Clinical trial NCT04272242
Conditions: HIV Infection LTBI
Keywords: LTBI HIV and LTBI Co-Infection Rifapentine Dolutegravir Interaction
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-02-27; Completion date: 2021-12-27
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study evaluated the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT was given with isoniazid (INH) daily for 4 weeks (1HP) as part of treatment for latent TB infection (LTBI) in HIV-1 and LTBI co-infected individuals.

Detailed description:
The purpose of this study was to evaluate the potential drug-drug interactions between dolutegravir (DTG) and steady state rifapentine (RPT) when RPT was given with isoniazid (INH) daily for 4 weeks (1HP) as part of treatment for latent TB infection (LTBI) in HIV-1 and LTBI co-infected individuals.

Participants received study-provided INH and RPT once daily for 4 weeks (1HP). During the 1HP treatment, DTG was administered twice daily in Arm 1. Arm 2 planned to administer DTG once daily.

At study entry, all participants were required to be on DTG-based antiretroviral (ARV) treatment with 2 nucleoside reverse transcriptase inhibitors (NRTIs) (tenofovir alafenamide \[TAF\] was prohibited) during the study. In Arm 1, DTG 50 mg was administered twice daily; the morning dose from non-study ARV supply and the evening dose from study supply.

Participants were also required to receive pyridoxine (vitamin B6) with each dose of INH based on the current local, national, or international dosing guidelines. NRTI therapy and pyridoxine (vitamin B6) was not provided by the study.

The majority of Arm 1 participants were on study for 6 weeks (a 4-week on-study treatment period and a 2-week follow-up period). Arm 1 participants could be on study for up to 11 weeks if the on-study treatment duration was extended or if participants needed additional follow-up visits to measure viral load.

The study began enrollment with Arm 1. Opening of Arm 2 was dependent upon assessment of DTG pharmacokinetics (PK) data from participants in Arm 1.

Arm 1 is complete and results are reported. Arm 2 was not conducted based on the Arm 1 PK assessment.

Arms: arm 1: Participants received 50 mg of DTG orally twice daily (\~12 hours apart). Participants received 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks.

Participants also received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH.

Participants remained on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. Participants took non-study supply of DTG for morning doses, and study-supplied DTG for evening doses. arm 2: Participants were to receive 50 mg of DTG orally each morning and 300 mg of INH and 600 mg of RPT orally each morning for 4 weeks.

Participants were also to have received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH.

Participants were to remain on once-daily DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study with DTG supplied from non-study ARV supply.

It was decided to not move forward with Arm 2 of the study based on the Arm 1 PK assessment and no participants were enrolled in Arm 2.
Interventions: intervention 1: Dolutegravir (DTG) intervention 2: Isoniazid (INH) intervention 3: Rifapentine (RPT) intervention 4: Antiretroviral Therapy (ART) intervention 5: Pyridoxine (Vitamin B6)
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally intervention 4: Participants remained on DTG-based ARV treatment with 2 NRTIs (excluding TAF) during the study. NRTIs were not provided by the study. Arm 1 participants took non-study supply of DTG for morning doses, and study-supplied DTG for evening doses. For Arm 2 participants, DTG was to have come from non-study ARV supply. intervention 5: Participants received 25 or 50 mg of pyridoxine (vitamin B6) with each dose of INH, based on the current local, national, or international dosing guidelines. Pyridoxine was not provided by the study.

Protocol documents:
Prot_ICF_002.pdf: 
 
 
 
A5372 
 
 
Drug-Drug Interactions Between Rifapentine and Dolutegravir 
in HIV/LTBI Co-Infected Individuals  
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
Industry Support Provided by: 
ViiV Healthcare, Ltd. 
 
 
IND # 146789 
 
The ACTG Tuberculosis  
Transformative Science Group: 
Gavin Churchyard, MBChB, Chair 
 
Protocol Chair: 
Anthony Podany, PharmD 
 
Protocol Co-Vice Chairs:  
Rodney Dawson, MBChB, FCP 
Annie Luetkemeyer, MD 
 
DAIDS Clinical Representatives: 
Irina Gelmanova, MD, MPH 
Richard Hafner, MD 
 
Clinical Trials Specialist: 
Parita Rathod, BS 
 
 
 
 
 
 
 
 
Final Version 2.0 
June 11, 2021 


 
A5372 
 
 
Final Version 2.0 
 
 
11Jun2021 
 
 
Drug-Drug Interactions Between Rifapentine and Dolutegravir  
in HIV/LTBI Co-Infected Individuals  
 
SIGNATURE PAGE 
 
 
I will conduct the 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. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 


 
A5372 
 
 
Final Version 2.0 
 
 
11Jun2021 
 
 
TABLE OF CONTENTS 
Page 
 
SIGNATURE PAGE .................................................................................................................... 2 
TABLE OF CONTENTS .............................................................................................................. 3 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 15 
1.1 
Hypothesis ......................................................................................................... 15 
1.2 
Primary Objectives ............................................................................................. 15 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Exploratory Objectives ....................................................................................... 15 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale ........................................................................................................... 19 
3.0 
STUDY DESIGN ........................................................................................................... 20 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 21 
4.1 
Inclusion Criteria ................................................................................................ 21 
4.2 
Exclusion Criteria ............................................................................................... 23 
4.3 
Study Enrollment Procedures............................................................................. 25 
4.4 
Co-enrollment Guidelines ................................................................................... 26 
5.0 
STUDY TREATMENT ................................................................................................... 26 
5.1 
Regimens and Duration ..................................................................................... 26 
5.2 
Administration and Dispensing ........................................................................... 27 
5.3 
Study Product Formulation ................................................................................. 27 
5.4 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 28 
5.5 
Concomitant Medications ................................................................................... 28 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 30 
6.1 
Schedule of Evaluations..................................................................................... 30 
6.2 
Timing of Evaluations ......................................................................................... 32 
6.3 
Instructions for Evaluations ................................................................................ 34 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 40 
7.1 
Definition of Adverse Event ................................................................................ 40 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 40 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 41 
7.4 
Study Monitoring ................................................................................................ 42 


 
A5372 
 
 
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Table of Contents (Cont’d) 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 43 
8.1 
Toxicity .............................................................................................................. 43 
8.2 
Rifamycin Hypersensitivity Syndrome (RHS) ..................................................... 44 
8.3 
Suspected Allergic Reactions to Dolutegravir ..................................................... 44 
8.4 
Other Toxicities .................................................................................................. 45 
8.5 
Pregnancy Outcomes and Reporting ................................................................. 47 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 47 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 47 
9.2 
Premature Study Discontinuation ....................................................................... 47 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 48 
10.1 
General Design Issues ....................................................................................... 48 
10.2 
Outcome Measures ............................................................................................ 48 
10.3 
Randomization and Stratification ........................................................................ 49 
10.4 
Sample Size and Accrual ................................................................................... 49 
10.5 
Data and Safety Monitoring ................................................................................ 50 
10.6 
Analyses ............................................................................................................ 51 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 51 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 51 
12.1 
Records to Be Kept ............................................................................................ 51 
12.2 
Role of Data Management ................................................................................. 52 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 52 
13.0 
PARTICIPANTS ............................................................................................................ 52 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 52 
13.2 
Participant Confidentiality ................................................................................... 53 
13.3 
Study Discontinuation ........................................................................................ 53 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 53 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 53 
16.0 
REFERENCES .............................................................................................................. 54 
APPENDIX I: PROHIBITED AND PRECAUTIONARY MEDICATIONS ..................................... 56 
APPENDIX II: SAMPLE INFORMED CONSENT ...................................................................... 57 
ATTACHMENT I: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES .......................... 74 
 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5372 is a multi-center study open to selected US and non-US ACTG clinical research sites. 
Refer to the Site tab on the protocol-specific web page (PSWP) on the ACTG member website 
for the list of eligible sites. 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Anthony Podany, PharmD 
College of Pharmacy 
University of Nebraska Medical Center 
986145 Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-1939 
Email: apodany@unmc.edu 
 
Co-Vice Chairs 
Rodney Dawson, MBChB, FCP 
Centre for TB Research Innovation 
University of Cape Town Lung Institute 
P.O. Box 34560 
George Street, Mowbray 
Cape Town 7700 
Western Cape 
SOUTH AFRICA 
Phone: 27-21-4066864 
Fax: 27-4066731 
Email: rodney.dawson@uct.ac.za 
 
Annie Luetkemeyer, MD 
HIV, Infectious Disease and Global 
Medicine  
San Francisco General Hospital 
University of California, San Francisco 
995 Potrero Avenue, Box 0874 
San Francisco, CA 94110 
Phone: 415-476-4082, x130 
Fax: 415-476-6953 
Email: annie.luetkemeyer@ucsf.edu 
 
DAIDS Clinical Representative  
Irina E. Gelmanova, MD, MPH 
TB Clinical Research Branch 
Therapeutic Research Program  
5601 Fishers Lane, 9E31A 
Rockville, MD 20852-9830 
Phone: 301-332-4057 
Email: irina.gelmanova@nih.gov 
 
DAIDS Clinical Representative (Cont’d) 
Richard Hafner, MD 
TB Clinical Research Branch 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E30 
Rockville, MD 20852 
Phone: 301-435-3766 
Email: rhafner@niaid.nih.gov 
 
Statisticians 
Yoninah Cramer, MS 
Statistical and Data Analysis Center 
Harvard Chan School of Public Health and 
Frontier Science Foundation 
1371 Beacon Street, Suite 203 
Brookline, MA 02446 
Phone: 617-632-2000, x5901 
Email: cramer@sdac.harvard.edu 
 
Susan Rosenkranz, PhD 
Statistical and Data Analysis Center 
Harvard Chan School of Public Health and 
Frontier Science Foundation 
1371 Beacon Street, Suite 203 
Brookline, MA 02446 
Phone: 617-632-2000, x5915 
Email: sue@sdac.harvard.edu 
 
Clinical Trials Specialist 
Parita Rathod, BS, RAC 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., a DLH 
Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
Email: parita.rathod@dlhcorp.com 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
 
Data Manager 
Rebecca Marshall, MPH 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 USA 
Phone: 716-834-0900 x7203 
Fax: 716-834-8432 
Email: marshall@frontierscience.org 
 
DAIDS Pharmacists 
Justine Beck, PharmD, BCPS, RPh  
Pharmaceutical Affairs Branch 
DAIDS/NIAID/NIH 
5601 Fishers Lane, 9D39, MSC 9829 
Rockville, MD 20852 
Phone: 301-761-5288 
Email: justine.beck@nih.gov 
 
Lynette Purdue, PharmD 
Pharmaceutical Affairs Branch 
DAIDS/NIAID/NIH 
5601 Fishers Lane, 9E28 
Rockville, MD 20852 
Phone: 240-627-3061 
Fax: 301-402-1506 
Email: lpurdue@niaid.nih.gov  
 
Pharmacometrician 
Rada Savic, PhD 
UCSF School of Pharmacy and Medicine 
Department of Bioengineering and 
Therapeutic Sciences 
University of California San Francisco 
1550 4th Street, Box 2911 
San Francisco, CA 94143-2911 
Phone: 415-502-0640 
Fax: 415-502-4361 
Email: rada.savic@ucsf.edu 
Pharmacologist 
Charles Maponga, PharmD 
Parirenyatwa CRS 
UZ-UCSF Central Pharmacy 
Milton Park, Harare A178 
ZIMBABWE 
Phone: 263-772-666-478 
Email: cmaponga@medsch.uz.ac.zw 
 
Investigators 
Kelly Dooley, MD, PhD 
Johns Hopkins University CRS 
Osler 527  
600 North Wolfe Street 
Baltimore, MD 21287 
Phone: 410-955-3100 
Fax: 410-614-9978 
Email: kdooley1@jhmi.edu 
 
Susan Swindells, MBBS 
University of Nebraska Medical Center 
Department of Internal Medicine 
988106 Nebraska Medical Center 
Omaha, NE 68198-8106 
Phone: 402-559-5392 
Fax: 402-553-5527 
Email: sswindells@unmc.edu 
 
Site Investigator  
Beatriz Grinsztejn, MD, PhD 
Instituto de Pesquisa Clinica Evandro 
Chagas CRS 
Fundacao Oswaldo Cruz 
Avenida Brasil 4365, Manguinhos 
Rio de Janeiro 21040-900  
BRAZIL 
Phone: 55-21-22707064 
Fax: 55-21-25644933 
Email: gbeatriz@ipec.fiocruz.br 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
 
Field Representative 
Susan Pedersen, RN, BSN 
Chapel Hill CRS 
Bioinformatics Building, Suite 2100 
130 Mason Farm Road 
Chapel Hill, NC 27599-7215 
Phone: 919-966-6713 
Email: spederse@med.unc.edu 
 
Laboratory Technologists 
Christopher Lane, BS 
Therapeutic Strategies Network CRS 
University of Rochester Adult HIV Box 689 
601 Elmwood Avenue 
Rochester, NY 14642 
Phone: 585-276-5574 
Fax: 585-442-9328 
Email: christopher_lane@urmc.rochester.edu 
 
Sasiwimol Ubolyam, MSc 
Thai Red Cross AIDS Research Centre 
(TRC-ARC) CRS 
104 Rajdamri Road 
Patumwan, Bangkok 10330 
THAILAND 
Phone: 66-2-2564648 
Fax: 66-2-2511380 
Email: sasiwimol.u@hivnat.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Flavia Miiro, MSc 
Theta African Solutions for African Challenges 
P.O. Box 25757 
Old Kira Road Bukoto 
Kampala 
UGANDA 
Phone: 256-702506386 
Email: flatmiiro@gmail.com 
ACTG International Site Specialist 
Morgan Gapara, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., a DLH 
Holdings Company 
4505 Emperor Boulevard, Suite 400 
Durham, NC 27703 
Phone: 919-287-4503 
Fax: 919-941-9349 
Email: morgan.gapara@dlhcorp.com 
 
Laboratory Specialists 
William A. Murtaugh, MPHTM 
ACTG Laboratory Center 
University of California, Los Angeles  
11075 Santa Monica Boulevard, Suite #200 
Los Angeles, CA 90027 
Phone: 310-794-9894 
Email: wmurtaugh@impaactlabcenter.org  
 
Samantha Solomon, BS 
ACTG Laboratory Center 
University of California, Los Angeles 
675 Charles E. Young Drive S 
Los Angeles, CA 90095 
Phone: 314-441-2356 
Email: ssolomon@milabcentral.org 
 
Industry Contacts 
Christopher Stainsby 
ViiV Healthcare, Inc. 
GSK House CN12, 980 Great West Road  
Brentford, Middlesex, TW8 9GS, UK 
Phone: +44 (0) 7880 179 182 
Email: chris.m.stainsby@viivhealthcare.com 
 
Jean van Wyk, MBChB, MFPM 
ViiV Healthcare, Inc. 
GSK House, 980 Great West Road 
Brentford, Middlesex, TW8 9GS, UK 
Phone: +44 (0) 7467 447 769 
Email: jean.x.andre-van-wyk@viivhealthcare.com 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
 
Laboratory Data Manager 
Kyle Whitson, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14221 
Phone: 716-340-0900 (Ext. 7273) 
Email: whitson@frontierscience.org 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5372@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5372@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5372 e-mail group. 
Include the protocol number in the e-mail subject line. Send an e-mail message to 
actg.user.support@fstrf.org.  
 
Clinical Management 
For questions concerning entry criteria, toxicity management, concomitant medications, and 
co-enrollment, contact the core team (actg.coreA5372@fstrf.org). Include the protocol number, 
patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to pharmacologic laboratory tests, contact the protocol 
leadership. Send an e-mail message to actg.teamA5372@fstrf.org (ATTENTION: Anthony 
Podany). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Rebecca 
Marshall (marshall@frontierscience.org) directly.  
• 
For other questions, send an e-mail message to actg.teamA5372@fstrf.org (ATTENTION: 
[Rebecca Marshall]). Include the protocol number, PID, and a detailed question. 
 
Participant Registration 
For participant registration questions or problems and study identification number SID lists: send 
an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at  
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. Send an e-mail message to actg.user.support@fstrf.org or call 
716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. Send an 
e-mail message to actg.teamA5372@fstrf.org (ATTENTION: Parita Rathod). 
 


 
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Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialist. 
Send an e-mail message to actg.teamA5372@fstrf.org (ATTENTION: Parita Rathod). 
 
For questions related to protocol activation at non-US sites contact the ACTG Site Coordination 
Group. Send an email message to ACTGSiteCoordination@dlhcorp.com. 
 
Study Product 
For questions or problems regarding A5372 study product, dose, supplies, records, and returns, 
call Justine Beck or Lynette Purdue, Protocol Pharmacists, at 301-761-5288 or 240-627-3061, 
respectively. 
 
Study Drug Orders 
For A5372 study drug orders, call the Clinical Research Products Management Center 
(CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number will be available on the protocol-specific web page (PSWP) within 30 days of 
submission to the Food and Drug Administration (FDA). For any questions related to the IND 
submission, contact the DAIDS RSC at regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710. 
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5372 team members.  
Send an e-mail message to actg.teamA5372@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 
 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
1HP 
4-week daily regimen of isoniazid and rifapentine 
ARV 
antiretroviral 
AUC 
area under the curve 
BID 
twice daily 
DTG 
dolutegravir 
EFV 
efavirenz 
ICF 
Informed Consent Form 
IGRA 
interferon gamma release assay 
INH 
isoniazid 
INSTI 
integrase strand transfer inhibitor 
LTBI 
latent TB infection 
MDR TB 
multi-drug-resistant tuberculosis 
MTB 
Mycobacterium tuberculosis 
NRTI 
nucleoside reverse transcriptase inhibitor 
OHRP 
Office for Human Research Protections 
PGP 
P-glycoprotein 
PK 
pharmacokinetics 
QD 
once daily 
RAL 
raltegravir 
RFB 
rifabutin  
RHS 
rifamycin hypersensitivity syndrome 
RIF 
rifampin 
RPT 
rifapentine 
SAE 
serious adverse event 
SNP 
single nucleotide polymorphism 
TAF 
tenofovir alafenamide 
TB 
tuberculosis 
TST 
tuberculin skin test 
XDR TB 
extensively drug-resistant tuberculosis 
 


 
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SCHEMA 
 
A5372 
Drug-Drug Interactions Between Rifapentine and Dolutegravir in  
HIV/LTBI Co-Infected Individuals 
 
DESIGN 
A5372 is an open-label, two-arm, multicenter pharmacokinetic (PK) study to 
investigate the potential interactions between dolutegravir (DTG) and steady 
state rifapentine (RPT) when RPT is given with isoniazid (INH) daily for 
4 weeks (1HP) as part of treatment for latent TB infection (LTBI) in HIV-1 and 
LTBI co-infected individuals.  
 
DURATION 
The majority of participants will be on study for 6 weeks (a 4-week on-
study treatment period and a 2-week follow-up period). The duration may 
be up to 8 weeks as participants will have up to 6 weeks from the time of 
study entry to complete 4 weeks of treatment. 
 
Participants who are required to return for confirmation of virologic failure 
within 1 to 3 weeks after the follow-up visit may be on study for up to 
11 weeks. 
 
SAMPLE SIZE 
Maximum of 72 participants – 36 in Arm 1 and 36 in Arm 2, to yield at 
least 32 evaluable participants in each arm.  
 
Evaluable participants are defined as those who have completed 28 daily 
doses of RPT/INH within the 6 week time period from study entry and 
who have at least 6 plasma sample collections on each of the two 
intensive PK visits (6 of these collections must include trough DTG 
concentration collections at 23- and 24-hr post-dose collection time 
points). Participants who do not have the required PK will be replaced. 
 
POPULATION 
Adults living with HIV-1 on stable once daily DTG based ART with 2 
nucleoside reverse transcriptase inhibitors (NRTI) and an indication for 
LTBI treatment. 
 
REGIMEN 
Participants will receive study-provided INH 300 mg and RPT 600 mg 
once daily for 4 weeks (1HP). During the 1HP treatment, DTG 50 mg will 
be administered twice daily (BID) in Arm 1, and 50 mg once daily (QD) in 
Arm 2. For Arm 1, the second dose of DTG will be provided by the study; 
NRTI therapy and pyridoxine (vitamin B6) will not be provided by the 
study. See details below. 
 
The study will begin enrollment with Arm 1. Opening of Arm 2 will depend 
on assessment of DTG PK data from participants in Arm 1.  
 
 


 
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Arm 1 
• 
DTG 50 mg orally BID (~12 hours apart) 
o 1st dose: DTG 50 mg each morning from non-study ARV supply 
o 2nd dose: DTG 50 mg each evening from study supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
 
Arm 2 (upon opening)  
• 
DTG 50 mg orally each morning from non-study ARV supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
 
All participants must also be on once-daily DTG-based ARV treatment 
with 2 NRTIs (excluding TAF) during the study. 
 
All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with 
each dose of INH based on the current local, national, or international 
dosing guidelines. 
 
 
 
Figure 1: Schema


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
1.1 
Hypothesis 
 
Dolutegravir (DTG) concentrations, when given twice daily (BID) or once daily (QD), with 
coadministration of 4 weeks daily rifapentine (RPT) (600 mg) and isoniazid (INH) (300 mg) 
[1HP], will maintain steady-state plasma trough DTG concentrations above 158 ng/mL 
in 95% of study participants. The value 158 ng/mL is the 5th percentile steady-state 
trough concentrations of DTG which has been demonstrated to be sufficient in 
maintaining viral suppression. 
 
1.2 
Primary Objectives 
 
1.2.1 To determine the dosing for DTG that, when given together with 1HP, achieves 
target exposures (Ctrough) of standard-dose DTG when it is given without RPT. 
 
1.2.2 To estimate the steady state plasma pharmacokinetics (PK) of DTG when DTG 
50 mg is dosed twice daily (BID) with 1HP. 
 
1.2.3 If Arm 2 opens, to estimate the steady state plasma PK of DTG when DTG 
50 mg is dosed once daily (QD) with 1HP. 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the safety of coadministration of DTG based ART with 1HP. 
 
1.3.2 To evaluate the tolerability of coadministration of DTG based ART with 1HP. 
 
1.3.3 To estimate the proportion of participants who maintain virologic suppression 
when DTG based ART is coadministered with 1HP. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To evaluate the steady state PK parameters of DTG in the presence or absence 
of 1HP, taking into account relevant pharmacogenetics across diverse 
populations (single nucleotide polymorphisms [SNPs] to be determined). 
 
1.4.2 To evaluate the steady state PK parameters of RPT achieved from 1HP dosing in 
people living with HIV and explore relevant pharmacogenetics associated with 
RPT exposures (SNPs to be determined). 
 
1.4.3 To develop a joint pharmacokinetic model of RPT and DTG PK and its drug-drug 
interaction (DDI) where relationship and interaction between dynamic RPT and 
DTG concentrations is modelled, quantified, and described. 


 
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2.0 
INTRODUCTION 
 
2.1 
Background 
 
2.1.1 Dolutegravir 
 
Dolutegravir (DTG) is now included in preferred regimens for antiretroviral (ARV)-
naïve individuals by the Department of Health and Human Services (DHHS), World 
Health Organization (WHO), and International AIDS Society (IAS) USA guidelines 
panels [1, 2, 3]. Moreover, the drug is being rolled out into resource poor settings 
(RPS) and was recently launched in South Africa. The drug combines high 
potency, excellent tolerability, and a high barrier to resistance (Tivicay Package 
Insert, ViiV, 2017) [4].  
 
The SPRING-1 study was a Phase IIb dose ranging trial of DTG given with two 
nucleoside reverse transcriptase inhibitors (NRTI) in antiretroviral naïve adults living 
with HIV. Data from this multicenter trial showed that DTG was well tolerated in the 
doses studied from 10 mg to 50 mg once daily. Efficacy analysis (% participants 
with viral load <50 copies mL) showed that at 48 weeks 90% of individuals in the 
50 mg arm achieved virologic suppression while 91% achieved this same endpoint 
in the 10 mg dosing arm (difference non-significant) [5]. The geometric mean (%CV) 
values for DTG trough concentrations in SPRING-1 were 0.3 ug/mL (71%) and 1.2 
ug/mL (62%) for the 10 and 50 mg doses of DTG, respectively. The efficacy and PK 
data from the SPRING-1 study are reassuring in that the 50 mg dose of DTG is the 
current standard of care, while efficacy data from the 10mg daily dose of DTG may 
provide insight into acceptable DTG trough thresholds that may arise when 
encountering drug-drug interactions such as those in the treatment of HIV/TB co-
infection when using rifamycin antibiotics in combination with DTG. To this end, this 
evaluation will target achieving 95% of DTG trough values above 158 ng/mL, the 5th 
percentile DTG trough value in the DTG 10 mg dosing arm of SPRING-1 and above 
the protein adjusted DTG IC90 of 64 ug/mL. 
 
Primarily metabolized by UGT1A, with CYP3A as a minor route, DTG has been 
studied with rifampin and rifabutin in healthy HIV-uninfected volunteers [6]. Given 
twice daily with standard-dose, daily rifampin, DTG total daily exposures were 
similar to or higher than those achieved with DTG given once daily alone. Overall 
plasma concentrations of DTG were only modestly reduced when DTG was 
given with (versus without) rifabutin, and no DTG dose adjustment is required. 
One out of 27 healthy volunteers (in the rifabutin arm) experienced a serious 
adverse reaction consistent with rifamycin hypersensitivity syndrome (RHS).  
 
In the INSPIRING study, a Phase IIIb trial of people living with HIV with drug 
susceptible TB receiving a rifampin based TB treatment, DTG given at a dose of 
50 mg twice daily was both effective and well tolerated. At week 48 the proportion of 
participants with HIV-1 RNA <50 copies/mL was 75%. No patients randomized to 
the DTG ARV arm discontinued DTG due to adverse events. Importantly, there 
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combined DTG and rifampin (n=69) based TB treatment. Rates of treatment related 
IRIS were low (6%) and no participant discontinued due to IRIS or liver events [7]. 
 
A similar study of DTG twice daily in combination with rifampin based TB 
treatment in adults living with HIV and TB has provided additional virologic and 
PK data on DTG use in this population. In 10 participants from Cameroon with a 
median baseline HIV-1 RNA of 520,440 copies/mL, patients started on DTG 
50 mg BID within the study all had HIV-1 RNA <200 copies/mL at week 48 with a 
median DTG trough (C12) value of 1,123 ng/mL (Inhibitory Quotient 
approximately 17.5) [8].  
 
A recent study explored the PK of DTG when dosed as 100 mg once daily in 
combination with daily rifampin. In this healthy volunteer study, participants 
sequentially received DTG 50 mg and DTG 100 mg once daily, both with and 
without rifampin. The GMR of the Cmax, AUC, and C24 of DTG for DTG 100 mg 
once daily + rifampin:DTG 50 mg alone were: 1.09, 0.74, and 0.24. DTG trough 
concentrations were substantially reduced, while overall dosing interval 
exposures of DTG decreased to a lesser extent [9].  
 
There are less data when DTG is given with RPT as compared to rifampin. In a 
small study assessing the PK and safety of DTG when given at a dose of 50 mg 
once-daily together with once-weekly INH and RPT (each dosed at 900 mg, 3HP) 
in HIV-uninfected healthy volunteers, DTG trough (Cτ) concentrations were 
reduced by 43%, 74%, and 53% 2, 3, and 6 days after the dose, respectively, 
compared to when DTG was given alone [10]. The lowest average Cτ, though, 
remained 5.3 times higher than the protein-adjusted IC90 for DTG, suggesting that 
even with these reductions in exposure, virologic suppression was likely to be 
maintained in individuals with HIV taking standard-dose DTG. The combination, 
however, was poorly-tolerated, with flu-like syndrome seen in two of three 
volunteers. Brisk immune responses have been seen in healthy volunteers given 
rifamycins previously [6, 11-13] and in individuals with TB. Rifamycin 
hypersensitivity is most common when rifamycins are dosed intermittently [14, 15].  
 
In a similar study of 3HP in HIV/latent TB infection (LTBI) co-infected individuals, 
Dooley and colleagues conducted PK sampling of patients receiving 50 mg DTG in 
combination with once weekly RPT and INH. The geometric mean (GM) trough 
concentration of DTG pre-HP treatment was 1003 ug/mL (5th-95th percentile: 500-
2080), and during HP treatment 546 (134-1616) with all trough concentrations except 
for one above the DTG IC90 of 64 ug/mL. Overall, although weekly HP decreased 
DTG bioavailability, which was associated with a modest decrease in trough 
concentrations, all trough concentration except for one were above the DTG IC90, 
and DTG clearance remained unchanged after the 8th weekly dose of RPT/INH. 
Notably, with regard to safety, co-administration of DTG and weekly HP was well-
tolerated, with no HP-related Grade >3 AEs. All viral loads were suppressed [16]. 
These data, combined with the week 48 results of the INSPIRING study [7] add to 
the evidence in that safety events such as those seen in the Brooks et al. study [10] 
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The safety and tolerability of DTG plus daily RPT remains to be established in 
individuals living with HIV and LTBI; moreover, the dose of DTG required to 
maintain HIV virologic suppression among patients with LTBI-HIV receiving 
RPT 600 mg daily for 4 weeks within the 1HP LTBI regimen (standard DTG dose 
of 50 mg once a day versus 50 mg twice a day) must be determined before these 
drugs can be safely used together. In Arm 2 of the present study, we will 
investigate DTG PK when DTG is given daily at the standard dose of 50 mg and 
RPT is administered daily as 600 mg for 28 days as part of the 1HP regimen. 
Recent data in healthy volunteers combining DTG 100 mg with rifampicin 600 mg 
daily yielded an approximate 28% and 75% reduction in plasma AUC and Ctrough 
values, respectively. However, reassuringly, these mean DTG trough values 
remained ~5-fold higher than the protein binding adjusted IC90 DTG plasma 
concentration of 64 mg/mL [17]. These data, combined with the Brooks et al. 
DTG PK data when using DTG 50 mg together with weekly RPT/INH each at 
900 mg showing similar maximum DTG trough reductions of ~75%, remaining 
5.3 times higher than the protein-adjusted IC90 for DTG, along with PK and 
efficacy data from the dose finding studies of DTG (SPRING-1) and data from 
Dooley et al. of 3HP+ DTG based ART (NCT 03435146) form the rationale for 
DTG dosing in Arm 2 of our study [5]. While overall RPT exposures are higher 
with daily RPT dosing, it remains to be studied what effect RPT dose and 
frequency (600 mg daily vs 900 weekly) has on DTG bioavailability and CYP 
enzyme induction and ultimately any subsequent drug interactions arising from 
this induction. Additionally, the participant population within the present study will 
be virologically suppressed prior to entering the study, suggesting the possibility 
of a lower threshold for DTG exposure and Ctrough values than what may be 
needed in HIV treatment-naïve individuals presenting with high viral loads. To 
date, there are no PK data available when combining DTG (either QD or BID) 
with daily RPT, at any dose.  
 
In an ongoing birth outcome surveillance study in Botswana, a numerically 
higher rate of neural tube defects was identified with exposure to DTG 
compared to non-DTG-containing antiretroviral regimens taken at the time 
of conception, however, the difference was not statistically significant. 
Seven cases of neural tube defects were reported in 3,591 deliveries 
(0.19%) to mothers taking DTG-containing regimens at the time of 
conception, compared with 21 cases in 19,361 deliveries (0.11%) to 
mothers taking non-DTG-containing regimens at the time of conception 
(prevalence difference 0.09%; 95% CI -0.03, 0.30) [20].  
 
Reproductive toxicology studies have not shown any relevant findings. 
DTG has been shown to cross the placenta.  
 
Data available from other sources including the Antiretroviral Pregnancy 
Registry (APR), other cohorts and clinical trials are insufficient to confirm or 
refute this potential risk. 
 


 
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Women will be counselled regarding the unknown risks that could be 
associated with DTG exposure to the foetus should they fall pregnant. All 
women will be given additional information on the potential risk of neural 
tube defects (NTDs) of infants born to women on DTG. 
 
2.1.2 Isoniazid and rifapentine (1HP) 
 
Tuberculosis is the leading cause of death in individuals living with HIV. 
Preventive therapy (treatment of latent tuberculosis infection) has been shown to 
significantly reduce development of active TB. Recently, an ultra-short course of 
isoniazid+rifapentine given daily for 1 month (1HP) was shown to be non-inferior 
to 9 months of daily isoniazid therapy (9H) at preventing TB in people living with 
HIV [21]. Additionally, the 1HP regimen had fewer adverse events, and was more 
likely to be completed than 9H in adults and adolescents living with HIV. 
Rifapentine in preventive treatments including 1HP treatment has been dosed 
according to weight bands, however, the rationale for this weight-banded 
approach has been lacking. A comprehensive analysis of RPT population 
pharmacokinetics in more than 400 TB patients receiving various daily doses of 
RPT confirmed the absence of any impact of weight on RPT pharmacokinetics, 
therefore justifying flat RPT dosing. Based on this scientific evidence, we will use 
a flat dose of RPT in this study, to avoid underdosing of lighter participants [22]. 
 
2.2 
Rationale 
 
Drug-drug interaction studies with daily RPT and DTG are still lacking and are urgently 
needed given that DTG is quickly becoming a first-line agent in the global context and it 
is important that 1HP treatment be available to patients with HIV/LTBI co-infection 
receiving DTG based ART. Combined regimens with the lowest pill burden and 
convenience of once daily dosing provide an ideal option for management of co-infected 
patients. Additionally, having a one month regimen (1HP) available for co-infected 
patients receiving DTG based ART will significantly reduce LTBI treatment duration, in 
which the only current option is 9 months of daily INH. The design of A5372 allows for a 
staged approach to achieving the most simplified DTG based ART regimen safely and 
effectively used in combination with 1HP LTBI treatment. Safety and efficacy data from 
both QD and BID DTG dosing will be collected so as to provide an ideal ultra-short 
course RPT containing treatment regimen for HIV/LTBI. Interactions in the other 
direction (e.g., effects on RPT/INH) are not anticipated given our knowledge of the 
metabolic pathways of RPT/INH and the effects of DTG on metabolizing enzymes and 
transporters. Thus, DTG is not expected to affect exposure of RPT/INH.  
 
Although safety concerns have arisen when combining rifamycin-based LTBI treatments 
with DTG-based ART [10], these studies have been conducted in healthy volunteers and 
rates of adverse events in HIV/LTBI co-infected individuals have been shown to be far 
less. The safety data from the INSPIRING study, which included 69 participants 
receiving DTG- and RIF-based TB treatment showed that no individuals stopped study 
drugs due to drug-related AEs [7]. In a study by Dooley et al., of HIV/LTBI co-infected 
individuals on DTG-based ART and 3HP LTBI treatment showed that of the 60 


 
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participants who started 3HP dosing, all 60 completed all 12 weekly doses of RPT/INH 
while none of the 60 participants discontinued study medications due to AEs [16]. The 
study population of A5372 largely mimics the study population enrolled in the Dooley et 
al. study, and provides an opportunity to develop safety data on HIV/LTBI co-infected 
individuals receiving an ultra-short course LTBI regimen of 1HP in combination with 
DTG-based ART. 
 
3.0 
STUDY DESIGN 
 
A5372 is an open-label, two-arm, multicenter PK study to investigate the potential 
interactions between DTG and steady state RPT when RPT is given with INH daily for 
4 weeks (1HP) in individuals living with HIV-1 and LTBI. 
 
The majority of participants will be on study for 6 weeks (a 4-week on-study treatment 
period and a 2-week follow-up period). The duration may be up to 8 weeks as participants 
will have up to 6 weeks from enrollment to complete 4 weeks of treatment. Participants 
who are required to return for confirmation of virologic failure within 1 to 3 weeks after the 
follow-up visit may be on study for up to 11 weeks. 
 
Initially, the study will begin enrollment with Arm 1. Once PK data are available from 
Arm 1 with at least 32 evaluable participants (participants with at least 6 plasma sample 
collections on each of the two intensive PK visits [6 of these collections must include 23- 
and 24-hr time points (trough levels) to ensure PK laboratory analysis can occur on at 
least 32 participants]), the clinical management committee (CMC) team and the SMC will 
review the DTG BID PK data to ensure sufficient plasma exposures of DTG (Ctrough) are 
achieved with twice-daily DTG dosing. Upon review of the Arm 1 PK data, the PK data 
will be used to model the anticipated PK of QD DTG when co-administered with 1HP. 
Based on these models and simulations of QD DTG dosing with 1HP, a decision will be 
made on whether to open Arm 2 for enrollment. Refer to section 7.4 for details on criteria 
for opening of Arm 2. 
 
Plasma PK profiles for DTG will be determined at two time points. At the first time point, 
plasma samples will be drawn in participants at steady state with respect to DTG when 
receiving once daily DTG prior to 1HP. At the second time point, DTG will be given BID in 
Arm 1 and QD in Arm 2 during the 1HP LTBI regimen and PK sampling for DTG will 
occur on Day 28 of the 1HP regimen. In addition, sparse PK sampling will be performed 
on days 3, 14, and 21 of the 1HP regimen. Remaining plasma from the DTG analysis will 
be used to determine RPT concentrations achieved from 1HP dosing to support 
exploratory study objectives.   
 
The study regimen will be as follows starting on Day 1 continuing through Day 28. 
 


 
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Arm 1  
• 
DTG 50 mg orally BID (~12 hours apart) 
o 1st dose: DTG 50 mg each morning from non-study ARV supply 
o 2nd dose: DTG 50 mg each evening from study supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
 
Arm 2 (upon opening)  
• 
DTG 50 mg orally each morning from non-study ARV supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks 
 
All participants must also be on stable once-daily DTG-based ART with 2 nucleoside 
reverse transcriptase inhibitors (NRTIs) (excluding TAF) during the study.  
 
All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH 
based on the current local, national, or international dosing guidelines. Pyridoxine is not 
provided by the study. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Males and females at least 18 but no more than 65 years of age at study entry. 
 
4.1.2 Ability and willingness of participant or legal guardian/representative to provide 
informed consent. 
 
4.1.3 Weight ≥40 kg and a body mass index (BMI) of greater than 18.5 kg/m2. 
 
4.1.4 Documentation of HIV-1 infection status, as below: 
 
HIV-1 infection, documented by any licensed rapid HIV test or HIV-1 E/CIA test 
kit at any time prior to entry and confirmed by a licensed Western blot or a 
second antibody test by a method other than the initial rapid HIV and/or E/CIA, 
or by HIV-1 antigen or plasma HIV-1 RNA viral load. Two or more HIV-1 RNA 
viral loads of >1,000 copies/mL are also acceptable as documentation of HIV-1 
infection. 
 
Note A: The term “licensed” refers to a US FDA-approved kit, which is required 
for all IND studies, or for sites that are located in countries other than the United 
States, a kit that has been certified or licensed by an oversight body within that 
country and validated internally. Non-US sites are encouraged to use US 
FDA-approved methods for IND studies. 
 
Note B: WHO and Centers for Disease Control and Prevention (CDC) guidelines 
mandate that confirmation of the initial test result must use a test that is different 
from the one used for the initial assessment. A reactive initial rapid test should 
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a different antigen preparation and/or different test principle (e.g., indirect versus 
competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
 
4.1.5 HIV-1 plasma viral load <50 copies/mL obtained within 30 days prior to study 
entry by any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, or at any network-approved 
non-US laboratory that is Virology Quality Assessment (VQA) certified. 
 
4.1.6 At US sites: Evidence of LTBI by tuberculin skin test (TST) reactivity ≥5 mm, or a 
positive interferon gamma release assay (IGRA) at any time prior to study entry. 
 
At non-US sites: Indication for LTBI treatment according to WHO latent TB 
guidelines (Note: TST/IGRA results not required). 
 
4.1.7 On a stable once daily DTG (50 mg) based ART with once daily 2 NRTIs and  
 
• 
With at least 28 total days of DTG and NRTI dosing prior to study entry  
• 
With no gaps in self-reported DTG and NRTI adherence of more than 3 
consecutive days in the 28 days prior to study entry 
• 
With no intention to change ART for the duration of the study 
 
NOTE A: Participants who switch from another ART regimen to DTG to meet 
eligibility requirements for this study will be eligible to enroll as long as the ART is 
switched at least 28 days prior to study entry. 
 
4.1.8 Chest radiograph (X-ray) or chest computed tomography (CT) scan performed 
within 30 days prior to study entry without evidence of active TB. 
 
NOTE: An existing chest X-ray or CT scan from within 30 days prior to 
entry can be used as qualifying chest imaging. If chest imaging will be 
performed for study evaluation (i.e., Screening), then chest X-ray should be 
performed. A CT scan will be used only if an existing scan is already 
available and will not be performed as part of study.  
 
4.1.9 The following laboratory values obtained within 30 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with GCLP 
and participates in appropriate external quality assurance programs. 
• 
Absolute neutrophil count (ANC) >750 cells/mm3 
• 
Hemoglobin ≥7.4 g/dL 
• 
Platelet count ≥50,000/mm3 
• 
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase 
[SGOT]) <2.5 X the upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase 
[SGPT]) <2.5 X ULN 
• 
Total bilirubin ≤1.5 x ULN 
• 
Creatinine <1.3 X ULN 


 
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4.1.10 For females of reproductive potential, negative serum or urine pregnancy test at 
Screening within 30 days prior to entry and within 48 hours prior to entry by any 
US clinic or laboratory that has a CLIA certification or its equivalent, or is using a 
point of care (POC)/CLIA-waived test, or at any network-approved non-US 
laboratory or clinic that operates in accordance with GCLP and participates in 
appropriate external quality assurance programs. 
 
NOTE A: If screening visit occurs within 48 hours prior to entry, only one test will 
occur prior to entry. 
 
NOTE B: Urine test must have a sensitivity of 15-25 mIU/mL. 
 
4.1.11 Female participants of reproductive potential must agree not to participate in the 
conception process (i.e., active attempt to become pregnant, in vitro fertilization), 
and if participating in sexual activity that could lead to pregnancy, must agree to 
use one reliable nonhormonal method of contraception, as listed below, while on 
study treatment and through study completion.  
 
Acceptable forms of contraception include: 
• 
Intrauterine device (IUD) or intrauterine system  
• 
Cervical cap with spermicide 
• 
Diaphragm with spermicide 
• 
Condoms (male or female)  
 
NOTE A: Hormonal methods may be used, however, one of the other 
acceptable forms of contraception listed above must also be used through 
the duration of the study because of potential interactions with RPT.  
 
NOTE B: Participant-reported history is acceptable documentation of menopause 
(i.e., at least 1 year amenorrheic), hysterectomy, or bilateral oophorectomy or 
bilateral tubal ligation; these candidates are considered not of reproductive 
potential and are eligible without the required use of contraception. 
 
4.2 
Exclusion Criteria  
 
4.2.1 Breastfeeding, pregnancy, or plans to become pregnant. 
 
4.2.2 Known allergy/sensitivity or any hypersensitivity to components of the study 
drugs, or their formulations. 
 
4.2.3 Presence of any confirmed or probable active TB based on criteria listed in the 
current ACTG Diagnosis Appendix at screening. 
 
4.2.4 History of rifamycin-monoresistant, INH-monoresistant, multi-drug resistant 
(MDR), or extensively-drug resistant (XDR) TB at any time prior to study entry. 
 


 
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4.2.5 Known exposure to rifamycin-monoresistant, INH-monoresistant, MDR- or XDR-
TB (e.g., household member of a person with rifamycin-monoresistant, 
INH-monoresistant, MDR- or XDR-TB) at any time prior to study entry by 
participant self report or medical records. 
 
4.2.6 History of peripheral neuropathy Grade ≥2 according to the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Corrected Version 2.1, July 2017, which can be found on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
4.2.7 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.8 Acute or serious illness requiring systemic treatment and/or hospitalization within 
7 days prior to study entry. 
 
4.2.9 Known cirrhosis, a history of decompensated liver disease (ascites, hepatic 
encephalopathy, or esophageal varices) or current Child Pugh Class B or C 
hepatic impairment. 
 
 
NOTE: Refer to section 6.3.10 for Child Pugh scoring and classification table.  
 
4.2.10 Initiated, discontinued, or changed doses of drugs that are P-glycoprotein (PGP) 
inducers, that are P-glycoprotein (PGP) inhibitors, or that are known to have drug 
interactions with DTG, within 30 days prior to study entry.  
 
NOTE: Refer to the list of prohibited and precautionary medications in  
Appendix I. 
 
4.2.11 Known porphyria at any time prior to study entry. 
 
4.2.12 Receipt of any other antiretroviral therapy other than DTG and 2 NRTI within 
28 days prior to study entry.  
 
4.2.13 Receipt of TAF within 28 days prior to study entry.  
 
4.2.14 Documented resistance that may confer reduced susceptibility to DTG, at 
any time prior to study entry. This includes the following integrase strand 
transfer inhibitor (INSTI) mutations: Q148 substitutions, T66A, L74I/M, 
E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, G193E/R, or N155H.  
 
4.2.15 Clinically suspected INSTI resistance, at any time prior to study entry, as 
evidenced by prior receipt of INSTI-containing ART, during which time two 
or more HIV-1 RNA levels of >200 copies/mL were observed after having 
attained virologic suppression to <200 copies/mL and without known 
interruption.  


 
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4.2.16 Consumption of more than 3 alcohol beverages on any day within 30 days 
prior to entry. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) 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. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, 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 ICF(s) 
WILL NOT be reviewed or approved by the DAIDS PRO. 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.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant (or, when necessary, the legal 
representative if the participant is under guardianship) will be asked to read and 
sign the approved protocol consent form.  
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Participant Enrollment System.  
 


 
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4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.3.3 Participant Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Co-enrollment in A5128 does not require permission from the 
A5372 protocol chairs.  
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-U.S. Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5372 protocol chairs.  
• 
For specific questions and approval for co-enrollment in other studies, sites should 
contact the team via e-mail as described in the Study Management section. 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as dolutegravir (DTG), rifapentine (RPT), and isoniazid (INH). 
 
5.1 
Regimens and Duration 
 
Arm 1  
• 
DTG 50 mg orally BID (~12 hours apart) 
o 1st dose: DTG 50 mg each morning from non-study ARV supply 
o 2nd dose: DTG 50 mg each evening from study supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
 
Arm 2 (upon opening)  
• 
DTG 50 mg orally each morning from non-study ARV supply 
• 
1HP: INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
 
All participants must be on stable once-daily DTG-based ART with 2 nucleoside reverse 
transcriptase inhibitors (NRTI).  
 


 
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All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH 
based on the current local, national, or international dosing guidelines. Pyridoxine is not 
provided by the study. 
 
5.2 
Administration and Dispensing 
 
Dolutegravir (DTG) will be administered orally as 50 mg either QD or BID. As RPT and 
INH will be given with food, the DTG dose when aligned with 1HP administration will be 
given with food as well. DTG doses not aligned with 1HP doses may be given with or 
without food with exception of DTG doses taken on Day 0 and Day 28, which should be 
taken with food. Separate each DTG 50 mg dose by 12 hours when giving BID. In 
Arm 1, 1HP should be taken with the first daily dose of DTG. 
 
Isoniazid (INH) will be administered orally as 300 mg QD. INH may be taken with food 
and at the same time as rifapentine. The 300 mg tablets must not be divided or crushed. 
 
Rifapentine (RPT) will be a administered orally as 600 mg QD with food. 
 
To align with the PK sample collections, participants should be on morning dosing regimen 
for the duration of the study (except the 2nd dose DTG in Arm 1), including at least 3 days 
prior to Day 0 intensive PK. The dose on the morning of PK sampling day will be an 
observed dose. Thus, participants will need to hold the dose until the clinic visit. 
 
1HP medications will be provided for Day 1 to Day 28. DTG 50 mg tablets will be 
dispensed to participants in Arm 1 of the study for the second daily dose of DTG. 
Participants will continue 2 NRTI plus one dose DTG 50 mg daily from their own supply 
while on the study treatment regimen in both Arm 1 and Arm 2 (Day 1 to Day 28). 
Participants will have up to 6 weeks from enrollment to complete 4 weeks of 1HP 
treatment. Following 1HP, participants will continue antiretroviral therapy prescribed by 
their routine HIV care provider. 
 
The 1HP treatment is ideally taken once daily for 28 consecutive days. If doses are 
interrupted, participants are allowed up to 42 days to complete the 1HP therapy. For 
Arm 1 participants, BID dosing of DTG should continue for the entire 1HP treatment, up 
to 42 days. Additional doses of DTG for Arm 1 may be dispensed as required, either in 
intact bottles or dispensed into prescription bottles. For Arm 2 participants, daily DTG 
and NRTIs should continue from their own supply for the entire 1HP treatment. 
 
5.3 
Study Product Formulation  
 
Dolutegravir (DTG): 50 mg tablets. Store at 25°C (77°F) with excursions between 
15° and 30°C (59°-86°F) permitted (see USP Controlled Room Temperature). 
 
Isoniazid (INH): 300 mg tablets. Store below 30°C (86°F) and in the original container. 
 
Rifapentine (RPT): 150 mg tablets. Store at 25°C (77°F) with excursions between 
15° and 30°C (59°-86°F) permitted (see USP Controlled Room Temperature). 


 
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5.4 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.4.1 Study Product Acquisition/Distribution 
 
DTG 50 mg (Tivicay) is supplied by ViiV Healthcare Ltd.   
 
INH is purchased from Macleods Pharmaceuticals Ltd. 
 
Rifapentine (Priftin®) will be manufactured by Sanofi and supplied through the study 
with funding support from the ACTG. 
 
DTG (where applicable), INH, and RPT will be made available through the NIAID 
Clinical Research Products Management Center (CRPMC). The site pharmacist 
should obtain the study products for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks.  
 
Pyridoxine (vitamin B6) will not be provided through the study and should be 
obtained locally by the site. 
 
Any study product not provided by the study must comply with the NIAID 
(DAIDS) policy that outlines the process for authorizing the use of study products 
not marketed in the US in NIAID (DAIDS)-supported and/or –sponsored clinical 
trials. This policy is available on the NIAID (DAIDS) website at: 
https://www.niaid.nih.gov/sites/default/files/NonFDAapprovedProducts.pdf. 
 
5.4.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC or other sources and subsequently dispensed. 
CRSs. At US CRSs, all unused study products must be returned to the NIAID 
CRPMC (or as otherwise directed by the sponsor) after the study is completed or 
terminated. The procedures to be followed are provided in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, 
the site pharmacist must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused 
study products. 
 
5.5 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 


 
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5.5.1 Required Medications (not provided by the study) 
 
Refer to Section 5.1 for the list of required medications. 
 
5.5.2 Prohibited Medications 
 
Prohibited medications are listed in Appendix I. 
 
5.5.3 Precautionary Medications 
 
Precautionary medications are listed in Appendix I. 
 


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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Arms 1 and 2  
 
Evaluation 
Screening 
Entry 
On-Study Treatment 
Follow Up 
Confirmation 
of Suspected 
Virologic 
Failure 
Premature 
Treatment/Study 
Discontinuation c 
-30 to -1 
days 
Day 0 
Day 1 
Day 3 
Day 14 
Day 21 
Day 28 
Day 42 
Day 49 
(Visit Window) 
 
 
(+2 Days) 
(±2 Day) 
(±2 Day) 
(-2/+14 Days) 
(-2/+14 days) 
(+28 days) 
 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Contraception Counseling 
X 
 
 
 
X 
 
X 
 
 
 
Chest X-Ray or Chest CT 
X 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
 
 
X 
 
 
X 
Liver Function Tests 
X 
X 
 
X 
X 
X 
X 
 
 
X 
Blood Chemistries 
X 
X 
 
X 
 
 
X 
 
 
X 
Pregnancy Testing 
X a 
X 
X (if indicated) 
X 
 
 
 
Plasma HIV-1 Viral Load 
X 
 
 
 
 
 
X  
X 
X 
 
TST or IGRA 
X 
 
 
 
 
 
 
 
 
 
Child Pugh Score for 
Hepatic Impairment 
X 
 
 
 
 
 
 
 
 
 


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Evaluation 
Screening 
Entry 
On-Study Treatment 
Follow Up 
Confirmation 
of Suspected 
Virologic 
Failure 
Premature 
Treatment/Study 
Discontinuation c 
-30 to -1 
days 
Day 0 
Day 1 
Day 3 
Day 14 
Day 21 
Day 28 
Day 42 
Day 49 
(Visit Window) 
 
 
(+2 Days) 
(±2 Day) 
(±2 Day) 
(-2/+14 Days) 
(-2/+14 days) 
(+28 days) 
 
PK Sampling (Intensive) b 
 
X 
 
 
 
 
X 
 
 
 
Dispensation of Study 
Medications 
 
X 
 
 
 
 
 
 
 
 
Start of Study Regimen 
 
 
X 
 
 
 
 
 
 
 
PK Sampling (Sparse) b 
 
 
 
X 
X 
X 
 
 
 
 
Whole Blood for 
Pharmacogenetic Testing 
(optional) 
 
X 
 
 
 
 
 
 
 
 
Stored Plasma for HIV 
Resistance Testing 
 
 
 
 
 
 
 
 
X 
 
a  Pregnancy test will be performed with a negative result available prior to Chest X-ray at Screening visit. 
b  PK sampling will occur after ensuring 3 days consecutive dosing of ART and/or RPT/INH prior to study visit. Day 3 sparse PK may have only 
2 prior doses of 1HP. Detailed information about last three doses will be collected per participant self report. See sections 6.2.2 and 6.2.3. 
c 
These evaluations should be performed at the time of study treatment discontinuation and/or at the time of study discontinuation, as 
applicable. No further evaluations can be performed on a participant after study discontinuation. 
 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions. 
 
Screening evaluations to determine eligibility must be completed within 30 days 
prior to entry, unless otherwise specified. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures and candidates 
who do not enroll will be captured in a Screening Failure Results form and 
entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur at least 24 hours after screening evaluations unless 
otherwise specified.  
 
On the day of registration, Entry/Day 0 evaluations must be completed after 
eligibility is determined from the screening evaluations. All Entry/Day 0 
evaluations must be completed prior to treatment administration. 
 
Participant must begin treatment (study provided DTG and 1HP) following 
completion of Entry/Day 0 intensive PK evaluations.  
 
Participants will be admitted to the Clinical Research Unit (CRU) or equivalent at 
Entry/Day 0 for intensive PK sampling. Hospitalization is recommended but is not 
mandatory and is at the discretion of the participant and/or investigator to allow 
for flexibility and feasibility. PK sampling may only occur after ensuring 3 days of 
consecutive dosing of ART prior to entry (participant self-report is sufficient). 
 
Study treatment will begin on what will be termed ‘Day 1’ following completion of 
Day 0 PK sampling. However, no additional Day 1 evaluations will occur. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations 
 
Day 3  
A study visit including sparse PK sampling will occur on Day 3 with a window of 
+2 days.  
 
Day 14  
A study visit including sparse plasma PK sampling will occur on Day 14, with a 
window of ±2 days. 


 
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Day 21  
A study visit including sparse plasma PK sampling will occur on Day 21, with a 
window of ±2 days. 
 
PK sampling at Day 3, Day 14, and Day 21 may only occur after ensuring 3 days 
of consecutive dosing of ART and/or RPT/INH prior to study visit. This will be 
recorded per participant self report. 
 
Day 28  
A study visit including intensive PK sampling will occur on Day 28 (window -2/+14 
days).  
 
PK sampling at Day 28 may only occur after ensuring 3 days of consecutive 
dosing of ART and RPT/INH prior to study visit (participant self report is 
sufficient). 
 
NOTE: Participants will have 6 weeks to complete 4 weeks of on-study 
treatment. 
 
Day 42 
A follow up study visit should occur approximately 14 days following the 
completion of study treatment. The window for the day 42 follow-up visit 
is -2/+14 days. 
 
NOTE: The timing of the day 42 visit may vary for some participants as 
participants will have up to 6 weeks from enrollment to complete 4 weeks of 
treatment. 
 
Event-Driven Evaluations 
 
Day 49 Confirmation of Suspected Virologic Failure 
Participants with plasma HIV RNA > 50 copies/mL at the Day 42 follow-up visit 
will return for a confirmatory plasma HIV RNA measurement approximately 
7 days after the original sample collection or as soon as testing results are 
available.  
 
At non-US sites, an additional plasma sample will also be collected for possible 
resistance testing, if viremia is confirmed. At US sites, the confirmatory sample 
should be sent to reflex for resistance testing if HIV viremia is confirmed, where 
feasible. If not feasible, an additional plasma sample for resistance testing should 
be collected at time of confirmation of viremia. Resistance testing should include 
integrase and reverse transcriptase resistance.  
 
The window for the day 49 confirmation of suspected virologic failure visit is 
+28 days. 
 


 
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NOTE: The timing of the day 49 visit may vary for some participants as 
participants have up to 6 weeks from the time of enrollment to complete 4 weeks 
of treatment. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Discontinuation Evaluations 
If a confirmation of suspected virologic failure visit is not necessary (i.e., plasma 
HIV RNA is determined to be <50 copies/mL at Day 42), participants should 
discontinue study once they complete their Day 42 follow-up visit. Refer to the 
Discontinuation Log in the A5372 eCRF completion guideline.  
 
If a confirmation of suspected virologic failure visit is necessary based on the Day 
42 follow-up visit plasma HIV RNA, participants should discontinue study after 
they complete their Day 49 Confirmation of Suspected Virologic Failure visit. 
Refer to the Discontinuation Log in the A5372 eCRF completion guideline. 
 
Premature Discontinuation Evaluations 
Participants who prematurely discontinue the study will have evaluations 
performed as indicated in the schedule of evaluations and then be taken off 
study.  
 
Participants who discontinue study participation due to Grade 3 or 4 toxicity 
attributed to study drug should have premature study discontinuation evaluations 
completed per the SOE when the toxicity has decreased to Grade ≤2 and then 
be taken off study. No further evaluations can be performed on a participant after 
study discontinuation. Refer to the Discontinuation Log in the A5372 eCRF 
completion guideline. 
 
6.3 
Instructions for Evaluations 
 
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/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document:  
https://www.niaid.nih.gov/sites/default/files/score-source-documentation-requirements.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and AE reporting of 
adverse events requirements. 


 
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6.3.1 Documentation of HIV-1 
 
Sections 4.1.4 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days prior to study entry. In 
addition, the following diagnoses should be recorded regardless of when the 
diagnosis was made: 
• 
AIDS-defining conditions 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Prior Tuberculosis 
• 
Chronic obstructive pulmonary disease (COPD) 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history. 
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or Timeframe 
Prescription drugs 
30 days prior to study entry 
Sex-hormone medications or sex-
hormone analogues or antagonists* 
12 months prior to study entry 
*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 5 years); oral, 
injectable, implanted, or patch contraceptives; vaginal ring, creams, or inserts; 
estrogen, progesterone, or testosterone therapy; leuprolide or other synthetic 
gonadotropin-releasing hormone; tamoxifen, raloxifene, aromatase inhibitors or any 
other androgen, estrogen, or progesterone analogue or antagonist therapy.  
 
6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination will be performed at Screening only and is to 
include, at a minimum: 


 
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• 
examination of the skin, head, mouth, and neck 
• 
auscultation of the chest 
• 
cardiac exam; abdominal exam 
• 
examination of the lower extremities for edema 
• 
signs and symptoms 
• 
diagnoses 
• 
height (in cm) 
• 
weight (in kg); calculated body mass index 
• 
vital signs (temperature, pulse, respiration rate, and blood pressure) 
 
Targeted Physical Exam 
Targeted physical examination will be performed at all visits after Screening 
(except for on Day 1) and is to be driven by any previously identified or new signs 
or symptoms including diagnoses or adverse events that the participant has 
experienced since the last visit. 
 
The exam must include: 
• 
vital signs (temperature, pulse, respiration rate, and blood pressure) 
• 
weight (in kg) 
 
Refer to section 7.2 for AE collection requirements. 
 
Concomitant Medications 
After entry, any new and discontinued concomitant medications must be 
recorded on the eCRFs. 
 
Study Treatment Modifications 
After entry, record all study drug modifications, including initial doses, 
participant-initiated and/or protocol-mandated modifications, and inadvertent and 
deliberate interruptions since the last visit. All interruptions of study-supplied 
drugs, regardless of duration, must be recorded. Record any permanent 
discontinuation of treatment. Interruptions to non-study ART will be recorded 
on the concomitant medications log. 
 
6.3.5 Contraception Counseling  
 
Due to the potential risk from neural tube defect associated with DTG treatment 
during the first trimester of pregnancy (see section 2.1.1), study staff must review 
the following information with all female participants of reproductive potential: 
• 
Importance of pregnancy avoidance and of adherence to contraception 
requirements; 
• 
Safer sexual practices and the proper use of their chosen contraceptive 
methods in accordance with the applicable contraceptive product label; 
• 
The importance of informing the core team immediately if they become 
pregnant or plan to become pregnant, as they must be withdrawn from the 
study. 


 
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In addition, at the Screening visit, study staff must review the following 
information with all female participants of reproductive potential: 
• 
In an early analysis of one observational study, women who were taking DTG 
when they became pregnant had an increased risk of having babies with 
serious brain and spine defects. These defects happen early in pregnancy, 
before many women even know they are pregnant. 
 
Documentation of contraception counseling is not recorded on the eCRF. 
 
6.3.6 Chest X-Ray or Chest CT 
 
Chest X-ray or chest CT is required within 30 days prior to entry and must not show 
evidence of active TB. 
 
An existing chest X-ray or CT scan from within 30 days prior to entry can 
be used as qualifying chest imaging. If chest imaging will be performed for 
study evaluation (i.e., Screening), then chest X-ray should be performed. A 
CT scan will be used only if an existing scan is already available and will 
not be performed as part of study.  
 
6.3.7 Laboratory Evaluations 
 
At screening and entry all laboratory values must be recorded on the eCRF. For 
post-entry assessments, record abnormal laboratory findings as per section 7.2.  
 
Hematology 
Hemoglobin, hematocrit, red blood cells, white blood cell count, absolute 
neutrophil count (ANC), and platelets.  
 
Liver Function Tests (LFTs) 
Total bilirubin, AST (SGOT), ALT (SGPT). 
 
Blood Chemistries 
Sodium, potassium, creatinine, and albumin.  
 
Pregnancy Testing 
For women with reproductive potential: Serum or urine β-HCG. Urine test must 
have a sensitivity of 15-25 mIU/mL.  
 
In addition to a pregnancy test at the Screening visit within 30 days prior to entry, 
negative pregnancy will be confirmed within 48 hours prior to Entry. A pregnancy 
test will be performed and a negative result available prior to Screening X-ray. 
 
NOTE: If screening visit occurs within 48 hours prior to entry, only one test will 
occur. 
 


 
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Record pregnancy and pregnancy outcome per section 8.5. 
 
6.3.8 Virologic Studies  
 
Plasma HIV-1 Viral Load 
Obtain HIV-1 viral load per the SOE at a laboratory that possesses a CLIA 
certification or equivalent (US sites) or VQA certification (non-US sites). 
Screening HIV-1 RNA must be performed within 30 days prior to study entry. 
Eligibility will be determined based on the screening value. 
 
6.3.9 Tuberculin Skin Test (TST) or Interferon Gamma Release Assay (IGRA)  
 
For participants at US sites, a TST or a licensed IGRA assay will be performed at 
screening if prior positive test results are not already available.  
 
For participants outside of the US, a TST or IGRA is not required, per the site 
investigator’s discretion and WHO latent TB guidelines. 
 
NOTE: TST and IGRA results will not be recorded on an eCRF.  
 
6.3.10 Child Pugh Score for Hepatic Impairment 
 
Child Pugh Score, if necessary, will be assessed at screening to determine 
eligibility. The scoring and classification table is provided below. 
 
Child Pugh Score will not be recorded on an eCRF.  
 
 
Figure 6.3.10-1: Child Pugh Score for Hepatic Impairment 
 


 
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6.3.11 Pharmacokinetic Sampling  
 
Intensive PK 
A 24 hour intensive PK sampling will occur per the SOE. 
 
Arm 1 
The intensive plasma PK samples will be collected at hours 0 (pre-dose), 1, 2, 4, 8, 12, 
13, 14, 23, and 24 hours post-DTG dose at Entry/Day 0 and on Day 28 (-2/+14 days).  
 
Arm 2  
The intensive plasma PK samples will be collected at hours 0 (pre-dose), 1, 2, 4, 8, 
12, 23 and 24 hours post-DTG dose at Entry/Day 0 and on Day 28 (-2/+14 days). 
 
NOTE: For Arms 1 and 2, a minimum of 6 samples must be collected, including the 
23- and 24-hour collections.   
 
All intensive samples should be collected within a 15 minutes window of the 
designated sampling time. The following should be recorded: 
• 
Date and time of sampling 
• 
Time of dosing of three prior days of ART and/or 1HP per participant self report 
• 
Time of dosing of ART and/or 1HP taken during the PK sampling 
• 
Whether DTG, RPT, INH, NRTI doses were taken with food 
 
NOTE: The Entry/Day 0 DTG dose is from participant’s existing ART regimen 
and should be taken with food. Entry/Day 0 PK sampling may only occur after 
ensuring 3 days of consecutive dosing of ART prior to entry. Day 28 visit may 
occur up to 2 weeks later as participants will have 6 weeks to complete 4  
weeks of on-study treatment. However, PK sampling at Day 28 may only occur 
after ensuring 3 days of consecutive dosing of ART and RPT/INH prior to study 
visit. Day 28 DTG dose should be taken with food. 
 
Sparse PK 
The sparse plasma PK samples will be collected per the SOE at 20 minutes 
(±15 minutes) (trough) before the dose.  
 
All sparse samples should be collected within the designated window above. The 
following should be recorded: 
• 
Date and time of sampling 
• 
Time of dosing of three prior days of ART and 1HP per participant self report. 
Of note, Day 3 sparse PK may have only two prior days of 1HP. 
• 
Time of dosing of ART and 1HP taken during the PK sampling 
• 
Whether DTG, RPT, INH, NRTI doses were taken with food 
 


 
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6.3.12 Whole Blood for Pharmacogenetic Testing (Optional) 
 
A whole blood sample will be obtained for genotyping of polymorphisms in 
human genes that may affect metabolism, disposition, and toxicity of the study 
drugs, as well as concomitant medications. 
 
6.3.13 Stored Plasma for HIV Resistance Testing 
 
For resistance testing, plasma may be collected and stored at the Confirmation of 
Suspected Virologic Failure visit. 
 
At non-US sites, an additional plasma sample will also be collected for possible 
HIV resistance testing for integrase and reverse transcriptase resistance, if 
viremia is confirmed.  
 
At US sites, the confirmatory sample should be sent to reflex for HIV resistance 
testing for integrase and reverse transcriptase resistance if HIV viremia is 
confirmed, where feasible. If not feasible, an additional plasma sample for 
resistance testing should be collected at time of confirmation of viremia  
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Event 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study regardless of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition.  
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met: 
• 
All Grade ≥2 AEs 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 


 
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• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above).  
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
The DAERS 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 on the DAIDS RSC website 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. Site 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 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are:  
o Dolutegravir (DTG) 
o Rifapentine (RPT) 
o Isoniazid (INH) 
 
7.3.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
must be used and is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-
tables.  
 


 
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7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is the entire study duration 
for an individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
• 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
suspected unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the DAIDS EAE Manual, will be reported to DAIDS if the study 
staff become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Study Monitoring 
 
The core team will monitor the conduct and safety of the study via regular summaries of 
accrual, study discontinuation (to ensure the total target number of evaluable 
participants is met), stored sample completeness (to ensure that samples for primary 
and secondary outcome measures are collected as expected), and adverse events. An 
evaluable participant will be considered any participant who has completed the 28 daily 
doses of RPT/INH within the 6 week time period from study entry and has additionally 
completed both intensive PK visits with a minimum of 6 samples collected at each PK 
visit. The 23- and 24-hour (trough) time points must be part of the 6 collected samples.  
 
The site should notify the core team within 72 hours (preferably within 48 hours) by email 
if a participant has not completed each of the two intensive PK visits with at least 6 
plasma sample collections including the 23- and 24-hr PK draws, or if a participant has 
not completed 28 daily doses of RPT/INH within the 6-week time period from study 
entry.  
 
During the study, the safety and tolerability of the study medication will be monitored by 
toxicity reports presenting laboratory and clinical data. The core team will discuss these 
reports on regularly-scheduled conference calls or by e-mail. It is the responsibility of the 
core team to interpret the toxicity data and make any decisions needed to protect 
participants from undue risk. Any concerns will be presented to the DAIDS Clinical 
Representative.  
 
The DAIDS clinical representative will review and assess EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs, as applicable. Additionally, the DAIDS clinical 
representative will review aggregated adverse event summaries by arm prepared 
quarterly by the SDAC. 
 
The study will undergo interim feasibility and safety review approximately every 
6 months after the enrollment of the first participant by an ACTG-appointed Study 
Monitoring Committee (SMC). The first interim review will occur no more than 6 months 
after the enrollment of the first study participant.  
 


 
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An SMC interim review may also be convened if a concern is identified by the DAIDS 
clinical representative, the study chairs, or study statistician in consultation with the CMC 
team. See section 10.0 for statistical and other considerations related to interim 
monitoring. 
 
For all SMC reviews, the SMC will be provided detailed information on safety (including 
treatment tolerability and mortality), and administrative aspects (including accrual, 
retention, compliance with study requirements). 
 
An interim review of DTG PK data will be conducted by the CMC team and the SMC 
once DTG PK data from participants in Arm 1 (n=32 evaluable) are available prior to 
opening Arm 2. 
 
A 10 mg daily dose of DTG was associated with virologic suppression in the SPRING-1 
study [18] and the pharmacokinetic parameters reached following this dose in SPRING-1 
are adequate to be considered as DTG Ctrough PK targets (5th, 50th, and 95th percentile of 
158, 316, and 555 ng/mL, respectively). These PK data form the basis for opening rules 
for Arm 2. Once DTG Ctrough PK data are available from 36 participants in Arm 1, an 
evaluation of DTG PK in these participants will occur. 
 
Arm 2 will open to enrollment if simulation of Arm 1 PK data suggest that 50 mg DTG dosed 
QD in combination with 1HP will result in DTG trough concentrations that mimic reported 
plasma concentrations following a 10 mg DTG QD dose. Based on the population 
pharmacokinetic model built and adequately evaluated based on the data from Arm 1, we 
will simulate the clinical trial population of Arm 2 (QD dosing) 1000 times, and generate 
troughs for each of these simulated participants. These trough values will be summarized in 
terms of reported statistics from the SPRING Study (5th, 50th, and 95th percentile for each 
repetition). The median value (from 1000 repetitions) of the 5th percentile of DTG trough 
concentrations (Ctau) assessed via simulations should not fall below the reported 5th 
percentile of 158 ng/mL which was observed in the 10 mg DTG dose from the SPRING-1 
study. If this criterion is met, A5372 will open Arm 2 for enrollment for evaluation of QD DTG 
50 mg given with 1HP. The estimation of expected lower boundary with QD dosing (derived 
from simulations) will be done using model-based analysis with the models derived from PK 
data collected data in Arm 1 receiving 50 mg BID + 1HP. 
 
Detailed plans for study monitoring will be outlined in a Study Progress Data Safety 
Monitoring Plan developed by the Statistical and Data Management Center (SDMC) 
prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity 
 
General instructions for management of Grades 1-4 AEs is provided in section 8.1. 
Refer to sections 8.2, 8.3, and 8.4 for information on the following specific toxicities: 
• 
Rifamycin Hypersensitivity Syndrome (RHS) 
• 
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• 
Cutaneous 
• 
Drug-associated fever 
• 
Elevated liver-associated enzymes 
• 
Peripheral neuropathy 
• 
Suicidal ideation 
 
8.1.1 Grade 1 or 2  
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue all 
study-supplied drugs (INH, RPT and DTG if receiving through the study) at the 
discretion of the site investigator, and will be followed carefully.   
 
If the site investigator or participant chooses to discontinue any study-supplied 
drug, the site should notify the A5372 core team within 72 hours (preferably 
within 48 hours). The premature treatment/study discontinuation evaluations 
must be completed, and then the participant will be taken off study.  
 
8.1.2 Grade 3 or 4 
 
For Grade 3 or 4 AE or toxicity that is definitely, probably, or possibly related to 
study-supplied drugs, study-supplied drugs as well as any other drugs suspected 
in the site investigator’s causality assessment must be permanently discontinued 
and participants followed carefully. Premature treatment discontinuation evaluations 
should be performed. In the event of Grade 3 or 4 toxicities, the A5372 core team 
should be notified within 72 hours (preferably within 48 hours).  
 
The participant should be followed until the AE has decreased to Grade ≤2. After 
the AE has decreased to Grade ≤2, the premature study discontinuation 
evaluations must be completed, and then the participant will be taken off study. 
 
8.2 
Rifamycin Hypersensitivity Syndrome (RHS) 
 
Participants who develop signs or symptoms suggestive of RHS (i.e., fever, myalgia, rash, 
hypotension, clinical hepatitis) should undergo clinical evaluation and laboratory testing 
including comprehensive metabolic panel, CBC with manual differential, and other tests that, 
at the discretion of the site investigator, are necessary to exclude likely alternative diagnoses 
(e.g., if symptoms suggest influenza, a nasopharyngeal aspirate for viral testing could be 
sent). Any participant in whom the investigator suspects RHS and no alternative etiology is 
identified must permanently discontinue INH, RPT, and other study-provided medications. 
Premature treatment discontinuation evaluations should be completed. The participant 
should be followed until the AE has decreased to Grade ≤2. After the AE has decreased to 
Grade ≤2, premature study discontinuation evaluations should be completed, and then the 
participant will be taken off study. 
 
8.3 
Suspected Allergic Reactions to Dolutegravir  
 
Participants with Grade ≥3 allergic reactions, which are considered possibly or probably 


 
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related to DTG should be evaluated by the investigator and must discontinue 
study-provided DTG and other study-provided medications. Locally provided DTG must 
be stopped as well. Premature treatment discontinuation evaluations should be 
completed. The participant should be followed until the AE has decreased to Grade ≤2. 
After the AE has decreased to Grade ≤2, premature study discontinuation evaluations 
should be completed, and then the participant will be taken off study. ART management 
will be at the discretion of the site investigator. 
 
8.4 
Other Toxicities 
 
Cutaneous 
Participants with an isolated Grade 1 or Grade 2 rash may continue study-supplied 
drugs at the study investigator’s discretion. Participants should be advised to contact the 
site staff immediately if there is any worsening of the rash, if any systemic signs or 
symptoms worsen, or if mucosal involvement develops.  
 
If Grade ≥3, all study-provided drugs must be discontinued, as well as any other drugs 
suspected in the site investigator’s causality assessment. Premature treatment 
discontinuation evaluations should be completed. The participant should be followed until 
the AE has decreased to Grade ≤2. After the AE has decreased to Grade ≤2, premature 
study discontinuation evaluations should be completed, and then the participant will be 
taken off study. ART management will be at the discretion of the site investigator.  
 
Drug-Associated Fever 
If Grade ≥3, all study-supplied drugs must be discontinued, as well as any other drugs 
suspected in the site investigator’s causality assessment. Premature treatment 
discontinuation evaluations should be completed. The participant should be followed 
until the AE has decreased to Grade ≤2. After the AE has decreased to Grade ≤2, 
premature study discontinuation evaluations should be completed, and then the 
participant will be taken off study. 
 
Elevated Liver-Associated Enzymes  
Sites must notify the core team within 72 hours and hold study-supplied drugs (INH, 
RPT, and DTG if applicable) if any of the following criteria are met.  
a) Grade 3 or 4 AST, ALT or total bilirubin values are recorded; 
b) ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin); 
c) ALT ≥3xULN with symptoms (new or worsening) believed to be related to liver injury 
or hypersensitivity 
 
For any Grade 1 AST (SGOT), ALT (SGPT) (1.25 to <2.5 x ULN) or total bilirubin (1.1 to 
<1.6 x ULN) elevation, repeat liver chemistries (ALT, AST, total bilirubin) should be 
conducted at regular intervals at the investigator’s discretion until resolution to ≤ULN or 
to baseline if abnormal at entry.  
 
For Grade 2 AST (SGOT), ALT (SGPT) (2.5 to 5 x ULN), or total bilirubin (1.6 to <2.6 x ULN) 
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chemistries repeated until resolution to <ULN or to baseline if abnormal at entry, as 
above. Reintroduce the study-supplied drug(s) with caution. Locally provided DTG should 
be discontinued if suspected in the site investigator’s causality assessment. 
 
INH, RPT, and study-supplied DTG will be permanently discontinued in the event of 
Grade 3 to 4 AST (SGOT), ALT (SGPT) (≥5 ULN) or total bilirubin (≥2.6 x ULN) toxicity 
that is definitely, probably, or possibly related to study-supplied drugs. Locally provided 
DTG should be discontinued if suspected in the site investigator’s causality 
assessment. Premature treatment discontinuation evaluations should be completed. 
The participant should be followed until the AE has decreased to Grade ≤2. After the AE 
has decreased to Grade ≤2, premature study discontinuation evaluations should be 
completed, and then the participant will be taken off study. ART management will be at 
the discretion of the site investigator.  
 
In consultation with the team, careful assessments should be done to rule out the use of 
alcohol, non-study medication-related toxicity, or viral hepatitis (including viral hepatitis 
complicated by immune reconstitution inflammatory syndrome) as the cause for any liver 
toxicity that warrants permanent study drug discontinuation based on the liver stopping 
criteria specified above. Specific tests that may be considered are listed on the PSWP. 
 
Peripheral Neuropathy 
Peripheral neuropathy associated with INH is usually avoided by the concurrent 
administration of pyridoxine (vitamin B6). In this study, all participants will take vitamin 
B6 concomitantly with INH. If peripheral neuropathy develops, every effort should be 
made to determine the etiology (i.e., whether the neuropathy is due to INH toxicity, 
alcohol, or other factors). Participants with peripheral neuropathy Grade ≤2 may be 
entered into the study, but should be monitored carefully for any progression of 
peripheral neuropathy. 
 
For Grade 1 or 2, continue study-supplied drugs and follow the participant more 
frequently for progression of peripheral neuropathy. Consider increase in vitamin B6 
dose.  
 
For Grade 3 or 4, study-supplied drugs must be permanently discontinued, as well as 
any other drugs suspected in the site investigator’s causality assessment. 
Premature treatment discontinuation evaluations should be completed. The participant 
should be followed until the AE has decreased to Grade ≤2. After the AE has decreased 
to Grade ≤2, premature study discontinuation evaluations should be completed, and 
then the participant will be taken off study. 
 
Suicidal Ideation 
Participants will be monitored appropriately and observed for suicidal ideation and 
behavior or any other unusual changes in behavior. It is recommended that the 
investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behavior. For Grade 3 or 4 suicidal ideation, 
study-supplied drugs must be permanently discontinued, as well as any other drugs 
suspected in the site investigator’s causality assessment. Locally provided DTG 


 
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must be stopped as well. Premature treatment discontinuation evaluations should be 
completed. The participant should be followed until the AE has decreased to Grade ≤2. 
After the AE has decreased to Grade ≤2, premature study discontinuation evaluations 
should be completed, and then the participant will be taken off study. 
 
Other toxicity 
Toxicity management will be performed per the standard clinical practice.  
 
8.5 
Pregnancy Outcomes and Reporting 
 
Pregnant women must discontinue study medication and study evaluations, but will be 
encouraged to remain on study to collect pregnancy outcome data. The outcome and 
the adverse events for the participant and infant will be recorded on an outcome eCRF.  
 
Pregnancies that occur on study should be reported prospectively to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Telephone: 
800-258-4263; Fax: 800-800-1052. (For studies conducted at sites outside the United 
States, report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-1598;  
Fax: 44-1628-789-666 or 910-256-0637.) 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Pregnancy 
• 
Drug-related toxicity (see sections 8.1, 8.2, 8.3, and 8.4) 
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, investigator, 
or industry supporter 
 
9.2 
Premature Study Discontinuation  
 
• 
Request by the participant to withdraw 
• 
Requirement for prohibited concomitant medications (see section 5.5) 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
the toxicity section of the protocol 
• 
Failure by the participant to complete either of the intensive PK visits 
• 
Participant repeatedly noncompliant (per investigator’s discretion) with study 
medications as prescribed 
• 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant  
• 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, investigator, 
or industry supporter 
 


 
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10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
This is an open-label, two-arm, multicenter PK study to examine drug-drug interactions 
between RPT and DTG in HIV-1 and LTBI co-infected participants.  
 
Participants in Arm 1 will receive DTG 50 mg BID in combination with 1HP for 4 weeks. 
After 36 participants from Arm 1 are enrolled and PK data are available, a review of DTG 
trough concentrations by the team and the SMC will take place to determine whether 
Arm 2 should open based on an analysis of DTG trough concentrations. There will be a 
pause in study enrollment between the completion of Arm 1 and the start of Arm 2. 
 
If the team decides to open Arm 2, participants in Arm 2 will receive DTG 50 mg QD in 
combination with 1HP for 4 weeks.  
 
Participants will serve as their own controls and PK parameters of DTG will be compared 
in the presence or absence of 1HP. The maximum sample size is 72 participants.  
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below 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 manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publications listed under “Other Outcome Measures”. 
 
10.2.1 Primary Outcome Measures 
 
Evaluation of effect of 1HP on the PK of DTG in plasma 
 
10.2.1.1 
Plasma DTG PK parameters (Cmax, area-under-the-curve (AUC0-12 for 
BID & AUC0-24 for QD dosing), Cmin) at Day 0 and Day 28 (-2/+14 days), 
by arm.   
 
10.2.1.2 
Plasma DTG PK parameter (Ctrough) at Day 28 (-2/+14 days), by arm. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 
Proportion of participants with all adverse events meeting the reporting 
criteria in Section 7.2 during administration of DTG with 1HP, by arm.  
 
10.2.2.2 
Proportion of participants who discontinue study or study drugs during 
DTG and 1HP dosing, by arm. 
 
10.2.2.3 
Proportion of participants with HIV-1 RNA levels >50 copies/mL at Day 
28 (-2/+14 days) and/or at the Follow Up visit. 


 
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10.2.3 Other Outcome Measures  
 
Model predicted dosing of DTG during concomitant 1HP 
 
10.2.3.1 
Dosing algorithm for DTG in the presence of RPT/INH dosing derived 
by simulation using nonlinear mixed effects models. 
 
Evaluation of the role of pharmacogenomics on DTG and RPT PK 
 
10.2.3.2 
PK parameters of DTG in the presence or absence of 1HP, taking into 
account relevant pharmacogenetics (SNPs TBD). 
 
10.2.3.3 
PK parameters of RPT after 1HP dosing taking into account relevant 
pharmacogenetics (SNPs TBD). 
 
Combined evaluation of DTG and RPT PK models 
 
10.2.3.4 
Joint pharmacokinetic model of RPT and DTG PK and its DDI where 
relationship and interaction between dynamic RPT and DTG 
concentrations is modelled, quantified and described. 
 
10.3 
Randomization and Stratification 
 
Participants will be enrolled into the study without randomization since the accrual for 
Arm 1 will be completed when the decision to open Arm 2 will be made.  
 
10.4 
Sample Size and Accrual 
 
Sample size estimates are aimed to provide data to support precise estimation of the 
pharmacokinetic model parameters for DTG in the presence and absence of 1HP. These 
models, once validated, will further be used to deliver dosing algorithms for DTG to be 
recommended for treatment of patients living with HIV and co-infected with LTBI, 
pending appropriate safety assessment. 
 
The sample size assessment was done by evaluating different study designs (varying 
number of participants and time points) using clinical trial simulations. The stochastic 
simulation-estimation (SSE) methodology for clinical trial simulation and re-estimation 
was employed to evaluate sample sizes required to evaluate key pharmacokinetic 
parameters with precision adequate for decision making on use of RPT + DTG at the 
proposed doses. This methodology simulates the data from the planned trial with 
proposed design (number of samples, participants) followed by the estimation of the 
parameters under the true and alternative models. This is repeated at least 1000 times 
and parameter estimates relative standard errors and between subject variability (BSV) 
estimates are assessed. This methodology was used to assess sample size calculations 
and probability of opening Arm 2. The effect of RPT on DTG PK parameters 


 
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(bioavailability) was assumed to be 30%-50% decrease based on a previously 
developed model of DTG + 3HP [16]. The range of inter-participant variability in PK 
parameters (CL and F) was assumed to be 25-40%. The team has assumed design 
where each participant is its own control and time course of RPT induction is considered. 
Under these assumptions, data from ≥32 participants will provide >80% power to detect 
the DDI effect on bioavailability and to unbiasedly (relative bias <5%) and precisely 
(RSE<25%) estimate PK parameters and inter-participant variability. These unbiased 
parameters will be then used for simulations of Arm 2 and derivation of the median 5th 
percentile of DTG troughs by simulations. Probability of opening Arm 2 will be dependent 
on magnitude of both, decrease in bioavailability due to DDI and between participant 
variability. Decrease in bioavailability of up to 35% coupled with acceptable inter-
participant variability (up to 30%) will provide 90% chance of satisfying criteria for 
opening Arm 2. 
 
The proposed design for DTG requires 32 evaluable participants with at least 6 plasma 
sample collections which must include the 23- and 24-hr samples on each of the two 
intensive PK visits in order to estimate pharmacokinetic parameters with required the 
precision defined as relative standard errors <10% for typical values and RSE <25% for 
random effects (between subject variability).  
 
To protect against loss of the primary outcomes (e.g., unevaluable PK measurements) 
after study accrual is closed, the study will enroll 36 participants in each arm. This is an 
increase of ~12% from the required sample size of 32 evaluable participants.  
 
Data from participants who drop out between sampling times or participants who do not 
have at least 6 sample collections on each of the two intensive PK visits will be utilized in 
the analysis, however, those participants will not be counted towards full sample size 
requirement (i.e., 36 participants in each arm) and will be replaced. 
 
10.5 
Data and Safety Monitoring  
 
10.5.1 Interim Monitoring Guidelines 
 
The core team will monitor adverse events (AEs) on a regular basis. Should 3 or 
more participants experience Grade 3 or higher AEs deemed to be definitely,  
probably, or possibly related to DTG or RPT or INH, the study will be halted while 
a safety review is conducted by the ACTG’s Tuberculosis Transformative 
Science Group (TB TSG) SMC. The core team will also monitor viral loads on 
Days 28, 42, and 49 on a regular basis. Specifically, at the time of the 
interim review for Arm 1, the proportion of participants with HIV-1 viral load 
above 50 c/mL will be reported. 
 
10.5.2 Analysis Plan 
 
For the interim PK assessment in Arm 1 participants, PK data from the 
SPRING-1 study [15] will form the basis of the opening rule for Arm 2. Refer to 
section 7.4 for criteria and considerations for opening Arm 2. 


 
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10.6 
Analyses 
 
Primary outcome plasma PK parameters (Cmin, AUC0-24h, and Cmax) will be determined 
using nonlinear mixed-effects population pharmacokinetic modeling. PK 
parameters will be log-transformed as needed. 
 
Primary PK analysis: 
The bootstrap method with replacement will be applied on the observed Ctrough values 
from Arm 1, and the mean and 95% CI of the 5th percentile Ctrough will be calculated. The 
lower bound of a 95% CI around the 5th percentile of Cmin from Arm 1 will be compared 
with the 5th percentile of Ctau in the DTG 10 mg dosing arm (i.e., 158 ng/mL) from the 
SPRING-1 study, which has been demonstrated to be sufficient in maintaining viral 
suppression. If the lower bound of the 95% CI around the 5th percentile Cmin is greater 
than 158 ng/mL, the dosing is considered acceptable. The same analysis will be 
conducted for Arm 2 if it opens. 
 
Geometric mean ratios and associated 90% confidence intervals within arm will be 
calculated to assess the overall effect of 1HP on DTG PK.  
 
For all PK parameters (including both primary and other outcome PK measures), 
descriptive statistics including mean, standard deviation, median, interquartile range, 
minimum, and maximum will be presented. All statistical tests will be performed without 
adjustment for multiple comparisons unless otherwise stated.  
 
Detailed analysis methods will be put in a Statistical Analysis Plan. 
 
Because PK variability has been associated with differences in drug response, 
understanding whether differences in DTG and RPT concentrations observed in A5372 
have a genetic basis will be explored as an exploratory objective. Polymorphisms in host 
genes involved in both DTG and RPT metabolism or transport will be explored. The 
primary genes of interest will include: CYP3A4/5, UGT1A1, PXR (pregnane x receptor), 
CAR (constitutive androstane receptor), as well as other metabolic enzymes and 
transporters that may play a role in either DTG or RPT disposition (TBD). 
 
11.0 
PHARMACOLOGY PLAN 
 
See section 6.3.11 for details on PK sampling and section 10.6 for details of 
population PK modeling. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
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Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for 
this purpose by NIAID. Remote monitoring visits may be performed in place 
of, or in addition to onsite visits to ensure the safety of study participants 
and data integrity [23]. The site will make available study documents for 
site monitors to review utilizing a secure platform that is HIPAA and 21 CFR 
Part 11 compliant. Potential platform options include: Veeva SiteVault, site-
controlled SharePoint or cloud-based portal, direct access to Electronic 
Medical Record (EMR), and Medidata Rave Imaging Solution. Other secure 
platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by 
the DAIDS Office of Clinical Site Oversight (OCSO). 
 
12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB/EC, the site monitors, the ACTG, the 
FDA, the NIAID, the OHRP, the industry supporter(s) or designee, and other 
local, US, and international regulatory entities for confirmation of the study data.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix II) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 


 
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of the study. A signed consent form will be obtained from the participant (or legal 
guardian, or person with power of attorney for participants who cannot consent for 
themselves). The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the participant, or legal guardian, and this fact will be documented in the 
participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, or other local, US, and international regulatory entities as part of their duties.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or other local, US, and international regulatory entities as part of their duties to ensure 
that research participants are protected. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.  
 
15.0 
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 CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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16.0 
REFERENCES 
 
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at 
https://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL003093.pdf. Accessed 
August 28, 2018. 
2. Gunthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and 
prevention of HIV infection in adults. 2016 Recommendations of the International Antiviral 
Society - USA Panel. JAMA 2016;316:191-210. 
3. World Health Organization. Updated recommendations on first-line and second-line 
antiretroviral regimens and post-exposure prophylaxis and recommendations on early 
infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated 
guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 
Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.51). 
4. Raffi F, Rachlis A, Stellbrink H-J, et al. Once-daily dolutegravir versus raltegravir in 
antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, 
double-blind, non-inferiority SPRING-2 study. Lancet 2013;381:735-43. 
5. van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in 
combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week 
results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 
2012;12:111-8. 
6. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the 
HIV integrase inhibitor dolutegravir given BID with rifampin or once daily with rifabutin: 
results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr 
2013;62:21-7.  
7. Dooley KE, Kaplan R, Mwelase T, et al. Inspiring: safety and efficacy of dolutegravir-
based ART in TB/HIV co-infected adults at week 48. 22nd International AIDS 
Conference; Amsterdam, Netherlands, July 23-27, 2018. 
8. Le MP, Cournil A, Kouanfack C, et al. Pharmacokinetic and virological efficacy of 
dolutegravir (50 mg BID) containing regimen in association with rifampin in HIV-infected 
patients using Dried Blood Spot: ANRS-12313 NAMSAL sub-study in Cameroon. 
[Abstract #7]. 19th International Workshop on Clinical Pharmacology of Antiviral 
Therapy. May 22, 2018. Baltimore, MD.  
9. Wang X, Cerrone M, Ferretti F, et al. Pharmacokinetics of Dolutegravir 100 mg once-
daily with Rifampicin. [Abstract #11]. 19th International Workshop on Clinical 
Pharmacology of Antiviral Therapy 2018. May 22, 2018. Baltimore, MD.  
10. Brooks KM, George JM, Pau AK, et al. Cytokine-mediated systemic adverse drug 
reactions in a drug–drug interaction study of dolutegravir with once-weekly isoniazid and 
rifapentine. Clin Infect Dis 2018;67:193-201.  
11. Barditch-Crovo P, Trapnell CB, Ette E, et al. The effects of rifampin and rifabutin on the 
pharmacokinetics and pharmacodynamics of a combination oral contraceptive. Clin 
Pharmacol Ther 1999;65:428-38. 


 
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12. Apseloff G. Severe neutropenia among healthy volunteers given rifabutin in clinical trials. 
Clin Pharmacol Ther 2003;74:591-2. 
13. Dooley KE, Savic RM, Park JG, et al. Novel dosing strategies increase exposures of the 
potent antituberculosis [drug rifapentine but are poorly tolerated in healthy volunteers. 
Antimicrob Agents Chemother 2015;59:3399-405. 
14. Martínez E, Collazos J, Mayo J. Hypersensitivity reactions to rifampin. Pathogenetic 
mechanisms, clinical manifestations, management strategies, and review of the 
anaphylactic-like reactions. Medicine (Baltimore) 1999;78:361-9. 
15. Grosset J, Leventis S. Adverse effects of rifampin. Rev Infect Dis 1983;5(Suppl 3):S440-
S446. 
16. Dooley KE, Churchyard G, Savic RM, et al. Safety & PK of Weekly Rifapentine/Isoniazid 
(3HP) in Adults with HIV on Dolutegravir. [Abstract #80]. CROI 2019. March 4-7, 2019, 
Seattle, WA. 
17. Boffito M. Pharmacokinetics of dolutegravir 100 mg once-daily with rifampicin. 
[Presentation]. Antiviral PK Workshop (Session 5), May 24, 2018, Baltimore MD. 
18. World Health Organization. Potential safety issue affecting women living with HIV using 
dolutegravir at the time of conception. WHO Statement on DTG. Geneva; 18 May 2018. 
19. Zash R, Holmes L, Diseko M, et al. Neural-tube defects and antiretroviral treatment 
regimens in Botswana. N Engl J Med 2019. https://doi.org/10.1056/NEJMoa1905230. 
Epub ahead of print. DOI: 10.1056/NEJMoa1905230. 
20. Zash R, Holmes L, Diseko M, et al. Antiretroviral Exposure in the Tsepamo Study, 
Botswana. International AIDS Conference 2020. July 6-10, 2020. 
21. Swindells S, Ramchandani R, Gupta A, et al. One month of rifapentine/isoniazid to 
prevent TB in people with HIV: BRIEF-TB/A5279. Abstract 37LB. Conference on 
Retroviruses and Opportunistic Infections (CROI 2018). Boston, MA, March 4-7, 2018.  
22. Savic R, Weiner M, MacKenzie WR, et al. Defining the optimal dose of rifapentine for 
pulmonary tuberculosis: exposure–response relations from two phase II clinical trials. 
Clin Pharmacol Ther 2017:102:321-31. 
23. FDA Guidance on Conduct of Clinical Trials of Medical Products During the 
COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and 
Institutional Review Boards, March 2020, Updated on January 27, 2021. Accessed 
at: https://www.fda.gov/media/136238/download. 
 


 
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APPENDIX I: PROHIBITED AND PRECAUTIONARY MEDICATIONS 
Division of AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
For Protocol A5372 
 
The prohibited and precautionary medications with dolutegravir (DTG), rifapentine (RPT), and 
isoniazid (INH) are listed below. 
 
I. 
Prohibited Medications 
 
• 
Phenytoin 
• 
Phosphenytoin 
• 
Lamotrigine 
• 
Perampanel 
• 
Phenobarbital 
• 
Primidone 
• 
Carbemezepine 
• 
Oxcarbazepine 
• 
Eslicarbazepine 
• 
Felbamate 
• 
St. John's wort 
• 
Dofetilide 
• 
Azole antifungals including fluconazole, itraonazole, ketoconazole and posaconazole 
(topical formulations are acceptable as they do not achieve systemic concentration) 
• 
Enzalutamide 
• 
Mitotane 
• 
Other rifamycin antibiotics including rifabutin and rifampicin 
• 
Tenofovir alafenamide (TAF) 
• 
Other antiretroviral drugs except DTG and 2 NRTI  
• 
Protease inhibitors (HIV or HCV) 
 
II. 
Precautionary Medications 
 
• 
Antacids – follow product labeling for instructions on separation with DTG 
• 
Buffered Medications – follow product labeling for instructions on separation with 
DTG 
• 
Divalent cations (e.g., calcium or iron supplements) – follow product labeling for 
instructions on separation with DTG 
• 
Ethinyl estradiol/norgestimate 
• 
Metformin 
• 
Methadone 
• 
Multivitamin – follow product labeling for instructions on separation with DTG 
• 
Omeprazole 
• 
Prucalopride 
• 
Sucralfate 
• 
Topiramate  


 
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APPENDIX II: SAMPLE INFORMED CONSENT 
Division of AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
Industry Support Provided by: 
Viiv Healthcare, Ltd. 
 
 
For protocol: A5372, “Drug-Drug Interactions Between Rifapentine and Dolutegravir in HIV/LTBI 
Co-Infected Individuals,” Final Version 2.0, dated 11Jun2021 
 
SHORT TITLE FOR THE STUDY: RPT-DTG DDI Study  
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to see if taking a medicine to treat 
tuberculosis (TB) called rifapentine (RPT), affects the levels of 
dolutegravir (DTG) (an HIV medicine) in the blood or not.  
 
NUMBER OF  
PARTICIPANTS 
There will be up to 2 treatment groups of people, for a total of up to 72 
participants. The study will open with one treatment group only. Based on 
the results from the first group in the study, the study team will decide if 
the second group will open. 
 
LENGTH OF  
STUDY  
Most people will be on this study for six weeks (4 weeks on study treatment 
and 2 weeks of follow-up). You may be on study up to 11 weeks if you have 
to have additional follow-up visits to check your viral load. 
 
REQUIRED  
ACTIVITIES 
Blood collections 
At all visits, some blood will be collected from a vein in your arm. Over the 
duration of the study, approximately 13 to 15 tablespoons of blood will be 
collected. 
 
Special procedures  
Chest X-ray/scan 
 
RISKS 
Possible risks related to the study drugs DTG, RPT, and isoniazid (INH) 
are listed later in this informed consent. 
 
There are also risks related to blood draws, TB skin test, chest X-ray, and 
social harm. All of these risks are explained in later in this informed 
consent. 
 


 
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BENEFITS 
As part of this drug interaction study, you will receive short-course 
therapy for latent TB (known as 1HP), which may benefit you.  
 
OTHER CHOICES 
You may choose to not participate in the study. This is a pharmacokinetic 
(PK) study to study interaction between a proven latent TB treatment (what is 
referred to as 1HP) and a DTG-2NRTIs regimen for HIV treatment. Instead of 
being in this study, you have the option of continuing with your current 
treatment or starting a new one under the care of your regular doctor or other 
health care provider. You may also check with your doctor about your options 
for treatment of latent TB under clinical care or other research studies. 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because the medicines you take to treat 
HIV include dolutegravir (DTG), and you have either tested positive for the bacteria that causes 
tuberculosis (TB) or you live in a place where TB infection occurs frequently.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study.  The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
This research study is being done to help us figure if taking medications to prevent TB affect the 
drug levels in blood of a commonly used HIV medication called dolutegravir (DTG) and if an 
extra dose of DTG is needed during this TB preventive treatment. The other medicines, 
rifapentine (RPT) and isoniazid (INH), are drugs used to prevent active TB in people who have 
been exposed to TB. This study will also help us make sure that people tolerate the medicines 
and that they are safe when given together. 
 
Some people are infected with the bacteria that cause TB, but their immune systems (the system 
in a person’s body that helps fight infections) prevent the bacteria from multiplying, and they do 
not have any symptoms from the infection. These people have latent TB infection (LTBI). Latent 
TB can develop into active disease and cause sickness, especially in people with weakened 
immune systems, such as those with HIV. One treatment to prevent latent TB from becoming 
active is to take RPT and INH daily for 4 weeks. This therapy is referred to as 1HP, and is an 
alternative recommendation by the World Health Organization (WHO) but not currently 
approved by the US FDA or recommended by the Centers for Disease Control and 
Prevention (CDC). In the BRIEF TB study, a large multicenter study, 1HP was compared to 
standard therapy with 9 months of INH; both regimens had similar low rates of TB and a 
similar rate of side effects. This study suggested that 1HP worked similarly to 9 months of 


 
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INH to prevent TB. However, it is still possible that 1HP is less effective than the currently 
approved regimens in preventing TB. A5372 is not intended to evaluate the ability of the 
1HP regimen to prevent TB. 
 
In many countries, DTG is the recommended first-line treatment for HIV. DTG, RPT, and INH 
are proven beneficial treatments for people living with HIV and latent TB, but it is unclear 
whether these treatments work differently when taken together. Understanding how DTG 
interacts with the short-term treatment for latent TB (1HP) is very important for delivering both 
treatments effectively.  
 
The study will have two (2) arms. Arm 2 will only open after the results from Arm 1 are reviewed. 
 
Below are the medicines that you may take during the study depending on which Group you are 
in: 
 
Arm 1 
• 
DTG 50 mg orally twice daily – about 12 hours apart  
o 1st dose will be taken in the morning; this will not be supplied by the study 
o 2nd dose will be taken in the evening; this will be supplied by the study for 4 weeks 
• 
1HP: INH 300 mg + RPT 600 mg orally once daily (in the morning) for 4 weeks (supplied by 
the study) 
 
Arm 2 (upon opening)  
• 
DTG 50 mg orally once daily (in the morning) (not supplied by the study) 
• 
1HP: INH 300 mg + RPT 600 mg orally once daily (in the morning) for 4 weeks (supplied by 
the study) 
 
You will continue taking your existing ART drugs while on the study – your ART must include 
two NRTIs (excluding TAF) during the study. Your ART will not be provided by the study. 
 
You will also receive pyridoxine (vitamin B6) 25 mg or 50 mg with each dose of INH based on 
the current local, national, or international dosing guidelines.  
 
Because the blood draws on study visits will be dependent on the time you take the drugs, you 
will need to take your HIV drugs and drugs provided by the study (except second dose of DTG if 
you are in Arm 1) in the morning during the duration of the study. If you generally take your HIV 
drugs in the evening, you will need to switch to taking them in the morning for this study, 
including at least 3 days before the Day 0 visit. On the study visit days, you will hold off on 
taking the drugs until you arrive at the clinic. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG study. As 
part of your screening visit, some demographic (for example, age, gender, race), clinical (for 


 
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example, disease condition, diagnosis), and laboratory (for example, viral load) information will 
be collected from you. We also collect information on whether you use (or have used) IV drugs. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may help determine whether there are patterns or common 
reasons why people do not join a study. 
 
If you agree to join this study, you will be asked to sign this consent form. After you have signed 
the form, the research staff will determine if you are eligible to join the study. 
 
Screening 
If you would like to be in this study, after you have read and signed this consent form, you will 
come to the clinic for a screening visit to make sure you meet the requirements for joining the 
study. This will take about 1 hour. At this visit: 
• 
You will have a physical exam and answer questions about your medical history and any 
medications you are taking or have taken in the past. 
• 
If your HIV status is unknown or not documented, blood will be drawn to confirm your HIV 
status. You may have to sign a separate consent form for this test. 
• 
You will have approximately 2 tablespoons of blood drawn. This blood will be used for the 
following tests: 
o For routine lab tests for safety 
o To measure the amount of HIV in your blood  
• 
You will be asked to give blood or a urine sample for a pregnancy test (applicable to 
individuals who can become pregnant). 
• 
You may have a skin test or a blood draw to check if you have latent TB unless you have 
had a positive test in the past, or site investigator determines a need for LTBI treatment. 
• 
After confirming a negative pregnancy test, if you have not had a chest X-ray or CT scan 
within the last month, you will have a chest X-ray to check you do not have active TB.  
• 
A member of the staff at your site will talk to you about the contraception requirements for 
the study and the information that is known about DTG and pregnancy. 
 
If you enter the study 
If the tests at screening show that you are eligible for the study, you will be assigned to Arm 1 at 
the study entry visit. If and when Arm 2 opens for enrollment, you will be assigned to Arm 2. For 
both Arm 1 and Arm 2, the study visit schedule will be the same. The difference will be the 
regimen for DTG – twice daily in Arm 1 and once daily in Arm 2. Treatment will be taken for 28 
days.  
 
Entry / Day 0 
After your screening visit, you will come in for an entry visit. Because this visit will take about 24 
hours, you may be able to stay overnight at the clinic or hospital for this visit. If you are not able 
to stay overnight, this visit will take about 14 hours on Day 0 and you will return to the clinic the 
next day for another 2-3 hour visit. 
At this visit: 
• 
You will have a physical exam and answer questions about your medical history and any 
medications you are taking or have taken in the past. 


 
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• 
You will answer questions about the specific times of your HIV medicine doses on the last 3 
days. 
• 
You will have approximately 4 tablespoons of blood drawn. This blood will be used for the 
following tests: 
o For pharmacokinetic (PK) testing (to see how the levels of the study drugs rise and fall in 
your blood over time). You will not receive the results of this testing. The PK sample 
collection time points will be at hour 0 (before you take your anti-HIV medicine), and at 1, 
2, 4, 8, 12, 13, 14, 23, and 24 hours after taking the anti-HIV medicine in Arm 1. Arm 2 
will follow the same schedule, but will not have the 13 and 14 hour time points. 
o For routine lab tests for safety. 
o With your permission, some of the blood will be stored for future protocol-required 
pharmacogenetic testing. You will not receive the results of this testing.  
• 
You will be asked to give blood or a urine sample for a pregnancy test (applicable to 
individuals who can become pregnant). 
 
For pharmacogenetic testing, some of your blood will be tested for the human genes that 
affect how drugs are broken down, interact with other drugs, and potentially lead to side 
effects in the body. This testing may include whole genome sequencing (WGS). In WGS, 
researchers look at all of your genes and at almost all of your DNA. In “standard” genetic 
testing, researchers look at specific genes or subsets of genes, but not at all genes. 
 
Day 1 
You will start taking the study-provided drugs on Day 1 (following completion of the Day 0 visit 
evaluations).  
 
Day 3  
At this visit:  
• 
You will have a physical exam. 
• 
You will answer questions about the times when you took medicines in the last 3 days. 
• 
You will have approximately 1 tablespoon of blood drawn for routine lab tests for safety. 
• 
You will have blood drawn about 20 minutes before you take your study medicine to check 
the levels of study drugs in your blood (you will not receive the results of this testing). 
• 
A pregnancy test may occur if indicated. 
 
Day 14 
At this visit:  
• 
You will have a physical exam. 
• 
A member of the staff at your site will remind you about the contraception requirements for 
the study. 
• 
You will answer questions about the times when you took medicines in the last 3 days. 
• 
You will have approximately 1 tablespoon of blood drawn for routine lab tests for 
safety. 
• 
You will have blood drawn about 20 minutes before you take your study medicines to check 
the levels of study drugs in your blood (you will not receive the results of this testing). 
• 
A pregnancy test may occur if indicated. 
 


 
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Day 21  
At this visit: 
• 
You will have a physical exam. 
• 
You will answer questions about the times when you took medicines in the last 3 days. 
• 
You will have approximately 1 tablespoon of blood drawn for routine lab tests for 
safety. 
• 
You will have blood drawn about 20 minutes before you take your study medicines to check 
the levels of study drugs in your blood (you will not receive the results of this testing). 
• 
A pregnancy test may occur if indicated. 
 
Day 28  
This visit will be similar to your Day 0 visit: 
• 
You will have a physical exam. 
• 
You will be asked to give blood or a urine sample for a pregnancy test (applicable to 
individuals who can become pregnant). 
• 
A member of the staff at your site will remind you about the contraception requirements for 
the study. 
• 
You will answer questions about the times when you took medicines in the last 3 days. 
• 
You will have approximately 4 tablespoons of blood drawn. This blood will be used for the 
following tests: 
o For pharmacokinetic (PK) testing (to see how the levels of the study drugs rise and fall in 
your blood over time). You will not receive the results of this testing. The PK sample 
collection time points will be at hour 0 (before you take your anti-HIV medicine), and at 1, 
2, 4, 8, 12, 13, 14, 23, and 24 hours after taking the anti-HIV medicine in Arm 1. Arm 2 
will follow the same schedule, but will not have the 13 and 14 hour time points. 
o For routine lab tests for safety. 
• 
You will have approximately 1 tablespoon of blood drawn. This blood will be used to 
measure the HIV levels in your blood and to store some blood for additional testing, if 
needed. 
 
Day 42 Follow-up 
At this visit: 
• 
You will have a physical exam. 
• 
You will have approximately 1 tablespoon of blood drawn. This blood will be used to 
measure the HIV levels in your blood and to store some blood for additional testing, if 
needed. 
 
Day 49 Additional Visit 
If your blood work at Day 42 shows that your anti-HIV drugs are not fighting your HIV infection 
well, you will come to the clinic for an additional visit within 1 to 4 weeks. This visit will take 
about 1 hour. At this visit, you will have a physical exam and blood drawn for additional HIV 
level test and possible HIV resistance testing. 
 
 


 
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CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood will be stored and used for study-required (pharmacokinetic, virologic) 
testing.  
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study.  
 
Research for Pharmacogenetics – OPTIONAL (for this study) 
If you agree, some of your blood will be tested for the human genes that affect how drugs are 
broken down, interact with other drugs, and potentially lead to side effects in the body. This is 
called pharmacogenetics.  
 
____ (initials) I understand and I agree to this storage and use of my blood for pharmacogenetic 
testing. 
OR 
____ (initials) I understand but I do not agree to this storage or use of my blood for 
pharmacogenetic testing. 
 
Please refer to Attachment I to consent for use of your samples in other studies. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 72 people will take part in this study—36 per arm. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
Most people will be on this study for six weeks (4 weeks on study treatment and two weeks of 
follow-up). You may be on study up to 11 weeks if you have to have additional follow-up visits to 
check your viral load.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled  
• 
You become pregnant 
• 
You are not able to attend the study visits as required by the study 


 
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• 
You are not able to take the study drugs as required by the study 
• 
You need a treatment that you may not take while on the study 
• 
Your primary care provider requests it if she or he thinks the study is no longer in your best 
interest  
• 
You are not able to complete the intensive PK study visits. 
 
If you have to stop taking the study drugs before you complete the study or you are taken off the 
study early, you will have the following evaluations as deemed appropriate by the study doctor: 
• 
You will have a physical exam. 
• 
You will have approximately 1 tablespoon of blood drawn for routine lab tests for safety. 
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED DRUGS OR ONCE I 
LEAVE THE STUDY, HOW WOULD DRUGS BE PROVIDED? 
 
The study will only provide study drugs for 28 days of the study.   
 
If you must permanently stop taking study-provided drugs before your study participation is 
over, you will just continue taking your regularly prescribed anti-HIV medicines. The study staff 
will discuss other options that may be of benefit to you. 
 
After the study 
After you have completed your study participation, the study will not be able to continue to 
provide you with drugs you received on the study. If continuing to take these or similar 
drugs/agents would be of benefit to you, the study staff will discuss how you may be able to 
obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The study will assess interaction of DTG with RPT and INH. As you may have discussed with 
your treating clinician, the benefits of DTG and RPT/INH, when taken in isolation, are 
considered to outweigh the risks. It is still important for you to be aware of the side effects of 
these treatments, so you and the study team can manage the risks.  
 
One risk of this study is that taking the study drugs together might cause the level of DTG in 
your blood to drop too low to fight your HIV. If DTG levels become too low, it is possible that 
HIV virus may start reproducing again in the body and that the current HIV medications 
could stop working to control the HIV virus due to development of drug resistance. The 
study plans to minimize this risk in the following ways: 
• 
Starting with a double dose of DTG in Arm 1 which, based on published data, is itself not 
known to carry risks 
• 
Moving to a single dose of DTG in Arm 2 only when the initial results of Arm 1 are 
encouraging 
• 
Testing your HIV viral load during the study 
 


 
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For Arm 1, the study requires participants to receive double the recommended dose of DTG for 
treatment-experienced individuals. However, there are no known risks of taking 50 mg of DTG 
twice a day or of DTG overdosage. Furthermore, if RPT causes the level of DTG to drop, 
additional dosing of DTG may compensate for this interaction. 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and before starting any new medications 
while on the study. You must also tell the study doctor or nurse before enrolling in any other 
clinical trials while on this study. 
 
Use of Combination Antiretroviral Drugs 
The side effects associated with combination of antiretroviral drugs may include immune 
reconstitution syndrome and abnormal placement of body fat. 
• 
Immune Reconstitution Syndrome: 
o In some people with advanced HIV infection, symptoms from other infections or certain 
diseases may occur soon after starting combination anti-HIV treatment but can also 
occur later. Some of these symptoms may be life threatening. If you start having new 
symptoms or notice that existing symptoms are getting worse after starting your 
antiretroviral therapy, tell your healthcare provider right away. 
 
• 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
o Increase in fat around the waist and stomach area 
o Increase in fat on the back of the neck 
o Thinning of the face, legs, and arms 
o Breast enlargement 
 
Dolutegravir (DTG, Tivicay) 
The side effects associated with dolutegravir include allergic (hypersensitivity) reactions and 
liver problems. See below: 
• 
Allergic reaction which may cause a rash. You may develop a rash with any of the following 
signs or symptoms: 
o Fever 
o General ill feeling 
o Extreme tiredness 
o Muscle or joint aches 
o Blisters or sores in your mouth 
o Blisters or peeling skin 
o Redness or swelling of your eyes 
o Swelling of your mouth, face, lips, or tongue 


 
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o Trouble breathing 
 
If you develop a rash with DTG, stop taking DTG and notify the study doctor right away. 
 
• 
Liver problems which may cause: 
o Yellowing of your skin or whites of your eyes (jaundice) 
o Dark or tea-colored urine 
o Pale-colored bowel movements 
o Nausea or vomiting 
o Loss of appetite 
o Pain, aching, or tenderness on your right side below your ribs 
o Changes in liver test results, more common in people with hepatitis B or C 
 
You are encouraged to abstain from alcohol while on the study to reduce any risk of 
experiencing liver problems. 
 
People with pre-existing history of depression or other mental health illness may be at greater 
risk for suicidal thoughts, or attempts, which may lead to death. If your mental health illness 
worsens, or if you develop suicidal thoughts, call your healthcare provider right away. 
 
Additional side effects include: 
• 
Trouble sleeping 
• 
Abnormal dreams 
• 
Tiredness 
• 
Headache 
• 
Anxiety (fear, worry) 
• 
Muscle and joint aches 
• 
Dizziness 
• 
Nausea/Vomiting 
• 
Flatulence (gas in the abdomen) 
• 
Increase in weight 
 
Dolutegravir and Pregnancy: 
Early results from a large study in Botswana of pregnant women showed a possible increased 
risk of certain types of serious birth defects involving the brain and spinal cord in babies born to 
women who were taking DTG for HIV treatment at the time of becoming pregnant or early in 
their pregnancy. Further data from this study show that 0.19% of women who were taking 
DTG at the time they became pregnant had babies with defects, compared to 0.11% of 
women who were not taking DTG, however this difference is small and not statistically 
significant. These defects happen early in pregnancy, before many women even know 
they are pregnant, however the analysis of all data available is insufficient to confirm that 
these defects are caused by the use of DTG. There is no increased risk of these types of 
birth defects among women who started dolutegravir later in pregnancy. 
 


 
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Rifapentine (RPT, Priftin) 
The following side effects have been associated with the use of rifapentine: 
• 
Reddish coloring of urine, sweat, sputum, saliva, tears, and breast milk. Contact lenses and 
dentures may be permanently stained.  
• 
Liver damage that may include abnormal liver function tests. If you develop any of the 
following symptoms of liver damage, you should call your doctor right away: 
o Unexplained loss of appetite 
o Nausea and/or vomiting 
o Pale-colored stools 
o Yellowing of the eyes or skin 
o Pain in the upper abdomen 
o Dark urine 
• 
Loss of appetite 
• 
Low blood counts 
• 
Low blood sugar 
• 
Upset stomach or vomiting 
• 
Decreased effectiveness of hormonal contraceptives and other medications, including some 
anti-HIV medications. Tell your doctor about all medications that you are taking. 
 
Although rare, flu-like symptoms and hypersensitivity reactions have also been associated with 
rifapentine (or rifamycin family of drugs). This reaction should resolve when rifapentine is 
stopped. This reaction may include the following: 
• 
Fever 
• 
Rash 
• 
Inflammation of the liver 
• 
Low blood pressure  
• 
Muscle aching  
• 
Temporary decrease in white blood cells called lymphocytes 
• 
Headache 
• 
Nausea 
• 
Vomiting 
 
Risk of Nitrosamine Impurities 
 
The US Food and Drug Administration (FDA) has been investigating the presence of 
impurities called nitrosamines in some types of medications, including rifapentine (RPT). 
Low amounts of nitrosamines are common in water and foods, including cured and 
grilled meats, dairy products, and vegetables. Everyone is exposed to some level of 
nitrosamines through their diet. Some types of nitrosamines have been shown to cause 
cancer in laboratory animals. Nitrosamine impurities may increase the risk of cancer if 
people are exposed to them above acceptable levels and over long periods of time (such 
as many years).  
 
The study drug RPT contains small amounts of a nitrosamine impurity that could increase 
cancer risk gradually over time. At these amounts in the RPT to be taken for one month in 


 
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this study, the risk of developing cancer is very low. The FDA recently noted that, because 
TB is a potentially deadly disease that affects the lungs and sometimes other parts of the 
body, the risk of not taking the medicine outweighs any potential risk from nitrosamine. 
 
Four weeks of daily RPT and isoniazid (1HP) has been shown to be safe and can prevent 
latent TB from becoming active. It is an accepted alternative regimen for LTBI treatment 
per the WHO. Use of the currently available RPT for treatment of latent TB for a short 
time has clear benefits, while the cancer risk is very low. All medications have risks and 
benefits. You should talk with your study doctor about any concerns. 
 
As an alternative to 1HP provided in this trial, you could take 6-9 months of INH regimen 
that might be available to you outside of this study as a preventive TB therapy regimen. 
This regimen does not have any known nitrosamine impurities. 
 
Risk of Antibacterials: Some medications used to treat TB may be associated with diarrhea 
(loose or watery bowels), including bloody diarrhea, which may be serious. 
 
Isoniazid (INH) 
The following side effects have been associated with the use of isoniazid: 
 
Serious and sometimes life threatening liver damage may develop even after many months of 
treatment. Older age, already having some liver disease, drinking alcohol regularly and using 
injection drugs are all associated with an increased risk of developing liver damage. Women, 
particularly black and Hispanic women, or if they are pregnant or recently gave birth to a baby, 
may also be at increased risk of life threatening liver damage. If you develop any of the following 
symptoms, you should call your doctor right away: 
• 
Unexplained loss of appetite 
• 
Nausea and or vomiting 
• 
Pale colored stools 
• 
Yellowing of the eyes or skin 
• 
Pain in the upper abdomen 
• 
Dark urine 
 
Additional side effects may include: 
• 
Tingling and numbness in the hands and feet 
• 
Memory loss, confusion, trouble sleeping, changes in behavior or mood 
• 
Unsteadiness or dizziness 
• 
Seizures 
• 
Low blood counts 
• 
Rash and itching 
• 
High blood sugar 
• 
Joint pain 
• 
Reduced vitamin B6 levels (a vitamin that helps with many functions in your body) 
 
Risks of Drawing Blood  
Taking blood may cause some discomfort, bleeding, bruising, and/or swelling where the needle 


 
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enters the body, lightheadedness, and in rare cases, fainting or infection.  
 
Risks of TB Skin Test 
In rare cases, a TB skin test can cause severe redness and swelling of the arm in people who 
had a positive TB skin test in the past. There have even been a few cases where this reaction 
was seen in people who had not had this test before.  
 
Risks of Chest X-ray  
The amount of high-energy radiation used in a chest X-ray is relatively small and does not pose 
any significant risk to you. 
 
Risks of Social Harm 
It is possible that participating in this study will make it difficult for you to keep your HIV status 
secret from people close to you. This may lead to unwelcome discussions about or reactions to 
your HIV status. Please talk with the study staff if you are worried about this. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Dolutegravir may be unsafe for unborn babies. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant while you are taking dolutegravir. You must 
use one of the following barrier methods of birth control that you discuss with the study staff: 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Condoms (male or female) 
 
A barrier method of birth control is required because rifapentine can prevent birth control pills 
and other hormonal birth control methods from working. Hormonal methods of contraception 
may continue to be used during the study, however another method listed above must 
also be used through the duration of the study. 
 
Note that condom method may not be as effective as using diaphragm, or IUD. 
 
There is also a further, relatively small, risk to an unborn baby due to ionising radiation 
exposure from the chest X-ray. Hence you will be required to have a confirmed negative 
pregnancy test before this procedure. 
 
If you become pregnant while on study, you must discontinue study medication and study 
evaluations. You will be encouraged to remain on study (but off study medication) to collect 
pregnancy outcome data. 
 
If you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 


 
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The study drugs include 28 days of RPT and INH, so participants have a prospect of benefiting 
from being treated for their latent tuberculosis (TB). An alternative for treatment of latent TB is 
nine months of daily isoniazid (INH). You may find taking 28 days of RPT and INH to be easier 
and more convenient. 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. For example, the TB treatment you receive could help prevent you from developing TB. It 
is also possible that you may receive no benefit from being in this study. Information learned 
from this study may help others who have HIV and risk the possibility of having TB.  
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Enrollment in the study is voluntary. You may choose to not participate in the study.   
 
This is a pharmacokinetic (PK) study to study interaction between a proven latent TB treatment 
(what is referred to as 1HP) and a DTG-2NRTIs regimen for HIV treatment. Instead of being in 
this study, you have the option of continuing with your current treatment or starting a new one 
under the care of your regular doctor or other health care provider. You may also check with 
your doctor about your options for treatment of latent TB under clinical care or other research 
studies. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For Sites in the US 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 


 
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A description of this clinical trial will be available on ClinicalTrials.gov. This website will not 
include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time.  
 
For Sites Outside the US 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees.  
 
All information collected about you as part of the study will be sent securely to the ACTG 
Statistical and Data Management Center in the United States. Your information will be 
combined with information from other study participants and will be used for statistical 
analysis of study results. Your name and other personal identifiers will not be sent to the 
ACTG Statistical and Data Management Center. Your research site will send your 
information in accordance with the laws, regulations, and policies of your country and 
research site. 
 
A description of this clinical trial will be available on ClinicalTrials.gov. This website will not 
include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this study may lead to added costs to you and your insurance company. In some 
cases it is possible that your insurance company will not pay for these costs because you are 
taking part in a research study. Costs may include but not limited to transportation costs, time 
away from work or home. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[This section will include information on any planned reimbursement or payment to the 
participants. The site will complete this based on their guidelines.] 
 
 


 
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WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry clinical trials insurance (CTI), this must be indicated in 
the informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. Your site will share a summary of the results when 
they are ready to be presented. Your study staff can answer any questions you may have.  
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 


 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) 
Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 


 
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ATTACHMENT I: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples”. The ACTG will only allow your extra samples to be used in other studies if 
you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has 
been collected about you. This means that no one looking at the labels or at other 
information will know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples 
will be stored in the ACTG repository located in the United States. There is no limit on 
how long your extra samples will be stored.   
[Site: Revise the previous sentence to insert limits if your regulatory authority 
imposes them.] 
 
When a researcher wants to use your samples and information, their research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or 
ethics committee (EC) will review their plan.  
[Site: If review by your institution’s IRB/EC/RE is also required, insert a sentence stating 
this.]  
 
IRBs/ECs protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your samples to the researcher’s location. This means that 
researchers who are not part of the protocol team may use your samples without asking 
you again for your consent. 
 
Your specimens will never be used for commercial profit. You will not be paid for your 
samples. Also, a researcher may make a new scientific discovery or product based on 
the use of your samples. If this happens, there is no plan to share any money with you.  
 
You may withdraw your consent for research on your extra samples at any time, and the 
specimens will be discarded. 
 
For each of the questions below, please choose the response that matches what you 
want by putting your initials in the space provided. Please ask the staff any questions 
that you have before you indicate your selection. If you wish to withdraw your consent at 
a later time, you should contact your site staff. 
 


 
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Research Without Human Genetic Testing  
 
If you agree, some of your blood that is left over after all required study testing is done 
may be stored (with usual protection of your identity) and used for ACTG-approved HIV-
related research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my blood.  
OR 
____ (initials) I understand but I do not agree to this storage or possible use of my blood. 
 
Research with Human Genetic Testing 
 
The ACTG has two studies that collect samples and consent for genetic testing: 
 
• 
A5128, Plan for Obtaining Informed Consent to use Stored Human Biological 
Materials (HBM) for Currently Unspecified Analyses 
 
• 
A5243, Plan for Obtaining Human Biological Samples at Non-U.S. Clinical Research 
Sites for Currently Unspecified Genetic Analyses 
 
Your site might ask you if you would like to participate in the study that is being done 
where you live. If you would like to participate, you will sign a separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign a consent 
form for A5128 or A5243. 
 

SAP_001.pdf: 
ACTG A5372 
Drug-Drug Interactions Between Rifapentine and Dolutegravir in 
HIV/LTBI Co-Infected Individuals  
 
ClinicalTrials.gov Identifier:  NCT 04272242 
 
 
Primary Statistical Analysis Plan 
Version 1.0 
July 7, 2021 
 
 
 This is ACTG A5372 SAP Version 1.0 with names of authors, names of 
publication writing team members and analysis timeline redacted. Study 
objectives related to Arm 2 will be addressed if Arm 2 opens.


A5372 Statistical Analysis Plan v1.0 
 
 
 
 
 
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Table of Contents 
TABLE OF CONTENTS ............................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................... 3 
1.1 
Purpose ........................................................................................................................................ 3 
1.2 
Version History ............................................................................................................................ 3 
1.3 
Abbreviations ............................................................................................................................... 3 
2 
STUDY OVERVIEW ............................................................................................................................... 4 
2.1 
Overview of Study Design .......................................................................................................... 4 
2.2 
Hypothesis ................................................................................................................................... 5 
2.3 
Study Objectives ......................................................................................................................... 5 
2.3.1 
Primary Objectives ............................................................................................................. 5 
2.3.2 
Secondary Objectives ........................................................................................................ 5 
2.4 
Overview of Sample Size Considerations ................................................................................. 6 
2.5 
Overview of Interim Monitoring Reviews by the TB TSG Study Monitoring Committee 
(SMC): Reviews for Safety and Study Conduct ............................................................ 6 
2.6 
Interim Core Team Reviews ....................................................................................................... 7 
3 
OUTCOME MEASURES ........................................................................................................................ 7 
3.1 
Primary Outcome Measures ....................................................................................................... 7 
3.2 
Secondary Outcome Measures .................................................................................................. 7 
4 
STATISTICAL CONSIDERATIONS....................................................................................................... 8 
4.1 
Times Used in the Primary and Secondary Outcome Measure Definitions .......................... 8 
4.2 
Analysis Populations .................................................................................................................. 8 
4.2.1 
Primary PK Analysis Population ........................................................................................ 8 
4.2.2 
Secondary PK Analysis Population ................................................................................... 9 
4.2.3 
Safety Analysis Population ................................................................................................ 9 
4.3 
General Statistical Considerations ............................................................................................ 9 
4.4 
PK Parameter Calculations (Conducted by Study Chair and Study Pharmacologist) ......... 9 
4.5 
Interim Analysis of DTG PK Data to Determine Decision for Opening Arm 2 ....................... 9 
4.5.1 
Preliminary Interim Analysis (Conducted by Study Statisticians) .................................... 10 
4.5.2 
Model-based Interim Analysis (Conducted by Study Pharmacologist) ........................... 10 
4.6 
Analysis of the Primary Objective 1 (Conducted by Study Pharmacologist) ..................... 10 
4.7 
Analysis of Primary Objectives 2 and 3 (outcome measures listed in Section 3.1; 
conducted by Study Pharmacologist) ......................................................................... 11 
4.8 
Primary Estimands .................................................................................................................... 11 
4.8.1 
First Primary Estimand .................................................................................................... 11 
4.8.2 
Second and Third Primary Estimands ............................................................................. 11 


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4.9 
Analysis Addressing the Safety, Tolerability and Virologic Suppression Secondary 
Objectives (Conducted by Statisticians) ..................................................................... 13 
5 
REPORT COMPONENTS .................................................................................................................... 13 
5.1 
Flow Diagram ............................................................................................................................. 13 
5.2 
Accrual ....................................................................................................................................... 13 
5.3 
Baseline Characteristics ........................................................................................................... 13 
5.4 
Study Retention ......................................................................................................................... 13 
5.5 
Study Treatment ........................................................................................................................ 13 
5.6 
Pregnancies (If Any) .................................................................................................................. 14 
5.7 
Mortality (If Any) ........................................................................................................................ 14 
5.8 
Primary Analysis Results ......................................................................................................... 14 
5.9 
Secondary Analysis Results (Safety, Tolerability, Day 28 Viral Load) ................................ 14 
6 
CALCULATION OF GEOMETRIC MEAN RATIO AND ASSOCIATED CONFIDENCE INTERVAL . 15 
6.1 
Introduction ................................................................................................................................ 15 
6.2 
Geometric Mean (GM) and Associated CI ............................................................................... 15 
6.3 
Geometric Mean Ratio (GMR) and Associated CI .................................................................. 15 
6.4 
GMR, Within-subject Design .................................................................................................... 16 
6.5 
Rationale for Use of 90% Coverage for CIs Around the GMR............................................... 16 
7 
REFERENCES ..................................................................................................................................... 17 
 
 


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1 
Introduction 
1.1 Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary, secondary, and selected exploratory 
outcome measures of the A5372 study that will be included in the primary manuscript addressing the 
major primary and secondary objectives of the study, as well as the primary and secondary outcome 
measures for which results will be posted on ClinicalTrials.gov. The Primary SAP also outlines the 
general statistical approaches that will be used in the analysis of the study. 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 statistical analysis report. 
1.2 Version History 
Version 
Changes Made 
Rationale 
Effective Date 
1.0 
Original Version 
(For protocol version 2.0.  Note that the 
original SAP was still in draft form when 
participants began enrolling under 
protocol version 1.0; no final version of 
the SAP was filed that corresponds to 
protocol version 1.0.  Issue Tracking ID 
40443 [deviation].) 
N/A 
7/7/2021 
 
1.3 Abbreviations 
Abbreviation 
Full text 
1HP 
4-week (1 month) daily regimen of isoniazid and rifapentine 
ART 
Antiretroviral therapy 
ARV 
Antiretroviral (drug) 
AUC 
Area under the concentration-time curve 
BID 
Twice daily 
Cmax 
Maximum concentration observed over the dosing interval 
Cmin 
Minimum concentration observed over the dosing interval 
DTG 
Dolutegravir; may refer to antiretroviral drug administered as part of an ARV 
regimen, or to concentrations of the drug as measured in plasma by pharmacology 
assay 
H 
One-letter abbreviation for isoniazid, used in the one-letter-per-drug notation for TB 
regimens 
HIV-1 
Human immunodeficiency virus, type 1 (the predominate type world-wide) 
INH 
Isoniazid 
LTBI 
Latent TB infection 
NRTI 
Nucleoside reverse transcriptase inhibitor 
P 
One-letter abbreviation for rifapentine, used in the one-letter-per-drug notation for 
TB regimens 
PK 
Pharmacokinetic 


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PWH 
People with HIV 
QD 
Once daily 
RPT 
Rifapentine 
 
2 
Study overview 
2.1 Overview of Study Design 
A5372 is an open-label, non-randomized, two-arm, multicenter PK study to investigate the potential 
interactions between DTG and steady state RPT when RPT is prescribed with INH daily for 4 weeks 
(1HP) in HIV-1 and LTBI co-infected individuals.  
The study regimen will be as follows, days 1 through 28. 
Arm 1 
• 
DTG 50 mg orally BID (~12 hours apart) 
o 
1st dose:  DTG 50 mg each morning from non-study ARV supply 
o 
2nd dose:  DTG 50 mg each evening from study supply 
• 
1HP:  INH 300 mg + RPT 600 mg orally orally each morning for 4 weeks  
 
Arm 2 (upon opening; contingent on assessment of DTG PK data from participants in Arm 1)  
• 
DTG 50 mg orally each morning from non-study ARV supply 
• 
1HP:  INH 300 mg + RPT 600 mg orally each morning for 4 weeks 
 
All participants must also be on once-daily DTG-based ARV treatment with 2 NRTIs (excluding TAF) 
during the study. All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH 
based on the current local, national, or international dosing guidelines. 
Initially, the study will open with Arm 1. Once DTG concentrations data from the first 32 evaluable 
participants in Arm 1 are available, the core team will review the DTG PK data to ensure sufficient plasma 
exposures of DTG (Ctau) are achieved with twice-daily DTG dosing. This review will consist summarizing 
data completeness, participant evaluability for PK, and observed minimum concentrations.  Provided:  (1) 
there are 32 evaluable participants with minimum concentrations, (2) these minimum concentrations are 
above 158 ng/mL, and (3) there are no worrisome outliers among these minimum concentrations, the PK 
data will be used to model the anticipated PK of QD DTG when coadministered with 1HP. Based on these 
models and simulations of QD DTG dosing with 1HP, a decision will be made on whether to open Arm 2 
for enrollment. Details on the criteria for opening Arm 2 are given in the protocol (Section 7.4) and herein 
(Section 4.5). 
Plasma PK profiles for DTG will be determined at two time points. At the first time point, plasma samples 
will be drawn in participants at steady state with respect to DTG when receiving once daily DTG prior to 
1HP. At the second time point, DTG will be given BID in Arm 1 and QD in Arm 2 during the 1HP LTBI 
regimen; PK sampling for DTG will occur on day 28 of the 1HP regimen.  


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In the final statistical analysis, inference will be based on geometric mean ratios for DTG PK parameters 
(with/without co-administered 1HP) where each participant serves as their own control (ie, within-subjects 
design). 
In addition, sparse PK sampling will be performed on days 3, 14, and 21 of the 1HP regimen.  
Leftover plasma from the DTG analysis will be used to determine RPT concentrations achieved from 1HP 
dosing to support exploratory study objectives.   
A participant is considered evaluable (for PK) if they (a) have completed 28 daily doses RPT/INH within the 
6-week study period, (b) have completed intensive PK sampling at both the day 0 and day 28 visits.  
Furthermore, each visit must have been conducted after 3 consecutive days of dosing, with at least 6 
plasma samples collected and (for Arm 1) with both the 23- and 24-hour samples collected.   
All participants must receive pyridoxine (vitamin B6) 25 or 50 mg with each dose of INH based on the 
current local, national, or international dosing guidelines. 
Participants enrolling to A5372 will not be randomized.  Enrollment will not be stratified. 
2.2 Hypothesis 
Dolutegravir (DTG) concentrations, when given twice daily (BID) or once daily (QD) with coadministration 
of 4 weeks daily rifapentine (RPT) (600 mg) and isoniazid (INH) (300 mg) [1HP], will maintain steady-
state plasma trough DTG concentrations above 158 ng/mL in 95% of study participants.  The value 158 
ng/mL is the 5th percentile steady-state trough concentrations of DTG which has been demonstrated to be 
sufficient in maintaining virologic suppression. 
2.3 Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study protocol. 
The remaining study objectives in the protocol will be addressed in subsequent analysis plans.  
2.3.1 
Primary Objectives 
1. To determine the dosing for DTG that, when given together with 1HP, achieves target 
exposures (Ctrough) of standard-dose DTG when it is given without RPT [Objective 1.2.1; this 
objective will be addressed by the study pharmacologists]. 
2. To estimate the steady-state plasma pharmacokinetic (PK) parameters of DTG when DTG 
50mg is dosed twice daily (BID) with 1HP [Objective 1.2.2]. 
3. If Arm 2 opens, to estimate the steady-state plasma PK parameters of DTG when DTG 50 
mg is dosed once daily (QD) with 1HP [Objective 1.2.3]. 
2.3.2 
Secondary Objectives 
1. To evaluate the safety of coadministration of DTG-based ART with 1HP [Objective 1.3.1]. 
2. To evaluate the tolerability of coadministration DTG-based ART with 1HP [Objective 1.3.2]. 


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3. To estimate the proportion of participants who maintain virologic suppression when DTG-
based ART is coadministered with 1HP [Objective 1.3.3]. 
2.4 Overview of Sample Size Considerations 
Sample size estimates are based on the desired precision model-based estimates of DTG PK parameters 
in the presence and absence of 1HP. These models, once validated, will further be used to determine 
recommended DTG dosing algorithms for the treatment of patients living with HIV and co-infected with 
LTBI, pending appropriate safety assessment. 
The sample size determination was done by evaluating different study designs (varying the numbers of 
participants and time points, assuming the design where each participant is its own control) using clinical 
trial simulations. See protocol version 1.0, Section 10.4 for details of clinical trial simulations. 
The effect of RPT on DTG PK parameters (bioavailability) was assumed to be a decrease of 30%-50%. 
Inter-participant variability in PK parameters (CL and F) was assumed to be 25-40%. The time course of 
RPT induction was considered.  
Under these assumptions, data from ≥32 participants in Arm 1 will provide >80% power to detect the 
hypothesized drug-drug interaction effect on bioavailability, and to unbiasedly (relative bias <5%) and 
precisely (RSE<25%) estimate PK parameters and inter-participant variability.  
These estimated unbiased parameters will be then used for simulations of Arm 2 and derivation of the 
median 5th percentile of DTG troughs by simulations. The probability of opening Arm 2 will be dependent 
on magnitude of both the decrease in bioavailability due to drug-drug interactions and the between-
participant variability. Precise estimate of drug-drug interaction coupled with acceptable between-
participant variability will provide 90% chance of making a correct decision if Arm 2 opens.  
The proposed design requires at least 32 evaluable participants, each of whom has intensive PK 
sampling conducted at both visits, conducted after 3 consecutive days of dosing recorded in participant 
diaries, the third of which is observed being taken in the clinical research site, with at least 6 plasma 
sample collections (per visit) which must include the 23- and 24-hr samples.  Such data is expected to 
provide estimated pharmacokinetic parameters with required the precision, defined as relative standard 
errors <10% for typical values, and RSE <25% for random effects (between subject variability).  
To protect against data loss after closure to accrual (e.g., lost specimens, assay problems), the study will 
enroll 36 participants in each arm. This is an increase of ~12% over the required sample size of 32 
evaluable participants. 
2.5 Overview of Interim Monitoring Reviews by the TB TSG Study Monitoring Committee (SMC): 
Reviews for Safety and Study Conduct 
The SMC will provide independent oversight to safeguard the well-being of study participants and to 
ensure study integrity. Interim analyses of study progress and conduct as well as participant safety will be 


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reviewed by the SMC approximately every 6 months. The first interim review will occur no more than 6 
months after the enrollment of the first study participant.  (If accrual is rapid enough that only a short 
period of time – 1 month, say – would elapse between analyses for the SMC review and for the interim 
PK analysis for Arm 1 participants, the SMC review will not be conducted.)  For all reviews, detailed 
information on safety (including treatment tolerability and mortality), and administrative aspects (including 
accrual, retention, compliance with study requirements) will be provided by study statisticians.  The 
A5372 Study Progress, Data, and Safety Monitoring Plan (SPDSMP) provides details of the contents of 
reports to the SMC. 
In the event that 3 or more participants experience Grade 3 or higher AEs deemed to be definitely, 
probably, or possibly related to DTG, RPT and/or INH, the study will be halted until an SMC review takes 
place.  (“Related to” values will be assigned by the core team on regular calls or emails.) 
An additional SMC review may also be convened if a concern is identified by the DAIDS clinical 
representative, study chairs, or study statisticians in consultation with the team. 
To determine whether Arm 2 (QD dosing) will open to accrual, an interim analysis will be conducted by 
the study pharmacologist (see Section 4.5 herein).  When this analysis has been completed, the team will 
inform the SMC of results and of the team’s decision. 
2.6 Interim Core Team Reviews 
The core team will meet regularly to review safety data.  Details can be found in the A5372 SPDSMP. 
In addition, when DTG PK data from the first 32 evaluable participants in Arm 1 are available, an interim 
analysis of Arm 1 DTG PK data will be conducted by protocol pharmacologist and reviewed by the core 
team. The main purpose of this review is to determine whether Arm 2 should open, or the study should 
proceed with Arm 1 only. This analysis is described in Section 4.5 herein. 
There will not be a formal SMC review to evaluate the interim DTG PK data; however, the SMC will be 
notified of the decision as soon as the PK interim review by the core team is completed. 
3 
Outcome measures 
3.1 Primary Outcome Measures 
The primary outcome measures are participant-specific estimates of the day 0 and day 28 plasma DTG 
PK parameters Cmax, Cmin, and area under the concentration-time curve over 24 hours (AUC0-24h) while on 
the Arm 1 regimen and, if Arm 2 opens, the Arm 2 regimen.  [Outcome Measure 10.2.1.1]. 
3.2 Secondary Outcome Measures 
The secondary outcome measures for addressing the study’s secondary objectives are listed in protocol 
Section 10.2.2 as: 


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1. Proportion of participants exhibiting each of the following events during administration of DTG 
with 1HP, by arm [Outcome Measure 10.2.2.1] 
a. Grade 3 adverse event(s) (AE(s)) 
b. Grade 4 AE(s) 
c. Grade 3 or 4 AE(s) 
d. AEs of grade 2 or higher 
e. AEs that led to a change in study treatment regardless of grade 
f. 
AEs meeting the serious adverse events (SAE) definition or EAE reporting requirements. 
2. Proportion of participants who discontinue study or study drugs during DTG and 1HP dosing, 
by arm [Outcome Measure 10.2.2.2].  This includes discontinuation of DTG, RPT, INH, and 
NRTIs. 
3. Proportion of participants with HIV-1 RNA levels >50 copies/mL at day 28 (-2/+14 days) 
and/or at the Follow Up visit [Outcome Measure 10.2.2.3]. 
4 
Statistical considerations 
4.1 Times Used in the Primary and Secondary Outcome Measure Definitions  
Day 0: The day of study enrollment and the first intensive PK sampling is conducted. At this point, 
participants have not taken any study provided medications. 
Day 1: Start of study provided medications. 
Day 3 (+2 days): First visit on study treatment. The first sparse PK sampling is conducted. 
Day 14 (±2 days): Second visit on study treatment. The second sparse PK sampling is conducted. 
Day 21 (±2 days): Third visit on study treatment. The third sparse PK sampling is conducted. 
Day 28 (-2/+14 days): Last visit onstudy treatment. The second intensive PK sampling is conducted. 
4.2 Analysis Populations 
We define three analysis populations used for estimation of the estimands described in Section 4.8.  
4.2.1 
Primary PK Analysis Population 
Primary PK Analysis Population (separately defined for Arm 1 and Arm 2 participants):  The primary PK 
analysis population consists of those participants who:  (1) met all study entry criteria, (2) initiated the 
1HP TB regimen and completed 28 daily doses RPT/INH within the 6-week study period, and (3) took 
DTG twice-daily (Arm 1) or once-daily (Arm 2) for days 1-28 (that is, for the participant, both PK profiles 
are available (before initiating 1HP and while taking 1HP).   


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4.2.2 
Secondary PK Analysis Population 
Secondary PK Analysis Population (separately defined for Arm 1 and Arm 2 participants):  The secondary 
PK analysis population consists of those participants who met all study entry criteria and for whom at 
least one DTG concentration is available where the dates, times and dose amounts of DTG doses in the 
three days leading up to the intensive PK sampling visit. Concentrations from all participants, not just 
evaluable participants, will be used (limited to those concentration for which the dates, times and dose 
amounts of DTG in the days leading up to the PK visit are available). 
4.2.3 
Safety Analysis Population 
Safety Analysis Population: The Safety Analysis Population consist of all participants who have taken at 
least one dose of RPT, at least one dose of INH, and at least 2 doses of DTG (Arm 1) or at least 1 dose 
of DTG (Arm 2). 
4.3 General Statistical Considerations 
Confidence intervals (CIs) around geometric mean ratios will have 90% coverage probability; all other CIs 
will have 95% coverage.  Hypothesis tests will have test size of 5%.  No adjustments will be made for 
multiple comparisons.  The justification for no such adjustment is as follows.  Rationale for multiple 
comparisons generally emphasizes control of a family-wise error rate when there is a global null 
hypothesis.  For example, in a multiple-arm clinical trial comparing different drugs to a placebo, a global 
null hypothesis would be of the form “at least one of the active arms performs better than the placebo” 
(Parker and Weir, 2020).  The emphasis in A5372 is on estimation (CIs) not hypothesis testing (p-values).  
Furthermore, within an arm, PK micro parameters are jointly estimated through modeling, and descriptive 
summaries of PK parameters are not independent (participants with low Cmin values are expected to have 
a low AUC values).  Therefore it would be incorrect to adjust as if these are independent estimands.  The 
same rationale holds across arms:  the null hypothesis is not that at least one of the two doses is effective 
but to estimate PK parameters based on all available data. 
4.4 PK Parameter Calculations (Conducted by Study Chair and Study Pharmacologist) 
In separate final analyses for Arms 1 and 2, DTG plasma PK parameters (primary outcomes) will be 
determined for evaluable participants (the primary analysis population) using nonlinear mixed-effects 
population PK modeling.  Participant-specific Cmin values will be estimated both from the model and as the 
observed minimum plasma concentration. 
4.5 Interim Analysis of DTG PK Data to Determine Decision for Opening Arm 2 
Prior to opening Arm 2, when DTG drug concentrations are available for at least 32 evaluable participants 
from Arm 1, an interim analysis of DTG PK data will be conducted by the pharmacologist.  Results will be 
reviewed by the core team.  Arm 2 will open to enrollment if simulations based on Arm 1 PK data support 
the hypothesis that 50 mg DTG dosed QD in combination with 1HP will result in DTG trough 
concentrations that mimic reported plasma concentrations following a 10 mg DTG QD dose without RPT.   


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There will not be a formal SMC review to evaluate the interim DTG PK data; however, the SMC will be 
notified of the decision as soon as the PK interim review by the core team is completed.  
Background.  In the SPRING-1 study, a 10 mg daily dose of DTG was associated with virologic 
suppression [18] and, as such, the DTG PK parameters achieved for this dose in SPRING-1 are 
considered adequate targets.  The 5th, 50th, and 95th percentiles for this dose were 158, 316, and 555 
ng/mL, respectively.  
4.5.1 
Preliminary Interim Analysis (Conducted by Study Statisticians) 
Initially, when DTG concentrations from the first 32 evaluable participants (ie, participants in the primary 
PK analysis population) in Arm 1 are available, the core team will review the DTG PK data to ensure 
sufficient plasma exposures of DTG (Ctau) are achieved with twice-daily DTG dosing.  This review will 
consist of summaries of data completeness, participant evaluability for PK, and observed minimum 
concentrations.  If: (1) there are at least 32 evaluable participants with minimum concentrations, (2) no 
more than 5% of these participants exhibit minimum DTG concentrations above 158 ng/mL, and (3) there 
are no worrisome outliers among these minimum concentrations, the PK data will be used to model the 
anticipated PK of QD DTG when coadministered with 1HP, as described in Section 4.5.2.  Based on 
model simulations of QD DTG dosing with 1HP, a decision will be made on whether to open Arm 2 for 
enrollment. Details on the criteria for opening Arm 2 are given in the protocol (Section 7.4) and above 
(beginning of Section 4.5). 
4.5.2 
Model-based Interim Analysis (Conducted by Study Pharmacologist) 
Criterion for opening Arm 2.  In addition to the three criteria above, when DTG concentrations from at 
least 32 evaluable participants (ie, participants in the primary PK analysis population) in Arm 1 are 
available, a model-based evaluation of DTG PK in these BID participants will occur.  The study 
pharmacologist will develop a nonlinear mixed-effects population pharmacokinetic model, based on 
available concentrations from all Arm 1 participants (ie, participants in the secondary PK analysis 
population).  From the developed and evaluated model, concentrations for 100 hypothetical participants 
will be simulated for Arm 2/QD dosing of DTG 1000 times.  The parameter of primary interest is C24, the 
expected DTG concentration at the end of the 24h dosing interval at steady state.  For each simulated 
trial, the 5th, 50th, and 95th percentile of DTG trough concentrations, C24, will be determined.    
Of the 1000 simulated trials, the median value of the 5th percentile of DTG C24 will be compared to 158 
ng/mL, which is the 5th percentile of DTG C24 observed for the 10 mg daily DTG dose in SPRING-1. If the 
median C24 value among simulated 5th percentiles is at or above 158 ng/mL, A5372 Arm 2 will open for 
enrollment, for evaluation of DTG 50 mg QD dosing with 1HP.  
4.6 Analysis of the Primary Objective 1 (Conducted by Study Pharmacologist) 
In order to determine the dosing for DTG that, when given together with 1HP, achieves target exposures 
(C24) of standard-dose DTG when it is given without RPT, the distribution of simulated DTG C24 values 
(based on concentrations from Arm 1 and develop population pharmacokinetic model) will be compared 


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with the historical data from SPRING Study (e.g., Ctau in the DTG 10 mg dosing arm) to examine whether 
dosing of DTG 50 mg BID will maintain above the trough concertation necessary for virologic 
suppression.  
The same analysis will be conducted for Arm 2 if it opens. For this objective, a separate population PK 
analysis will be conducted (as described in Section 4.5.2). 
There is no specific outcome measure associated with this analysis.  The “outcome” is the 
characterization (through modeling) of the relationship between dosing (amounts, frequencies) and CIs 
around predicted Cmin values; this analysis will be performed by the study pharmacologist.  
4.7 Analysis of Primary Objectives 2 and 3 (outcome measures listed in Section 3.1; conducted 
by Study Pharmacologist) 
For all PK parameters, the following descriptive statistics will be reported by arm and visit:  mean, 
standard deviation, coefficient of variation, median, 5th and 95th percentiles, minimum, and maximum, as 
well as mean and standard deviation on the natural log (base e) scale.  This analysis is conducted using 
the primary PK analysis population.  To assess the overall effect of 1HP on DTG PK parameters, 
geometric mean ratios (GMRs) and associated 90% CIs will be calculated by arm.  The ratio is with (after 
initiation of 1HP; numerator) vs without (before initiation of 1HP; denominator) co-administered 1HP.  The 
DTG PK parameters are Cmin, Cmax, and total daily exposure as measured by AUC0-24h.  (For Arm 1, day 
28 (BID dosing), participant-specific AUC0-24h will be estimated by combining (summing) areas for the two 
BID dosing intervals. For Arm 1 day 0, and for Arm 2 days 0 and 28 (QD dosing), participant-specific 
AUC0-24h values will be estimated from concentrations collected over the single 24-hour dosing interval.) 
4.8 Primary Estimands 
The CBAR requirement of defining estimands was enacted after the protocol had been finalized.  As a 
“grandfather clause” compromise, we are only defining estimands for primary objectives with analyses 
lead by statisticians.   
4.8.1 
First Primary Estimand 
This objective will be addressed by the pharmacologist; the corresponding estimand is not defined in this 
analysis plan. 
4.8.2 
Second and Third Primary Estimands 
Objectives 2 and 3 will use the same estimand. The principal stratum strategy is applied for the handling 
of intercurrent events in the primary analysis of this estimand. This strategy aligns with the definition of 
participant evaluability as specified in the protocol, and also agrees with the European Medicines Agency 
bioequivalence guideline, as interpreted in Ring and Wolfsegger (2020).  (Bioequivalence is a way to 
assess drug-drug interactions.)  The primary inference approach is estimation of geometric mean ratios, 
and associated 90% CIs, based on within-subject pairs of PK parameters, where the numerator condition 
is BID DTG dosed with 1HP, and the denominator condition is QD DTG without TB agents.  


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Primary Objective 2:  To estimate the steady state plasma pharmacokinetics (PK) of DTG 
when DTG 50 mg is dosed twice daily (BID) with 1HP. 
 
Primary Objective 3 (Addressed only if Arm 2 opens):  To estimate the steady state plasma PK 
parameters of DTG when DTG 50 mg is dosed once daily (QD) with 1HP. 
Estimand 
description 
Geometric mean ratio of steady state Cmax, Cmin, and AUC0-24h of DTG taken as prescribed 
before and after completing the TB regimen 1HP in PWH with LTBI 
Treatment 
Arm 1 
• 
DTG 50 mg orally BID (~12 hours apart) 
o 
1st dose:  DTG 50 mg each morning from non-study ARV supply 
o 
2nd dose:  DTG 50 mg each evening from study supply 
• 
1HP:  INH 300 mg + RPT 600 mg orally each morning for 4 weeks  
Arm 2 (upon opening; contingent on assessment of DTG PK data from participants in Arm 1)  
• 
DTG 50 mg orally each morning from non-study ARV supply 
• 
1HP:  INH 300 mg + RPT 600 mg orally each morning for 4 weeks 
Target population   
Analysis set  
PWH with LTBI taking DTG as prescribed and completing 
28 doses of 1HP within 6 weeks 
The primary PK analysis population (defined above 
in Section 4.2.1).  
 
Variables 
Outcome measure(s)  
Steady-state (after 28 days) plasma DTG PK parameters:  
• Cmax,  
• Cmin,  
• Area under the concentration-time curve (AUC0-24). 
Participant-specific estimates of the day 0 and day 
28 steady-state plasma DTG PK parameters Cmax, 
Cmin, and area under the concentration-time curve 
(AUC0-24h). 
Handling of intercurrent events  
Handling of missing data 
IE: Failure to take DTG as prescribed (1) for 3 days prior to 
starting 1HP (Principal Stratum strategy) 
 
IE: Failure to take DTG (1) and 1HP (2)  as prescribed 
prior to steady state (Principal Stratum strategy) 
 
(1) 6 BID 50 mg doses (Arm 1) or 3 QD 50 mg doses 
(Arm 2)   
(2) 3 QD doses of 300 INH mg and 3 doses of 600 mg 
QD doses of RPT 
 
For both intercurrent events the Principal Stratum is 
defined as having taken DTG and 1HP treatment as 
prescribed  
Missing data may occur because of: 
• 
Failure to appear at study visit (Day 0 or Day 
28) 
• 
Incomplete sampling (≥6 timepoints including 
both 23- and 24-hour samples) 
• 
Incomplete/unevaluable concentrations when 
sampled (≥6 timepoints including both 23- and 
24-hour samples) 
 
Missing samples and PK concentrations for 
participants otherwise meeting the dosing criteria will 
be assumed missing completely at random and 
participants excluded from the analysis. 
Population-level summary measure 
Analysis approach 
Geometric mean ratio of DTG Cmax, Cmin, and AUC0-24h 
with (after initiating 1HP; numerator) and without (prior to 
initiating 1HP; denominator) 1HP  
Geometric mean ratio with associated 90% CIs.  
See Section 8 for details. 
 
Sensitivity Analyses 
No sensitivity analyses are planned. 
Supplementary analyses 
No supplementary analyses are planned. 


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4.9 Analysis Addressing the Safety, Tolerability and Virologic Suppression Secondary Objectives 
(Conducted by Statisticians) 
For the Safety Analysis Population (see Section 4.2.3), proportions of the events listed in Section 3.2 will 
be reported by arm:  (a) the proportion of participants with Grade 3 or 4 AE during administration of DTG 
with 1HP; (b) the proportion of participants who discontinue study or study drugs during administration of 
DTG with 1HP; and (c) the proportion of participants with HIV-1 RNA levels >50 copies/mL at the second 
intensive PK measure and/or at the Follow Up visit.  Proportions will be reported along with 95% exact 
Clopper-Pearson CIs around the proportions.    
5 
Report components 
5.1 Flow Diagram 
• 
The flow diagram will include, but not be limited to, the following: 
o 
Number of screened patients 
o 
Summary of reasons not enrolled  
o 
Number of enrolled participants by arm 
o 
Summary of off-treatment and off-study reasons 
o 
Number of participants in primary and secondary analysis populations. 
5.2 Accrual 
• 
Summary of participants enrolled by month (and arm).  
• 
Summary of participants enrolled by site (and arm).  
5.3 Baseline Characteristics 
The following characteristics (day 0) will be summarized by arm  
• 
Summary of age, sex, race, and ethnicity. 
• 
Summary of body weight and body mass index (BMI). 
• 
Summary of plasma HIV-1 RNA (number below lower limit of quantification and, for participants 
with detectable viral load, statistical summary of log10 copies); ARV regimen.  
5.4 Study Retention 
• 
Summary of off-study reasons. 
5.5 Study Treatment 
• 
Summary of reasons for not starting study treatment. 
• 
Summary of days from study entry to first dose of study drug. 
• 
Summary of days from study entry to permanent discontinuation of study drug. 
• 
Summary of the reasons for permanently discontinuing study drug, sorted so discontinuations 
due to treatment-related AEs are together. 


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5.6 Pregnancies (If Any) 
• 
Summary of women who become pregnant while on study, including weeks from study entry, 
pregnancy outcome if known, and maternal AE if any.  (Safety analysis population.) 
5.7 Mortality (If Any) 
• 
Summary of the number of deaths and the primary and contributing causes of death, with weeks 
from study entry.  (Safety analysis population.) 
5.8 Primary Analysis Results 
• 
Descriptive summary of DTG PK parameters (Cmax, AUC0-24h, and Cmin) at each of the two PK 
intensive time points, by arm.  (Primary analysis population.) 
• 
Geometric mean ratios of DTG PK parameters (Cmax, AUC0-24h, Cmin), day 28 relative to day 0, 
and associated 90% CIs, by arm. (Primary analysis population.) 
5.9 Secondary Analysis Results (Safety, Tolerability, Day 28 Viral Load) 
• 
Summary of all new, post-entry reportable AEs by MedDRA high-level term and grade occurring 
during administration of DTG with 1HP, by arm. (Safety analysis population) 
• 
Summary of SAEs by MedDRA code, by arm. (Safety analysis population) 
• 
Discontinuation of study drugs during DTG and 1HP dosing, by arm (study drugs to include RPT, 
INH, DTG and NRTIs). (Safety analysis population) 
• 
Discontinuation of study during DTG and 1HP dosing, by arm. (Safety analysis population) 
• 
HIV-1 RNA levels >50 copies/mL at Day 28 (-2/+14 days) and/or at the Follow Up visit. (Safety 
analysis population) 
• 
Analyses done for the Safety Analysis Population.  Proportion of participants exhibiting each 
event is reported, along with the associated exact, 95% Clopper-Pearson binomial confidence 
intervals (CIs).  For the AEs, each participant is counted only once, in the highest grade observed 
for the participant. 
 
 


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6 
Calculation of geometric mean ratio and associated confidence interval 
6.1 
Introduction 
A log-normal distribution is often used for analyzing positive, right-skewed data, including AUCs and other 
concentrations-based pharmacokinetic parameters (Cτ, C0, Cmax) (Van Belle, 2002). For a variable X that 
is assumed to be log-normally distributed, we write 𝑋𝑋 ~ LN(𝜇𝜇, 𝜎𝜎); here, 𝜇𝜇 and 𝜎𝜎 are considered location 
and scale parameters, but do not denote expected value or variance.  For log-normally distributed 𝑋𝑋, if a 
new variable 𝑌𝑌 is defined as the natural (base e) log of 𝑋𝑋, written  𝑌𝑌 = ln(𝑋𝑋), then 𝑌𝑌 is normally distributed 
–  written 𝑌𝑌 ~ N(𝜇𝜇, 𝜎𝜎2) – with mean (expected value) 𝜇𝜇 and variance 𝜎𝜎2. 
In order to exploit theorems that apply to normally distributed data (eg, sums and differences of normally 
distributed random variables are also normally distributed), analyses of PK parameters are often 
conducted on the log scale.  For example, one might calculate and report the sample mean 𝑌𝑌ത and sample 
standard deviation 𝑠𝑠 on the log scale, and use the standard formula: 
(𝑌𝑌ത  ±  𝑡𝑡1−𝛼𝛼
2, 𝑛𝑛−1 
𝑠𝑠
√𝑛𝑛)    [1] 
to estimate 100*(1 - α)% CI around the log-scale PK parameter.  The question then arises of how to 
convert findings back to the original scale, the scale with which pharmacologists and others are most 
familiar. 
In what follows, we define the sample mean and variance for the normally distributed, log-transformed PK 
parameter 𝑌𝑌: 
𝑌𝑌ത= Σ𝑖𝑖=1
𝑛𝑛 
𝑌𝑌𝑖𝑖
𝑛𝑛    [2] 
𝑠𝑠2 = Σ𝑖𝑖=1 
𝑛𝑛
(𝑌𝑌𝑖𝑖 −𝑌𝑌ത)2
𝑛𝑛−1     [3] 
 
6.2 
Geometric Mean (GM) and Associated CI 
An approach to calculating a CI around the GM would be to exponentiate (take the antilogarithm of) the 
mean 𝑌𝑌ത and the CI endpoints (Equation [1]).  This approach is standard in the literature, and it is the 
approach taken here.   
6.3 
Geometric Mean Ratio (GMR) and Associated CI 
In assessing drug-drug interactions, pharmacologists and clinicians often characterize the effect of co-
administered drug(s) (inhibitor or inducer; “perpetrator”) on the PK parameter of another, target, drug 
(substrate; “victim”) as the ratio of a PK parameter when measured under 2 different conditions.  
Generally, the numerator of the ratio represents PK parameter of the target drug when taken with the co-
administered drug(s), and the denominator represents the target drug PK parameter when the target drug 


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is taken alone.  Estimates near 100% indicate co-administered drug has no effect; estimates significantly 
below 100% indicate that the co-administered drug up-regulates the metabolism of target drug thereby 
decreasing systemic exposure to the target drug; and estimates significantly above 100% indicate that the 
co-administered drug down-regulates the metabolism of target drug thereby increasing exposure. 
The geometric mean ratio (GMR) is used to estimate the effects of the interacting drug, with the 
corresponding CI providing inference.  To estimate the ratio on the original scale, the sample mean and 
standard deviation on the log scale are used, along with the logarithmic identity log ቀ
B
Aቁ= log(B) −log (A) 
[4]. 
6.4 
GMR, Within-subject Design  
In the within-subjects design, PK parameters are estimated for an individual participant under both 
conditions of interest.  For the individual participant i, PK parameter differences on the log scale Yi are 
calculated:  Yi = log൫Xi
B൯− log (Xi
A), where Xi
B and Xi
A are untransformed PK parameters for participant i 
for conditions B and A, respectively.  The sample mean and sample standard deviation of the Yi are 
calculated.  With 𝑌𝑌ത and 𝑠𝑠 defined as the sample mean and sample standard deviation of the within-
participant differences on the log scale (Equations [2] and [3]), the GMR is estimated by exponentiating 
[2] and the corresponding CI is given by exponentiating the endpoints of [1]. 
6.5 
Rationale for Use of 90% Coverage for CIs Around the GMR 
Schuirmann (1987) presents the “two one-sided tests” procedure to assessing average pharmacokinetic 
bioequivalence as follows: 
H0:   𝜇𝜇𝑇𝑇− 𝜇𝜇𝑅𝑅≤𝜃𝜃1 or 𝜇𝜇𝑇𝑇− 𝜇𝜇𝑅𝑅≥𝜃𝜃2 
H1:  𝜃𝜃1 < 𝜇𝜇𝑇𝑇− 𝜇𝜇𝑟𝑟< 𝜃𝜃2 
(subscripts T and R denote “test” and “reference” conditions).  The null hypothesis, H0, states that 𝜇𝜇𝑇𝑇 and 
𝜇𝜇𝑅𝑅 are not equivalent.  The alternative hypothesis, H1 states that they are equivalent.  If, on the basis of 
the study data, we reject H0, then we may conclude that H1 is true, ie, that 𝜇𝜇𝑇𝑇 and 𝜇𝜇𝑅𝑅 are equivalent.  (If 
we do not reject H0, we do not conclude that H1 is true.  Rather, we say that it has not been shown that H1 
is true.  Further studies of the two conditions could conceivably establish that 𝜇𝜇𝑇𝑇 and 𝜇𝜇𝑅𝑅 are equivalent, 
even though the study in hand does not.)  The statistical hypotheses H0 and H1 given above are referred 
to as the "interval hypotheses."  The interval [𝜃𝜃1. 𝜃𝜃2] may be called the “equivalence interval.”  The limits 
𝜃𝜃1.and 𝜃𝜃2 (𝜃𝜃1.<  𝜃𝜃2) may be stated as known numbers, expressed in the same units as the bioavailability 
variable of interest, or 𝜃𝜃1.and 𝜃𝜃2 may be defined as proportions of the unknown reference 𝜇𝜇𝑅𝑅.   
The “two one-sided tests” procedure with test size α for each subtest is operationally identical to the 
procedure of declaring equivalence if and only if the ordinary (1-2α)% CIs for 𝜇𝜇𝑇𝑇− 𝜇𝜇𝑅𝑅 is completely 
contained in the equivalence interval [𝜃𝜃1. 𝜃𝜃2]. For this reason, it is sometimes referred to as the CIs 
approach. 


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7 
References 
Parker RA and Weir CJ.  Non-adjustment for multiple testing in multi-arm trials of distinct treatments:  
Rationale and Justification.  Clinical Trails 2020:17(5): 562-566.  DOI: 10:1177-1740774520941419. 
Ring A and Wolfsegger MJ.  The potential of the estimands framework for clinical pharmacology trials:  
Some discussion points.  Br J Clin Pharmacol 2020;86:1240-1247.  DOI: 10.1111/bcp.14233. 
Schuirmann,DJ. A comparison of the two one-sided tests procedure and the power approach for 
assessing the equivalence of average bioavailability.  Journal of Pharmacokinetics and 
Biopharmaceutics, 1987; 15: 657. doi:10.1007/BF01068419). 
Van Belle G.  Statistical Rules of Thumb.  Wiley, 2002.