Conditions: HIV Infections
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 57
Healthy volunteers: no

Brief summary:
The purpose of this study was to examine the pharmacokinetics, safety, and tolerability of abacavir/dolutegravir/lamivudine dispersible and immediate release tablets in children living with HIV less than 12 years of age.

Detailed description:
This study examined the pharmacokinetics (PK), safety, and tolerability of fixed-dose combination abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) dispersible and immediate release tablets in children living with HIV less than 12 years of age.

Children were enrolled into one of five ABC/DTG/3TC dosing groups based on their weight. The first 5-7 children within each weight-band underwent intensive PK assessments 5-10 days after starting ABC/DTG/3TC to confirm dose selection. Children remained on their initial dose of ABC/DTG/3TC through Week 4. After Week 4, ABC/DTG/3TC dosing was adjusted based on PK results at the individual or weight-band level, and/or an individual child's growth and weight gain over time.

Follow-up study visits for all participants occurred at Weeks 1, 4, 12, 24, 36, and 48. If participants had a known M184 resistance mutation, they had additional study visits at Weeks 8, 16, and 20. Study visits included physical examination, study drug adherence and tolerability questionnaires, blood collection, and intensive PK sampling. Following the Week 48 study visit, some children were allowed to continue follow-up through up to 144 weeks if alternative post-study drug supply was not yet available.

Arms:
arm 1: Children weighing 6 to less than 10 kg at study entry. These children received 3 dispersible tablets of ABC/DTG/3TC daily while weighing 6-\<10 kg; as their weight increased, they received higher doses consistent with their new weight band. arm 2: Children weighing 10 to less than 14 kg at study entry. These children received 4 dispersible tablets of ABC/DTG/3TC daily while weighing 10-\<14 kg; as their weight increased, they received higher doses consistent with their new weight band. arm 3: Children weighing 14 to less than 20 kg at study entry. These children received 5 dispersible tablets of ABC/DTG/3TC daily while weighing 14-\<20 kg; as their weight increased, they received higher doses consistent with their new weight band. arm 4: Children weighing 20 to less than 25 kg at study entry. These children received 6 dispersible tablets of ABC/DTG/3TC daily while weighing 20-\<25 kg; as their weight increased, they received higher doses consistent with their new weight band. arm 5: Children weighing 25 kg or greater at study entry. These children received 1 immediate release tablet of ABC/DTG/3TC daily.

Interventions: intervention 1: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets intervention 2: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release)
Intervention descriptions: intervention 1: Fixed-dose combination dispersible tablets containing 60 mg ABC, 5 mg DTG, and 30 mg 3TC; administered orally once daily with or without food intervention 2: Fixed-dose combination immediate release tablets containing 600 mg ABC, 50 mg DTG, and 300 mg 3TC; administered orally once daily with or without food

Protocol document:
Prot_000.pdf: 
 
 
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine  
Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
 
 
 
IND#: 141,131 
DAIDS Study ID #38504 
 
 
 
This file contains the current IMPAACT 2019 protocol, 
which is comprised of the following documents, 
presented in reverse chronological order: 
 
• Clarification Memorandum #2, dated 14 August 2020 
• Clarification Memorandum #1, dated 11 June 2020 
• Protocol Version 2.0, dated 4 September 2019 


Clarification Memorandum #2 
Page 1 of 5 
14 August 2020 
IMPAACT 2019 Protocol Version 2.0 
Clarification Memorandum #2 for:  
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of 
Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, dated 4 September 2019 
 
DAIDS Study ID #38504 
IND #141,131 
 
Clarification Memorandum Date: 14 August 2020 
 
 
 
Table of Contents 
 
Summary of Clarifications ............................................................................................................................ 1 
Implementation ............................................................................................................................................. 2 
A. Addition of Protocol Appendix VII ........................................................................................................ 2 
B. Protocol Team Roster Updates ............................................................................................................... 4 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) is being issued to safeguard the health and well-being of 
IMPAACT 2019 study participants in the context of circulating severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19).  
 
As the study Sponsor, the Division of AIDS (DAIDS) has determined that this CM should be 
implemented immediately upon issuance. Consistent with United States Food and Drug Administration 
guidance, institutional review board/ethics committee (IRB/EC) approval of this CM is not required by 
the Division of AIDS prior to implementation. However, given the context of COVID-19 and the 
importance of the guidance provided in this CM, sites should submit this CM to IRBs/ECs for their 
information or, if required by the IRBs/ECs, for their review and approval.  
 
The purpose of this CM is to provide operational flexibility for conducting study visits and procedures 
when needed to ensure ongoing access to study drug and to prioritize the conduct of clinically and 
scientifically important evaluations. The CM also updates the Protocol Team Roster. 
 
Please file this CM and any applicable IRB/EC correspondence in your essential document files for 
IMPAACT 2019. 
 
 
 
 


Clarification Memorandum #2 
Page 2 of 5 
14 August 2020 
IMPAACT 2019 Protocol Version 2.0 
Implementation 
 
This CM provides operational guidance to study sites from the IMPAACT 2019 Protocol Team. This 
guidance is provided in a new protocol appendix, Appendix VII, as shown in Section A. This guidance to 
be followed at sites experiencing operational disruptions due to COVID-19. Sites should continue to 
follow protocol specifications for communication with the Protocol Team and/or Clinical Management 
Committee (CMC) and should contact the CMC (impaact.2019cmc@fstrf.org) with any questions or 
concerns regarding this CM or the management of study participants. 
 
This CM also updates the Protocol Team Roster, as shown in Section B. 
 
 
A. Addition of Protocol Appendix VII  
 
Appendix VII 
Guidance for Study Implementation at Sites Experiencing Operational Disruptions Due to COVID-19 
 
To safeguard the health and well-being of study participants in the context of circulating SARS-CoV-2 
and the associated coronavirus disease 2019 (COVID-19), the guidance provided in this appendix may be 
implemented at sites experiencing operational disruptions due to COVID-19.  
 
The extent to which site operations may be disrupted by COVID-19 may vary across sites and over time. 
All sites should follow applicable government, health authority, and institutional policies with 
respect to conduct of study visits and procedures, with utmost importance placed on the health and 
well-being of study participants and study staff. All sites must also comply with any directives 
received from the study sponsor, the IMPAACT Network, and/or the IMPAACT 2019 Protocol Team. 
Should a determination be made in the future that the guidance provided in this appendix is no longer 
applicable, sites will be formally notified and instructed to inform their IRBs/ECs and other applicable 
regulatory entities. 
 
Visit Scheduling 
• 
Sites are advised that potential participants who are screened for the study should only be enrolled if 
the site investigator has confidence that local conditions will allow for, at a minimum, the Week 1 and 
Week 4 Visits to be conducted in-person at the study site. For participants who will be undergoing 
intensive PK evaluations at the Week 1 Visit, the site investigator should also have confidence that 
directly observed dosing can be performed and that intensive PK samples can be collected, processed, 
and shipped consistent with protocol Section 6 and relevant sections of the study-specific Manual of 
Procedures and Laboratory Processing Chart. In the absence of such confidence, screening and 
enrollment should not proceed. 
• 
Sites are advised to make use of the allowable visit windows specified in protocol Section 6 when 
scheduling study visits during periods of operational disruption. For example, sites that are able to 
anticipate operational disruptions are advised to conduct study visits early in the allowable visit 
window before the disruption occurs. Visits conducted outside of allowable windows are also 
preferred to missed visits. In the event of a missed visit (i.e., visit not conducted before the allowable 
window closes) or in situations of overlapping windows, the CMC should be contacted for guidance 
on visit completion on a case-by-case basis. 
• 
When visits must be delayed or missed, sites should make every effort to avoid gaps in study drug 
supply (see further guidance for study drug supply below). 
 


Clarification Memorandum #2 
Page 3 of 5 
14 August 2020 
IMPAACT 2019 Protocol Version 2.0 
Prioritization of Study Visit Procedures 
• 
If it is not possible to conduct study visits in-person at the study site, visit procedures may be 
performed off-site or remotely (e.g., by telephone) as described below. Site investigators must ensure 
that standard operating procedures (SOPs) are in place for off-site and remote procedures. These 
SOPs must include feasible options for measurement of participant weight to guide weight-based 
prescribing and dosing of study drug. 
• 
Sites may conduct study visits — in full or in part — off-site if permitted by applicable government, 
health authority, and institutional policies. Where this option is permitted, site staff should 
communicate with participant families to determine in advance where and when such visits will take 
place, with adequate protections for safety, privacy, and confidentiality. Off-site visit procedures 
should be conducted by site staff who are adequately qualified and trained to conduct the procedures, 
as determined by the site investigator, with attention paid to occupational health, biohazard 
containment, and specimen and data chain of custody. These staff should also be adequately qualified 
and trained to immediately assess and/or manage any adverse events or social impacts that may occur 
during the visits. If adverse events requiring further evaluation or management are identified during 
an off-site visit, staff conducting the visit should arrange for appropriate clinical management, in 
consultation with the site investigator as needed.  
• 
As indicated under Visit Scheduling, it is generally expected that Week 1 and Week 4 Visits will be  
conducted in-person at the study site. For subsequent visits, sites with limited capacity to conduct in-
person visits should perform safety evaluations to the extent possible and should prioritize laboratory 
evaluations consistent with protocol Section 6.20.1. If laboratory tests cannot be performed consistent 
with a site’s Protocol Analyte List, the tests may be performed in alternate laboratories using alternate 
assays (alternate laboratories must adhere to local regulations for clinical laboratory testing). Sites 
should identify feasible options for performing pregnancy testing for female participants of 
reproductive potential, including use of home test kits. When necessary: 
- Medical and medication histories may be obtained remotely. 
- Adherence assessment, counseling, and support may be performed remotely.  
- Contraception counseling may be performed remotely. Sites should discuss options for and assist 
with ongoing access to contraception throughout the duration of study participation. 
- Questionnaires may be administered remotely or may be skipped. 
 
Study Drug Supply 
• Sites are advised to maintain frequent communication with participant families (e.g., by telephone) to 
inquire about each participant’s health, use of study drug, and study drug supplies.  
• Study visits are scheduled at Week 1 and Week 4 and then approximately quarterly, with additional 
visits for selected participants. To avoid gaps in study drug supply, sites are encouraged to dispense 
study drug in quantities sufficient for at least three months; quantities sufficient for up to six months 
should be considered at the Week 24 Visit. As noted above, SOPs must be in place to guide weight-
based dosing of study drug; when dose adjustments are needed due to participant growth, site 
investigators must provide appropriate instructions to caregivers and actively follow-up to ensure 
correct understanding and implementation of these instructions.   
• Sites are encouraged to implement study drug dispensing and delivery options involving outdoor pick-
up or drop-off. Sites are also advised that, when other options are not feasible, the Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks permit shipment or courier of study 
drug from the site directly to participants. This method should only be used in the short-term and if 
permissible per local institutional and IRB/EC policies. Refer to the Guidelines for additional details 
on this method. 
 


Clarification Memorandum #2 
Page 4 of 5 
14 August 2020 
IMPAACT 2019 Protocol Version 2.0 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2019.  
• 
Documentation should be entered in participant study charts in real-time (or close to real-time) if any 
of the following occur: 
- Missed visits  
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts  
- Use of alternate laboratories or alternate laboratory assays 
- Alternate provision of study drug  
• 
In consultation with the Division of AIDS, the IMPAACT Network has developed and disseminated 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures due to COVID-19. Please contact the IMPAACT 
Operations Center Clinical Trials Specialists with any questions related to documentation and 
reporting requirements.  
 
 
B. Protocol Team Roster Updates 
 
To reflect current Protocol Team membership, Rohan Hazra, Rajendra Singh, and Dale Dayton are 
removed from the roster (deletions not shown) and the persons listed below are added; Dwight Yin, Sai 
Majji, and Jack Moye are also added to the protocol cover page. 
 
NIAID Medical Officers 
Dwight Yin, MD, MPH 
Maternal Adolescent and Pediatric Research Branch  
Prevention Sciences Program  
DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 8B25  
Rockville, MD 20852 
Phone: 240-292-4791 
Email: dwight.yin@nih.gov 
 
NICHD Medical Officers 
Sai Majji, PhD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
6710B Rockledge Drive, Room 2159C 
Bethesda, MD 20817 
Phone: 301-661-9816 
Email: sai.majji@nih.gov 
 
 
 


Clarification Memorandum #2 
Page 5 of 5 
14 August 2020 
IMPAACT 2019 Protocol Version 2.0 
Jack Moye, MD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
6710B Rockledge Drive, Room 2130  
Bethesda, MD  20817 
Phone: 301-594-8624 
Email: john.moye@nih.hhs.gov 
 
Pharmaceutical Representatives 
Gilda Bontempo, MD 
ViiV Healthcare 
Five Moore Drive 
PO Box 13398 
Mailstop A.2400 
Research Triangle Park, NC 27709 
Phone: (914) 330-6975 
Email: gilda.x.bontempo@viivhealthcare.com  
 
Hardik Chandasana, PhD 
GlaxoSmithKline 
1250 S Collegeville Road 
Collegeville, PA 19426 
Phone: (352) 213-9228 
Email: hardik.x.chandasana@gsk.com  
 
Karen Davis, MS, RN 
GlaxoSmithKline 
1250 S Collegeville Road 
Collegeville, PA 19426 
Phone: 610-917-4588 
Email: karen.m.davis@gsk.com  
 
Laboratory Data Managers 
Lauren Harriff, BS 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: (716) 834-0900 x7348 
Email: harriff@frontierscience.org 
 
Laboratory Technologists 
Amy James Loftis, BSc 
University of North Carolina Global HIV Prevention and Treatment Clinical Trials Unit 
Bioinformatics Building 
130 Mason Farm Road, Suite 2144  
Chapel Hill, NC 27599 
Phone: (919) 966-5462 
E-mail: amy_james@med.unc.edu 


Clarification Memorandum #1 for 
IMPAACT 2019 Protocol Version 2.0  
Page 1 of 2 
11 June 2020 
Clarification Memorandum #1 for:  
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of 
Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, dated 4 September 2019 
 
DAIDS Study ID #38504 
IND #141,131 
 
Clarification Memo Date: 11 June 2020 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) clarifies the types of tests that may be used for confirmation of 
HIV-1 infection in participants who are less than two years of age or have been exposed to breast milk in 
the past 28 days. 
 
 
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 information included in this 
memorandum will be incorporated into the next protocol amendment. 
 
Inclusion criterion 4.1.7 specifies the tests that may be performed to confirm HIV-1 infection prior to 
enrollment in the study. For participants who are less than two years of age, or who have been exposed to 
breast milk in the past 28 days, nucleic acid tests must be used for this purpose. These tests are indicated 
with an asterisk (*) in the protocol text shown below; added protocol text is shown using bold type. 
  
In protocol Section 4.1, Inclusion Criteria 
 
4.1.7 
Confirmed HIV-1-infection based on documented testing of two samples collected at different 
time points: 
 
Sample #1 may be tested using any of the following: 
• 
Two rapid antibody tests from different manufacturers or based on different principles and 
epitopes 
• 
One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR 
chemiluminescence assay 
• 
One HIV DNA polymerase chain reaction (PCR)* 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay)* 
• 
One qualitative HIV RNA PCR* 
• 
One HIV total nucleic acid test* 


Clarification Memorandum #1 for 
IMPAACT 2019 Protocol Version 2.0  
Page 2 of 2 
11 June 2020 
Sample #2 may be tested using any of the following: 
• 
Rapid antibody test. If this option is used in combination with two rapid tests for Sample #1, 
at least one of the three rapid tests must be FDA-approved, and the third rapid test must be 
from a third manufacturer or based on a third principle or epitope. 
• 
One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR 
chemiluminescence assay 
• 
One HIV DNA PCR* 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay)* 
• 
One qualitative HIV RNA PCR* 
• 
One HIV total nucleic acid test* 
 
For participants who are less than two years of age, or who are two years of age and older 
with any exposure to breast milk in the past 28 days, HIV-1 infection must be confirmed 
using the tests indicated above with an asterisk (*) for Sample #1 and Sample #2. 
 
Whole blood, plasma, or serum samples must be tested. If both samples are tested using antibody 
tests, at least one of the samples must be tested in a laboratory that operates according to Good 
Clinical Laboratory Practice guidelines and participates in an appropriate external quality 
assurance program. If nucleic acid testing is used, at least one test must be performed in a Clinical 
Laboratory Improvement Amendments (CLIA) certified (for US sites) or Virology Quality 
Assurance (VQA) certified (for non-US sites) laboratory. For tests performed in other settings, 
adequate source documentation including the date of specimen collection, date of testing, test 
performed, and test result must be available. FDA approved testing methods should be used when 
possible.  
 
 
 


IMPAACT 2019 
 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine  
Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
Study Drug Provided by: 
ViiV Healthcare Ltd 
 
 
 
DAIDS Study ID #38504 
IND #141,131 Held By DAIDS 
 
 
 
Protocol Co-Chairs: 
Patricia Flynn, MD 
 
Helena Rabie, MBChB, MMED, FCPaed 
 
NIAID Medical Officer:  
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer: 
Rohan Hazra, MD 
 
Clinical Trials Specialists: 
Emily Brown, MA  
Anne Coletti, MS 
 
Kathryn Lypen, MPH 
 
 
 
 
 
Final Version 2.0 
4 September 2019


IMPAACT 2019, FINAL Version 2.0    
Page 2 of 139 
4 September 2019 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of 
Abacavir/Dolutegravir/Lamivudine 
Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
TABLE OF CONTENTS 
 
 
ABBREVIATIONS AND ACRONYMS ............................................................................ 6 
PROTOCOL TEAM ROSTER ......................................................................................... 7 
STUDY SITE ROSTER ................................................................................................. 10 
SCHEMA ....................................................................................................................... 13 
1 
INTRODUCTION ................................................................................................ 15 
1.1 
Background ..................................................................................................................................... 15 
1.2 
Prior Research................................................................................................................................. 15 
1.3 
Rationale ......................................................................................................................................... 21 
1.4 
Hypotheses ..................................................................................................................................... 24 
2 
OBJECTIVES ..................................................................................................... 25 
2.1 
Primary Objectives .......................................................................................................................... 25 
2.2 
Secondary Objectives ...................................................................................................................... 25 
2.3 
Exploratory Objectives ..................................................................................................................... 26 
3 
STUDY DESIGN................................................................................................. 26 
3.1 
Overview ......................................................................................................................................... 26 
3.2 
Approach to Dose Confirmation ...................................................................................................... 27 
4 
STUDY POPULATION ....................................................................................... 29 
4.1 
Inclusion Criteria .............................................................................................................................. 29 
4.2 
Exclusion Criteria............................................................................................................................. 32 
4.3 
Co-Enrollment Considerations ......................................................................................................... 33 
4.4 
Recruitment, Screening, and Enrollment Process ........................................................................... 33 
4.5 
Participant Retention ....................................................................................................................... 34 
4.6 
Participant Withdrawal or Termination from the Study .................................................................... 34 
5 
STUDY DRUG .................................................................................................... 35 
5.1 
Study Drug Regimen and Administration ........................................................................................ 35 
5.2 
Study Drug Formulation and Preparation ........................................................................................ 36 
5.3 
Study Drug Supply........................................................................................................................... 38 
5.4 
Study Drug Accountability ............................................................................................................... 39 
5.5 
Final Disposition of Study Drug ....................................................................................................... 39 
5.6 
Study Drug Adherence Assessment and Counseling ...................................................................... 39 
5.7 
Concomitant Medications ................................................................................................................ 39 
6 
STUDY VISITS AND PROCEDURES ................................................................ 40 
6.1 
Screening Visit................................................................................................................................. 42 
6.2 
Entry Visit ........................................................................................................................................ 43 
6.3 
Week 1 Visit .................................................................................................................................... 44 
6.4 
Week 2 Visit .................................................................................................................................... 48 
6.5 
Week 4 Visit .................................................................................................................................... 49 
6.6 
Week 6 Visit .................................................................................................................................... 50 
6.7 
Week 8 Visit .................................................................................................................................... 51 
6.8 
Week 12 Visit .................................................................................................................................. 52 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
6.9 
Week 16 and Week 20 Visits ........................................................................................................... 53 
6.10 
Week 24 Visit .................................................................................................................................. 54 
6.11 
Week 36 Visit .................................................................................................................................. 55 
6.12 
Week 48 Visit .................................................................................................................................. 56 
6.13 
Q12 Week Visits through Week 144 ................................................................................................ 57 
6.14 
Confirmation of Virologic Failure Visit .............................................................................................. 58 
6.15 
Early Discontinuation from Study Visit ............................................................................................. 59 
6.16 
Post Exit Visit for Children on Contraception at Last Study Visit ..................................................... 60 
6.17 
Medical and Medication History ....................................................................................................... 60 
6.18 
Physical Examinations ..................................................................................................................... 62 
6.19 
Questionnaire Evaluations ............................................................................................................... 62 
6.20 
Additional Considerations for Laboratory Procedures ..................................................................... 63 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING .......................... 64 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 64 
7.2 
Safety-Related Data Collection ....................................................................................................... 65 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 66 
8 
PARTICIPANT MANAGEMENT ........................................................................ 67 
8.1 
Management of Adverse Events ..................................................................................................... 67 
8.2 
Criteria for Premature Discontinuation of Study Drug ...................................................................... 72 
8.3 
Monitoring and Management of HIV Viral Load ............................................................................... 72 
8.4 
Management of Tuberculosis .......................................................................................................... 74 
8.5 
Management of Participants with Intensive PK Outcomes Outside the Targeted Range ................ 75 
8.6 
Contraception and Pregnancy ......................................................................................................... 75 
9 
STATISTICAL CONSIDERATIONS ................................................................... 76 
9.1 
General Design Issues .................................................................................................................... 76 
9.2 
Outcome Measures ......................................................................................................................... 77 
9.3 
Randomization and Stratification ..................................................................................................... 78 
9.4 
Sample Size and Accrual ................................................................................................................ 78 
9.5 
Monitoring ........................................................................................................................................ 80 
9.6 
Analyses .......................................................................................................................................... 86 
10 
CLINICAL PHARMACOLOGY PLAN ................................................................ 89 
10.1 
Pharmacology Objectives ................................................................................................................ 89 
10.2 
Pharmacology Outcome Measures ................................................................................................. 90 
10.3 
Pharmacology Study Design, Modeling, and Data Analysis ............................................................ 91 
10.4 
Sample Size Justification ................................................................................................................. 94 
10.5 
PK Analyses .................................................................................................................................... 95 
11 
DATA HANDLING AND RECORD KEEPING ................................................... 97 
11.1 
Data Management Responsibilities ................................................................................................. 97 
11.2 
Essential and Source Documents and Access to Source Data ....................................................... 98 
11.3 
Quality Control and Quality Assurance ............................................................................................ 98 
12 
CLINICAL SITE MONITORING ......................................................................... 98 
13 
HUMAN SUBJECTS PROTECTIONS ............................................................... 99 
13.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................... 99 
13.2 
Vulnerable Participants .................................................................................................................... 99 
13.3 
Informed Consent ............................................................................................................................ 99 
13.4 
Potential Benefits........................................................................................................................... 101 
13.5 
Potential Risks ............................................................................................................................... 101 
13.6 
Reimbursement/Compensation ..................................................................................................... 101 
13.7 
Privacy and Confidentiality ............................................................................................................ 102 
13.8 
Communicable Disease Reporting ................................................................................................ 102 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
13.9 
Management of Incidental Findings ............................................................................................... 102 
13.10 
Management of New Information Pertinent to Study Participation ................................................ 103 
13.11 
Post-Trial Access to Study Drug .................................................................................................... 103 
14 
ADMINISTRATIVE PROCEDURES ................................................................. 103 
14.1 
Regulatory Oversight ..................................................................................................................... 103 
14.2 
Protocol Registration ..................................................................................................................... 104 
14.3 
Study Implementation .................................................................................................................... 104 
14.4 
Protocol Deviation Reporting ......................................................................................................... 104 
14.5 
Critical Event Reporting ................................................................................................................. 105 
14.6 
ClinicalTrials.gov ........................................................................................................................... 105 
15 
PUBLICATIONS............................................................................................... 105 
16 
REFERENCES ................................................................................................. 105 
Appendix I: Schedule of Evaluations through Week 48 ......................................................... 109 
Appendix II: Sample Informed Consent Form for Study Participation ...................................... 112 
Appendix III: Sample Informed Consent Form for Specimen Storage and Future Use ................ 128 
Appendix IV: Sample Informed Assent Form for Study Participation ....................................... 132 
Appendix V: Sample Assent Form for Specimen Storage and Future Use ................................ 135 
 
 
LIST OF TABLES 
 
Table 1. Adult Clinical Trials of DTG Film-Coated Tablets ...................................................................... 16 
Table 2. DTG Pharmacokinetics by Age or Weight and Formulation in IMPAACT P1093 and ODYSSEY
 .................................................................................................................................................................... 17 
Table 3. Predicted Once-Daily ABC and 3TC Exposures in Children Using WHO Dosing Nomogram .. 20 
Table 4. Weight Band and Individual AUC0-24h and C24h Targets Based on Adult Exposure Data ............ 22 
Table 5. Weight Band AUC0-24h Targets Based on Pediatric Exposure Data.............................................. 23 
Table 6. IMPAACT 2019 Weight Band Dosing of Study Drug ................................................................. 27 
Table 7. IMPAACT 2019 Study Drug Regimen and Administration ......................................................... 35 
Table 8. Dispersion Volumes for ABC/DTG/3TC Dispersible Tablets...................................................... 37 
Table 9. Alternate Dispersion Volumes for ABC/DTG/3TC Dispersible Tablets ...................................... 37 
Table 10. IMPAACT 2019 Documentation Requirements for Medical and Medication Histories ............ 60 
Table 11. General Guidelines for Adverse Event Management in IMPAACT 2019 ................................. 68 
Table 12. Second Daily Dose of DTG for Children in IMPAACT 2019 Who Require Rifampin-
Containing TB Treatment ........................................................................................................................... 74 
Table 13. Percent of Participants Experiencing Grade 3 or Higher Adverse Events with Exact 95% CIs . 79 
Table 14. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity ....................... 84 
Table 15. AUC0-24h and C24h Targets for Each Weight Band in IMPAACT 2019 ...................................... 91 
Table 16. IMPAACT 2019 Sparse PK Sampling Schedule ........................................................................ 94 
Table 17. Power Estimates for Total and Individual Weight Band Sample Sizes ...................................... 95 
 
 
 
 


IMPAACT 2019, FINAL Version 2.0    
Page 5 of 139 
4 September 2019 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine  
Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
 
DAIDS Study ID #38504 
 
 
Version 2.0 
Protocol Signature Page 
 
 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine  
Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
ABBREVIATIONS AND ACRONYMS 
3TC 
Lamivudine 
AE 
Adverse event  
ABC 
Abacavir 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine transaminase 
APR 
Antiretroviral Pregnancy Registry 
ART  
Antiretroviral therapy 
ARV  
Antiretroviral 
AST 
Aspartate aminotransferase 
AUC0-24h 
 Area under the plasma concentration-time curve from time 0 to 24 hours 
C24h 
Concentration at 24 hours post-dose 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CRF  
Case report form 
Cmax 
Maximum concentration 
DAIDS 
Division of AIDS  
DAERS 
DAIDS Adverse Event Reporting System 
DBS  
Dried blood spot 
DTG 
Dolutegravir 
EC 
Ethics committee 
eCRF  
Electronic case report form 
FDA 
United States Food and Drug Administration 
HIV 
Human Immunodeficiency Virus 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB  
Institutional review board 
INSTI 
Integrase strand inhibitor 
LPC 
Laboratory processing chart 
MOP 
Manual of procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NRTI 
Nucleoside/nucleotide reverse transcriptase inhibitors 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
PI 
Protease inhibitor  
PID 
Participant identification number 
PIP 
Paediatric Investigative Plan 
PBMC 
Peripheral blood mononuclear cell 
PSP 
Pediatric Study Plan 
RBC 
Red blood cell 
SES 
Subject Enrollment System 
SOP 
Standard operating procedure 
US 
United States 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability 
of Abacavir/Dolutegravir/Lamivudine 
Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chair 
Patricia Flynn, MD 
Department of Infectious Diseases  
St. Jude Children’s Research Hospital  
262 Danny Thomas Place 
MS 282  
Memphis, TN 38105 
Phone: 901-595-4662 
Email: Pat.Flynn@stjude.org  
 
Protocol Co-Chair 
Helena Rabie, MBChB, MMED, FCPaed 
Stellenbosch University 
Department of Pediatrics and Child Health 
Francie Van Zijl Drive, Parow Valley,  
Cape Town, South Africa 
Phone: +27 21 938 4292 
Email: hrabie@sun.ac.za 
 
Protocol Vice Chair and Pharmacologist 
Jennifer Kiser, PharmD, PhD  
University of Colorado Skaggs School of 
Pharmacy and Pharmaceutical Sciences 12850 E 
Montview Blvd, V20-C238  
Aurora, CO 80045  
Phone: 303-724-6131 or (303) 724-6132  
Email: jennifer.kiser@cuanschutz.edu 
 
Protocol Pharmacologist 
Kristina Brooks, PharmD 
University of Colorado Skaggs School of 
Pharmacy and Pharmaceutical Sciences 
12850 E Montview Blvd, Room V20-4107  
Aurora, CO 80045 
Phone: 303-724-0395 
Email: kristina.brooks@cuanschutz.edu 
 
Clinical Trials Specialists 
Emily Brown, MA 
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040, x11123 
Email: embrown@fhi360.org 
 
Anne Coletti, MS  
IMPAACT Operations Center 
FHI 360  
359 Blackwell Street, Suite 200  
Durham, NC 22701 
Phone: 919-544-7040 x11238  
Email: acoletti@fhi360.org 
 
Kathryn Lypen, MPH 
IMPAACT Operations Center  
FHI 360  
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040, x11684 
Email: klypen@fhi360.org 
 
NIAID Medical Officer 
Ellen Townley, MSN, FNP 
Maternal Adolescent Pediatric Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane, Rm 8B37 
Rockville, MD 20852-9831 
Phone: 240-292-4784 
Email: ellen.townley@nih.gov 
 
NICHD Medical Officer 
Rohan Hazra, MD 
Maternal and Pediatric Infectious Disease 
Branch 
Eunice Kennedy Shriver National Institute for 
Child Health and Human Development 
National Institutes of Health 
6710B Rockledge Drive, Room 2113 
Bethesda, MD 20892 
Phone: 301-435-6868 
E-mail: hazrar@mail.nih.gov 


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4 September 2019 
Protocol Pharmacists 
Kelly Parsons, PharmD 
PAB, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E15 
Rockville, MD 20852 
Phone: 240-669-5721 
Email: kelly.parsons@nih.gov 
 
Lynette Purdue, PharmD 
PAB, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9E28 
Rockville, MD 20852 
Phone: 240-627-3061 
Email: lpurdue@niaid.nih.gov 
 
Protocol Statisticians 
Kathryn Gray, PhD 
Center for Biostatistics in AIDS Research 
Harvard TH Chan School of Public Health and 
Frontier Science Foundation 
1371 Beacon Street, Suite 203 
Brookline MA 02446 
Phone: 617-632-2000 x4000 
Email: kgray@sdac.harvard.edu 
 
Pearl Samson, MS 
Center for Biostatistics in AIDS Research 
Harvard TH Chan School of Public Health and 
Frontier Science Foundation 
1371 Beacon Street, Suite 203 
Brookline MA 02446 
Phone: 617-632-2000 x4030 
Email: psamson@sdac.harvard.edu 
 
Yan Wang, MS 
Center for Biostatistics in AIDS Research 
Harvard TH Chan School of Public Health and 
Frontier Science Foundation 
1371 Beacon Street, Suite 203 
Brookline MA 02446 
Phone: 716-834-0900 x7215 
Email: ywang@sdac.harvard.edu 
 
 
 
 
 
 
 
 
Pharmaceutical Representatives 
Annie Buchanan, MD, MPH 
Dolutegravir Pediatric Program 
ViiV Healthcare 
Five Moore Drive 
PO Box 13398 
Mailstop A.2400 
Research Triangle Park, NC 27709 
Phone: 919-906-4969 
Email: ann.m.buchanan@viivhealthcare.com 
 
Cindy Brothers 
Dolutegravir Pediatric Program  
ViiV Healthcare 
5 Moore Drive 
Research Triangle Park, NC 27709 
Phone: 919-414-1184 
Email: cindy.h.brothers@viivhealthcare.com 
 
Judy Hopking, MsC 
Statistics, Programming and Data Strategy  
GlaxoSmithKline 
Stockley Park West, 1-3 Ironbridge Road  
Uxbridge, Middlesex, UB11 1BT 
United Kingdom 
Phone: +44 0145 329 7423  
Email: judy.x.hopking@gsk.com 
 
Michael McKenna, MBChB 
Safety Evaluation and Risk Management   
GlaxoSmithKline 
Stockley Park West, 1-3 Ironbridge Road, 
Uxbridge, Middlesex, UB11 1BT 
United Kingdom 
Email: michael.8.mckenna@gsk.com 
Phone: +44 7557 290 283 
 
Rajendra Singh 
RD Projects Clinical Platforms & Sciences 
GlaxoSmithKline 
709 Swedeland Road 
King of Prussia, PA 19406 
Phone: 610-270-6863 
Email: rajendra.8.singh@gsk.com 
 
 
 
 
 
 


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Protocol Data Managers 
Barbara Heckman, BS  
Frontier Science and Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7231  
Email: bheckman@frontierscience.org 
 
Lindsey Miller, PhD 
Frontier Science and Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7374 
Email: lmiller@frontierscience.org 
 
Laboratory Data Manager 
Mark Lojacono, MA, MSc 
Frontier Science and Technology Research 
Foundation (FSTRF) 
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7346 
Email: lojacono@frontierscience.org 
 
Laboratory Center Representative 
Dale Dayton, RN, CCRA 
University of California Los Angeles 
MacDonald Research Laboratories 
675 Charles E Young Drive South 
Los Angeles, CA 90095 
Phone: 301-742-9077 
Email: ddayton@impaactlabcenter.org  
 
Rose Lagattuta, BS, CLS 
University of California Los Angeles 
11075 Santa Monica Boulevard, Suite 200 
Los Angeles, CA 90025 
Phone: 310-794-9979 
Email: RLagattuta@milabcentral.org 
 
Laboratory Technologist 
Bernadette Malunda, HBS, DMLS 
Harare Family Care Clinic 
Parirenyatwa, Harare 
Zimbabwe 
Phone +263 772 807 167 
Email: bmalunda@uzchs-ctu.org 
 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability 
of Abacavir/Dolutegravir/Lamivudine 
Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
STUDY SITE ROSTER 
 
Site 4001, Lurie Children’s Hospital of Chicago 
Lurie Children’s Hospital 
225 East Chicago Ave. Box 155 
Chicago IL 60611-2605 
 
Ellen Chadwick, MD 
Investigator of Record 
Phone: 312-227-4080 
Email: echadwick@luriechildrens.org 
 
Margaret Ann Sanders 
Study Coordinator 
Phone: 312-227-8275 
Email: msanders@luriechildrens.org 
 
Site 4201 Pediatric Perinatal HIV Clinical Trials 
Unit 
University of Miami School of Medicine 
Pediatric Infectious Diseases and Immunology 
Batchelor Children's Research Institute 
1580 N.W. 10th Ave., Suite 286 
Miami, FL 33136 
United States 
 
Gwendolyn B. Scott, MD 
Investigator of Record 
Phone: 305-243-6522 
Email: gscott@med.miami.edu 
 
Grace A. Alvarez, FMD/MPH 
Study Coordinator 
Phone: 305-243-4447 
Email: galvarez2@miami.edu 
 
 
 
 
 
 
 
 
 
Site 5052, University of Colorado Denver 
NICHD CRS 
University of Colorado Denver 
Department of Pediatrics 
13123 E. 16th Ave. B055 
Aurora, CO, 80045 
United States 
 
Lisa Abuogi, MD, MSc 
Investigator of Record 
Phone: 303-358-5061  
Email: lisa.abuogi@ucdenver.edu 
 
Emily Barr 
Study Coordinator 
Phone: 720-777-6752 
Email: emily.barr@childrenscolorado.org 
 
Site 5083, Rush University Cook County 
Hospital Chicago NICHD CRS 
Rush University – CORE Center 
2020 West Harrison Street 
Chicago, IL, 60612 
United States 
 
Mariam Aziz, MD 
Investigator of Record 
Phone: 312-942-4265 
Email: mariam_aziz@rush.edu 
 
Maureen McNichols, RN, MSN, CCRP 
Study Coordinator 
Phone: 312-572-4541 
Email: Maureen_mcnichols@rush.edu 
 
 
 
 
 
 
 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
Site 5112, David Geffen School of Medicine at 
UCLA NICHD CRS 
10833 Le Conte Avenue, MDCC 22-442 
Los Angeles, CA, 90095-1752 
United States 
 
Jaime G. Deville, MD 
Investigator of Record 
Phone: 310-825-9660 
Email: jdeville@mednet.ucla.edu 
 
Michele Carter, RN 
Study Coordinator 
Phone: 310-206-6369 
Email: mfcarter@mednet.ucla.edu 
Site 5115, Siriraj Hospital, Mahidol University 
NICHD CRS 
Department of Pediatrics 
Faculty of Medicine Siriraj Hospital 
Mahidol University 
2 Wanglang Rd. 
Bangkoknoi, Bangkok, 10700 
Thailand 
 
Kulkanya Chokephaibulkit, MD 
Investigator of Record 
Phone: 66-2-419-5671 
Email: sikch@mahidol.ac.th 
 
Watcharee Lermankul 
Study Coordinator 
Phone: 66-2-419-5695 
Email: watchareeped@gmail.com 
 
Site 5116, Chiangrai Prachanukroh Hospital 
NICHD CRS 
PHPT 
187/10, Changklan Road 
Changklan, Muang 
Chiang Mai, 50100 
Thailand 
 
Pradthana Ounchanum 
Investigator of Record 
Phone: +66 8 5617 3329 
Email: doctorbaiplu@windowslive.com 
 
Tim Cressey 
Study Coordinator 
Phone: +66 8 9634 1672 
Email: tim.cressey@phpt.org 
Site 6501, St. Jude Children’s Research Hospital 
CRS 
262 Danny Thomas Place 
Memphis, TN, 38105-2794 
United States 
 
Patricia Flynn, MD 
Investigator of Record 
Phone: 901-595-4662 
Email: pat.flynn@stjude.org 
 
Jill Utech 
Study Coordinator 
Phone: 901-595-3490  
Email: jill.utech@stjude.org 
 
Site 8051, Wits RHI Shandukani Research 
Centre CRS 
Shandukani Research, Wits RHI, 2nd floor, 
Hillbrow Health Precinct 
Corner Esselen and Klein Street, Hillbrow 
Johannesburg, Gauteng, 2001 
South Africa 
 
Lee Fairlie, MD 
Investigator of Record 
Phone: 27-11-358-5317 
Email: lfairlie@wrhi.ac.za 
 
Hermien Gous, Pharm D 
Study Coordinator 
Phone: 27-11-358-5502 
Email: hgous@wrhi.ac.za 
 
Site 8052, Soweto IMPAACT CRS 
Perinatal HIV Research Unit (PHRU) 
12th Floor, New Nurses Home 
Chris Hani Baragwanath Academic Hospital 
Chris Hani Road, Diepkloof 
Johannesburg, Gauteng, 1862 
South Africa 
 
Avy Violari MD 
Investigator of Record 
Phone: 27-11-989-9703 
Email: violari@mweb.co.za 
 
Nasreen Abrahams MBA., BTech 
Study Coordinator 
Phone: 27-11-989-9742 
Email: abrahamsn@phru.co.za 


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Site 8950, FAM_CRU CRS 
KIDCRU, Ward J8 
Tygerberg Hospital 
Francie Van Zijl Drive 
Parow Valley 
Tygerberg, Western Cape Province, 7505 
South Africa 
 
Mark Cotton, MD 
Investigator of Record 
Phone: 27-21-938-4219 
Email: mcot@sun.ac.za 
 
Joan Coetzee 
Study Coordinator 
Phone: 27-21-938-4157 
Email: joan@sun.ac.za 
 
Site 12701, Gaborone CRS  
Botswana Harvard AIDS Institute Partnership,  
Gaborone Prevention and Treatment Trials Unit 
Plot 2731 Hospital Way, 
Behind Princess Marina Hospital 
Private Bag BO 320 
Gaborone 
Botswana 
 
Gaerolwe R. Masheto, MD 
Investigator of Record 
Phone: 267 397-5999 
Email: gmasheto@bhp.org.bw 
 
Tebogo J. Kakhu, RN, BSN 
Study Coordinator 
Phone: 267 393-1353 
Email: tkakhu@bhp.org.bw 
 
Site 12702, Molepolole CRS 
Botswana Harvard AIDS Institute Partnership 
Molepolole Prevention and Treatment Trials 
Unit 
Scottish Livingstone Hospital 
Molepolole Road 
Molepolole 
Botswana 
 
Gaerolwe R. Masheto, MD 
Investigator of Record 
Phone: 267 397-5999 
Email: gmasheto@bhp.org.bw 
Tebogo J. Kakhu, RN, BSN 
Study Coordinator 
Phone: 267 393-1353 
Email: tkakhu@bhp.org.bw 
 
Site 30300, Umlazi CRS 
1358 Mangosuthu Highway 
Prince Mshiyeni Memorial Hospital 
Umlazi 
Durban-Kwa Zulu Natal 
4066 
South Africa 
 
Kimesh L Naidoo 
Investigator of Record 
Phone: 27-31-260-4350 
Email: naidook9@ukzn.ac.za 
 
Vani Chetty  
Study Coordinator 
Phone: 27-31-260-1998 
Email: chettyvi@ukzn.ac.za 
 
Site 31784, CMU HIV Treatment CRS 
Chiang Mai University, Research Institute for 
Health Sciences 
110 Intavaroros Road 
Chiang Mai, 50200 
Thailand 
 
Linda Aurpibul, MD, MPH 
Investigator of Record 
Phone: +66 53 936148 ext. 445 
Email: lindaa@rihes.org 
 
Chintana Khamrong, MSc  
Study Coordinator 
Phone: +66 53 936148 ext. 446 
Email: chintanak@rihes.org 
 
 
 
 
 


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IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine 
Dispersible and Immediate Release Tablets  
in HIV-1-Infected Children Less than 12 Years of Age 
 
SCHEMA 
 
Purpose: 
To assess the pharmacokinetics (PK), safety, and tolerability of fixed 
dose combination abacavir (ABC)/ dolutegravir (DTG)/ lamivudine 
(3TC) in HIV-1-infected children 
 
Design: 
Phase I/II, multi-site, open-label, multiple dose, non-
comparative study 
 
Study Population: 
HIV-1-infected children less than 12 years of age 
 
Sample Size: 
Up to 75 to achieve at least five dose-evaluable participants in each 
weight band and at least 50 participants overall (at least 25 less than six 
years of age and at least 25 six to less than 12 years of age) 
 
Study Drug: 
Dispersible tablets containing 60 mg ABC, 5 mg DTG, and 30 mg 3TC 
and immediate release tablets containing 600 mg ABC, 50 mg DTG, and 
300 mg 3TC, administered for at least 48 weeks and up to 144 weeks in 
weight bands as follows: 
 
 
Weight Band 
Formulation 
(Daily Dose of ABC/DTG/3TC) 
#1 
6 to less than 10 kg 
3 dispersible tablets  
(180/15/90 mg) 
#2 
10 to less than 14 kg 
4 dispersible tablets 
(240/20/120 mg) 
#3 
14 to less than 20 kg 
5 dispersible tablets 
(300/25/150 mg) 
#4 
20 to less than 25 kg 
6 dispersible tablets 
(360/30/180 mg) 
#5 
25 kg or greater 
 
1 immediate release tablet 
(600/50/300 mg) 
 
Study Duration: 
Up to approximately 48 months total. Accrual is expected to require 
approximately 12 months; enrolled children will be followed for at least 
48 and up to 144 weeks. 
 
Primary Objectives 
• 
To determine the steady-state AUC0-24h, Cmax, and C24h of ABC, DTG, and 3TC and confirm the 
dosing of ABC/DTG/3TC dispersible and immediate release tablets that achieves protocol-defined 
PK targets for ABC, DTG, and 3TC in children less than 12 years of age 
• 
To evaluate the safety profile of 24 weeks of treatment with ABC/DTG/3TC dispersible tablets and 
ABC/DTG/3TC immediate release tablets among children less than 12 years of age 
 


IMPAACT 2019, FINAL Version 2.0    
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4 September 2019 
Secondary Objectives 
• 
To determine the PK of ABC, DTG, and 3TC, and the clinical covariates that influence PK 
disposition, among children less than 12 years of age using population PK analysis of intensive and 
sparse PK samples collected over 48 weeks of treatment with ABC/DTG/3TC dispersible and 
immediate release tablets 
• 
To evaluate the safety profile of 48 weeks, and additionally up to 144 weeks, of treatment with 
ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets among children less 
than 12 years of age 
• 
To evaluate virologic and immunologic responses at 4, 24, and 48 weeks, and additionally up to 144 
weeks, of treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release 
tablets among children less than 12 years of age 
• 
To evaluate changes in lipid profiles at 24 and 48 weeks of treatment with ABC/DTG/3TC dispersible 
tablets and ABC/DTG/3TC immediate release tablets among children less than 12 years of age 
• 
To evaluate adherence to and palatability and acceptability of ABC/DTG/3TC dispersible tablets and 
ABC/DTG/3TC immediate release tablets among children less than 12 years of age at 4, 24 and 48 
weeks of treatment 
• 
To evaluate HIV-1 genotypes and phenotypes among children less than 12 years of age who 
experience virologic failure while receiving treatment with ABC/DTG/3TC dispersible tablets or 
ABC/DTG/3TC immediate release tablets 
 
Exploratory Objectives 
• 
To describe central nervous system effects, including sleep and behavioral changes, that may occur 
over 24 weeks of treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate 
release tablets among children less than 12 years of age  
• 
To describe pharmacogenetic associations among children less than 12 years of age receiving 
treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets  
• 
To determine concentrations of phosphorylated ABC and 3TC anabolites in PBMCs and DBS over 48 
weeks of treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release 
tablets among children less than 12 years of age 
• 
To examine relationships between PK-based adherence measures and other adherence measures 
 
 
 
 


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1 
INTRODUCTION  
 
1.1 
Background  
 
Three drug therapy consisting of two nucleoside/nucleotide reverse transcriptase inhibitors 
(NRTI) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), 
or an integrase strand transfer inhibitor (INSTI) is the standard of care worldwide for the 
treatment of HIV-1 infection across the age spectrum (1-3). Many factors including patient age, 
co-morbidities, antiretroviral (ARV) safety, dosing recommendation, drug-drug interactions, prior 
ARV exposure and viral resistance are considered when selecting a HIV-1 treatment regimen. 
INSTIs block the integrase enzyme, and in so doing prevent the integration of viral genome into 
the host cell. Raltegravir was the first INSTI approved in the United States (US) in 2007. Since 
then, three additional INSTIs — elvitegravir (EVG; approved by the US Food and Drug 
Administration (FDA) in 2012), dolutegravir (DTG; approved by the FDA in 2014), and 
bictegravir (BIC; approved by the FDA in 2018) — have been marketed. Based on their potency, 
safety profile and lack of drug-drug interactions, INSTIs are currently recommended as part of 
preferred or alternative regimens for adults, children, and infants (from birth). DTG can be 
administered once daily without boosting and has a higher genetic barrier to resistance than RAL 
and EVG (4). The availability of a once daily immediate release tablet containing DTG, abacavir 
(ABC) and lamivudine (3TC) has resulted in increasing popularity of the regimen.  
 
DTG is currently available in three formulations: a single agent film-coated tablet containing 10 
mg, 25 mg, or 50 mg marketed in the US and European Union as Tivicay®; a fixed dose 
combination immediate release tablet containing DTG (50 mg), ABC (600 mg), and 3TC (300 
mg) marketed as Triumeq®, and a fixed dose combination tablet containing DTG (50 mg) and 
rilpivirine (25 mg) marketed as Juluca®. A 5 mg dispersible tablet is currently being evaluated 
for pediatric use in other studies. This study, IMPAACT 2019, will evaluate two fixed dose 
combination formulations of DTG, ABC, and 3TC for pediatric use, a dispersible tablet 
formulation and the immediate release tablet formulation marketed as Triumeq®. The objectives 
and design of this study correspond with ViiV Healthcare Ltd’s currently agreed Paediatric 
Investigation Plan (PIP; dated 23 June 2017) and Pediatric Study Plan (PSP; dated 9 November 
2017). 
 
1.2 
Prior Research 
 
1.2.1 
Efficacy and Safety of DTG in Adults 
 
Three large clinical trials support the efficacy and safety of DTG in HIV-1 infected adults. The 
design and key findings of these trials are summarized in Table 1. In all three trials, DTG was 
well-tolerated; the most common adverse events involved headache, fatigue, and insomnia, all of 
which were reported in less than 3% of participants.  
 
 
 
 


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4 September 2019 
Table 1. Adult Clinical Trials of DTG Film-Coated Tablets 
 
SPRING-25 
SINGLE6,7 
FLAMINGO8-10 
DTG-Based 
Regimen 
DTG 50 mg once daily + 
(ABC/3TC or TDF/FTC) 
DTG 50 mg once daily + 
ABC/3TC 
DTG 50 mg once daily + 
(ABC/3TC or TDF/FTC) 
Comparator ARV 
Regimen 
RAL 400 mg twice daily 
+ (ABC/3TC or 
TDF/FTC) 
EFV 600 mg + TDF/FTC 
once daily 
DRV/r 800/100 once 
daily + (ABC/3TC or 
TDF/FTC) 
Sample Size  
822 
833 
484 
Duration 
96 weeks 
144 weeks 
96 weeks 
Key Findings 
DTG non-inferior to RAL 
DTG regimen superior to 
EFV regimen at 48 and 
144 weeks. Time to viral 
suppression shorter and 
discontinuation of 
regimen for toxicity less 
frequent with DTG 
regimen. 
DTG non-inferior to 
DRV/r at 48 weeks and 
superior at 96 weeks 
ABC = abacavir, ARV = antiretroviral, DC = discontinuation, DRV/r – darunavir boosted with ritonavir, DTG = dolutegravir, EFV = 
efavirenz, FTC = emtricitabine, RAL = raltegravir, TDF = tenofovir disoproxil fumarate, 3TC = lamivudine 
 
1.2.2 
PK and Safety of DTG in Pediatric Populations 
 
IMPAACT P1093 (NCT01302847) is a Phase I/II, multi-center, open-label study of the 
pharmacokinetics (PK), safety, tolerability, and antiviral activity of DTG in combination 
regimens among HIV-1 infected infants, children, and adolescents. In Stage I of this study, a dose 
of DTG is studied among ten children with intensive PK and four weeks of safety data. If 
exposures and safety data are acceptable, Stage II enrollment begins and additional participants 
are evaluated over 48 weeks of follow-up. The study’s PK targets are specified to achieve a 
concentration-time profile similar to that observed in adults at the approved dose of 50 mg daily.  
 
Data from IMPAACT P1093 have led to FDA-approved dosing with DTG film-coated tablets for 
children weighing at least 30 kg (35 mg or 50 mg once daily based on weight). Doses of 20 mg, 
25 mg, and 35 mg daily have been approved by the European Medicines Agency (EMA) for 
children at least six years of age weighing at least 15 kg (based on age and weight) (5). Pediatric 
friendly dosing options for younger children who are unable to swallow film-coated tablets — 
granules for suspension and dispersible tablets — have also been evaluated in IMPAACT P1093. 
PK data currently available from IMPAACT P1093 for all three formulations are presented in 
Table 2. The granule formulation has been phased out of development, with regulatory approval 
planned to be sought for the dispersible tablet formulation.  
 
In addition to IMPAACT P1093, PENTA’s ODYSSEY study (NCT02259127) is also evaluating 
DTG-based ART in children. This study includes two groups of children, those ART-naïve and 
those in need of second line ART. Participants are randomized to initiate or switch to a regimen 
containing DTG tablets or to receive standard of care ART with a boosted PI, an NNRTI, or 
another INSTI. The study also includes two PK sub-studies of DTG film coated tablets for weight 
bands from 14 kg to less than 40 kg. WB-PK1 is examining the PK of DTG in children weighing 
3 kg to less than 25 kg according to WHO weight bands. WB-PK2 is a crossover study examining 
the PK of DTG in children weighing 25 kg to less than 40 kg switching to the 50 mg film-coated 
tablet (6). Available results are summarized in Table 2.  
 


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Table 2. DTG Pharmacokinetics by Age or Weight and Formulation in IMPAACT P1093 and ODYSSEY 
Cohort 
n 
Formulation 
Age or 
Weight 
Dose 
(mg/kg) 
Cmax 
(µg/mL) 
C24h 
(µg/mL) 
AUC0-24h 
(µg*hr/mL) 
IMPAACT P1093 
I 
10 
Film Coated 
Tablet 
≥12 to <18 yrs 
0.88 
[0.55, 1.09] 
3.49 [38] 
0.902 [59] 
45.97 [43] 
IIA  
11 
Film Coated 
Tablet 
≥6 to <12 yrs 
1.09 
[0.93, 1.25] 
3.96 [50] 
0.926 [89] 
50.46 [64] 
IIB 
11 
Granules 
0.93 
[0.78, 1.06] 
4.95 [30] 
0.643 [77] 
53.62 [47] 
III 
10 
Granules 
≥2 to <6 yrs 
0.84 
[0.58, 1.06] 
4.41 [32] 
0.507 [55] 
44.68 [37] 
III-DT 
10 
Dispersible 
Tablet 
1.07 
[0.80, 1.55] 
3.94 [31] 
0.461 [59] 
40.49 [36] 
IV 
7 
Granules 
≥6 mos to  
<2 yrs 
1.35 
[1.02, 1.56]  4.99 [33] 
0.567 [48] 
53.47 [36] 
IV-DT 
10 
Dispersible 
Tablet 
1.21 
[1.02, 1.40] 
4.40 [27] 
0.711 [60] 
50.52 [38] 
V-DT 
10 
Dispersible 
Tablet 
≥4 wks to  
<6 mos 
1.17 
[0.88, 1.68] 
4.46 [38] 
1.207 [55] 
61.20 [44] 
ODYSSEY 
WB-PK1 
14 
Film Coated 
Tablet 
20 to <25 kg 
1.1 
[1.0, 1.2] 
3.20 [40] 
0.32 [94] 
30.1 [41] 
WB-PK1 
8 
Dispersible 
Tablet 
20 to <25 kg 
1.4  
[1.3, 1.5] 
7.42 [25] 
0.71 [74] 
71.8 [28] 
WB-PK1 
7 
Film Coated 
Tablet 
20 to <25 kg 
2.2 
[2.0, 2.4] 
6.07 [29] 
0.77 [51] 
62.8 [30] 
WB-PK2 
9 
Film Coated 
Tablet 
30 to <40 kg 
1.1 
[0.9, 1.2] 
3.98 [28] 
0.45 [63] 
40.3 [35] 
10 
Film Coated 
Tablet 
30 to <40 kg 
1.5 
[1.3, 1.7] 
5.22 [25] 
0.63 [49] 
53.5 [32] 
17 
Film Coated 
Tablet 
25 to <30 kg 
0.9 
[0.8, 1.0] 
3.16 [24] 
0.38 [48] 
33.1 [23] 
16 
Film Coated 
Tablet 
25 to <30 kg 
1.8 
[1.6, 2.0] 
5.41 [25] 
0.75 [42] 
58.7 [27] 
PK parameters are presented as Geometric mean [%CV];  
Dose is presented as Geometric mean [min, max]  
 
 
 


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Based on adult data, the initial dose of the granules studied in IMPAACT P1093 for children two 
to less than six years was approximately 0.8 mg/kg. The C24h was below the target (0.51 µg/mL 
with target minimum of 0.77 µg/mL) but above the pharmacodynamic threshold of approximately 
0.3 µg/mL reported in adults (7). In bioavailability studies of the granules for suspension in 
adults, plasma DTG exposure exceeded that of the tablet formulation by 55-83% regardless of the 
type of fluid suspended in or administration directly into the mouth (8).  
 
ODYSSEY also identified challenges with achieving target trough concentrations in children, 
resulting in additional studies to assess the use of 50 mg adult dose in children weighing at least 
25 kg. A recent PK sub-study in children weighing 20 to less than 25 kg demonstrated similar 
AUC and trough concentrations with both DTG 30 mg dispersible tablets and DTG 50 mg film-
coated tablets (6). Exposures for both formulations were within the range of exposures measured 
in adults receiving DTG 50 mg once or twice daily. Trough concentrations were also comparable 
to historical data in adults and were markedly higher than trough concentrations with the 25 mg 
film-coated tablets in children weighing 20 to less than 25 kg. However, peak concentrations in 
children with the 50 mg film-coated tablet were ~12-82% higher than those measured in adults on 
DTG 50 mg once or twice daily. In children receiving 30 mg dispersible tablets, peak 
concentrations were 37-122% higher than historical data. Children in both groups were followed 
for a median of 12-13 weeks, and no drug discontinuations or serious adverse events occurred 
during this period. 
 
The PK of a dispersible tablet formulation, developed as an alternative to the granule for 
suspension formulation, has also been evaluated in an adult study. The DTG dispersible tablet 
showed equivalent exposures compared to the granule formulation following oral administration 
in adults, indicating these two formulations are interchangeable (9).  
 
An additional relative bioavailability study in adults compared single doses of the immediate 
release ABC/DTG/3TC (Triumeq®) formulation with the dispersible tablet formulation as a 
dispersion or directly to mouth, and to dispersible DTG with 3TC alone using a four-period 
crossover design. DTG exposures with the dispersible ABC/DTG/3TC tablet were 65% higher 
when dispersed in water compared to the immediate release ABC/DTG/3TC tablet. When 
dispersible ABC/DTG/3TC tablets were administered direct-to-mouth, DTG exposures were 25% 
higher compared to the immediate release ABC/DTG/3TC tablet. ABC and 3TC exposures were 
bioequivalent to the immediate release ABC/DTG/3TC tablet whether administered as a 
dispersion or direct-to-mouth (10).  
 
1.2.3 
DTG in Pregnancy  
 
In May of 2018, a preliminary analysis of the Tsepamo study, a large observational study of 
pregnant women in Botswana, showed an increased rate of neural tube defects (NTDs) among 
infants born to women who were taking DTG at the time of conception (11-13). This analysis 
included data collected between 15 August 2014 and 1 May 2018. Among women taking DTG at 
conception, the prevalence of NTDs was 0.94% (95% CI 0.37%, 2.4%) compared to 0.12% (95% 
CI 0.07%, 0.21%) among women taking a non-DTG-containing regimen. This signal had not 
been seen in other post marketing surveillance (14). The Tsepamo study was expanded from eight 
to eighteen sites in 2018, and additional results were reported in July 2019 (15, 16). From August 
2014 through March 2019, surveillance captured 119,477 deliveries. The prevalence of NTD 
among women taking DTG at conception (0.30%, 95% CI 0.13%, 0.69%) remained higher than 
among women taking a non-DTG-containing regimen at conception (0.10%, 95% CI 0.06%, 
0.17%). Although the prevalence of NTDs appears to be slightly higher among women taking 
DTG at conception, the WHO has noted that the absolute risk is very low and has re-confirmed 


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their recommendation for use of DTG-containing regimens as preferred for first- and second-line 
ART across all populations, including pregnant women  (17). Ongoing surveillance will continue 
to inform these recommendations. 
 
 
1.2.4 
ABC/3TC in Pediatric Populations 
 
ABC and 3TC form the backbone of several recommended ART regimens. These medications are 
available separately in tablet and liquid formulations and have also been co-formulated in fixed 
dose combination tablets (ABC/3TC). Currently, ABC and 3TC are approved for use in children, 
ABC from three months of age and 3TC from birth. ABC and 3TC were initially approved for 
pediatric use in 1997 and 1998, respectively, for twice-daily dosing. Support for once-daily 
dosing in this population originated from multiple PK and efficacy studies, primarily PENTA 13 
(18), PENTA 15 (19), and ARROW (20, 21). PENTA 13 examined the PK of once-daily 
ABC/3TC in children 2-12 years of age, and PENTA 15 examined the PK in children 3 to less 
than 36 months of age. ARROW found bioequivalent AUCs between once-daily and twice-daily 
dosing in addition to determining that once-daily dosing was non-inferior to twice-daily dosing 
with regard to virologic suppression and grade 3 and grade 4 adverse events (20).  
 
Efficacy and PK of ABC/3TC  
 
ABC is administered at doses of 16 mg/kg/day (maximum dose of 600 mg/day), and 3TC is 
dosed at 8 mg/kg/day (maximum dose of 300 mg/day) per the FDA-approved dosing nomograms 
for these agents. The WHO weight bands fall in line with this dosing schema, and are expected to 
yield mean AUC24 exposures of ~7.9-13.6 μg∙h/mL for 3TC, and ~13.8-19.4 μg∙h/mL for ABC in 
patients <35 kg based on population PK modeling simulations (see Table 3). Peak absorption of 
ABC occurs 0.6-2.5 hours after oral administration, and between ~1-2 hours with 3TC. The 
plasma half-lives of ABC and 3TC in children are relatively short, at ~1.2 and ~1.5-2 hours, 
respectively. The active moieties of these agents, carbovir-triphosphate and lamivudine-
triphosphate, have longer half-lives of ~14.1 and 17.7 hours, respectively, in PBMCs (22).  
 
Exposure-response analyses with ABC suggest a weak relationship between the PK parameters of 
AUC24 and Ctau and virologic response in HIV-infected adults (23, 24). Carbovir-triphosphate, the 
active ABC moiety, also does not show a relationship between intracellular PBMC levels and 
plasma exposures to the parent drug, though differences in intracellular levels were detected 
between males and females (22). ABC 50% maximal effect (EC50) values against HIV-1 clades 
A-G range from 0.00042 to 0.29 μg/mL (25), with a reported mean of 0.07 μg/mL against clinical 
isolates (26). 
 
Dose-response data for 3TC in pediatrics primarily originated from a study that examined doses 
of 1-20 mg/kg/day divided twice daily for 24 weeks (27). Optimal virologic responses were seen 
at doses above 4 mg/kg/day, though other studies pointed to a concern of pancreatitis at higher 
doses. Collectively, studies in pediatric and adult patients led to doses of ~8 mg/kg/day being 
identified as an optimal target that balanced both therapeutic efficacy and possible safety 
concerns with this agent. Exposure-response data with 3TC have not been published to date. 
However, intracellular levels of lamivudine-triphosphate in PBMCs have been shown to correlate 
with its anti-HIV activity (28). Relationships between antiviral activity and plasma levels of 3TC 
in its parent form were not seen. EC50 values reported for 3TC range between 0.0007 and 0.021 
μg/mL (29). 
 


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Table 3. Predicted Once-Daily ABC and 3TC Exposures in Children Using WHO Dosing Nomogram 
Weight 
Band 
Daily Dose 
(mg/kg) 
AUC0-24h  
(∙μg•h/mL) 
Cmax  
(μg/mL) 
C24h  
(μg/mL) 
ABC  
<14kga 
16.4 
(15.8-17.3) 
13.8a 
(5.3, 34.2) 
5.0 
(2.1, 11.3) 
0.03 
(0.001, 0.22) 
14- <20kg 
17.9 
(15.3-21.2) 
16.9 
(6.3, 42.1) 
6.6 
(2.8, 14.8) 
0.021 
(NQ, 0.18) 
20- <25kg 
20.3 
(18.0-22.5) 
19.9 
(7.5, 49.9) 
7.9 
(3.3, 7.9) 
0.02 
(NQ, 0.13) 
25- <35kg 
18.5 
(11.1-23.7) 
19.3 
(7.1, 50.4) 
7.9 
(3.2, 18.5) 
0.01 
(NQ, 0.13) 
Adult  
600 mg 
9.3 
(4.6, 14.8) 
4.3 
(2.1, 6.0) 
NQ 
(NQ, 0.03) 
3TC  
<14kga 
8.5 
(7.8-9.3) 
7.9 
(4.5, 14.6) 
1.8 
(0.9, 3.4) 
0.05 
(0.02, 0.13) 
14- <20kg 
9.0 
(7.6-10.6) 
11.6 
(6.3, 21.9) 
2.8 
(1.4, 5.4) 
0.05 
(0.02, 0.14) 
20- <25kg 
10.1 
(9.0-11.2) 
13.8 
(7.3, 26.2) 
3.4 
(1.7, 6.4) 
0.05 
(0.02, 0.14) 
25- <35kg 
9.3 
(5.6-11.8) 
13.6 
(7.0, 26.5) 
3.4 
(1.6, 6.7) 
0.05 
(0.02, 0.14) 
Adult  
300 mg 
8.4 
(7.0, 11.7) 
2.0 
(1.3, 3.0) 
0.04  
(0.03, 0.07) 
Table adapted from Clinical Pharmacology Review for Ziagen® (abacavir sulfate) and Epivir® (lamivudine) to support once-daily 
dosing in pediatric populations. Daily dose reported as median (range), PK parameters reported as median (90% CI).  
aLevels with oral solution. 
NQ=not quantifiable. 
 
Safety of ABC/3TC  
 
The most common side effects reported with ABC include nausea, vomiting, diarrhea, headache, 
fever, and rash. Nausea may be an exposure-related effect, particularly AUC and Cmax, based on 
previous dose-finding studies in adults (23, 24). No relationships with other commonly reported 
side effects in these studies were found. Rare but potentially fatal hypersensitivity reactions can 
occur and are associated with the presence of the HLA-B*5701 allele. Other rare but serious side 
effects of ABC include elevated liver transaminases, hyperglycemia, hypertriglyceridemia, lactic 
acidosis, severe hepatomegaly with steatosis, and pancreatitis. 
 
Common side effects of 3TC include headache, nausea, diarrhea, and insomnia. Less common but 
more severe side effects include peripheral neuropathy, lipodystrophy, and elevated liver 
transaminases. Decreases in neutrophil counts by ~30% from baseline were observed in adults at 
doses of 20 mg/kg/day (mean ± SD AUC24h 29.1 ± 9.1 μg∙h/mL) (30). Pancreatitis was also 
reported in pediatric patients in 3TC dose-finding studies, though this finding was also attributed 
to advanced HIV disease and the presence of opportunistic infections associated with an 
increased risk of developing this condition (27). 
 
Available data from the APR show no difference in the overall risk of birth defects for ABC or 
3TC compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta 
Congenital Defects Program reference population (29). 
 


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1.3 
Rationale  
 
1.3.1 
Overall Rationale  
 
To date, DTG has only been studied as a single ARV formulation in children. ABC/DTG/3TC 
(immediate release tablet marketed as Triumeq®) is a safe, effective, and well-tolerated “one pill, 
once daily” regimen approved by the FDA and EMA for use in adults and children weighing at 
least 40 kg (the EMA approval for pediatric use is limited to children at least 12 years of age). 
DTG has rapidly become a “preferred” agent for initial treatment of HIV in adults, and more 
recently, children and adolescents six years of age and older. Much of the safety, PK and dose-
finding evaluation for DTG in children was completed in the ongoing IMPAACT P1093 and 
ODYSSEY studies. Internationally, the WHO supports harmonization of ARV regimens across 
populations including using the same regimen of ARVs in adult and pediatric populations. As 
more experience with INSTIs become available, it is presumed that this drug class will be 
identified as the candidate for a universal regimen for adults, pregnant women and children. To 
facilitate this goal, the safety and PK of dispersible tablet ABC/DTG/3TC in young children must 
be defined.  
 
This Phase I/II study will investigate the PK, safety and tolerability of ABC/DTG/3TC in HIV-
infected children less than 12 years of age. Given that DTG has demonstrated excellent virologic 
activity in P1093 and has an increasing role as initial ARV therapy in adults and older children, 
this study will include both ART-naïve and ART-experienced children. ABC/DTG/3TC will be 
dosed by weight bands across the age spectrum, consistent with the intended future marketing of 
the product. Age-based quotas have been specified to help ensure that adequate PK, safety, and 
tolerability data are collected among children less than six years of age as well as children six 
years of age and older.  
 
Previous experience in adults has demonstrated that the exposure to DTG, ABC and 3TC in a 
fixed dose combination formulation is consistent with each drug administered individually. This 
information was provided as part of the application for Triumeq®. Therefore, the DTG dosing 
recommendations from IMPAACT P1093 are not expected to differ when DTG is administered in 
a fixed dose combination. Nonetheless, a subset of children in each weight band will undergo 
intensive PK approximately one week after initiating ABC/DTG/3TC to evaluate for similar 
exposure to DTG. Population PK will be evaluated among all study participants.  
 
1.3.2 
Rationale for Initial Dose Selection 
 
The DTG doses selected for evaluation in this study are expected to achieve DTG exposures 
similar to those observed with DTG 50 mg twice-daily in adults. The DTG doses are higher than 
those previously evaluated but consistent with doses currently being studied in IMPAACT P1093. 
The higher expected exposures of DTG are due to the coformulation of DTG, ABC, and 3TC in a 
single tablet; whereas the doses of 3TC and ABC increase in sync to each other with body weight, 
the increase is not the same for DTG. Safety data available from adults with higher DTG doses 
and exposures support the DTG doses selected for evaluation in this study (31-33).  
 


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The DTG doses selected for evaluation in this study are specified within weight bands and are 
expected to be applicable to children less than 12 years of age who weigh at least 6 kg. However, 
as of the date of this protocol, limited data are available on DTG dosing for children less than six 
months of age. Additional data from the IMPAACT P1093 and ODYSSEY studies are expected 
to become available for this age group in the near future. When these data become available, the 
IMPAACT 2019 Protocol Team will review them to determine whether the dosing specified for 
this study is appropriate for children less than six months of age. Until this review is conducted, 
accrual into this study will be restricted to children six months of age and older. Once this review 
is conducted, if the Protocol Team determines that the dosing specified for this study is 
appropriate for children less than six months of age, the restriction on accrual will be lifted. If the 
Protocol Team determines that the dosing is not appropriate for children less than six months of 
age, the restriction on accrual will be maintained while alternative dosing and/or other protocol 
modifications are developed for children less than six months of age. Study sites will be notified 
of the outcome of the team’s review and decision-making via email. 
 
The doses of ABC/3TC proposed for use in this study are consistent with WHO recommended 
doses of ~16 mg/kg for ABC and ~8 mg/kg for 3TC in children. Exposures from these doses are 
expected to achieve AUCs similar to those measured in ARROW, PENTA13, and PENTA15, 
which examined the PK and efficacy of once-daily ABC/3TC in pediatric patients. A relative 
bioavailability study is planned to provide reassurance of similar exposures of ABC/3TC with use 
of the dispersible fixed dose combination tablet compared with the marketed immediate release 
fixed dose combination tablet.  
 
1.3.3 
Rationale for PK Targets 
 
A minimum of five children in each weight band will undergo intensive PK sampling with real 
time testing and review of intensive PK outcomes for ABC, DTG, and 3TC to confirm 
appropriate dose selection for each weight band. Dose confirmation for each weight band will be 
based on PK (AUC0-24h for ABC, DTG, and 3TC, in addition to C24h for DTG) and safety 
outcomes. Dose confirmation based on all three agents reflects ViiV’s currently agreed PIP and 
PSP. 
 
As indicated in Table 4 and Table 5, the goal is to achieve the following:  
 
• Geometric mean DTG AUC0-24h between 35.1 and 134 μg∙h/mL  
• Geometric mean DTG C24h between 0.67 and 2.97 μg/mL  
• Geometric mean ABC AUC0-24h between 6.3 and 50.4 μg∙h/mL 
• Geometric mean 3TC AUC0-24h between 6.3 and 26.5 μg∙h/mL  
 
Table 4. Weight Band and Individual AUC0-24h and C24h Targets Based on Adult Exposure Data 
PK 
Parameter 
DTG Values in Adultsa 
 
Weight Band Targets 
 
Individual Targets 
Once-
daily DTG  
Twice-daily 
DTG  
 
Lower 
Bound 
Upper 
Bound 
 
Lower 
Boundb 
Upper 
Bound 
AUC0-24h 
(μg∙h/mL) 
53.6  
(26.9%) 
75.1  
(35.1%) 
 
35.1c 
134d 
 
25.0 
134d 
C24h 
(μg/mL) 
1.11  
(46%) 
2.12  
(47%) 
 
0.67e 
2.97f 
 
0.5 
— 
 aGeometric mean (CV%) value reported in adults bEstimated AUC0-24h and C24h values to produce EC95 cLower 90% CI bound for once-
daily DTG exposures in adults dUpper 90% CI bound for twice-daily DTG exposures in adults eTargets based on 60% of once-daily 
DTG exposures in adults fTargets based on 140% of twice-daily DTG exposures in adults  
 


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Table 5. Weight Band AUC0-24h Targets Based on Pediatric Exposure Data 
ARV 
Agent 
ARROW 
PK results 
(n=35)a 
Predicted AUC0-24h Values by Weight Bandb 
 
Weight Band Targetsc 
14 to <20 kg 
20 to <25 kg 
≥25 kg 
 
Lower 
Bound 
Upper 
Bound 
ABC 
15.3 
(42%) 
16.9 
(6.3, 42.1) 
19.9 
(7.5, 49.9) 
19.3 
(7.1, 50.4) 
 
6.3 
50.4 
3TC 
13.0 
(38%) 
11.6  
(6.3, 21.9) 
13.8 
(7.3, 26.2) 
13.6  
(7.0, 26.5) 
 
6.3 
26.5 
aMean (CV%) values measured in children enrolled in ARROW  bMedian (90% CI) predicted values based on population PK 
modeling of ARROW, PENTA13, PENTA15, and other single-dose PK studies in children  cMinimum lower and maximum upper 
90% CI bounds for predicted once-daily exposures in children  
 
The DTG targets are similar to current targets for IMPAACT P1093. These targets will continue 
to be evaluated and updated if needed based on new findings from P1093. The weight band target 
AUC0-24h target range for DTG is based on the lower and upper bounds of the 90% CIs for once- 
and twice-daily DTG dosing in adults, respectively. The weight band target C24h target range for 
DTG is based on 60% of once-daily geometric mean exposures and 140% of twice-daily 
geometric mean exposures in adults. The ABC and 3TC AUC0-24h targets are based on the 
minimum lower and maximum upper bounds of the 90% CIs for predicted exposures with once-
daily ABC/3TC weight band dosing with the tablet formulation in children (summarized Table 3). 
If the geometric mean AUC0-24h for ABC, DTG, or 3TC and/or C24h for DTG among the dose-
evaluable (refer to Section 3.2) children in each weight band falls outside of the targeted range, 
the Protocol Team will re-evaluate the dose for that weight band using all available PK data from 
this study in addition to PK results from previous and ongoing studies of ABC, DTG, and 3TC. 
Individual dose adjustments may also be performed if a child’s DTG AUC0-24h or C24h falls 
outside of the individual target ranges outlined in Table 5. If a child requires an individual dose 
adjustment, a repeat PK assessment may be performed for that child, with an appropriate 
sampling strategy determined by the Protocol Pharmacologists. 
 
1.3.4 
Rationale for Deferred Enrollment of Children Switching from an NNRTI-Containing Regimen  
 
Children switching to the study drug regimen from an NNRTI-containing regimen (particularly a 
regimen containing etravirine, efavirenz, or nevirapine) will not be included in the intensive PK 
sampling as they may have decreased DTG exposure subsequent to enzymatic induction by these 
agents. These children, however, will have additional sparse sampling to better understand the PK 
of DTG when switching from an NNRTI-containing regimen. A sub-study in adult patients 
switched from efavirenz or nevirapine to DTG with rilpivirine (SWORD 1 and 2) examined 
trough levels at Weeks 2, 4, 8, 24, and 48 following the switch, and revealed that DTG trough 
concentrations were similar to levels in patients not on an NNRTI regimen by Week 4 (34). No 
dose adjustments to DTG were made following the transition from efavirenz or nevirapine to 
DTG with rilpivirine, and trough levels remained above the DTG IC90 at all time points 
examined. 
 
Note: Under certain pre-specified conditions, and in consultation with the Study Monitoring 
Committee (SMC), the Protocol Team may consider expanding intensive PK sampling to children 
switching to the study drug regimen from an NNRTI-containing regimen; refer to Section 9.5.1 
for more information regarding this potential option. 
 


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1.3.5 
Rationale for Exploratory Evaluations  
 
In addition to plasma PK evaluations, this study will characterize phosphorylated 3TC and ABC 
moieties in PBMCs and dried blood spots (DBS). The active moieties of ABC and 3TC are found 
intracellularly and have been shown to correlate with ARV activity in previous studies (28). Thus, 
examining intracellular levels of carbovir-triphosphate and lamivudine-triphosphate in PBMCs 
may provide additional insight into exposure-response relationships at the site of action with 
these agents.  
 
DBS will be collected to characterize drug levels in this matrix and compare levels to self-
reported adherence. This approach has been studied with tenofovir disoproxil fumarate, tenofovir 
alafenamide, and emtricitabine, for which concentrations of the phosphorylated moieties can 
serve as measures of long- and short-term adherence to ARV therapy, respectively (35-37). 
Tenofovir-diphosphate concentrations increase proportionally with the number of doses taken per 
week, and thus this measure has been integrated as a surrogate measure of adherence and 
treatment outcomes in several HIV pre-exposure prophylaxis (PrEP) (25, 38-40) and treatment 
(41, 42) studies. This same approach could be applied with the phosphorylated moieties of ABC 
and 3TC.  
 
Pharmacogenetic analyses will focus on single nucleotide polymorphisms (SNPs) in genes that 
encode drug transporters and metabolizing enzymes involved in the PK disposition of ABC, 
DTG, and 3TC. The primary focus for initial pharmacogenetic analyses will focus on SNPs that 
influence the PK of DTG, such as UGT1A1 (rs8175317), for which individuals with low and 
reduced activity (presence of *28 and/or *37 alleles) exhibit slower clearance and higher DTG 
exposure (43). 
 
1.3.6 
Rationale for Adherence Evaluations 
 
A variety of methods will be used to evaluate adherence to daily administration of 
ABC/DTG/3TC in this study. For all children, questionnaires will be administered at time points 
designated in the Schedule of Evaluations. In addition, for children undergoing intensive PK 
sampling, more objective methods of assessing adherence such as texted video, video streaming, 
and in-person directly observed therapy will be used to confirm daily dosing between enrollment 
and the day of intensive PK sampling. Data obtained through these methods will assist with 
determining whether failure to reach PK targets is due to challenges with adherence or 
administration versus actual PK differences in the pediatric study population. Relationships 
between PK-based adherence measures and other adherence measures will be explored, which 
may provide useful insights into selection of adherence measures to be used in future pediatric 
studies. 
 
1.4 
Hypotheses 
 
The hypotheses of this study are:  
 
• 
Selected doses of ABC/DTG/3TC dispersible and immediate release tablets will achieve 
protocol-defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age 
 
• 
ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets will be 
described as safe for treatment in children less than 12 years of age 
 


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2 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
The primary objectives of this study are to:  
 
2.1.1 
Determine the steady-state AUC0-24h, Cmax, and C24h of ABC, DTG, and 3TC and confirm 
the dosing of ABC/DTG/3TC dispersible and immediate release tablets that achieves 
protocol-defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age 
 
2.1.2 
Evaluate the safety profile of 24 weeks of treatment with ABC/DTG/3TC dispersible 
tablets and ABC/DTG/3TC immediate release tablets among children less than 12 years 
of age 
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to:  
 
2.2.1 
Determine the PK of ABC, DTG, and 3TC, and clinical covariates that influence PK 
disposition, among children less than 12 years of age using population PK analysis of 
intensive and sparse PK samples collected over 48 weeks of treatment with 
ABC/DTG/3TC dispersible and immediate release tablets 
 
2.2.2 
Evaluate the safety profile of 48 weeks, and additionally up to 144 weeks, of treatment 
with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets 
among children less than 12 years of age 
 
2.2.3 
Evaluate virologic and immunologic responses at 4, 24, and 48 weeks, and additionally 
up to 144 weeks, of treatment with ABC/DTG/3TC dispersible tablets and 
ABC/DTG/3TC immediate release tablets among children less than 12 years of age 
 
2.2.4 
Evaluate changes in lipid profiles at 24 and 48 weeks of treatment with ABC/DTG/3TC 
dispersible tablets and ABC/DTG/3TC immediate release tablets among children less 
than 12 years of age 
 
2.2.5 
Evaluate adherence to and palatability and acceptability of ABC/DTG/3TC dispersible 
tablets and ABC/DTG/3TC immediate release tablets among children less than 12 years 
of age at 4, 24 and 48 weeks of treatment 
 
2.2.6 
Evaluate HIV-1 genotypes and phenotypes among children less than 12 years of age who 
experience virologic failure while receiving treatment with ABC/DTG/3TC dispersible 
tablets or ABC/DTG/3TC immediate release tablets  
 


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2.3 
Exploratory Objectives 
 
The exploratory objectives of this study are to:  
 
2.3.1 
Describe central nervous system effects, including sleep and behavioral changes, that 
may occur over 24 weeks of treatment with ABC/DTG/3TC dispersible tablets and 
ABC/DTG/3TC immediate release tablets among children less than 12 years of age  
 
2.3.2 
Describe pharmacogenetic associations among children less than 12 years of age 
receiving treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC 
immediate release tablets  
 
2.3.3 
Determine concentrations of phosphorylated ABC and 3TC anabolites in PBMCs and 
DBS over 48 weeks of treatment with ABC/DTG/3TC dispersible tablets and 
ABC/DTG/3TC immediate release tablets among children less than 12 years of age 
 
2.3.4 
Examine relationships between PK-based adherence measures and other adherence 
measures 
 
3 
STUDY DESIGN 
 
3.1 
Overview 
 
This is a Phase I/II, multi-site, open-label, multiple dose, non-comparative PK and safety study of 
ABC/DTG/3TC dispersible tablets and immediate release tablets in ART-naïve and ART-
experienced HIV-1-infected children less than 12 years of age.  
 
The study will be conducted among at least 50 and up to 75 children. Refer to Section 4 for the 
study eligibility criteria and a description of the study recruitment, screening, and enrollment 
process. Children are expected to be enrolled at study sites in Botswana, South Africa, Thailand, 
and the US.  
 
At least 25 children will be less than six years of age and at least 25 will be six to less than 12 
years of age. Children will be enrolled in weight bands and will receive study drug as shown in 
Table 6. Two alternative dispersion volumes for preparation of dispersible tablets will be 
considered, as described in Sections 5.2.1 and 9.6.2. 
 
Accrual into all weight bands will occur concurrently, and the age-based quotas will apply across 
weight bands. Accrual into the study overall will continue until study drug dosing has been 
confirmed for each weight band and the age-based quotas have been met. There is no pre-
specified maximum number of children who may be enrolled in each weight band; the Protocol 
Team will closely monitor accrual into each weight band and may pause and subsequently close 
or resume accrual into individual weight bands in an effort to assure balance across the weight 
bands (as described further in Sections 9.4.1 and 9.5.1). 
 


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Table 6. IMPAACT 2019 Weight Band Dosing of Study Drug 
 
Weight Band 
Study Drug Formulation 
(Daily Dose of ABC/DTG/3TC) 
#1 
6 to less than 10 kg 
3 dispersible tablets  
(180/15/90 mg) 
#2 
10 to less than 14 kg 
4 dispersible tablets 
(240/20/120 mg) 
#3 
14 to less than 20 kg 
5 dispersible tablets 
(300/25/150 mg) 
#4 
20 to less than 25 kg 
6 dispersible tablets 
(360/30/180 mg) 
#5 
25 kg or greater 
1 immediate release tablet 
(600/50/300 mg) 
 
At the outset of study implementation, accrual into weight band #1 will be restricted to children 
six months (180 days) of age and older (see Section 1.3.2). Once the Protocol Team has 
confirmed that data are available to support the specified weight band dosing for children less 
than six months of age, this restriction will be lifted. If the Protocol Team determines that the 
specified dosing is not appropriate for children less than six months of age, the restriction on 
accrual will be maintained while alternative dosing and/or other protocol modifications are 
developed for children less than six months of age. 
 
ART-naive children will initiate treatment with the study drug regimen, ABC/DTG/3TC, at 
enrollment. ART-experienced children will switch from their pre-study ART regimen to 
ABC/DTG/3TC at enrollment. For all children, the first dose of study drug is expected to be taken 
on the day of enrollment or the day after enrollment.  
 
Use of ABC/DTG/3TC and evaluations to assess safety, adherence, tolerability (i.e., palatability 
and acceptability), virologic and immunologic response, and lipid profiles will continue through 
48 weeks of follow-up. Specimen collection for PK evaluations will also continue through 48 
weeks of follow-up. Scheduled follow-up is generally expected to be completed at the Week 48 
Visit, but may be continued for up to an additional 96 weeks for children who are deriving benefit 
from ABC/DTG/3TC but do not otherwise have access to ABC/DTG/3TC from a non-study 
source (see also Sections 6.13 and 13.11). For these children once ABC/DTG/3TC becomes 
available from a non-study source, study participation will be discontinued with transition into 
local standard HIV care and treatment. For children who are not deriving benefit from 
ABC/DTG/3TC, or who are deriving benefit and have access to ABC/DTG/3TC from a non-
study source, the transition into local standard HIV care and treatment will occur upon 
completion of the Week 48 Visit.  
 
Refer to Sections 5, 9, and 10, respectively for more detailed information on study drug 
considerations, data analysis and statistical considerations, and pharmacology considerations,  
 
3.2 
Approach to Dose Confirmation 
 
Accrual will begin with enrollment of children who will undergo intensive PK sampling 
approximately one week after initiating ABC/DTG/3TC and will continue while intensive PK 
evaluations are performed and the appropriateness of each weight band dose is determined. 
Accrual will continue (i.e., will not be paused) while intensive PK evaluations are performed 


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because there is no evidence to suggest that PK, safety, or efficacy activity will differ when ABC, 
DTG, and 3TC are administered as a fixed dose combination rather than as individual agents. 
 
A minimum of five dose-evaluable children will be enrolled in each weight band. The term dose-
evaluable is used in this protocol to refer to children who will be included in the dose 
confirmation analyses described in Section 9.5.1. To be considered dose-evaluable, children must 
be both safety-evaluable and PK-evaluable for the study drug dose being evaluated for their 
weight band. Safety-evaluable and PK-evaluable are defined as follows: 
 
• 
Safety-evaluable: To be considered safety-evaluable, children must have exclusively received 
the study drug dose being evaluated for their weight band between study Entry and the Week 
4 Visit or have experienced a grade 3 or higher adverse event that is assessed as related to 
study drug or an adverse event assessed as related to study drug that results in permanent 
discontinuation of study drug prior through the Week 4 Visit. 
 
• 
PK-evaluable: To be considered PK-evaluable, children must have exclusively received the 
study drug dose being evaluated for their weight band, administered as described in Section 
5.2, between study Entry and the day of intensive PK sampling. Children must have an 
observed dose on the day of intensive PK sampling; blood samples collected; and ABC, 
DTG, and 3TC concentration data available from all intensive PK sampling time points 
specified in Section 6.3. Profiles with missing samples will be assessed for evaluability by the 
Protocol Team on a case-by-case basis. Every effort should be made to collect all time points 
of interest. If the Protocol Team determines that intensive PK sampling was performed 
incorrectly or that results seem inaccurate, participants may be asked to repeat the sampling 
within 5-10 days after receipt of the team’s recommendation to repeat the sampling. In this 
case, the child must continue to exclusively receive the study drug dose being evaluated for 
their weight band until the day of repeat intensive PK sampling. 
 
The first five children enrolled in each weight band will undergo intensive PK sampling; the sixth 
and seventh children enrolled in each weight band may also undergo intensive PK sampling as 
described below. Intensive PK samples will be tested in real time and the number of safety-
evaluable, PK-evaluable, and dose-evaluable children enrolled in each weight band will be 
closely monitored by the Protocol Team. The Protocol Team will provide frequent updates to 
study sites as enrollment proceeds.  
 
If the first five children enrolled in a given weight band have been confirmed as dose-evaluable 
before additional children are enrolled in that weight band, intensive PK sampling will not be 
performed among the sixth and seventh children enrolled in that weight band. Alternatively, if the 
first five children enrolled in a given weight band have not (yet) been confirmed as dose-
evaluable before the sixth and seventh children are enrolled in that weight band, intensive PK 
sampling will be performed among the sixth and seventh children enrolled. If fewer than five of 
the first seven children enrolled in each weight band are determined to be dose-evaluable, 
additional children (beyond the first seven) will be enrolled and undergo intensive PK sampling 
to achieve five dose-evaluable in that weight band. Additional children may also be enrolled and 
undergo intensive PK sampling if, in the opinion of the Protocol Pharmacologists, a confident 
determination regarding achievement of PK targets cannot be made based on the first 5-7 dose-
evaluable children in a given weight band. 
  


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Guidelines for determining the appropriateness of the weight band doses are provided in Section 
9.5.1. Safety-related guidelines are based on the occurrence of adverse events through the Week 4 
Visit. PK-related guidelines are based on DTG, ABC, and 3TC exposures. Because prior use of 
NNRTIs may affect observed concentrations of DTG (as described in Section 1.3.4), and thereby 
affect variability and interpretation of PK outcomes, children who undergo intensive PK sampling 
will either be ART-naïve or will be switching to the study drug regimen from a non-NNRTI-
containing regimen. Further requirements for administration of study drug to children undergoing 
intensive PK sampling are provided in Sections 5.2 and 10.3.  
 
Note: Under certain pre-specified conditions, and in consultation with the SMC, the Protocol 
Team may consider expanding intensive PK sampling to children switching to the study drug 
regimen from an NNRTI-containing regimen; refer to Section 9.5.1 for more information 
regarding this potential option. 
 
If the safety and PK guidelines are met for a given weight band, the restriction on enrollment with 
respect to prior NNRTI exposure will be lifted for that weight band. If these guidelines are not 
met, dosing for the weight band may be adjusted and additional children may be enrolled in the 
weight band and undergo intensive PK sampling.  
 
 
4 
STUDY POPULATION 
 
This study will be conducted among at least 50 and up to 75 HIV-1-infected children who will be 
selected according to the criteria in Sections 4.1 and 4.2 and the guidelines in Section 4.3. At least 
25 children will be less than six years of age and at least 25 will be six to less than 12 years of 
age. The study-specific approach to recruitment, screening, and enrollment is described in Section 
4.4. Considerations related to monitoring enrollment within and across weight bands are provided 
in Section 9.5.1. Considerations related to participant retention and withdrawal/termination from 
the study are provided in Sections 4.5 and 4.6, respectively.  
 
4.1 
Inclusion Criteria 
 
 
 
Potential participants must meet all of the following criteria to be included in this study; in these 
criteria, “at entry” is used to refer to the day of enrollment in the study: 
 
4.1.1 
Less than 12 years of age at entry 
 
Note: Accrual will initially be restricted to children six months (180 days) of age and 
older. Once the Protocol Team has confirmed that data are available to support the 
specified weight band dosing for children less than six months of age, this restriction will 
be lifted. 
 
4.1.2 
Weight 6 kg to less than 40 kg at entry 
 
4.1.3 
ART-naïve at entry or has been taking a stable ART regimen for at least six consecutive 
months at entry 
 
Note: For ART-naïve children, receipt of ARV prophylaxis prior to diagnosis of HIV 
infection is permitted. For these children, ascertainment of this criterion may be based on 
parent or guardian report only, but available medical records should also be reviewed in 
relation to this criterion. 


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Note: For ART-experienced children (on a stable ART regimen), dose and formulation 
changes (e.g., for growth) within the six months prior to entry are permitted. For these 
children, ascertainment of this criterion must be based on medical records.  
 
4.1.4 
For ART-experienced children (on a stable ART regimen), has had a suppressed HIV 
viral load (HIV-1 RNA less than 200 copies/mL) for at least six consecutive months prior 
to entry 
 
Note: To fulfill this criterion, at least two documented HIV-1 RNA results less than 200 
copies/mL must be available, one based on a specimen collected at least six months prior 
to entry and one based on a specimen collected within 30 days prior to entry. 
 
Note: Any documented HIV-1 RNA result greater than or equal to 200 copies/mL based 
on a specimen collected within six months prior to entry is exclusionary (see exclusion 
criterion 4.2.2). 
 
4.1.5 
At screening, has normal, Grade 1, or Grade 2 laboratory test results for all of the 
following, based on testing of specimens collected within 30 days prior to entry and 
grading per the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (refer to Section 7.3.3 for guidance on severity grading): 
 
4.1.5.1 Hemoglobin (≥8.5 g/dL or ≥5.25 mmol/L) 
4.1.5.2 Absolute neutrophil count (≥600 cells/mm3 or ≥0.600 x 109 cells/L) 
4.1.5.3 Platelet count (≥50,000 cells/mm3 or ≥50.00 x 109 cells/L) 
4.1.5.4 Estimated glomerular filtration rate (eGFR; bedside Schwartz formula; ≥60 
ml/min/1.73 m2) 
4.1.5.5 ALT (<5.0 x ULN) 
4.1.5.6 AST (<5.0 x ULN) 
4.1.5.7 Total bilirubin (<2.6 x ULN) 
4.1.5.8 Direct bilirubin (≤ULN) 
 
 
Note: Laboratory tests may be repeated during the screening period (i.e., within 30 days 
prior to entry), with the latest results used for eligibility determination. 
 
Note: For treatment-experienced children on an atazanavir-containing ART regimen, 
Grade 3 or higher total bilirubin is permitted.  
 
4.1.6 
At screening, has a negative test result for hepatitis B surface antigen based on testing of 
a specimen collected within 30 days prior to entry 
 
4.1.7 
Confirmed HIV-1-infection based on documented testing of two samples collected at 
different time points: 
 
Sample #1 may be tested using any of the following: 
• 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes 
• 
One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR 
chemiluminescence assay 
• 
One HIV DNA polymerase chain reaction (PCR) 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 


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• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
Sample #2 may be tested using any of the following: 
• 
Rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved, and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope. 
• 
One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR 
chemiluminescence assay 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
Whole blood, plasma, or serum samples must be tested. If both samples are tested using 
antibody tests, at least one of the samples must be tested in a laboratory that operates 
according to Good Clinical Laboratory Practice guidelines and participates in an 
appropriate external quality assurance program. If nucleic acid testing is used, at least one 
test must be performed in a Clinical Laboratory Improvement Amendments (CLIA) 
certified (for US sites) or Virology Quality Assurance (VQA) certified (for non-US sites) 
laboratory. For tests performed in other settings, adequate source documentation 
including the date of specimen collection, date of testing, test performed, and test result 
must be available. FDA approved testing methods should be used when possible.  
 
4.1.8 
HLA-B*5701-negative based on documented testing at any time prior to entry 
 
Note: Documented testing is required even if the potential participant has received ABC 
prior to study entry. 
 
4.1.9 
For females of reproductive potential (defined as having experienced menarche), not 
pregnant based on testing performed at screening  
 
4.1.10 For females of reproductive potential who are engaging in sexual activity that could lead 
to pregnancy, willing to use two methods of contraception while receiving study drug, 
based on participant and parent or guardian report at entry  
 
One of the two methods must be highly effective; highly effective methods include 
surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, tubal ligation, or 
salpingectomy) and the following: 
 
• 
Contraceptive intrauterine device or intrauterine system 
• 
Subdermal contraceptive implant 
• 
Progestogen injections  
• 
Combined estrogen and progestogen oral contraceptive pills 
• 
Percutaneous contraceptive patch 
• 
Contraceptive vaginal ring 
 


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The highly effective method must be initiated prior to study entry. The second method 
should ideally be a barrier method. Male or female condom use is recommended with all 
other methods of contraception for dual protection against pregnancy and to avoid 
transmission of HIV and other sexually transmitted infections. 
 
4.1.11 Based on parent or guardian report at entry, child is expected to be available for 48 weeks 
of follow-up  
 
4.1.12 Parent or legal guardian is willing and able to provide written informed consent for 
child’s study participation and, when applicable per local institutional review 
board/ethics committee (IRB/EC) policies and procedures, child is willing and able to 
provide written informed assent for study participation  
 
4.2 
Exclusion Criteria 
 
Children must be excluded from this study if any of the following are identified any time prior to 
study entry: 
 
4.2.1 
Documented resistance to ABC, DTG, or 3TC  
 
Note: Testing to rule out resistance is not required, and the M184V resistance mutation is 
not exclusionary. 
 
4.2.2 
For ART-experienced children (on a stable ART regimen), documented HIV-1 RNA 
result greater than or equal to 200 copies/mL based on a specimen collected within six 
months prior to entry 
 
4.2.3 
History of any of the following as determined by the site investigator based on 
participant/parent/guardian report and available medical records: 
 
4.2.3.1 Malignancy (ever) 
4.2.3.2 Hypersensitivity reaction to ABC (ever) 
4.2.3.3 Receipt of any prohibited medication (refer to Section 5.7) within 30 days prior 
to study entry 
4.2.3.4 Receipt of systemic interferon or any chronic systemic immunosuppressant 
medication within 30 days prior to study entry 
 
Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg) taken for 
replacement or short course therapy are permitted. Intranasal or inhaled steroid use is also 
permitted. 
 
4.2.4 
Has any of the following as determined by the site investigator based on 
participant/parent/guardian report and available medical records 
 
4.2.4.1 Current clinical evidence of pancreatitis 
4.2.4.2 Currently-active TB and/or currently receiving rifampicin-containing TB 
treatment  
4.2.4.3 Currently-active AIDS-defining (WHO Clinical Stage 4) opportunistic infection 
 


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4.2.5 
Has any documented or suspected clinically significant medical condition or any other 
condition that, in the opinion of the site investigator, would make participation in the 
study unsafe, complicate interpretation of study outcome data, or otherwise interfere with 
achieving the study objectives 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in other studies is not precluded, although careful consideration must be given to 
study visit burden, blood draw volumes, and interpretation of outcome data across studies. Given 
these considerations, requests for co-enrollment must be approved in advance by the Protocol 
Teams of both studies. Requests for such approval should be emailed to the IMPAACT 2019 
Clinical Management Committee (CMC; refer to Section 7.1.2 for more information regarding 
the role of the CMC for this study). 
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
Participant recruitment methods for this study may vary across sites but, for treatment-
experienced participants, are expected to draw from the population of HIV-infected children 
currently in care at participating study sites. For treatment-naïve participants, recruitment is 
expected to rely on active identification and referral of children newly diagnosed with HIV-
infection in study site communities. 
 
Upon identification of a potentially eligible child, study staff will provide information about the 
study to the child’s parent or guardian. Each parent or guardian who expresses interest in learning 
more about the study will be provided additional information, education, and counseling as part 
of the study informed consent process. The process will include detailed review of the study 
informed consent form and time to address any questions or concerns the parent or guardian may 
have, and an assessment of the parent or guardian’s understanding before proceeding to the 
informed consent decision. In addition, children who meet local IRB/EC criteria for provision of 
assent will undergo an age-appropriate assent process. Informed consent and assent processes will 
be fully documented, consistent with the Division of AIDS (DAIDS) policies referenced in 
Section 11.2. Refer to Section 13.3 for further information on informed consent procedures for 
this study.  
 
Eligibility screening will be initiated after written informed consent, and assent if applicable, are 
obtained (i.e., informed consent, and assent if applicable, must be obtained before any study-
specific screening procedures are performed). Screening evaluations must be performed within 30 
days prior to enrollment and may be repeated during the 30-day period, with the latest outcomes 
used for eligibility determination. Screening evaluations may be performed on the day of 
enrollment (i.e., at the Entry Visit); however, all required screening outcomes must be available 
prior to enrollment. In the event that the 30-day screening period is exceeded, the screening 
process may be repeated; in this case, most but not all screening evaluations must be repeated, as 
specified in Section 6.1. 
 


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Each site must establish standard operating procedures (SOPs) for eligibility determination that 
describe where and when screening procedures will be performed; roles and responsibilities for 
performing the required procedures; roles and responsibilities for assessing and confirming 
eligibility; and procedures for documenting the process, taking into consideration the required 
timing of enrollment. For treatment-naïve children, study sites should minimize the time from 
screening to enrollment so that initiation of study-supplied ART is not unduly delayed. 
Treatment-naïve children who do not meet the study eligibility criteria should be actively referred 
to non-study sources of HIV care and treatment to initiate non-study ART as soon as possible.  
 
The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to assist with tracking the screening and enrollment process, within and across weight bands and 
age-based quotas. When informed consent is obtained, a participant identification number (PID) 
will be assigned to the child and a study-specific screening number will be obtained through the 
SES. For children found to be eligible, enrollment will occur upon successful entry of required 
eligibility data into the SES. Successful entry into the SES will generate a study identification 
number and study drug prescribing information. For children found to be ineligible for the study, 
or who do not enroll in the study for any reason, limited demographic information and reasons for 
non-enrollment will be entered into electronic case report forms (eCRFs). Refer to Section 9.5 for 
more information on monitoring participant accrual in this study.  
 
4.5 
Participant Retention 
 
Once a child is enrolled in this study, study staff will make every effort to retain him or her in 
follow-up for the protocol-specified duration of follow-up (through Week 48), thereby 
minimizing potential biases and loss of statistical power associated with loss-to-follow-up. Refer 
to Section 9.5 for more information on monitoring participant retention in this study. 
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced above, children may be voluntarily 
withdrawn from the study by their parents or guardians. Children may also be terminated from the 
study by the site investigator under the following circumstances: 
 
• 
Child is not exposed to ABC/DTG/3TC for any reason 
• 
Child permanently discontinues ABC/DTG/3TC (see also Sections 5.7 and 8.2; reasons for 
permanent discontinuation may include but are not limited to management of an adverse 
event and required use of a contraindicated concomitant medication) 
• 
Child of reproductive potential who reports sexual activity that could lead to pregnancy is not 
willing or able to use two methods of contraception (see also Section 8.6) 
• 
Child re-locates away from the study site (with no options for transfer to another site) or is 
otherwise determined to be lost-to-follow-up 
• 
Investigator or designee determines that continued participation in the study would be unsafe 
or otherwise not in the best interest of the child, after consultation with the CMC 
• 
After Week 48, investigator or designee determines that child is not deriving benefit from 
ABC/DTG/3TC or is deriving benefit and has access to ABC/DTG/3TC from a non-study 
source  
• 
The study is stopped or canceled by the sponsors, government or regulatory authorities, or 
site IRBs/ECs 
 


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Refer to Section 8.2 for further information on procedural expectations and timelines for 
termination from the study due to permanent discontinuation of ABC/DTG/3TC.  
 
For any child who is withdrawn or terminated from the study prior to scheduled completion of 
follow-up, study staff will document the reason for the withdrawal or termination in detail. If the 
withdrawal or termination occurs before the Week 48 Visit is conducted, study staff will make 
every effort to complete final evaluations as described in Section 6.15. If the circumstances that 
led to a child’s withdrawal or termination change (e.g., he or she returns to the study site area 
after having re-located previously), the site investigator should contact the CMC to discuss the 
possibility of resuming of follow-up based on the child’s original study entry date and follow-up 
schedule. 
 
 
5 
STUDY DRUG 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations. For this study, the term study drug refers to 
ABC/DTG/3TC dispersible tablets, ABC/DTG/3TC (Triumeq®) immediate release tablets, and 
other formulations of ABC, DTG, and 3TC listed in Section 5.2. Refer to the investigator’s 
brochures and package inserts for further information about these drugs.  
 
5.1 
Study Drug Regimen and Administration 
 
Abacavir/dolutegravir/lamivudine tablets (60 mg/5 mg/30 mg dispersible tablets or 600 mg/50 
mg/300 mg immediate release [Triumeq®] tablets) will be taken once daily, generally with or 
without food, at doses specified in Table 7. For children undergoing intensive PK evaluations, 
food intake around the time of these evaluations will be managed as described in Section 
6.3. Enrolled children will receive study drug for at least 48 weeks (through the Week 48 Visit) 
and up to 144 weeks.  
 
Table 7. IMPAACT 2019 Study Drug Regimen and Administration 
 
Weight Band 
Study Drug Regimen and Administration 
(Daily Dose of ABC/DTG/3TC) 
#1 6 to less than 10 kg 
3 dispersible tablets taken orally once daily with or without food 
(180/15/90 mg) 
#2 10 to less than 14 kg 
4 dispersible tablets taken orally once daily with or without food 
(240/20/120 mg) 
#3 14 to less than 20 kg 
5 dispersible tablets taken orally once daily with or without food 
(300/25/150 mg) 
#4 20 to less than 25 kg 
6 dispersible tablets taken orally once daily with or without food 
(360/30/180 mg) 
#5 25 kg or greater 
1 immediate release tablet taken orally once daily with or without 
food (600/50/300 mg) 
 
Children will initiate ABC/DTG/3TC dosing based on their weight at study entry and will remain 
on their initial dose through Week 4. After completing the Week 4 Visit, children will undergo 
individual dose adjustments when indicated based on their growth and weight gain over time. For 
children who grow into weight band #2, #3, or #4, increased dosing with additional dispersible 
tablets will be initiated at the first study visit (after Week 4) when the child has grown into the 
next higher weight band. For children who grow into weigh band #5, increased dosing with 


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immediate release tablets will be initiated at the first study visit (after Week 4) when the child has 
grown to 25 kg or more. For children whose weight may fluctuate over time, it is generally not 
expected that dosing will be decreased when weight decreases. However, if a child’s weight 
persists in a lower weight band for two consecutive scheduled study visits, dosing should be 
decreased consistent with the lower weight band. All dose and formulation changes will be source 
documented and entered into eCRFs, along with the date of each change and measured weight on 
the date of each change. 
 
There are no restrictions on the time of day at which study drug can be taken. However, to 
facilitate the preferred timing of study drug dosing on the day of intensive PK sampling (refer to 
Section 6.3), the parents or guardians of children undergoing intensive PK sampling will be 
counseled to administer study drug in the morning between enrollment and the Week 1 Visit. 
Parents or guardians will also be counseled on the co-administration of common concomitant 
medications as described in Section 5.7.  
 
For children who may spit out a dose of study drug or vomit within 15 minutes after taking study 
drug, parents or guardians will be instructed to administer a replacement dose. If vomiting occurs 
more than 15 minutes after taking study drug, a replacement dose should not be administered (the 
next scheduled dose should be taken the next day). Refer to Section 6.3 for additional information 
pertaining to vomiting on the day of intensive PK sampling.  
 
Note: In addition to the triple-agent fixed dose combination formulations of study drug noted 
above, single agent formulations will be available for use among children who require dose 
adjustments that cannot be achieved with the fixed dose combination formulations; refer to 
Sections 5.2 and 5.3 for more information about these formulations.  
 
5.2 
Study Drug Formulation and Preparation 
 
5.2.1 
ABC/DTG/3TC Dispersible Tablets 
 
ABC 60 mg/DTG 5 mg/3TC 30 mg pediatric dispersible tablets are pale yellow, biconvex, 
oval, film-coated, debossed with ‘SV WTU’ on one side and plain on the opposite side. Each 
tablet contains 70.2 mg abacavir sulfate, which is equivalent to 60 mg of abacavir free base; 5.26 
mg dolutegravir sodium, which is equivalent to 5 mg of dolutegravir free acid; and 30 mg of 
lamivudine. The tablets are packaged in HDPE bottles with child-resistant closures that include 
an induction seal and a desiccant. Store and dispense in the original package, protect from 
moisture, and keep bottles tightly closed. Do not remove desiccant. In the study site pharmacy, 
store up to 30°C (86°F). 
 
ABC/DTG/3TC dispersible tablets will be dispersed in water for oral administration. From study 
entry through the Week 4 Visit, caregivers will be instructed to disperse the appropriate number 
of dispersible tablets in the volume of water shown in Table 8. For children in weight band #3 or 
#4 who report poor palatability and/or acceptability at the Week 4 Visit, caregivers will be 
provided the option of dispersing the appropriate number of dispersible tablets in the volume of 
water shown in Table 9. As palatability and acceptability data are accumulated in the study, if the 
Protocol Team determines that the dispersion volumes shown in Table 8 are not sufficiently 
acceptable for children in weight band #3 or #4, the volumes shown in Table 9 may be 
recommended for all applicable participants. Further guidance on assessing palatability and 
acceptability and adjusting dispersion volumes is provided in the study-specific Manual of 
Procedures (MOP). 
 


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Table 8. Dispersion Volumes for ABC/DTG/3TC Dispersible Tablets 
 
Weight Band 
Number of Dispersible 
Tablets per Dose 
 
Dispersion Volume 
#1 
6 to less than 10 kg 
3 
15 mL 
#2 
10 to less than 14 kg 
4 
20 mL 
#3 
14 to less than 20 kg 
5 
20 mL 
#4 
20 to less than 25 kg 
6 
20 mL 
 
Table 9. Alternate Dispersion Volumes for ABC/DTG/3TC Dispersible Tablets 
 
Weight Band 
Number of Dispersible 
Tablets per Dose 
 
Dispersion Volume 
#1 
6 to less than 10 kg 
3 
15 mL 
#2 
10 to less than 14 kg 
4 
20 mL 
#3 
14 to less than 20 kg 
5 
25 mL 
#4 
20 to less than 25 kg 
6 
30 mL 
 
The tablets disperse within three minutes. Following dispersion, the suspension should be 
administered from the supplied dosing cup or from an oral syringe within five minutes. The 
dosing cup and syringe should be rinsed with an additional 15 mL of water and the rinse 
administered to the child. Dispersible tablets should not be chewed or swallowed whole. 
 
5.2.2 
ABC/DTG/3TC Immediate Release (Triumeq®) Tablets 
 
ABC/DTG/3TC immediate release (Triumeq®) tablets are purple, biconvex, oval, film-coated, 
debossed with “572 Trı” on one side, and plain on the opposite side. Each tablet contains 702 mg 
abacavir sulfate, which is equivalent to 600 mg of abacavir free base; 52.62 mg dolutegravir 
sodium, which is equivalent to 50 mg of dolutegravir free acid; and 300 mg of lamivudine. Store 
and dispense in the original package, protect from moisture, and keep bottles tightly closed. Do 
not remove desiccant. In the study site pharmacy, store at 25°C (77°F) with excursions between 
15° and 30°C (59° to 86°F) permitted (See USP Controlled Room Temperature). For any child 
who is not able to swallow whole immediate release tablets, the tablets can be crushed and mixed 
with a liquid or semi-solid food such as applesauce or mashed banana (44). For children 
undergoing intensive PK sampling; however, swallowing of whole tablets will be required from 
enrollment through the day of intensive PK sampling (crushing, if needed, would be permitted 
thereafter). Refer to Section 10.3.3 for additional information. 
 
5.2.3 
DTG Dispersible Tablets 
 
DTG 5 mg pediatric dispersible tablets are white, round, film-coated, and debossed with ‘SV 
H7S’ on one side and ‘5’ on the opposite side. Each tablet contains 5.26 mg dolutegravir sodium, 
which is equivalent to 5 mg of dolutegravir free acid. The tablets are packaged in HDPE bottles 
with child-resistant closures that include an induction seal and a desiccant. Store and dispense in 
the original package, protect from moisture, and keep bottles tightly closed. Do not remove 
desiccant. In the study site pharmacy, store up to 30°C (86°F). 
 


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DTG dispersible tablets will be dispersed in water for oral administration (5 mL for one, two, or 
three tablets; 10 mL for four, five, or six tablets). Following dispersion, the suspension should be 
administered from the supplied dosing cup or from an oral syringe within 30 minutes. The dosing 
cup and syringe should be rinsed with an additional 5 mL of water and the rinse administered to 
the child. Dispersible tablets may also be swallowed whole with water. Dispersible tablets should 
not be chewed. 
 
5.2.4 
DTG (Tivicay®) Tablets 
 
DTG 50 mg (Tivicay®) tablets are yellow, biconvex, round, film-coated, and debossed with 
“SV 572” on one side and “50” on the other side. Each tablet contains dolutegravir sodium 
equivalent to 50 mg of dolutegravir. In the study site pharmacy, store at 25°C (77°F) with 
excursions between 15° and 30°C (59° to 86°F) permitted (See USP Controlled Room 
Temperature). 
 
5.2.5 
ABC (Ziagen®) Tablets 
 
ABC 300 mg scored (Ziagen®) tablets are yellow, biconvex, scored, capsule-shaped, film-
coated, and imprinted with “GX 623” on both sides. Each tablet contains abacavir sulfate 
equivalent to 300 mg of abacavir, In the study site pharmacy, store at 20° to 25°C (68° to 77°F) 
(See USP Controlled Room Temperature). 
 
5.2.6 
3TC (EPIVIR®) Tablets 
 
3TC 150 mg scored (EPIVIR®) tablets are white, diamond-shaped, scored, film-coated tablets 
debossed with “GX CJ7” on both sides. Each tablet contains 150 mg of 3TC. Store and dispense 
in the original package. In the study site pharmacy, store at controlled room temperature of 20° to 
25°C (68° to 77°F) (See USP Controlled Room Temperature).  
 
5.3 
Study Drug Supply 
 
ABC 60 mg/DTG 5 mg/3TC 30 mg dispersible tablets will be supplied by ViiV Healthcare Ltd in 
bottles with child-resistant closure. Dosing cups will be supplied for use with dispersible tablets. 
Oral syringes will be provided for administering dispersed medication.  
 
ABC 600 mg/DTG 50 mg/3TC 300 mg immediate release (Triumeq®) tablets will be supplied by 
ViiV Healthcare Ltd in bottles with child resistant closure.  
 
In addition to the triple-agent fixed dose combination formulations noted above, the following 
will also be supplied by ViiV Healthcare Ltd for use among children who require dose 
adjustments that cannot be achieved with the triple-agent fixed dose combination formulations: 
 
• 
DTG 5 mg dispersible tablets  
• 
DTG 50 mg film-coated tablets  
• 
ABC 300 mg scored tablets 
• 
3TC 150 mg scored tablets  
 


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All of the above-listed formulations and dosing cups will be made available to study sites through 
the NIAID Clinical Research Products Management Center (CRPMC). Upon successful 
completion of protocol registration procedures (refer to Section 14.2), these supplies may be 
obtained by the site pharmacist following instructions provided in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
5.4 
Study Drug Accountability 
 
Site pharmacists must maintain complete records of all study drugs received from the CRPMC 
and subsequently dispensed. 
 
5.5 
Final Disposition of Study Drug 
 
Any unused study drug remaining at US sites after the study is completed or terminated will be 
returned to the CRPMC (unless otherwise directed by the sponsor). At non-US sites, any unused 
study drug will be destroyed. Site pharmacists will follow the relevant instructions for return or 
destruction of unused study drug provided in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks.  
 
5.6 
Study Drug Adherence Assessment and Counseling 
 
Study staff will provide adherence counseling to enrolled participants (and/or their parents or 
guardians) throughout the period of study participation. Counseling may be provided by clinic 
and/or pharmacy staff consistent with local standards of care and site SOPs. Counseling should be 
provided in a client-centered manner, tailored as needed to the information, skills building, and 
support needs of each participant/parent/guardian. Information on correct storage, preparation, 
and administration of study drugs will be provided, particularly at the time of enrollment and in 
the early stages of follow-up, as well as at the time of any dose, formulation, or preparation 
changes. Counseling will also address challenges to consistent use of study drug over time, with 
the aim of supporting participants (and/or their parents or guardians) in identifying strategies to 
address any such challenges. 
 
For children undergoing intensive PK sampling, adherence to daily study drug dosing will ideally 
be confirmed on each day prior to intensive PK sampling by texted video, video streaming, in-
person directly observed therapy, or other method approved by the Protocol Team; at a minimum, 
dosing must be confirmed using an approved method for the four days prior to intensive PK 
sampling. For all children, adherence will be assessed by questionnaire administered at weeks 4, 
24, and 48. After study drug dosing has been confirmed for a given weight band, results of HIV 
viral load testing may be used as a biologic measure of adherence to guide feedback to 
participants/parents/ guardians and associated adherence counseling (refer to Section 8.3 for more 
information on virologic monitoring and management).  
 
5.7 
Concomitant Medications  
 
The term concomitant medication is used in this study to refer to medications other than the study 
drugs listed in Section 5.1.  
 


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All concomitant medications received by study participants must be source documented as part of 
the medical and medications histories obtained at each study visit (refer to Section 0). This 
includes prescription and non-prescription (over-the-counter) medications, vaccines and other 
preventive medications, antacids, vitamins and other nutritional supplements, and alternative, 
complementary, and traditional medications and preparations. Except for traditional medications 
and preparations, all concomitant medications must be entered into eCRFs.  
 
Due to interactions that decrease the concentration of DTG, the following should not be co-
administered with ABC/DTG/3TC: etravirine, efavirenz, nevirapine, fosamprenavir/ritonavir, 
tipranavir/ritonavir, dofetilide, oxcarbazepine, phenytoin, phenobarbital, carbamazepine, and St. 
John’s wort. If an enrolled participant is identified as requiring a contraindicated medication, the 
CMC should be consulted as soon as possible and within three business days regarding options 
for clinical and ART regimen management. If use of a contraindicated medication cannot be 
avoided, permanent discontinuation of study drug, with subsequent termination from the study, 
may be required. 
 
Liquid medications containing sorbitol or other sugar alcohols (e.g., mannitol, xylitol, maltitol, 
isomalt) should be avoided as these excipients, which are used to sweeten pediatric liquid 
formulations, have been shown to reduce 3TC concentrations (45). Site investigators should 
carefully review all liquid concomitant medications received by enrolled participants. If any such 
medications are not clinically indicated, they should be discontinued. Otherwise, they should be 
switched to a solid dosage forms when possible or to a liquid formulation that does not contain 
sorbitol or other sugar alcohols. Site investigators should be particularly cognizant of liquid 
cotrimoxazole formulations, which tend to contain high concentrations of sorbitol and are 
commonly used in HIV-infected children. Liquid formulation concomitant medications should 
not be consumed with study drug on the day of intensive PK sampling.  
 
Study participants who require cation-containing antacids or laxatives, sucralfate, oral 
supplements containing iron or calcium, or buffered medications should take these medications at 
least six hours before or at least two hours after taking ABC/DTG/3TC. Alternatively, 
ABC/DTG/3TC and supplements containing calcium or iron can be taken together with food. 
 
Refer to Section 8.4 for additional information on management of study participants who require 
rifampin-containing treatment for active tuberculosis. 
 
 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of the study visit and evaluation schedule is provided in Appendix I; blood draw 
volumes for each visit are also detailed in Appendix I. Presented in this section is additional 
information on visit-specific study procedures.  
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent and 
assent; scheduling visits; providing instructions for contacting study staff between visits; 
providing visit reminders; and following up on missed visits. When applicable, visit reminders 
will include details related to study drug dosing and food intake prior to the next visit. All such 
tasks should be documented consistent with site SOPs. Study staff should inform parents or 
guardians of clinically meaningful physical exam findings and laboratory test results when 
available. 


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All visits should be conducted as close as possible to specified target visit dates and within 
specified allowable visit windows. For visits with specified targeted windows, every effort should 
be made to conduct the visit within the targeted window. Unless otherwise specified, visits may 
be split, with required procedures performed on more than one day within the allowable visit 
window if necessary.  
 
All enrolled participants are expected to complete follow-up visits at Weeks 1, 4, 12, 24, 36, and 
48 on-study. With the exception of the Week 1 Visit, the allowable windows for these visits 
overlap by one day; the day of overlap should be prioritized, when applicable, for completion of 
the earlier of the two visits. For example, there is one day of overlap between the allowable 
windows for the Week 4 and Week 12 Visits. If a participant were to present to the study site on 
this day, the Week 4 Visit should be conducted on this day, if not previously conducted; 
otherwise, the Week 12 Visit may be conducted on this day. 
 
In addition to the follow-up visits noted above, some enrolled participants are expected to 
complete visits at Weeks 2, 6, 8, 16, and/or 20. The Week 2 and Week 6 Visits are expected for 
children switching to the study drug regimen from an NNRTI-containing regimen. The Week 8, 
Week 16, and Week 20 Visits are expected for children with a known M184V resistance 
mutation. The allowable windows for these visits overlap with the windows for other visits noted 
above. Because the purpose of these visits is to perform additional evaluations at additional time 
points for selected participants, these visits should be conducted as close as possible to the 
specified target visit dates and should not be combined with other scheduled visits.  
 
Following completion of the Week 48 Visit, children who are deriving benefit from 
ABC/DTG/3TC may remain on-study for up to an additional 96 weeks if ABC/DTG/3TC is not 
otherwise available from a non-study source. During this time, study visits are targeted to occur 
every 12 weeks. For each child who remains on-study beyond Week 48, once ABC/DTG/3TC 
becomes available from a non-study source, or if it is determined that the child is no longer 
deriving benefit from ABC/DTG/3TC, study participation will be discontinued, with transition 
into local standard HIV care and treatment.  
 
All visits and procedures must be documented in accordance with the DAIDS policies for source 
documentation; refer to Section 11 for more information on documentation requirements and 
entry of eCRFs. Refer to Section 7 for information on expedited adverse event (EAE) reporting, 
which may be required at any time during follow-up. 
 


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6.1 
Screening Visit 
 
Refer to Section 4.4 for a description of the participant recruitment, screening, and enrollment 
process.  
 
Screening procedures may be performed within 30 days prior to enrollment. Multiple visits may 
be conducted to complete all required screening procedures if necessary. Written informed 
consent, and assent if applicable, must be obtained before screening procedures are performed. 
For potential participants who do not meet the eligibility criteria, screening may be discontinued 
once ineligibility is determined.  
 
Screening Visit Procedures (within 30 days prior to enrollment) 
Administrative 
and Regulatory 
• Obtain written informed consent; additionally obtain written assent 
if applicable per IRB/EC policies and procedures 
• Assign PID 
• Obtain screening number from SES 
Clinical 
• Obtain available medical records and medical and medications 
history (refer to Section 0) 
• Perform complete physical examination (refer to Section 0) 
Laboratory 
Blood  
Collect blood for: 
• Confirmatory HIV testing (if needed per criterion 4.1.7) 
• HLA-B*5701 (if needed per criterion 4.1.8) 
• Hepatitis B surface antigen 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Total cholesterol, HDL, LDL, and triglycerides (non-fasting) 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
In the event that a potential participant is initially found to be ineligible, or that the 30-day 
screening period is exceeded before eligibility can be determined, the screening process may be 
repeated. In this case, all screening procedures listed above must be repeated, except that: 
 
• 
A new PID should not be assigned 
• 
Confirmatory HIV testing need not be repeated 
• 
HLA-B*5701 testing need not be repeated 
• 
Previously documented medical and medications history information should be reviewed and 
updated through the date of re-screening (it is not necessary to re-record history information 
that was previously documented) 
 


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6.2 
Entry Visit 
 
Refer to Section 4.4 for a description of the participant recruitment, screening, and enrollment 
process. 
 
All Entry Visit procedures are expected to be performed on the day of enrollment; procedures that 
may provide information relevant to eligibility for the study (e.g., medical and medications 
history, physical examination), should be performed first, prior to final eligibility determination. 
In the event that a potential participant is found to be ineligible on the scheduled day of 
enrollment, enrollment should not occur.  
 
Additional requirements for sequencing of procedures at the Entry Visit are as follows: 
 
• 
Final eligibility determination and confirmation must precede enrollment 
• 
Enrollment must precede prescribing of study drug  
• 
Prescribing must precede dispensing of study drug 
 
Enrollment Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data 
into SES to enroll the participant, print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit (refer to 
Section 0) 
• Perform complete physical exam (refer to Section 0) 
• Administer mood and sleep questionnaire 
Study Drug 
• Prescribe and dispense study drug 
• Provide information on potential study drug side effects and 
provide and explain ABC hypersensitivity alert card 
• Provide study drug storage and use instructions and adherence 
counseling 
• If child is expected to undergo intensive PK sampling at Week 1, 
explain and schedule procedures for daily confirmation of study 
drug dosing and provide instructions for study drug dosing on the 
day of the Week 1 Visit 
• If child is expected to undergo sparse PK sampling at Week 1, 
provide instructions for study drug dosing on the day of the Week 
1 Visit 
Laboratory 
 
Blood 
 
Collect blood for: 
•  HIV-1 RNA 
• Stored whole blood for possible ARV resistance testing 
• Stored whole blood for exploratory evaluations 
 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test** 
*Perform prior to enrollment 
**Collect specimen prior to enrollment and ideally obtain test result prior to enrollment; if result cannot be 
obtained prior to enrollment, it must be obtained by the day after enrollment.  
 
 


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For children expected to undergo intensive PK sampling at the Week 1 Visit, study drug dosing 
will be confirmed on each day between the Entry Visit and the day of intensive PK sampling by 
texted video, video streaming, in-person directly observed therapy, or other method approved by 
the Protocol Team. The Week 1 Visit should be scheduled to occur following confirmed dosing 
on at least four consecutive days prior to the visit. For each day between the Entry Visit and the 
day of intensive PK sampling, all of the following should be source documented and entered into 
eCRFs: 
 
• 
Whether dosing was directly observed and, if so, by what method 
• 
Date and time of observed dose 
• 
Formulation and preparation of observed dose 
• 
Observer’s assessment of whether the observed dose was prepared and administered correctly 
• 
Observer’s assessment of ease of administration 
• 
Observer’s assessment of child’s response to administration 
• 
Any issues or problems with administration identified by the observer 
 
6.3 
Week 1 Visit 
 
The Week 1 Visit is targeted to take place on Day 7, counted from the date of enrollment as Day 
0, with an allowable window of -2 to +3 days (i.e., the visit may take place between Day 5 and 
Day 10, inclusive). Sites are encouraged to schedule this visit early in the allowable window, to 
accommodate re-scheduling if needed (as described below). For children undergoing intensive 
PK sampling, the visit may be re-scheduled up to Day 14 to permit four consecutive days of 
confirmed dosing prior to the visit. Contact the CMC with questions related to whether and when 
intensive PK sampling should be re-scheduled; this may be necessary, for example, due to issues 
involving missed, mis-timed, spit out, or vomited study drug doses or due to non-compliance with 
food intake instructions.  
 
This visit will be conducted for all enrolled children. For each child, either intensive or sparse PK 
sampling will be performed.  
 
• 
Intensive PK sampling will be performed among the first 5-7 children enrolled in each weight 
band. As described in Section 3, these children will either be ART-naïve or switching to the 
study drug regimen from a non-NNRTI-containing regimen. If fewer than five of the first 
seven children enrolled in each weight band are determined to be dose-evaluable, intensive 
PK sampling will be conducted among additional children in order to achieve five dose-
evaluable in each weight band. Additional children may also undergo intensive PK sampling 
if, in the opinion of the Protocol Pharmacologists, a confident determination regarding 
achievement of PK targets cannot be made based on the first 5-7 dose-evaluable children in a 
given weight band.  
 
Note: The Protocol Team will provide frequent updates to all study sites via email regarding 
the number of dose-evaluable children enrolled in each weight band and will notify all sites 
when intensive PK sampling should be discontinued in each weight band. In the event that 
the Protocol Team determines that additional intensive PK sampling is required in a given 
weight band, all sites will be similarly notified.  
 


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For children undergoing intensive PK sampling:  
 
– On each day prior to the Week 1 Visit, study drug should be administered at 
approximately the same time, ideally in the morning. Children receiving dispersible 
tablets should be administered the appropriate number of tablets for their weight band 
following dispersion in the appropriate volume of water. Children receiving immediate 
release tablets should swallow the tablet whole. Study drug administration should be 
confirmed as described in Section 6.2. 
 
– If for any reason administration of study drug is not confirmed on the four days preceding 
the scheduled Week 1 Visit, the visit should be re-scheduled to a later date within the 
allowable visit window, with adherence support provided to help ensure consistent study 
drug administration on the four days preceding the re-scheduled visit date. 
 
– On the day of the Week 1 Visit, the child may eat a low-fat light snack (approximately 
100-150 calories) at least two hours prior to study drug dosing at the study site. Within 
the two hours prior to study drug dosing, and the first hour after study drug dosing, only 
water may be consumed. Liquid formulation concomitant medications should not be 
administered with study drug. 
 
Note: If intensive PK data from this or other pediatric DTG studies indicate a food effect, 
and the Protocol Team determines that further data should be collected for evaluation of 
PK in a non-fasted state, the team will notify all study sites and provide accrual targets, 
guidance for food intake, and other operational instructions for evaluation of additional 
participants. The Schedule of Evaluations in Appendix I and the intensive PK procedures 
described in this section will be followed for any additional participants enrolled for this 
evaluation.  
 
– On the day of the Week 1 Visit, study drug administration should be observed at the 
study site in relation to intensive PK sampling, as indicated below. Study drug 
administration should also ideally occur 22-26 hours after the previous dose.  
 
– If the child spits out the observed dose of study drug or vomits after observed dosing, re-
dosing and intensive PK sampling should be managed as follows: 
 
• 
If the child spits out the observed dose or vomits within 15 minutes after the observed 
dose, study drug should be re-administered and the intensive PK sampling should be 
re-scheduled to occur on another day within the allowable visit window.  
 
• 
If the child vomits more than 15 minutes but within four hours after the observed 
dose, study drug should not be re-administered (the next scheduled dose should be 
taken the next day) and the intensive PK sampling should be re-scheduled to occur on 
another day within the allowable visit window. Intensive PK samples collected 
before the child vomited may be used for analysis. 
 
• 
If the child vomits more than four hours after the observed dose, study drug should 
not be re-administered and the intensive PK sampling should proceed based on the 
timing of the observed dose. All intensive PK samples may be used for analysis. 
 


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Depending on site capacity and participant preferences, children undergoing intensive PK 
sampling and their parents or guardians may stay at the clinical research site overnight. 
Alternatively, they may leave the study site after the 8-hour sampling and return the next day 
for the 24-hour sampling. It is generally expected that a heparin or saline lock will be used to 
avoid multiple needle sticks for intensive PK sampling. 
 
• 
Sparse PK sampling will be performed among all children not undergoing intensive PK 
sampling. On the day of the Week 1 Visit, study drug administration should be observed at 
the study site in relation to sparse PK sampling, as indicated below.  
 
 
 


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Week 1 Visit Procedures (Day 7 -2 to +3 days) 
 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Review documentation of observed daily study drug dosing since the 
Entry Visit  
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• For children undergoing intensive PK sampling:  
– Record last food intake (date and time) 
– Observe and record timing of study drug administration in 
relation to intensive PK sampling 
• For children undergoing sparse PK sampling: 
– If ART-experienced at study entry, record whether pre-study 
ART regimen was NNRTI-containing and, if so, which NNRTI 
was included in the regimen 
– Record details of last food intake (full meal or light snack, high 
or low fat) 
– Record timing of last three doses of study drug 
– Observe and record timing of study drug administration in 
relation to sparse PK sampling 
• If child is expected to complete a Week 2 Visit, provide instructions 
for study drug dosing on the day of the Week 2 Visit 
Laboratory 
 
Blood 
 
For children undergoing intensive PK sampling, collect blood: 
• Prior to observed dosing of study drug (1 mL)  
• 1 hour (±30 minutes) after observed dosing of study drug (1 mL) 
• 2 hours (±30 minutes) after observed dosing of study drug (4 mL) 
• 3 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 4 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 6 hours (±60 minutes) after observed dosing of study drug (1 mL) 
• 8 hours (-15 to +120 minutes) after observed dosing of study drug   
(1 mL) 
• 24 hours (±120 minutes) after observed dosing of study drug (1 mL) 
Note: The 2-hour sample will also be processed for storage of plasma, 
DBS, and PBMC.  
For children undergoing sparse PK sampling, collect blood: 
• Following observed dosing of study drug (4 mL) 
• At least two hours after collection of the first sparse sample (1 mL) 
Note: The first sample will also be processed for storage of plasma, 
DBS, and PBMC. 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
 


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6.4 
Week 2 Visit 
 
The Week 2 Visit will be conducted only for children who switched from a pre-study 
NNRTI-containing ART regimen to the study drug regimen.  
 
The main purpose of this visit is to collect an additional sparse PK sample to enrich population 
PK modeling for these participants, given the potential for prior NNRTI exposure to affect 
observed concentrations of DTG. This visit should not be combined with any other scheduled 
visit. 
 
This visit is targeted to take place on Day 14, counted from the date of enrollment as Day 0, with 
an allowable window of -3 to +7 days (i.e., the visit may take place between Day 11 and Day 21, 
inclusive).  
 
With the exception that study drug should be prescribed and/or dispensed (as needed) after weight 
has been measured as part of the targeted physical exam, there is no required sequencing of 
procedures at this visit. Sparse PK sampling should ideally occur 22-26 hours after the previous 
dose of study drug. 
 
Week 2 Visit Procedures (Day 14 -3 to +7 days) 
Clinical 
Only if clinically indicated based on medical condition at the prior or 
current visit: 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 


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6.5 
Week 4 Visit 
 
The Week 4 Visit is targeted to take place on Day 28, counted from the date of enrollment as Day 
0, with an allowable window of ±14 days (i.e., the visit may take place between Day 14 and Day 
42, inclusive). With the exception that study drug should be prescribed and/or dispensed (as 
needed) after weight has been measured as part of the targeted physical exam, there is no required 
sequencing of procedures at this visit.  
 
Week 4 Visit Procedures (Day 28 ± 14 days) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Administer mood and sleep questionnaire 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Administer adherence questionnaire 
• Administer tolerability (palatability and acceptability) questionnaire 
• For children in weight band #3 or #4, determine whether a change of 
dispersion volume is indicated (see Section 5.2.1) 
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
• If child is expected to complete a Week 6 Visit, provide instructions 
for study drug dosing on the day of the Week 6 Visit 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 


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6.6 
Week 6 Visit 
 
The Week 6 Visit will be conducted only for children who switched from a pre-study 
NNRTI-containing ART regimen to the study drug regimen.  
 
The main purpose of this visit is to collect an additional sparse PK sample to enrich population 
PK modeling for these participants, given the potential for prior NNRTI exposure to affect 
observed concentrations of DTG. This visit should not be combined with any other scheduled 
visit. 
 
This visit is targeted to take place on Day 42, counted from the date of enrollment as Day 0, with 
an allowable window of ±7 days (i.e., the visit may take place between Day 35 and Day 49, 
inclusive).  
 
With the exception that study drug should be prescribed and/or dispensed (as needed) after weight 
has been measured as part of the targeted physical exam, there is no required sequencing of 
procedures at this visit. Sparse PK sampling should ideally occur 22-26 hours after the previous 
dose of study drug. 
 
Week 6 Visit Procedures (Day 42 ± 7 days) 
Clinical 
Only if clinically indicated based on medical condition at the prior or 
current visit:  
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
 
 


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6.7 
Week 8 Visit 
 
The Week 8 Visit will be conducted only for children with a documented M184V mutation.  
 
The main purpose of this visit is to perform additional HIV-1 RNA testing to permit closer 
virologic monitoring for these participants. This visit should not be combined with any other 
scheduled visit. 
 
This visit is targeted to take place on Day 56, counted from the date of enrollment as Day 0, with 
an allowable window of ±7 days (i.e., the visit may take place between Day 49 and Day 63, 
inclusive).  
 
With the exception that study drug should be prescribed and/or dispensed (as needed) after weight 
has been measured as part of the targeted physical exam, there is no required sequencing of 
procedures at this visit.  
 
Week 8 Visit Procedures (Day 56 ± 7 days) 
Clinical 
Only if clinically indicated based on medical condition at the prior or 
current visit:  
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Record timing of last three doses of study drug and food intake 
prior to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
 


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6.8 
Week 12 Visit 
 
The Week 12 Visit is targeted to take place on Day 84, counted from the date of enrollment as 
Day 0, with a targeted window of ±14 days (i.e., Day 70 to Day 98, inclusive) and an allowable 
window of ±42 days (i.e., Day 42 to Day 126, inclusive). Every effort should be made to conduct 
the visit within the targeted window; however, the visit may be conducted on any day within the 
allowable window. With the exception that study drug should be prescribed and/or dispensed (as 
needed) after weight has been measured as part of the targeted physical exam, there is no required 
sequencing of procedures at this visit.  
 
Week 12 Visit Procedures (Day 84 ± 14 days targeted and ± 42 days allowable) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Administer adherence questionnaire  
• Administer tolerability (palatability and acceptability 
questionnaire) 
• Record timing of last three doses of study drug and food intake 
prior to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• 
Pregnancy test 
 


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6.9 
Week 16 and Week 20 Visits 
 
The Week 16 and Week 20 Visits will be conducted only for children with a documented 
M184V mutation.  
 
The main purpose of these visits is to perform additional HIV-1 RNA testing to permit closer 
virologic monitoring for these participants. These visits should not be combined with any other 
scheduled visits.  
 
The Week 16 Visit is targeted to take place on Day 112, counted from the date of enrollment as 
Day 0, with an allowable window of ±14 days (i.e., the visit may take place between Day 98 and 
Day 126, inclusive).  
 
The Week 20 Visit is targeted to take place on Day 140, counted from the date of enrollment as 
Day 0, with an allowable window of ±14 days (i.e., the visit may take place between Day 126 and 
Day 154, inclusive).  
 
With the exception that study drug should be prescribed and/or dispensed (as needed) after weight 
has been measured as part of the targeted physical exam, there is no required sequencing of 
procedures at these visits.  
 
Week 16 and Week 20 Visit Procedures (Day 112 ± 14 days and Day 140 ± 14 days) 
Clinical 
Only if clinically indicated based on medical condition at the prior or 
current visit:  
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Record timing of last three doses of study drug and food intake 
prior to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 


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6.10 
Week 24 Visit 
 
The Week 24 Visit is targeted to take place on Day 168, counted from the date of enrollment as 
Day 0, with a targeted window of ±14 days (i.e., Day 154 to Day 182, inclusive) and an allowable 
window of ±42 days (i.e., Day 126 to Day 210, inclusive). Every effort should be made to 
conduct the visit within the targeted window; however, the visit may be conducted on any day 
within the allowable window. With the exception that study drug should be prescribed and/or 
dispensed (as needed) after weight has been measured as part of the targeted physical exam, there 
is no required sequencing of procedures at this visit.  
 
Week 24 Visit Procedures (Day 168 ± 14 days targeted and ± 42 days allowable) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Administer mood and sleep questionnaire 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Administer adherence questionnaire 
• Administer tolerability (palatability and acceptability) questionnaire  
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Total cholesterol, HDL, LDL, and triglycerides (non-fasting) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
 
 


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6.11 
Week 36 Visit 
 
The Week 36 Visit is targeted to take place on Day 252, counted from the date of enrollment as 
Day 0, with a targeted window of ±14 days (i.e., Day 238 to Day 266, inclusive) and an allowable 
window of ±42 days (i.e., Day 210 to Day 294, inclusive). Every effort should be made to 
conduct the visit within the targeted window; however, the visit may be conducted on any day 
within the allowable window. With the exception that study drug should be prescribed and/or 
dispensed (as needed) after weight has been measured as part of the targeted physical exam, there 
is no required sequencing of procedures at this visit.  
 
Week 36 Visit Procedures (Day 252 ± 14 days targeted and ± 42 days allowable) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Record timing of last three doses of study drug and food intake 
prior to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
 


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6.12 
Week 48 Visit 
 
The Week 48 Visit is targeted to take place on Day 336, counted from the date of enrollment as 
Day 0, with a targeted window of ±14 days (i.e., Day 322 to Day 350 inclusive) and an allowable 
window of ±42 days (i.e., Day 294 to Day 378, inclusive). Every effort should be made to 
conduct the visit within the targeted window; however, the visit may be conducted on any day 
within the allowable window. With the exception that study drug should be prescribed and/or 
dispensed (if applicable and as needed) after weight has been measured as part of the targeted 
physical exam, there is no required sequencing of procedures at this visit. 
 
 
Week 48 Visit Procedures (Day 336 ± 14 days targeted and ± 42 days allowable) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Administer adherence questionnaire 
• Administer tolerability (palatability and acceptability) questionnaire 
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
• If child is exiting the study following completion of this visit, collect 
all remaining study drug supplies.  
• If child is remaining on-study, prescribe and/or dispense study drug 
as needed and provide study drug storage and use instructions, 
adherence counseling, and support as needed 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Total cholesterol, HDL, LDL, and triglycerides (non-fasting) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
At this visit, the site investigator will be required to determine whether the child is deriving 
benefit from ABC/DTG/3TC and, if so, whether ABC/DTG/3TC is available to the child from a 
non-study source.  
 
Children who are not deriving benefit from ABC/DTG/3TC, as well as children who are deriving 
benefit and for whom ABC/DTG/3TC is available from a non-study source, should be 
discontinued from study participation and transitioned into local standard HIV care and treatment. 
At the time of discontinuation, arrangements should be made to provide clinically meaningful test 
results to the parent or guardian; the parent or guardian should also be informed of how to contact 
study staff with any post-study questions and how to learn about the results of the study when 
available. 
 
Children who are deriving benefit from ABC/DTG/3TC for whom ABC/DTG/3TC is not 
available from a non-study source may continue study participation as described in Section 6.13.  
 
Refer to Section 13.11 for considerations related to post-study access to study drug. 


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6.13 
Q12 Week Visits through Week 144 
 
Refer to Section 13.11 for considerations related to post-study access to study drug. 
 
Following completion of the Week 48 Visit, children who are deriving benefit from 
ABC/DTG/3TC may remain on-study for up to an additional 96 weeks if ABC/DTG/3TC is not 
otherwise available from a non-study source. During this time, study visits will be targeted to 
occur every 12 weeks (i.e., at Weeks 60, 72, 84, 96, 108, 120, 132, and 144, counted from the 
date of enrollment as Day 0), with a targeted window of ±14 days and an allowable window of 
±42 days. Every effort should be made to conduct each visit within the targeted window; 
however, these visits may be conducted on any day within the allowable window.  
 
With the exception that study drug should be prescribed and/or dispensed (if applicable and as 
needed) after weight has been measured as part of the targeted physical exam, there is no required 
sequencing of procedures at this visit. 
 
Q12 Week Visit Procedures (Week 60 through Week 144) 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• If child is exiting the study following completion of this visit, collect 
all remaining study drug supplies.  
• If child is remaining on-study following completion of this visit, 
prescribe and/or dispense study drug as needed and provide study 
drug storage and use instructions, adherence counseling, and 
support as needed 
Laboratory 
 
Blood 
 
At Weeks 72, 96, 120, and 144, collect blood for:  
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
For each child who remains on-study beyond Week 48, once ABC/DTG/3TC becomes available 
from a non-study source, or if it is determined that the child is no longer deriving benefit from 
ABC/DTG/3TC, study participation should be discontinued with transition into local standard 
HIV care and treatment. At the time of discontinuation, arrangements should be made to provide 
clinically meaningful test results to the parent or guardian; the parent or guardian should also be 
informed of how to contact study staff with any post-study questions and how to learn about the 
results of the study when available. 
 
 
 


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6.14 
Confirmation of Virologic Failure Visit 
 
Refer to Section 8.3 for more information on monitoring HIV viral load and managing virologic 
failure.  
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥ 200 copies/mL: 
 
• 
For participants who were ART-naïve at enrollment, the two consecutive results should be 
from specimens collected at or after Week 24, counted from the date of enrollment. Any 
ART-naïve participant with an HIV-1 RNA result ≥ 200 copies/mL at or after Week 24 
should be recalled to the clinic to complete a Confirmation of Virologic Failure Visit, per the 
table below and the “Confirm VF” column of the Schedule of Evaluations. The visit should 
take place at least seven days and within 28 days after specimen collection for the initial test. 
 
• 
For participants who were ART-experienced at enrollment, the two consecutive results may 
be from specimens collected at any time after enrollment. Any ART-experienced participant 
with an HIV-1 RNA result ≥ 200 copies/mL at any time after enrollment should be recalled to 
the clinic for a Confirmation of Virologic Failure Visit, per the table below and the “Confirm 
VF” column of the Schedule of Evaluations. The visit should take place at least seven days 
and within 28 days after specimen collection for the initial test.  
 
With the exception that study drug should be prescribed and/or dispensed (as needed) after weight 
has been measured as part of the targeted physical exam, there is no required sequencing of 
procedures at this visit. The required procedures may be combined with regularly scheduled visit 
procedures if they are performed within the allowable window of a regularly scheduled visit.  
 
Confirmation of Virologic Failure Visit Procedures 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
• Prescribe and/or dispense study drug as needed 
• Provide study drug storage and use instructions, adherence 
counseling, and support as needed 
• Administer adherence questionnaire 
• Administer tolerability (palatability and acceptability) questionnaire 
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
Laboratory 
 
Blood 
 
Collect blood for:  
• HIV-1 RNA 
• Genotypic and phenotypic ARV resistance testing (real-time if 
virologic failure is confirmed; otherwise store plasma) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 


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6.15 
Early Discontinuation from Study Visit 
 
Refer to Section 4.6 for criteria for withdrawal from the study. For any participant who is 
withdrawn from the study prior to Week 48, every effort should be made to perform a final series 
of evaluations, if possible, per the table below and the “Early D/C” column of the Schedule of 
Evaluations. However, any evaluations performed within the 28 days prior to the Early 
Discontinuation Visit need not be repeated at the visit.  
 
Premature Discontinuation Visit Procedures 
Clinical 
• Obtain interval medical/medications history (refer to Section 0) 
• Perform targeted physical exam (refer to Section 0) 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically 
indicated (consult CMC if indicated) 
Study Drug 
 
 
• Administer adherence questionnaire 
• Administer tolerability (palatability and acceptability) questionnaire  
• Record timing of last three doses of study drug and food intake prior 
to last dose (full meal or light snack, high or low fat) 
• Collect all remaining study drug supplies 
Laboratory 
 
Blood 
 
Collect blood for: 
• HIV-1 RNA 
• Complete blood count with differential and platelets 
• CD4+ cell count and percentage 
• ALT, AST, total bilirubin, direct bilirubin, creatinine, and eGFR 
(bedside Schwartz formula) 
• Sparse PK sampling with storage of plasma, DBS, and PBMC 
Blood or  
Urine 
If female of reproductive potential, collect blood or urine for: 
• Pregnancy test 
 
Arrangements should be made to provide the participant’s parent or guardian with clinically 
meaningful test results from the Early Discontinuation Visit. The parent or guardian should be 
provided information on how to remain in contact with study staff (if desired) and learn about the 
results of the study when available. The parent or guardian should also be provided information, 
counseling, and referrals to non-study sources of care and treatment for the participant, as 
applicable.  
 
 
 


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Post Exit Visit for Children on Contraception at Last Study Visit  
 
The Post Exit Visit will be conducted only for children who were on contraception at their 
last study visit.  
 
Refer to Section 8.6.1 for study contraception and pregnancy testing requirements. Any 
participant who is on contraception at her last study visit will ideally undergo additional 
evaluations approximately four weeks after her last study visit to update her medical and 
medications history, including her contraceptive history, and test for pregnancy. Other clinical 
evaluations may be performed at the discretion of the examining clinician. There is no required 
sequencing of procedures at this visit. The visit should be source documented in participant study 
records but no eCRF data entries are expected or required. 
 
Post Exit Visit (approximately four weeks after the last study visit)  
Clinical 
• Obtain interval medical/medications history, including but not 
limited to documentation of contraceptive method and other 
concomitant medications since the last study visit 
• Perform targeted physical exam and/or other clinical 
evaluations if clinical indicated as determined by the 
examining clinician 
Laboratory 
 
Blood or  
Urine 
• Collect blood or urine for pregnancy test 
 
6.17 
Medical and Medication History  
 
Collection of medical and medication history information is required at each scheduled visit. A 
baseline history is established at the Screening and Entry Visits and interval (since the last visit) 
histories are obtained at follow-up visits. All history information may be obtained based on 
participant/parent/guardian report, but available medical records should also be obtained when 
possible to supplement reported information.  
 
Documented medical conditions will be assessed for severity as described in Section 7.3.3 and 
new conditions occurring during follow-up will be assessed for relationship to study drug as 
described in Section 8.1. Relevant dates will be recorded for all conditions and medications; refer 
to Section 5.7 for more information on concomitant medications. Table 10 specifies the baseline 
and interval medical and medications history elements that must be source documented, as well 
as associated eCRF entry requirements.  
 
Table 10. IMPAACT 2019 Documentation Requirements for Medical and Medication Histories 
Assess for and  
Source Document 
Enter into  
eCRFs or SES 
Baseline Medical and Medication History Elements 
Date of birth, sex at birth, race, ethnicity  
 
Yes 
Date of HIV diagnosis and current WHO 
clinical stage 
Yes 
All documented HLA-B*5701 test results 
(ever) 
Yes 
Documented resistance to ABC, DTG, and/or 
3TC (ever) 
Yes 


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Assess for and  
Source Document 
Enter into  
eCRFs or SES 
All documented HIV-1 RNA test results 
within the six months prior to enrollment 
Yes 
History of allergy and/or hypersensitivity 
(including to ARVs) 
Yes 
Medical conditions ongoing or occurring 
within the 30 days prior to enrollment  
Yes 
ARVs and all other medications taken within 
the 30 days prior to enrollment  
Yes 
(for liquid formulation medications, includes  
brand name and/or manufacturer,  
dose volume, and sugar alcohol content  
if available) 
For females nine years of age and older, 
reproductive history as applicable: menstrual 
history, sexual activity, and contraceptive use 
Yes 
Any other information needed to determine 
eligibility for the study 
No 
Interval Medical and Medication History Elements 
Current status of conditions that were 
ongoing at the previous visit 
Any updates of previous entries 
(e.g., resolution dates) 
Occurrence of any new conditions since the 
last visit 
All newly identified adverse events 
Current status of medications that were 
ongoing at the previous visit 
Any updates of previous entries  
(e.g., stop dates) 
Use of any new medications since the last 
visit 
All ARVs and concomitant medications 
(including ARV formulation, preparation, and 
administration details, all ARV dose and formulation 
changes, the date of each change, and  
measured weight on the date of each change) 
(for liquid formulation medications, includes  
brand name and/or manufacturer, dose volume, and 
sugar alcohol content if available) 
For females nine years of age and older, 
updates of reproductive history as applicable: 
menstrual history, sexual activity, and 
contraceptive use 
Yes 
For females who become pregnant: 
pregnancy outcome, any congenital 
anomalies identified in the fetus or infant 
Yes 
All ARV resistance test results obtained after 
enrollment 
Transferred electronically to DMC  
using data submission utilities 
(not entered into eCRFs) 
 
 
 


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6.18 
Physical Examinations 
 
Physical examinations are required at most scheduled visits. Complete exams are required at the 
Screening and Entry Visits; targeted exams are required at other visits. 
 
Complete exams should include the following: 
 
• 
Height measurement 
• 
Weight measurement 
• 
Neurologic assessment 
• 
Examination of:  
– General appearance 
– Head 
– Eyes 
– Ears 
– Nose 
– Neck 
– Mouth and throat 
– Lymph nodes 
– Lungs 
– Heart 
– Abdomen 
– Extremities 
– Skin 
– Other body systems driven by identified signs and symptoms  
 
Targeted exams should include the following: 
 
• 
Height measurement 
• 
Weight measurement 
• 
Examination of body systems driven by prior and newly identified signs and symptoms 
 
Additional assessments may be performed at any time at the discretion of the examining clinician. 
Also at all visits, the measurements listed above should be used to determine weight-for-height z-
scores (for children up to five years of age) or body mass index z-scores (for children greater than 
five years of age), which will be assessed in relation to WHO growth standards.  
 
All exam findings should be source documented and all height and weight measurements will be 
entered into eCRFs. Abnormal findings identified prior to enrollment will be entered into medical 
history eCRFs. Abnormal findings identified after enrollment will be entered into adverse event 
eCRFs. 
 
6.19 
Questionnaire Evaluations 
 
Questionnaires will be administered at designated timepoints to collect information on adherence 
to study drug, tolerability (palatability and acceptability) of study drug, and participant mood and 
sleep patterns. All questionnaire data will be entered into eCRFs. 
 


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6.20 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-management 
 
6.20.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the Laboratory Processing Chart (LPC), which will be available on 
the study-specific website: http://impaactnetwork.org/studies/IMPAACT2019.asp. 
 
In accordance with US National Institutes of Health (NIH) recommendations, pediatric blood 
collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg in any eight-week period. In the 
event that blood collection must be limited, available specimens should be prioritized for use in 
the following order: (1) chemistry, (2) hematology, (3) plasma PK, (4) HIV-1 RNA, (5) CD4+ 
cell count and percentage, and (5) stored plasma, DBS, and PBMCs. 
 
6.20.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.20, site and local 
laboratory SOPs, and the LPC. The frequency of specimen collection and testing will be directed 
by the Schedule of Evaluations and specifications for clinical management provided in Section 8. 
The Laboratory Data Management System (LDMS) will be used to document specimen 
collection, testing, storage, and shipping as specified in LPC.  
 
HIV-1 RNA assays must be performed in a laboratory that is CLIA-certified (for US sites) or 
VQA-certified (for non-US sites) for the assay performed. At least one of the diagnostic tests to 
confirm HIV infection per criterion 4.1.7 must be performed in CLIA- certified (for US sites) or 
VQA-certified (for non-US sites) laboratory. For children who experience virologic failure, 
genotypic and phenotypic resistance testing will be performed in real time. Specimens collected 
for resistance testing at Confirmation of Virologic Failure Visits will be processed locally, with 
plasma retained at the site laboratory pending HIV-1 RNA testing to confirm virologic failure. If 
failure is confirmed, plasma from the Confirmation of Virologic Failure Visit will be shipped to a 
designated VQA-certified testing laboratory (residual aliquots will be stored at the site 
laboratory); if failure is not confirmed; all aliquots will remain stored at the site laboratory. 
Testing of Entry Visit samples will be directed by the Protocol Team. 
 
Specimens collected, processed, and stored at site laboratories for intensive PK evaluations are 
expected to be shipped to the designated testing laboratory in real time, or as otherwise directed 
by the Protocol Team. Specimens collected for sparse PK evaluations will be processed for 
storage of plasma, DBS and PBMC consistent with a study-specific SOP that is available on the 
study-specific website: http://impaactnetwork.org/studies/IMPAACT2019.asp. These specimens, 
and all specimens collected, processed, and stored at site laboratories for exploratory evaluations, 
are expected to be shipped to designated central testing laboratories after all participants have 
completed 48 weeks of follow-up, unless otherwise directed by the Protocol Team. 
 


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After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use. Participants’ parents or guardians will be asked to provide written 
informed consent for future research use of these specimens, if permitted by site IRBs/ECs and 
other applicable review bodies; participants will also be asked to provide assent for future 
research use of these specimens when applicable per IRB/EC policies and procedures. 
Participants/parents/guardians may choose to provide or decline this consent/assent with no 
impact on other aspects of study participation.  
 
6.20.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies. All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650. 
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study. Sections 7.1, 7.2, and 7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators. The safety monitoring roles of the CMC and the IMPAACT 
Study Monitoring Committee (SMC) are briefly referenced in Section 7.1 and described in 
greater detail in Section 9.5. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the Protocol Team if unexpected concerns arise. Site investigators will enter safety-
related data into eCRFs as indicated in Section 7.2 and complete EAE reporting as indicated in 
Section 7.3. Site investigators are also responsible for prompt reporting to their IRBs/ECs and 
other applicable review bodies of any unanticipated problems involving risks to participants or 
others. 
 
7.1.2 
Clinical Management Committee 
 
The following Protocol Team members comprise the CMC: Co-Chairs and Vice Chair, Medical 
Officers, Pharmacologists, Statisticians, Data Managers, ViiV representatives, IMPAACT 
Laboratory Center representatives, and Clinical Trial Specialists. The CMC will provide guidance 
as needed to site investigators regarding all aspects of participant management, including but not 
limited to questions of participant eligibility, management of adverse events, and management of 
study drug and other concomitant medications. Refer to Section 8 for more information on 
participant management. 
 


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On behalf of the Protocol Team, the CMC will monitor participant safety through routine review 
of study data reports as described in Section 9.5.1.  
 
7.1.3 
Study Monitoring Committee (SMC)  
 
An independent IMPAACT Study Monitoring Committee (SMC) will monitor participant safety 
through routine and as needed reviews of study data. Refer to Section 9.5.2 for more information 
on the composition and role of the SMC in monitoring of this study.  
 
7.2 
Safety-Related Data Collection 
 
Note: This section describes eCRF data collection for pre-existing conditions and adverse events. 
As part of this description, reference is made to severity grading and criteria for EAE reporting; 
refer to Sections 7.3.3 and 7.3.2, respectively, for detailed information on these topics.  
 
The definition of the term adverse event provided in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) will be used in this study. This 
definition will be applied to all participants, beginning at the time of enrollment, regardless of 
subsequent exposure to study drug. Any untoward medical conditions identified prior to 
enrollment will be considered pre-existing conditions. Refer to Section 4.4 for more information 
on defining the effective point of enrollment in the study. 
Pre-existing conditions and adverse events will be entered into eCRFs as specified below. 
 
Pre-Existing Conditions  
 
All pre-existing conditions (i.e., all grade 1 or higher) identified during the 30 days prior to study 
entry will be entered into medical history eCRFs. Among other details, the severity of all such 
conditions will be entered into these eCRFs. 
 
Adverse Events  
 
All adverse events (i.e., all grade 1 or higher) identified after enrollment will be entered into 
adverse event eCRFs. For any event involving a hypersensitivity reaction to ABC, additional data 
will also be entered into other designated eCRFs.  
 
Laboratory Test Results  
 
All safety-related laboratory test results will be entered into laboratory eCRFs, regardless of 
severity grade and regardless of whether the test was protocol-specified or ordered by the site 
investigator for clinical purposes.  
 
All pregnancy test results will also be entered into laboratory eCRFs; HIV-1 RNA will be entered 
into laboratory eCRFs or transferred electronically to the DMC through the LDMS. ARV 
resistance test results will be transferred electronically to the DMC using data submission 
utilities. 
 


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7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
EAE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE 
Manual), which is available at: 
https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted using the DAIDS EAE Form. This form is available at: 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting 
 
For questions about DAERS, please contact NIAID CRMS Support at: 
CRMSSupport@niaid.nih.gov 
 
Queries may also be sent from within the DAERS application itself.  
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at: 
DAIDSRSCSafetyOffice@tech-res.com 
 
7.3.2 
EAE Reporting Requirements for this Study 
 
The Serious Adverse Event (SAE) reporting category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study. In addition to all serious adverse events, the following 
must also be reported in an expedited manner (i.e., as EAEs): 
 
• 
Hypersensitivity reactions to ABC 
• 
Pregnancy complications that result in medically indicated and/or elective termination of the 
pregnancy  
• 
Spontaneous abortions and fetal deaths 
 
The study drugs for which expedited reporting are required are: 
  
• 
Abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) dispersible tablets 
• 
Abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) immediate release tablets 
• 
Dolutegravir (DTG) dispersible tablets 
• 
Dolutegravir (DTG) tablets 
• 
Abacavir (ABC) tablets 
• 
Lamivudine (3TC) tablets 
 
7.3.3 
Grading Severity of Events (applies to EAEs and all other adverse events) 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study. 
This table is available at: 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables 
 


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7.3.4 
EAE Reporting Period  
 
The EAE reporting period for this study is the protocol-specified period of follow-up, beginning 
at the time of enrollment and continuing through the date of the Week 48 Visit for all participants. 
For participants who continue in follow-up after the Week 48 Visit, the EAE reporting period will 
continue through the last follow-up visit (up to the Week 144 Visit).  
 
After the above-specified period, only suspected, unexpected, serious adverse reactions 
(SUSARs), as defined in Version 2.0 of the DAIDS EAE Manual will be reported if study staff 
become aware of such events on a passive basis (e.g., from publicly available information). 
 
8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
All adverse events identified in this study will be source documented in participant research 
records, consistent with the policies and procedures referenced in Section 11. Among other 
details, source documentation will include the severity of each event (graded as described in 
Section 7.3.3) and its relationship to study drug, assessed by the site investigator according to the 
following categories and definitions: 
 
Related 
There is a reasonable possibility that the adverse event may be related to 
ABC/DTG/3TC 
 
Not related 
There is not a reasonable possibility that the adverse event may be related to 
ABC/DTG/3TC 
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual (referenced in Section 7.3.1). An assessment 
of relationship should be documented for each component agent of the study drug and for the 
combination of agents. As described in greater detail below, adverse events will be managed 
based on their severity and assessed relationship to study drug. 
 
All adverse events must be followed to resolution (return to baseline) or stabilization, with the 
frequency of repeat evaluations determined by the clinical significance of each event. Grade 3 or 
higher laboratory tests should be repeated as soon as possible (within three business days) and all 
grade 3 or higher adverse events should be re-evaluated at least weekly until improvement to 
grade 2 or lower or until stabilized and no longer in need of frequent monitoring, as determined 
by the site investigator in consultation with the CMC. Additional evaluations may be performed 
at the discretion of the site investigator to determine the etiology of a given event and/or further 
assess its severity or relationship to study drug. Clinical management of all adverse events should 
be provided consistent with the best medical judgment of the site investigator and local clinical 
practice standards.  
 
When management of an adverse event requires consultation with the CMC, the CMC 
should be contacted as soon as possible and within three business days of site awareness of 
the event. The CMC should be notified of any interruption of study drug lasting for more 
than three business days. 
 


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The remainder of this section provides further guidance on management of adverse events. 
General guidance is provided in Section 8.1.1. This guidance should be followed for all adverse 
events except the hepatic and renal events addressed in Sections 8.1.2 and 8.1.3. Criteria for 
premature discontinuation of study drug are presented in Section 8.2.  
 
8.1.1 
General Guidance for Management of Adverse Events 
 
Adverse events other than the hepatic and renal events addressed in Sections 8.1.2 and 8.1.3 
should be managed consistent with the guidelines in Table 11.  
 
Table 11. General Guidelines for Adverse Event Management in IMPAACT 2019 
Grade 1 
Continue study drug with routine monitoring per the Schedule of Evaluations 
unless more frequent monitoring is considered clinically indicated in the 
opinion of the site investigator.  
Grade 2 
Continue study drug with routine monitoring per the Schedule of Evaluations 
unless more frequent monitoring is considered clinically indicated in the 
opinion of the site investigator. Evaluate for non-study drug explanations for 
the event. 
Grade 3 
Upon initial identification of a Grade 3 event, the CMC should be notified (as 
soon as possible and within three business days). Non-study drug explanations 
for the event should be considered. The child should be re-evaluated at least 
weekly until improvement to Grade 2 or lower or until stabilized and no longer 
in need of frequent monitoring, as determined by the site investigator in 
consultation with the CMC. 
 
If the initial Grade 3 event is a laboratory abnormality, the test should be 
repeated as soon as possible (within three business days). If an initial Grade 3 
laboratory abnormality is assessed as not related to study drug, study drug may 
be continued while awaiting the repeat test result; otherwise study drug should 
be held. If the repeat test does not yield a Grade 3 result, the event should be 
managed according to the grade of the repeat result. 
 
For Grade 3 clinical events and confirmed Grade 3 laboratory events: 
• If the event is assessed as not related to study drug, study drug should be 
continued (or resumed if previously held). The CMC should be notified of 
the event, the assessment of relationship, and immediate management action 
taken; any subsequent management action should be taken in consultation 
with the CMC. 
• If the event is assessed as related to study drug, study drug should be held 
unless the site investigator feels that continuation of the study drug is in the 
child’s best interest. The CMC should be notified of the event, the 
assessment of relationship, and immediate management action taken; any 
subsequent management action should be taken in consultation with the 
CMC. 
 
If study drug is held, resumption may be considered in consultation with the 
CMC once the event has improved to Grade 2 or lower. If study drug is 
resumed and the event recurs at Grade 3 or higher (confirmed), study drug 
must be permanently discontinued. 


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Grade 4 
Upon initial identification of a Grade 4 event, study drug should be held unless 
the site investigator feels that continuation of the study drug is in the 
participant’s best interest. The CMC should be notified as soon as possible and 
within three business days; notification should occur within one business day if 
study drug is not held. Non-study drug explanations for the event should be 
considered. The child should be re-evaluated at least weekly until 
improvement to Grade 2 or lower or until stabilized and no longer in need of 
frequent monitoring, as determined by the site investigator in consultation with 
the CMC. 
 
If the initial Grade 4 event is a laboratory abnormality, the test should be 
repeated as soon as possible (within three business days). If the repeat test does 
not yield a Grade 4 result, the event should be managed according to the grade 
of the repeat result. 
 
For Grade 4 clinical events and confirmed Grade 4 laboratory events: 
• If the event is assessed as not related to study drug, study drug may be 
resumed with approval from the CMC. If study drug is resumed and the 
event recurs at Grade 3 or higher (confirmed), study drug must be 
permanently discontinued. 
• If the event is assessed as related to study drug, study drug must be 
permanently discontinued. 
 
8.1.2 
Management of Hepatic Toxicity 
 
ALT, AST, total bilirubin, and direct bilirubin will be routinely monitored in this study. If any 
results of severity grade 3 or higher are obtained, all four tests should be repeated as soon as 
possible and within three business days, and re-evaluation should continue at least weekly until 
improvement to grade 2 or lower or until stabilized and no longer in need of frequent monitoring, 
as determined by the site investigator in consultation with the CMC. 
 
Note: Treatment-experienced children on an atazanavir-containing ART regimen prior to 
enrollment are permitted to enter the study with a Grade 3 or higher total bilirubin level. Upon 
enrollment, these children will switch to the study drug regimen; any residual atazanavir should 
be cleared within 2-3 days after switching regimens and total bilirubin levels should normalize 
within two weeks after switching regimens. 
 
Study drug must be held in the following circumstances: 
 
• 
Grade 2 ALT or AST with total bilirubin greater than two times the upper limit of normal 
(>2xULN) and direct bilirubin greater than 35% of total bilirubin. In this case, study drug 
should be permanently discontinued and the CMC should be notified.  
 
• 
Grade 2 or higher ALT or AST with signs or symptoms of clinical hepatitis (e.g., fatigue, 
nausea, vomiting, right upper quadrant pain, jaundice) or hypersensitivity (e.g., rash, fever, 
facial edema, eosinophilia, difficulty breathing). In this case, if another cause of the ALT or 
AST elevation is identified, consideration may be given to resuming study drug with approval 
from the CMC. 
 


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• 
Grade 3 ALT or AST for more than two weeks (with total bilirubin ≤2xULN and no signs or 
symptoms of clinical hepatitis or hypersensitivity). In this case, if another cause of the ALT 
or AST elevation is identified, consideration may be given to resuming study drug, with 
approval from the CMC. 
 
• 
Grade 4 ALT or AST. Hold study drug upon first identification of the Grade 4 result, i.e., 
pending receipt of the repeat test result; inform the CMC of the initial result and the repeat 
result. In the case of a confirmed grade 4 result, if another cause of the ALT or AST elevation 
is identified, consideration may be given to resuming study drug, with approval from the 
CMC. 
 
• 
Grade 3 (confirmed) total or direct bilirubin (with normal or Grade 1 ALT and AST) or any 
occurrence of direct bilirubin greater than 35% of total bilirubin. In this case, if another cause 
of the bilirubin elevation is identified, consideration may be given to resuming study drug, 
with approval from the CMC. 
 
• 
Grade 4 total or direct bilirubin (with normal or grade 1 ALT and AST) or any occurrence of 
direct bilirubin greater than 35% of total bilirubin. Hold study drug upon first identification of 
the Grade 4 result, i.e., pending receipt of the repeat test result; inform the CMC of the initial 
result and the repeat result. In the case of a confirmed Grade 4 result, if another cause of the 
bilirubin elevation is identified, consideration may be given to resuming study drug, with 
approval from the CMC. 
 
Note: Children with Hepatitis B infection will be excluded from this study. If any enrolled 
children are diagnosed with incident Hepatitis B infection during follow-up, the CMC should be 
consulted as soon as possible and within three business days regarding options for clinical and 
ART regimen management. A change to an ART regimen containing TDF and 3TC or FTC 
would generally be expected, if consistent with local HIV and Hepatitis B treatment guidelines, 
thereby necessitating permanent discontinuation of ABC/DTG/3TC (see also Section 8.2). 
However, each case will be managed individually by the site investigator in consultation with the 
CMC. 
 
8.1.3 
Management of Renal Toxicity 
 
Note: DTG can inhibit the tubular secretion of creatinine and can therefore be associated with a 
slight increase in serum creatinine and apparent decrease in the estimated glomerular filtration 
rate (generally by 10% or less). This typically occurs within the first four weeks of treatment with 
DTG and remains stable thereafter and is not associated with renal damage or true decline in renal 
function. 
 
Serum creatinine and eGFR rates will be routinely monitored in this study. At each time point 
when serum creatinine testing is performed, the eGFR rate should be calculated using the bedside 
Schwartz formula:  
 
eGFR (mL/min/1.73 m2) = 0.413 * height (in cm) ÷ serum creatinine (in mg/dL) 
 
Both the serum creatinine level and the eGFR rate should be graded for severity and assessed for 
change from baseline and clinical significance. When abnormal results are obtained, confounding 
factors and other non-study drug explanations (e.g., concomitant medications, concomitant 
illness, dehydration) should be considered and a nephrology consult may be obtained. 


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Children who experience an increase to Grade 2 from a baseline normal or Grade 1 serum 
creatinine level, or an increase to Grade 3 from a baseline Grade 2 creatinine level should 
undergo confirmatory testing within 2-4 weeks. Serum creatinine testing should be repeated and 
if the elevation is confirmed, the CMC should be consulted regarding further follow-up and 
management. 
 
Children who experience a Grade 3 or higher eGFR rate should undergo confirmatory testing 
within 2-4 weeks. If the Grade 3 eGFR rate is confirmed, study drug should be held and the CMC 
should be consulted regarding further follow-up and management.  
 
8.1.4 
Management of Hypersensitivity Reaction to ABC  
 
Serious and sometimes fatal hypersensitivity reactions have occurred with ABC-containing 
products. These reactions have been characterized by two or more of the following signs or 
symptoms: fever; rash; gastrointestinal symptoms (including nausea, vomiting, diarrhea, or 
abdominal pain); constitutional symptoms (including generalized malaise, fatigue, or achiness); 
respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all ABC 
hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and 
symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. 
Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, 
respiratory failure, myolysis, and death have occurred in association with these hypersensitivity 
reactions. Physical findings have included lymphadenopathy, mucous membrane lesions 
(conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some 
patients had other types of rashes and others did not have a rash). There were reports of erythema 
multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine 
phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings 
(predominantly infiltrates, which were localized). 
 
Persons who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity 
reaction. Children screened for this study will be tested for the HLA-B*5701 allele and only 
enrolled if HLA-B*5701-negative. However, the incidence of suspected hypersensitivity 
reactions in clinical trials of ABC was 1% when persons carrying the HLA-B*5701 allele were 
excluded. An association with ABC hypersensitivity reaction has been described with HLA- 
B*5701, HLA-DR7, and HLA-DQ3; if all three of these markers are present, the positive 
predictive value for hypersensitivity reaction is 100%, with a negative predictive value of 97%. 
HLA-B*5701 alone is highly predictive (46). 
 
Children and their parents/guardians will be provided with an ABC hypersensitivity alert card and 
instructed to contact the study sites if they develop a rash at any time while receiving study drug. 
Children with rash should be evaluated for the possibility of a hypersensitivity reaction or serious 
skin reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema 
multiforme (which have been reported very rarely in persons taking ABC). If a serious skin 
reaction develops, ABC and all other concurrent medications suspected by the site investigator as 
potentially causal should be held and the CMC should be consulted. If a diagnosis of ABC 
hypersensitivity is made — or cannot be excluded — in consultation with the CMC, ABC must 
be permanently discontinued, i.e., ABC should never be re-started. The site investigator may also 
discontinue any other concurrent medications suspected as potentially causal. 
 


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8.2 
Criteria for Premature Discontinuation of Study Drug  
 
Administration of study drug will be permanently discontinued in the following circumstances: 
 
• 
A child experiences an adverse event requiring discontinuation of study drug 
• 
A child is diagnosed with Hepatitis B or any other condition requiring a change of ART 
regimen as determined by the site investigator in consultation with the CMC 
• 
A child with confirmed virologic failure is identified with ARV resistant virus requiring a 
change of ART regimen as determined by the site investigator in consultation with the CMC 
• 
A child is unable or unwilling to take study drug or a child’s parent or guardian refuses 
further administration of study drug 
• 
A child becomes pregnant  
• 
The site investigator determines that further administration of study drug would be 
detrimental to the child’s health or well-being 
• 
New data become available indicating that study drug should be discontinued as determined 
by the CMC 
 
Any child who permanently discontinues ABC/DTG/3TC will be transitioned to an alternative 
locally-available ART regimen obtained from non-study standard of care sources. The site 
investigator should make every effort to facilitate this transition and minimize gaps in ART 
coverage to the extent possible.  
 
Any child who permanently discontinues ABC/DTG/3TC for reasons other than an adverse event 
or pregnancy should be discontinued from the study as soon as transition to non-study care and 
treatment is assured. If discontinuation from the study occurs before the Week 48 Visit has been 
conducted, an Early Discontinuation Visit should ideally be conducted as the child’s final study 
visit. 
 
Any child who permanently discontinues ABC/DTG/3TC due to an adverse event should remain 
on-study in order to follow the event to resolution or stabilization of the event at severity grade 2 
or lower. Following resolution or stabilization of the event, the child should be discontinued from 
the study. If discontinuation from the study occurs before the Week 48 Visit has been conducted, 
an Early Discontinuation Visit should ideally be conducted as the child’s final study visit.  
 
Any child who permanently discontinues ABC/DTG/3TC due to pregnancy should remain on-
study until delivery or other outcome of the pregnancy. Study visits and procedures should be 
completed per Section 6 and the Schedule of Evaluations, with the exception that no further PK 
sampling will be performed and no further adherence and tolerability (palatability and 
acceptability) questionnaires will be administered after study drug is discontinued. 
 
8.3 
Monitoring and Management of HIV Viral Load  
 
Monitoring 
 
HIV-1 RNA (viral load) will be monitored closely with frequent testing as specified in the 
Schedule of Evaluations. All HIV-1 RNA assays must be performed in CLIA-certified (US) or 
VQA-certified (non-US) laboratories. Site investigators should review the results of each test as 
well as trends over time and consult with the CMC regarding any individual test results or trends 
of concern. As noted in Section 5.6, viral load results should be provided to 
participants/parents/guardians and used to guide adherence counseling. 


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Definition of Virologic Failure 
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥200 copies/mL. 
For participants who were ART-naïve at enrollment, the two consecutive results should be from 
specimens collected at or after Week 24, counted from the date of enrollment. For participants 
who were ART-experienced at enrollment, the two consecutive results may be from specimens 
collected at any time after enrollment. 
 
Confirmation of Virologic Failure 
 
Any ART-naïve participant with an HIV-1 RNA result ≥200 copies/mL at or after Week 24  
should be recalled to the clinic for confirmatory testing at least seven days and within 28 days 
after specimen collection for the initial test.  
 
Likewise, any ART-experienced participant with an HIV-1 RNA result ≥200 copies/mL at any 
time after enrollment should be recalled to the clinic for confirmatory testing at least seven days 
and within 28 days of specimen collection for the initial test.  
 
As indicated in Section 6.14, specimen collection for genotypic and phenotypic ARV resistance 
testing will also be performed at the time of specimen collection for confirmatory HIV-1 RNA 
testing. All procedures should be performed regardless of reported adherence to study drug or any 
other factors that may affect HIV-1 RNA results. 
 
Management of Confirmed Virologic Failure 
 
The CMC should be consulted regarding management of all participants with confirmed virologic 
failure. 
 
For participants with confirmed virologic failure, upon receipt of the confirmatory HIV-1 RNA 
test result, specimens collected for ARV resistance testing at the Confirmation of Virologic 
Failure Visit should be shipped to a designated VQA-certified testing laboratory. Genotypic and 
phenotypic resistance test results will be provided in real time to help guide ART regimen 
management, as described below. 
 
If the virologic failure is assessed as likely due to non-adherence, the current study drug regimen 
may be continued, with enhanced adherence support per site SOPs and continued virologic 
monitoring. Likewise, if the failure is assessed as due to intercurrent illness or other factors not 
associated with the current study drug regimen, the regimen may be continued. Otherwise, the 
regimen should generally be modified in consultation with the CMC. Recommendations for 
alternative regimens should take into consideration the participant’s preferences and medical 
history, current regimen, current local standard guidelines for first- and second-line regimens, and 
resistance test results.  
 


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8.4 
Management of Tuberculosis 
 
Children who develop active tuberculosis (TB) and need rifampin-containing treatment during 
follow-up may have their study drug regimen modified in consultation with the CMC. It is 
generally expected that the frequency of DTG dosing will be increased from once daily to twice 
daily, using a single agent formulation of DTG for the second daily dose; doses and formulations 
to be provided are shown in Table 12. The CMC should be informed of each TB diagnosis and 
consulted on study drug regimen management on a case-by-case basis. After the period of 
rifampin treatment is completed, the study drug regimen corresponding to the child’s current 
weight should be resumed.  
 
Table 12. Second Daily Dose of DTG for Children in IMPAACT 2019 Who Require Rifampin-Containing TB Treatment 
 
Weight Band 
 
Second Daily Dose of DTG 
#1 6 to less than 10 kg 
DTG 15 mg (three 5 mg dispersible tablets) 
 
#2 10 to less than 14 kg 
DTG 20 mg (four 5 mg dispersible tablets)  
 
#3 14 to less than 20 kg 
DTG 25 mg (five 5 mg dispersible tablets)  
 
#4 20 to less than 25 kg 
DTG 30 mg (six 5 mg dispersible tablets) OR 
DTG 50 mg (one film coated tablet) 
#5 25 kg or greater 
DTG 50 mg (one film coated tablet) 
 
 
To confirm DTG dosing in the therapeutic range, intensive PK sampling will be performed 14-21 
days after initiating rifampin-containing TB treatment. In general, the operational approach to 
intensive PK sampling described in Section 6.3 will be followed. Samples will be collected at the 
following time points and will be shipped and analyzed in real time: 
 
• 
Prior to observed dosing of study drug (1 mL) 
• 
1 hour (±30 minutes) after observed dosing of study drug (1 mL) 
• 
2 hours (±30 minutes) after observed dosing of study drug (4 mL) 
• 
3 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 
4 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 
6 hours (±60 minutes) after observed dosing of study drug (1 mL) 
• 
8 hours (-15 to +120 minutes) after observed dosing of study drug (1 mL) 
• 
12 hours (±120 minutes) after observed dosing of study drug (1 mL) 
 
If analysis of the intensive PK samples indicates that DTG dosing in the therapeutic range has not 
been achieved, together with the site investigator, the CMC will review all available clinical, 
pharmacologic, immunologic, and virologic data for the child and determine whether another 
DTG dose adjustment may be indicated. If a child requires a dose adjustment, a repeat PK 
assessment may be performed for that child, with an appropriate sampling strategy determined by 
the Protocol Pharmacologists, to confirm PK targets are achieved. 
 


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8.5 
Management of Participants with Intensive PK Outcomes Outside the Targeted Range 
 
Refer to Section 10.3.4. For children undergoing intensive PK sampling, PK outcomes will be 
reviewed by the Protocol Team in relation to minimum and maximum tolerated exposure targets 
and consideration will be given to individual dose modification for children whose PK outcomes 
fall outside the targeted exposure range. If a child requires an individual dose adjustment, a repeat 
PK assessment may be performed for that child, with an appropriate sampling strategy 
determined by the Protocol Pharmacologists, to confirm PK targets are achieved. 
 
8.6 
Contraception and Pregnancy 
 
8.6.1 
Contraception and Pregnancy Testing Requirements 
 
Medical history information will be collected at each scheduled visit. For female participants, 
starting at nine years of age, this will include reproductive history information. Date of menarche 
will be recorded (when applicable) and female participants will be considered “of reproductive 
potential” upon experiencing menarche. For female participants of reproductive potential, 
pregnancy testing will be routinely performed and information on sexual activity will be routinely 
collected at each scheduled study visit. Additional pregnancy testing may be performed at any 
time pregnancy is suspected. Pregnancy test results and reported sexual activity will be entered 
into eCRFs.  
 
For female participants of reproductive potential who report sexual activity that could lead to 
pregnancy, use of two methods of contraception will be required while receiving study drug. Use 
of contraception is also recommended following discontinuation of study drug, until such time 
that a clinically insignificant amount of study drug medication is present in the participant (i.e., at 
least five terminal phase half-lives, which corresponds to approximately three days). One of the 
two methods of contraception must be highly effective (see listing in criterion 4.1.10). The 
second method should ideally be a barrier method; male or female condom use will be 
recommended with all other methods of contraception for dual protection against pregnancy and 
to avoid transmission of HIV and other sexually transmitted infections. All methods of 
contraception will be entered into eCRFs. Any female participant of reproductive potential who 
reports sexual activity that could lead to pregnancy who is not willing or able use two methods of 
contraception will be discontinued from the study. 
 
Study staff should actively facilitate access to contraceptive services and, to the extent possible, 
should provide these services to participants on-site. At sites where full service provision is not 
possible, study staff should actively refer participants to local service providers for methods that 
cannot be provided on site. Access to effective contraception should be provided or facilitated for 
all applicable participants. Among other considerations, potential interactions with other 
medications, including but not limited to ARVs, should be considered when selecting an 
appropriate contraceptive method.  
 
Contraceptive counseling should be routinely provided to help ensure adherence to selected 
methods; counseling should also include reminders to inform study staff if participants experience 
issues or problems in accessing or adhering to contraception and/or if they wish to stop using 
contraception. All counseling should be documented in participant study records. 
 


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8.6.2 
Management of Pregnancy 
 
Any participant who becomes pregnant while on-study must be discontinued from study drug and 
transitioned to an alternative locally-available ART regimen obtained from non-study standard of 
care sources as rapidly as possible. The site investigator should make every effort to facilitate this 
transition and minimize gaps in ART coverage to the extent possible. The site investigator should 
also refer the participant to standard of care antenatal services with proactive communication of 
clinical considerations related to conception of the pregnancy while receiving DTG.  
 
The CMC should be informed of the pregnancy and consulted on ARV and clinical management 
for the participant. The participant should remain on-study through delivery or other outcome of 
the pregnancy. Study visits and procedures will be completed per Section 6 and the Schedule of 
Evaluations, with the exception that no further PK sampling will be performed and no further 
adherence and tolerability (palatability and acceptability) questionnaires will be administered. 
 
Study sites are strongly encouraged to prospectively register participants who become pregnant in 
the APR prior to pregnancy outcome by calling the following number in the US: +1-800-258-
4263. Outside the US, see the APR website (www.apregistry.com) for additional toll-free 
numbers. 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is a Phase I/II, multi-site, open-label, multiple dose non-comparative PK and safety study of 
ABC/DTG/3TC dispersible tablets and immediate release tablets in ART-naïve and ART-
experienced HIV-1-infected children less than 12 years of age. The study will be conducted 
among at least 50 and up to 75 children. Children will be enrolled in weight bands and will 
receive ABC/DTG/3TC dispersible tablets or ABC/DTG/3TC immediate release tablets as shown 
in Table 6. Refer to Section 3 for a more complete description of the study design and to Section 
9.4 for a description of the study accrual plan.  
 
PK data analyses will be performed as described in Section 10; all other statistical and data 
analysis considerations are described in the remainder of this section. Refer to Section 9.5.1 for a 
description of dose confirmation analyses and to Section 3.2 for definitions of dose-evaluable, 
safety-evaluable, and PK-evaluable. 
 
Children with no study drug dose adjustments, or with dose adjustments due to weight gain or 
decrease, will be analyzed in the original weight band in which they enrolled. For children whose 
study drug dose is adjusted for reasons other than weight gain or decrease, safety data up to the 
date of dose adjustment will be analyzed in the original weight band, and sensitivity analyses will 
be performed to assess whether conclusions drawn from primary dose confirmation evaluations 
would be affected by inclusion of these data. Children whose study drug regimen is modified due 
to receipt of rifampin-containing TB treatment will be described separately. 
 


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9.2 
Outcome Measures 
 
Note: The numbering of the outcome measures in this section corresponds to the numbering of 
the objectives in Section 2. Details of PK-related outcome measures are provided in Section 10.2.  
 
The primary and secondary outcome measures listed in Sections 9.2.1 and 9.2.2 through Week 24 
will be addressed in the study’s primary statistical analysis plan, which will define the content of 
the primary analysis report. This report will form the basis for the primary study publication and 
initial result reporting to ClinicalTrials.gov. Secondary outcomes listed in Section 9.2.2 through 
Week 48 and Week 144 will be addressed in one or more secondary analysis reports which will 
form the basis for secondary publications and additional result reporting to ClinicalTrials.gov. 
Outcomes of interest for exploratory objectives (intended for subsequent publications) are listed 
in Section 9.2.3. 
 
9.2.1 
Primary Outcome Measures 
9.2.1.1 
 • 
See Section 10.2.1  
 
9.2.1.2 
 • 
All adverse events occurring through Week 24 
• 
Participants with the following through Week 24: 
- Grade 3 or Grade 4 adverse events assessed as related to study drug 
- Grade 5 adverse events assessed as related to study drug 
- Life-threatening adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug 
- Adverse events assessed as related to study drug that lead to permanent 
  discontinuation of study drug 
9.2.2 
Secondary Outcome Measures 
9.2.2.1 
 • 
See Section 10.2.2   
 
9.2.2.2 
 • 
All adverse events occurring through Week 48 
• 
Participants with the following through Week 48: 
- Grade 3 or Grade 4 adverse events assessed as related to study drug 
- Grade 5 adverse events assessed as related to study drug 
- Life-threatening adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug 
- Adverse events assessed as related to study drug that lead to permanent  
  discontinuation of study drug 
• 
All adverse events occurring through Week 144 
• 
Participants with the following through Week 144: 
- Grade 3 or Grade 4 adverse events assessed as related to study drug 
- Grade 5 adverse events assessed as related to study drug 
- Life-threatening adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug 
- Adverse events assessed as related to study drug that lead to permanent    
         discontinuation of study drug 


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9.2.2.3 
 • 
HIV-1 RNA through Week 48 
• 
HIV-1 RNA through Week 144 
• 
Participants with: 
- HIV-1 RNA ≥200 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm) 
- HIV-1 RNA ≥50 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm) 
• 
CD4+ cell count and percentage at Weeks 4, 24, and 48 
• 
CD4+ cell count and percentage through Week 144 
9.2.2.4 
 • 
Total cholesterol, HDL, LDL, and triglycerides at Weeks 24 and 48 
 
9.2.2.5 
 • 
Parent/guardian reported adherence to study drug at Weeks 4, 24, and 48 
• 
Parent/guardian reported tolerability (i.e., palatability and acceptability) of 
study drug at Weeks 4, 12, 24, and 48 
9.2.2.6 
 • 
ARV resistance mutations at time of virologic failure (and at entry for 
children with resistance identified at time of virologic failure) 
9.2.3 
Exploratory Outcome Measures 
9.2.3.1 
 • 
Parent/guardian report of child’s mood and sleep habits at Weeks 4 and 24 
 
9.2.3.2 
• 
See Section 10.2.3   
 
9.2.3.3 
 • 
See Section 10.2.3  
 
9.2.3.4 
 • 
See Section 10.2.3 
 
 
9.3 
Randomization and Stratification  
 
This study does not involve randomization. Enrolled participants will be stratified into weight 
bands based on their weight at the study Entry Visit. Enrollment will also be monitored by the 
Protocol Team to ensure that at least 25 participants are less than six years of age at entry and at 
least 25 are six to less than 12 years of age at entry.  
 
 
9.4 
Sample Size and Accrual 
 
 
 
9.4.1 
Sample Size 
 
The targeted sample size of at least 50 children, with at least 25 less than six years of age and at 
least 25 six to less than 12 years of age, was selected based on the currently agreed PIP and PSP 
for ABC/DTG/3TC. Within the overall target of 50 children, at least 25 — five in each of the 
weight bands shown in Table 6 — must be dose-evaluable for ABC, DTG, and 3TC (defined in 
Section 3.2). A total sample size of up to 75 children has been specified to ensure that at least five 
dose-evaluable children are enrolled in each weight band, to permit additional enrollments if 
confident determinations regarding PK targets cannot be made based on the first 5-7 dose-
evaluable children in each weight band, and to permit additional enrollments if dose adjustment 
and further evaluation of an adjusted dose is needed within any weight band. 
 
Table 13 presents exact 95% confidence intervals (CIs) around potential proportions of 
participants experiencing grade 3 or higher adverse events that may be observed in sample sizes 
ranging from five to 50. The lower sample size of five corresponds to the minimum number to be 
enrolled in each weight band; the middle sample size of 25 corresponds to the minimum number 


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to be enrolled in each age group; and the upper sample size of 50 corresponds to the overall study 
accrual target. Other numbers between five and 50 correspond to possible sample sizes within and 
across weight bands. CIs will be quite wide with the minimum sample size of five participants per 
weight band but considerably more precise with the overall target study accrual target of 50 
participants. 
 
 
Table 13. Percent of Participants Experiencing Grade 3 or Higher Adverse Events with Exact 95% CIs 
N* 
n (%) with  
Grade 3 or Higher Adverse Events 
95% CI 
5 
0 (0%) 
0.0, 52.2 
10 
0 (0%) 
0.0, 30.9 
15 
0 (0%)  
0.0, 21.8 
20 
0 (0%) 
0.0, 16.8 
25 
0 (0%) 
0.0, 13.7 
30 
0 (0%) 
0.0, 11.6 
40 
0 (0%) 
0.0, 8.8 
50 
0 (0%) 
0.0, 7.1 
 
 
 
5 
1 (20%) 
0.5, 71.6 
10 
2 (20%) 
2.5, 55.6 
15 
3 (20%) 
4.3, 48.1 
20 
4 (20%) 
5.7, 43.7 
25 
5 (20%) 
6.8, 40.7 
30 
6 (20%) 
7.7, 38.6 
40 
8 (20%) 
9.1, 35.7 
50 
10 (20%) 
10.0, 33.7 
 
9.4.2 
Accrual 
 
To achieve the targeted sample size described above, accrual is expected to require approximately 
12 months. Accrual into all weight bands will occur concurrently.  
 
Within each weight band, accrual will initially be limited, for purposes of dose confirmation, to 
children who are ART-naïve or switching to the study drug regimen from a non-NNRTI-
containing regimen. Accrual into weight band #1 will initially be restricted to children six months 
(180 days) of age and older. Once the Protocol Team has confirmed that data are available to 
support the specified weight band dosing for children less than six months of age, this restriction 
will be lifted. 
 
A minimum of five dose-evaluable children will be enrolled in each weight band. Refer to 
Section 3.2 for a more detailed description of the number of children who will undergo intensive 
PK evaluations to achieve a minimum of five dose-evaluable in each weight band.  
 


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Guidelines for assessing safety and intensive PK outcomes for purposes of dose confirmation are 
provided in Section 9.5.1. Once the dose confirmation guidelines are met for a given weight band, 
accrual into that weight band will continue with no restriction on enrollment with respect to prior 
NNRTI exposure. As noted in Section 9.5.1, the Protocol Team may consider whether to permit 
enrollment of children switching to the study drug regimen from an NNRTI-containing regimen 
among the dose-evaluable in each weight band. 
 
If the dose confirmation guidelines are not met, the Protocol Team will determine whether to 
adjust the dose for the weight band, as described in Section 10.3.2. If a weight band dose 
adjustment is deemed necessary, 5-7 additional dose-evaluable children will be enrolled to 
confirm the appropriateness of the adjusted dose.  
 
The Protocol Team will closely monitor accrual into each weight band as well as progress made 
toward the age-based quotas, which apply across all weight bands. Accrual into the study overall 
will continue until study drug dosing has been confirmed for each weight band and the age-based 
quotas have been met. The Protocol Team may pause or close accrual into any weight band to 
ensure that these accrual targets are met. 
  
9.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
IMPAACT procedures. A study monitoring plan that details monitoring roles and responsibilities 
and data to be reviewed at each level will be prepared before the study opens to accrual. Sections 
11 and 12 provide for more information on on-site monitoring and quality management at the site 
level. Further information on monitoring of study progress, quality of study conduct, participant 
safety, and PK outcomes across sites is provided below. 
 
9.5.1 
Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and quality of study conduct.  
 
The team will closely monitor participant accrual based on reports that will be generated at least 
monthly by the SDMC. The team has developed a study accrual plan that includes site-specific 
and total enrollment projections over the course of the accrual period, and actual accrual will be 
monitored relative to these projections.  
 
The team will monitor the timing of site-specific study activation, which will determine when 
each site will begin accruing participants, and actual accrual following activation. The number of 
potential participants screened, reasons for screen failures, and the number of participants 
enrolled will be closely monitored. Accrual performance will be reported by the DMC — by site 
and across sites, within and across weight bands, and within and across age groups — and the 
team will review and discuss study progress at least monthly. For any site that is delayed in 
completing the study activation process, or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers the site has encountered and the operational 
strategies and action plans to address these.  
 


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Across sites, the team will closely monitor accrual into each weight band as well as progress 
made toward the age-based quotas. As needed, the team may pause or close accrual into any 
weight band to ensure that the accrual targets and quotas are met. For example, if accrual into one 
of the weight bands is initially much more rapid than accrual into other weight bands, the team 
may pause accrual into that weight band to ensure adequate enrollment into the other weight 
bands. Given that ABC/DTG/3TC immediate release tablets are being evaluated in other studies, 
consideration may be given to limiting accrual into weight band #5 in particular, to ensure that 
accrual targets for all other weight bands (in which dispersible tablets will be evaluated) are met. 
 
The team may also consider, in consultation with the SMC, whether to permit enrollment of 
children switching to the study drug regimen from an NNRTI-containing regimen among the 
dose-evaluable in each weight band. This option would only be considered (i) six months after 
half of the participating study sites have been activated; (ii) if observed rates of accrual into one 
or more weight bands have fallen substantially short of projected rates; and (iii) if PK data from 
other studies (e.g., ODYSSEY) suggest that DTG PK and clinical outcomes among children 
switching from an NNRTI-containing regimen are not likely to differ substantially from PK and 
clinical outcomes among children switching from a non-NNRTI-containing regimen. Should the 
team determine that these conditions have been met, the team will notify the SMC and request 
SMC input on whether to permit enrollment of children switching from an NNRTI-containing 
regimen among the dose-evaluable in a given weight band. The SMC will have the option to 
review the team’s notification, with supporting documentation, via email or to convene a 
teleconference review before providing a recommendation to the team.  
 
The intent of the intensive PK evaluation in this study is to confirm dosing for use of the 
dispersible and immediate release tablets as directed. Consideration may be given, however, to 
permitting alternative preparation and administration of study drug (e.g., crushing immediate 
release tablets) among children undergoing intensive PK sampling if observed rates of accrual 
into one or more weight bands fall substantially short of projected rates, additional data from 
bioavailability studies are supportive of this approach, and potential differences in PK are deemed 
acceptable by the Protocol Team. If these conditions are met, allowances for alternative 
preparation and/or administration of study drug will be specified in a future protocol 
modification.  
 
Additionally, if intensive PK data from this or other pediatric DTG studies indicate a food effect, 
and the Protocol Team determines that further data should be collected for evaluation of PK in a 
non-fasted state, the team will notify all study sites and provide accrual targets, guidance for food 
intake, and other operational instructions for evaluation of additional participants. 
 
The Protocol Team will also monitor participant retention. On behalf of the Protocol Team, the 
CMC will monitor other key indicators of the quality of study conduct (e.g., adherence to study 
drug, specimen completeness, data completeness, data quality, protocol deviations). This 
monitoring will be based on reports generated by the SDMC, and team members will take action 
with study sites as needed to ensure high quality study conduct throughout the period of study 
implementation.  
 


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Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety data reports generated by the SDMC. These reports will be based on the safety-
related data collection described in Section 7.2 and will provide listings and/or tabulations of 
adverse events and laboratory test results. The CMC will assess the relationship of adverse events 
listed in toxicity summary reports and these assessments will be recorded by the SDMC. Except 
in the two specific scenarios listed in this section and in Section 9.5.2, the CMC’s assessments 
will not be used for study-related decision-making. 
 
The CMC will review these reports via conference call or other meeting at least monthly. At the 
time of each call, the DAIDS Medical Officer will also review any EAEs (defined in Section 7.3) 
reported to the DAIDS Safety Office that are not yet reflected in the data reports. The CMC will 
continually evaluate the pattern and frequency of reported events and assess for any individual 
occurrences or trends of concern. The CMC will also monitor for the occurrence of adverse 
events meeting criteria to pause participant accrual and/or convene an ad hoc SMC review, as 
described in the remainder of this section and in Section 9.5.2.  
 
Dose Confirmation for Each Weight Band 
 
Note: Throughout this section the term “dose confirmation” is used to refer to the CMC’s 
determination of the appropriateness of the ABC/DTG/3TC dose for each weight band.  
 
An initial group of 5-7 children will be enrolled in each weight band and undergo intensive PK 
sampling at Week 1. The CMC will review intensive PK and four-week safety data for these 
children at least monthly until dose confirmation has been completed for each weight band. Dose 
confirmation will be based on dose-evaluable children as defined in Section 3.2. The CMC will 
take action as needed according to the PK guidelines described in Section 10.3.1 and the safety 
guidelines described below.  
 
• 
If data from the dose-evaluable children in the weight band meet the PK and safety 
guidelines, and there are no safety concerns based on all available data from all weight bands, 
the dose will be considered appropriate for the weight band and the SMC will be notified as 
described in Section 9.5.2. 
 
• 
If data from the dose-evaluable children in the weight band fail the PK or safety guidelines, 
or there are safety concerns from other weight bands, and the Protocol Team determines that 
an adjusted dose and/or alternative dosing strategy is needed to safely achieve targeted drug 
concentrations, accrual into the weight band will be paused and the SMC will be notified as 
described in Section 9.5.2. Following consultation with the SMC, and unless other 
recommendations are provided by the SMC, 5-7 additional dose-evaluable children will be 
enrolled into the weight band and the adjusted dose will be evaluated as described above. 
 
• 
If data from other children who are evaluable for safety or PK but not both (i.e., are not dose-
evaluable), are available when dose confirmation analyses are performed, these data may be 
included in the analyses. 
 


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• 
If a confident determination regarding achievement of the PK targets cannot be made, 
additional children enrolled in the weight band will undergo intensive PK sampling. The PK 
analysis for the weight band will then be repeated with data from the initial 5-7 children and 
the additional children.  
 
• 
Unless the criteria specified below for pausing participant accrual are met, enrollment into 
each weight band and into the study overall will not be paused while PK and safety data are 
being reviewed. 
 
Safety Guidelines for Dose Confirmation 
 
 
The frequency of adverse reactions occurring among the first 5-7 participants through Week 4 
will be closely monitored. Accrual into all weight bands will be paused if: 
 
(1) Any of the first 5-7 participants in a given weight band experience a fatal or life-threatening 
adverse event assessed as related to study drug  
 
OR 
 
(2) Two or more of the first 5-7 participants in a given weight band experience a grade 3 or 
higher non-fatal and non-life-threatening adverse event assessed as related to study drug or an 
adverse event assessed as related to study drug that results in permanent discontinuation of 
study drug 
 
The above-listed criteria will be applied to safety-evaluable participants. For these criteria, the 
site investigator’s assessment of relationship to study drug will be used. If the CMC has questions 
about or disagrees with the site investigator’s assessment, the CMC will discuss the adverse event 
further with the investigator and ideally come to consensus with the investigator. If consensus 
cannot be achieved, the CMC will request adjudication of the relationship assessment by the 
SMC.  
 
If either of the above-listed criteria are met, accrual will remain paused until a safety review for 
the weight band is conducted by the CMC. All relevant PK and safety data from the weight band, 
as well as all available data from other weight bands, will be reviewed to determine whether it is 
safe to proceed with further evaluation of dosing for the weight band, either at the current dose or 
at an adjusted dose. The SMC will then review all relevant safety and PK data, along with the 
recommendations of the CMC, and will determine whether and under what conditions further 
dose evaluation for the weight band may proceed. Accrual will only be resumed if the CMC 
determines that it is safe to do so, and the SMC agrees. If the safety review leads to a 
recommendation that the dose for the weight band be decreased, the CMC and SMC will also 
review relevant PK data to determine whether a lower dose is likely to achieve adequate drug 
exposures. 
 
If neither of the above-listed criteria are met, and there are no safety concerns from other weight 
bands, the dose for the weight band will be considered to have passed safety guidelines. If PK 
guidelines are also met, the dose will be considered appropriate for the weight band. 
 


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Given the small sample sizes within each weight band, the information available for safety-
related decisions will be imperfect. Two types of sampling errors are possible: 
  
• 
In a group in which the true rate of toxicity is too high to warrant further exposure to the 
selected dose, the sample data may pass the safety guidelines. 
• 
In a group in which the true rate of toxicity is low enough that further exposure to the 
selected dose is warranted, the sample data may fail the safety guidelines.  
 
The extent to which the safety guidelines protect against these errors can be assessed by 
examining various hypothetical rates of "true toxicity" which could occur if the study drug were 
used extensively among the participant population at the dose under evaluation.  
 
 
Table 14 uses a multinomial response model to assess the probability of failing the safety 
guidelines under each of the hypothetical situations in the table. The calculations are performed 
as follows: Each of the total number of participants represents a trial that may have one of three 
mutually exclusive outcomes: (1) a fatal or life-threatening adverse event assessed as related to 
study drug; (2) a grade 3 or grade 4 non-life-threatening adverse event assessed as related to study 
drug or an adverse event assessed as related to study drug that results in permanent 
discontinuation of study drug; and (3) a relatively benign outcome, satisfying neither (1) nor (2).  
 
Table 14. Probability of Failing Dose Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Safety Guideline (2) 
Grade 3 or 4 Non-Life-Threatening  
Related Adverse Events or 
Related Adverse Events that 
Result in Permanent 
Discontinuation of Study Drug 
Safety Guideline (1) 
Life-Threatening or Fatal 
Related Adverse Events  
 
0.50 
0.00 
0.81 
0.50 
0.05 
0.88 
0.50 
0.25 
0.99 
0.25 
0.00 
0.37 
0.25 
0.05 
0.53 
0.25 
0.25 
0.89 
0.05 
0.00 
0.02 
0.05 
0.05 
0.25 
0.05 
0.25 
0.77 
0.00 
0.05 
0.23 
0.00 
0.25 
0.76 
 
 


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Table 14 has its sets of results under which the set of trials would pass the safety guidelines. For 
each of the hypothetical situations, it is assumed that a sample of five participants is drawn from 
the participant population and that the safety guidelines, summarized above, are followed. The 
probability of passing the safety guidelines represents the sum of the probabilities of these sets of 
results, and “1 minus the probability of passing the safety guidelines” represents the probability 
of failing the guidelines. The “True Toxicity Rates” presented in the table, along with the true rate 
of having neither of the two types of adverse events represented by the true toxicity rates (which 
is “1 minus the sum of the true toxicity rates”), provide the probabilities for the outcomes that are 
used in the multinomial calculations for each of the hypothetical situations. 
As an example of how to read  
Table 14, the second row shows that there is an 88% chance of failing the safety guidelines at 
doses in which the true rate of drug related life-threatening adverse events is 5% and the true rate 
of drug-related non-life-threatening adverse events is 50%. 
 
Under the conditions specified in row 2 of the table, assuming that further exposure to a dose that 
has these true rates of adverse events would be undesirable, the 12% chance of NOT failing the 
safety guidelines would represent the probability of error. As a further example, the table also 
shows that there is 2% chance of failing when the true rate of a drug-related grade 3 or 4 non-life-
threatening adverse event is only 5% and the true rate of drug-related life-threatening or fatal 
adverse event is zero. Assuming that the potential benefits associated with further exposure to this 
dose would outweigh the risks associated with this relatively low rate of toxicity, failing the 
safety guidelines under these conditions would be an error. 
 
Note that the Protocol Team may pause accrual across all weight bands if a fatal or life-
threatening adverse event occurring in a given weight band is assessed as related to study 
drug. Thus, the probability of pausing accrual into a given weight band (pending a safety review) 
is somewhat higher than that of failing the safety guidelines within a given weight band (as 
presented in  
Table 14), because accrual into a given weight band may be paused due to events occurring in 
other weight bands. 
 
Safety Guidelines Applicable When Additional Participants are Enrolled in a Weight Band to Attain 
Better Confidence in Evaluation of PK Targets 
 
If additional participants are accrued to attain better confidence in achieving the PK targets, the 
number of participants evaluated for safety will be higher than the N=5 assumed in  
Table 14. In such cases the safety guidelines will be as follows: if any of these participants 
experiences a fatal or life-threatening event that is assessed as related to study drug, or if more 
than 25% of the participants experience a related grade 3 or higher non-fatal and non-life-
threatening adverse event or a related adverse event that results in permanent discontinuation of 
study drug, the dose under evaluation will be considered to have failed the safety guidelines. 
Otherwise, and absent any safety concerns from other weight bands, the dose will be considered 
to have passed the safety guidelines. 
 


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9.5.2 
Monitoring by the SMC 
 
An independent IMPAACT Study Monitoring Committee (SMC) will review this study regularly, 
following policies described in the IMPAACT Manual of Procedures (MOP). The composition of 
the SMC will include the SMC Chair; IMPAACT Chair or Vice Chair; IMPAACT Treatment 
Scientific Committee Chair or Vice Chair; representatives of the IMPAACT Operations Center, 
Statistical and Data Management Center, and Laboratory Center; and representatives of NIAID 
and NICHD.  
 
Routine SMC reviews will occur at least annually and on a more frequent or ad hoc basis if any 
safety issues or concerns arise. The first routine review will take place approximately six months 
after the first participant is enrolled in the study, unless otherwise specified by the SMC. Based 
on any of its reviews, the SMC may recommend that the study proceed as currently designed, 
proceed with design modifications, or be discontinued. The SMC may also provide operational 
recommendations to help address any study implementation challenges that may be identified 
during their reviews.  
 
The SMC will routinely monitor study progress, quality of study conduct, and participant safety. 
The SMC will generally review the same types of data reports as the Protocol Team and CMC; 
for ad hoc reviews, more limited data may be reviewed, focusing on the safety issue or concern 
that triggered the review. 
 
The SMC will also review safety and intensive PK outcomes and the CMC’s assessment of the 
appropriateness of each weight band dose. For each weight band, after the CMC review described 
in Section 9.5.1 has occurred, the CMC will prepare a summary report for the SMC. The SMC 
will then have the option to review the CMC’s notification via email or to convene a 
teleconference review before providing a recommendation with respect to confirmation of the 
dose for each weight band.  
 
In addition to the above, the SMC may conduct ad hoc or triggered safety reviews, for which 
more limited data may be provided, focusing on the events that triggered the reviews. Triggered 
reviews will occur in the following scenarios: 
 
(1) In the event of any adverse event that is fatal or life-threatening, the CMC will review the 
event as soon as possible (ideally within three business days of site awareness) and assess its 
relationship to study drug: 
 
• 
If either the site investigator or the CMC assesses the event as related to study drug, 
accrual into all weight bands will immediately be paused. An ad hoc SMC review will be 
convened as soon as possible to discuss how the study should proceed. 
• 
If the site investigator and the CMC assess the event as not related to study drug, 
participant accrual will continue. The SMC will be informed of the event along with the 
CMC’s assessment and decision-making. 
 
(2) If, after dose confirmation for a given weight band is completed, more than 25% of the 
children enrolled in that weight band experience grade 3 or higher non-fatal and non-life-
threatening adverse events assessed by the site investigator as related to study drug or adverse 
events assessed by the site investigator as related to study drug that result in permanent 
discontinuation of study drug, an ad hoc SMC review will be convened. The SMC will 
review all relevant safety and PK data, along with the recommendations of the CMC, and 
determine whether and under what conditions further accrual into the study may proceed.  


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The CMC may also request an SMC review of any other adverse event or trend of concern. The 
CMC may likewise request an SMC review in the event of an unresolvable disagreement within 
the CMC on an issue that would impact decision-making. The CMC may choose to pause 
participant accrual and/or administration of study drug pending the outcome of the requested 
SMC review.  
 
9.6 
Analyses 
 
9.6.1 
Primary Analyses 
 
Primary safety analyses will include safety outcomes through Week 24. To ensure that these 
analyses yield results that can be generalized to the overall patient population, the primary 
analyses will only include children who were treated with the team’s final dosing 
recommendation. This will include children: (1) whose starting dose of ABC/DTG/3TC is the 
final confirmed dose for their weight band and (2) whose dose may have been increased due to 
weight gain putting them in a higher weight band, provided that the dose received in the higher 
weight band is the dose that would be recommended in the overall patient population who 
experience a similar weight band progression. Participants whose treatment is consistent with (1) 
and (2) above, but who discontinue treatment due to toxicity before Week 24 will be included and 
treated as safety failures in the primary safety analyses. 
 
These primary analyses will be performed after the last participant has completed his or her Week 
24 Visit. Results will be presented by weight band and in aggregate, as well by age group and 
study drug formulation. 
 
All adverse events of all severity grades will be summarized.  
 
Each participant’s safety outcomes will be summarized as (1) the worst grade of adverse events, 
and (2) the worst grade of adverse events assessed as related to study drug. Proportions, bounded 
by exact 95% CIs, will be presented for participants experiencing the following:  
 
• 
Grade 3 or higher adverse events  
• 
Grade 3 or 4 adverse events assessed as related to study drug  
• 
Grade 5 adverse events assessed as related to study drug  
• 
Life-threatening adverse events assessed as related to study drug 
• 
Serious adverse events assessed as related to study drug  
• 
Adverse events assessed as related to study drug that result in permanent discontinuation of 
study drug  
 
Overall proportions of participants experiencing any of these events will be presented, in addition 
to proportions experiencing each type of event.  
 
Listings of all grade 3 or higher adverse events, grade 3 or grade 4 adverse events assessed as 
related to study drug, grade 5 adverse events assessed as related to study drug, life-threatening 
adverse events assessed as related to study drug, serious adverse events assessed as related to 
study drug, and adverse events assessed as related to study drug that result in permanent 
discontinuation of study drug will be provided by System Organ Class and Preferred Terms. 
  
 


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The proportion of participants meeting each of the criteria that trigger an SMC safety review will 
be presented descriptively. 
 
Details concerning the analyses will be included in a separate statistical analysis plan. 
 
For regulatory submission purposes, all the above analyses will be performed and will include all 
participants. Frequency distributions of the safety outcomes will be presented by weight band and 
in aggregate, as well by age group and study drug formulation.  
 
9.6.2 
Secondary Analyses 
 
Safety  
 
The primary safety analyses described in Section 9.6.1 will be repeated as secondary analyses for 
the same participants specified for the primary analyses, but including safety outcomes through 
Week 48, and separately through Week 144. 
 
In addition, further analyses that include safety outcomes through Week 24, Week 48, and Week 
144 for all children who received study drug will be performed. Descriptive and exposure-related 
analyses will present safety outcomes for children whose study drug doses were modified due to 
weight band dose adjustment or who otherwise received doses other than the final confirmed dose 
for their weight band. This will include data representing the final dose for each weight band, as 
well as data representing doses considered to have failed. 
 
For each starting dose, all grade 3 or higher adverse events will be listed, along with participant 
demographics, the dose prescribed to the participant at the time of the event, and the site 
investigator’s assessment of relationship to study drug. 
 
Virologic Response 
 
 
HIV-1 RNA data will be analyzed descriptively and using the FDA snapshot algorithm. 
 
Descriptive analyses will include HIV-1 RNA data available at all timepoints and will present the 
number and percentage of participants with a suppressed viral load at each time point and the 
distribution of non-suppressed viral load values at each timepoint. Data may be presented 
separately for participants who were ART-naïve versus ART-experienced at study entry, as well 
as for participants with a documented M184V mutation, who will undergo additional HIV-1 RNA 
testing per the Schedule of Evaluations. 
  
For analyses using the FDA snapshot algorithm, HIV-1 RNA values for participants who only 
received the final confirmed dose of ABC/DTG/3TC for their weight band will be assessed at 
Weeks 4, 24 and 48. At each time point, the FDA’s snapshot algorithm will be used for the 
definition of virologic outcome, with cutoffs of 200 copies/mL or 50 copies/mL (analyses will be 
performed twice, once at the 200 copies/mL threshold and separately at the 50 copies/mL 
threshold). In addition, participants will be classified as virologic failures if they prematurely 
discontinued study drug prior to Week 4, Week 24, or Week 48.  
 
Otherwise, virologic success or failure will be determined by the last available HIV-1 RNA 
assessment while the participant is on study drug within the visit of interest window (this window 
will be defined in the statistical analysis plan). The proportions of participants meeting the criteria 


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for virologic failure or success at each time point will be bounded by exact 95% CIs and will be 
presented both in the aggregate and by weight band.  
 
In addition, virologic response analysis results will also be presented for all participants who 
received study drug. 
 
Immunologic Response 
 
Median and the associated interquartile range for changes in CD4+ count and percentage from 
baseline to Weeks 4, 24, 48, and up to Week 144, for participants who only received the final 
confirmed dose of ABC/DTG/3TC for their weight band will be presented by weight band and 
aggregated, bounded by 95% CIs. Missing CD4+ values for participants who discontinued study 
drug prior to the time point of interest due to safety or virologic failure will be replaced with their 
baseline CD4+ values. 
 
In addition, immunologic response analysis results will also be presented for all participants who 
received study drug. 
 
Total Cholesterol, HDL, LDL, and Triglycerides 
 
Median and the associated interquartile range for changes in total cholesterol, HDL, LDL, and 
triglycerides from baseline to Weeks 24 and 48 for participants who only received the final 
confirmed dose of ABC/DTG/3TC for their weight band will be presented by weight band and 
aggregated. Missing total cholesterol, HDL, LDL, and triglyceride values for participants who 
discontinued study drug prior to the time point of interest due to safety or virologic failure will be 
replaced with their baseline values. 
 
In addition, changes in total cholesterol, HDL, LDL, and triglycerides from baseline to Weeks 24 
and 48 will also be presented for all participants who received study drug. 
 
Adherence, Palatability and Acceptability 
 
Adherence, palatability and acceptability measures — based on questionnaire responses — will 
be summarized by weight band and aggregated for all participants who received study drug. 
 
As indicated in Section 5.2, acceptability and palatability measures will be reviewed by the 
Protocol Team to determine preferred dispersion volumes for children in weight bands #3 and #4. 
It is generally expected that these data will be reviewed after approximately 20-30 children in 
these weight bands have completed their Week 4 Visits; however, this determination may be 
made at any time in response to accumulating study data.  
 
These data will be presented descriptively. 
 
Antiretroviral Resistance  
 
Participants with confirmed virologic failure (refer to Section 8.3) will be evaluated for viral 
resistance to the components of the study drug regimen. For these participants, resistance 
mutations will be presented descriptively. 
 


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9.6.3 
Exploratory Analyses 
 
Mood and sleep measures — based on questionnaire responses — will be summarized by weight 
band and aggregated for all participants who received study drug. 
 
 
10 
CLINICAL PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
The clinical pharmacology evaluations for this study are designed to determine the steady-state 
PK of DTG, ABC, and 3TC when given as a fixed dose combination dispersible or immediate 
release tablet to children less than 12 years of age. The pharmacology objectives reflect ViiV’s 
currently agreed PIP and PSP and are listed below. For the primary and secondary PK objectives, 
drug concentrations will be quantified in plasma. For the exploratory PK objectives, drug 
concentrations will also be quantified in PBMCs and DBS. 
 
All PK samples will be registered in the LDMS and shipped to the designated central 
pharmacology laboratory; refer to the LPC for shipping details. Intensive PK samples, collected 
at the Week 1 Visit, will be shipped and analyzed in real-time, with results reported to and 
discussed with the Protocol Team as they become available. Sparse PK samples will be analyzed 
in batch after follow-up of all participants has been completed unless otherwise requested by the 
Protocol Team. 
 
Primary 
• 
To determine the steady-state AUC0-24h, Cmax, and C24h of ABC, DTG, and 3TC and confirm 
the dosing of ABC/DTG/3TC dispersible and immediate release tablets that achieve protocol-
defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age 
 
Secondary  
• 
To determine the PK of ABC, DTG, and 3TC, and clinical covariates that influence PK 
disposition, among children less than 12 years of age using population PK analysis of 
intensive and sparse PK samples collected over 48 weeks of treatment with ABC/DTG/3TC 
dispersible and immediate release tablets 
 
Exploratory  
• 
To describe pharmacogenetic associations among children less than 12 years of age receiving 
treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release 
tablets  
• 
To determine concentrations of phosphorylated 3TC and ABC anabolites in PBMCs and DBS 
over 48 weeks of treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC 
immediate release tablets among children less than 12 years of age 
• 
To examine relationships between PK-based adherence measures and other adherence 
measures  
 


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10.2 
Pharmacology Outcome Measures 
 
Note: The numbering of the outcome measures in this section corresponds to the numbering of 
the objectives in Section 2.  
 
 
10.2.1 Primary PK Outcome Measures 
10.2.1.1  • Geometric mean AUC0-24h, Cmax, and C24h for ABC, DTG, and 3TC based on 
analysis of intensive PK samples collected at Week 1 (AUC0-24h and C24h to 
be compared within each weight band to the PK targets specified in Section 
10.3.1)  
10.2.2 Secondary PK Outcome Measures 
10.2.2.1  • AUC0-24h, C0h, C24h, Cmax, Tmax, CL/F, and t1/2 derived from population PK 
modeling with sampling through Week 48 
10.2.3 Exploratory PK Outcome Measures 
10.2.3.2 
• UGT1A1, CYP2B6, and other polymorphisms of interest with respect to 
DTG, 3TC, and/or ABC 
• Association of polymorphisms with PK outcomes 
10.2.3.3  • Concentrations of phosphorylated ABC and 3TC anabolites in PBMCs  
• Concentrations of phosphorylated ABC and 3TC anabolites in DBS  
10.2.3.4  • Associations between phosphorylated ABC and 3TC anabolites and directly 
observed dosing, participant/parent/guardian reported adherence, and drug 
concentrations 
 
10.3 
Pharmacology Study Design, Modeling, and Data Analysis 
 
10.3.1 PK Criteria for Weight Band Dose Confirmation 
 
The steady-state AUC0-24h of ABC, DTG, and 3TC and C24h of DTG will be the primary PK 
parameters used to determine the appropriateness of initial selected weight band doses of 
ABC/DTG/3TC. These parameters will be determined based on analysis of intensive PK samples 
collected from the first five dose-evaluable children enrolled in each weight band (refer to Section 
10.5.1 for analytic methods); if evaluable intensive PK data are also available from other children 
enrolled in each weight band, these data will be included in the analysis (see Section 3.2 for 
definitions of dose-evaluable and PK-evaluable). Children undergoing intensive PK sampling are 
expected to be ART-naïve or switching from a non-NNRTI-containing regimen at enrollment; 
however, consideration may be given to expanding intensive PK sampling to children switching 
from an NNRTI-containing regimen under the conditions pre-specified in Section 9.5.1. 
 
Dose confirmation within each weight band will be based on achieving a geometric mean DTG 
AUC0-24h between 35.1 and 134 μg∙h/mL and C24 between 0.67 and 2.97 μg/mL, and geometric 
mean ABC and 3TC AUC0-24h between 6.3 and 50.4 μg∙h/mL and 6.3 and 26.5 μg∙h/mL, 
respectively, as shown in Table 15. The rationale for these PK targets is described in Section 
1.3.3.  
 
Table 15. AUC0-24h and C24h Targets for Each Weight Band in IMPAACT 2019 
PK 
Parameter 
DTG Targets 
 
ABC Targets 
 
3TC Targets 
Lower  
Upper  
 
Lower  
Upper  
 
Lower  
Upper  
AUC0-24h 
(μg∙h/mL) 
35.1 
134 
 
6.3 
50.4 
 
6.3 
26.5 


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C24h 
(μg/mL) 
0.67 
2.97 
 
— 
— 
 
— 
— 
 
10.3.2 Initial Dose Selection and Weight Band Dose Adjustment 
 
The initial doses selected for evaluation in this study are based on modeling/simulations with 
available data from IMPAACT P1093 and published PK data for DTG, ABC, and 3TC. The 
selected doses of DTG are expected to achieve DTG AUC0-24h similar to that observed with DTG 
50 mg twice-daily in adults. The dosing for ABC and 3TC aligns with WHO weight band dosing 
recommendations of ~16 mg/kg and ~8 mg/kg once-daily, respectively. The selected doses of 
DTG are higher than those previously evaluated in IMPAACT P1093. This is because the doses 
for ABC and 3TC increase in sync with each other and body weight, whereas the increase is not 
the same for DTG. Safety data available from adults with higher DTG doses and exposures 
support the DTG doses selected for evaluation in this study.  
 
For children switching to the study drug regimen from an NNRTI-containing regimen, no pre-
emptive DTG dose adjustments will be made. That is, these children will receive the 
ABC/DTG/3TC dose selected for their respective weight band. In the SWORD 1 and 2 studies in 
adults, no DTG dose adjustments were made following transition from efavirenz or nevirapine to 
DTG with rilpivirine, and trough levels remained above the IC90 at all time points examined (34).  
If the ABC, DTG, or 3TC geometric mean AUC0-24h and/or DTG C24h for a given weight band fall 
outside the targeted range, the Protocol Team will determine whether to adjust the dose for the 
weight band taking into consideration the AUC0-24h and C24h values; clinical, virologic, and 
immunologic responses; and other available data from this and other ongoing and previously 
conducted studies. If the weight band AUC0-24h or C24h fall below or above the targeted PK 
ranges, the Protocol Team may adjust the weight band doses and/or recommend alternative 
dosing strategies, selecting from alternative dosing tables provided in Appendix VI. 
 
The alternative dosing tables are based on currently available PK data and may be updated in the 
future as new data become available from this and other studies. If the Protocol Team deems that 
an adjusted dose and/or alternative dosing strategy is required to achieve the appropriate PK 
targets within a specific weight band, 5-7 additional dose-evaluable children will be enrolled in 
that weight band to confirm the appropriateness of the adjusted dose or alternative dosing 
strategy. Children who received the initial dose for the weight band will be managed on a case-
by-case basis by the site investigator in consultation with the Protocol Pharmacologists and other 
Protocol Team members. Children whose PK outcomes fell outside the targeted range would 
generally be expected to undergo an individual dose adjustment to the same dose to be evaluated 
in the new group of 5-7 children. For children whose PK outcomes fell within the targeted range, 
the Protocol Pharmacologists will discuss options and recommendations with the site investigator, 
who will further discuss these with the child and/or the child’s parent or guardian and determine 
whether to adjust the child’s dose. For any child whose dose is adjusted, a repeat PK assessment 
may be performed in consultation with the Protocol Pharmacologists. 
 
10.3.3 Intensive PK Evaluations 
 
Analyses to determine the appropriateness of initial selected weight band doses of 
ABC/DTG/3TC will be based on a minimum of five children in each weight band. Depending on 
the pace of enrollment and availability of PK results, intensive PK data from additional children 
may also be included in these analyses. Additional children may also undergo intensive PK 
sampling if, in the opinion of the Protocol Pharmacologists, a confident determination regarding 


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achievement of PK targets cannot be made based on the first 5-7 dose-evaluable children in a 
given weight band. Accrual will continue while intensive PK evaluations are performed and the 
appropriateness of each weight band dose is determined.  
 
Children undergoing intensive PK sampling should receive the formulation and preparation of 
study drug specified for their weight band between enrollment and the day of intensive PK 
sampling; i.e., children in weight bands #1-#4 should ingest dispersible tablets following 
dispersion in water and children in weight band #5 should swallow immediate release tablets 
whole. For weight band #5, all efforts should be made to ensure that children are able to swallow 
immediate release tablets whole prior to entry. If a child is enrolled and then found to be unable 
to swallow immediate release tablets whole prior to intensive PK sampling, he or she will be 
permitted to take crushed tablets and will undergo intensive PK sampling, but he or she will not 
be considered PK-evaluable for the weight band. If three or more participants enrolled in weight 
band #5 are unable to swallow the immediate release tablets whole, the Protocol Team may then 
decide to consider children who receive crushed tablets as PK-evaluable. 
 
Children undergoing intensive PK sampling must have confirmed study drug dosing for at least 
four consecutive days leading up to the date of sampling at the Week 1 (Day 5-10) Visit. Dosing 
will be confirmed by texted video, video streaming, in-person directly observed therapy, or other 
method approved by the Protocol Team. If a child misses a dose within the four days prior to the 
intensive PK sampling, the sampling will be postponed (within the allowable visit window) until 
dosing is confirmed for at least four days leading up to the sampling.  
 
The Week 1 Visit should be scheduled so that an observed dose of ABC/DTG/3TC is taken at the 
study site within 22-26 hours of the previous dose. Refer to Section 6.3 for procedures to be 
followed. A heparin or saline lock should be used for intensive PK sample collection if at all 
possible. Samples will be collected as follows:  
 
• Prior to observed dosing of study drug (1 mL) 
• 1 hour (±30 minutes) after observed dosing of study drug (1 mL) 
• 2 hours (±30 minutes) after observed dosing of study drug (4 mL) 
• 3 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 4 hours (±30 minutes) after observed dosing of study drug (1 mL) 
• 6 hours (±60 minutes) after observed dosing of study drug (1 mL) 
• 8 hours (-15 to +120 minutes) after observed dosing of study drug (1 mL) 
• 24 hours (±120 minutes) after observed dosing of study drug (1 mL) 
 
10.3.4 Individual PK Evaluations and Dose Adjustments 
 
Section 10.3.2 provides information on weight band dose adjustments that may be made based on 
AUC0-24h and C24h values observed among dose-evaluable children in each weight band. For 
children undergoing intensive PK sampling, individual dose adjustments may also be considered 
based on individual AUC0-24h and C24h values for DTG.  
 
Consideration will be given to individual dose adjustments if a child’s DTG AUC0-24h or the C24h 
falls outside of the ranges described in the remainder of this section. Individual dose adjustments 
may be made either using ABC/DTG/3TC fixed dose combination tablets or single agent tablets, 
as deemed appropriate by the Protocol Team. Dose adjustments will not be made before the Week 
4 Visit to permit accurate analysis of safety and virologic response to ABC/DTG/3TC. 
 


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The targeted DTG AUC0-24h range for individual participants is 25-134 µg∙h/mL. The lower limit 
is based on maximum effect (Emax) models, where the estimated DTG AUC0-24h required to 
produce 95% of the maximum virologic response (EC95) is 25 μg∙h/mL. The upper limit is based 
on the upper bound of the 90% CI in adults receiving twice-daily DTG in the VIKING studies. 
The geometric mean AUC0-24h at steady state following 50 mg twice daily exposure was 75.1 
µg∙h/mL, with a 90% CI of 40-134 µg∙h/mL. The minimum C24h threshold for individual 
participants is 0.5 µg/mL. This value is based on the EC95 for this PK measure and is significantly 
above the in vivo EC90 (0.3 μg/mL). There have been no toxicities observed in association with 
C24h values, thus no upper limit is defined for individual participants. 
 
Based on the above-described data, the Protocol Team has determined that children undergoing 
intensive PK sampling with an observed DTG AUC0-24h value falling below 25 µg∙h/mL or above 
134 µg∙h/mL, or C24h value falling below 0.5 µg/mL, will be considered for an individual dose 
adjustment.  
 
If a child requires an individual dose adjustment, a repeat PK assessment may be performed for 
that child, to confirm that PK targets are achieved, with an appropriate sampling strategy 
determined by the Protocol Pharmacologists. The Protocol Pharmacologists may also recommend 
that procedures for directly observed therapy (described in Section 6.2) be followed prior to the 
repeat PK assessment, if logistically feasible for the site and the child’s parent or guardian. 
Note: Refer to Section 8.4 for a description of intensive PK evaluations to be performed for 
children who require rifampin-containing TB treatment.  
 
10.3.5 Population PK Evaluations 
 
Blood samples for population PK analysis will be collected as shown in Table 16. At most of 
these visits, one sparse PK sample will be collected. At Week 1, two samples will be collected, 
following observed administration of study drug, at least two hours apart. At Weeks 2 and 6, 
samples should be collected 22-26 hours after the previous dose of study drug. At all visits listed 
below, there is no restriction on the timing of sample collection. However, across participants, 
samples should be collected at different times throughout the 24-hour dosing interval (i.e., not all 
samples collected at the same time post-dose). 
 
Table 16. IMPAACT 2019 Sparse PK Sampling Schedule 
Study Visit 
Population Sampled 
Week 1 
All children not undergoing intensive PK sampling at 
Week 1 (4 mL and 1 mL) 
Week 2 
Only children switching to the study drug regimen 
from an NNRTI-containing regimen (4 mL) 
Week 4 
All children (4 mL) 
 
Week 6 
Only children switching to the study drug regimen 
from an NNRTI-containing regimen (4 mL) 
Weeks 8 
Only children with a documented M184V resistance 
mutation (4 mL) 
Week 12  
 
All children (4 mL) 
 
Weeks 16 and 20 
Only children with a documented M184V resistance 
mutation (4 mL) 


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Weeks 24, 36, and 48 
 
All children (4 mL) 
Confirmation of 
Virologic Failure 
All children completing these visits (4 mL) 
Early Discontinuation 
 
All children completing these visits (4 mL) 
 
10.4 
Sample Size Justification 
 
Power calculations were performed using SAS version 9.4 (Cary, NC) for sample sizes of five 
participants per weight band and 25 total participants undergoing intensive PK assessments for 
the initial dose confirmation of the ABC/DTG/3TC fixed dose combination. Power estimates 
were based on comparison of the minimum and maximum AUC0-24h weight band targets for DTG 
to the geometric mean AUC0-24h value of 53.6 μg∙h/mL (CV 26.9%) reported for once-daily DTG 
in adults (n=449). The lower and upper weight band targets of 35.1 and 134 μg∙h/mL were log-
transformed, equating to 3.558 and 4.898, respectively. The corresponding log-transformed mean 
(SD) for adult data was 3.982 (0.264). Using these inputs with a total sample size of 25 total 
participants, the study has >99.9% power to detect a change from the geometric mean values 
measures in adults to either the lower or upper AUC0-24h targets for DTG using a two-sample t-
test at a significance level of 0.05. For a sample size of five participants within each weight band, 
the study has 94.6% and >99.9% power to detect a difference between the reference data in adults 
and the lower and upper PK targets, respectively.  
 
Power calculations were also performed for comparisons of the geometric mean (%CV) C24h in 
adults of 1.11 μg/mL (46.3%) with the minimum and maximum C24h weight band targets of 0.67 
and 2.97 μg/mL. These calculations were performed using the same procedures detailed for 
AUC0-24h above, results of which are detailed in Table 17 below.  
 
Greater variability in the PK of ABC, DTG, and 3TC will likely be observed in children due to 
differences in formulations, preparations, and adherence in comparison to the historical data used 
for the power estimates above.  
 
Table 17. Power Estimates for Total and Individual Weight Band Sample Sizes 
 
AUC0-24h (Primary) 
 
C24h (Secondary) 
 
Lower Bound 
Upper Bound 
 
Lower Bound 
Upper Bound 
Adult Ln-transformed mean 
3.982 
3.982 
3.982 
3.982 
 
0.104 
0.104 
0.104 
0.104 
2019 Ln-transformed target 
3.558 
3.558 
4.898 
4.898 
 
-0.4 
-0.4 
1.089 
1.089 
Ln-transformed SD 
0.264 
0.264 
0.264 
0.264 
 
0.441 
0.441 
0.441 
0.441 
Adult (reference) sample size 
449 
449 
449 
449 
 
449 
449 
449 
449 
IMPAACT 2019 sample size 
25 
5 
25 
5 
 
25 
5 
25 
5 
Computed power 
>.999 
0.946 
>.999 
>.999 
 
>.999 
0.718 
>.999 
0.999 
 
10.5 
PK Analyses 
 
10.5.1 Noncompartmental PK Analysis 
 
Steady-state PK parameters for DTG, 3TC, and ABC will be determined using non-
compartmental methods based on intensive PK samples collected at the Week 1 (Day 5-10) Visit 
(Phoenix WinNonlin v7.0, Pharsight Corp, Mountain View, CA). PK parameters of interest 
include: area-under-the-concentration-time curve from time 0 to 24 hours (AUC0-24h), maximum 


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plasma concentration (Cmax), time to Cmax (Tmax), plasma concentrations at the beginning (C0h) and 
end of the 24-hour dosing interval (C24h), minimum plasma concentration (Cmin), apparent oral 
clearance (CL/F), apparent volume of distribution (Vz/F), elimination rate constant (ke), and 
terminal half-life (t1/2). Cmax, Tmax, C0h, C24h, and Cmin will be determined from direct observation 
of the concentration versus time profiles. Ke will be determined by calculating the slope of the 
log-linear regression using at least three points during the elimination phase, not including Cmax, 
and t1/2 will be calculated as 0.693 ÷ ke. AUC0-24h will be determined using the linear up-log down 
trapezoidal rule. CL/F will be calculated using the equation CL/F = dose ÷ AUC0-24h. Vz/F will be 
calculated using the equation Vz/F = CL/F ÷ ke.  
 
PK results for ABC, DTG, and 3TC will be reported on an individual basis for each participant 
who undergoes an intensive PK evaluation. Following the completion of PK evaluations in 5-7 
dose-evaluable participants, geometric mean (%CV) AUC0-24h, Cmax, and C24h values will be 
calculated for ABC, DTG, and 3TC. Summary PK results within each weight-band will then be 
compared to relevant PK targets of interest for dose confirmation. 
 
 
 


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10.5.2 Population PK Analysis 
 
The PK characteristics of ABC, DTG, and 3TC will be evaluated using non-linear mixed effects 
modeling (NLME). NLME uses mixed effects (random and fixed) regression to estimate 
population means and variances of PK parameters and to identify intrinsic and extrinsic factors, 
such as body weight, sex or concomitant drug that may influence these parameters. Base models 
will be developed using first-order conditional estimation with or without interaction. A stepwise 
procedure will be used to determine whether a one- or two-compartment model best fits the 
plasma data under the principle of parsimony. A log-normal error distribution will be assumed for 
the description of both interparticipant and intraparticipant (residual) PK parameter variability. If 
necessary, poorly identified structural parameters, such as the absorption rate constant, may be 
fixed. The following covariates will be collected at baseline or during follow-up visits: sex, age, 
weight, race, adherence, etc. The influence of each covariate on the PK characteristics of DTG 
will be tested sequentially. At each step, the goodness of fit plots will also be evaluated. At the 
end of the analysis, all covariates that show an influence on the parameters will be evaluated 
again by comparison of the full model (with all factors included) with a model from which each 
of the factors is deleted sequentially. For forward addition and backward, elimination, a decrease 
in objective function value by 3.84 (p ≤ 0.05) and 6.64 (p ≤ 0.01), respectively, would indicate 
influential covariates. Data from this study may be supplemented with pediatric PK data from 
other DTG studies (e.g., IMPAACT P1093, ODYSSEY) to support structural model and/or 
parameter precision if needed. 
 
NLME uses extended least squares to calculate the objective function and the difference in the 
value of the objective function between models is approximately chi square distributed. A 
difference in objective function of greater than 6.6 is considered significant (6.6 corresponds to a 
chi square for p = 0.01 with 1 degree of freedom) when one parameter is added or the covariate 
(e.g., body weight) is replaced. This is analogous to the commonly used F test to select among 
regression models. The primary outcome of this analysis is to identify the model that best 
describes the plasma PK of DTG and to investigate whether any of the covariates influences the 
PK of DTG. The final model will include all significant covariates (if any) and the parameter 
estimates for all parameters together with the estimates of residual and inter-individual 
variability.  
 
Another objective of this combined analysis will be to develop a linked population PK/PD model 
in NLME to evaluate potential relationships between these PK parameters and therapeutic 
outcomes (e.g., HIV viral load and adverse events).  
 
10.5.3 Exploratory PK Analyses 
 
In addition to plasma PK evaluations, drug concentrations will be characterized in other matrices 
as follows: 
 
• 
Phosphorylated ABC and 3TC moieties in PBMCs 
• 
Phosphorylated ABC and 3TC moieties in DBS 
 


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The active moieties of ABC and 3TC are found intracellularly; thus, examining intracellular 
levels in PBMCs may provide additional insight into exposure-response relationships at the site 
of action for these agents. PBMCs will be processed and stored at time points indicated in Section 
6 and the Schedule of Evaluations, concurrent with sparse PK sampling. Summary statistics and 
graphical representations for concentrations of these active moieties will be generated for each 
time point of interest and may also be used to examine exposure-response relationships with 
therapeutic outcomes. 
 
Drug concentrations in DBS will be quantified and compared to self-reported adherence 
measures. DBS collection is less invasive for quantifying drug levels and may provide improved 
measures of long-term adherence in comparison to plasma PK samples. DBS will be processed 
and stored at time points indicated in Section 6 and the Schedule of Evaluations, concurrent with 
sparse PK sampling. Summary statistics and graphical representations of drug levels in DBS will 
be generated for each time point of interest. Results will be compared to available historical data. 
The effect of covariates such as time post-dose, self-reported adherence leading up to the time 
point of interest, time on ABC/DTG/3TC, and other factors that may influence drug levels will be 
explored. 
 
 
11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC SES. 
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled children, including paper-based CRFs (if 
used), eCRFs, and supporting source data. In maintaining these records, sites must comply with 
the standards of source documentation specified in the DAIDS policy on Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials (available on the 
website referenced in Section 11.2). For participants undergoing directly observed dosing via 
electronic communication, study staff who receive the communication will document the date and 
time of the communication and the required data elements specified in Section 6.2; electronic text 
and/or video data will then be deleted. Electronic files will not be stored as part of participant 
research records. 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC. Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data. Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner. Selected laboratory data 
will be transferred electronically to the DMC through the LDMS or through other secure 
mechanisms. 
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC. A User Manual for the SES is available on the DMC portal at: 
https://www.frontierscience.org 
 


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11.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies. 
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed. Records must be retained for a minimum of 
three years after the completion of the study. Per 21 CFR 312.62, records must be maintained for 
two years after the date a marketing application is approved for the study drug for the indication 
evaluated in this study; or, if no application is filed, or if the application is not approved for this 
indication, records must be retained two years after the study is discontinued and the FDA is 
notified. 
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, ViiV Healthcare Ltd, the FDA, site drug regulatory authorities, site 
IRBs/ECs, OHRP, and other US, local, and international regulatory entities. Records must be kept 
on-site throughout the period of study implementation; thereafter, instructions for off-site storage 
may be provided by NIAID or NICHD. No study records may be removed to an off-site location 
or destroyed prior to receiving approval from NIAID or NICHD.  
 
11.3 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
 
12 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records — including informed consent and assent forms, paper-
based CRFs (if used), eCRFs, medical records, laboratory records, and pharmacy records — to 
ensure protection of study participants, compliance with the IRB/EC approved protocol, and 
accuracy and completeness of records. The monitors also will review essential document files to 
ensure compliance with all applicable regulatory requirements. Site investigators will make study 
facilities and documents available for inspection by the monitors.  
 
 


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13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific informed consent and assent forms in accordance with 45 CFR 46; 
subsequent to initial review and approval, IRBs/ECs must review the study at least annually. Site 
investigators must also promptly report to the IRB/EC any changes in the study and any 
unanticipated problems involving risks to participants or others. 
 
All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files. 
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (see also Section 14.2). 
 
13.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that children be included in clinical research when 
appropriate (47). This study responds to that mandate and will provide clinical research data to 
inform study drug dosing guidelines for children. Nonetheless, the children enrolled in this study 
are considered vulnerable participants per 45 CFR 46 Subpart D. Site IRBs/ECs must consider 
the potential benefits, risks, and discomforts of the study children and assess the justification for 
their inclusion in this study. As part of this assessment, IRBs/ECs must determine the level of risk 
to children in the categories specified in 45 CFR 46.404-407. Documentation of this 
determination is required to complete the DAIDS protocol registration process described in 
Section 14.2, and the risk category assigned by the IRB/EC determines the parental informed 
consent requirements for the study at each site. Per 45 CFR 46.408 (b), the IRB/EC may find that 
the consent of one parent is sufficient for research to be conducted under 46.404 or 46.405. If the 
IRB/EC finds that the research is covered by 46.406 or 46.407, both parents must give their 
consent, unless one parent is deceased, unknown, incompetent, or not reasonably available or 
when only one parent has legal responsibility for the care and custody of the child (as determined 
locally). IRBs/ECs must document their risk determination, and study sites should adapt the 
signature pages of their site-specific informed consent forms as needed to accommodate the 
parental consent requirements associated with the IRB/EC determination. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research: Clinical Research Requirements, which is available 
at: https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
In addition to the US regulations cited above, sites in Botswana, South Africa, and Thailand must 
also comply with all applicable local and national guidelines and regulations.  
 
13.3 
Informed Consent 
 
Refer to Section 4.4 and the study-specific MOP for further information on informed consent 
procedures for this study. Refer to Appendices II-III for sample informed consent forms and to 
Appendices IV-V for sample assent forms. 
 


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Written informed consent for study participation will be obtained from each child’s parent or 
legal guardian before any study-specific procedures are performed. It is generally expected that 
the consent of one parent (or legal guardian) will be sufficient for child participation in this study. 
However, consenting requirements at each site will depend on the IRB/EC risk determination as 
described in Section 13.2; all IRB/EC requirements must be followed. When applicable per site 
IRB/EC policies and procedures, written assent will also be obtained from each child before any 
study-specific procedures are performed. For participants who do not meet IRB/EC criteria for 
providing assent at the time of screening and enrollment, if such criteria are met during follow-
up, assent should be obtained when the criteria are met. 
 
Informed consent process will include information exchange, detailed discussion, and assessment 
of understanding of all required elements of informed consent, including the potential risks, 
benefits, and alternatives to study participation. The process will include a description of what is 
currently known about the safety and efficacy of the study drug and the context of current local 
standards of care for HIV care and treatment. The assent process will include a similar but age-
appropriate discussion. The amount of information and level of detail provided as part of the 
assent process should be tailored to the age and maturity of the potential participant, guided by 
IRB/EC policies and procedures. Sites may develop multiple assent forms, if desired, in 
anticipation of different information needs across the study age range. When preparing site-
specific assent forms, sites may remove or modify the wording included in the sample assent 
forms in order to provide the most appropriate information and level of detail, consistent with 
IRB/EC policies and procedures. 
 
Separate from the main study informed consent and assent processes, parents, legal guardians, 
and/or children will be asked whether they agree to storage and future research testing of 
biological specimens remaining after all protocol-specified testing has been completed. This 
storage and future research testing is optional and may be declined with no impact on other 
aspects of study participation. This informed consent and assent process should ideally be 
conducted at the study Screening or Entry Visit but may be completed at any time up until the 
Week 4 Visit. 
 
Should the consenting parent or legal guardian of an enrolled child die or no longer be available 
for any reason, all applicable IRB/EC policies and procedures should be followed. If the child is 
doing well on study drug, it is generally expected that he or she will stay on study drug with 
safety monitoring evaluations performed consistent with the local standard of care. Other study-
specific evaluations (outside the standard of care) should not be performed until informed consent 
for continued study participation is obtained from the child’s authorized guardian, as defined 
locally. If an authorized guardian cannot be identified, or if the guardian does not consent to 
continued study participation, the child must be withdrawn from the study. In accordance with the 
DAIDS policy on Enrolling Children (including Adolescents) in Clinical Research (available at 
the website referenced in Section 13.2), all sites must establish and maintain written procedures 
describing the standards that will be followed to identify who may serve as guardian for an 
enrolled child, reflective of applicable IRB/EC guidance for conduct of human subjects research 
within the context of available local law, regulation, or government policy. 
 


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13.4 
Potential Benefits 
 
There may or may not be direct benefit to children who take part in this study. Although direct 
benefit cannot be guaranteed, the fixed dose combination of ABC/DTG/3TC has been 
demonstrated as safe, effective, and well-tolerated in adults, and is expected to provide similar 
therapeutic benefits to children. The once daily ABC/DTG/3TC regimen may also facilitate 
correct and consistent dosing for children, compared to other currently available pediatric 
regimens, which often involve twice daily dosing.  
 
Information learned in this study may be of benefit to participating children and others in the 
future, particularly information that may lead to more treatment options for HIV-infected 
children. Children may also appreciate the opportunity to contribute to HIV-related research.  
 
13.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of study drug. 
 
Most study procedures are routine medical procedures that are associated with minimal to no risk. 
Blood collection may cause pain, bruising, swelling, or fainting. There is a very small chance of 
infection where the needle is inserted. 
 
Refer to Section 0, the investigator’s brochures for ABC/DTG/3TC dispersible tablets, and the 
package insert for ABC/DTG/3TC immediate release tablets for a description of the potential 
risks associated with the use of these drugs. For virologically suppressed ART-experienced 
children switching to use of ABC/DTG/3TC, there is a potential additional risk that the 
ABC/DTG/3TC may not be as well-tolerated or as effective in maintaining viral suppression as 
the child’s pre-study ART regimen.  
 
DTG taken at the time of conception or very early pregnancy may be associated with NTDs in the 
fetus. There is no evidence that the risk of NTDs or other birth defects is increased when DTG is 
started after the early first trimester of pregnancy. Every effort will be made in this study to avoid 
the occurrence of new pregnancies among participants taking DTG. 
 
Refer to Section 13.7 for further information on privacy and confidentiality. Despite efforts to 
maintain confidentiality, children’s involvement in this study could become known to others, 
possibly leading to unfair treatment, discrimination, or other social impacts (e.g., because 
participants could become known as having HIV). For example, children could be treated unfairly 
or discriminated against or could have problems being accepted by their families and/or 
communities. For children who undergo directly observed therapy with texted or streaming video, 
there is an additional risk of loss of confidentiality. Videos may not be encrypted and could be 
decoded and viewed by persons not involved in the study. Telephone numbers may also be visible 
to others. Every effort will be made to protect participant information, but this cannot be 
guaranteed. 
 
13.6 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific 
informed consent forms and/or other materials as applicable per IRC/EC policies and procedures.  


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13.7 
Privacy and Confidentiality 
 
Study procedures will be conducted in private and every effort will be made to protect participant 
privacy and confidentiality to the extent possible. Participant information will not be released 
without written permission to do so except as necessary for review, monitoring, and/or auditing as 
described in Section 11.2. 
 
All study-related information will be stored securely. Participant research records will be stored 
in locked areas with access limited to study staff. All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms) will be identified by PID 
only. Likewise, communications between study staff and Protocol Team members regarding 
individual participants will identify participants by PID only.  
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID. All local 
databases must be secured with password protected access systems. Lists, logbooks, appointment 
books, and any other documents that link PID numbers to personal identifying information should 
be stored in a separate locked location in an area with limited access.  
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services. This certificate protects study staff from being 
compelled to disclose study-related information by any US Federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. It thus serves to protect the identity and privacy 
of study participants. Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
13.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
infection identified among study participants to health authorities. Parents and guardians will be 
made aware of all applicable reporting requirements as part of the study informed consent 
process. 
 
13.9 
Management of Incidental Findings 
 
Study staff will inform parents or guardians of all clinically meaningful physical exam findings 
and laboratory test results. When applicable, site investigators will provide referrals to non-study 
sources of medical care for further evaluation and/or treatment of these findings. 
 
The results of intensive PK evaluations will be provided to parents or guardians in real time with 
an explanation as to whether the results fall within the targeted range described in Section 10.3.4. 
The results of other PK evaluations are not planned to be provided to parents or guardians as 
these evaluations will be performed after follow-up has been completed and are not expected to 
be relevant to children’s clinical care and management. If, however, new information becomes 
available during the course of the study indicating that the results of these evaluations are of 
clinical relevance, the results will be provided.  
 


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13.10 Management of New Information Pertinent to Study Participation 
 
Study staff will provide parents or guardians with any new information learned over the course of 
the study that may affect their willingness to allow their children to continue receiving study drug 
and/or remain in follow-up in the study. 
 
13.11 Post-Trial Access to Study Drug 
 
ViiV Healthcare Ltd currently plans to seek licensure of ABC/DTG/3TC for pediatric use in all 
countries where this study will be conducted.  
 
Participants will be transitioned into local standard HIV care and treatment at the end of their 
study participation. If ABC/DTG/3TC is not locally available at that time, ABC/DTG/3TC will 
be provided by ViiV Healthcare Ltd through a mechanism outside of the study until one or more 
of the following occur:  
 
• 
The age-appropriate formulation of ABC/DTG/3TC is locally available from another source  
• 
The participant is no longer deriving benefit from ABC/DTG/3TC  
• 
Clinical development of ABC/DTG/3TC is terminated 
 
For children who are deriving benefit from ABC/DTG/3TC as they complete their Week 48 
Visits, if ABC/DTG/3TC is not otherwise available from a non-study source, follow-up in the 
study — with provision of study supplies of ABC/DTG/3TC — may continue for up to 96 
additional weeks, as described in Section 6.13. For these children, once ABC/DTG/3TC becomes 
available from a non-study source, study participation should be discontinued with transition into 
local standard HIV care and treatment. 
 
 
14 
ADMINISTRATIVE PROCEDURES 
 
14.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the US National Institutes of 
Health (NIH). ViiV Healthcare Ltd will provide study drugs for this study but is not involved in 
sponsorship or regulatory oversight of this study.  
 
Within the NIAID, DAIDS is responsible for regulatory oversight of this study. DAIDS will 
distribute safety-related information pertaining to the study drugs prior to and during the conduct 
of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted. Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 12. As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 


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14.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol informed consent and assent forms approved, as 
appropriate, by their local IRBs/ECs and any other applicable regulatory entity. Upon receiving 
final approval, sites will submit all required protocol registration documents to the DAIDS PRO 
at the RSC. The DAIDS PRO will review the submitted protocol registration packet to ensure that 
all required documents have been received.  
 
Site-specific informed consent and assent forms will be reviewed and approved by the DAIDS 
PRO and sites will receive an Initial Registration Notification from the DAIDS PRO that 
indicates successful completion of the protocol registration process. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC. The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all required documents 
have been received. Site-specific informed consent and assent forms will not be reviewed and 
approved by the DAIDS PRO and sites will receive an Amendment Registration Notification 
when the DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available at:  
 https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
14.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations. Study implementation will also be guided 
by the IMPAACT MOP, study-specific MOP, LPC, and other study implementation materials, 
which will be available on the study-specific website: 
http://impaactnetwork.org/studies/IMPAACT2019.asp. 
 
Study implementation at each site will also be guided site-specific SOPs. The DAIDS policy on 
Requirements for Manual of Operational Procedures specifies the minimum set of SOPs that must 
be established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 11.2). These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
14.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 11.2), all protocol deviations must 
be documented in participant research records. Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 


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Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies. Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT MOP. 
 
14.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity. All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-event-reporting-safety-monitoring 
 
14.6 
ClinicalTrials.gov 
 
This protocol is subject to the Food and Drug Administration Amendments Act of 2007 
(FDAAA), including registration in ClinicalTrials.gov. 
 
 
15 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT MOP.  
 
 
16 
REFERENCES 
 
1. 
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infectedadults and adolescents. Department of Health and Human 
Services. Available at https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf.  
2. 
Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines 
for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at 
https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf.  
3. 
Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations – 
2018 update.  Available at https://www.who.int/hiv/pub/guidelines/ARV2018update/en/. 
4. 
Brenner BG, Wainberg MA. Clinical benefit of dolutegravir in HIV-1 management related to the 
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5. 
Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, et al. Safety, Pharmacokinetics 
and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-
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6. 
Bollen P, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A, et al. Steady-state 
pharmacokinetics and early safety data in HIV-infected African children weighing 14 to <25kg 
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Pediatrics; 2018 Jul 21-22; Amsterdam, Netherlands2018. 
7. 
Ruel T, Acosta E, Singh R, Alvero C, George K, Popson S, et al. Dolutegravir pharmacokinetic, 
safety and efficacy in HIV+ children 2 to < 6 years old.  Conference on Retroviruses and 
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Patel PS, I; Borland, J; Chen, S; Peppercorn, A; Wajima, T; Funaki, T; Fujita, N; Hughes, J; 
Piscitelli, S. Relative bioavailability of a paediatric granule formulation of the HIV integrase 
inhibitor dolutegravir in healthy adult subjects. Antivir Ther. 2014;19(3):5. 
9. 
Buchanan AM, Holton M, Conn I, Davies M, Choukour M, Wynne BR. Relative Bioavailability 
of a Dolutegravir Dispersible Tablet and the Effects of Low- and High-Mineral-Content Water on 
the Tablet in Healthy Adults. Clin Pharmacol Drug Dev. 2017. 
10. 
Singh R AK, Skoura N, Peddiraju K, Davies M, Sewell N, Buchanan A. Comparison of Relative 
Bioavailability of Pediatric Triumeq and Pediatric Dolutegravir/Lamivudine Dispersible Tablets 
to Conventional Film Coated Tablets in Healthy Adults 20th International Workshop on Clinical 
Pharmacology of HIV Hepatitis & Other Antiviral Drugs; May 14-16; Noordwijk, the 
Netherlands 2019. 
11. 
Shapiro R. Birth Outcomes Surveillance in Botswana. United States National Institutes of Health; 
2018. 
12. 
Zash R, Jacobson DL, Diseko M, Mayondi G, Mmalane M, Essex M, et al. Comparative Safety 
of Antiretroviral Treatment Regimens in Pregnancy. JAMA Pediatr. 2017;171(10):e172222. 
13. 
WHO Statement on DTG: Potential safety issue affecting women living with HIV using 
dolutegravir at the time of conception [press release]. Geneva, 18 May 2018. 
14. 
Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim 
Report for 1 January 1989 through 21 January 2018. 2018 ed. Wilmington, NC: Registry 
Coordinating Center; 2018. 
15. 
Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, et al. Neural tube defects 
by antiretroviral and HIV exposure in the Tsepamo Study, Botswana.  IAS Conference on HIV 
Science 2019 Jul 21-24; Mexico City, Mexico 2019. 
16. 
Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G, et al. Neural-Tube Defects 
and Antiretroviral Treatment Regimens in Botswana. N Engl J Med. 2019. 
17. 
Update of recommendations on first-and-second-line antiretroviral regimens. Geneva, 
Switzerland: World Health Organization, 2019 (WHO/CDS/HIV/19.15). 
18. 
LePrevost M, Green H, Flynn J, Head S, Clapson M, Lyall H, et al. Adherence and acceptability 
of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected 
children. Pediatr Infect Dis J. 2006;25(6):533-7. 
19. 
Paediatric European Network for Treatment of A. Pharmacokinetic study of once-daily versus 
twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir 
Ther. 2010;15(3):297-305. 
20. 
Musiime V, Kasirye P, Naidoo-James B, Nahirya-Ntege P, Mhute T, Cook A, et al. Once vs 
twice-daily abacavir and lamivudine in African children. AIDS. 2016;30(11):1761-70. 
21. 
Musiime V, Kendall L, Bakeera-Kitaka S, Snowden WB, Odongo F, Thomason M, et al. 
Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV 
type-1-infected Ugandan children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-24. 
22. 
Moyle G, Boffito M, Fletcher C, Higgs C, Hay PE, Song IH, et al. Steady-state pharmacokinetics 
of abacavir in plasma and intracellular carbovir triphosphate following administration of abacavir 
at 600 milligrams once daily and 300 milligrams twice daily in human immunodeficiency virus-
infected subjects. Antimicrob Agents Chemother. 2009;53(4):1532-8. 
23. 
Weller S, Radomski KM, Lou Y, Stein DS. Population pharmacokinetics and pharmacodynamic 
modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy 
trial with human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. 
2000;44(8):2052-60. 
24. 
McDowell JA, Lou Y, Symonds WS, Stein DS. Multiple-dose pharmacokinetics and 
pharmacodynamics of abacavir alone and in combination with zidovudine in human 
immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000;44(8):2061-7. 


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25. 
Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure 
Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health 
Services. JAMA Intern Med. 2016;176(1):75-84. 
26. 
Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, et al. 1592U89, a novel 
carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. 
Antimicrob Agents Chemother. 1997;41(5):1082-93. 
27. 
Lewis LL, Venzon D, Church J, Farley M, Wheeler S, Keller A, et al. Lamivudine in children 
with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute 
Pediatric Branch-Human Immunodeficiency Virus Working Group. J Infect Dis. 1996;174(1):16-
25. 
28. 
Fletcher CV, Kawle SP, Kakuda TN, Anderson PL, Weller D, Bushman LR, et al. Zidovudine 
triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected 
persons. AIDS. 2000;14(14):2137-44. 
29. 
Epzicom [package insert]. Research Triangle Park, NC: ViiV Healthcare, Inc.; 2017. 
30. 
Pluda JM, Cooley TP, Montaner JS, Shay LE, Reinhalter NE, Warthan SN, et al. A phase I/II 
study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced human 
immunodeficiency virus infection. J Infect Dis. 1995;171(6):1438-47. 
31. 
Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, et al. Safety and efficacy of 
dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-
week results of the VIKING Study. J Infect Dis. 2013;207(5):740-8. 
32. 
Castagna A, Maggiolo F, Penco G, Wright D, Mills A, Grossberg R, et al. Dolutegravir in 
antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week 
results of the phase III VIKING-3 study. J Infect Dis. 2014;210(3):354-62. 
33. 
Akil B, Blick G, Hagins DP, Ramgopal MN, Richmond GJ, Samuel RM, et al. Dolutegravir 
versus placebo in subjects harbouring HIV-1 with integrase inhibitor resistance associated 
substitutions: 48-week results from VIKING-4, a randomized study. Antivir Ther. 
2015;20(3):343-8. 
34. 
Adkison K KL, Blair E, et al. Pharmacokinetics of dolutegravir and rilpivirine after switching to 
the two-drug regimen from an efavirenz- or nevirapine-based antiretroviral regimen: SWORD-1/2 
pooled PK analysis.  18th International Workshop on Clinical Pharmacology of Antiviral 
Therapy; June 14-17, 2017; Chicago, IL2017. 
35. 
Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, et al. 
Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent 
and cumulative drug exposure. AIDS Res Hum Retroviruses. 2013;29(2):384-90. 
36. 
Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, et al. 
Emtricitabine-Triphosphate in Dried Blood Spots as a Marker of Recent Dosing. Antimicrob 
Agents Chemother. 2016;60(11):6692-7. 
37. 
Anderson PL, Liu AY, Castillo-Mancilla JR, Gardner EM, Seifert SM, McHugh C, et al. 
Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots 
following Directly Observed Therapy. Antimicrob Agents Chemother. 2018;62(1). 
38. 
Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure 
Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. N Engl J Med. 
2010;363(27):2587-99. 
39. 
Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, et al. Uptake of pre-
exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who 
have sex with men: a cohort study. The Lancet Infectious Diseases. 2014;14(9):820-9. 
40. 
Hosek SG, Rudy B, Landovitz R, Kapogiannis B, Siberry G, Rutledge B, et al. An HIV 
Preexposure Prophylaxis Demonstration Project and Safety Study for Young MSM. J Acquir 
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Seifert SM, Castillo-Mancilla JR, Erlandson K, Morrow M, Gandhi M, Kuncze K, et al. Brief 
Report: Adherence Biomarker Measurements in Older and Younger HIV-Infected Adults 
Receiving Tenofovir-Based Therapy. J Acquir Immune Defic Syndr. 2018;77(3):295-8. 
42. 
Castillo-Mancilla JR, Searls K, Caraway P, Zheng J-H, Gardner EM, Predhomme J, et al. Short 
Communication: Tenofovir Diphosphate in Dried Blood Spots As an Objective Measure of 
Adherence in HIV-Infected Women. AIDS Res Hum Retroviruses. 2015;31(4):428-32. 
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Chen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect of 
UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 2014;15(1):9-
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McCoig C.,. Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in 
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46. 
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence 
of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase 
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Participants in Research Involving Human Subjects. 1998 March 6. Report No. 
 


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Appendix I: Schedule of Evaluations through Week 48 
 
 
Screen 
Entry 
Weeks on Study 
Confirm 
VF 
Early 
DC 
Post 
Exit6 
Study Visit 
up to  
-30 days 
Day 0 
1 
21 
4 
61 
82 
12 
162 
202 
24 
36 
48 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and medication history 
X 
X 
X 
[X] 
X 
[X] 
[X] 
X 
[X] 
[X] 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
[X] 
X 
[X] 
[X] 
X 
[X] 
[X] 
X 
X 
X 
X 
X 
[X] 
Study drug adherence and 
tolerability questionnaires 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Mood and sleep questionnaire 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmatory HIV testing  
(if needed)  
0-6mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-B*5701 (if needed) 
0-3mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B surface antigen 
2mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
X 
HIV-1 RNA 
3mL 
3mL 
 
 
3mL 
 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
 
CBC with differential and platelets 
1mL 
 
 
 
1mL 
 
 
1mL 
 
 
1mL 
1mL 
1mL 
 
1mL 
 
CD4+ cell count and percentage 
1mL 
 
 
 
1mL 
 
 
1mL 
 
 
1mL 
 
1mL 
 
1mL 
 
ALT, AST, total bilirubin, direct 
bilirubin, creatinine, eGFR  
2mL 
 
 
 
2mL 
 
 
2mL 
 
 
2mL 
2mL 
2mL 
 
2mL 
 
Total cholesterol, HDL, LDL, and 
triglycerides (non-fasting) 
1mL 
 
 
 
 
 
 
 
 
 
1mL 
 
1mL 
 
 
 
ARV resistance testing4 
 
 
 
 
 
 
 
 
 
 
 
 
 
3mL 
 
 
Intensive PK sampling5 
(store plasma, DBS, and PBMC) 
 
 
11mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sparse PK sampling5  
(store plasma, DBS, and PBMC) 
 
 
5mL 
4mL 
4mL 
4ml 
4mL 
4ml 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
4mL 
 
Stored whole blood  
 
4mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Blood Volume 
10-19 
mL 
7 
mL 
5 or 11 
mL 
4 
mL 
11 
mL 
4 
mL 
7 
mL 
11 
mL 
7 
mL 
7 
mL 
12 
mL 
10 
mL 
12 
mL 
10 
mL 
11 
mL 
0-1  
mL 
 
 
 


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Appendix I: Schedule of Evaluations through Week 48 Footnotes 
 
[X] = if clinically indicated. 
1The Week 2 and Week 6 Visits will be conducted only for participants switching to the study drug regimen from an NNRTI containing regimen. 
2The Week 8, Week 16, and Week 20 Visits will be conducted only for children with a documented M184V mutation.  
3Pregnancy tests are required only for female participants of reproductive potential. Urine (5 mL) or blood (1 mL) tests may be performed. At sites 
performing blood tests, the total blood volume would be 1 mL greater than shown in the table above. 
4Genotypic and phenotypic ARV resistance testing of plasma collected at the Confirmation of Virologic Failure Visit will be performed in real time 
if virologic failure is confirmed; otherwise, the plasma sample collected for this purpose will be stored. Refer to Section 6.14 and Section 8.3 for 
additional detailed information. 
5At Week 1, each participant will either undergo either intensive PK sampling or sparse PK sampling. After Week 1, all participants will undergo 
sparse PK sampling. Refer to Section 6.3 and Section 10 for additional detailed information on sampling volumes and time points. Refer to the LPC 
for sample processing, storage, and shipping instructions. 
6The Post Exit Visit will be conducted only for participants who are on contraception at their last study visit.  
 


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Appendix I: Schedule of Evaluations after Week 48 
 
Study Visit 
Q12 Weeks1 
Confirm VF 
Post Exit5 
CLINICAL EVALUATIONS 
 
 
 
Medical and medication history 
X 
X 
X 
Physical examination 
X 
X 
[X] 
Study drug adherence and tolerability 
questionnaires 
 
X 
 
LABORATORY EVALUATIONS 
 
 
 
Pregnancy test2 
[X] 
[X] 
X 
HIV-1 RNA 
3mL (Q24) 
3mL 
 
CBC with differential and platelets 
1mL (Q24) 
 
 
CD4+ cell count and percentage 
1mL (Q24) 
 
 
ALT, AST, total bilirubin, direct bilirubin, 
creatinine, eGFR  
2mL (Q24) 
 
 
ARV resistance testing3 
 
3mL 
 
Sparse PK sampling4  
(store plasma, DBS, and PBMC) 
 
4 mL 
 
Total Blood Volume 
7mL (Q24) 
10mL 
 
 
1Refer to Section 6.13. Following completion of the Week 48 Visit, children who are deriving benefit from 
ABC/DTG/3TC may remain on-study for up to an additional 96 weeks if ABC/DTG/3TC is not otherwise available 
from a non-study source. During this time, study visits will be targeted to occur every 12 weeks (i.e., at Weeks 60, 
72, 84, 96, 108, 120, 132, and 144 with clinical evaluations performed every 12 weeks and laboratory performed at 
every 24 weeks (i.e., at Weeks 72, 96, 120, and 144). 
2Pregnancy tests are required only for female participants of reproductive potential. Urine (5 mL) or blood (1 mL) 
tests may be performed. At sites performing blood tests, the total blood volume would be 1 mL greater than shown 
in the table above. 
3Genotypic and phenotypic ARV resistance testing will be performed in real time if virologic failure is confirmed; 
otherwise, the sample collected for this purpose will be stored. Refer to Section 6.14 and Section 8.3 for additional 
detailed information. 
4Refer to the LPC for sample processing, storage, and shipping instructions. 
5The Post Exit Visit will be conducted only for participants who are on contraception at their last study visit.   
 
 


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Appendix II: Sample Informed Consent Form for Study Participation 
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, 4 September 2019 
 
 
Introduction 
 
Your child is being asked to take part in the research study named above. 
 
This form gives information about the study. Please read it or have it read to you. Ask any questions you 
may have. We will take as much time as needed for you to fully understand the study. We will ask you 
questions to see if we have explained the study clearly. 
 
Here is a summary of important information about the study: 
 
• 
The study is testing a new combination of anti-HIV medicines (ARVs) for children less than 12 years 
of age. 
• 
The new combination is a tablet that contains 3 ARVs. The ARVs are called abacavir, dolutegravir, 
and lamivudine.  
• 
The new combination is approved for older children and adults. It has not yet been tested for younger 
children. 
• 
Children will be in the study for at least 1 year and up to 3 years. 
• 
While in the study, children will have clinic visits with physical examinations and blood draws for 
laboratory tests. Parents will answer questions about children’s health, the tablets being tested, and 
other medicines. 
• 
There are possible risks for children in the study. One possible risk is that the tablets being tested 
could cause side effects. The most severe side effects include allergic reactions, liver problems, and 
mental health problems. These side effects are rare.   
• 
There are possible benefits for children in the study. One possible benefit is that the tablets being 
tested will work well for children.  
• 
Your decision on your child’s participation in the study will have no effect on the medical care your 
child receives at this clinic. Your child’s access to services, and the benefits and rights he or she 
normally has, will not be affected.  
 
More information is given in this form about the study, its risks and benefits. You should feel that you 
understand the study before deciding whether your child will participate. If you decide your child will 
participate, you will be asked to sign or make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [ 
site name] are doing this study. The person in charge of the study at [site name] is [name of Investigator 
of Record]. 
 


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The study is testing a new combination of anti-HIV medicines (ARVs) for children who have HIV. The 
study will include about 50-75 children from Botswana, South Africa, Thailand, and the United States. 
The children will be less than 12 years old.  
 
The United States National Institutes of Health and the company that makes the ARVs being tested, ViiV 
Healthcare Ltd, are paying for this study.  
 
1. The study is testing a new combination of ARVs for children. 
 
Children with HIV usually take a combination of 3 or more ARVs to stay healthy. There are not as many 
ARVs available for children as for adults because many ARVs have not been tested in children. This 
study will test a new tablet that contains 3 ARVs. The ARVs are called abacavir (ABC), dolutegravir 
(DTG), and lamivudine (3TC). In this form, we use “ABC/DTG/3TC” to refer to tablets that contain these 
ARVs. 
 
ABC and 3TC are approved and used by adults and children throughout the world. DTG is a newer ARV 
that is approved for adults and children in the United States and Europe. In the United States, DTG is 
approved for adults and children who weigh at least 30 kg. In Europe, DTG is approved for adults and 
children 6 years and older who weigh at least 15 kg. [Sites add site-specific approval information here if 
applicable, for example: DTG is also approved for adults in Botswana]. The combination tablet of 
ABC/DTG/3TC is approved for adults and children weighing at least 40 kg in the United States and 
Europe. In Europe, this approval is for children 12 years and older. 
 
This study will be the first study to test the combination tablet of ABC/DTG/3TC for younger children. 
The study will test different doses (amounts) of ABC/DTC/3TC to find out the correct dose for younger 
children. It will also look at whether ABC/DTG/3TC causes bad effects when given to younger children.  
 
More information about the study, and the tablets being tested, is given in the rest of this form.  
 
2. Only children who qualify can participate in the study. 
 
If you decide to have your child join this study, we will first do some tests to find out if your child 
qualifies. More information about the tests is given in #4. If your child qualifies, he or she will be entered 
in the study. If your child does not qualify, he or she cannot be entered in the study. 
 
3. It is your decision whether to have your child participate in the study. 
 
Deciding to have your child to join the study is voluntary (your choice). You are free to have your child 
join or not join. If you decide to have your child join, you can change your mind and take your child off 
the study. Your decisions will have no effect on the medical care your child receives at this clinic. Your 
child’s access to services, and the benefits and rights he or she normally has, will not be affected.  
 
Take your time and consider your decision carefully. If you wish, you can talk to other people about the 
study before you decide. You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, it is important for your child to receive medical care and take 
ARVs. Taking ARVs is the best known way for children with HIV to stay healthy.  
 


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Finding out if your child qualifies 
 
4. We will ask questions, examine your child, and test your child’s blood. 
 
To find out if your child qualifies for the study, we will: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health and medicines.  
• 
Give your child a physical examination. 
• 
Draw your child’s blood (up to 19 mL or about 4 teaspoons) for tests. The tests will check: 
– Your child’s blood cells, liver, and kidneys. This includes checking for an infection called 
hepatitis B. 
– The amount of fat in your child’s blood.  
– The amount of HIV in your child’s blood. This is called your child’s “viral load.” Your child’s 
viral load should go down and stay down when your child is taking ARVs.  
– Your child’s CD4 cells. These cells help the body fight infection. HIV attacks CD4 cells. The 
number of CD4 cells should go up and stay up when your child is taking ARVs. 
– A gene called HLA-B*5701. People with this gene can have a serious allergic reaction to ABC. If 
your child has this gene, he or she cannot join the study. 
The tests will also confirm your child has HIV. Certain HIV tests are required for the study. If the 
required tests are not in your child’s medical records, we will do the tests that are needed.  
 
If your child can become pregnant, we will ask about her sexual activity and collect blood (1 mL or a few 
drops) or urine for a pregnancy test. If your child is pregnant, she will not qualify for the study.  
 
These procedures will take about 2-3 hours [here and throughout this form, sites may modify the expected 
visit duration as needed].  
 
 
Some test results will be ready quickly. Others may take about 2-3 weeks. We will schedule your child to 
come back when the results are ready. We may ask you to bring your child back for more tests if needed 
to find out if he or she qualifies for the study.  
 
Entering the study 
 
5. If your child qualifies, he or she will enter the study. 
 
When you come back for your child’s results, we will explain the results to you.  
 
If your child’s results do not qualify for the study, your child will not be entered in the study. We will tell 
you where your child can go for medical care or other services he or she may need. If your child does not 
enter the study, we will still use some information collected about your child (for example, age, sex, and 
race). We will use this information to look at patterns or common reasons for not entering the study.  
 
If your child’s results qualify for the study, we will: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health and medicines. 
• 
Give your child a physical examination. 
 


IMPAACT 2019, FINAL Version 2.0    
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If your child can become pregnant, we will ask about her sexual activity and collect blood (1 mL or a few 
drops) or urine for a pregnancy test.  
 
 
If these procedures confirm that that your child qualifies, your child will enter the study. We will: 
 
• 
Ask about your child’s mood, behavior, and sleep. 
• 
Draw your child’s blood (7 mL or about 1½ teaspoons). Some blood will be used to test your child’s 
viral load. Some will be saved for later tests. The later tests may look for resistance to ARVs. 
Resistance means that ARVs may not work against the HIV in your child’s body.  
• 
Give you ABC/DTG/3TC tablets for your child. If your child was taking other ARVs before joining 
the study, he or she will stop taking those ARVs and start taking ABC/DTG/3TC tablets.  
 
We will show you how to give ABC/DTG/3TC tablets to your child. There are two types of tablets. Each 
type is given once a day, every day.  
 
• 
One type of tablet is dissolved in water; the child then drinks the water. This type of tablet is called a 
“dispersible tablet.” It is given to children who weigh less than 25 kg. 3-6 tablets will be given 
depending on how much your child weighs.  
 
• 
The other type of tablet is swallowed whole. This type of tablet is called an “immediate release” 
tablet. It is given to children who weigh 25 kg or more. If your child cannot swallow the tablet whole, 
it can be crushed and mixed with liquid or soft food.  
 
It is very important to give your child ABC/DTG/3TC tablets as instructed. We will take as much time as 
needed for you to understand the instructions. We will help you come up with strategies to give the tablets 
to your child each day as instructed. 
 
These procedures will take about 4 hours.  
 
During the study 
 
6. All children will have 6 visits over 1 year.  
 
Your child will have visits 1 week after entering the study and 4 weeks after entering the study. After that, 
your child will have visits every 12 weeks (3 months).  
 
Each visit will take about 2-3 hours. At these visits we will:  
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines. At 4 visits, this will include asking how 
you feel about giving ABC/DTG/3TC tablets to your child, how your child feels about taking the 
tablets, and how the tablets taste.  
• 
Ask about your child’s mood, behavior, and sleep. This will be done at only 2 visits. 
• 
Give your child a physical examination. 
• 
Draw your child’s blood for tests. The amount drawn will range from 4 ml to 12 mL (about 1-3 
teaspoons). At different visits, the tests will check: 
– Your child’s blood cells, liver, and kidneys. 
– The amount of fat in your child’s blood.  
– Your child’s viral load. 
– Your child’s CD4 cells. 


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Some blood will be saved for later tests. The later tests will check the amount of ABC, DTG, and 
3TC in the blood.  
• 
Give you ABC/DTG/3TC tablets for your child as needed. As your child grows, we may change the 
number or type of tablets your child takes. We may change the amount of water used to dissolve the 
tablets. We will keep giving you instructions on how to give the tablets to your child. For some visits, 
we will ask your child to take his or her tablets at the clinic (instead of at home). 
 
In addition to the 6 visits described above, some children will have more visits. Children may have more 
visits if they are sick or if more tests are needed to check on their health or viral load. Children may also 
have more visits to check the amount of ABC, DTG, and 3TC in their blood. These visits are described in 
#9.  
 
After your child has been in the study for 1 year, he or she may leave the study at that time. Or, your child 
may stay in the study longer. More information about this is given in #10. 
 
7. Some children will be selected to very closely measure the amount of ABC, DTG, and 3TC in the blood.  
 
One reason for doing this study is to find out the correct dose of ABC/DTG/3TC for children. To do this, 
we need to very closely measure the amount of ABC, DTG, and 3TC in the blood after children take 
ABC/DTG/3TC tablets. This is called a pharmacokinetic or “PK test.” At least 25 children will be 
selected to have a PK test. For the children selected, the PK test will be done at the visit 1 week after 
entering the study.  
 
We will tell you if your child is selected to have the PK test.  
 
If your child is selected, we will ask you to bring your child to the clinic at a specified time. We will give 
you instructions for what your child should eat and drink before and during this visit. This may include 
limiting your child’s food and drink for up to 3 hours.  
 
At the clinic, your child will have blood drawn and then take his or her ABC/DTG/3TC tablets. Your 
child will then have blood drawn 7 more times over 24 hours (1 full day). The blood must be drawn at 
specified times. [Sites may modify this wording as needed to describe local intensive PK 
scheduling/logistics/ procedures:] Your child will need to stay at the clinic for 8-10 hours. Your child 
may then be able to go home and come back to the clinic 14-16 hours later. Or, your child may stay at the 
clinic for a total of 24 hours. We will explain the options for this to you.  
 
[Sites may modify this wording as needed to describe local intensive PK procedures:] We will place a 
small plastic tube (like a “drip”) in your child’s arm to draw blood for the PK test. The tube is attached to 
a plastic needle. The tube and needle will stay in place until all the blood draws are done. We will not 
need to stick your child with a needle each time.  
 
Most of the blood draws will collect 1 mL (a few drops) of blood. One of the blood draws will collect 4 
mL (about 1 teaspoon). For all the blood draws added together, a total of 11 mL (about 2 teaspoons) will 
be collected. 
 
We will give you the results of your child’s PK test. If the test shows the amount of ABC, DTG, or 3TC 
in the blood is too high or too low, we will talk with you about changing your child’s dose. If your child’s 
dose is changed, we may ask your child to have a second PK test. The second PK test will check the 
amount of ABC, DTG, and 3TC in the blood after the dose is changed. For the second PK test, we might 
need to collect the same amount of blood as in the first test. Or, we might be able to do the test with less 
blood. We will explain the options to you and determine the most appropriate plan for your child. 


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8. We will watch children who have the PK test take ABC/DTG/3TC tablets. 
 
For children who have the PK test, it is important to know the specific times when they take 
ABC/DTG/3TC tablets, from the day of entering the study to the day of the PK test. To help with this, if 
your child has the PK test, we will contact you every day until the day of the PK test.  
 
[Sites may modify this wording as needed to describe local dose observation procedures:] There are 
different ways we can do these contacts. One way is to bring your child to the clinic to take 
ABC/DTG/3TC tablets in front of a study staff member. Another way is for a study staff member to go to 
your home or other location to watch your child take the tablets. If you have a mobile phone or computer, 
we may be able to watch your child take tablets (live) by video. You may also be able to send a video or 
text message to us. We will explain the options for this to you, and then agree on a plan with you to do 
these contacts.  
 
If your child has a second PK test, we may repeat these types of contacts before the second test.  
 
9. Some children will have additional visits.  
 
There are 3 reasons why children may have additional visits.  
 
Your child was taking an NNRTI. 
If your child was taking ARVs before joining the study, he or she may have been taking a type of ARV 
called an “NNRTI.” Two examples of this type of ARV are nevirapine and efavirenz. Taking this type of 
ARV before the study may affect the amount of ABC, DTG, and 3TC found in your child’s blood during 
the study. Because of this, children who were taking this type of ARV before the study will have 2 
additional visits during the study. The visits will be 2 weeks and 6 weeks after entering the study.  
 
Each visit will take about 1 hour. We will draw your child’s blood (4 mL or about 1 teaspoon) for later 
tests. The later tests will check the amount of ABC, DTG, and 3TC in the blood. If needed, we will also: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines.  
• 
Give your child a physical examination. 
• 
Give supplies of ABC/DTG/3TC tablets for your child. 
 
Your child has resistance. 
Children with HIV can have resistance to ARVs. One type of resistance is called “M184V.” Children who 
have this type of resistance will have 3 extra visits during the study. The visits will be 8 weeks, 16 weeks, 
and 20 weeks after entering the study.  
 
Each visit will take about 1 hour. We will draw your child’s blood (7 mL or about 1½ teaspoons). Some 
blood will be used to check your child’s viral load. Some will be saved for later tests. The later tests will 
check the amount of ABC, DTG, and 3TC in your child’s blood. If needed, we will also: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines.  
• 
Give your child a physical examination. 
• 
Give supplies of ABC/DTG/3TC tablets for your child. 
 


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Your child’s HIV is not controlled. 
When taking ABC/DTG/3TC tablets, your child’s viral load should stay controlled at a very low level. If 
tests show that your child’s viral load is higher than expected, your child will have an additional visit. At 
this visit we will: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines.  
• 
Ask how you feel about giving ABC/DTG/3TC tablets to your child, how your child feels about 
taking the tablets, and how the tablets taste. 
• 
Give your child a physical examination. 
• 
Draw your child’s blood (up to 10 mL or about 2 teaspoons) for tests. The tests will re-check your 
child’s viral load. If the viral load is still higher than expected, we will test for resistance.  
• 
Save some blood for later tests. The later tests will check the amount of ABC, DTG, and 3TC in your 
child’s blood. 
• 
Give supplies of ABC/DTG/3TC tablets for your child as needed. If the tests show that your child has 
resistance, we may change your child’s ARVs (see #13).  
 
10. Some children may stay in the study for more than 1 year.  
 
After your child has been in the study for 1 year, we will tell you about your child’s options for receiving 
ARVs in the study and outside the study.  
 
If your child is not gaining benefit from ABC/DTG/3TC tablets, your child will leave the study after 1 
year.  
 
If your child is gaining benefit from ABC/DTG/3TC tablets, and can get the tablets outside the study, 
your child will leave the study after 1 year.  
 
If your child is gaining benefit from ABC/DTG/3TC tablets, but cannot get the tablets outside the study, 
your child may stay in the study for up to 2 more years. During this time, your child will have visits every 
12 weeks. Each visit will take about 1 hour.  
 
At each visit (every 12 weeks), we will:  
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines.  
• 
Give your child a physical examination. 
• 
Give supplies of ABC/DTG/3TC tablets for your child as needed. As your child grows, we may 
change the number of tablets or the type of tablets your child takes. We will keep giving you 
instructions on how to give the tablets to your child. 
 
At every other visit (every 24 weeks), we will draw your child’s blood (7 mL or about 1½ teaspoons) for 
tests. The tests will check: 
• 
Your child’s blood cells, liver, and kidneys. 
• 
Your child’s viral load. 
• 
Your child’s CD4 cells. 
 
At each visit, we will tell you if your child is still gaining benefit from ABC/DTG/3TC tablets. We will 
also tell you if your child’s options for getting ABC/DTG/3TC have changed. When your child can get 
ABC/DTG/3TC tablets from outside the study, your child will leave the study.  
 


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At the latest, your child will leave the study after a total of 3 years. After a total of 3 years, the study 
cannot keep giving ABC/DTG/3TC tablets for your child. The company that makes the tablets will try to 
provide the tablets for your child. If this is possible, the tablets will be provided until they are available 
locally or until your child is no longer gaining benefit. However, there is no guarantee this will be 
possible. If this is not possible, your child will need to switch to other ARVs that are available locally. 
[Sites may modify the preceding sentence to define or explain “available locally.”] 
 
No matter when your child leaves the study, we will talk with you about your child’s options and help 
make sure your child can get ARVs from outside the study. We will plan for this in advance to avoid gaps 
in your child taking ARVs when he or she leaves the study. 
 
11. There are additional requirements for children who can become pregnant.  
 
Women and girls taking DTG should not become pregnant. This is because taking DTG at the time of 
becoming pregnant may increase the risk of serious birth defects of the baby’s brain or spine. 
 
If your child can become pregnant, we will collect blood (1 mL or a few drops) or urine for a pregnancy 
test at all visits. We will ask your child about sexual activity. If your child is having sex that could lead to 
pregnancy, she will be required to use contraception. We will talk with you and your child about the 
importance of avoiding pregnancy and about the contraceptive methods that can be used in this study. We 
will help you and your child choose the best contraceptive methods for your child. At each visit, we will 
talk again about contraception, to see how your child is doing with her chosen methods. We will ask you 
and your child to tell us if you want to stop or change methods. We will ask you and your child to tell us 
if your child may be pregnant at any time. If you or your child do not want your child to use 
contraception, your child will leave the study.  
 
If your child becomes pregnant, she will stop taking ABC/DTG/3TC tablets. She will stay in the study 
until she is no longer pregnant, with the same schedule of visits as originally planned. After that, she will 
leave the study. We will tell you about other ARVs your child can take instead of ABC/DTG/3TC tablets. 
We will tell you if your child can get other ARVs here at this clinic or if you must go to another clinic. 
We will also tell you where you can take your child for health care related to the pregnancy. We will 
collect information on the outcome of the pregnancy and whether the baby has any birth defects.  
 
If your child is using contraception at her last study visit, we will ask your child to come back one more 
time, about 4 weeks after her last visit. When your child comes back, we will: 
 
• 
Review her medical records. 
• 
Ask about her health, ARVs, contraception, and other medicines.  
• 
Collect blood (1 mL or a few drops) or urine for a pregnancy test.  
• 
If needed, give your child a physical examination. 
 
12. Different tests will be done at different laboratories. 
 
We will do most tests of your child’s blood at our laboratory. We will give you the results of these tests at 
the next scheduled visit, or sooner if necessary. We will explain the results to you. If the results show that 
your child may need medical care that cannot be provided by the study, we will tell you where you can go 
for this care. 
 


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Other tests will be done in the United States or other countries. This includes tests for resistance and tests 
of the amount of ABC, DTG, and 3TC in your child’s blood. We will give you resistance test results and 
explain these to you. If your child has a PK test (see #7), we will give you the results and explain these to 
you. Other tests of ABC, DTG, and 3TC will be done after the study is completed. The results of these 
tests will not be given to you.  
 
If you agree, some of your child’s blood will be used for tests of his or her genes. Genes are passed to 
children from their birth parents. They affect how people look and how their bodies work. Differences in 
people’s genes can help explain why some people get a disease while others do not. For this study, only 
genes related to HIV, ARVs, and the immune system will be tested. The immune system is the part of the 
body that fights infections. The results of these tests are for research purposes only and will not be given 
to the study staff or to you. Testing of all your child’s genes, which is sometimes called whole genome 
sequencing, will not be done.  
 
13. We may stop or change your child’s ARVs. 
 
Some children may need to change the tablets they are taking. This may happen if we find that the dose of 
ABC/DTG/3TC tablets is too high or too low. This may also happen for children with tuberculosis (see 
#14). If this happens for your child, we will explain the changes to you.  
 
Some children may need to stop taking ABC/DTG/3TC tablets. This may happen for children who: 
 
• 
Are not able to take the tablets 
• 
Have bad effects from the tablets 
• 
Need to take other medicines that cannot be taken with ABC/DTG/3TC tablets 
• 
Have resistance to ABC, DTG, or 3TC 
• 
Become pregnant 
 
If your child stops taking ABC/DTG/3TC tablets, your child will leave the study. More information is 
given about this in #15.  
 
14. There may be other changes if your child has tuberculosis (TB). 
 
Children who get TB during the study will need to take medicines for TB. Some TB medicines change the 
effects of ARVs. Because of this, children need to take more ARVs when are they are taking TB 
medicines. For example, if your child gets TB during the study, he or she will need to take an extra tablet 
of DTG every day, in addition to taking ABC/DTG/3TC tablets every day. In this case, we would give 
you the extra DTG tablets and tell you how to give them to your child. When your child no longer needs 
TB medicines, he or she can stop taking extra DTG tablets.  
 
Because some TB medicines change the effects of ARVs, we will do a PK test for children with TB. This 
will be like the test described in #7. However, all the blood draws will be done within 12 hours.  
 
15. We may take your child off the study. 
 
All children are expected to stay in the study for about 1 year. Some children may stay in the study for up 
to 3 years. However, we may take your child off the study early if: 
 
• 
The study is stopped for any reason. 
• 
Your child stops taking ABC/DTG/3TC tablets. 


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• 
We determine that your child cannot meet the study requirements. 
• 
We determine that staying in the study might harm your child. 
 
If your child must leave the study early, we will explain this and tell you where your child can go for the 
care and treatment he or she may need. It is very important for your child to keep taking ARVs after 
leaving the study. We will talk with you about your child’s options and help make sure your child can get 
ARVs from outside the study.  
 
16. Please tell us if you want your child to leave the study. 
 
You are free to take your child off the study at any time for any reason. The care your child receives at 
this clinic will not be affected, but it is important that we know your decision. We will ask you to bring 
your child to the clinic for one last visit. At this visit, we will: 
 
• 
Review your child’s medical records. 
• 
Ask about your child’s health, ARVs, and other medicines. This will include asking how you feel 
about giving ABC/DTG/3TC tablets to your child, how your child feels about taking the tablets, and 
how the tablets taste.  
• 
Give your child a physical examination. 
• 
Draw your child’s blood (11 mL or about 2 teaspoons) for tests. The tests will check: 
– Your child’s blood cells, liver, and kidneys. 
– Your child’s viral load. 
– Your child’s CD4 cells. 
Some blood will be saved for later tests. The later tests will check the amount of ABC, DTG, and 
3TC in your child’s blood.  
 
We will answer any questions you may have and tell you how to contact us in the future, if you wish. 
 
Risks of the study 
 
17. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to your child. Drawing 
blood can cause pain, swelling, bruising, or bleeding where the needle is inserted. Rarely, drawing blood 
can cause fainting or infection.  
 
18. There are risks from ARVs.  
 
All ARVs can cause side effects. This includes ARVs your child would receive outside the study. Some 
side effects are minor, others can be severe. Some side effects are common, others are rare. Some people 
have some of the side effects. Other people have no side effects.  
 
Some of the most common and most severe side effects of ABC/DTG/3TC tablets are listed below. This 
form does not list all possible side effects. At each visit, we will check on whether your child may be 
having side effects. If you have questions or concerns about side effects at any time, please tell us.  
 


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19. Some side effects can be severe.  
 
First, you should know about the possible severe side effects. These effects are rare but can cause serious 
health problems and can result in death. Please contact us right away or go to the nearest hospital if your 
child has any of these side effects.  
 
ABC can cause a severe allergic reaction. 
This type of reaction is more likely in people who have the HLA-B*5701 gene. Children who have this 
gene cannot join the study. However, children who do not have this gene can still have the reaction. 
 
This type of reaction can involve several organs of the body. When this type of reaction happens, it 
usually happens in the first 6 weeks of taking ABC. Children who have this reaction should stop taking 
ABC and never take ABC again. This is because the reaction can get worse if ABC is not stopped. If 
ABC is taken again (after stopping), the reaction can happen again. If the reaction happens again, it can 
be even worse, and can result in death.  
 
If your child has an allergic reaction, he or she may have a rash; fever; poor appetite, upset stomach, 
vomiting (throwing up), diarrhea (loose or watery stools), or pain in the belly. He or she may feel sick or 
tired or weak. He or she may have aches or pains or have trouble breathing, a cough, or sore throat. We 
will give you a card to remind you of these signs of a reaction. If your child has 2 or more of these signs, 
stop giving ABC to your child and contact us right away. If you stop giving ABC to your child for any 
reason, always tell us and do not re-start ABC without contacting us first.  
 
DTG can cause a severe allergic reaction. 
DTG can cause a reaction that may look like the reaction described above. Children could also have 
blisters or sores in the mouth; blisters or peeling of the skin; redness or swelling of the eyes; swelling of 
the face, mouth, lips, or tongue. Contact us right away if your child has any signs of a reaction.  
 
DTG can cause severe mental health problems. 
Some people have had anxiety or depression when taking DTG. This may include feeling very sad or 
having thoughts or acts of hurting or killing oneself (suicide). These effects are more likely in people with 
a history of mental health problems. Please tell us if your child has ever had any mental health problems. 
Contact us right away if your child has any unusual or distressing thoughts or feelings, including any 
thoughts of hurting himself or herself.  
 
DTG, ABC, and 3TC can cause severe liver problems. 
The liver is an organ near the stomach. It helps digest food and keep the body healthy. Problems of the 
liver can be seen with abnormal blood test results. Children with liver problems may have yellowing of 
the skin or eyes; dark or tea colored urine; pale colored stools; upset stomach or vomiting; poor appetite; 
weight loss; pain, aching, or tenderness in the belly, especially on the right side below the ribs. Children 
may feel tired or weak or dizzy, or have difficulty breathing. When these types of problems happen, they 
can lead to failure of the liver and can result in death. Contact us right away if your child has any signs of 
liver problems. 
 
20. There can be other side effects.  
 
Other side effects have been seen in people taking ABC, DTG, or 3TC. These are listed below. These can 
be more or less common. They are not usually severe. 
 
 
 


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Uncommon: expected in 1 of every 1000 people taking ABC/DTG/3TC  
(0.1%) 
• Weight gain 
• Tingling or numbness of the arms, legs, hands, or feet 
• Breakdown of the muscles 
• Swelling of the pancreas (an organ in the belly involved in digesting food) 
• Decreased blood cell counts 
• Changes in blood tests that may show problems with the liver (an organ in the belly involved in 
digesting food and keeping the body healthy) 
 
21. There may be other possible risks. 
 
Resistance 
All ARVs can cause resistance. To avoid resistance, it is important to give your child ARVs as instructed 
and avoid missing doses.  
 
Switching ARVs  
If your child was taking other ARVs before the study, he or she will stop taking those ARVs and start 
taking ABC/DTG/3TC tablets. It is possible that ABC/DTG/3TC tablets will not work as well for your 
child as the ARVs he or she was taking before the study.  
Immune reconstitution syndrome 
In some people with advanced HIV infection, symptoms of other infections or diseases may occur soon 
after starting ARVs. Some of these symptoms may be life threatening. If your child starts having new 
symptoms, or if any existing symptoms get worse after starting ABC/DTG/3TC tablets, please contact us 
immediately. 
Very Common: expected in 1 of every 10 people taking ABC/DTG/3TC  
(100 of every 1000 people or 10%) 
• Headache 
• Upset stomach 
• Diarrhea 
Common: expected in 1 of every 100 people taking ABC/DTG/3TC  
(10 of every 1000 people or 1%) 
• Skin rash or itching 
• Gas or pain in the belly 
• Indigestion or heartburn 
• Loss of appetite 
• Vomiting  
• Fever 
• Tiredness 
• Pain in the muscles or joints 
• Hair loss  
• Difficulty sleeping  
• Abnormal dreams 
• Depression 
• Dizziness (feeling light headed) 
• Increased sugar or fat in the blood 
• Changes in blood tests that may show problems with the muscles 


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Hepatitis B 
Children who have hepatitis B cannot join this study. However, children could get hepatitis B while in the 
study. If your child gets Hepatitis B, your child’s ARVs may need to be changed. This is because some 
ARVs can be used to treat both HIV and hepatitis B, and it may be better for your child to take those 
ARVs. If your child needs to change ARVs, we will explain this to you. We will also explain if your child 
needs to leave the study (see #16).  
 
Pregnancy 
Early results from a large study in Botswana showed that DTG may increase the risk of serious birth 
defects of the baby’s brain or spine. The increased risk was seen among babies whose mothers were 
taking DTG when they became pregnant. These birth defects happen during the first few weeks of 
pregnancy, before mothers may know they are pregnant. These birth defects have not been seen among 
babies whose mothers started taking DTG later in pregnancy. 
 
22. There may be risks of disclosure of your child’s information. 
 
We will make every effort to keep your child’s information private and confidential. Study records and 
blood samples will be kept in secure locations. All samples and most records will be labeled only with a 
code number. However, your and your child’s name will be written on some records. Despite our best 
efforts to keep your child’s information private, it is possible that your child’s information, could be 
obtained by someone who should not have it. If this were to happen, your child could be treated badly or 
unfairly.  
 
For children who have videos or text messages sent to study staff, those messages could be seen by 
someone who should not see them. The videos and messages may not be encrypted (scrambled), so 
someone with the right knowledge and equipment could see or listen to them. Telephone numbers used 
for these communications could also be seen.  
 
[US sites insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify your child, such as by the courts or 
police. The certificate cannot be used in all situations, but it can be used to resist demands for information 
that would identify your child. The certificate does not protect against requests for information from the 
United States federal government or from the United States Food and Drug Administration. Regardless of 
the certificate, you can release information about your child’s participation in the study to others, if you 
wish.] 
 
Information collected for this study may be used for other research in the future. For example, researchers 
may use information from this study to try to answer different questions about children with HIV. Any 
future research done with the information from this study must be approved by the IMPAACT Network. 
If any future research is done, information about your child may be used. Your child’s information will be 
labeled with a code number, and the only link between the code number and your child’s name will be 
kept here at [site name]. Your child’s name will not be given to other researchers.  
 
 
Benefits of the study 
 
23. There may be benefits to your child from being in the study. 
 
By joining the study, your child will be part of the search for new treatments for children with HIV. 
ABC/DTG/3TC is a new treatment for young children. This treatment has been shown to be safe and 
effective for adults. Although there are no guarantees, we expect the same for children. Therefore, taking 


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ABC/DTG/3TC may be of benefit for your child. Also, ABC/DTG/3TC tablets are given once per day. 
This may be of benefit for children, compared to other ARVs that are given two times per day.   
 
Your child will have regular visits here and frequent checks on his or her health. It is possible that the 
examinations and tests done in the study may help your child stay healthy. If these procedures show that 
your child may need medical care that cannot be provided through the study, we will tell you where you 
can go for the care your child needs. 
 
Other information about the study 
 
24. There are no costs to you for your child being in the study. 
 
There are no costs to you or your child for study visits or procedures or the ARVs given in the study. 
 
[Sites insert information about compensation/reimbursement here, e.g., You will be reimbursed for the 
cost of transport to study visits. For each visit, you will be given (specify amount).] 
 
25. Your child’s records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other United States, local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
The company that makes ABC/DTG/3TC tablets, ViiV Healthcare Ltd  
 
Like the study staff, these groups are required to make efforts to keep study records private and 
confidential. 
 
The results of the study may be presented publicly or published. However, no presentation or publication 
will use your child’s name or identify your child personally. 
 
A description of this study will be available on ClinicalTrials.gov as required by United States law. This 
website will not include information that can identify your child. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
Your child’s study information may be disclosed to other authorities if required by law. [Sites may add 
more specific detail here describing local laws that may be applicable.]  
 
26. If your child gets sick or injured, contact us immediately. 
 
Your child’s health is important to us. We will make every effort to protect your child’s well-being and 
minimize risks. It is possible, however, that your child could have an illness or injury that is study-related. 
This means that the illness or injury occurred as a direct result of being in the study.  
 


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[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.] If a study-
related illness or injury occurs, we will treat your child or tell you where you can get the treatment your 
child needs. The cost for this treatment may be charged to you or your health insurance. There is no 
program to pay money or give other forms of compensation for study-related illness or injury through 
[site name] or the United States National Institutes of Health. 
 
Who to contact 
 
27. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study, contact:  
[Sites insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your child’s rights as a study participant, or problems or concerns about 
how your child is being treated in the study, contact:  
[Sites insert name and telephone number of IRB contact person or other appropriate 
person/organization] 
 
• 
If your child has any health or other problems that may be related to study participation, contact:  
[Sites insert name and telephone number of investigator or other study staff] 
 
• 
If you want your child to leave the study, contact:  
[Sites insert name and telephone number of investigator or other study staff] 
 
 


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Signatures 
 
28. If you decide to have your child join this study, please sign or make your mark below. 
 
Before deciding whether to have your child join this study, make sure you have read this form or had it 
read to you. Make sure all your questions have been answered. You should feel that you understand the 
study, its risks and benefits, and what is expected of you and your child. 
 
We will tell you any new information from this study or other studies that may affect your willingness to 
keep your child in the study. You are welcome to ask questions or request more information at any time.  
 
You do not give up any rights by signing this form. 
 
[Sites insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions 
must be documented for genetic testing]. 
 
Please write your initials or make your mark next to your choices:  
 
 
__________ 
I agree to have my child join this study. 
 
 
 
 
For genetic testing:  
 
__________ 
I agree to testing of my child’s genes related to HIV, ARVs, and the 
immune system. 
 
__________ 
I do not agree to testing of my child’s genes.  
 
 
 
 
 
 
 
 
 
Name of Child (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent  
 
 
Parent Signature 
  
 
Date 
(or Legal Guardian; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 


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Appendix III: Sample Informed Consent Form for Specimen Storage and Future Use 
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, 4 September 2019 
 
 
You have decided to have your child join the study named above. As part of the study, your child will 
have blood drawn. After the blood is tested, there may be some samples left over. We call these extra 
samples. The IMPAACT Network would like to keep these extra samples and use them for other research 
in the future. 
 
This form gives information about use of extra samples. Please read it or have it read to you. Ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use 
of extra samples at the end of this form.  
 
1. It is your decision whether to allow extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time. Your decision will not affect your 
child’s participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your child’s extra samples will be kept in a repository.  
 
[Sites should insert one of the two options shown below. Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the 
United States. If you agree to have extra samples stored, the samples will be kept in this repository. There 
is no limit on how long the samples will be kept [sites may insert time limits or additional site-specific 
requirements here if required by local authorities]. 
 
A repository is a secure facility that is used to store samples. The IMPAACT Network has a repository in 
the United States. However, our local regulations require that extra samples be stored in our country. 
Therefore, we will keep the samples here at our laboratory. There is no limit on how long the samples will 
be kept [sites may insert time limits or additional site-specific requirements here if required by local 
authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, anti-HIV medicines (ARVs), the immune system, and 
other diseases. The research may be done in the United States or other locations.  
 
If you agree, extra samples could be used for research that looks at your child’s genes. Genes are passed 
to children from their birth parents. They affect how people look and how their bodies work. Differences 
in people’s genes can help explain why some people get a disease while others do not. Your child’s 
samples would only be used to look at genes related to HIV, ARVs, and the immune system. Testing of 
all your child’s genes, which is sometimes called whole genome sequencing, will not be done. 


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Research done with extra samples must be approved by the IMPAACT Network. The research must also 
be approved by an ethics committee. The role of an ethics committee is to review the research plan and 
protect the rights and well-being of children whose samples will be used.  
 
The research done with extra samples is not expected to give any information relevant to your child’s 
health. Therefore, the results will not be given to the study staff or to you. The results will not be placed 
in your child’s study records.  
 
4. There is little risk to your child.  
 
When extra samples are used for research, they are labeled with a code number only. To protect your 
child’s privacy, no names are used. However, information such as age, gender, HIV status, and other 
health information may be linked to the samples. Information on the ARVs your child received and your 
child’s response to the ARVs may also be linked to the samples. The only link between the code number 
and your child’s name is kept here at [site name]. Your child’s name will not be given to other 
researchers. 
 
There may be some risks from tests of your child’s genes. If others found out the results of these tests, 
they could treat your child badly or unfairly. However, this is almost impossible because the results of 
these tests will not be given to the study staff or to you and will not be in your child’s study records. 
 
5. There may be no benefit to your child.  
 
By allowing your child’s extra samples to be used for research, your child will be part of the search for 
new information that may benefit children with HIV in the future. However, the research done with the 
extra samples is not expected to directly benefit your child in any way. 
 
6. You will not be paid for use of your child’s extra samples. 
 
There is no cost to you for use of your child’s extra samples. The samples will not be sold, and you will 
not be paid for use of the samples. It is possible that research done with the samples could lead to a new 
discovery or a new product. If this happens, there is no plan to share any money with you or your child.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:  
 
• 
The IMPAACT Network  
• 
Ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other United States, local, and international regulatory entities 
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to keep information private and confidential. 
 
The results of research done with extra samples may be presented publicly or published. However, no 
presentation or publication will use your child’s name or identify your child personally.  
 
 
 


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8. If you have any questions, concerns, or problems related to your child’s extra samples, use these 
contacts. 
 
• 
If you have questions about use of your child’s extra samples, contact:  
[Sites insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your child’s extra samples, contact:  
[Sites insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your child’s rights as a study participant, or problems or concerns about 
how your child is being treated in the study, contact:  
[Sites insert name and telephone number of IRB contact person or other appropriate 
person/organization].  
 
 
 


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Signatures 
 
Before deciding whether to allow your child’s samples to be used for research, make sure you have read 
this form or had it read to you. Make sure all your questions have been answered. You should feel that 
you understand your options and the possible risks and benefits before making your decision.  
 
You do not give up any rights by signing this form.  
 
[Sites insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions 
must be documented for genetic testing] 
 
Write your initials or make your mark next to your choice. 
 
 
__________ 
I allow my child’s extra samples to be used for research on HIV, ARVs, the immune 
system, and other diseases. I also allow my child’s samples to be used for tests of his or 
her genes.  
 
__________ 
I allow my child’s extra samples to be used for research on HIV, ARVs, the immune 
system, and other diseases. I do not allow my child’s samples to be used for tests of his or 
her genes.  
 
__________ 
I do not allow my child’s extra samples to be used for any research.  
 
 
 
 
 
 
 
 
 
Name of Child (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Parent  
 
 
Parent Signature 
  
 
Date 
(or Legal Guardian; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Witness Signature 
 
 
Date 
(if applicable, print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 


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Appendix IV: Sample Informed Assent Form for Study Participation 
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, 4 September 2019 
 
[Instructions for sites: The amount of information and level of detail provided in site-specific assent forms 
should be tailored to the age and maturity of study participants, guided by IRB/EC policies and 
procedures. Sites may develop multiple assent forms, if desired, in anticipation of different information 
needs across the study age range. When preparing site-specific assent forms, the wording included in this 
sample form may be modified, added to, or removed in order to provide the most appropriate information 
and level of detail for participants, consistent with IRB/EC policies and procedures.] 
 
 
Introduction 
 
You are being asked to take part in a research study. In order for you to take part, you must give your 
permission. Your parent/guardian must also give permission.  
 
This form gives information about the study. Please read it or have it read to you. Ask any questions you 
may have. After we talk with you about this, if you decide to take part in the study, you will record your 
decisions at the end of this form. You will be offered a copy to keep. 
 
About the study 
 
The study is testing new tablets for children with HIV. The tablets contain 3 medicines. The medicines 
are abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC). The study will test different doses 
(amounts) of these medicines to find out the correct dose for children. 
 
For small children, the tablets being tested are dissolved in water and swallowed as a liquid. For larger 
children, the tablets are swallowed whole or crushed and mixed with food.  
 
Children in the study will take the tablets and be checked by nurses and doctors to see if the tablets cause 
bad effects. Children will have blood drawn to test for bad effects. Tests will also check the amount of 
medicine that can be found in the blood.  
 
Your rights  
 
It is up to you and your parent/guardian to decide if you will take part in this study. You can say yes or 
no. If you say yes now, you can change your mind later. Your decision will have no effect on the medical 
care you receive at this clinic. 
 


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What happens in the study 
 
If you decide to take part in the study, we will first examine you (check your body), draw blood, and do 
some tests to see if you qualify. If you qualify, you will be in the study for at least 1 year. You may stay 
in the study for up to 3 years. While in the study, you will take the tablets being tested. We will remind 
you and your parent/guardian that you should take the tablets every day.  
 
In the first year, you will come to this clinic for at least 8 visits. The visits will be closer together at the 
beginning and further apart later. In the second and third years, you will come for 4 visits per year. Most 
visits will take 2-3 hours.  
 
At these visits, we will ask you and your parent/guardian about your health and the medicines you take. 
We will ask questions about the tablets being tested. We will examine you and draw blood for tests.  
 
You may be asked to have a visit when you stay at the clinic for a full day and have your blood drawn 8 
times. This is done to very closely measure the amount of medicine in the blood at each time. If you are 
asked to have this visit, we will need to know the specific time when you take the tablets being tested on 
each day before the visit. We will tell you more about how we will contact you and your parent/guardian 
to find out these times. On the day of the visit, we will place a small plastic tube (like a “drip”) in your 
arm. The tube is attached to a plastic needle. The tube will stay in your arm until all the blood draws are 
done. We use the tube so we do not have to stick you with a needle each time blood is drawn.  
 
If you agree, some of your blood could be used for tests of your genes. Genes are passed to children from 
their parents. They affect how people look and how their bodies work. Differences in people’s genes can 
help explain why some people get a disease while others do not.  
 
We will tell you as much information as you want about the tablets being tested and what will happen 
when you come here for visits. Please ask any questions you may have. Please tell us if anything bothers 
you or scares you. We will do our best to explain the study and help you feel more comfortable.  
 
What good and bad effects could happen  
 
By taking part in this study, you will be helping test new medicines that may benefit (have good effects 
for) people with HIV in the future. You may also have good effects from the medicines. For example, the 
medicines could work well for you and help you stay healthy.  
 
However, we do not know this for sure. The medicines may not work well for you. They could cause bad 
effects. For example, they could make you feel sick. We will ask you to tell your parent/guardian any 
time you do not feel well. You and your parent/guardian should also tell us if you do not feel well. We 
will ask you to come here so we can check on you and try to make you feel better. 
 
Having your blood drawn may cause pain, bleeding, bruising, swelling, or infection where the needle 
goes in your arm.  
 
Another possible risk is to your privacy. For example, other people could find out that you are in the 
study or learn other information about you. We will make every effort to avoid this. For example, most of 
the records we keep here for the study will be labeled with a code number (not your name). [Sites may 
modify this wording as needed per local institutional policies and/or site SOPs:] We will share 
information about you, including information that you tell us, with your parent or guardian. We will not 
share your information with other people unless you or your parent or guardian ask us to.  
 


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Who to contact 
You and your parent/guardian can contact us at any time. Please talk to your parent/guardian and to us 
about any questions or problems you may have.  
 
If you have questions about the study:  
[Sites insert name and telephone number of investigator or other study staff].  
 
If you have problems related to being in the study: 
[Sites insert name and telephone number of investigator or other study staff].  
 
If you have questions about your rights or how you are treated in the study:  
[Sites insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
If you want to leave the study: 
[Sites insert name and telephone number of investigator or other study staff].  
 
Signatures 
 
Before deciding whether to take part in this study, make sure you have read this form or had it read to 
you. Make sure all your questions have been answered. 
 
[Sites insert initial and signature blocks as required by site IRB/EC policies. Follow site SOPs and 
IRB/EC policies as to whether separate assent decisions must be documented for genetic testing among 
children in the age range for this study]. 
 
Please write your initials or make your mark next to your choices:  
 
__________ 
I agree to take part in this study.  
 
__________ 
I allow tests of my genes to be done for this study.  
 
__________ 
I do not agree to take part in this study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 


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Appendix V: Sample Assent Form for Specimen Storage and Future Use 
 
IMPAACT 2019 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability  
of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
 
Version 2.0, 4 September 2019 
 
[Instructions for sites: The amount of information and level of detail provided in site-specific assent forms 
should be tailored to the age and maturity of study participants, guided by IRB/EC policies and 
procedures. Sites may develop multiple assent forms, if desired, in anticipation of different information 
needs across the study age range. When preparing site-specific assent forms, the wording included in this 
sample form may be modified, added to, or removed in order to provide the most appropriate information 
and level of detail for participants, consistent with IRB/EC policies and procedures.] 
 
 
Introduction 
 
 
You have joined the study named above. As part of the study, samples of your blood will be collected. 
After these samples are tested for the study, some may be left over. We call these extra samples.  
 
You are being asked for permission to keep your extra samples and use them for other research in the 
future. Your parent/guardian will also be asked for permission.  
 
This form gives information about extra samples. Please read it or have it read to you. Ask any questions 
you may have. After we talk with you about this, you will record your decisions at the end of this form. 
You will be offered a copy to keep. 
 
What happens with extra samples 
 
If you allow your extra samples to be kept, they may be used for research on HIV and the medicines used 
to treat HIV. They may also be used for research on other diseases and the immune system. The immune 
system is the part of the body that fights off infections.  
 
There is no limit on how long extra samples will be kept or when they will be used.  
 
If you agree, extra samples could be used for research that looks at your genes. Genes are passed to 
children from their parents. They affect how people look and how their bodies work. Differences in 
people’s genes can help explain why some people get a disease while others do not.  
 
The results of research done with your samples will not be given to you or your parent/guardian. 
 
What good or bad effect could happen 
 
Allowing your extra samples to be used for research is not expected to have any good or bad effects for 
you.  
 
By allowing your extra samples to be used, you will be helping with research that may benefit (have good 
effects for) people with HIV in the future. However, there is no expected benefit (good effects) for you. 


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4 September 2019 
By allowing your extra samples to be used, there is very little risk (chance of bad effects) for you. One 
possible risk is to your privacy. For example, other people could find out that you are in a study or learn 
other information about you. To avoid this, your extra samples will be labeled only with a code number. 
Your name will not be used.  
 
Your rights  
 
It is up to you and your parent/guardian to decide if your extra samples can be used for research. You can 
say yes or no. If you say yes now, you can change your mind later. Your decision will have no effect on 
your being in the study. If you say no, all extra samples will be destroyed. 
 
Who to contact 
 
If you have questions about use of your extra samples:  
[Sites insert name and telephone number of investigator or other study staff].  
 
If you change your mind about use of your extra samples:  
[Sites insert name and telephone number of investigator or other study staff].  
 
If you have questions about your rights or how you are treated in the study:  
[Sites insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
Signatures 
 
Before deciding whether to allow your extra samples to be used for research, make sure you have read 
this form or had it read to you. Make sure all your questions have been answered. 
 
[Sites insert initial and signature blocks as required by site IRB/EC policies. Follow site SOPs and 
IRB/EC policies as to whether separate assent decisions must be documented for genetic testing among 
children in the age range for this study]. 
 
Please write your initials or make your mark next to your choices:  
 
 
__________ 
I allow my extra samples to be used for research on HIV, medicines used to treat HIV, 
other diseases, and the immune system.  
 
 
__________ 
I allow my extra samples to be used for tests of my genes.  
 
 
__________ 
I do not allow my extra samples to be used for any research.  
 
 
 


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4 September 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Participant (print) 
 
Signature of Participant   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Assent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
(as appropriate; print) 
 
 
 
 


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Appendix VI: IMPAACT 2019 Alternative Weight Band Dosing Tables 
 
Dolutegravir dose adjustments may be required if protocol-defined AUC0-24h or C24h targets are not met. 
Abacavir and lamivudine dose adjustments may be required if protocol-defined plasma AUC0-24h targets 
are not met. In the event dolutegravir, abacavir, or lamivudine targets are not achieved for a particular 
weight band, PK data from prior studies including IMPAACT P1093 and ODYSSEY will be used to 
model the doses that best achieve desired targets.  
 
The following tables show potential dose adjustments when concentrations for all three drugs within a 
weight band are below target (Dosing Table 1) or above target (Dosing Table 2). Actual dose adjustments 
may vary once additional data are available. Other alternative dosing strategies may also include, but are 
not limited to, the following: 
 
1. Dividing the dose (e.g., administering twice daily) if meeting an AUC0-24h or C24h target would result in 
maximum concentrations (Cmax) higher than those with established safety.  
2. Administering with food as an alternative to increasing by an additional tablet.  
3. Single agent entity adjustments (e.g., using separate doses of dolutegravir, abacavir, and/or 
lamivudine) if, based on modeling, the fixed dose combination tablets are unlikely to achieve target 
exposures for each individual drug. 
 
Dosing Table 1. Proposed dose increases if AUC0-24h or C24h are below the protocol-defined targets 
 
Weight Band 
Study Drug Formulation 
(Daily Dose of ABC/DTG/3TC) 
#1 
6 to less than 10 kg 
4 dispersible tablets 
(240/20/120 mg) 
#2 
10 to less than 14 kg 
5 dispersible tablets 
(300/25/150 mg) 
#3 
14 to less than 20 kg 
6 dispersible tablets 
(360/30/180 mg) 
#4 
20 to less than 25 kg 
TBDa 
 
#5 
25 kg or greater 
TBDa 
 
a TBD = to be determined following additional modeling and simulations. 
 
Dosing Table 2. Proposed dose reductions if AUC0-24h or C24h are above the protocol-defined targets 
 
Weight Band 
Study Drug Formulation 
(Daily Dose of ABC/DTG/3TC) 
#1 
6 to less than 10 kg 
2 dispersible tablets 
(120/10/60 mg) 
#2 
10 to less than 14 kg 
3 dispersible tablets  
(180/15/90 mg) 
#3 
14 to less than 20 kg 
4 dispersible tablets 
(240/20/120 mg) 
#4 
20 to less than 25 kg 
5 dispersible tablets 
(300/25/150 mg) 
#5 
25 kg or greater 
TBDa 
 
a TBD = to be determined following additional modeling and simulations. 

SAP_001.pdf: 
 
 
 
This is the IMPAACT 2019 SAP Version 1.0 with names of authors, names 
of publication writing team members and analysis timeline redacted. 
 
 
IMPAACT 2019 
Primary Statistical Analysis Plan 
Version 1.0 
 
Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability 
of Abacavir/Dolutegravir/Lamivudine 
Dispersible and Immediate Release Tablets 
in HIV-1-Infected Children Less than 12 Years of Age 
Protocol Version 2.0 
 
ClinicalTrials.gov Identifier: NCT03760458 
 
December 05, 2019 
 
 
 


IMPAACT 2019 SAP 
 
December 5, 2019 
 
Table of Contents 
 
TABLE OF CONTENTS................................................................................................... 2 
VERSION HISTORY........................................................................................................ 3 
1 
INTRODUCTION....................................................................................................... 4 
1.1 Purpose .......................................................................................................... 4 
2 
STUDY OVERVIEW .................................................................................................. 4 
2.1 Study Design ................................................................................................... 4 
2.2 Hypotheses ..................................................................................................... 5 
2.3 Study Objectives.............................................................................................. 5 
2.3.1 
Primary Objectives and Outcome Measures ................................................ 5 
2.3.2 
Secondary Objectives and Outcome Measures ............................................ 6 
2.4 Overview of Formal Interim Monitoring.............................................................. 8 
2.5 Dose Confirmation for Each Weight Band.......................................................... 8 
3 
STATISTICAL PRINCIPLES..................................................................................... 10 
3.1 Definition of Baseline ..................................................................................... 10 
3.2 General Considerations.................................................................................. 10 
3.3 Analysis Approaches ..................................................................................... 10 
3.3.1 
Primary Safety Outcome......................................................................... 10 
3.3.2 
Secondary Outcome Measures ................................................................ 11 
 
 
 


IMPAACT 2019 SAP 
 
December 5, 2019 
 
Version History 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
12/5/2019 
 
 
 
 
 
 


IMPAACT 2019 SAP 
 
December 5, 2019 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcome 
measures of the IMPAACT 2019 study that will be included in the primary manuscript. The 
Primary SAP outlines the general statistical approaches that will be used in the analyses. It has 
been developed to facilitate discussion of the statistical analysis components among the study 
team, and to provide agreement between the study team and statisticians regarding the statistical 
analyses to be performed and presented in the primary analysis report. It also describes the 
results for the primary and secondary outcome measures that will be posted on ClinicalTrials.gov.  
It is noted here that all PK analyses including individual and summary tables will be done by the 
study pharmacologists and will be included in a separate PK analysis plan.   
Analyses for the Primary Analysis Report will be finalized once the last participant has completed 
the Week 24 study visit, all queries have been resolved, and the study database closure/data lock 
through Week 24 has been completed. The Primary Analysis Report will include the primary and 
secondary outcome measures through Week 24. This report will form the basis for initial result 
reporting to ClinicalTrials.gov. Initial result reporting needs to happen within one year of the 
primary completion date (PCD), which is the date the last participant is examined for the 
purposes of data collection for the primary outcome measure.  For this study, the PCD is the date 
of the last Week 24 visit.  
Secondary outcomes through Week 48 will be addressed in a secondary analysis report which 
will form the basis for additional results reporting to ClinicalTrials.gov.  The second submission to 
ClinicalTrials.gov will be done within one year after the last Week 48 visit, at which time point the 
relevant analyses through Week 24 will be updated.  
A final submission to ClinicalTrials.gov will be done within one year after the last Week 144 visit, 
at which time point the relevant analyses will be updated. 
The tables, figures and listings of this Primary Statistical Analysis Report will be shared with the 
industry sponsor.  
As this study will have regulatory submission, all analyses covered in this primary SAP will be 
included as part of the regulatory submission. The exploratory outcome measures will be 
described separately. 
2 
Study Overview 
2.1 
Study Design 
IMPAACT 2019 is a Phase I/II, multi-site, open-label, multiple dose, non-comparative study to 
assess the pharmacokinetics (PK), safety, and tolerability of fixed dose combination abacavir 
(ABC)/dolutegravir (DTG)/lamivudine (3TC) in HIV-infected children less than 12 years of age.   


IMPAACT 2019 SAP 
 
December 5, 2019 
 
Up to 75 participants will be enrolled to achieve at least five dose evaluable participants in each 
weight band and at least 50 participants overall (at least 25 less than six years of age and at least 
25 six to less than 12 years of age).  
Dispersible tablets containing 60 mg ABC, 5 mg DTG, and 30 mg 3TC and immediate release 
tablets containing 600 mg ABC, 50 mg DTG, and 300 mg 3TC, administered for at least 48 weeks 
and up to 144 weeks in weight bands as follows: 
 
Weight Band 
Formulation 
(Daily Dose of ABC/DTG/3TC) 
#1 
6 to less than 10 kg 
3 dispersible tablets (180/15/90 mg) 
#2 
10 to less than 14 kg 
4 dispersible tablets (240/20/120 mg) 
#3 
14 to less than 20 kg 
5 dispersible tablets (300/25/150 mg) 
#4 
20 to less than 25 kg 
6 dispersible tablets (360/30/180 mg) 
#5 
25 kg or greater 
1 immediate release tablet (600/50/300 mg) 
 
 
Accrual is expected to require approximately 12 months; enrolled participants will be followed for 
at least 48 and up to 144 weeks, so the whole study will take approximately 48 months in total.   
2.2 
Hypotheses 
1. Selected doses of ABC/DTG/3TC dispersible and immediate release tablets will achieve 
protocol-defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age. 
 
2. ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets will be 
described as safe for treatment in children less than 12 years of age. 
 
 
2.3 
Study Objectives 
2.3.1 
Primary Objectives and Outcome Measures 
1. Determine the steady-state AUC0-24h, Cmax, and C24h of ABC, DTG, and 3TC and confirm the 
dosing of ABC/DTG/3TC dispersible and immediate release tablets that achieves protocol-
defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age 
 
Outcome measures (will be included in the PK report generated by the study 
pharmacologist):  
• 
Geometric mean AUC0-24h, Cmax, and C24h for ABC, DTG, and 3TC based on analysis of 
intensive PK samples collected at Week 1 (AUC0-24h and C24h to be compared within each 
weight band to the PK targets specified in Section 10.3.1 of protocol) 
 


IMPAACT 2019 SAP 
 
December 5, 2019 
 
2. Evaluate the safety profile of 24 weeks of treatment with ABC/DTG/3TC dispersible tablets 
and ABC/DTG/3TC immediate release tablets among children less than 12 years of age 
 
Outcome measures:  
• 
All adverse events occurring through Week 24 
• 
Participants with the following adverse events through Week 24: 
o Grade 3 or Grade 4 adverse events assessed as related to study drug 
o Grade 5 adverse events assessed as related to study drug 
o Life-threatening adverse events assessed as related to study drug 
o Serious adverse events assessed as related to study drug 
o Adverse events assessed as related to study drug that lead to permanent 
discontinuation of study drug 
2.3.2 
Secondary Objectives and Outcome Measures 
1. Determine the PK of ABC, DTG, and 3TC, and clinical covariates that influence PK 
disposition, among children less than 12 years of age using population PK analysis of 
intensive and sparse PK samples collected over 48 weeks of treatment with ABC/DTG/3TC 
dispersible and immediate release tablets 
 
Outcome measures (will be included in the PK report generated by the study 
pharmacologist):   
• 
AUC0-24h, C0h, C24h, Cmax, Tmax, CL/F, and t1/2 derived from population PK modeling with 
sampling through Week 48 
 
2. Evaluate the safety profile of 48 weeks, and additionally up to 144 weeks, of treatment with 
ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC immediate release tablets among 
children less than 12 years of age 
 
Outcome measures:   
• 
All adverse events occurring through Week 48 
• 
Participants with the following adverse events through Week 48: 
o Grade 3 or Grade 4 adverse events assessed as related to study drug 
o Grade 5 adverse events assessed as related to study drug 
o Life-threatening adverse events assessed as related to study drug 
o Serious adverse events assessed as related to study drug 
o Adverse events assessed as related to study drug that lead to permanent 
discontinuation of study drug 
 
• 
All adverse events occurring through Week 144 
• 
Participants with the following adverse events through Week 144:          
o Grade 3 or Grade 4 adverse events assessed as related to study drug 
o Grade 5 adverse events assessed as related to study drug 
o Life-threatening adverse events assessed as related to study drug 
o Serious adverse events assessed as related to study drug 


IMPAACT 2019 SAP 
 
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o Adverse events assessed as related to study drug that lead to permanent 
discontinuation of study drug 
 
3. Evaluate virologic and immunologic responses at 4, 24, and 48 weeks, and additionally up to 
144 weeks, of treatment with ABC/DTG/3TC dispersible tablets and ABC/DTG/3TC 
immediate release tablets among children less than 12 years of age 
 
Outcome measures:   
Virologic responses: 
• 
HIV-1 RNA through Week 48 
• 
HIV-1 RNA through Week 144 
• 
Participants with: 
o HIV-1 RNA ≥200 copies/mL at Weeks 4, 24, and 48 (the FDA’s snapshot 
algorithm) 
o HIV-1 RNA ≥50 copies/mL at Weeks 4, 24, and 48 (the FDA’s snapshot 
algorithm) 
 
Immunologic responses: 
• 
CD4+ cell count and percentage at Weeks 4, 24, and 48 
• 
CD4+ cell count and percentage through Week 144 
 
4. Evaluate changes in lipid profiles at 24 and 48 weeks of treatment with ABC/DTG/3TC 
dispersible tablets and ABC/DTG/3TC immediate release tablets among children less than 12 
years of age 
 
Outcome measures:   
• 
Total cholesterol, HDL, LDL, and triglycerides at Weeks 24 and 48 
 
5. Evaluate adherence to and palatability and acceptability of ABC/DTG/3TC dispersible tablets 
and ABC/DTG/3TC immediate release tablets among children less than 12 years of age at 4, 
24 and 48 weeks of treatment 
 
Outcome measures:   
• 
Parent/guardian reported adherence to study drug at Weeks 4, 24, and 48 
• 
Parent/guardian reported tolerability (i.e., palatability and acceptability) of study drug at 
Weeks 4, 12, 24, and 48 
 
6. Evaluate HIV-1 genotypes and phenotypes among children less than 12 years of age who 
experience virologic failure while receiving treatment with ABC/DTG/3TC dispersible tablets 
and ABC/DTG/3TC immediate release tablets 
 
Outcome measures:   
• 
ARV resistance mutations at time of virologic failure (and at entry for children with 
resistance identified at time of virologic failure) 


IMPAACT 2019 SAP 
 
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2.4 
Overview of Formal Interim Monitoring 
An independent IMPAACT Study Monitoring Committee (SMC) will review this study regularly. 
Routine SMC reviews will occur at least annually and on a more frequent or ad hoc basis if any 
safety issues or concerns arise (Details about these reviews are outlined in protocol Section 9.5.2 
and the SPDSMP). The first routine review will take place approximately six months after the first 
participant is enrolled in the study, unless otherwise specified by the SMC. The SMC will also 
review safety and intensive PK outcomes and the Clinical Management Committee (CMC)’s 
assessment of the appropriateness of each weight band dose. In addition to the above, the SMC 
may conduct ad hoc or triggered safety reviews, for which more limited data may be provided, 
focusing on the events that triggered the reviews. Triggered reviews will occur in the following 
scenarios: 
(1) In the event of any adverse event that is fatal or life-threatening, the CMC will review the 
event as soon as possible (ideally within three business days of site awareness) and 
assess its relationship to study drug: 
• 
If either the site investigator or the CMC assesses the event as related to study drug, 
accrual into all weight bands will immediately be paused. An ad hoc SMC review will 
be convened as soon as possible to discuss how the study should proceed. 
• 
If the site investigator and the CMC assess the event as not related to study drug, 
participant accrual will continue. The SMC will be informed of the event along with the 
CMC’s assessment and decision-making. 
 
(2) If, after dose confirmation for a given weight band is completed, more than 25% of the 
children enrolled in that weight band experience grade 3 or higher adverse events 
assessed by the site investigator as related to study drug or adverse events assessed by 
the site investigator as related to study drug that result in permanent discontinuation of 
study drug, an ad hoc SMC review will be convened. The SMC will review all relevant 
safety and pharmacokinetic data, along with the recommendations of the CMC, and 
determine whether and under what conditions further accrual into the study may proceed. 
The CMC may also request an SMC review of any other adverse event or trend of concern. The 
CMC may likewise request an SMC review in the event of an unresolvable disagreement within 
the CMC on an issue that would impact decision-making. The CMC may choose to pause 
participant accrual and/or administration of study drug pending the outcome of the requested 
SMC review. 
2.5 
Dose Confirmation for Each Weight Band  
An initial group of 5-7 children will be enrolled in each weight band and undergo intensive PK 
sampling at Week 1. The CMC will review intensive PK and four-week safety data for these 
children at least monthly until dose confirmation has been completed for each weight band. Dose 
confirmation will be based on dose-evaluable children as defined in Section 3.2 of protocol 
Version 2.0. The CMC will take action as needed according to the PK guidelines and the safety 
guidelines.  
• 
If data from the dose-evaluable children in the weight band meet the PK and safety 
guidelines, and there are no safety concerns based on all available data from all weight 


IMPAACT 2019 SAP 
 
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bands, the dose will be considered appropriate for the weight band and the SMC will be 
notified. 
• 
If data from the dose-evaluable children in the weight band fail the PK or safety guidelines, 
or there are safety concerns from other weight bands, and the Protocol Team determines 
that an adjusted dose and/or alternative dosing strategy is needed to safely achieve 
targeted drug concentrations, accrual into the weight band will be paused and the SMC 
will be notified. Following consultation with the SMC, and unless other recommendations 
are provided by the SMC, 5-7 additional dose-evaluable children will be enrolled into the 
weight band and the adjusted dose will be evaluated as described above.  
• 
If data from other children who are evaluable for safety or PK but not both (i.e., are not 
dose-evaluable), are available when dose confirmation analyses are performed, these 
data may be included in the analyses.  
• 
If a confident determination regarding achievement of the PK targets cannot be made, 
additional children enrolled in the weight band will undergo intensive PK sampling. The PK 
analysis for the weight band will then be repeated with data from the initial 5-7 children 
and the additional children.  
Unless the criteria specified below for pausing participant accrual are met, enrollment into each 
weight band and into the study overall will not be paused while PK and safety data are being 
reviewed.  
Safety Guidelines for Dose Confirmation: 
The frequency of adverse reactions occurring among the first 5-7 participants through Week 4 will 
be closely monitored. If any of these safety-evaluable participants experiences a fatal or life-
threatening event that is assessed as related to study drug, or if more than 25% of the 
participants experience a related grade 3 or higher non-fatal and non-life-threatening adverse 
event or a related adverse event that results in permanent discontinuation of study drug, the dose 
under evaluation will be considered to have failed the safety guidelines. Otherwise, and absent 
any safety concerns from other weight bands, the dose will be considered to have passed the 
safety guidelines. 
PK Guidelines for Dose Confirmation: 
Dose confirmation within each weight band will be based on achieving a geometric mean DTG 
AUC0-24h between 35.1 and 134 μg∙h/mL and C24h between 0.67 and 2.97 μg/mL, and geometric 
mean ABC and 3TC AUC0-24h between 6.3 and 50.4 μg∙h/mL and 6.3 and 26.5 μg∙h/mL, 
respectively. Note: please see Section 10.3.1 of Protocol Version 2.0 for detailed information 
regarding PK guidelines for dose confirmation. In addition, the protocol pharmacologists will 
prepare the PK analysis plan to describe how the PK data will be described and summarized. 
 


IMPAACT 2019 SAP 
 
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3 
Statistical Principles 
3.1 
Definition of Baseline 
For some outcome measures, baseline values will be determined and changes from baseline will 
be analyzed. For analyses purposes, baseline value is defined as the latest pre-dose assessment 
with a non-missing value, including those from unscheduled visits. If time is not collected, Day 1 
(First dose date is considered as Day 1.) assessments are assumed to be taken prior to first dose 
and used as baseline.  
Unless otherwise stated, if baseline data are missing, no derivation will be performed and 
baseline will be set to missing. 
3.2 
General Considerations 
For participants who were inadvertently enrolled and later found to be ineligible, if they received 
the study treatment drug, their safety data will be summarized separately; if they never started the 
study treatment drug, together with other participants who never started treatment drug, they will 
only be included in the accrual tables and will be excluded from all analyses. 
Participants with dose adjustments due to weight change, i.e., participants who have dose 
adjustments due to weight gain or decrease, will be analyzed in their original weight band in 
which they enrolled.  
For participants whose study drug dose is adjusted for reasons other than weight gain or 
decrease (including participants whose study drug regimen is modified due to receipt of rifampin-
containing TB treatment), safety data up to the date of dose adjustment will be analyzed in the 
original weight band, and sensitivity analyses will be performed to assess whether conclusions 
drawn from primary dose confirmation evaluations would be affected by inclusion of these data. 
Safety data for these participants after the date of dose adjustment will be described separately. 
Primary and secondary analyses will be done for the “primary safety population”, which is defined 
as participants (1) whose starting dose of ABC/DTG/3TC is the final confirmed dose for their 
weight band and (2) whose dose may have been increased due to weight gain putting them in a 
higher weight band, provided that the dose received in the higher weight band is the dose that 
would be recommended in the overall patient population who experience a similar weight band 
progression. Participants whose treatment is consistent with (1) and (2) above, but who 
discontinue treatment due to toxicity before Week 24 will be included and treated as safety 
failures in the primary safety analyses. In addition, secondary analyses will also be done for 
participants who received at least one dose of study drug, which includes participants whose 
study drug doses were modified due to other reasons (not due to weight gain) or who received 
doses other than the final confirmed dose for their weight band. Results will be presented by 
weight band and in aggregate. 
3.3 
Analysis Approaches 
3.3.1 
Primary Safety Outcome 
The primary safety analyses will be done for the “primary safety population” as defined in Section 
3.2. These primary analyses will be performed after the last participant has completed his or her 
Week 24 Visit, all queries have been resolved, and the study database closure/data lock through 


IMPAACT 2019 SAP 
 
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Week 24 has been completed. Results will be presented by weight band and in aggregate, as 
well as by age group and study drug formulation. 
A listing of all adverse events of all severity grades will be summarized. When analyses involve 
assessment of relationship to study drug, the site investigator’s assessment will be used. 
In addition, overall proportions (bounded by exact 95% CIs) of participants experiencing any of 
the following events and proportions (bounded by exact 95% CIs) experiencing each type of 
event will be presented: 
• 
Grade 3 or higher adverse events  
• 
Grade 3 or Grade 4 adverse events assessed as related to study drug 
• 
Grade 5 adverse events assessed as related to study drug 
• 
Life-threatening adverse events assessed as related to study drug 
• 
Serious adverse events assessed as related to study drug 
• 
Adverse events assessed as related to study drug that lead to permanent discontinuation 
of study drug 
Each participant would only be counted once for each of the proportion, even if they experience 
more than one event of that category.  
Listings of all grade 3 or higher adverse events, grade 3 or grade 4 adverse events assessed as 
related to study drug, grade 5 adverse events assessed as related to study drug, life-threatening 
adverse events assessed as related to study drug, serious adverse events assessed as related to 
study drug, and adverse events assessed as related to study drug that result in permanent 
discontinuation of study drug will be provided by System Organ Class and Preferred Terms. 
The proportion of participants meeting each of the criteria above that trigger an SMC safety 
review will be presented descriptively.  
For regulatory submission purposes, all the above analyses will be performed and will include all 
participants. Frequency distributions of safety outcomes will be presented by weight band and in 
aggregate, as well by age group and study drug formulation. 
3.3.2 
Secondary Outcome Measures 
Secondary Safety Outcome  
The primary safety analyses described in Section 3.3.1 will be repeated as secondary analyses 
for the “primary safety population” as defined in Section 3.2, but include safety outcomes from the 
on-treatment date through Week 48, and separately from the on-treatment date through Week 
144. 
In addition, further analyses that include safety outcomes from on-treatment date through Week 
24, Week 48, and Week 144 for all participants who received at least one dose of study drug will 
be performed.  


IMPAACT 2019 SAP 
 
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Descriptive and exposure-related analyses will present safety outcomes for participants whose 
study drug doses were modified due to weight band dose adjustment or who otherwise received 
doses other than the final confirmed dose for their weight band. This will include data 
representing the final dose for each weight band, as well as data representing doses considered 
to have failed.  
For each starting dose, all grade 3 or higher adverse events will be listed, along with participant 
demographics, the dose prescribed to the participant at the time of the event, and the site 
investigator’s assessment of relationship to study drug. 
 
Virologic Response 
Analyses for virologic response will be done for participants “primary safety population” as 
defined in Section 3.2 and for all participants who received at least one dose of study drug, 
respectively. Results will be presented by weight band and in aggregate. 
HIV-1 RNA data will be analyzed descriptively and using the FDA snapshot algorithm.  
Descriptive analyses will include HIV-1 RNA available at all time points and will present the 
number and percentage of participants with a suppressed viral load (with cutoff of 200 copies/mL) 
at each time point and the distribution of non-suppressed viral load values at each time point. 
HIV-1 RNA at each time point for each participant will use the last available HIV-1 RNA 
assessment while the participant is on study drug within the allowable study visit window. Data 
will be presented separately for participants who were ART-naïve versus ART-experienced at 
study entry, as well as for participants with a documented M184V mutation, who will undergo 
additional HIV-1 RNA testing per the Schedule of Evaluations. 
For analysis using the FDA snapshot algorithm, HIV-1 RNA values for participants will be 
assessed at Weeks 4, 24 and 48. At each time point, the FDA’s snapshot algorithm will be used 
for the definition of virologic outcome, with cutoffs of 200 copies/mL or 50 copies/mL (analyses 
will be performed twice, once at the 200 copies/mL threshold and separately at the 50 copies/mL 
threshold). In addition, participants will be classified as virologic failures if they prematurely 
discontinued study drug prior to Week 4, Week 24, or Week 48. Otherwise, virologic success or 
failure will be determined by the last available HIV-1 RNA assessment while the participant is on 
study drug within the visit of interest window. The proportions of participants meeting the criteria 
for virologic failure or success at each time point will be bounded by exact 95% CIs and will be 
presented both in the aggregate and by weight band. 
Immunologic Response 
Analyses for immunologic response will be done for participants “primary safety population” as 
defined in Section 3.2 and for all participants who received at least one dose of study drug, 
respectively. Results will be presented by weight band and in aggregate. 
Median and the associated interquartile range for changes in CD4+ count and percentage from 
baseline to Weeks 4, 24, 48 for participants will be presented by weight band and aggregated, 
bounded by 95% CIs. Missing CD4+ values for participants who discontinued study drug prior to 
the time point of interest due to safety or virologic failure will be replaced with their baseline CD4+ 
values. 
 
Total Cholesterol, HDL, LDL, and Triglycerides  


IMPAACT 2019 SAP 
 
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Analyses for total cholesterol, HDL, LDL, and triglycerides will be done for participants “primary 
safety population” as defined in Section 3.2 and for all participants who received at least one 
dose of study drug, respectively. Results will be presented by weight band and in aggregate. 
Median and the associated interquartile range for changes in total cholesterol, HDL, LDL, and 
triglycerides from baseline to Weeks 24 and 48 for participants will be presented by weight band 
and aggregated. Missing total cholesterol, HDL, LDL, and triglyceride values for participants who 
discontinued study drug prior to the time point of interest due to safety or virologic failure will be 
replaced with their baseline values. 
 
Adherence, Palatability and Acceptability 
Adherence, palatability and acceptability measures — based on questionnaire responses — will 
be summarized by weight band and aggregated for all participants who received study drug. 
As palatability and acceptability data are accumulated in the study, if the Protocol Team 
determines that the dispersion volumes shown in protocol Table 8 are not sufficiently acceptable 
for children in weight band #3 or #4, the volumes shown in protocol Table 9 may be 
recommended for all applicable participants. It is generally expected that these data will be 
reviewed after approximately 20-30 children in these weight bands have completed their Week 4 
visits; however, this determination may be made at any time in response to accumulating study 
data. The Protocol Team will use responses to item 3 of the Palatability Assessment (QLW10081) 
and item 7 of the Acceptability Assessment (QLW10080) at Week 4 to make this determination. 
More specifically, the volumes specified in protocol Table 8 will be considered preferred if at least 
half of children (their caregivers) answer QLW10081 item 3 with a response of very good, good, 
or average and at least half of children (their caregivers) answer QLW10080 item 7 with a 
response of it is acceptable. 
These data will be presented descriptively. 
 
Antiretroviral Resistance  
Participants with confirmed virologic failure will be evaluated for viral resistance to the 
components of the study drug regimen. For these participants, both phenotypic and genotypic 
resistance results will be presented descriptively.