Clarification Memorandum #1 for:
IMPAACT P1093
Phase I/II, Multi-Center, Open-Label Pharmacokinetic Safety, Tolerability and Antiviral Activity
of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants,
Children and Adolescents
Version 4.0 dated 13 April 2016
DAIDS ES # 11773
IND# 110,847
Clarification Memorandum Date: 8 December 2016
Summary of Clarifications
This Clarification Memorandum (CM) addresses inconsistencies in the protocol regarding the study drug
regimen in Cohort II; the maximum in-use period of the granule formulation after reconstitution; and
selection of the optimized background therapy (OBT) for participants entering Stage II. In addition,
clarification regarding the intended interpretation of inclusion criterion 4.1.3.1, and the requirement for
collection of samples for genotyping during long-term follow-up are added.
Implementation
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if
required by the IRBs/ECs, for their approval prior to implementation. The clarifications included in this
memorandum will be incorporated into the next protocol amendment. Modifications are shown below,
using strikethrough for deletions and bold type for additions.
1. Section 4.1.3.1, ARV-treatment experienced (not including receipt of ARVs as prophylaxis or
PMTCT), the following note is added:
 Currently taking ARVs for treatment but failing:

Must be on an unchanged, failing therapeutic regimen within the 4 to 12 weeks prior to
screening (≤1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening).
NOTE: To meet this criterion, two HIV RNA levels are required: one from a date
between 4-12 weeks prior to study screening and a second one at study screening. The
HIV RNA level at screening must be higher than, equal to or ≤ 1 log lower than the
prior HIV RNA level.
NOTE: Dose adjustments for growth or formula substitutions (i.e. switching from single
agent to fixed dose combination) are permitted during this 4 to 12 week period, sSubstitutions
of one ARV within the same class for toxicity or tolerability management, or discontinuation
Clarification Memorandum #1
IMPAACT P1093 Protocol Version 4.0
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8 December 2016
of ARVs are permitted between the HIV RNA measurements and screening or
enrollment. also allowed within the 4 to 12 weeks period.
2. Section 5.1 Drug Regimens, Stage II, 1st paragraph
Subjects enrolling in Stage II of each of the following eight cohorts will receive the Stage I
approved age and formulation of dolutegravir to be administered orally taken orally once daily
or, twice daily if on EFV, NVP, FPV/r, or TPV/r as part of OBT, dolutegravir will be dosed
twice daily.
3. Section 5.2.2, Dolutegravir Granules for Oral Suspension
1st paragraph
Dolutegravir granules for suspension 1.6 mg/1 mL suspension. When the granules in the bottle are
reconstituted with 73 mL of potable (drinkable) water as directed, each container contains 160 mg
per 100 mL. Once reconstituted, the suspension is stable for 8 12 weeks in the manufacturer’s
container. The reconstituted product should be stored at temperatures up to 30ºC (86ºF). Storage in
a refrigerator is fully acceptable and preferred, if available.
3rd paragraph, 6th sentence
The maximum in-use period of the pediatric formulation after it has been reconstituted with water
is 8 12 weeks and should may be refrigerated or stored at room temperature up to 30ºC (86ºF).
Storage in a refrigerator is fully acceptable and preferred, if available.
3rd paragraph,12th sentence
The reconstituted suspension should be used within 8 12 weeks of the initial reconstitution, but
preferably within a single month.
4. Section 6.2.3.2, Initiation of Dolutegravir and selection of Optimized Background Therapy (OBT),
Stage II, 1st sentence
Stage II: Subjects in cohorts I, II, III and III-DT entering Stage II of the trial will have OBT based
on screening results, and start that regimen simultaneously with DTG. Subjects in cohorts IV, IVDT, V, and V-DT will optimize OBT as soon as genotype results are available (See section
6.2.3.3)
5. Appendix IE, Schedule of Evaluations, Long-term Safety Follow-up for Subjects who Continue to
Receive Dolutegravir (study-provided or locally), header row, Footnotes 2 and 3
Header Row: Every 12 Weeks [Weeks 60, 72, 84, 96, 108, 120, 132, 144, 156, 168,180, and 192
(End of Study Visit)]
2. If determined by the protocol team genotyping may be done at a frequency ≥24 weeks post
virologic failure if HIV-1 RNA is >400 c/mL
2. Genotyping to be done for participants post virologic failure, ONLY if requested to do so
by the protocol team.
Clarification Memorandum #1
IMPAACT P1093 Protocol Version 4.0
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8 December 2016
3. Specimens for genotyping and phenotyping should be obtained and stored at this visit, but
only sent for processing if the confirmatory HIV RNA test at this visit is > 400 c/ml. A
baseline specimen should also be sent with the genotype virologic failure specimen. This
specimen may be a baseline (Day 0 entry) storage sample or left over sample from baseline
genotyping (screening). Please refer to protocol Section 6.2.5 and the Laboratory Processing
Chart (LPC) for additional details.
Clarification Memorandum #1
IMPAACT P1093 Protocol Version 4.0
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8 December 2016