion modified to be more flexible:
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Mother has documented drug resistant virus to at
least one class of ARV drugs.
P1026s data listed as potentially being used for
modeling/ simulation exercise for Cohort 2 RALexposed dosing
LoA #3 Modifications
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Volume for reconstitution of oral granules for
suspension has been increased from 5mL to
10mL.
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For participants newly enrolled upon implementation
of LoA #3, after reconstitution the concentration of the
suspension is 10 mg/ mL.
New Dosing Tables: Tables G-I are for participants
newly enrolled upon implementation of LoA #3.
Tables J-L are placeholders for potential future dose
adjustments (not to be used yet).
RAL Granules Dosing Table 10 mg/mL
(Tables G-I added to Appendix III)
Weight Band (kg)
Dose (mg)
Volume (mL)
1.5 mg/kg
2 to <3
4 mg
0.4 mL
3 to <4
5 mg
0.5 mL
4 to <5
7mg
0.7 mL
3 mg/kg
2 to <3
8 mg
0.8 mL
3 to <4
10 mg
1 mL
4 to <5
15 mg
1.5 mL
6 mg/kg
2 to <3
20 mg
2 mL
3 to <4
25 mg
2.5 mL
4 to <5
30 mg
3 mL
LoA #3 Modifications: Volume for
reconstitution of oral granules for suspension
LoA #3 Modifications
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Suspected adverse drug reaction (SADR) term
was defined in Version 1.0 of the DAIDS EAE
Manual. However, P1110 Protocol Section 7
references that Version 2.0 of the DAIDS EAE
Manual will be used for the study.
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Therefore, the SADR definition was added to the
protocol with LoA #3: A suspected adverse drug
reaction (SADR) is an adverse event that could
potentially have a causal relationship to the study
agent (definitely, probably, or possibly related).
Lab Reminders
Highlights from the LPC for
Cohort 2
Infant Cohort 2
Specimen Collections
 Hematology
and Chemistries-may be
obtained any time on the first day of life
WITH THE EXCEPTION THAT
 Chemistries
must be obtained prior to
enrollment of the infant (bilirubin is an
eligibility criteria)
Infant Cohort 2
Specimen Collections
 HIV nucleic acid test (HIV NAT) may be either
HIV RNA or HIV DNA. Obtain if not Standard
of Care.
 Collect 1-3mL depending on the type of
platform performed at the site.
 Process and store blood per assay instructions
for HIV nucleic acid testing (i.e. plasma, cell
pellets, whole blood, DBS)
Infant Cohort 2
Specimen Collections
 Genotyping (optional) for UGT1A1 and
SLCO1B1 polymorphisms may be obtained
with any blood sample
 Prepare
paper
5 x 50µl dried blood spots on filter
Infant Cohort 2
PK Specimen Collections
 Collect 0.2mL K2 spray dried EDTA blood per
time point
 Send to lab on ice for processing within 1 hour
 Spin blood at 1000xg for 10 min at 4C
 Freeze 1 aliquot plasma at –70°C or colder
 Ship to Lab 191 UAB immediately after
collecting Day 15-18 of Life visit PK specimens
AND after collection of Week 5-6 of Life PK
specimens
Confirmed Vertical
Transmission
 Infants should have 2mL of blood drawn for
viral resistance testing to raltegravir and other
ARVs as soon as possible
 Safety assessments must be performed as
described in Appendix II-C
Questions?
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