Conditions: HIV Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 147
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine if people with HIV and obesity taking an antiretroviral treatment regimen containing an integrase strand transfer inhibitor (INSTI) with (tenofovir alafenamide/emtricitabine (TAF/FTC) would either slow their rate of weight gain, or even lose weight, over the span of about 1 year after a switch to a regimen containing doravirine (DOR; a newer, non-nucleoside reverse transcriptase inhibitor medication) combined with either TAF/TFC or tenofovir disoproxil fumarate (TDF)/FTC.

Detailed description:
The study evaluated whether a switch from an INSTI to a DOR-based regimen would result in less weight gain or weight loss at 48 weeks among obese individuals with HIV and a suppressed viral load. The study also evaluated whether an additional switch from TAF/FTC to TDF/FTC, both in combination with DOR, had an effect on weight over 48 weeks. Participants enrolled in A5391 were taking INSTI-class medications, including bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL), all in combination with TAF/FTC. Additionally, the study examined whether a change in the HIV treatment regimen affects other health indicators, including waist circumference, metabolic and cardiovascular disease markers, body composition (fat and lean mass), bone density, and maintenance of virologic suppression. Finally, the study looked at the safety and tolerability of DOR with either TAF/FTC or TDF/FTC.

As originally designed, the trial's target population included individuals with an unintentional \>10% weight gain in the 1-3 years after initiating or switching to an INSTI-based treatment regimen. Due to not meeting accrual targets during the first year of enrollment (July 2021 - July 2022), the trial protocol was updated to amend the target population (and associated eligibility criteria) to individuals with obesity (a screening body mass index \[BMI\] of ≥30 kg/m2) irrespective of weight history on INSTI-based ART. This update was implemented on November 17, 2022, at which time 64 participants had enrolled under the original trial design. The remaining participants enrolled using the revised eligibility criterion.

At a planned interim analysis in 2023, the method of blinded sample size re-estimation was used to assess if the trial's primary objective could be met with a sample size smaller than originally planned (n=222). Based on the pooled (e.g. over all arms) standard deviation of the primary outcome (weight change at 48 weeks), 150 participants would provide over 80% statistical power to detect the originally hypothesized 5% points change in weight between arms, assuming that this interim estimate was representative of the true variability about the primary outcome. As a result, the accrual goal was adjusted accordingly. The trial closed to enrollment in October 2024, having reached 147 participants.

Arms:
arm 1: By mouth daily with or without food arm 2: By mouth daily with or without food arm 3: By mouth daily with or without food

Interventions: intervention 1: Doravirine 100 Mg intervention 2: Integrase strand transfer inhibitors intervention 3: Tenofovir alafenamide/emtricitabine intervention 4: tenofovir disproxil fumarate/emtricitabine
Intervention descriptions: intervention 1: Participants received a 100 mg tablet by mouth daily with or without food. intervention 2: INSTIs were acquired through the standard of care locally. intervention 3: NRTIs (TAF/FTC) were acquired through the standard of care locally. intervention 4: NRTIs (TDF/FTC) were acquired through the standard of care locally.

Protocol document:
Prot_ICF_000.pdf: 
 
 
 
A5391 
 
 
Doravirine for Obese Persons on Integrase Inhibitors and 
Tenofovir Alafenamide (The Do IT Study) 
 
A Multicenter Trial of Advancing Clinical Therapeutics 
Globally (ACTG) 
 
 
 
NIAID CRMS # 38678 
 
 
 
 
This file contains the current ACTG A5391 protocol, which 
includes the following document:  
 
• Clarification Memo #1, dated 09 Feb 2023 
• Protocol Version 2.0, dated 19 Aug 2022 
 
 


Clarification Memo #1 
          Page 1 of 2 
09 Feb 2023 
ACTG A5391 Protocol Version 2.0 
Clarification Memo #1 for: 
A5391 
Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide 
(The Do IT Study) 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
NIAID CRMS # 38678 
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 
CLARIFICATION MEMO 
DATE: 
February 9, 2023 
TO: 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
FROM: 
A5391 Protocol Team  
SUBJECT: 
Clarification Memo #1 for Protocol A5391, Version 2.0 
This clarification memo (CM) does not result in a change in the protocol informed 
consent document. The Division of AIDS does not require you to forward it to your 
institutional review board (IRB); however, you must follow your IRB’s policies and 
procedures. If IRB review of clarification memos is required at your site, please submit 
this document for review. 
Each site should file a copy of this CM with the protocol for reference. 
The protocol clarification(s) contained in this memo should be implemented immediately. 
The reason for this CM is to correct an error in the list of prohibited medications, and to provide 
clarification on the use of topiramate by A5391 participants.  
The following is a clarification (noted in strikethrough) to Protocol A5391, Version 2.0, 19 Aug 
2022, titled, “Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide 
(The Do IT Study).” This clarification will be included in the next version of the A5391 protocol if 
it is amended at a future date. 


Clarification Memo #1 
          Page 2 of 2 
09 Feb 2023 
ACTG A5391 Protocol Version 2.0 
1.
In section 4.2.8, Anticipated start or cessation of any of the following drugs during study
period, second bullet, the use of topiramate is clarified with the following information:
The use of the anticonvulsant/mood stabilizer topiramate is permitted by A5391 participants
entering the study on a stable dose, as long as there is not an intent to change the dose or
stop this medication during the 48-week study follow-up period.
2.
In section 5.4.1, Prohibited Medications, the term “topiramide” has been removed from the
list of Prohibited Medications as shown below:
5.4.1 
Prohibited Medications
1.
Rifampin/rifabutin
2.
Enzalutamide
3.
Anticonvulsants contraindicated in co-administration with any of the study
drugs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital,
phenytoin, primidone, topiramide)
4.
Mitotane
5.
St. John’s wort
6.
FDA-approved weight loss agents (e.g., bupropion-naltrexone, liraglutide,
orlistat, lorcaserin, phentermine-topiramate)
7.
Non-prescription weight loss drugs (e.g., Hydroxycut; additional non-
prescription agents at the discretion of the site investigator)
8.
Chronic oral steroid use (prednisone equivalent of ≥5 mg for >2 weeks)
9.
Bisphosphonates or other treatments for osteoporosis
10.
Any antiretrovirals not included in the study treatment


A5391 
Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide 
(The Do IT Study) 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
Sponsored by: 
National Institute of Allergy 
and Infectious Diseases 
Industry Support Provided by: 
Merck & Co. 
Non-IND Protocol 
The ACTG Comorbidities 
Transformative Science Group (CTSG): 
Netanya Utay, MD, Chair 
Protocol Chair: 
John Koethe, MD 
Protocol Co-Vice Chairs: 
Roy Gulick, MD 
Jordan E. Lake, MD, MSc 
DAIDS Clinical Representative: 
Pablo Belaunzaran Zamudio, MD
Clinical Trials Specialist:   
Mwenda Kudumu, BS, PMP 
FINAL Version 2.0 
August 19, 2022 


A5391 
FINAL Version 2.0 
19Aug2022 
 
 
A5391 
 
Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide 
(The Do IT Study) 
 
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 
 
 
 


A5391 
FINAL Version 2.0 
19Aug2022 
 
 
 
TABLE OF CONTENTS 
 
 
 
Page 
 
SIGNATURE PAGE ...................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 5 
PROTOCOL TEAM ROSTER ....................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................... 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 11 
SCHEMA ..................................................................................................................................... 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .................................................................... 15 
1.1 
Hypothesis ........................................................................................................... 15 
1.2 
Primary Objective ................................................................................................ 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 ............................................................................................................. 19 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 20 
4.1 
Inclusion Criteria .................................................................................................. 20 
4.2 
Exclusion Criteria ................................................................................................ 22 
4.3 
Study Enrollment Procedures .............................................................................. 24 
4.4 
Plans for Enrollment of Women ........................................................................... 25 
4.5 
Plans for Enrollment of Minorities ........................................................................ 25 
4.6 
Co-enrollment Guidelines .................................................................................... 26 
5.0 
STUDY TREATMENT ..................................................................................................... 26 
5.1 
Regimens, Administration, and Duration ............................................................. 26 
5.2 
Study Product Formulation and Preparation ....................................................... 27 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 27 
5.4 
Concomitant Medications .................................................................................... 27 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 29 
6.1 
Schedule of Evaluations (SOE) ........................................................................... 29 
6.2 
Timing of Evaluations .......................................................................................... 32 
6.3 
Instructions for Evaluations ................................................................................. 34 
7.0 
ADVERSE EVENTS AND STUDY MONITORING.......................................................... 41 
7.1 
Definition of Adverse Events ............................................................................... 41 
7.2 
Adverse Event Collection Requirements for This Protocol .................................. 41 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 42 
7.4 
Study Monitoring ................................................................................................. 43 


A5391 
FINAL Version 2.0 
19Aug2022 
 
 
CONTENTS (Cont’d) 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 44 
8.1 
Toxicity ................................................................................................................ 44 
8.2 
Pregnancy ........................................................................................................... 46 
9.0 
CRITERIA FOR DISCONTINUATION............................................................................. 47 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 47 
9.2 
Premature Study Discontinuation ........................................................................ 47 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 47 
10.1 
General Design Issues ........................................................................................ 47 
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 ............................................................................................... 52 
12.0 
DATA COLLECTION AND MONITORING ...................................................................... 52 
12.1 
Records to Be Kept ............................................................................................. 52 
12.2 
Role of Data Management .................................................................................. 53 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 53 
12.4 
Reporting Protocol Deviations ......................................................................... 53 
13.0 
PARTICIPANTS .............................................................................................................. 53 
13.1 
IRB Review and Informed Consent ..................................................................... 53 
13.2 
Participant Confidentiality .................................................................................... 54 
13.3 
Study Discontinuation .......................................................................................... 54 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 54 
15.0 
BIOHAZARD CONTAINMENT ........................................................................................ 54 
16.0 
REFERENCES ................................................................................................................ 55 
APPENDIX I: SAMPLE INFORMED CONSENT ........................................................................ 57 
ATTACHMENT A ........................................................................................................................ 71 
 


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A5391 
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SITES PARTICIPATING IN THE STUDY 
 
A5391 is a multicenter study open to all ACTG US clinical research sites (CRSs) and select 
non-US CRSs (dependent on availability of study medications at the site). A list of selected non-
US sites will be maintained on the protocol-specific web page (PSWP). 
 
 


6 
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PROTOCOL TEAM ROSTER 
 
Chair 
John R. Koethe, MD, MSCI 
Division of Infectious Diseases 
Vanderbilt University Medical Center 
A2200-MCN, 1161 21st Avenue South 
Nashville, TN 37232 
Phone: 615-322-2035 
E-mail: john.r.koethe@vumc.org 
 
Co-Vice Chairs 
Roy Gulick, MD, MPH 
Division of Infectious Diseases 
Weill Cornell Medicine 
Box 125, 1300 York Avenue 
New York, NY 10065 
Phone: 212-746-4184 
E-mail: rgulick@med.cornell.edu 
 
Jordan E. Lake, MD, MSc 
Division of Infectious Diseases 
University of Texas Health Science Center 
at Houston, 6431 Fannin Street, MSB 2.112 
Houston, TX 77030 
Phone: 713-500-6759 
E-mail: jordan.e.lake@uth.tmc.edu 
 
DAIDS Clinical Representative 
Pablo Belaunzaran Zamudio, MD, DTM&H 
HIV Research Branch 
Therapeutics Research Program 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E40, MSC 9830 
Rockville, MD 20852 
Phone: 240-292-4423 
E-mail: belaunzaranzapabf@niaid.nih.gov 
 
Clinical Trials Specialist 
Mwenda Kudumu, BS, PMP 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
ACTG Network Coordinating Center 
4505 Emperor Boulevard, Suite 400 
Durham, NC 27703 
Phone: 919-287-4351 
E-mail: mwenda.kudumu@dlhcorp.com 
Statisticians 
Laura Smeaton, MS 
Statistical & Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 511 
Boston, MA 02115 
Phone: 617-432-2525 
E-mail: smeaton@sdac.harvard.edu 
 
Amy Kantor, MS 
Statistical & Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 543 
Boston, MA 02115 
Phone: 617-432-7129 
E-mail: akantor@sdac.harvard.edu 
 
Data Manager 
Scott Anderson, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7402 
E-mail: sanders@frontierscience.org 
 
DAIDS Pharmacist 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
Division of AIDS/OCSO/NIAID/NIH 
5601 Fishers Lane, Room 9E16, MSC #9829 
Rockville, MD 20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov 
 
Immunologist 
Alan Landay, PhD 
Division of Geriatrics, Gerontology and 
Palliative Medicine 
Rush Medical College 
1735 West Harrison Street, Suite 306, POB1 
Chicago, IL 60612 
Phone: 312-942-2849 
E-mail: alan_landay@rush.edu 
 


7 
A5391 
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TEAM ROSTER (Cont'd) 
19Aug2022 
 
Investigators 
Caroline Apovian, MD 
Section of Endocrinology, Diabetes, 
Nutrition and Weight Management 
Boston Medical Center 
720 Harrison Avenue, Suite 8100 
Boston, MA 02118 
Phone: 617-638-8556 
E-mail: caroline.apovian@bmc.org 
 
Jaclyn Bennet, MBChB 
University of the Witwatersrand Helen Joseph 
(WITS HJH) CRS 
PO Box Postnet, Suite 176, Private Bag X2600 
Johannesburg, Gauteng 2041 
SOUTH AFRICA 
Phone: 27-11-2768800 
E-mail: jbennet@witshealth.co.za 
 
Paula Debroy, MD 
Houston AIDS Research Team CRS 
6431 Fannin Street, MSB 1.112 
Houston, TX 77030 
E-mail: paula.debroymonzon@uth.tmc.edu 
 
Kristine Erlandson, MD 
Division of Infectious Diseases 
University of Colorado, Denver 
Mail Stop B168, 12700 East 19th Avenue 
Aurora, CO 80045 
Phone: 303-724-4941 
E-mail: kristine.erlandson@ucdenver.edu 
 
Win Han, MD, MS 
Thai Red Cross AIDS Research Centre 
(TRC-ARC) CRS, 104 Ratchadamri Road 
Patumwan, Bangkok, 10330 
THAILAND 
Phone: 66-2-6523040 
E-mail: win.m@hivnat.org 
 
Investigators (Cont'd)  
Jane O'Halloran, MBBCh 
Division of Infectious Diseases 
Washington University 
4523 Clayton Avenue, CB 8051 
St. Louis, MO, 63110 
Phone: 314-454-8354 
E-mail: janeaohalloran@wustl.edu 
 
Sudipa Sarkar, MD, MSCI 
Johns Hopkins University 
5501 Hopkins Bayview Circle 
Asthma and Allergy Center 2B.74D 
Baltimore, MD 21224 
Phone: 901-550-9828 
E-mail: ssarka19@jhmi.edu 
 
Esperanza Vicente, MD 
San Miguel CRS 
Jiron Putumayo 177, San Miguel 
Lima, 32 
PERU 
Phone: 515-621-600 
E-mail: evicente@impactaperu.org 
 
Field Representative 
Jonathan Oakes 
Chapel Hill CRS 
2nd Floor, Bioinformatics Building 
130 Mason Farm Road, Suite 2100 
Chapel Hill, NC 27514 
Phone: 919-966-6712 
E-mail: jonathan_oakes@med.unc.edu 
 
Laboratory Technologists 
Christopher Lane, BS, AAS 
University of Rochester Adult HIV Therapeutic 
Strategies Network CRS 
Infectious Diseases Division 
Department of Medicine, Box 689 
601 Elmwood Avenue 
Rochester, NY 14642 
Phone: 585-276-5574 
E-mail: christopher_lane@urmc.rochester.edu 
 


8 
A5391 
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TEAM ROSTER (Cont'd) 
19Aug2022 
 
Laboratory Technologists (Cont’d) 
Michael Leonard, MS 
Vanderbilt University Medical Center 
One Hundred Oaks, 719 Thompson Lane 
Suite 57180 
Nashville, TN 37204 
Phone: 615-875-1570 
E-mail: michael.leonard@vumc.org 
 
Community Scientific Subcommittee (CSS) 
Representative 
Martha Mensah-King 
Parirenyatwa CRS 
1193 Sunningdale 3 
Harare 00263 
ZIMBABWE 
Phone: 263-71790228 
E-mail: martha.tholanah@gmail.com 
 
International Site Specialist 
Allan-Michael Bills, MSc, BS 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
ACTG Network Coordinating Center 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910 
Phone: 301-628-3273 
E-mail: allan-michael.bills@dlhcorp.com 
 
Industry Representative 
Rebeca Plank, MD, MPH 
Merck Research Laboratories 
33 Avenue Louis Pasteur 
Boston, MA 02115 
Phone: 617-992-3239 
E-mail: Rebeca.plank@merck.com 
 
Laboratory Data Manager 
Kacey Matecki, BS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900, Ext. 7272 
E-mail: matecki@frontierscience.org 
 
 
Laboratory Specialist 
Faith Landsman 
ACTG Laboratory Center at UCLA (ALC-UCLA) 
10990 Wilshire Boulevard, Suite 260 
Los Angeles, CA 90024 
Phone: 323-806-8836 
E-mail: flandsman@milabcentral.org 
  
 


9 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5391@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5391@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.protA5391 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 Clinical Management Committee (CMC). 
• 
Send an e-mail message to actg.cmca5391@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic laboratory tests, contact the Protocol 
Immunologist. 
• 
Send an e-mail message to actg.teamA5391@fstrf.org (ATTENTION: Alan Landay). 
 
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 managers. 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 Scott 
Anderson and Rebecca Marshall directly. 
• 
For other questions, send an e-mail message to actg.teamA5391@fstrf.org (ATTENTION: 
Scott Anderson and Rebecca Marshall). 
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration 
For randomization/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. 
 


10 
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STUDY MANAGEMENT (Cont'd) 
19Aug2022 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. 
• 
Send an e-mail message to actg.teamA5391@fstrf.org (ATTENTION: Mwenda Kudumu). 
 
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.teamA5391@fstrf.org (ATTENTION: Mwenda Kudumu). 
 
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 study product, dose, supplies, records, and returns, call 
Oladapo Alli, Protocol Pharmacist, at 240-627-3593. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
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 A5391 team members. 
• 
Send an e-mail message to actg.teamA5391@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


11 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
3TC 
ABC 
AE 
lamivudine 
abacavir 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
ANC 
alanine aminotransferase 
absolute neutrophil count 
ART 
ARV 
antiretroviral therapy 
antiretroviral 
AST 
AZT 
aspartate aminotransferase 
zidovudine 
BIC 
BMI 
bictegravir 
body mass index 
CDC 
CLIA 
CrCl 
Centers for Disease Control and Prevention (US) 
Clinical Laboratory Improvement Amendments 
creatinine clearance 
CRPMC 
NIAID Clinical Research Products Management Center 
DAERS 
DBS  
DEXA 
DAIDS Adverse Events Reporting System 
dried blood spot 
dual-energy X-ray absorptiometry 
DMC 
DOR 
DRV/r 
DTG 
Data Management Center 
doravirine 
ritonavir-boosted darunavir 
dolutegravir 
EAE 
expedited adverse event 
EC 
Ethics Committee 
eCRF 
EFV 
EVG 
electronic case report form 
efavirenz 
elvitegravir 
FDA 
FTC 
FTC-TP 
GCLP  
GLP-1 
Food and Drug Administration (US) 
emtricitabine 
emtricitabine triphosphate 
Good Clinical Laboratory Practice 
glucagon-like peptide-1 


 
12 
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GLOSSARY (Cont'd) 
19Aug2022 
 
HDL 
HIV 
HOMA-IR 
IND 
INSTI 
high-density lipoprotein cholesterol 
human immunodeficiency virus 
homeostatic model assessment of insulin resistance 
investigational new drug 
integrase strand transfer inhibitor 
IQA 
IRB 
Immunology Quality Assurance 
Institutional Review Board 
IUD 
intrauterine device 
LDL 
low-density lipoprotein cholesterol 
LPC 
mg 
MOPS 
NNRTI 
NRTI 
laboratory processing chart 
milligram 
Manual of Procedures 
non-nucleoside reverse transcriptase inhibitor 
nucleoside(tide) reverse transcriptase inhibitor 
PBMC 
PI 
peripheral blood mononuclear cell 
protease inhibitor 
PSWP 
PWH 
RAL 
Protocol-Specific Web Page 
people with HIV 
raltegravir 
RSC 
Regulatory Support Center 
SAE 
serious adverse event 
SOE 
SOP  
TAF 
TDF 
TFV-DP 
VQA 
Schedule of Evaluations 
Standard Operating Procedure 
tenofovir alafenamide 
tenofovir disoproxil fumarate 
tenofovir-diphosphatemtricitabine 
Virology Quality Assurance 
WHO 
World Health Organization 


13 
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SCHEMA 
 
A5391 
 
Doravirine for Persons with Excessive Weight Gain on Integrase Inhibitors and Tenofovir 
Alafenamide (The Do IT Study) 
 
DESIGN 
A phase IV, 48-week, 3-arm, open-label, randomized study to assess 
whether an antiretroviral therapy (ART) switch from bictegravir (BIC), 
dolutegravir (DTG), or raltegravir (RAL) with tenofovir 
alafenamide/emtricitabine (TAF/FTC) or TAF/lamivudine (TAF/3TC) to 
either a regimen containing doravirine (DOR) with TAF/FTC (or TAF/3TC 
depending on location), or DOR with tenofovir disproxil fumarate 
(TDF)/FTC (or TDF/3TC depending on location) results in reduced weight 
gain, or weight loss, as compared to continuation of current BIC-, DTG-, 
or RAL-containing ART. 
 
DURATION 
 
48 weeks 
 
SAMPLE SIZE 
222 participants (74 per arm) 
 
POPULATION 
Persons living with human immunodeficiency virus (HIV) aged ≥18 years 
with a BMI ≥30 kg/m2 on an integrase strand transfer inhibitor (INSTI) + 
TAF/FTC (or TAF/3TC) regimen for at least 48 weeks prior to entry 
with maintenance of virologic suppression (HIV-1 RNA <50 copies/mL 
or below the lower limit of HIV-1 RNA detection available at the site). 
 
STRATIFICATION 
Enrollment will be stratified by sex assigned at birth and race (African 
American/Black vs. non-African American/Black). 
 
REGIMEN 
Participants on BIC, DTG, or RAL-containing ART with TAF/FTC (or 
TAF/3TC) for at least 48 weeks prior to entry, will be randomized 1:1:1 to 
switch to DOR + TAF/FTC (or TAF/3TC) (Arm 1), or DOR + TDF/FTC (or 
TDF/3TC) (Arm 2), or to continue on their current INSTI +TAF/FTC (or 
TAF/3TC) (Arm 3). Total duration of study treatment in all arms will be 48 
weeks. 
 
DOR will be provided to Arms 1 and 2 participants through the study. 
Nucleoside reverse transcriptase inhibitors (NRTIs) and INSTIs will not be 
provided by the study. 
 


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Schema Figure 1: Schema Diagram 
 
 


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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
Compared to continued bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL) + 
tenofovir alafenamide/emtricitabine (TAF/FTC) or TAF/lamivudine (TAF/3TC) therapy 
(Arm 3), a switch to doravirine (DOR) + TAF/FTC (or TAF/3TC) (Arm 1) will result in less 
weight gain or an overall weight loss at 48 weeks among obese persons (i.e., a BMI ≥30 
kg/m2). A switch from TAF/FTC (or TAF/3TC) to tenofovir disproxil fumarate (C)/FTC (or 
TDF/3TC) (Arm 2) will result in further reduction in weight gain or overall weight loss 
compared to Arm 1. 
 
1.2 
Primary Objective 
 
To assess if an antiretroviral therapy (ART) switch to DOR (either switch to DOR and 
remain on TAF/FTC [or TAF/3TC, Arm 1] or switch to DOR and TDF/FTC [or TDF/3TC, 
Arm 2]) results in differences in weight change over 48 weeks, compared to a strategy of 
remaining on current ART (INSTI + TAF/FTC [or TAF/3TC, Arm 3]). 
 
1.3 
Secondary Objectives 
 
1.3.1 To assess if a switch to TDF/FTC (or TDF/3TC) from TAF/FTC (or TAF/3TC) 
results in differences in weight changes over 48 weeks by contrasting the 2 
DOR-containing switch strategies (i.e., DOR+TAF/FTC [or TAF/3TC] versus DOR 
+ TDF/FTC [or TDF/3TC] [Arm 1 versus Arm 2]). 
 
1.3.2 To assess the effects of a switch from INSTI + TAF/FTC (or TAF/3TC) to DOR + 
TAF/FTC (or TAF/3TC), or DOR + TDF/FTC (or TDF/3TC) over 48 weeks on: 
 
i. 
Safety and tolerability. 
ii. Maintenance of virologic suppression. 
iii. Minimum waist circumference. 
iv. Fasting cardiometabolic parameters: glucose and insulin, homeostatic model 
assessment of insulin resistance (HOMA-IR) and lipids (triglycerides, low-
density lipoprotein [LDL], high-density lipoprotein [HDL]). 
v. Dual-energy X-ray absorptiometry (DEXA) body composition measurements 
of total and regional fat and lean mass, and hip and lumbar spine bone 
mineral density.  
vi. Change in categorization of bone mass (by WHO classification) from 
baseline to week 48 based on minimum reported T score from left/right 
femoral neck, left/right total femur/hip, and lumbar spine. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To assess the effects of a switch from INSTI + TAF/FTC (or TAF/3TC) to DOR + 
TAF/FTC (or TAF/3TC), or DOR + TDF/FTC (or TDF/3TC) over 48 weeks on: 
 


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i. 
Circulating immunologic parameters, including plasma biomarkers (e.g., high-
sensitivity C-reactive protein, high-sensitivity interleukin-6, sCD163, and 
interleukin-18), and CD4+ and CD8+ T cell subsets (e.g., activated, 
senescent, and memory), and invariant NK T cells (iNKT cells). 
ii. Circulating metabolic biomarkers, including adipokines (e.g., leptin, 
adiponectin), oxidized LDL, (1,3)-beta-D-glucan, and free fatty acids. 
 
1.4.2 To assess relationships between blood concentrations of tenofovir diphosphate 
(TFV-DP) (both from TDF and TAF) and emtricitabine triphosphate (FTC-TP), 
measured from dried blood spots (DBS) testing, with changes in weight and 
metabolic markers over 48 weeks. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Early in the HIV epidemic, weight loss was a sign of more advanced disease, and 
weight gain following ART initiation was often regarded as a “return to health” 
phenomenon. In the current era, however, a rising proportion of people with HIV (PWH) 
are obese (body mass index [BMI] ≥30 kg/m2), which increases the risk of developing 
multiple comorbid conditions. In a multi-cohort analysis of over 14,000 PWH in the 
United States and Canada, the percentage of obese individuals at ART initiation 
increased from 9% to 18% between 1998 and 2010, and 18% of individuals 
overweight at the start of treatment became obese within 3 years after ART 
initiation [1]. Other studies have confirmed increasing prevalence of obesity in 
PWH [2, 3, 4], which parallels similar trends in the general population [5]. Women, 
minorities, and persons of lower socioeconomic status with HIV carry a 
disproportionate burden of obesity. The risk for metabolic diseases including 
diabetes mellitus, neurocognitive impairment, liver disease, and cardiovascular 
disease rises with increased body weight [6, 7, 8, 9]. Furthermore, weight gain in 
PWH confers greater risk of metabolic disease compared with HIV-negative 
individuals [6, 10, 11]. 
 
Several prospective and retrospective studies report that PWH starting or switching to 
INSTI-containing ART regimens have significantly greater weight gain compared to 
protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-
containing regimens, which may be further compounded by the use of TAF as a second 
agent. At present, it is unknown whether obese PWH on INSTI + TAF/FTC (or TAF/3TC) 
could either attenuate their rate of weight increase over time or reduce body weight with 
a change to a different ART regimen. 
 
In the prospective AIDS Clinical Trial Group (ACTG) study A5257, the use of RAL with 
TDF/FTC as an initial regimen was associated with greater increases in waist 
circumference and higher odds of a >10% weight gain at 96 weeks compared to 
ritonavir-boosted darunavir (DRV/r) and ritonavir-boosted atazanavir, each in 
combination with TDF/FTC [12]. In a large analysis of >22,000 treatment-naïve PWH in 
the multi-site North American AIDS Cohort Collaboration on Research and Design (NA-


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ACCORD), those initiating INSTI-
containing regimens gained an 
estimated 5.9 kg after 5 years of 
treatment, compared to 3.7 kg for 
NNRTI, and 5.5 kg for PI [13]. However, 
most of this weight gain occurred in the 
first 2 years following ART initiation for 
all classes, and among INSTIs there 
was considerable heterogeneity: 
estimated weight gain at 2 years was 
7.2 kg for DTG, 5.8 kg for RAL, and 4.1 
kg for elvitegravir (EVG) (Figure 2.1-1). 
The NA-ACCORD analysis period was 
2007-2016 and the first-line regimens 
primarily contained TDF, abacavir 
(ABC), FTC, and/or 3TC. Smaller 
observational studies also report greater 
weight gain among PWH initiating 
INSTI-containing regimens, which 
generally has been greater among 
women, African American/Black people, 
and those with lower pre-ART weight 
and CD4+ T cell counts [13, 14, 15, 16]. 
 
A switch from an NNRTI- or PI-
containing regimen to an INSTI-containing regimen may also be accompanied by weight 
gain. In a single-site report, PWH with virologic suppression on efavirenz (EFV)-
containing regimens who switched to INSTI-containing regimens experienced 
significantly more weight gain compared to those who remained on EFV, and weight 
gain was greatest among those who switched to DTG [17]. Similarly, in ACTG protocols 
A5001 and A5322, women, African American/Black people, and persons age ≥ 60 who 
switched from PI- and NNRTI-
containing regimens to INSTI-
containing regimens while 
virologically suppressed had 
significantly greater weight gain in 
the 2 years following the switch 
versus the 2 years prior to switch 
(Figure 2.1-2) [18]. 
Figure 2.1-1: NA-ACCORD: Predicted weight at 2-years 
of ART among PWH starting INSTI-containing regimens 
compared to those starting PI- or NNRTI-class regimens.
Figure 2.1-2: ACTG A5001 and A5322: Change in weight 
before and after switch to INSTI-containing regimens. 
 


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While initial studies focused on the 
relationship of INSTI-class medications 
and weight change, more recent data 
from prospective studies indicate the 
combination of an INSTI and TAF may 
have compounding effects on weight 
gain. TAF, approved in the US in 
November 2015, represented a low 
proportion of nucleoside(tide) reverse 
transcriptase inhibitor (NRTI) use in the 
above ART-naïve observational studies, 
but use of this agent is rapidly increasing 
given the lower incidence of bone loss 
and adverse renal effects compared to 
TDF. In the ADVANCE study, ART-naïve 
South African women randomized to 
DTG/TAF/FTC gained an average of 10 kg at 
96 weeks of treatment (representing an 
average 16% weight gain), as compared to 5 
kg on DTG/TDF/FTC and 3 kg on 
EFV/TDF/FTC (Figure 2.1-3) [19]. 
 
For men, average weight gain at 96 weeks was 
5 kg, 4 kg, and 1 kg, respectively, on the same 
regimens. Over the 96 weeks, weight 
continued to increase in women, while 
plateauing in men. Lastly, a pooled analysis of 
weight gain in 8 randomized controlled clinical 
trials of treatment-naïve PWH initiating ART 
between 2003-2015, comprising over 5,000 
participants and 10,000 person-years of follow-
up, found greater weight gain over 96 weeks 
among those receiving TAF-containing regimens as compared to other NRTIs (Figure 
2.1-4; error bars depict the 95% CI, and asterisks are color-coded to denote p≤0.05 
compared to zidovudine [AZT]. At 96 weeks, mean weight gains by NRTI were: TAF 
4.25 kg [95% CI 3.94-4.56], ABC 3.08 kg [95% CI 2.36-3.81], TDF 2.07 kg [95% CI 1.84-
2.30]), and AZT 0.39 kg [95% CI -0.57-1.34] after adjusting for age, race, sex, baseline 
clinical factors, and additional ART agents [20]. 
 
Taken together, these studies suggest that NNRTI- and non-TAF-containing regimens 
are accompanied by lower weight gain among PWH [13, 17, 20], raising the possibility 
that a switch to this ART combination may offer a weight stabilization or reduction benefit 
among obese PWH on an INSTI/TAF regimen. DOR is an NNRTI that was approved by 
the Food and Drug Administration (FDA) in 2018 on the basis of phase 3 studies 
demonstrating non-inferiority compared to EFV- or DRV/r-containing regimens, in 
addition to a superior neuropsychiatric profile compared to EFV [21, 22, 23]. In the 
DRIVE-SHIFT trial, a switch to DOR with TDF/3TC among virally suppressed 
Figure 2.1-4: Analysis of pooled clinical RCT 
data: Estimated weight change over 96 weeks. 
  
 
Weeks of Treatment
Weight Change
Figure 2.1-3: ADVANCE: Mean change in weight to week 
96 in women. 
 
 


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participants demonstrated non-inferior maintenance of HIV-1 suppression compared with 
boosted PI, boosted EVG, and other NNRTI-containing regimens [24]. Data presented at 
the 17th European AIDS Conference showed weight gain at 48 weeks among ART-
naïve persons initiating DOR was similar to those initiating DRV/r (1.0 vs. 0.6 kg, p=0.12) 
in pooled phase 2 and 3 studies, but higher compared to EFV (1.0 vs. 0.0 kg, p<0.001). 
The difference in weight gain between DOR and EFV was smaller, though still 
significant, at 96 weeks (1.5 vs. 1.0 kg, p=0.02) [25]. 
 
This study will determine whether a switch to a DOR-based ART regimen results in less weight 
gain, weight stability or an overall weight loss at 48 weeks among obese persons currently on 
an INSTI + TAF/FTC (or TAF/3TC) regimen, and whether cardiovascular and metabolic health 
biomarkers improve. All study medications are FDA-approved for the treatment of HIV, but the 
study is not without risks to participants. Major risks include the potential for treatment failure 
on the new regimen, the development of side effects specific to the medications, and a 
reduction in bone density among those randomized to DOR + TDF/FTC (or TDF/3TC). The 
protocol includes procedures to exclude persons at higher risk of these adverse events, and to 
monitor participants for the development of adverse events during the study. Participants in the 
study may also derive potential benefits, including a stabilization or reduction in body weight, 
and/or improved cardiovascular and/or metabolic health. The risks and benefits of this study 
are described in more detail in the informed consent. 
 
2.2 
Rationale 
 
Given that a 5% weight loss is associated with a substantial reduction in diabetes risk, a 
reduction in intrahepatic triglyceride content, and improved adipose tissue, liver, and 
muscle insulin sensitivity, interventions to reverse or attenuate weight gain among obese 
PWH exposed to INSTI/TAF regimens could improve cardiometabolic health outcomes. 
 
3.0 
STUDY DESIGN 
 
A5391 is a phase IV, 48-week, three-arm, open label, randomized study of an ART 
regimen switch from BIC, DTG, or RAL + TAF/FTC (or TAF/3TC) to a DOR-containing 
regimen with TAF/FTC (or TAF/3TC depending on location) or TDF/FTC (or TDF/3TC 
depending on location) versus continuation of current ART. 
 
Persons aged ≥18 years with a BMI ≥30 kg/m2 and a minimum of 48 weeks of an 
INSTI + TAF/FTC (or TAF/3TC) regimen will be randomized 1:1:1 to switch to DOR + 
TAF/FTC (or TAF/3TC) (Arm 1) or DOR + TDF/FTC (or TDF/3TC) (Arm 2) versus 
continued current INSTI + TAF/FTC (or TAF/3TC) regimen (Arm 3). 
 
NOTE: TAF and INSTI do not have to have been initiated simultaneously (see section 4.1.4). 
 
The proposed sample size is 222 participants (74 per arm). 
 


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4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Age ≥18 years. 
 
4.1.2 Ability and willingness of participant or legal guardian/representative to provide 
informed consent. 
 
4.1.3 HIV-1, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study 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. If a rapid HIV test or any FDA-approved HIV-1 E/CIA test kit is not 
available, two HIV-1 RNA values ≥2000 copies/mL at least 24 hours apart may be 
performed by any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, or by any non-US laboratory that is 
DAIDS Good Clinical Laboratory Practice (GCLP) compliant and, if performing HIV-1 
RNA testing, is Virology Quality Assurance (VQA)-certified. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, or for sites 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. 
 
World Health Organization (WHO) and CDC (Centers for Disease Control and 
Prevention) 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 be confirmed by either another type of rapid assay or an 
E/CIA that is based on 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. 
 
4.1.4 Currently on a BIC, DTG, or RAL + TAF/FTC (or TAF/3TC) regimen with ≥48 
weeks dosing prior to study entry. 
 
NOTE A: Participants who did not start TAF at the same time as they started an 
INSTI will be eligible if they started TAF/FTC (or TAF/3TC) ≥48 weeks prior to 
study entry. 
 
NOTE B: Participants who underwent within-INSTI class substitutions (including 
from EVG to BIC, DTG, or RAL) will be eligible if substitution occurred ≥24 weeks 
prior to study entry. 
 
NOTE C: Participants are permitted ART adherence gaps of ≤7 days (i.e., 
missed doses), with a maximum of 3 gaps in the 48 weeks prior to study entry. 
 


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4.1.5 Ability to acquire NRTIs (TAF/FTC or TAF/3TC, and TDF/FTC or TDF/3TC) and 
INSTI through usual care for the duration of the study. 
 
4.1.6 A BMI ≥30 kg/m2 at screening. 
 
4.1.7 No known plans to change or to initiate medications known to be associated with 
significant weight changes during study period. 
 
NOTE: Complete list of medications known to be associated with significant 
weight changes will be maintained on the PSWP. 
 
4.1.8 Agree to adhere to assigned ART during the study period 
 
4.1.9 At least one HIV-1 RNA level <50 copies/mL (or below the lower limit of HIV-1 
RNA detection available at the site if the lower limit of detection is >50) 
performed in the 48 weeks prior (≤48 weeks) to study screening, and at least one 
HIV-1 RNA level <50 copies/mL ≥48 weeks prior to study screening, using an 
FDA-approved assay performed by any US laboratory that has a CLIA 
certification or its equivalent, or at any network-approved non-US laboratory that 
is VQA certified. HIV-1 RNA values prior to the screening visit will be assessed 
for eligibility by the site and assay dates and values do not need to be entered on 
an eCRF. 
 
4.1.10 Screening HIV-1 RNA <50 copies/mL (or below the lower limit of HIV-1 RNA 
detection available if the lower limit of detection is >50) performed within 45 days 
prior to study entry by any US laboratory that possesses a CLIA certification or its 
equivalent, or at any network-approved non-US laboratory that is VQA certified. 
 
4.1.11 For participants capable of becoming pregnant, negative serum or urine 
pregnancy test within 45 days prior to study 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:  Participants capable of becoming pregnant are defined as individuals 
who were assigned a female sex at birth and of reproductive potential (i.e., have 
reached menarche and who have not been post-menopausal for at least 24 
consecutive months, and have not undergone surgical sterilization such as 
hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy). This 
includes transgender men who could become pregnant if menstruation were not 
suppressed. Participant-reported history is acceptable documentation of 
menopause. 
 
4.1.12 Participants engaging in sexual activity and capable of becoming pregnant must 
agree to use contraception while on study drug (approximately 48 weeks) and for 


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8 weeks after the end of the study. At least one of the following contraceptive 
methods must be used: 
 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
• 
Partner sterilization (i.e., vasectomy) and is the sole partner for the 
participant. 
 
NOTE: Participant report of partner sterilization is acceptable. 
 
4.1.13 Transgender participants who are currently taking hormones must be on a stable 
hormone dose for >12 weeks prior to study entry. Transgender participants 
should not have active plans to change their hormone regimen or dose during the 
study period. 
 
NOTE: As some transgender participants may also use hormones purchased 
outside of the medical system (e.g., street hormones), the medication history 
should include questions about the use of these agents. 
 
4.1.14 The following laboratory values obtained within 45 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 >10 g/dL for males and >9 g/dL for females (based on sex at 
birth) 
• 
Calculated creatinine clearance ≥50 mL/min as estimated by the CKD-EPI 
equation (a calculator is available at: 
https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi) 
• 
Aspartate aminotransferase (AST) (SGOT) <3x ULN 
• 
Alanine aminotransferase (ALT) (SGPT) <3x ULN 
 
4.2 
Exclusion Criteria 
 
4.2.1 Historical or current evidence of the K65R/E/N or M184V/I mutations (for 
participants who have undergone HIV-1 genotyping), due to the potential for viral 
rebound after switch from an INSTI- to NNRTI-based regimen. 
 
4.2.2 Historical or current evidence of major mutations associated with NNRTI 
resistance. 
 
NOTE: Refer to the IAS-USA 2019 mutations list, including significant 
substitutions at positions 100, 101, 103, 106, 138, 179, 181, 188, 190, 221, 225, 
227, 230, or 234 [26]. 
 


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4.2.3 History of prior virologic failure in the opinion of the site investigator. For 
example, a confirmed plasma HIV-1 RNA >1000 copies/mL after having achieved 
viral suppression. 
 
4.2.4 Prior exposure to single-dose nevirapine for the prevention of parent-to-child 
transmission of HIV. 
 
4.2.5 Any history of significant renal toxicity while taking TDF (as determined by site 
investigator). 
 
4.2.6 Currently breast-feeding or pregnant, or intending to become pregnant during the 
duration of the study. 
 
4.2.7 Current use, use in the 4 weeks preceding study entry, or anticipated use of 
drugs specified in section 5.4.1 during the study period. 
 
4.2.8 Anticipated start or cessation of any of the following drugs during study period: 
 
• 
Antipsychotics (e.g., clozapine, olanzapine, risperidone, etc.) and 
antidepressants (tricyclic antidepressants, e.g., amitriptyline, nortriptyline, 
etc.; selective serotonin reuptake inhibitors, e.g., fluoxetine, paroxetine, 
sertraline, etc.; and monoamine oxidase inhibitors, e.g., selegiline) associated 
with weight gain 
• 
Anticonvulsants/mood stabilizers associated with weight gain (e.g., lithium, 
valproic acid) or weight loss (e.g., topiramate) 
• 
Thyroid replacement hormones 
• 
Anti-diabetic agents known to cause weight loss (e.g., GLP-1 receptor 
agonists such as exenatide, dulaglutide, semaglutide, metformin, and SGLT-
2 inhibitors such as canagliflozin, dapagliflozin, etc.). 
 
NOTE A: Participants currently receiving antipsychotics, antidepressants, 
anticonvulsants/mood stabilizers, and thyroid replacement hormones with no 
dose modifications for at least 12 weeks prior to entry are eligible. 
 
NOTE B: Participants currently receiving anti-diabetic agents known to cause 
weight loss with no dose modifications for at least 24 weeks prior to entry are 
eligible. 
 
4.2.9 Planning to undergo bariatric surgery or initiate significant dietary or exercise 
changes within the study period (e.g., structured weight loss programs such as 
Weight Watchers), as determined by participant report. 
 
4.2.10 Known allergy/sensitivity or any hypersensitivity to components of study drug or 
its formulation. 
 


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4.2.11 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with ability to adhere to study requirements, or 
cessation of regular methamphetamine use, as determined by the site 
investigator, within 60 days prior to study entry. 
 
4.2.12 Acute or serious illness requiring systemic treatment and/or hospitalization within 
30 days prior to entry. 
 
4.2.13 A history of a diagnosis of osteoporosis or osteopenia. 
 
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 
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 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 approval(s) 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 the required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
issued by the DAIDS PRO 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 potential participant has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form prior to the initiation of study procedures. 
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 


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must be entered through the Data Management Center (DMC) Subject 
Enrollment System. 
 
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 Randomization/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 
Plans for Enrollment of Women 
 
Given the greater weight gain observed among women receiving INSTI-containing 
regimens, the study will enroll a greater number of women (defined as female sex 
assigned at birth) compared to men (>50%). 
 
NOTE A: Since the numbers of transgender men enrolling are expected to be small, 
requiring a minimum of 50% persons assigned female sex at birth at enrollment will 
guarantee the population of women in our study, which includes both cis and 
transgender women, will be >50% of all participants. Enrollment based on sex assigned 
at birth was selected to account for study sites that do not record gender, or settings 
where participants may be hesitant to report gender. 
 
NOTE B: The protocol team may assign study enrollment limits for sex assigned at birth 
as needed (see section 7.4). 
 
4.5 
Plans for Enrollment of Minorities 
 
Given the greater weight gain observed among persons of African American/Black race 
receiving INSTI-containing regimens, the study will enroll a greater number of African 
American/Black participants compared to non-African American/Black participants 
(>50%) at US (i.e., non-international) sites. The over-enrollment of African 
American/Black participants at US sites (relative to their representation in the general 
US population) is justified as these individuals comprise >40% of new HIV acquisitions 
in the US annually, and may disproportionately benefit from a switch to DOR. Increasing 
the representation of African American/Black participants in the trial will facilitate the 
assessment of race as a factor in the response to ART switch. 
 
NOTE: The protocol team may assign study enrollment limits for race at US sites as 
needed (see section 7.4). 


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4.6 
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 
A5391 protocol chairs. 
• 
Participants in A5332 REPRIEVE can be co-enrolled in A5391. 
• 
Non-US sites are encouraged to co-enroll participants in A5243, “Plan for Obtaining 
Human Biological Samples at Non-US Clinical Research Sites for Currently 
Unspecified Genetic Analyses.” Co-enrollment in A5243 does not require permission 
from the A5391 protocol chairs. 
• 
US and non-US sites are encourage to co-enroll participants in A5379, “B-
Enhancement of HBV Vaccination In Persons Living With HIV (BEe-HIVe): 
Evaluation of HEPLISAV-B.” Co-enrollment in A5379 does not require 
permission from the A5391 protocol chairs. 
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the protocol team via e-mail as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as DOR + TAF/FTC (or TAF/3TC), DOR + TDF/FTC (or 
TDF/3TC), or BIC, DTG, or RAL + TAF/FTC (or TAF/3TC). 
 
DOR will be provided to Arms 1 and 2 participants through the study, NRTIs and INSTIs 
will not be provided by the study and participants will receive them from their regular 
care provider. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens/Administration 
 
Participants on BIC, DTG, or RAL-containing regimens with TAF/FTC (or 
TAF/3TC) will be randomized 1:1:1 to: 
• 
Arm 1: DOR 100 mg + TAF/FTC (or TAF/3TC, depending on location) by 
mouth daily with or without food 
• 
Arm 2: DOR 100 mg + TDF/FTC (or TDF/3TC, depending on location) by 
mouth daily with or without food 
• 
Arm 3: Continuation of entry INSTI+TAF/FTC (or TAF/3TC) 
 
5.1.2 Duration 
 
Total study duration for all arms will be 48 weeks (a brief extension may be 
required for some participants to complete all study evaluations). 
 


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5.2 
Study Product Formulation and Preparation 
 
DOR is supplied as white film-coated tablets, each containing 100 mg of doravirine. 
 
Store DOR at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F 
to 86°F) [see USP Controlled Room Temperature] in the original bottle. 
 
Keep the bottle tightly closed to protect from moisture; do not remove the desiccant. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
DOR will be supplied through the study. 
 
NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for 
Arm 3 will be acquired through standard of care locally. 
 
DOR will be provided by Merck & Company and is available through the NIAID 
Clinical Research Products Management Center (CRPMC). The site pharmacist 
should obtain the study product for this protocol by following the instructions in the 
manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all DOR received 
from the NIAID CRPMC and subsequently dispensed. At US CRSs, all unused 
DOR 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. 
 
5.4 
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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5.4.1 Prohibited Medications 
 
1. 
Rifampin/rifabutin 
2. 
Enzalutamide 
3. 
Anticonvulsants contraindicated in co-administration with any of the study 
drugs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, 
phenytoin, primidone, topiramide) 
4. 
Mitotane 
5. 
St. John’s wort 
6. 
FDA-approved weight loss agents (e.g., bupropion-naltrexone, liraglutide, 
orlistat, lorcaserin, phentermine-topiramate) 
7. 
Non-prescription weight loss drugs (e.g., Hydroxycut; additional non-
prescription agents at the discretion of the site investigator) 
8. 
Chronic oral steroid use (prednisone equivalent of ≥5 mg for >2 weeks) 
9. 
Bisphosphonates or other treatments for osteoporosis 
10. Any antiretrovirals not included in the study treatment 
 
5.4.2 Precautionary Medications 
 
A list of precautionary medications is provided on the PSWP. 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations (SOE) 
 
Table 6.1-1: Schedule of Evaluations 
Evaluation 
Screening 
Entry 
Post-Entry Evaluations 
(Weeks) 
Prem. 
Disc. 
Confirmation 
of virologic 
failure 
4 
12 
24 
36 
48, Study 
Completion 
Visit Window 
<45 days 
and ≥24 
hours 
prior to 
entry 
Day 0 
-3/+7 
days 
±14 days 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
Complete Physical Exam 
 
X 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
 
 
X 
X 
X 
X 
X 
X 
 
Height Measurement 
X 
 
 
 
 
 
 
 
 
Weight Measurement 
X 
X 
X 
X 
X 
X 
X 
X 
 
Waist Circumference 
 
X 
 
 
X 
 
X 
X 
 
Body Mass Index 
X 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
X 
 
X 
X 
 


 
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Evaluation 
Screening 
Entry 
Post-Entry Evaluations 
(Weeks) 
Prem. 
Disc. 
Confirmation 
of virologic 
failure 
4 
12 
24 
36 
48, Study 
Completion 
Visit Window 
<45 days 
and ≥24 
hours 
prior to 
entry 
Day 0 
-3/+7 
days 
±14 days 
Liver Function Tests 
X 
X 
X 
X 
X 
 
X 
X 
 
Fasting Lipid Profile 
 
X 
 
 
X 
 
X 
X 
 
Chemistry 
X 
X 
X 
X 
X 
 
X 
X 
 
Fasting glucose 
 
X 
 
 
X 
 
X 
X 
 
Calculated Creatinine 
Clearance 
X 
X 
X 
X 
X 
 
X 
X 
 
Dipstick Urinalysis 
 
X 
 
 
X 
 
X 
X 
 
Pregnancy Testing 
X 
X 
 
 
 
 
X 
 
 
CD4+/CD8+ T cells 
 
X 
 
 
X 
 
X 
X 
 
Plasma HIV-1 RNA  
X 
X 
Xa 
Xa 
Xa 
 
Xa 
Xa 
X 
HIV-1 viral genotype 
 
 
 
 
 
 
 
 
X 
Hemoglobin A1c 
 
X 
 
 
X 
 
X 
X 
 
Stored plasma and serum 
(fasting) for insulin, 
immunologic, and 
cardiometabolic testing 
 
X 
 
 
X 
 
X 
X 
 
Dried Blood Spot for drug 
concentration measurements 
 
X 
 
 
X 
 
X 
X 
 


 
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Evaluation 
Screening 
Entry 
Post-Entry Evaluations 
(Weeks) 
Prem. 
Disc. 
Confirmation 
of virologic 
failure 
4 
12 
24 
36 
48, Study 
Completion 
Visit Window 
<45 days 
and ≥24 
hours 
prior to 
entry 
Day 0 
-3/+7 
days 
±14 days 
Stored PBMCs 
 
X 
 
 
 
 
X 
X 
 
Adherence Assessment 
 
 
X 
X 
X 
X 
X 
X 
 
DEXA Scan 
 
X 
 
 
 
 
X 
X 
 
Food Security and Physical 
Activity Questionnaires 
 
X 
 
 
 
 
 
 
 
Exercise and Diet Education  
 
X 
 
 
 
 
 
 
 
 
a. Plasma HIV-1 RNA >200 copies/mL will have an additional visit with repeat viral load testing within 2 weeks of receipt of the result. 
The specimen for the HIV-1 viral genotype will be drawn at the same time as the second HIV-1 RNA level; if virologic failure is 
confirmed the reserved specimen will be sent for genotype 
 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations 
 
Screening evaluations to determine eligibility must be completed within 45 days, 
but at least 24 hours, prior to study 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 will be captured in a Screening 
Failure Results form and entered into the ACTG database. 
 
6.2.2 Entry Evaluations 
 
Participants must arrive fasting for the entry visit. Fasting is defined as nothing to 
eat or drink except for prescription medications and water for at least 8 hours 
before the visit. If the study participant is not fasting, the participant should return 
to the clinic for fasting evaluations within 7 days. Entry evaluations must occur at 
least 24 hours after screening evaluations unless otherwise specified. All entry 
evaluations must occur after randomization. Study treatment should be 
initiated as soon as possible after entry evaluations have been completed 
and within 14 days of entry. If study treatment is initiated more than 7 days 
post randomization, please consider scheduling the week 4 post-entry visit 
near the end of the allowed visit window. 
 
Entry evaluations (excluding DEXA imaging) must be completed prior to 
the initiation of study medications. Refer to section 6.3.17, DEXA Scan, for 
scheduling guidance for the DEXA scan at entry (baseline). 
 
6.2.3 Post-Entry Evaluations 
 
Participants must arrive fasting for the weeks 24 and 48 visits, or at a premature 
discontinuation visit. Fasting is defined as nothing to eat or drink except for 
prescription medications and water for at least 8 hours before the visit. If the 
study participant is not fasting, the participant should return to the clinic within the 
visit window per the SOE. 
 
If a participant experiences an acute inflammatory condition within 14 days prior to 
a scheduled visit, any scheduled blood collection evaluation should be postponed 
for an additional 7 days from the initial scheduled visit. Examples of inflammatory 
conditions that would justify delaying blood collection evaluation include an 
infection requiring hospitalization, a systemic viral illness such as an influenza-like 
illness, a severe drug hypersensitivity reaction, myocardial infarction, fever on the 
day of visit (defined as T° >38.5°C), and major trauma. Sites are encouraged to 
contact the A5391 CMC via email (actg.cmcA5391@fstrf.org) with any questions 
regarding whether a specific situation would require a delay in blood collection, 
and determination of whether the inflammatory condition has resolved. 
 


 
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Because of diurnal variations in values that may be measured on stored 
samples, all blood collections should be collected prior to 11:00 AM local time. If 
this is not possible, then participants’ samples should be collected at 
approximately the same time of day (morning or afternoon) throughout the study. 
 
Evaluations at week 4 must occur -3/+7 days of the target visit. 
 
NOTE: If treatment initiation was 7 or more days post-randomization, 
please schedule this visit towards the end of the visit window. 
 
Evaluations at weeks 12, 24, 36, and 48 must occur ±14 days of the target visit. 
 
Study Completion 
The week 48 evaluations will be the participant’s final scheduled study visit. 
Participants must arrive fasting for the study completion visit. Fasting is defined 
as nothing to eat or drink except for prescription medications and water for at 
least 8 hours before the visit. If the study participant is not fasting, the participant 
should return to the clinic for fasting evaluations within the visit window (±14 
days). If additional HIV-1 RNA testing for virologic failure visit is not necessary 
(i.e., plasma HIV-1 RNA is determined to be ≤200 copies/mL at week 48), 
participants should discontinue the study and study treatment once they 
complete their week 48 visit evaluations. Refer to the Discontinuation Log in the 
A5391 electronic case report form (eCRF) completion guideline. 
 
If additional HIV-1 RNA testing for virologic failure visit is necessary (i.e., plasma 
HIV-1 RNA is determined to be >200 copies/mL at week 48 visit), participants 
should discontinue the study only after a repeat HIV-1 RNA is determined to be 
≤200 copies/mL or virologic failure is confirmed and a genotype is sent. In this 
circumstance, the participant should continue on his or her randomized regimen 
until HIV-1 RNA and/or viral genotype results are obtained. Additional DOR can 
be provided to participants in Arms 1 and 2 to ensure continued administration 
until all required testing is completed. Refer to the Discontinuation Log in the 
A5391 eCRF completion guideline. 
 
6.2.4 Event-Driven Evaluations 
 
Confirmation of virologic failure 
• 
Participants with HIV-1 plasma RNA >200 copies/mL on a post-entry 
sample should receive repeat viral load testing within 2 weeks of site receipt 
of the initial result. A genotype can be drawn with the blood for the second 
viral load, but not sent to the lab until virologic failure is confirmed with a 
second viral load >200. 
• 
If virologic failure is confirmed with second HIV-1 plasma RNA >200, then the 
participants will undergo HIV-1 viral genotyping. Participants will discontinue 
treatment after this specimen has been collected. 
 


 
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Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Premature Treatment Discontinuation Evaluations  
Participants who prematurely discontinue/modify any component of their study 
regimen should ideally complete the premature discontinuation evaluations 
(listed in the (SOE)) prior to treatment discontinuation or within 7 days of 
discontinuation. Participants must arrive fasting for the treatment discontinuation 
visit. Fasting is defined as nothing to eat or drink except for prescription 
medications and water for at least 8 hours before the visit. If the study participant 
is not fasting, if possible, the participant should return to the clinic for fasting 
evaluations within 7 days. The premature discontinuation evaluations are listed in 
the SOE. Participants who discontinue the study treatment will still be 
encouraged to remain in study follow-up through 48 weeks. Refer to section 
6.3.17, DEXA Scan, for scheduling guidance for the DEXA scan at 
premature discontinuation. 
 
Premature Study Discontinuation 
Participants who prematurely discontinue from the study will have the study 
discontinuation evaluations performed prior to being taken off the study (listed in 
the SOE). Refer to section 6.3.17, DEXA Scan, for scheduling guidance for 
the DEXA scan at premature discontinuation. 
 
6.3 
Instructions for Evaluations 
 
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 Division of AIDS AE Grading Table and AE 
reporting of adverse events requirements. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per 
protocol should be entered into eCRFs so that the data can be used for analysis 
or to otherwise assist with interpretation of study findings. In such cases, sites 
will be officially instructed to enter the additional data into eCRFs from available 
source documentation. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.3 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 


 
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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 prior 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures (non-traumatic and in adulthood; verbal history accepted) 
• 
Coronary heart disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
Bariatric or other weight loss surgery 
 
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 
Antiretroviral therapy 
Complete ART history, as available 
Immune-based therapy 
Within 2 years prior to entry 
Blinded study treatment 
Complete history 
HIV-1-related vaccines 
Complete history 
Prescription drugs for treatment of 
opportunistic infections 
Within 4 weeks prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 4 weeks prior to study entry 
Prescription drugs (other) 
Within 4 weeks prior to study entry 
Alternative therapies 
Within 4 weeks prior to study entry 
Dietary supplements 
Within 4 weeks prior to study entry 
Diet or weight loss therapy, either 
prescribed or over the counter 
Within 48 weeks prior to study entry 
Sex-hormone medications or sex-
hormone analogues or antagonists* 
Last 48 weeks except as noted below 
Growth hormones 
Complete history 
Other category 
Within 4 weeks prior to study entry 


 
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*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. Also includes hormones 
purchased outside the medical system (i.e., “street hormones”). 
 
6.3.4 Weight History 
 
If/as documentation is available: Weight prior to initiating/switching to 
INSTI-based ART; and annual weight over the following 3 years (i.e., 
approximately 1, 2, and 3 years after initiating or switching to INSTI-based 
ART). Recalled values will not be accepted as documentation. If/as 
available, documentation of known medical reason for weight changes (as 
per investigator opinion), during the time period above―for example, 
concomitant medication use, Cushing’s disease, prolonged hospitalization, 
and so forth. 
 
6.3.5 Clinical Assessments 
 
Complete Physical Examination 
A complete physical examination at entry to include at a minimum an 
examination of the skin, head, mouth, and neck; auscultation of the chest; 
cardiac examination; abdominal examination; and examination of the lower 
extremities for edema. The complete physical examination will also include signs 
and symptoms, diagnoses, and vital signs (temperature, pulse, respiration rate, 
and blood pressure). 
 
Targeted Physical Examination 
A targeted physical examination at study visits after entry is to include vital signs 
(temperature, pulse, respiration rate, and blood pressure), and is to be driven by 
any previously identified or new adverse event, that the participant has 
experienced since the last visit or at this visit. 
 
Post entry, see section 8.2 for collection requirements for pregnancy. 
 
Refer to section 7.2 for AE collection requirements. 
 
Concomitant Medications 
Post-entry, the following new or discontinued concomitant medications must be 
recorded: 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.3 for examples). 
• 
Anti-diabetic medications, antipsychotics, antidepressants, 
anticonvulsants/mood stabilizers, smoking cessation treatments (including 
over the counter), dietary supplements, and weight loss agents (including 
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• 
Growth hormone or growth hormone-releasing analogs 
• 
Any drugs with anti-inflammatory properties 
• 
Any weight loss drugs (including non-prescription) 
• 
Any drugs expected to increase weight 
• 
Thyroid hormones 
 
Study Treatment Modifications 
Record all study drug modifications including initial doses, participant-initiated, 
site investigator-initiated, and/or protocol-mandated modifications, inadvertent 
and deliberate interruptions of more than 5 consecutive days since the last visit, 
and overdose. Record any permanent discontinuation of treatment. 
 
6.3.6 Height Measurement 
 
Height in centimeters should be measured per the SOE. 
 
6.3.7 Weight Measurement 
 
All weight measurements should be conducted with the participant wearing an 
examination gown or a minimum amount of additional clothing (e.g., socks, light 
pants/dress, and thin blouse/shirt are acceptable, but no shoes, outer coat, or 
sweatshirt), and after removal of heavy jewelry (e.g., large necklace) or belt 
buckle, and removal of contents of pockets. Weight should be measured per the 
SOE and with approximately the same type (examination gown) or amount of 
clothing (as described above) on each time. 
 
6.3.8 Waist Circumference 
 
Minimum waist circumference in centimeters should be measured with a 
flexible tape on bare skin at the smallest horizontal circumference above 
the umbilicus and below the xiphoid process per the SOE. 
 
6.3.9 Body Mass Index 
 
Body mass index should be calculated using weight and height collected at 
screening and the formula: BMI = (weight in kilograms)/(height in meters, 
squared). A BMI calculator is available on the Frontier Science Portal. 
 
6.3.10 Laboratory 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 for on-study testing, which is available at 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 


 
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At screening and entry, all laboratory values must be recorded on the eCRF. For 
post-entry assessments, record on the eCRF all laboratory values for ALT, AST, 
serum creatinine, calculated creatinine clearance, alkaline phosphatase, total 
bilirubin, total cholesterol, HDL, calculated LDL, triglycerides, WBC cell count and 
differential and glucose regardless of grade as indicated on SOE; record 
abnormal laboratory findings per section 7.2. 
 
Hematology 
Hemoglobin, hematocrit, white blood cell count [WBC], differential WBC, absolute 
neutrophil count (ANC), and platelets 
 
Liver Function Tests 
Total and direct bilirubin, AST [SGOT], ALT [SGPT], alkaline phosphatase, total 
protein, albumin 
 
Fasting Lipid Profile 
Total cholesterol, triglycerides, HDL, calculated LDL 
 
Chemistry 
Sodium, potassium, chloride, phosphate, bicarbonate, serum creatinine, and 
blood urea nitrogen 
 
Fasting Glucose 
Glucose 
 
Calculated Creatinine Clearance 
Calculated creatinine clearance will be estimated by the CKD-EPI equation (a 
calculator is available at: https://qxmd.com/calculate/calculator_251/egfr-using-
ckd-epi). 
 
Dipstick Urinalysis 
Total protein. 
 
Pregnancy Test 
For participants capable of becoming pregnant: serum or urine β-HCG (urine test 
must have a sensitivity of <25 mIU/mL) performed at Screening, Study Entry, and 
Study Completion visits. Record pregnancy and pregnancy outcome per section 8.0. 
 
NOTE: Additional pregnancy testing should be performed by the site investigator 
if there is concern for pregnancy after study entry. 
 


 
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6.3.11 Immunologic Studies 
 
CD4+/CD8+ T cells 
Obtain absolute CD4+/CD8+ count and percentages at entry and post-entry 
evaluations from a laboratory that possesses a CLIA certification or equivalent 
(US sites) or Immunology Quality Assurance (IQA) certification (non-US sites). 
 
For entry and post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent (US sites) or IQA certification (non-US sites). 
 
6.3.12 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 45 days prior to study entry by a 
laboratory that possesses a CLIA certification or equivalent, or at any network-
approved non-US laboratory that is VQA-certified. Eligibility will be determined 
based on the screening value. 
 
HIV-1 RNA testing will occur at entry, weeks 4, 12, 24, and 48, or at premature 
discontinuation. Participants with one plasma HIV-1 RNA >200 copies/mL on a 
post entry sample will have an additional visit with repeat viral load testing 
within 2 weeks of site receipt of the result (refer to Event-Driven Evaluations in 
section 6.2.4). Screening HIV-1 RNA tests will be performed by the site, while 
entry and post-entry HIV-1 RNA measurements will be performed centrally. 
 
HIV-1 viral genotype 
Participants with two sequential post-entry plasma HIV-1 RNA >200 copies/mL 
measurements will have HIV-1 viral genotype performed (refer to Event Driven 
Evaluations in section 6.2.4). The specimen for the HIV-1 viral genotype will be 
drawn at the same time as the second HIV-1 RNA level; if virologic failure is 
confirmed the reserved specimen will be sent for genotype (refer to laboratory 
processing chart [LPC]). 
 
6.3.13 Metabolic Studies (refer to LPC) 
 
Hemoglobin A1c  
Hemoglobin A1c will be collected at entry, week 24, and week 48 or premature 
discontinuation. 
 
Fasting stored plasma and serum for insulin, immunologic and cardiometabolic 
assays 
Fasting plasma will be collected at entry, week 24, and week 48 or at premature 
discontinuation. 
• 
Insulin will be measured at the end of the study from batched stored samples. 
HOMA-IR (incorporates fasting glucose and insulin levels) to be calculated 
during data analysis, not by the site. 


 
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• 
Measurement of metabolic, cardiovascular, and immunologic biomarkers will 
be performed at central laboratories. Collection, processing, and shipping 
instructions are provided in the current A5391 LPC, which is posted on the 
PSWP. 
 
If a participant arrives for a fasting visit (entry, week 24, and week 48) in a non-
fasting state, the visit should be re-scheduled within the visit window noted in the 
SOE. Participants should be fasting for premature discontinuation visits if possible. 
 
Samples will be stored according to the LPC and are expected to be used for 
measurement of immune biomarkers. Separate samples will be collected (in 
fasting state) to measure insulin, 1,3 beta-glucan, and free fatty acids, in 
addition to stored plasma for immunologic and cardiometabolic testing, 
and stored serum for immunologic and cardiometabolic testing. 
 
6.3.14 Dried Blood Spots (DBS) for drug concentration measurements 
 
DBS cards will be stored to measure concentrations of TFV-DP, both from TDF 
and TAF, and FTC-TP at entry, week 24, week 48, and also at any premature 
discontinuation. Refer to section 11.0. 
 
6.3.15 Stored Peripheral Blood Mononuclear Cells (PBMCs) 
 
PBMCs will be collected and stored at entry and week 48 or premature discontinuation. 
 
PBMCs will be stored according to the LPC and are expected to be used for the 
following advanced flow assays: 
• 
CD4+ and CD8+ T cell subsets (e.g., activated, senescent, and memory) 
• 
Invariant NK T cells (iNKT cells) 
 
NOTE: Advanced flow analysis requires a CD4+/CD8+ and WBC with differential 
from a sample obtained at the same time. 
 
6.3.16 Adherence Assessment 
 
The adherence questionnaire will be administered per the SOE and is posted 
on the DMC Portal in the Forms Management Utility. Responses will be recorded 
on an eCRF in Rave. 
 
6.3.17 DEXA Scan 
 
A whole body DEXA scan for body composition and bone mineral density will be 
obtained. Sites will record requested DEXA scan findings on an eCRF. 
Additional information about reporting requirements and expected 
evaluations is provided in the Manual of Procedures (MOPS). 
 


 
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The DEXA imaging evaluation at entry (baseline) should be completed 
within 14 days prior to or 14 days after the initiation of study treatment. If a 
participant prematurely discontinues the study, the second DEXA imaging 
evaluation should be completed within 14 days prior to or 14 days after the 
premature discontinuation visit. 
 
6.3.18 Food Security and Physical Activity Questionnaires 
 
Food security will be assessed using the USDA Adult Food Security 
Questionnaire. Physical activity will be assessed using the International Physical 
Activity Questionnaire. The questionnaires will be collected from all participants 
at entry only, as indicated in the SOE. The questionnaires are posted on the 
DMC Portal in the Forms Management Utility. Responses will be recorded on an 
eCRF in Rave. 
 
6.3.19 Exercise and Diet Education 
 
At the time point indicated in the SOE, participants will receive general 
recommendations on a balanced diet and regular exercise. Educational materials 
are posted on the PSWP. 
 
Documentation of exercise and diet education is not recorded on the eCRF. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
7.1 
Definition of Adverse Events 
 
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 ≥3 AEs 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting serious adverse event (SAE) definition or expedited adverse event 
(EAE) reporting requirement 
 
NOTE A: SAEs or events meeting EAE reporting requirements should also be entered 
into the DAIDS Adverse Experience Reporting System (DAERS), an Internet-
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NOTE B: Creatinine and eGFR should be graded using the categorical mL/min values 
from the DAIDS AE Grading Table. The percent change criteria will not apply 
to A5391. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the 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. 
 
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 
• 
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 AEs 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.  
 
DAERS, an internet-based reporting system, must be used for EAE reporting to 
DAIDS. In the event of system outages or technical difficulties, EAEs may be 
submitted using the DAIDS EAE Form. This form is available 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. Please note that 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 
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• 
The study agents for which expedited reporting are required are: DOR, TAF, 
TDF, FTC, and 3TC. 
 
7.3.3 Grading Severity of Events 
 
The 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. 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as per the EAE manual. 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the 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 
 
Members of the protocol team will monitor the conduct and safety of the study via 
regular pooled summaries of accrual, baseline characteristics, treatment and study 
discontinuation, and data completeness. 
 
The study will enroll >50% women and >50% African American/Black participants. For 
the purpose of enrollment limits, a woman is defined as someone assigned female sex 
at birth. The protocol team may assign overall study enrollment limits for sex at all sites 
and race at US sites, or site-specific enrollment limits. 
 
The protocol team will monitor enrollment by sex and race, with periodic updates issued 
to sites to inform on current study enrollment by sex and race, as needed. At the outset 
of the study, sites will be encouraged to prioritize enrollment of women and African 
American/Black participants, and will be alerted that restrictions on enrollment may later 
be enacted to achieve enrollment targets. The protocol team, in consultation with the 
Statistical and Data Management Center, will review the sex and race distributions after 
approximately 25%, 50%, and 75% of enrollment has occurred. 
 
The DAIDS Clinical Representatives will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct per DAIDS policies, 
guidance documents, and Standard Operating Procedures (SOPs), as applicable. 
Additionally, the DAIDS clinical representatives and the protocol monitoring team will 
review aggregated AE summaries and virological failures pooled across treatment arms 
prepared quarterly by the SDAC. 
 
The study will undergo interim review at least annually by an ACTG-appointed Study 
Monitoring Committee (SMC). The SMC will review unblinded, by-arm summaries of 
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discontinuations), data availability/completeness, virologic failures, and AEs. The first 
interim review will occur no more than 1 year after the enrollment of the first study 
participant. An interim review may also be convened if a concern is identified by the DAIDS 
clinical representatives, the study chairs, or study statisticians in consultation with the team. 
See section 10.0 for statistical and other considerations related to interim monitoring. 
 
Detailed plans for study monitoring are outlined in a Study Progress, Data, and Safety 
Monitoring Plan (SPDSMP) developed by the Statistical and Data Management Center 
(SDMC) prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity 
 
Only toxicities related to antiretroviral drugs (study-provided or participant-supplied) will 
be considered in the toxicity management section. The grading system is located in the 
DAIDS AE Grading Table, corrected Version 2.1, July 2017: 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
The general guidelines presented in sections 8.1.1, 8.1.2, and 8.1.3 apply to toxicities 
that are not specifically discussed elsewhere. 
 
8.1.1  Grade 1 or 2 
 
Participants who develop a Grade 1 or 2 AE or toxicity may continue study 
treatment without alteration of the dosage. For participants experiencing Grade 1 
or 2 AEs who choose to discontinue all study treatment, the site investigator 
should complete premature treatment discontinuation evaluations, contact the 
study leadership team (actg.cmca5391@fstrf.org), and the participant should be 
encouraged to stay in study follow-up until 48 weeks. 
 
NOTE: If participants discontinue study treatment due to experiencing Grade 1 or 
2 AEs, the AEs should be recorded as the reason for discontinuation. 
 
8.1.2 Grade 3 
 
Grade 3 AEs or toxicity should be evaluated and managed by the site 
investigator. The A5391 CMC should be notified at actg.cmca5391@fstrf.org 
regarding AEs or toxicities that result in a change of study treatment. If the site 
investigator has compelling evidence that the AE or toxicity was NOT caused by 
the study treatment, dosing may continue. 
 
If the study treatment is temporarily held, the participant should be re-evaluated 
frequently until the AE or toxicity returns to Grade ≤2, at which time the study 
treatment may be reintroduced at the discretion of the site investigator or 
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If the site investigator determines that an isolated Grade 3 laboratory abnormality 
(lab abnormality without a clinical AE) is related to study treatment, the site has 
the option of confirming the AE or toxicity before holding the study treatment. 
 
If the same Grade 3 AE or toxicity recurs within 4 weeks of reintroducing the 
study treatment and is thought to be related to the study treatment (per the site 
investigator), the study treatment must be permanently discontinued. However, if 
the same Grade 3 AE or toxicity recurs after 4 weeks, and is not thought to be 
related to the study treatment (per the site investigator), the management 
scheme outlined above may be repeated. 
 
If a participant permanently discontinues study treatment as a result of the Grade 3 
AE, the site should complete the premature study treatment discontinuation 
evaluations as defined in the SOE as soon as possible and the participant should 
be followed frequently until resolution of the AE. See section 6.2.4 for management 
of participants who prematurely discontinue study treatment. Participants should be 
encouraged to stay in study follow-up until week 48. 
 
8.1.3 Grade 4 
 
Participants who develop a Grade 4 symptomatic AE (clinical or laboratory) 
related to study drug will have all study treatment permanently discontinued. The 
study leadership team (actg.cmca5391@fstrf.org) must be notified by e-mail 
regarding these toxicities to discuss further management. If participants 
experience Grade 4 AEs requiring permanent discontinuation of all study 
medications, the site should ideally complete the premature study treatment 
discontinuation evaluations as soon as possible per the SOE and the participants 
should be followed frequently until resolution of the AE. See section 6.2.4 for 
management of participants who prematurely discontinue study treatment. 
Participants should be encouraged to stay in study follow-up until week 48. 
 
The participant should be re-evaluated frequently until the AE returns to Grade ≤2 
or baseline. 
 
8.1.4 Creatinine Clearance 
 
Creatine clearance should be calculated at screening, entry, and weeks 4, 12, 
24, and 48 weeks (or premature discontinuation). Any participant experiencing a 
calculated CrCl <50 mL/min should have the value repeated within 7 days. 
 
8.1.4.1 FTC/3TC 
 
All study participants will be on FTC or 3TC as part of their regimen. Participants 
who experience a confirmed (two consecutive) reduction in CrCl to <50 mL/min 
should have their FTC or 3TC dose reduced as indicated on the package insert, 
at the discretion of the site investigator. 
 


 
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8.1.4.2 TDF 
 
Participants who experience a confirmed (two consecutive) reduction in CrCl to 
<50 mL/min on TDF should have their TDF dose reduced as indicated on the 
package insert, at the discretion of the site investigator. 
 
8.1.4.3 TAF 
 
Participants who experience a confirmed (two consecutive) reduction in CrCl to 
<30 mL/min on TAF should have their TAF dose reduced as indicated on the 
package insert, at the discretion of the site investigator. 
 
8.1.5 Hyperlactatemia/Lactic Acidosis 
 
The following case definition of symptomatic hyperlactatemia/lactic acidosis will 
be used in this protocol: 
 
New, otherwise unexplained and persistent (≥2 weeks) occurrence of one or 
more of the following symptoms: 
 
• 
Nausea and vomiting 
• 
Abdominal pain or gastric discomfort 
• 
Abdominal distention 
• 
Elevated liver function tests 
• 
Unexplained fatigue 
• 
Dyspnea 
• 
Concern for hyperlactatemia/lactic acidosis should be confirmed by 
measurement of serum lactate level at the discretion of the site investigator. If 
a lactate level >2 x ULN is confirmed, participants should immediately 
discontinue their study medications and the team (actg.cmca5391@fstrf.org) 
should be contacted to plan further treatment. 
 
8.2 
Pregnancy 
 
Participants in Arm 1 or 2 who become pregnant on study must discontinue DOR and 
should receive a new regimen in accordance with current WHO guidelines for treatment 
of PWH who become pregnant while on ART. Participants who become pregnant may 
remain in follow-up off study treatment. All participants who become pregnant while on 
study will be followed through the end of pregnancy to determine the effects of the study 
regimens on outcomes in the exposed infants. For participants who become pregnant 
while receiving DTG please see the MOPS for further management. 
 
Participants who become pregnant, and who have access to an International Maternal 
Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) trial site, should be 
encouraged to enroll in appropriate IMPAACT studies. 
 


 
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The intrapartum complications, pregnancy, and pregnancy outcome will be recorded on 
the eCRFs. Pregnancies that occur on study should be reported prospectively to the 
Antiretroviral Pregnancy Registry. More information is available at www.apregistry.com. 
Phone: 1-800-258-4263; Fax: 1-800-800-1052. 
 
Pregnancy Reporting 
Participants who become pregnant while on study drugs and discontinue DOR due to 
their pregnancy will be asked to remain on study, off study treatment. Sites will complete 
the premature discontinuation visit within 7 days after stopping treatment (except for 
DEXA scan and any aspects deemed by the site investigator to be potentially harmful). If 
a participant has completed the study or chooses to discontinue from the study before 
the end of the pregnancy, then site staff should complete a study discontinuation visit 
within 7 days and request permission to contact the participant regarding pregnancy 
outcome at the end of the pregnancy. Any intrapartum complications, pregnancy, and 
pregnancy outcome for the participant and infant (if known) should be recorded on the 
eCRFs. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.1 Toxicity). 
• 
Requirement for concomitant medications (see section 5.4). 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
the Toxicity section of the protocol. 
• 
Pregnancy 
 
9.2 
Premature Study Discontinuation 
 
• 
Request by the participant to withdraw. 
• 
Failure/inability of participant to attend study visits. 
• 
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 IRB/EC, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
The study’s primary objective is to evaluate if a switch to either DOR + TAF/FTC (or 
TAF/3TC) or DOR + TDF/FTC (or TDF/3TC) results in a difference (less weight gain or 
overall weight loss) in weight change over 48 weeks compared to continued use of RAL, 
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switch arms (DOR + TAF/FTC [or TAF/3TC] versus DOR + TDF/FTC [or TDF/3TC]) to 
assess if there are additional weight benefits with a switch to TDF/FTC (or TDF/3TC) 
from TAF/FTC (or TAF/3TC). 
 
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 are to be listed under “Other Outcome 
Measures.” 
 
10.2.1 
Primary Outcome Measures 
 
Change (percent) in body weight (kg) from entry to week 48. 
 
10.2.2 
Secondary Outcome Measures 
 
10.2.2.1 Change (percent) in body weight (kg) from entry to week 24. 
 
10.2.2.2 Change (absolute) in waist circumference from entry to weeks 24 and 48. 
 
10.2.2.3 Change (absolute) in fasting cardiometabolic parameters (glucose, 
insulin, HOMA-IR, triglycerides, LDL, HDL) from entry to weeks 24 
and 48. 
 
10.2.2.4 Occurrence of confirmed plasma HIV-1 RNA >200 copies/mL. 
 
10.2.2.5 Occurrence of Grade ≥3 AEs or >10% reduction in CrCl as estimated 
by the CKD-EPI equation. 
 
10.2.2.6 Occurrence of premature discontinuation of study treatment. 
 
10.2.2.7 Change (percent) in DEXA body composition measures (total fat and 
lean mass, trunk fat, limb fat, appendicular lean mass) from entry to 
week 48. 
 
10.2.2.8 Change (percent) in DEXA hip and lumbar spine bone mineral density 
from entry to week 48. 
 
10.2.2.9 Change in categorization of bone mass (by WHO classification) 
from baseline to week 48 based on minimum reported T score 
from left/right femoral neck, left/right total femur/hip, and lumbar 
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10.2.3 
Other Outcome Measures 
 
10.2.3.1 Change (absolute) in immunologic parameters from entry to weeks 
24 and 48. 
 
10.2.3.2 Change (absolute) in plasma adipokines from entry to weeks 24 and 48. 
 
10.2.3.3 Change in blood concentrations of TFV-DP both from TDF and TAF, 
and FTC-TP, measured from DBS, from entry enrollment to weeks 24 
and 48. 
 
10.3 
Randomization and Stratification 
 
All eligible participants will be randomized using a 1:1:1 ratio to one of three study arms: 
switch to DOR + TAF/FTC (or TAF/3TC), switch to DOR + TDF/FTC (or TDF/3TC), or 
continued INSTI + TAF/FTC (or TAF/3TC), using permuted blocks with institutional 
balancing. Participants will be stratified at randomization by sex assigned at birth and 
race (African American/Black vs. non-African American/Black). Participant enrollment 
targets are >50% participants assigned female sex at birth across all sites and >50% 
African American/Black participants at US sites. 
 
10.4 
Sample Size and Accrual 
 
The proposed sample size is 222 participants (74 per arm). It is anticipated that 
participants will accrue to the study at a rate of 20 participants per month at an estimated 
14 sites (12 US and 2 non-US); at this rate, the study should fully accrue in 
approximately 11-12 months. 
 
A total of 222 participants will be randomized at a 1:1:1 ratio to the three arms. Allowing 
for 15% loss to follow-up this will yield 189 evaluable participants (63 per arm). This 
sample size will provide 80% power to detect an absolute difference of 5% at week 48 
between each switch arm and the control arm (continuing INSTI), assuming the standard 
deviation (SD) of within-participant changes is 9%, using two-sided t-tests with 2.5% 
alpha level. Each switch arm will be compared to the control arm using a 2.5% alpha 
level to control the overall type-I error rate. The study is powered to detect a 5% 
difference in weight between arms, as a 5% absolute difference is considered clinically 
meaningful. 
 
At present, prospective, randomized controlled trial data on weight changes on INSTI + 
TAF/FTC are only available from sub-Saharan African studies (ADVANCE trial, see 
above), which may differ from the majority of ACTG sites by clinical, social, behavioral, 
genetic, and other factors. There are also limited data on DOR aside from recent 
abstract data, which showed a median 1.0 kg (IQR -1.2 to 3.9) weight gain at 48 weeks 
among ART-naïve persons initiating DOR in pooled phase 2 and 3 studies [25]. 
Therefore, the sample size, and specifically the assumed SD, for A5391 is based on 
ACTG A5257 trial data comparing INSTI + TDF/FTC vs non-INSTI + TDF/FTC. 
 


 
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In A5257, among individuals who remained on RAL and who had BMI ≥30 at 48 weeks, 
the SD for the change in weight from week 48 to week 96 (i.e., approximately 48 weeks) 
was 7% (mean change -0.03%). During the first 96 weeks, however, where larger 
changes in weight occurred, the SD for the change in weight was 11%. The 9% SD 
chosen for this study is intermediate of the SDs observed from A5257 and is a 
conservative approach to ensure that A5391 is well powered to detect differences 
between arms. 
 
The table below provides a summary of statistical power based on a range of possible 
SD estimates. 
 
Table 10.4-1: Statistical Power under Different Scenarios Assuming: N=63 Evaluable 
per Arm 
Two Sample T-test with Two-sided 2.5% Alpha 
Power 
Mean Difference between 
arms 
Standard Deviation for 
change within arm 
99% 
5% 
5% 
96% 
5% 
7% 
80% 
5% 
9% 
61% 
5% 
11% 
 
10.5 
Data and Safety Monitoring 
 
An ACTG-appointed Study Monitoring Committee (SMC) will undertake reviews of 
interim data to ensure safety of study participants and to possibly recommend 
termination or modification of the study. At SMC reviews, data will be considered as 
detailed in section 7.4. 
 
At each interim review, the SMC will review unblinded summaries, by randomized arm, 
of study status and, including loss to follow-up (LTFU), treatment discontinuations and 
cross-over, and safety, including virologic failures and adverse events. Interim efficacy 
analyses are not planned. 
 
There are no pre-specified stopping guidelines for this study, but the SMC should 
consider possible modifications or termination on bases of safety concerns or 
operational futility. With regards to safety, if 10% or more of participants on the DOR-
containing arms experienced virologic failure or treatment-related AEs, this would be 
concerning to the study team. However, the DRIVE-SHIFT phase 3, open-label, 
randomized noninferiority trial showed comparable maintenance of virologic suppression 
among ART-treated persons switched from INSTI-based regimens to DOR/3TC/TDF. 
With respect to operational futility the SMC should consider the overall and within arm 
LTFU rates, and treatment cross-over rates (particularly those switching from DOR-
containing arm back to an INSTI-containing arm). As a benchmark, an overall LTFU rate 
of 20% or higher would be cause for concern, particularly if a higher rate is observed in 
the INSTI-containing arm where participants are not switched to DOR. 
 


 
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10.6 
Analyses 
 
The primary analysis will contrast each switch arm (DOR + TAF/FTC [or TAF/3TC] or 
DOR + TDF/FTC [or TDF/3TC]), separately, with the control arm (remaining on INSTI + 
TAF/FTC [or TAF/3TC]). A secondary analysis will then compare the two switch arms 
with each other to determine if there are added effects of switching from TAF/FTC (or 
TAF/3TC) to TDF/FTC (or TDF/3TC); the switch arms will be compared regardless of the 
observed results for the primary comparisons. Figure 10.6-1 depicts the planned 
comparisons. 
 
 
Figure 10.6-1: Planned comparisons. 
 
NOTE: Analyses will be conducted on the entire trial sample, irrespective of 
history of weight gain (i.e., protocol version at enrollment). History of >10% weight 
gain will be a prespecified subgroup, but this subgroup analysis could be limited 
by the availability of historical weight information among participants enrolling to 
the trial under the current version, when this information is not required. 
 
10.6.1 
Primary Analysis  
 
The primary analysis will compare the percent change in weight (kg) from entry 
to week 48. The mean percent change in weight at week 48 will be compared 
separately between each of the investigational switch arms and the control arm 
using linear regression adjusting for stratification factors, with a 2.5% type-I 
error rate; corresponding 97.5% confidence intervals (CIs) will also be provided. 
It is of secondary interest to contrast the two switch arms (see below). The 
primary analysis will be conducted using intent-to-treat (ITT) principles, in which 
participants will be analyzed according to their randomized study arm, 
regardless of whether they changed treatment during study follow-up. A 
supplemental analysis will restrict the analysis population to only those who 
remained on their randomized regimens through week 48. 
 
In the event that participants discontinue the study prior to week 48, imputation 
methods will be used to estimate weight at week 48. Modern statistical methods 
to account for loss to follow-up will be considered, such as multiple imputation, 
global sensitivity analysis, or inverse probability of censoring weighting; specific 
details will be discussed in the Statistical Analysis Plan. 
 


 
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10.6.2 
Secondary Analysis 
 
To further understand the effect of TAF on weight gain, the two switch arms will 
be compared to each other. The mean percent change in weight at week 48 will 
be compared between the DOR + TAF/FTC (or TAF/3TC) arm and the DOR + 
TDF/FTC (or TDF/3TC) arm using linear regression adjusting for stratification 
factors with a 5% type-I error; corresponding 95% CI will be provided. 
 
Changes in weight from entry to week 24, changes in minimum waist 
circumference, and fasting cardiometabolic parameters from entry to weeks 24 
and 48, and changes DEXA measures from entry to week 48 will be analyzed in 
a similar manner as the analyses of weight changes. Sensitivity analyses of 
changes in triglycerides, LDL, and HDL will consider on-study use of lipid-
lowering medications by participants. 
 
Safety, tolerability, and maintenance of virologic suppression will be evaluated 
by estimating the proportion of participants who experienced any Grade 3 or 
higher AE or >10% reduction in CrCl, who prematurely discontinued study 
treatment, or who have confirmed post-entry plasma HIV-1 RNA > 200 
copies/mL, and will be compared separately between each switch arm and the 
control arm via two-sided mid-p Fisher’s exact test, each evaluated with 2.5% 
type-I error. 
 
Additional longitudinal analyses will evaluate changes in weight across all study 
visits. Details will be provided in the Statistical Analysis Plan. 
 
11.0 
PHARMACOLOGY PLAN 
 
DBS cards will be stored to measure concentrations of TFV-DP, both from TDF and 
TAF, and FTC-TP at entry, week 24, and week 48 (or at premature discontinuation). 
Interpretation of the FTC-TP levels requires information on the timing of ART doses over 
the preceding 3 days. Therefore, the date/time of INSTI, DOR, TDF, TAF, and FTC (or 
3TC) doses, depending on study arm, for the three days preceding the entry, week 24, 
and week 48 study visits should be recorded on the eCRF. 
 
12.0 
DATA COLLECTION AND MONITORING 
 
12.1 
Records to Be Kept 
 
eCRF screens will be made available to sites for data entry. Participants must not be 
identified by name on any data submitted to the DMC. Participants will be identified by 
the patient identification number (PID) and study identification number (SID) provided by 
the ACTG DMC upon randomization. 
 


 
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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 
 
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 [27]. 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 
Solutions. Other secure platforms that are 21 CFR Part 11 compliant may be utilized, 
as allowed by the DAIDS Office of Clinical Site Oversight (OCSO). 
 
12.4 
Reporting Protocol Deviations 
 
The site principal investigator and staff are responsible for identifying and 
reporting deviations. If protocol deviations are identified, corrective actions are to 
be developed by the site and implemented promptly. Protocol deviations must be 
reported to the IRB/EC per their guidelines. 
 
Refer to the MOPS for the definition of protocol deviation and instructions for 
completing the study protocol deviation eCRF. 
 
13.0 
PARTICIPANTS 
 
13.1 
IRB Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study. A signed consent form will be obtained from the participant (or parent, 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 and this fact will be documented in the participant’s record. 
 


 
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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, NIAID, OHRP, 
other local, US, and non-US regulatory entities as part of their duties, or the industry 
supporter or designee. 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, NIAID, OHRP, other 
country-specific government agencies as part of their duties to ensure that research 
participants are protected, or by the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission. 
 
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 US CDC and 
the US 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. Koethe JR, Jenkins CA, Lau B, et al. Rising obesity prevalence and weight gain among 
adults starting antiretroviral therapy in the United States and Canada. AIDS Res Hum 
Retroviruses 2016;32:50-8. 
2. Hasse B, Iff M, LedergerberB, et al. Obesity trends and body mass index changes after 
starting antiretroviral treatment: the Swiss HIV Cohort Study. Open Forum Infect Dis 
2014;1(2):ofu040. PMID: 25734114 
3. Ilozue C, Howe B, Shaw S, et al. Obesity in the HIV-infected population in Northeast 
England: a particular issue in Black-African women. Int J STD AIDS 2017;28:284-9.  
4. Tate T, Willig AL, Willig JH, et al. HIV infection and obesity: where did all the wasting 
go? Antivir Ther 2012;17:1281-9. PMID: 22951353 
5. Amorosa V, Synnestvedt M, Gross R, et al. A tale of 2 epidemics: the intersection between 
obesity and HIV infection in Philadelphia. J Acquir Immune Defic Syndr 2005;39:557-61. 
6. Herrin M, Tate JP, Akgun KM, et al. Weight Gain and incident diabetes among HIV-
infected veterans initiating antiretroviral therapy compared with uninfected individuals. J 
Acquir Immune Defic Syndr 2016;73:228-36. PMID: 27171741 
7. Yuh B, Tate J, Butt AA, et al. Weight change after antiretroviral therapy and mortality. 
Clin Infect Dis 2015;60:1852-9. PMID: 25761868 
8. McCutchan JA, Marquie-Beck JA, Fitzsimons CA, et al.; CHARTER Group. Role of 
obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder. 
Neurology 2012;78:485-92. PMID: 22339412 
9. Mohammed SS, Aghdassi E, Salit IE, et al. HIV-positive patients with nonalcoholic fatty 
liver disease have a lower body mass index and are more physically active than HIV-
negative patients. J Acquir Immune Defic Syndr 2007;45:432-8. PMID: 17558337 
10. Achhra AC, Mocroft A, Reiss P, et al.; D:A:D Study Group. Short-term weight gain after 
antiretroviral therapy initiation and subsequent risk of cardiovascular disease and 
diabetes: the D:A:D study. HIV Med 2016 ;17:255-68. PMID: 26216031 
11. Rebeiro PF, Jenkins CA, Bian A, et al. Risk of incident diabetes mellitus, weight gain, 
and their relationships with integrase inhibitor-based initial antiretroviral therapy among 
persons with human immunodeficiency virus in the United States and Canada. Clin 
Infect Dis 2021;73:e2234-e2242. PMID: 32936919 
12. Bhagwat P, Ofotokun I, McComsey GA, et al. Changes in waist circumference in HIV-
infected individuals initiating a raltegravir or protease inhibitor regimen: effects of sex 
and race. Open Forum Infect Dis 2018;5:ofy201. PMID: 30465010 
13. Bourgi K, Jenkins C, Rebeiro P, et al. Greater weight gain among treatment-naive 
persons starting integrase inhibitors compared to non-nucleoside reverse transcriptase 
inhibitors or protease inhibitors in a large observational cohort in the United States and 
Canada. J Int AIDS Soc 2020;23:e25484. PMID: 32294337 
14. Bakal DR, Coelho LE, Luz PM, et al. Obesity following ART initiation is common and 
influenced by both traditional and HIV-/ART-specific risk factors. J Antimicrob 
Chemother 2018;73:2177-85. 


 
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15. Rizzardo S, Lanzafame M, Lattuada E, et al. Dolutegravir monotherapy and body weight 
gain in antiretroviral naive patients. AIDS 2019;33:1673-4. PMID: 31305333 
16. Bourgi K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment-naive persons 
starting dolutegravir-based antiretroviral therapy. Clin Infect Dis 2020;70:1267-74. 
17. Norwood J, Turner M, Bofill C, et al. Brief Report: Weight gain in persons with HIV 
switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. J 
Acquir Immune Defic Syndr 2017;76:527-31. PMID: 28825943 
18. Erlandson KM, Wu K, Lake JE, et al.; A5501, A5322 Protocol Teams. Mitochondrial DNA 
haplogroups and weight gain following switch to integrase strand transfer inhibitor-based 
antiretroviral therapy. AIDS 2021;35:439-45. PMID: 33252493 
19. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of 
tenofovir to treat HIV. N Engl J Med 2019;381:803-15. PMID: 31339677 
20. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral 
therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis 
2020;71:1379-89. PMID: 31606734 
21. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in 
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a 
randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 2018;5:e211-e20.  
22. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil 
fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in 
treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results 
of the DRIVE-AHEAD trial. Clin Infect Dis 2019;68:535-44. PMID: 30184165 
23. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Doravirine dose selection and 96-
week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults 
with HIV-1 infection in a Phase IIb trial. Antivir Ther 2019;24:425-35. PMID: 
31355775 
24. Johnson M, Kumar P, Molina JM, et al.; DRIVE-SHIFT Study Group. Switching to 
doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains HIV-1 
virologic suppression through 48 weeks: results of the DRIVE-SHIFT trial. J Acquir 
Immune Defic Syndr 2019;81:463-72. PMID: 30985556 
25. Orkin C, Elion RA, Thompson M, et al. Changes in weight and BMI with first-line 
doravirine-based therapy. AIDS 2021;35:91-9. PMID: 33048879 
26. IAS-USA drug resistance chart 2019. Available at https://www.iasusa.org/wp-
content/uploads/2019/07/2019-drug-resistance-mutations-figures.pdf. Accessed 
December 26, 2019. 
27. 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: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
For protocol: A5391 
 
Doravirine for Obese Persons on Integrase Inhibitors and Tenofovir Alafenamide 
 (The Do IT Study) 
FINAL Version 2.0, dated 19Aug2022 
 
 
 
SHORT TITLE FOR THE STUDY: The Do IT Study 
 
SUMMARY 
 
PURPOSE 
This is a research study, and your participation in this study is voluntary. 
 
The purpose of this study is to see whether obese (body mass index 
≥30 kg/m2) people living with HIV who are receiving an antiretroviral 
therapy (ART) regimen that includes an integrase strand transfer inhibitor 
(INSTI) in combination with tenofovir alafenamide/emtricitabine 
(TAF/FTC) or tenofovir alafenamide/lamivudine (TAF/3TC) could gain 
less weight, or might lose weight, after an ART regimen switch. The study 
will also assess if a switch in ART leads to differences in metabolic 
conditions (i.e., how the body stores and uses energy), cardiovascular 
health (i.e., the heart and blood vessels), and bone health. 
 
NUMBER OF  
PARTICIPANTS 
There will be 3 treatment groups of 74 people each, for a total of 222 
participants. 
 
LENGTH OF  
STUDY  
The study will last for 48 weeks (about 1 year). Following the first visit, 
you will need to come back to the clinic after about 4, 12, 24, 36, and 48 
weeks. You will need to fast for 8 hours before a few visits. Each visit may 
take up to 3 hours. You will not need to stay overnight. 
 
STUDY 
TREATMENT 
Participants age ≥18 years on bictegravir (BIC), dolutegravir (DTG), or 
raltegravir (RAL) with TAF/FTC or TAF/3TC (depending on location) will 
be assigned by chance 1:1:1 (i.e., equally) to: 
• 
Doravirine (DOR) with TAF/FTC (or TAF/3TC) 


 
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• 
DOR with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (or 
TDF/3TC) 
• 
Continue on their current regimen 
 
DOR will be provided to study participants through the study but 
nucleoside reverse transcriptase inhibitors (TAF/FTC [or TAF/3TC] and 
TDF/FTC [or TDF/3TC]) and the INSTI medications for those remaining 
on their current regimen will not be provided by the study. 
 
REQUIRED  
ACTIVITIES 
Blood and urine collections 
At most visits, some blood (about 2 to 6 tablespoons) will be collected 
from a vein in your arm. 
At a few visits, you will be asked to provide a urine sample. 
 
Questionnaires 
At the Entry Visit, you will complete questionnaires on food security and 
physical activity. At each visit after entry you will complete a 
questionnaire on medication adherence. 
 
Special procedures 
You will have a dual-energy X-ray absorptiometry (DEXA) scan at two 
visits to measure your lean muscle and body fat, and your bone density. 
 
RISKS 
Risks of participating in this study include side effects from drugs used in 
this study or the risk of loss of HIV-1 viral suppression (i.e., a rise in the 
level of virus in the blood, which may require a change in your HIV 
medications). 
 
BENEFITS 
No direct benefits should be expected from participating in this study. 
 
You may have weight loss, but no guarantee can be made. 
 
OTHER CHOICES  
Instead of being in this study, you have the option of continuing with your 
current treatment or starting a new treatment under the care of your 
regular doctor or other health care provider. 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you have HIV (the virus that 
causes AIDS), you have a body mass index that is in the obese range, and you are taking 
an antiretroviral therapy (ART) regimen that contains an integrase strand transfer inhibitor 
(INSTI; a class of drug that includes bictegravir, dolutegravir, and raltegravir) combined with 
tenofovir alafenamide/emtricitabine (TAF/FTC) or tenofovir alafenamide/lamivudine (TAF/3TC). 
 


 
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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? 
 
Weight gain after starting ART is common, but recent studies have found that some people with 
HIV who are taking an INSTI combined with TAF/FTC (or TAF/3TC) may gain more weight than 
people taking other drug combinations. Weight gain on ART can be healthy for persons who are 
underweight when they start treatment. However, an increasing number of people with HIV 
(PWH) are obese, which may increase their risk for cardiovascular (heart) and metabolic 
diseases (such as diabetes).  
 
It is currently unknown whether people who are obese and taking an INSTI + TAF/FTC (or 
TAF/3TC) regimen could either slow the rate of weight gain or could actually lose weight by 
changing their ART. 
 
The primary purpose of this study is to see if obese PWH who are taking an INSTI + TAF/FTC 
(or TAF/3TC) regimen could either slow their rate of weight gain or lose weight within about 1 
year if they switch to a regimen containing doravirine (DOR; a newer, non-nucleoside reverse 
transcriptase inhibitor medication). The study will also try to see if participants changing from 
TAF/FTC (or TAF/3TC) to TDF/FTC (or TDF/3TC) will experience less additional weight gain or 
a reduction in overall body weight at 48 weeks compared to persons continued on an INSTI + 
TAF/FTC (or TAF/3TC) combination. Additionally, the study will see whether a change in ART 
can affect things like waist circumference, metabolic and cardiovascular health, fat and lean 
mass body composition, bone health, and maintenance of virologic suppression. Finally, the 
study will look at the safety and tolerability of DOR plus either TAF/FTC (or TAF/3TC) versus 
TDF/FTC (or TDF/3TC). 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
When you enter this study, you will be randomized (assigned by chance, as if by roll of dice) to 
one of three study groups. Because the randomization is equal, you will have a 33% chance of 
being in any of the following study groups:  
1. Group 1: You will continue taking TAF/FTC (or TAF/3TC) but will stop your INSTI and take 
DOR; your ART will be DOR + TAF/FTC (or TAF/3TC) for 48 weeks. 
2. Group 2: You will stop your INSTI and TAF/FTC (or TAF/3TC) and will switch to DOR + 
TDF/FTC (or TDF/3TC) for 48 weeks. 
3. Group 3: You will continue your current ART of an INSTI + TAF/FTC (or TAF/3TC) for 48 
weeks. 
 


 
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DOR will be provided to study participants in Groups 1 and 2 through the study. Nucleoside 
reverse transcriptase inhibitors (TAF/FTC [or TAF/3TC] and TDF/FTC [or TDF/3TC]) will not be 
provided by the study. 
 
The study will last 48 weeks (approximately 1 year). After the Entry Visit, you will return to the 
clinic at 4, 12, 24, 36, and 48 weeks. Each visit may take up to 3 hours. You will not need to 
stay overnight for any of the visits.  
 
You must fast (have nothing to eat or drink other than medications and water for at least 8 
hours) before the first visit. You will be asked to fast again before the visits 24 and 48 weeks 
later.  
 
You will remain on your study group ART for the entire study unless your usual health provider 
or the study doctor makes a change. If you leave the study early, you will have a final study visit 
which may take up to 3 hours. 
 
At most visits, some blood (about 2 to 6 tablespoons) will be collected from a vein in your arm, 
you will have a brief physical exam including measurement of weight and waist circumference, 
and you will be asked a series of questions about your health, how you are taking your study 
treatment, what you have been eating and drinking while in the study, and your recent physical 
activity. At a few visits, you will be asked to provide a urine sample. At the Entry Visit you will 
also have a complete physical exam, medication and medical histories, and exercise and diet 
education. At the Entry Visit and then again after 48 weeks, you will have a dual-energy X-ray 
absorptiometry (DEXA) scan to measure your lean muscle and body fat, and your bone density. 
This will take approximately 30 minutes.  
 
Persons capable of becoming pregnant will have serum or urine pregnancy testing at the 
Screening, Entry, and Study Completion Visits, and if there is a concern for pregnancy after 
study entry. 
 
The level of HIV virus in your blood will be measured at Study Entry and at 4, 12, 24 and 48 
weeks. Participants found to have more than 200 copies of HIV virus per milliliter of blood will 
have an additional visit to repeat the test measuring HIV virus within 2 weeks of the study site 
receiving the first result. 
 
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 
example, disease condition, diagnosis, height, and weight), and laboratory (for example, CD4 
cell count, viral load) information will be collected from you. We also will collect information on 
whether you use (or have used) injection drugs. 
  
We will collect this information even if you do not enroll in this study so that ACTG researchers 
may determine whether there are patterns and/or common reasons why people do not join a study. 
 
 


 
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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 as what we call “samples” and used for study-required 
metabolic, cardiovascular, immunologic, study drug levels, and virologic testing.  
Identifiers (for example, your name and date of birth) 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.  
  
More information about the storage of extra samples and use in other studies are provided in 
Attachment A. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 222 people will take part in this study (3 treatment groups of 74 people each). 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 48 weeks.  
 
 
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 are not able to attend the study visits as required by the study 
 
The study doctor may also need to take you off the study treatment without your permission if: 
 
• 
Continuing the study treatment may be harmful to you 
• 
You need a drug that you may not take while on the study 
• 
You are not able to take the study treatment as required by the study 
• 
You become pregnant  
• 
Your doctor (primary care provider) requests that you come off the study because they 
think that the study is no longer in your best interest 
 
If you must stop taking the study treatment before the study is over, the study doctor may ask 
you to continue to be part of the study and return for some study visits and procedures. 
 


 
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If I have to permanently stop taking study-provided drug, or once I leave the study, how would 
that drug be provided? 
During the study: 
 
If you must permanently stop taking DOR before your study participation is over, 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 DOR. If continuing to take this or similar drugs would be of benefit to you, the 
study staff will discuss how you may be able to obtain them through your usual health care. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks from participating in this study include risks from the study procedures and risks 
associated with a switch to different ART. 
 
Study procedures: 
• 
Blood collection: The study staff will use a standard-sized blood-drawing needle, but this 
may still cause pain, redness, soreness, bruising, or infection at the needle entry point. 
Rarely, some people faint. 
• 
Whole body DEXA scan: This test requires exposure to x-rays. The amount of exposure is 
approximately equal to the exposure you would receive over a period of about 9 days from 
natural background sources. 
 
Study medications: 
Participation in this study may include changing one or two of your current anti-HIV medications. 
All medications used in this study have obtained regulatory approval by the Food and Drug 
Administration (US sites) or appropriate national regulatory bodies (non-US sites). This means 
that regulators have reviewed the existing evidence and concluded that the medications’ clinical 
benefits (i.e., how much the medications improve health) for patients outweigh the risks. The 
drugs 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 to the study drugs. It is 
very important that you tell your study doctor about any changes in your medical condition while 
taking part in the study. At any time during the study, if you believe you are experiencing any of 
these side effects, you have the right to ask questions about possible and/or known risks.  
 
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 you must ask for approval before 
taking any new medication while you are on the study. If you have questions about additional 
side effects, please ask the medical staff at your site. 
 


 
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Adverse Reactions Related to All Combination Antiretroviral Drugs 
Treatment failure: 
When people with viral suppression switch to a different ART regimen, there is a risk that the 
HIV virus will become detectable again in the blood. This is called “treatment failure,” and it is 
usually caused by the virus’ resistance to the new drug. This type of resistance is usually 
caused by mutations (or changes) in the virus that can be found by analyzing the genetic 
information of the virus (i.e., the molecular ‘code' which is copied each time the virus replicates, 
and determines how a virus affects the body and responses to treatment). This is known as 
performing an HIV genotype (i.e., a test that determines the molecular code of the HIV virus to 
predict which medications will be effective against it). HIV genotypes are often performed when 
someone’s ART regimen appears to fail. Sometimes, the genotype does not find a resistance 
mutation, but this is rare. Before enrollment, the study staff will review any prior genotypes in 
your record to check for mutations that are known to affect how well DOR or TDF might work for 
you. If any are found, you will be told about them. You will not be eligible for the study if you 
have any of these mutations. If you are at a site that does not perform routine HIV genotypes, 
the study staff will review your record for any suspected instances of treatment failure; if these 
are present, you will be informed that you do not qualify to participate in the study. 
 
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 additional study drug side effects please ask the medical staff at your site.  
 
Use of Combination Antiretroviral Drugs:  
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.  
 
Adverse Reactions Related to all Nucleoside Analogues 
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged 
liver) with steatosis (fatty liver) that may result in liver failure, and other complications and death 
have been reported with the use of antiretroviral nucleoside analogues alone or in combination. 
The liver complications and death have been seen more often in women on these drug 
regimens. Some nonspecific symptoms that might indicate lactic acidosis include:  
• 
Unexplained weight loss 
• 
Stomach discomfort 
• 
Nausea 
• 
Vomiting 
• 
Fatigue 
• 
Cramps 
• 
Muscle pain 
• 
Cold or blue hands and feet 
• 
Weakness 


 
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• 
Dizziness 
• 
Shortness of breath 
 
Please contact your provider if any of these symptoms occur. 
 
Rarely, TDF, TAF, 3TC and FTC are associated with severe liver problems that can cause 
death. Some symptoms associated with this include: 
• 
Skin or the white part of your eyes turns yellow 
• 
Dark “tea-colored” urine 
• 
Light-colored stools 
• 
Loss of appetite for several days or longer 
• 
Nausea, or stomach-area pain 
 
If you are infected with both hepatitis B and HIV, the use of 3TC, FTC, TDF, and TAF have an 
additional risk related to liver problems. Your liver function tests may increase, and symptoms 
(listed above) associated with hepatitis (an acute inflammation of the liver) may worsen if these 
drugs are stopped. Although most of these cases have resolved without treatment, some deaths 
have been reported. 
 
Risks of doravirine (DOR), tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), 
emtricitabine (FTC), and Lamivudine (3TC) 
The most common adverse reactions reported with use of any of these drugs are: 
• 
Nausea 
• 
Upset stomach 
• 
Headache 
• 
Fatigue or feeling tired 
• 
Diarrhea 
• 
Abdominal pain 
• 
Dizziness 
 
Less common adverse reactions reported with use of DOR, FTC, and 3TC are:  
• 
Sleeping problems such as insomnia or sleepiness during the day  
• 
Elevation of liver function tests, which indicates some degree of liver inflammation 
 
Other Adverse Reactions Associated with DOR 
• 
Abnormal dreams or nightmares 
• 
Distraction 
• 
Rash 
 
Other Adverse Reactions associated with TDF  
• 
Worsening or new kidney damage or failure  
• 
Bone pain  
• 
Bone changes such as thinning and softening (this may increase the risk of breakage)  
• 
Muscle pain and muscle weakness  
 


 
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Less common adverse reactions to TDF include:  
• 
Shortness of breath  
• 
Rash  
• 
Allergic reaction. Symptoms may include: 
o Fever 
o Rash 
o Upset stomach  
o Vomiting 
o Loose or watery stools 
o Abdominal pain 
o Body achiness 
o Shortness of breath  
o A general feeling of illness 
o Swelling of the face, lips, and/or tongue.  
 
Other side effects associated with Lamivudine (3TC) or Emtricitabine (FTC):  
• 
Numbness, tingling, and pain in the hands or feet 
• 
Depression  
• 
Rash  
• 
Pancreatitis (inflammation of the pancreas), which may cause death. If you develop 
pancreatitis, you may have one or more of the following: stomach pain, nausea, and vomiting.  
• 
Abnormal pancreatic and liver function blood tests 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Persons who are pregnant, intend to become pregnant during the duration of the study, or are 
currently breast-feeding are not eligible to enroll. Anyone who is participating in sexual activity 
that could lead to the participant becoming pregnant must agree to use contraception while on 
DOR (approximately 48 weeks) and for 8 weeks after the end of the study.  
 
Acceptable forms of contraception are: 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
• 
Partner/s’s sterilization (in other words, vasectomy, and sterilized partner must be the sole 
partner of the participant)  
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking ART when you become pregnant, your pregnancy will be reported to an 
international database that collects information about pregnancies in persons taking ART. This 
report will not use your name or other information that could be used to identify you. 
 
 


 
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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, you may have weight loss, but no guarantee can be made. It is 
likely that you will not receive any benefit from being in this study. Information learned from this 
study may help others who have HIV and have experienced unintentional weight gain on ART. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you 
• 
Treatment with experimental drugs, if you qualify  
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of your choices. 
 
 
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 obtained a Certificate of Confidentiality 
from the US 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 ACTG, the US Office for Human Research Protections 
(OHRP), or other local, US, and non-US regulatory entities as part of their duties, institutional 
review boards (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. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site 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. 
 


 
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Your records may be reviewed by the ACTG, the US Office for Human Research Protections 
(OHRP), or other local, US, and non-US 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 for combining with 
information from other study participants and statistical analysis of study results. Your 
name and other personal identifiers will not be sent. Your research site is responsible for 
sending 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 http://www.ClinicalTrials.gov, as required 
by US law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site 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.  
 
Only DOR will be provided by the study. If you are randomized to one of the two treatment arms 
receiving DOR you will have that medication provided without charge.  
 
You must obtain TAF/FTC (or TAF/3TC) or TDF/FTC (or TDF/3TC) through your regular source 
of medications. If you are randomized to remain on your current ART, you should continue to 
get it through your regular source. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will receive monetary compensation for your time as a participant in this study (sites to 
insert amount here). This money can be used for transportation to study visits, meals, 
childcare, medication co-pays, or other expenses.  
 
 
WILL I RECEIVE THE RESULTS OF ANY TESTS? 
 
You will receive the results of routine lab tests (for example, blood glucose, liver and kidney 
tests, hemoglobin A1c test, pregnancy test, viral load, and CD4 count) that are performed at the 
study visits. You have the option to receive the results of your DEXA scans, either at the time of 
the procedure or at a later date. 
 


 
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You will not receive results from some of the testing that your blood is used for. This testing 
includes: 
• 
The levels of proteins and other compounds related to the risk of diabetes and heart disease 
• 
The levels of immune system proteins and immune cells in the blood 
• 
The levels of ART medications 
• 
Other research tests that will be done in the future on stored blood samples 
 
You will be told of any new information learned during the course of the study that might cause you 
to change your mind about staying in the study. At the end of your time in the study, you will be 
told when study results may be available and how to learn about them. As with all studies, if we 
find out important information that may affect your care, you will be provided with those results. 
 
 
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 CTI, this must be indicated in the 
informed consent. 
• 
There is no program for compensation through the NIH. 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.  
OR 
• 
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. If you want the results of the study, let the study staff 
know. 
 
 


 
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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 A 
 
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 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, his or her research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review his or her 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.  
 
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. The researcher is not likely to ever know who you are. 
 
You may withdraw your consent for research on your extra samples at any time and the 
specimens will be discarded. 
 
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. 
 
Research without Human Genetic Testing  
If you agree, your extra samples 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 samples.  
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples. 
 
Research with Human Genetic Testing  
The ACTG has two different studies that collect samples for genetic testing. 


 
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If you live in the US, this study is called ACTG A5128, Plan for Obtaining Informed Consent to 
Use Stored Human Biological Materials (HBM) for Currently Unspecified Analyses. 
 
If you live outside of the US, this study is called ACTG A5243, Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses. 
 
Your site might ask you if you would like to participate in one of these studies if it 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 and date 
a consent form for A5128 or A5243. 
 

SAP_001.pdf: 
 
 
 
 
ACTG A5391  
Primary Statistical Analysis Plan 
Version 3.0 
 
 Doravirine for Obese Persons on Integrase Inhibitors and 
Tenofovir Alafenamide (The Do IT Study) 
 
Based on Protocol Version 2.0 (August 19, 2022 ) 
Released for activation on 04FEB2025 
ClinicalTrials.gov Identifier: NCT04636437 
 
 
This is ACTG A5391 SAP Version 3.0 with names of authors, 
names of publication writing team members and analysis 
timeline redacted. 
 


ACTG A5391 
 
Version 3.0 
Primary Statistical Analysis Plan 
 
February 4, 2025 
 
Page 1 of 22 
 
 
Table of Contents 
 
TABLE OF CONTENTS ............................................................................................................................... 1 
VERSION HISTORY ..................................................................................................................................... 2 
1 
INTRODUCTION .................................................................................................................................... 3 
1.1 
Purpose ........................................................................................................................................ 3 
1.2 
Version History ............................................................................................................................ 3 
2 
TRIAL OVERVIEW ................................................................................................................................. 5 
2.1 
Trial Design .................................................................................................................................. 5 
2.2 
Primary Hypothesis ..................................................................................................................... 5 
2.3 
Trial Objectives ............................................................................................................................ 5 
2.3.1 
Primary Objective .............................................................................................................. 5 
2.3.2 
Secondary Objectives [key secondary objectives identified] ............................................. 5 
2.4 
Overview of Sample Size Considerations ................................................................................. 6 
2.5 
Overview of Formal Interim Monitoring .................................................................................... 7 
3 
OUTCOME MEASURES ........................................................................................................................ 7 
3.1 
Primary Outcome Measure ......................................................................................................... 7 
3.2 
Secondary Outcome Measures .................................................................................................. 7 
4 
STATISTICAL PRINCIPLES ................................................................................................................ 10 
4.1 
General Considerations ............................................................................................................ 10 
5 
ANALYSIS APPROACHES ................................................................................................................. 12 
5.1 
Analyses of the Primary Objective .......................................................................................... 12 
5.2 
Analysis of Secondary Objectives ........................................................................................... 16 
5.2.1 
Analyses of the safety and tolerability objective .............................................................. 16 
5.2.2 
Analyses of the maintenance of virologic suppression .................................................... 17 
5.2.3 
Analyses of minimum waist circumference and fasting cardiometabolic parameters ..... 18 
5.2.4 
Analyses of body composition by DEXA ......................................................................... 18 
5.2.5 
Analyses of bone mass by DEXA .................................................................................... 18 
6 
ANALYSES SPECIFIC TO INTERIM MONITORING .......................................................................... 19 
7 
REPORT CONTENTS .......................................................................................................................... 19 
8 
CITATIONS .......................................................................................................................................... 22 
9 
ASSOCIATED DOCUMENTS .............................................................................................................. 23 
 
 
 
 


ACTG A5391 
 
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February 4, 2025 
 
Page 2 of 22 
 
 
Version History 
 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
Aug 12, 2021 
2 
Update for protocol revision to version 2 
Jan 11, 2023 
3 
Updates for final primary analysis 
Feb 4, 2025 
 
 
 


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Primary Statistical Analysis Plan 
 
February 4, 2025 
 
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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary estimands and other secondary 
outcome measures that will address specific study objectives and interim monitoring of the A5391 trial. 
The Primary SAP includes general analytic approaches for all primary estimands, secondary and other 
outcome measures in the primary manuscript(s) or submitted to ClinicalTrials.gov (regardless of the 
reporting timeline). The Primary SAP facilitates discussion of the statistical analysis components among 
the lead study investigators and statisticians, helping them agree on the statistical analyses to be 
performed and presented in the primary analysis report. 
Analyses for the primary analysis report will be initiated once the last participant has completed the week 
48 study visit; details on the analysis timeline will be finalized at a later time. In addition, all primary and 
secondary outcomes outlined in this SAP will be submitted to ClinicalTrials.gov within 1 year of the 
Primary Completion Date (PCD); PCD defined as 48 weeks after the last participant enrolls.  
Additional specifications and details on other key elements of the primary analysis report, including 
tables, figures, and coding descriptions, are provided in the Analysis Implementation Plan (AIP).  
Details for analyses of other objectives and outcome measures not included in the Primary SAP will be 
provided in a separate SAP.  
1.2 
Version History 
1.2.1 
Version 3 
Major modification in v3 include the following: 
• 
Update to handling of participants found ineligibile after randomization (note: those never 
starting treatment already excluded, so this revision applies to exclusion from efficacy 
analyses (but not safety) for participants found ineligibile who received study treatment 
• 
Update to sample size considerations to account for change to accrual goal following final 
SMC interim review 
• 
Updating analysis range for follow-up visits to be more inclusive of available data (i.e. wider 
intervals without gaps) 
• 
Updating analysis set for insulin and insulin resistance (per HOMA-IR) outcomes to exclude 
persons taking exogenous insulin per clinical database reporting. 
Minor updates: 
• 
Updating ACTG network roster for members notified of final analysis completion 
• 
Removing analysis timeline (as timeline maintained and updated in a separate document) 
• 
Updated typo (vs rather than or) in the subgroup formulation for race and ethnicity 
 


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February 4, 2025 
 
Page 4 of 22 
 
 
1.2.2 
Version 2 
Major modifications in v2 include the following: 
• 
Update to align with updates in the trial protocol  
o 
participant eligibility criteria  which defines the target population 
o 
added secondary outcome to incorporate reporting and analysis of BMD T scores from 
DXA evaluations 
• 
Removal of exploratory objectives which are not covered by this SAP 
• 
Updating of anchor time for calculation timing of evaluations 
• 
Report contents section added 
• 
Template analysis timeline added 
• 
Writing team roster added 
Minor modifications include the following: 
• 
Update to language based on template updates (e.g. references to estimands in section 1.1.) 
 
 
 


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February 4, 2025 
 
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2 
Trial Overview 
2.1 
Trial Design 
A5391 is a phase IV, 48-week, 3-arm, open-label, randomized study to assess whether switching from an 
integrase strand transfer inhibitor (INSTI)-based regimen with tenofovir alafenamide/emtricitabine 
(TAF/FTC) or TAF/lamivudine (TAF/3TC) to a regimen containing doravirine (DOR) with TAF/FTC (or 
TAF/3TC) or DOR with tenofovir disoproxil fumarate (TDF)/FTC (or TDF/3TC) will result in reduced weight 
gain or weight loss compared with continuation of their current regimen.  
The trial population consists of adults (≥ 18 years of age) living with HIV who have a body mass index 
(BMI) ≥30 kg/m2, and who have maintained virologic suppression (HIV-1 RNA <50 copies/mL or below 
the lower limit of HIV-1 RNA detection available at the site) on an INSTI + TAF/FTC (or TAF/3TC), 
regimen for the 48 weeks prior to entry. [Note: in the previous version of the protocol, the target 
population were persons with BMI > 2.75 and with excessive weight gain under their INSTI-based 
regimen.] 
The trial aims to enroll up to 150 (formerly 222) participants, targeting >50% participants assigned female 
sex at birth across all sites and >50% African American/Black participants at US sites.  Randomization is 
stratified by sex assigned at birth and race (African American/Black vs non-African American/Black).  
2.2 
Primary Hypothesis 
Compared to continued INSTI (bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL)) + TAF/FTC (or 
TAF/3TC), a switch to DOR+TAF/FTC (or TAF/3TC) will result in less weight gain or overall weight loss at 
48 weeks among obese  persons (i.e. BMI ≥30 kg/m2). A switch from INSTI+TAF/FTC (or TAF/3TC) to 
DOR+TDF/FTC (or TDF/3TC) will result in further reduction in weight gain or overall weight loss 
compared to DOR+TAF/FTC (or TAF/3TC). 
2.3 
Trial Objectives 
The following sections list the primary and secondary objectives from the trial protocol; corresponding 
protocol section numbering is shown in brackets.  
2.3.1 
Primary Objective 
To assess if an antiretroviral therapy (ART) switch to DOR (either switch to DOR and remain on 
TAF/FTC [or TAF/3TC] or switch to DOR and TDF/FTC [or TDF/3TC]) results in differences in 
weight change over 48 weeks, compared to a strategy of remaining on current ART 
(INSTI+TAF/FTC [or TAF/3TC]) [Protocol Objective 1.2]. 
2.3.2 
Secondary Objectives [key secondary objectives identified] 
1) To assess if a switch to TDF/FTC (or TDF/3TC) from TAF/FTC (or TAF/3TC) results in 
differences in weight changes over 48 weeks by contrasting the 2 DOR-containing switch 
strategies (i.e., DOR+TAF/FTC [or TAF/3TC] versus DOR+TDF/FTC [or TDF/3TC]) [Protocol 
Objective 1.3.1]. [key] 
 


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2) To assess the effects of a switch from INSTI+TAF/FTC (or TAF/3TC) to DOR+TAF/FTC (or 
TAF/3TC), or DOR+TDF/FTC (or TDF/3TC) over 48 weeks on [Protocol Objective 1.3.2]: 
 
• 
Safety and tolerability;  
• 
Maintenance of virologic suppression;  
• 
Minimum waist circumference;  
• 
Fasting cardiometabolic parameters: glucose and insulin, homeostatic model assessment 
of insulin resistance (HOMA-IR) and lipids (triglycerides, low-density lipoprotein [LDL], 
high-density lipoprotein [HDL]); 
• 
Dual-energy X-ray absorptiometry (DEXA) body composition measurements of total and 
regional fat and lean mass, and hip and lumbar spine bone mineral density.  
2.4 
Overview of Sample Size Considerations 
The original targeted sample size is 222 participants was updated to up to 150 participants following 
the final SMC review on June 5, 2023. 
The study is designed to evaluate whether an ART switch from BIC, DTG, or RAL with TAF/FTC or 
TAF/3TC to a regimen containing DOR with TAF/FTC (or TAF/3TC) or DOR with TDF/FTC (or TDF/3TC) 
results in reduced weight gain, or weight loss, as compared to continuation of current BIC-, DTG-, or RAL-
containing ART. The primary comparison will examine the change (percent) in body weight (kg) from 
entry to week 48.   
Original sample size justification (n=222) 
The sample size is based on two-sided t-tests with 2.5% significance level and 80% statistical power to 
detect an absolute difference of 5% at week 48 between each switch arm and the control arm (continuing 
INSTI), assuming the standard deviation (SD) of within-participant changes is 9%. 
Updated sample size justification (up to n=150) 
While the trial was designed on the assumption that the standard deviation (sd) on the primary 
outcome (from external data) would be 9, an interim look of available sd from 37 participants (all 
accrued during v1) was much smaller at 5.3 (and similar sd between women (4.84) and men (5.05)). 
Using this observed standard deviation, using a smaller sample size (n=152) the trial would still 
have 80% power (using same assumptions of 2-sided t-test at 2.5% significance level of 2 pairwise 
comparisons), to detect a between arm difference in weight changes at 48 weeks of 3.58 
percentage point (%pts), which was smaller than the originally specified ‘clinical difference of 
interest’ of 5 %pts. Under a slightly larger sd of 7, sample size (n=152) would provide 80% 
statistical power for a group difference of 4.73 %pts, similar to the original design. Finally, the 
total width of the 2-sided, 97.5% confidence interval about the treatment effect estimate was 
calculated with smaller sample size and was 5.2 %pts (for sd 5.3), and 6.9 %pts (for sd 7). 
 


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2.5 
Overview of Formal Interim Monitoring 
The study will be monitored by an independent ACTG-appointed Study Monitoring Committee (SMC). 
The SMC will review the study at least annually, with the first review occurring no more than 1 year after 
the first participant enrolls; interim reviews may also be convened if a concern is identified. The SMC will 
review unblinded, by-arm summaries of accrual, baseline characteristics, study and treatment 
status (including premature discontinuations), data availability/completeness, virologic failures, 
and AEs. Summaries of primary efficacy will not be provided during interim reviews.  
There are no pre-specified stopping guidelines for this study, but the SMC should consider possible 
modifications or termination on bases of safety concerns or operational futility. With regards to safety, if 
10% or more of participants on the DOR-containing arms experience virologic failure or treatment-
related AEs, this would be concerning to the study team. With respect to operational futility, the SMC 
would consider the overall and within arm LTFU rates, and treatment cross-over rates (particularly 
those switching from DOR-containing arm back to an INSTI-containing arm). As a benchmark, an 
overall LTFU rate of 20% or higher would be cause for concern, particularly if a higher rate is 
observed in the INSTI-containing arm where participants are not switched to DOR. 
3 
Outcome Measures 
Outcome measures are copied from the protocol, with slight changes shown with underline text. Only 
primary and secondary outcome measures, which are addressed in this SAP are included below. 
3.1 
Primary Outcome Measure 
1) Change (percent) in body weight (kg) from entry to week 48.   
[For Primary Objective and Secondary Objective 1] 
3.2 
Secondary Outcome Measures 
1) Change (percent) in body weight (kg) from entry to week 24. 
[For Primary Objective and Secondary Objective 1] 
 
2) Change (absolute) in minimum waist circumference from entry to weeks 24 and 48. 
[For Secondary Objective 2] 
 
Minimum waist circumference is defined as the smallest horizontal circumference above the 
umbilicus and below the xiphoid process.  The minimum waist circumference summarized in 
analysis is the average of three measurements taken in triplicate by the site investigators. 
 
3) Change (absolute) in fasting cardiometabolic parameters (glucose, insulin, HOMA-IR, 
triglycerides, LDL, HDL) from entry to weeks 24 and 48.  [italicized based on batched, 
retrospective testing on stored plasma and serum at central labs} 
[For Secondary Objective 2] 
 
 


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4) Occurrence of confirmed plasma HIV-1 RNA >200 copies/mL following treatment initiation 
[For Secondary Objective 2] 
 
Confirmed plasma HIV-1 RNA > 200 copies/mL is defined as two consecutive results above 200 
copies, with the testing of the second specimen within 2 weeks of site receipt of the first result, 
and the first result being from a specimen drawn after treatment initiation. 
 
 
5) Occurrence of new Grade ≥3 AEs, through week 48.  [For Secondary Objective 2] 
New Grade 3 or higher AEs are defined as Grade 3 or higher AEs that are new in onset or are 
aggravated in severity or frequency from the entry condition (e.g., Grade 1 or 2 at entry that 
escalates to Grade 3 or higher, or Grade 3 at entry that escalates to Grade 4 or higher), following 
treatment initiation   
6) Occurrence of >10% reduction in CrCl as estimated by the CKD-EPI equation, relative to entry, 
through week 48.  [For Secondary Objective 2] 
 
7) Occurrence of premature discontinuation of study treatment through week 48.  
[For Secondary Objective 2] 
 
Premature discontinuation of study treatment is defined as stopping any component of the 
randomized study regimen, prior to the week 48 visit.  
 
8) Change (percent) in DEXA body composition measures (total fat and lean mass, trunk fat, limb 
fat, and appendicular lean mass) from entry to week 48.  
[For Secondary Objective 2] 
 
Total fat, lean mass in kg as well as total fat % (i.e. %fat in tissue defined as [total fat mass / (total 
fat mass+ lean mass)];  will have %change outcome calculated 
 
Limb fat (in kg and %) ,where  %fat in tissue, will be calculated  from sum of arm/upper extremity 
& leg/lower extremity lean and fat masses reported 
 
Trunk fat (in kg and %) changes will be calculated 
 
Limb (appendicular) lean mass changes will be calculated 
 
 
9) Change (percent) in DEXA hip and lumbar spine bone mineral density from entry to week 48.  
[For Secondary Objective 2] 
Hip BMD is defined via the following 4 outcome measures:  left femoral neck, right femoral neck, 
left total hip (femur), and right total hip (femur) (each measured in g/cm3) 


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Lumbar spine BMD is defined as the arithmetic average of L1-L4 BMD in g/cm3 
10) Change in categorization of bone mass (WHO classification) from baseline to week 48 based on 
minimum T score from left/right femoral neck, left/right total femur/hip, and lumbar spine(L1-L4). 
 
 


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Primary Statistical Analysis Plan 
 
February 4, 2025 
 
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4 
Statistical Principles 
4.1 
General Considerations 
The following analysis populations are defined for A5391: 
- 
Screened Population: 
 
All participants who were screened for enrollment into  
the study. 
 
- 
Randomized Population: 
All participants who were enrolled to the study (this is an  
intent-to-treat [ITT] population). 
 
- 
Treated Population: 
 
All participants who received at least one dose of their  
randomized study treatment (this is a modified ITT population). 
For participants randomized to switch arms this includes those 
who took at least one dose of their randomized regimen; for 
participants randomized to remain on their current regimen this 
includes those who took at least one dose of their current 
regimen after study entry.   
 
- 
Eligible treated Population: 
All participants who received at least one dose of 
randomized study treatment  and who were eligible as per eligibility criteria (this is an  
intent-to-treat [ITT] population). 
 
The following will be considered for timing of study visits:  
Study Entry: 
 
 
This is an interval defined by the first entry evaluations and 
finalization of study evaluations (including DEXA).  If all entry evaluations completed on 
one day this is an interval of 1 day.  The start of study entry evaluation may be delayed 
following randomization for the requirement of being evaluated in a fasting state.  From the 
protocol:  Study treatment should be initiated as soon as possible after entry evaluations have 
been completed and within 14 days of entry.  
 
- 
Treatment Initiation: 
 
Study treatment may be initiated following completion of study 
entry evaluations (except DEXA). (Note : this definition applies regardless of treatment 
assignment, and so control arm initiation will be the first dose taken following completion of entry 
evaluations.). Study treatment should be initiated as soon as possible after entry evaluations 
have been completed and within 14 days of entry 
 
- 
Entry DEXA: 
 
 
Entry DEXA may occur up to 14 days post initiation of study 
treatment 
Study week analysis windows are based on the Schedule of Evaluations (SOE) defined in the protocol 
and will be derived based on a given visit/specimen collection date, and the entry start of evaluation date 


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(i.e. the start date of the entry evaluation visit). Therefore, the date of the first entry evaluations visit 
is day 0 (note:  SVSDT from the entry visit).  In the event multiple results fall within the same analysis 
window, the one closest to the target time will be prioritized, or if equidistant, the earlier result will be 
prioritized.      
SOE Visit 
Protocol Range (days) 
Analysis Range (days) 
Screening 
-45, -1 
-45, -1 
Entry  
0 (date of start of entry 
evaluations) 
[randomization, study 
entry visit end date] 
Week 4  
25, 35 
21, 55   
Week 12 
70, 98 
56, 124 
Week 24 
154, 182 
125, 209 
Week 36 
238, 266 
210, 287 
Week 48 
322, 350 
288, 413 
 
 
Key study visits occur at entry, week 24, and week 48.  
Entry:  
See above. These evaluations will also be referred to as baseline.  
Week 24: 
The study visit at which key secondary outcomes will be evaluated. 
Week 48: 
End of study treatment and last on-study visit. 
There are three study arms under consideration in A5391, two investigational arms that involve switching 
from an INSTI-based regimen to DOR with or without a switch from TAF to TDF, and one control arm.  
Participants who are randomized to the control arm are expected to continue on their current ART 
regimen of INSTI+TAF/FTC (or TAF/3TC), where INSTI regimens may include BIC, DTC, or RAL.  
Analysis of primary and secondary outcomes will be compared, separately, between each of the 
investigational switch arms and the control arm (remaining on current INSTI-based regimen).  Each 
comparison will use a 2.5% type-I error rate to control for multiple comparisons. Secondary analysis will 
compare each of the primary and secondary outcomes between each of the switch arms using a 5% type-
I error rate. No other adjustments for multiple comparisons will be made. 
Continuous variables will be summarized using mean, standard deviation, median, interquartile range (Q1 
and Q3), 10th and 90th percentile, and min and max; categorical variables will be summarized using 
frequency and percentage.  


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Analyses of occurrence outcomes (e.g. safety, tolerability) which are summarized across the trial sample 
as the proportion of participants who experienced the outcome of interest will include only those 
participants who were “at risk” for the outcome being observed during trial follow-up.  In addition to 
excluding participants who never initiated study treatment (as those participants are taken off study 
follow-up), these also exclude participants who leave the study so early that the outcome of interest was 
not evaluated or measured.  Details as to how these principles apply to specific outcomes are detailed 
below. 
Analyses other than those related to screening and accrual will be utilizing the treated population analysis 
set (safety) or eligible treated population set (efficacy). This is due to protocol language that directs 
participants who never initiate treatment to be discontinued from trial follow-up.  Any exceptions to this 
analysis approach are noted below. 
5 
Analysis Approaches 
5.1 
Analyses of the Primary Objective  
The following table summarizes the primary objective and the associated estimand. Further details are 
provided after the table.  
Primary Objective: To assess if ART switch to DOR + TAF/FTC (or TAF/3TC) or to DOR + TDF/FTC 
(or TDF/3TC) results in differences in weight change over 48 weeks compared to a strategy of 
remaining on current ART (INSTI+TAF/FTC (or TAF/3TC)). 
Estimand 
description 
Absolute difference (switch arm minus control arm) in the mean percent change in 
weight over 48 weeks, among adults living with HIV who have BMI ≥30 kg/m2, while 
having maintained virologic suppression for the last year on an INSTI-based regimen.  
Treatment 
DOR+TAF/FTC (or TAF/3TC), DOR+TDF/FTC (or TDF/3TC), or INSTI (BIC, DTG, or 
RAL)+TAF/FTC (or TAF/3TC)  
Target population   
Analysis set (analysis population)  
Adults (≥ 18 years of age) living with HIV who 
have BMI ≥30 kg/m2, on an INSTI-containing 
regimen + TAF/FTC (or TAF/3TC), and have 
maintained virologic suppression (HIV-1 RNA <50 
copies/mL or below the lower limit of HIV-1 RNA 
detection available at the site) for at least 48 
weeks prior to entry on this regimen. 
Eligible Treated population 
Variable(s) 
Outcome measure(s)  
Body weight (kg) at entry and week 48.   
Change (percent) in body weight from entry to 
week 48. 
 
The 48-week period will be based on the date of 
the week 48 visit, occurring between weeks 44 
and 52 based on the analysis window. 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to 
the estimand:  
- 
Death; 
- 
Receipt of or change in medications 
known to cause changes in weight or 
interfere with DOR**; 
- 
Change in randomized regimen; 
Participants who discontinued follow-up before 
week 48 are considered ignorable will be 
excluded from analysis.  Sensitivity analyses will 
consider participants who discontinue follow-up 
before week 48, using the last collected weight.  


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- 
Confirmed virology failure; 
- 
Pregnancy. 
 
Death is the only intercurrent event that will be 
accounted for in the primary analysis, other 
intercurrent events will be ignored according to a 
treatment policy strategy, but their impact will be 
assessed in supplementary analyses. 
 
For deaths, a while alive strategy is being taken to 
evaluate treatment effects. If deaths occur, the 
last observation taken before the death will be 
used to determine the variable. 
 
Similarly, participants who having a missing 
baseline value will be missing for the change 
outcome to week 48.  See sensitivity analysis 
below to address this contingency if it occurs. 
Population-level summary measure 
Analysis approach 
Absolute differences (each switch arm minus 
control arm) in the mean percent change in weight 
from entry to week 48. 
Absolute differences in the mean percent change 
in weight will be obtained using linear regression, 
with an indictor variable for treatment arm and 
adjustment for each stratification factor and 
weight at entry. This analysis will be done 
separately for each switch arm compared to the 
control arm.  
 
** New Receipt of medications would include prohibited and precautionary medications outlined in the 
protocol and on the protocol specific webpage, changes to medications would include those outlined in 
the inclusion/exclusion criteria of the protocol. See AIP for list of medications.  
 
 
 


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Analysis Approach 
 
The analysis of the primary outcome will compare the change (percent) in body weight (kg) from entry to 
week 48 between each switch arm and the control arm. The mean percent change in weight at week 48 
will be compared separately between each of the investigational switch arms and the control arm using 
linear regression adjusting for stratification factors and weight at entry with a 2.5% type-I error rate; 
treatment arm will be included in each model as an indicator variable. The absolute difference in the 
mean percent change will be calculated, as well as a corresponding 97.5% confidence interval (CIs); p-
values will also be provided. Participants who prematurely discontinue from the study, and therefore do 
not have a weight measurement at week 48 will be excluded from the primary analysis; the exception to 
this is if participants prematurely discontinue due to death, in which case their last weight measurement 
obtained prior to death will be used instead of the week 48 measurement.  The primary analysis will be 
conducted according to an intent-to-treat principle, and therefore participants will be analyzed according 
to their randomized regimens, regardless if they change their ART regimen during follow-up (i.e. 
prematurely discontinue treatment). 
 
Note:  persons enrolled under the previous version of the protocol, with different target population, will be 
included in the primary analysis.  Two  supplementary analyses will be conducted  (see below for more 
details): 
1)  Excludes persons enrolled who did not have screening BMI >= 30 kg/m2, and thus would not 
have qualified under version 2 of the protocol. 
2) By subgroup defined by history of weight gain:  those with documented weight gain as per version 
1 requirements;  those who did not have weight gain;  those without historical weight gain 
information to meet the first 2 subgroups 
 
Sensitivity Analyses – contingency  
A.  If any participants are missing their entry weight for change from baseline, a sensitivity analysis using, 
the screening weight used for trial eligibility will be conducted. 
 
B. To evaluate the impact of missing data at week 48, controlled multiple imputation (MI) will be used only 
if more than 10% of week 48 weight values are missing overall or in one arm [1]. 
 
 
In this sensitivity analysis, missing data will be considered Missing at Random (MAR) and Missing Not at 
Random (MNAR). Under the MAR assumption, the conditional distribution of the unobserved data given 
the observed data (see below) will be same, regardless of whether the data were observed or not (i.e. 
missing week 48 weight values does not depend on the week 48 weight value); however, under the 
MNAR assumption, the probability a participant is missing their week 48 weight depends on what the 
value was of the unobserved week 48 weight (e.g. those who do not improve their weight trajectory may 
be more likely to drop out).  
 
1. MAR Assumption  
 


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Standard MI will be conducted assuming data are MAR.  The analysis model will be as defined for the 
primary analysis, and will adjust for treatment arm, weight at entry, and stratification factors.  The 
imputation model used for MI will include all variables defined for the analysis model, and the addition 
of all weight measures observed prior to the participant being loss to follow up. Number of 
imputations will be determined by the percent of missing data, and will be assessed for precision. 
This analysis does not account for missing data pattern or reason for missingness.  
 
2. MNAR Assumption 
 
To assess the impact of data being MNAR, we assume those missing week 48 weight outcomes have 
poorer responses than those with observed values at week 48 (i.e. those without an improved weight 
trajectory were more likely to drop out, or those on control arm more likely to drop out), and will utilize 
δ-based MI methods where δ corresponds to a fixed constant that will be added or subtracted to the 
MAR-imputed weight values at week 48, among those missing their week 48 weight. In this analysis, 
the choice of δ will be based on a percentage of the observed mean percent change in weight (entry 
to week 48), specifically will corresponds to 10%, 20%, 30%, 40% and 50% of this change in weight.  
This analysis will explore the impact of a range of fixed mean differences in the outcome for the 
unobserved data and evaluate the impact of the MNAR assumption on inference of the primary 
outcome. Note: Differences in observed effects are possible and expected in sensitivity analysis 
assuming data are MNAR. 
 
The primary analysis will be considered robust to missing data, if overall interpretation of results are not 
impacted by the sensitivity analyses. 
 
Supplementary Analyses 
 
The following supplementary analyses are included to evaluate the impact of different assumptions on the 
inference of the primary outcome due to possible intercurrent events or other factors.  
 
1. Evaluate impact of participants who, prior to week 48, used or changed medications known to 
cause changes in weight or that interfere with DOR as defined in the protocol (see AIP for list of 
medications), changed their randomized regimen (regardless of reason), had a confirmed 
virologic failure, or became pregnant. 
 
Approach:  Repeat the primary analysis, but exclude participants who met the criteria above. 
 
2. Evaluate impact of persons who were not obese (i.e. eligible as enrolled under version 1 but 
would not have been eligible per version 2 criteria) 
 
Approach:  Repeat the primary analysis, but exclude those participants who enrolled under 
version 1 and whose screening BMI was < 30 kg/m2 (i.e. and thus would not have qualified under 
version 2.) 
 
3. Evaluate impact of persons with historical weight gain in INSTI regimen. 
 


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Approach:  See subgroup analysis below .  
 
Supportive Analyses 
Secondary outcome 1 (weight at wk 24) is included as supportive to the primary objective. Percent 
change in weight from entry to week 24 will be summarized in the same manner as the primary outcome. 
Sensitivity and supportive analyses noted above will also be examined. 
In support of the primary analysis, comparing each switch arm to the control arm, an additional analysis 
will contrast the 48-week changes in weight between the switch arms (1 vs 2) to determine if there are 
additional benefits of a switch from TDF- to TAF-based treatment. The mean percent change in weight at 
week 48 will be compared between switch arms using the same methods outlined for the primary 
analysis, except a 5% type-I error rate will be used for this supportive comparison.  
 
Subgroup Analyses  
To evaluate the effects of switching to DOR from an INSTI-based ART regimen in specific populations, 
subgroup analyses will be conducted. Descriptive summaries of change (percent) in weight within each 
subgroups will be provided.  The same approaches outlined for the primary analysis will be implemented 
for each subgroup.  Within each type of subgroup, the difference between treatment arms will be 
determined, and compared between subgroups by a test of interaction and 97.5% CI and corresponding 
p-value. In the linear regression models, subgroup will be included as an indicator variable and an 
interaction term between treatment arm and subgroup will also be included; other model terms (weight at 
entry and stratification factors) will be included, as approproiate, as defined in the primary analysis. Pre-
specified subgroups of interest include:   
1. Sex (male sex at birth, female sex at birth) [stratification factor] 
2. Gender (cis-female or trans-female on hormones at entry vs other)  
3. Race (African American/Black vs non-African American/Black) [stratification factor] 
4. Race/Ethnicity (African American/Black vs Hispanic vs other) 
5. Age  (<50, ≥ 50 years)  
6. INSTI-regimen at entry (BIC, DTG, RAL)  
7. History of weight gain in INSTI (yes, no, unknown/missing) 
5.2 
Analysis of Secondary Objectives 
5.2.1 
Analyses of the safety and tolerability objective  
The outcomes for this objective includes participants who experience one of the following: 
• 
Severity grade 3 or higher reportable AE 
• 
> 10% reduction in calculated creatinine clearance (CRCL) compared to baseline 
• 
Prematurely discontinue study treatment (as defined above) 
Outcome calculation and descriptive analyses specifics: 


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The number and estimated proportion of participants experiencing each outcome will be summarized by 
arm.  The denominator (i.e. at risk population set) will be the treated population analysis set with the 
following contingencies:  for AEs -- the denominator will exclude any participants who left the study 
without any reportable AEs (including reportable AEs below grade 3), and before having any post-
treatment initiation evaluations for AEs;  for CRCL  -- the denominator will exclude  any participants who 
did not have any post-treatment initiation serum creatinine results available for CRCL calculation.  
Only observed creatinine clearance values will be used to determine those participants meeting the 
CRCL reduction outcome. Screening values will be used as baseline if the entry value is missing;  
missing post-entry data will be ignored (and those assumed to have not met criteria for the outcome).  All 
discontinuations of any component of ART regimen for any reason prior to the week 48 visit will be 
considered to have met the tolerability outcome.  Timing and reasons for discontinuation will be 
summarized. 
For each outcome, a summary of appropriate details about each outcome will also be included.   
For example, the type, and severity of grade 3+ AEs will be summarized with MeDDRA categories, as 
well as summaries of which of these were related to study treatment, and the timing in relation to 
treatment initiation.  For reductions in CRCL the distribution of % reduction among those meeting the 
outcome will also be given, as well as distribution of actual CRCL values meeting the outcome, and the 
distribution of timing of meeting the outcome post treatment initiation.   
Hypothesis testing and Inference: 
The proportion of participants will be compared between each switch (1 or 2) arm and the control (3) arm 
using mid-P Fisher’s exact tests at the 2.5% significance level.   As a supportive analysis, the two switch 
arms will be compared (1 vs. 2) using the same test, but at a 5% significance level. 
2-sided, Wilson-based, exact score confidence intervals (coverage determined by significance testing in 
paragraph above) will be calculated for each estimated proportion.   
5.2.2 
Analyses of the maintenance of virologic suppression 
The outcome for this objective is confirmed virologic failure defined as post-treatment and confirmed 
plasma HIV-1 RNA > 200 copies/mL.  The denominator for the proportion summary statistic for this 
outcome will be based on the treated population analysis set minus any participants without any post-
treatment initiation viral loads, and will use available HIV-1 RNA values for determining the numerator. 
The proportion of participants meeting the outcome of virologic failure will be compared between each 
switch arm and the control arm using mid-p Fisher’s exact tests at the 2.5% significance level.  As a 
supportive analysis, the two switch arms will be compared (1 vs. 2) using the same test, but at a 5% 
significance level. 
Corresponding 95% 2-sided Wilson-based exact score confidence intervals will be calculated for each 
estimated proportion with VF.   


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5.2.3 
Analyses of minimum waist circumference and fasting cardiometabolic parameters 
These outcomes will use methods parallel to those in the primary estimand, but with substituting for the 
appropriate variable measure. The following exceptions to this plan are as follows: 
1) If entry/baseline lab measures are missing, then the change from baseline to outcome will also  
be missing as the fasting labs for these outcomes (glucose, insulin, HOMA-IR, triglycerides, LDL 
and HDL) were not scheduled to be collected at screening.  Because it is assumed that missing 
baseline values (or samples to measure baseline values) will not be related to the outcomes (i.e 
MAR assumption), persons with missing data will be excluded, and contingencies for sensitivity 
analyses using MI as specified above will only be triggered if more than 20% of participants in a 
single arm or overall are missing outcomes at wk 48. 
 
2)  Supplementary analysis for triglycerides, LDL and HDL to adjust for lipid lower medication use 
during the study.  
 
This analysis will utilize subgroups based on reported lipid lower medication use during the study 
(yes/no), and use the subgroup analysis approach as outlined in the primary estimand section. 
 
3) The analysis set for insulin and HOMA-IR will exclude persons taking exogenous insulin 
(per concom meds) since these measurements are not interpretable among those taking 
insulin.  
5.2.4 
Analyses of body composition by DEXA 
Percent change in the following between baseline and week 48 will be calculated:  total fat, lean 
mass, trunk fat, limb fat, appendicular lean mass. 
The modeling and inference approach parallel to the primary estimand will be performed with the 
following considerations:  
1) Persons missing DEXA at either baseline or week 48 will be excluded.  Sensitivity analysis 
for missing data will not be performed.  
2) A sensitivity analysis excluding persons whose DEXA measurements came from a different 
machine between baseline and week 48 will be performed. 
5.2.5 
Analyses of bone mass by DEXA 
Percent change in the following bone mass measurements between baseline and week 48 will be 
calculated:  total hip (left and right) and total lumbar spine (L1-L4) 
The modeling and inference approach parallel to the primary estimand will be performed with the 
following considerations:  
1) Persons missing DEXA at either baseline or week 48 will be excluded.  Sensitivity analyses 
for missing data will not be performed.  


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2) A sensitivity analysis excluding persons whose DEXA measurements came from a different 
machine between baseline and week 48 will be performed. 
Change in bone mass categorization from baseline to week 48 using minimum T-score at each 
time point among the following collection of Tscores:  left &right femoral neck, left.&right total 
femur (hip), and lumbar spine (L1-L4). Missing subsets will be ignored (e.g. for example if DEXA 
only taken one side, then just available values will be used). 
 
 
6 
Analyses specific to interim monitoring 
From section 2.5 above, there are a few key benchmarks for interim monitoring.  To assure that observed 
rates (ie. proportions) reported do not include participants recently accrued but not yet with any post-
randomization information, and thus not yet at risk for the monitoring outcomes such as virologic failure, 
treatment related AEs, loss to follow-up or treatment crossover; the following approach will be employed.   
For virologic failure, participants are at risk for virologic failure once any post-treatment initiation HIV-1 
viral load is available for analysis in the pushed clinical database (anticipated by ~ 8 weeks following 
randomization). For treatment related AEs, participants are at risk the earlier of a) first post-Rx clinic visit 
(initial visit scheduled at wk 4), or b) an AE is reported.  For loss to follow-up, participants are at risk the 
earlier of a) 8 weeks lapsed since randomization, or b) person has prematurely discontinued from the 
study for any reason.  For treatment crossover, participants are at risk once a post-treatment initiation 
clinic visit has occurred and is recorded in the clinical database pushed to the statistical center.   
7 
Report Contents 
Report sections (outline) 
Supporting tables, figures and listings 
Background (study design, objectives, monitoring 
plan and history, trial milestones and updates); 
Statistical methods (sample size, analysis sets, 
any changes from specifications in SAP & AIP, 
hypothesis testing and inference summary) 
CONSORT flow diagram for RCT 
Screening (interim reports only)  and Accrual 
Summary of reasons for screen failure (interim 
only) 
Accrual tables by site, time, and stratification 
factors 


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Baseline characteristics of trial sample (overall 
and by assigned arm) italics included in 
clinicaltrial.gov record 
Demographics: age, sex, gender identity, race 
and ethnicity (DAIDS categories), and country 
Body composition: weight, BMI, waist 
circumference, history of weight gain on INSTI 
Food security and Physical exercise 
questionnaires 
HIV disease status:  ART regimen at screening, 
HIV-1R RNA , CD4 cell count 
Laboratory values (see AIP for list) 
Targeted concomitant medications (see protocol 
section 5.4 ) related to weight change 
Selected medical history (reportable diagnoses, 
signs/symptoms, other non-targeted medications) 
Study Conduct (Participant and Study Treatment 
Disposition) italics for clinicaltrials.gov results 
record 
Participant self-report of Study treatment 
adherence 
 
 
Monitoring benchmarks (interim reports only) 
Study status:  reasons, timing for premature study  
discontinuation 
Study treatment disposition:  timing of initiation, 
reasons for not initiating (if applicable), reasons 
and timing for premature discontinuation (received 
study treatment, completed and not completed 
study treatment), reasons and timing for changes 
Summary of 4-day recall of study treatment 
adherence by visit 
Monitoring benchmarks (interim only) 
Targeted Concomitant Medications (section 5.4) 
Summary of initiations or changes to pre-existing 
use during study follow-up 
Adverse Events (standardized reports of italicized 
elements included in clinical trials.gov results 
record) 
Summary of New AEs by severity grade (grouped 
by Primary SOC and PT) 
Summary (Listing of) SAEs, grade 4 AEs; AEs 
related to study treatment 


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Listings of targeted events: deaths, pregnancies 
and virologic failures 
 
 
 
Note: For each estimand in the Primary SAP, include summaries of the number and timing of each 
intercurrent event in each treatment group. 
• 
Analysis of primary outcome measures (reported in ClinicalTrials.gov) 
• 
Analysis of secondary outcome measures (reported in ClinicalTrials.gov) 
• 
Anything else relevant to the study (e.g., subgroup analyses, association analyses of primary, 
secondary or other outcome measures) 
 
 


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8 
Citations 
1. Cro S, Morris TP, Kenward MG, Carpenter JR. Sensitivity analysis for clinical trials with missing 
continuous outcome data using controlled multiple imputation: a practical guide. Statistics in 
medicine. 2020 Sep 20;39(21):2815-42. 
 
 
 


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9 
Associated Documents 
 
Attachment 1: Writing Team Roster 
Redacted.