Clinical trial NCT04216589
Conditions: HIV Infections Non-Alcoholic Fatty Liver Disease
Keywords: NAFLD HIV semaglutide
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2021-02-19; Completion date: 2023-09-15
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the effects of semaglutide on intra-hepatic triglyceride (IHTG) content in people living with HIV (PLWH), central adiposity, insulin resistance or pre-diabetes, and hepatic steatosis.

Detailed description:
This study evaluated the effects of semaglutide on intra-hepatic triglyceride (IHTG) content in people living with HIV (PLWH), central adiposity, insulin resistance or pre-diabetes, and hepatic steatosis.

All participants received semaglutide subcutaneously once weekly for 24 weeks, followed by 24 weeks of observation off of the study drug. IHTG was quantified by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) evaluations at two time points during the study.

Participants attended several study visits through Week 48. Participants completed food diaries, adherence and strength assessments, and report on hypoglycemia, vision changes, physical activity, diet, quality of life, and acceptability of study drug. Blood was collected at all visits and stool samples at two visits.

Participants remained on their non-study-provided antiretroviral therapy (ART) throughout the study.

Arms: arm 1: All participants received a dose of 0.25 mg of semaglutide weekly starting at study entry, followed by 0.5 mg weekly starting at Week 2, and then 1.0 mg weekly from Weeks 4 through 24.
Interventions: intervention 1: Semaglutide
Intervention descriptions: intervention 1: Administered subcutaneously

Protocol documents:
Prot_000.pdf: 
 
A5371 
 
A Single-Arm, Open-Label, Pilot Study of Semaglutide for Non-Alcoholic Fatty 
Liver Disease (NAFLD), a Metabolic Syndrome with Insulin Resistance, Increased 
Hepatic Lipids, and Increased Cardiovascular Disease Risk  
(The SLIM LIVER Study) 
 
 
A Limited-Center Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
N/A 
 
 
IND # 146667 
 
 
The ACTG End-organ Disease and Inflammation  
Transformative Science Group 
 
 
 
Turner Overton, MD, Chair 
 
The ACTG Hepatitis Transformative Science Group 
Susanna Naggie, MD, Chair 
 
Protocol Co-Chairs: 
 
Kristine Erlandson, MD, MS 
 
 
Jordan Lake, MD, MSc 
 
Protocol Vice Chair: 
 
Fred Sattler, MD 
 
DAIDS Clinical Representatives: 
 
 
 
Pablo Belaunzaran Zamudio, MD, 
  DTM&H, MSc 
 
Clinical Trials Specialist: 
 
Christina Vernon, MPH 
 
 
 
FINAL Version 2.0 
June 22, 2020 


 
 
A5371 
 
 
FINAL Version 2.0 
 
 
06/22/20 
 
 
A5371 
 
A Single-Arm, Open-Label, Pilot Study of Semaglutide for Non-Alcoholic Fatty Liver 
Disease (NAFLD), a Metabolic Syndrome with Insulin Resistance, Increased Hepatic 
Lipids, and Increased Cardiovascular Disease Risk 
(The SLIM LIVER 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 U.S. 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 
 
 
 


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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 ...................................................................... 12 
SCHEMA ..................................................................................................................................... 14 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES .................................................................... 17 
1.1 
Hypotheses ......................................................................................................... 17 
1.2 
Primary Objective ................................................................................................ 17 
1.3 
Secondary Objectives ......................................................................................... 17 
1.4 
Exploratory Objectives ........................................................................................ 17 
2.0 
INTRODUCTION ............................................................................................................. 18 
2.1 
Background ......................................................................................................... 18 
2.2 
Rationale ............................................................................................................. 21 
3.0 
STUDY DESIGN ............................................................................................................. 27 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 27 
4.1 
Inclusion Criteria .................................................................................................. 27 
4.2 
Exclusion Criteria ................................................................................................ 31 
4.3 
Study Enrollment Procedures .............................................................................. 34 
4.4 
Co-enrollment Guidelines .................................................................................... 35 
5.0 
STUDY TREATMENT ..................................................................................................... 36 
5.1 
Regimens, Administration, and Duration ............................................................. 36 
5.2 
Study Product Formulation and Preparation ....................................................... 36 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ............................... 37 
5.4 
Concomitant Medications .................................................................................... 37 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 39 
6.1 
Schedule of Evaluations ...................................................................................... 39 
6.2 
Timing of Evaluations .......................................................................................... 42 
6.3 
Instructions for Evaluations ................................................................................. 44 
7.0 
ADVERSE EVENTS AND STUDY MONITORING.......................................................... 53 
7.1 
Definition of Adverse Events ............................................................................... 53 
7.2 
Adverse Event Collection Reporting Requirements for this protocol ................... 53 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 54 
7.4 
Study Monitoring ................................................................................................. 55 
8.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 56 
8.1 
Toxicity ................................................................................................................ 56 
8.2  
Other Conditions ................................................................................................. 57 
8.3 
Pregnancy ........................................................................................................... 61 


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CONTENTS (Cont’d) 
Page 
 
9.0 
CRITERIA FOR DISCONTINUATION............................................................................. 62 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 62 
9.2 
Premature Study Discontinuation ........................................................................ 62 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 62 
10.1 
General Design Issues ........................................................................................ 62 
10.2 
Outcome Measures ............................................................................................. 63 
10.3 
Randomization and Stratification ......................................................................... 64 
10.4 
Sample Size and Accrual .................................................................................... 65 
10.5 
Data and Safety Monitoring ................................................................................. 66 
10.6 
Analyses .............................................................................................................. 66 
11.0 
PHARMACOLOGY PLAN ............................................................................................... 67 
12.0 
DATA COLLECTION AND MONITORING ...................................................................... 67 
12.1 
Records to Be Kept ............................................................................................. 67 
12.2 
Role of Data Management .................................................................................. 67 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 68 
13.0 
PARTICIPANTS .............................................................................................................. 68 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 68 
13.2 
Participant Confidentiality .................................................................................... 68 
13.3 
Study Discontinuation .......................................................................................... 68 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 68 
15.0 
BIOHAZARD CONTAINMENT ........................................................................................ 69 
16.0 
REFERENCES ................................................................................................................ 70 
APPENDIX I: PROTOCOL SYNOPSIS ...................................................................................... 77 
APPENDIX II: SAMPLE INFORMED CONSENT ....................................................................... 83 
ATTACHMENT A: A5371 STUDY VISITS AND PROCEDURES ............................................... 96 
ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES ........................ 99 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
This is a limited-center study being conducted at both US and non-US ACTG clinical research 
sites (CRSs) with the ability to perform magnetic resonance imaging-proton density fat fraction 
(MRI-PDFF). Refer to the Sites tab on the protocol web page on the ACTG Member 
website for the list of eligible sites.


 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Kristine Erlandson, MD, MS 
University of Colorado Hospital CRS 
Department of Medicine, Division of 
Infectious Diseases, Mail Stop B168 
12700 East 19th Avenue 
Aurora, CO 80045 
Phone: 303-724-4941 
Fax: 303-724-4962 
E-mail: kristine.erlandson@cuanschutz.edu 
 
Jordan E. Lake, MD, MSc 
Houston AIDS Research Team CRS 
6431 Fannin Street, MSB 2.112 
Houston, TX 77030 
Phone: 713-500-6759 
Fax: 713-500-5495 
E-mail: jordan.e.lake@uth.tmc.edu 
 
Vice Chair 
Fred Sattler, MD 
University of Southern California CRS 
IRD Building, Room 436, 2020 Zonal Ave. 
Los Angeles, CA 90033 
Phone: 323-226-4635 
Fax: 323-226-7726 
E-mail: fsattler@usc.edu 
 
DAIDS Clinical Representative  
Pablo Belaunzaran Zamudio, MD, 
DTM&H, MSc 
HIV Research Branch,  
TRP, DAIDS, NIAID, NIH  
5601 Fishers Lane, Room 9E40B 
Rockville, MD 20852 
Phone: 240-292-4423 
E-mail: pablo.zamudio@nih.gov 
 
 
 
 
 
 
 
 
Clinical Trials Specialist 
Christina Vernon, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3341 
Fax: 301-628-3302 
E-mail: christina.vernon@dlhcorp.com 
 
Statisticians 
Amy Kantor, MS 
Statistical & Data Analysis Center 
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue, FXB 543 
Boston, MA 02115 
Phone: 617-432-7129 
Fax: 617-432-2829 
E-Mail: akantor@sdac.harvard.edu 
 
Carlee Moser, PhD 
Statistical & Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 513 
Boston, MA 02115 
Phone: 617-432-2526 
Fax: 617-432-2829 
E-mail: cmoser@sdac.harvard.edu 
 
Data Managers 
Kathleen Donahue, MA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: 716-834-0900, Ext. 7329 
Fax: 716-834-8432 
E-mail: donahue@fstrf.org 
 
 
 
 
 
 
 


 
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Data Managers (Cont’d) 
Autumn Rolack, MPH 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: 716-834-0900, Ext. 7406 
E-mail: rolack@frontierscience.org 
 
DAIDS Pharmacists 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9E16 MSC #9830 
Rockville, MD 20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov 
 
Justine Beck, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9D39 
Rockville, MD 20852 
Phone: 301-761-5288 
E-mail: justine.beck@nih.gov 
 
Immunologists  
Jennifer Kinslow, PhD 
Rush-Presbyterian-St. Luke’s Medical 
Center ISL 
1735 W. Harrison Street, Suite 641 
Chicago, IL 60612 
Phone: 312-942-3514 
Fax: 312-942-5206 
E-mail: jennifer_kinslow@rush.edu 
 
Alan Landay, PhD 
Rush University CRS 
Immunology/Microbiology 
1725 West Harrison Street, Suite 306 POB1 
Chicago, IL 60612 
Phone: 312-942-6554 
E-mail: alanday@rush.edu 
 
Endocrinologist 
Todd Brown, MD, PhD 
Johns Hopkins University CRS 
Division of Endocrinology and Metabolism 
1830 East Monument Street 
Baltimore, MD 21287 
Phone: 410-502-2327 
E-mail: tbrown27@jhmi.edu 
 
Hepatologist 
Kathleen Corey, MD, MPH 
Massachusetts General Hospital 
Gastroenterology Associates 
55 Fruit Street 
Boston, MA 02114-2696 
Phone: 617-724-1685 
Fax: 617-724-5997 
E-mail: kcorey@partners.org 
 
Investigators 
Anchalee Avihingsanon, MD, PhD 
Thai Red Cross AIDS Research Center 
Treatment (TRC-ARC Treatment) CRS 
104 Rajdamri Road 
Patumwan, Bangkok 10330 
Thailand 
Phone: 66-2-6523040 Ext. 107 
E-mail: anchalee.a@hivnat.org 
 
Raja Muthupillai, PhD, DABMP, DABR 
Department of Diagnostic and Interventional 
Radiology 
Baylor St. Luke’s Medical Center 
CHI St. Luke’s Health 
Houston, TX 77030 
Phone: 832-641-0025 
E-mail: rmuthup@gmail.com 
 
Hugo Perazzo, MD, PhD 
Instituto de Pesquisa Clinica Evandro 
Chagas CRS 
Av. Brasil, 4365. LaPClin - INI/FIOCRUZ 
Rio de Janeiro 21040-360 
Brazil 
Phone: +55-21-38659129 
E-mail: perazzohugo@gmail.com 
 


 
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Field Representative 
Michelle Saemann, RN 
University of Cincinnati CRS 
Eden Avenue and Albert Sabin Way 
Cincinnati, OH 45267-0405 
Phone: 513-584-2245 
E-mail: saemanmd@uc.edu 
 
Laboratory Technologists 
Joan Dragavon, MLM 
University of Washington AIDS Clinical 
Trials Unit CRS 
Virology Specialty Laboratory 
Research & Training Building 
325 Ninth Avenue 
Seattle, WA 98104-2499 
Phone: 206-897-5210 
E-mail: dragavon@u.washington.edu 
 
Brian Greenfelder, BA 
Ohio State University CRS 
Division of Infectious Diseases 
Department of Internal Medicine 
Starling Loving B002 
320 West 10th Avenue 
Columbus, OH 43210 
Phone: 614-293-8938 
E-mail: brian.greenfelder@osumc.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Lionel M. Hillard 
Trinity Health and Wellness Center CRS 
219 Sunset Avenue, Suite 116A 
Dallas, TX 75208 
E-mail: hillardlionel@gmail.com 
 
Consultant to the Protocol Team 
Jacy Wasoski, BS 
Rush-Presbyterian-St. Luke’s Medical 
Center ISL 
1725 West Harrison Street  
Chicago, IL 60612 
Phone: 312-942-2122 
E-mail: jacy.wasoski@rush.edu 
 
International Site Specialist 
Allan-Michael Bills, MSc 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 30-628-3273 
Fax: 301-628-3302 
E-mail: allan-michael.bills@dlhcorp.com 
 
Laboratory Data Manager 
Lauren Harriff, BS 
ACTG Data Management Center 
Frontier Science and Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7348 
E-mail: harriff@frontierscience.org 
 
Laboratory Specialist 
Rose Lagattuta 
ACTG Laboratory Center at UCLA (ALC-
UCLA) 
11075 Santa Monica Boulevard 
Suite 200 
Los Angeles, CA 90025 
Phone: 310-794-9979  
E-mail: rlagattuta@milabcentral.org 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5371@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5371@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.protA5371 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail 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.cmcA5371@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 
immunologists, Alan Landay and Jennifer Kinslow.  
• 
Send an e-mail message to alanday@rush.edu and jennifer_kinslow@rush.edu, with a cc 
to: actg.teamA5371@fstrf.org. 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Kathleen 
Donahue and Autumn Rolack directly.  
• 
For other questions, send an e-mail message to actg.teamA5371@fstrf.org (ATTENTION: 
Kathleen Donahue and Autumn Rolack). 
• 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration  
For participant registration questions or problems and study identification number (SID) lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 


 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
• 
Send an e-mail message to actg.teamA5371@fstrf.org (ATTENTION: Christina Vernon).  
 
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 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.teamA5371@fstrf.org (ATTENTION: Christina Vernon). 
 
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 
Justine Beck or Dapo Alli, Protocol Pharmacists, at 301-496-8213.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number is available on the protocol-specific web page (PSWP). For any questions 
related to the IND submission, contact the DAIDS RSC at Regulatory@tech-res.com or call 301-
897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax to 1-800-275-7619 or 301-897-1710.  
 


 
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Telephone Calls 
Sites are responsible for documenting telephone calls made to A5371 team members.  
• 
Send an e-mail message to actg.teamA5371@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP).


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
AASLD 
American Association for the Study of Liver Diseases 
ART 
antiretroviral treatment 
BMI 
body mass index 
CrCl 
creatinine clearance 
CRP 
C-reactive protein 
CVD 
cardiovascular disease 
DPP-4 
dipeptidyl peptidase-4 
FFA 
free fatty acid 
GLP 
glucagon-like peptide 
HAV IgM 
hepatitis A virus immunoglobulin M 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HOMA-IR 
homeostatic model assessment of insulin resistance 
HS 
high-sensitivity 
IHTG 
intra-hepatic triglyceride 
iNKT 
invariant natural killer T 
IQA 
immunology quality assurance 
LDL 
low-density lipoprotein 
LPS 
lipopolysaccharide 
MACS 
Multicenter AIDS Cohort Study  
MCP-1 
monocyte chemoattractant protein-1 
MEN2 
multiple endocrine neoplasia type 2  
 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging-proton density fat fraction 
MRS 
magnetic resonance spectroscopy 
NAFLD 
non-alcoholic fatty liver disease 
NASH 
non-alcoholic steatohepatitis 
NRTI 
nucleoside reverse transcriptase inhibitor 
PE 
physical exam 
PLWH 
people living with HIV 
SAT 
subcutaneous adipose tissue 
SC 
subcutaneous 


 
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GLOSSARY OF TERMS (Cont'd) 
06/22/20 
 
TG 
triglyceride 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
VAT 
visceral adipose tissue 
VLDL 
very low-density lipoprotein 
VQA 
Virology Quality Assurance 
WC 
waist circumference


 
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SCHEMA 
 
A5371 
 
A Single-Arm, Open-Label, Pilot Study of Semaglutide for Non-Alcoholic Fatty Liver 
Disease (NAFLD), a Metabolic Syndrome with Insulin Resistance, Increased Hepatic 
Lipids, and Increased Cardiovascular Disease Risk 
(The SLIM LIVER Study) 
 
DESIGN 
A5371 is a phase II, single-arm, open-label, pilot study of the effects of 
semaglutide on intra-hepatic triglyceride (IHTG) content in people living 
with HIV (PLWH), central adiposity, insulin resistance or pre-diabetes, 
and hepatic steatosis. IHTG will be quantified by magnetic resonance 
imaging-proton density fat fraction (MRI-PDFF) at two time points. 
Participants will also complete food diaries, adherence and strength 
assessments, and report on physical activity. Stool and blood samples 
will be collected at several visits. Refer to the Protocol Synopsis for 
more details (Appendix I).   
 
 
DURATION 
Approximately 48 weeks.  
 
 
SAMPLE SIZE 
50 participants. 
 
 
POPULATION 
Adults ≥18 years of age with HIV, not meeting criteria for diabetes but 
with central adiposity (i.e., minimum waist circumference (WC) of ≥95 cm 
for individuals assigned male sex at birth or ≥94 cm for individuals 
assigned female sex at birth), ≥5% IHTG content, plus at least one of the 
following indicators of insulin resistance or pre-diabetes: fasting plasma 
glucose 100-125 mg/dL, HbA1c between 5.7 and <6.5%, or HOMA-IR 
>3.0.  
 
REGIMEN 
Participants will all receive semaglutide subcutaneously once weekly for 
24 weeks. Participants will receive a dose of 0.25 mg weekly starting at 
entry, followed by 0.5 mg weekly starting at week 2, and then 1.0 mg 
weekly from weeks 4 through 24. During weeks 25-48, all participants will 
be off study drug. 
 






 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Primary Hypothesis 
 
Among antiretroviral therapy (ART)-treated, virologically suppressed adults with 
HIV, hepatic steatosis, central adiposity, and insulin resistance or pre-diabetes, 
24 weeks of semaglutide will result in reductions in intra-hepatic triglyceride 
(IHTG) content, as quantified by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF). 
 
1.1.2 Secondary Hypotheses 
 
1.1.2.1 Semaglutide will be safe and well tolerated. 
 
1.1.2.2 Semaglutide will improve cardiometabolic parameters central to the 
pathogenesis of atherosclerosis and increased cardiovascular risks. 
 
1.2 
Primary Objective 
 
To evaluate whether semaglutide will reduce IHTG content, as quantified by MRI-PDFF, 
among ART-treated adults with HIV, hepatic steatosis, central adiposity, and insulin 
resistance or pre-diabetes.  
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate the safety and tolerability of semaglutide in adults with HIV, hepatic 
steatosis, central adiposity, and insulin resistance or pre-diabetes.  
 
1.3.2 To evaluate the effects of semaglutide on weight, minimum waist circumference 
(WC), and body mass index (BMI). 
 
1.3.3 To evaluate the effects of semaglutide on insulin resistance or pre-diabetes, lipid 
profiles, and the prevalence of metabolic syndrome. 
 
1.3.4 To evaluate relationships between observed changes in IHTG (refer to 1.2) and 
changes in metabolic parameters (refer to 1.3.2). 
 
1.4 
Exploratory Objectives  
 
NOTE: Exploratory objectives will be explored dependent on results of primary and 
secondary outcomes. 
 
1.4.1 To evaluate the durability of semaglutide on weight, minimum WC, and BMI after 
cessation of study therapy.  


 
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1.4.2 To evaluate the relationships between systemic measures of carbohydrate and 
lipid metabolism and a) IHTG and b) visceral adipose tissue (VAT) area in 
participants treated with semaglutide. 
 
1.4.3 To evaluate the effects of semaglutide on MRI-quantified VAT and abdominal 
subcutaneous adipose tissue (SAT) area and density. 
 
1.4.4 To evaluate the effects of semaglutide on circulating inflammatory biomarker and 
adipocytokine levels. 
 
1.4.5 To evaluate the effects of semaglutide on muscle function, muscle area, and 
muscle fat. 
 
1.4.6 To evaluate the effects of semaglutide adherence on primary and secondary 
outcomes. 
 
1.4.7 To evaluate the effects of semaglutide on self-reported quality of life. 
 
1.4.8 To evaluate the effects of semaglutide on the gut microbiome. 
 
1.4.9 To evaluate relationships between changes in IHTG content and changes in VAT 
and SAT area and muscle fat quantity.  
 
1.4.10 To evaluate the effects of semaglutide on circulating immune cell profiles. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Epidemiology  
Thirty to 40% of adults with HIV also have Non-Alcoholic Fatty Liver Disease (NAFLD, 
defined as ≥5% hepatic steatosis without other demonstrable causes) [Guaraldi 2008, 
Crum-Cianflone 2009, Hadigan 2007, Morse 2015]. NAFLD is universally associated 
with steatosis, may progress to non-alcoholic steatohepatitis (NASH), and may be 
further complicated by cirrhosis, liver failure, and hepatocellular carcinoma [Schuppan 
2013].  
 
However, most of the excess morbidity and mortality associated with NAFLD is due to 
cardiovascular disease (CVD) [Targher 2005, Targher 2007, Targher 2010, Haring 2009, 
Adams 2005, Bhala 2011, Rafiq 2009, Ekstedt 2006, Musso 2011]. This is not 
surprising, since 80-90% of adults with NAFLD have generalized obesity, visceral 
adiposity, metabolic syndrome, or type 2 diabetes [Guaraldi 2008]. Further, IHTG 
accumulation is more closely linked to metabolic complications than VAT quantity in HIV 
and the general population [Alderete 2013, Fabbrini 2009, Korenblat 2008, Reeds 2017].  
For example, in a study of over 358 adolescents, liver fat was more strongly associated 
with insulin sensitivity than visceral fat, with a greater prevalence in African Americans 
than Hispanics [Alderete 2013]. Additionally, NAFLD promotes a pro-inflammatory 






 
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are associated with greater weight gain compared to non-INSTI based regimens both 
among patients initiating or switching therapy. Multiple studies have identified that a low 
CD4 count, high HIV-1 RNA, female sex, and black race seem to be consistent risk 
factors predicting a greater weight gain. The metabolic consequences of this weight gain 
are also not well understood, though the added weight gain is expected to further 
contribute to the incidence of NAFLD in HIV. As the mechanisms of this weight gain are 
not understood, there are currently no treatment recommendations to prevent or reverse 
the weight gain outside of lifestyle modification. Although A5371 will not be specifically 
focused on INSTI-associated weight gain, the study will provide preliminary data in 
persons with HIV (PWH) on the safety, tolerability, and efficacy of weight loss of a 
therapy with demonstrated weight loss efficacy in the general population. 
 
Current Therapeutic Options 
A critically important goal of NAFLD treatment is the reduction of IHTG storage to 
improve insulin signaling and attenuate cardiometabolic risk. IHTG reduction may also 
attenuate immunopathologic processes, including those leading to chronic liver damage. 
We propose a pilot, single-arm, pharmacologic approach to reduce IHTG treatment in 
adults with HIV on suppressive ART and with central adiposity, hepatic steatosis, and 
insulin resistance.  
 
The American Association for the Study of Liver Diseases (AASLD) Guidelines for 
NAFLD treatment currently recommend 5-10% weight loss as first line therapy 
[Chalasani 2012, Harrison 2007, Musso 2010]. However, weight loss is often difficult to 
achieve and sustain with diet and exercise alone. Additionally, traditional diet and 
exercise regimens for weight loss may have insufficient efficacy in persons with HIV, 
although data are mixed [Lake 2017, O’Brien 2017]. Comorbid states like cardio-
autonomic dysfunction [Cade 2008], frailty, peripheral neuropathy, and gait disturbances 
are common among aging persons with HIV [Berner 2017], and can affect exercise 
capacity, which may also be limited by obesity that accompanies NAFLD. Thus, 
alternative interventions are needed for this population.   
 
2.2 
Rationale 
 
Semaglutide  
Semaglutide is a long-acting glucagon-like peptide (GLP)-1 receptor agonist that is FDA-
approved at doses of up to 1 mg subcutaneous (sc) weekly for the treatment of diabetes, 
and is in phase III trials at doses between 1.0 and 2.4 mg weekly (mostly commonly max 
2.4 mg weekly, titrated to participant tolerance) for weight loss and cardiovascular risk 
reduction in both diabetic adults and overweight and obese adults without diabetes 
[www.clinicaltrials.gov]. In registrational trials of semaglutide 1.0 mg weekly for the 
treatment of diabetes, significantly greater weight loss occurred with semaglutide than 
placebo or active comparator in all BMI groups (SUSTAIN 1-5), and CVD events were 
reduced over 2 years with semaglutide therapy (SUSTAIN 6) [Ahrén 2018]. 
 
In Phase II studies of semaglutide for weight loss in non-diabetic adults with BMI ≥30 
kg/m2, significant weight loss occurred proportional to the semaglutide dose (mean 
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At 1.0 mg weekly in obese adults (n=30), semaglutide for 12 weeks led to a 24% 
decrease in caloric intake, improved satiety, and a 5.0 kg mean body weight loss that 
was predominantly fat mass [Blundell 2017]. Other benefits in non-diabetic persons 
receiving semaglutide included reduced WC, blood pressure, glucose, HbA1c, and high-
sensitivity-C-reactive protein (hs-CRP), improved lipid profiles and dose-dependent 
trends towards improvements in physical function scores [O’Neil 2018].  
 
Additional GLP-1 agonist class data 
GLP-1 agonism reduces intra-hepatic fat in diabetic adults without HIV [Cuthbertson 
2012, Tang 2016, Feng 2017, Ishii 2019], as well as visceral fat content [Ishii 2019]. We 
postulate that semaglutide will reduce fat mass (and thus circulation of FFAs from 
lipolysis), improve insulin glucose homeostasis, and decrease circulating TG levels, 
which are together expected to reduce IHTG. Indeed, among 57 women with polycystic 
ovarian syndrome who were not required to have hepatic steatosis at entry, liraglutide 
1.8 mg daily resulted in a 44% relative reduction in magnetic resonance spectroscopy 
(MRS)-quantified liver fat over 26 weeks [Frossing 2017]. Similarly, in obese, non-
diabetic Asian adults with NAFLD, liraglutide 3 mg resulted in a 7.2% absolute reduction 
in liver fat over 26 weeks [Khoo 2017], and a 53% relative reduction/17% absolute 
reduction in obese, diabetic Japanese adults [Ishii 2019].  
 
 
Figure 2.2-2: Proposed mechanisms for a GLP-1RA 
induced anti-atherosclerotic effect. 
 
Regarding NASH, in a mouse model, semaglutide therapy reduced fibrosis and 
inflammation in addition to IHTG [Rakipovski 2018]. In the LEAN trial, liraglutide 1.8 mg 
daily prevented worsening of fibrosis [Armstrong 2016]. Finally, reduced circulating GLP-


 
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1 levels and reduced hepatic GLP-1 and dipeptidyl peptidase-4 (DPP-4) receptor 
expression has been demonstrated in NAFLD patients [Miyazaki 2012], suggesting a 
role for GLP-1 in NAFLD. 
 
GLP-1 agonism increases prandial insulin secretion, decreases prandial glucagon 
secretion, reduces TG levels and oxidized low-density lipoprotein (LDL) cholesterol 
uptake, suppresses appetite, improves hepatic and subcutaneous insulin sensitivity, and 
reduces lipotoxicity [Armstrong 2016, Tashiro 2014]. Together, loss of fat mass, reduced 
IHTG and improved metabolism may result in reduced systemic inflammation [Hannah 
2016]. Semaglutide induces greater weight loss than liraglutide [O’Neil 2018], and weight 
loss does not plateau early in use, as with liraglutide [Astrup 2009, Pratley 2011]. As 
such, the benefits on IHTG are expected to be at least as great with semaglutide 
therapy, if not greater. 
 
Other potential benefits of GLP-1 agonism include delay of diabetes onset in overweight 
and obese adults with pre-diabetes (hazard ratio 0.21, 95% confidence interval 0.13, 
0.34) [le Roux 2017], in vitro and in vivo cardioprotective effects [Hu 2017, Rakipovski 
2018, Marso 2016], and similar rates of serious adverse events as placebo [le Roux 
2017]. Importantly, CVD risk reduction with GLP-1 agonism is not thought to be 
secondary to glucose-lowering [Kaul 2017], but other secondary effects, potentially 
including reduced visceral fat and NAFLD burden, which reduce systemic inflammation 
(Figure 2.2-2).  
 
Indeed, GLP-1 agonism has been associated with reduced systemic inflammation, 
including reduced interleukins 1β and 6, tumor necrosis factor (TNF)-α, soluble CD163 
[Hogan 2014], plasminogen activator inhibitor-1 [Forst 2012] and hs-CRP [Pi-Sunyer 
2015], which may be of benefit to persons with HIV. Finally, HIV infection is also 
associated with greater non-calcified atherosclerotic plaque burden [Post 2014, Metkus 
2015]. Non-calcified plaques are less stable than calcified plaques, and semaglutide 
may reduce atherosclerotic plaque inflammation and promote plaque stabilization 
[Balestrieri 2015].  
 
Increased GLP-1 levels have been reported in men with HIV and impaired vs normal 
glucose tolerance [Andersen 2005], a finding hypothesized to be compensatory rather 
than causative of their impaired glucose tolerance. This compensatory hypothesis may 
be supported by the fact that gut barrier disruption and lipopolysaccharide leak in HIV 
should be associated with depletion of the neuro-endocrine cells that secrete GLP-1, 
and need for support by drugs such as GLP-1 agonists to maintain homeostasis [Culha 
2016]. In mice, GLP-1 agonism has been shown to upregulate genes encoding mucins 
and other GI-protective proteins [Bang-Berthelsen 2016]; improve gut barrier function  
[Yusta 2015]; and, when given prior to lipopolysaccharide (LPS) exposure, reduce TNF-
α, interferon-γ, and immune cell recruitment (as assessed by decreased circulating 
osteopontin levels) [Rakipovski 2018]. As such, semaglutide could have unique benefit 
in PLWH, who are known to have gut barrier disruption and microbial translocation, a 
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In summary, semaglutide may improve HIV-/ART-specific contributors to NAFLD in 
addition to traditional NAFLD risk factors. The mechanism of action of the proposed 
intervention should lessen perturbations in insulin sensitivity and fatty acid metabolism, 
which are linked to increased IHTG content, the core problem of NAFLD. Furthermore 
semaglutide should lead to weight loss in a population with a growing obesity epidemic, 
and ultimately reducing other obesity-associated comorbidities. Semaglutide has not 
been studied for the prevention or treatment of NAFLD in HIV infection, but reduces fat 
mass and improves dysmetabolism, a critical driver of metabolic dysregulation in NAFLD 
and HIV infection. 
 
Study Design 
No standard of care for NAFLD exists in HIV infection or in the general population 
beyond routine diet and exercise recommendations, which are notoriously difficult to 
achieve and sustain and may have reduced efficacy in PLWH. The proposed 
intervention has the potential to reduce hepatic steatosis in PLWH. However, before 
recommending semaglutide as a therapeutic option, its safety and efficacy must be 
tested in this population. Therefore, we propose a phase II, single arm, pilot study of 
semaglutide sc weekly to reduce IHTG and attenuate immuno-metabolic dysregulation in 
adults with HIV and central adiposity, hepatic steatosis, and insulin resistance or pre-
diabetes (a population at high risk of NAFLD and its consequences). 
 
Notably, increased VAT-to-BMI ratios and HIV-/ART-induced alterations in lipid and 
glucose metabolism in PLWH predispose them to “lean NAFLD” in addition to the more 
traditional obese NAFLD paradigm. Increased minimum WC is 1) the best method for 
non-invasive assessment of VAT quantity, 2) a better screening tool for NAFLD than BMI 
in this population, and 3) similar to important BMI cutoffs for disease risk in populations 
without HIV.   
 
All participants will receive semaglutide for 24 weeks, a common initial assessment point 
for NAFLD evaluation by MRI-PDFF in clinical trials. A 24-week primary endpoint was 
chosen as 1) it will take participants 4 weeks to titrate to the therapeutic dose of 
semaglutide; 2) weight loss with semaglutide begins early and does not plateau early (as 
with liraglutide, refer to section 2.1), giving participants time to reach therapeutic weight 
loss (and IHTG reduction) goals on study; and 3) given the cost of the drug, assessing 
for preliminary efficacy after 24 weeks should allow determination of whether further 
study is warranted without undue commitment of resources and participant time. If 
semaglutide improves IHTG, this would be a significant clinical advancement and may 
aid mechanistic understanding of NAFLD pathogenesis in HIV infection. This study will 
also inform knowledge of the pathogenesis of NAFLD in treated HIV infection, and 
issues related to quality of life and therapeutic selection for PLWH and NAFLD. Finally, a 
secondary benefit of this study is the assessment of the safety and efficacy of 
semaglutide as a weight loss therapy in PLWH, which is greatly needed given the 
current obesity epidemic in the population. 
 
Of note, since NAFLD therapy should occur concomitant with lifestyle optimization, 
general diet and exercise recommendations will be provided at study entry. Importantly, 
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cardiovascular activity and dietary guidance are expected to have previously been part 
of routine clinical recommendations for enrolled participants who have been in routine 
care. However, we will offer these recommendations again to be consistent with clinical 
care guidelines. Examples of such standard diet and exercise materials and a link to the 
American Diabetes Association websites will be provided to all sites, which will include 
recommendations for 1) moderate-to-vigorous intensity cardiovascular activity according 
to the American Heart Association, American College of Cardiology, American Diabetes 
Association, and American College of Sports Medicine guidelines, and 2) information on 
healthy diet, including target calorie goals.  
 
Study population 
Children 13-17 years of age will not be included in this study as, compared to adults ≥18 
years of age, 1) the pathogenesis of NAFLD may vary in that population, 2) the 
prevalence of NAFLD may be much lower, and 3) semaglutide is not approved for use in 
pediatric populations. 
 
Primary outcome 
MRI-PDFF is a non-invasive, image-based biomarker for NAFLD that is readily available 
and can accurately and precisely quantify IHTG content, which is the primary outcome. 
MRI-PDFF is strongly correlated with biopsy-proven hepatic steatosis, and changes in 
PDFF correlate with histologic response [Patel 2016, Middleton 2017, Hong 2018]. In a 
recent meta-analysis, the pooled sensitivity and specificity of MRI-PDFF for classifying 
grade versus 1-3 hepatic steatosis were 0.93 and 0.94, respectively [Qu 2019]. 
 
Other measures 
Loss of muscle mass often accompanies weight loss, and may be associated with loss 
of muscle function (manifested by slowing in the time to rise from a chair, for example).  
Conversely, among obese persons, weight loss may be accompanied by small loss in 
muscle mass but improvements in muscle function and improved mobility. NAFLD has 
also been associated with impaired muscle function (grip strength) in men with HIV 
[Debroy 2019]. Gait speed is a commonly used measure of physical function, is strongly 
associated with disability and mortality [Studenski 2011, Perera 2016], and has been 
proposed as a key component of sarcopenia in a recent sarcopenia consensus definition 
in several populations including PLWH (manuscripts under review). Repeat chair stand 
is a functional test of lower extremity performance that is highly affected by changes in 
muscle strength and has been proposed as a proxy measure of lower-extremity strength 
for the clinical setting. These tests require minimal equipment (a stopwatch and a chair 
without arms or wheels), can be completed within approximately 1 minute each, are 
responsive to interventions, and are assessments that ACTG sites already have 
experience conducting. 
 
Changes in muscle and VAT and SAT will likely occur with semaglutide therapy, have 
important physiologic consequences, and will thus be evaluated in this study through 
measures of muscle function (chair rise), muscle area and fat infiltration (MRI), and VAT 
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Stool samples will be collected for microbiome assessment as microbiome changes are 
linked with NAFLD development [Zhu 2015, Doulberis 2017], and 1) differences in the 
microbiome could account for potential differences in observed treatment response, 
and/or 2) it is unknown whether semaglutide therapy has microbiome effects in humans. 
 
Finally, circulating immune cell profiles will be evaluated, with a focus on invariant 
natural killer T (iNKT) cells, which are required for maximal weight loss for GLP-1 
therapy [Lynch 2016] and mucosal-associated invariant T cells (MAIT) cells, which are 
important for epithelial barrier function and are reduced in NAFLD [Hegde 2018]. These 
have not yet been studied in PLWH, but may have a role in dysmetabolism and NAFLD. 
 
3.0 
STUDY DESIGN 
 
A5371 is a phase II, open-label, single arm, 48-week pilot study of the effects of 24 
weeks of semaglutide on MRI-PDFF-quantified IHTG content in PLWH and central 
adiposity, insulin resistance or pre-diabetes, and hepatic steatosis. 
 
A total of 50 participants will be enrolled and followed on study for 24 weeks on 
treatment and an additional 24 weeks off study treatment to understand the durability of 
observed effects. All participants will receive semaglutide 1 mg sc weekly through week 
24 (after 4 weeks of initial titration), followed by 24 weeks of observation off study drug. 
 
Each participant will have two MRI-PDFF evaluations during the study. The first will 
occur at study pre-entry to determine eligibility; the second will occur at week 24 or 
Premature Study/Treatment Discontinuation (if the participant has received study drug 
for at least 12 weeks). Blood samples will be collected for measurement of immunologic, 
metabolic, and inflammatory biomarkers. Stool samples will be self-collected for 
microbiome assessment, and participants will perform repeat chair stands and gait 
speed measurement as measures of physical performance. 
 
Because moderate weight loss and increased physical activity are considered first line 
therapy for NAFLD, participants will receive standardized recommendations for 1) 
moderate-to-vigorous intensity cardiovascular activity (refer to section 2.2) and  
2) general information on a healthy diet, including target calorie goals at study entry.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, 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, plasma HIV-1 
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NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies, 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. Non-US sites are encouraged to use US FDA-approved 
methods for IND studies. 
 
WHO (World Health Organization) 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. 
 
4.1.2 Two separate reports of HIV-1 RNA measurements <50 copies/mL, and no HIV-1 
RNA measurement >500 copies/mL, during the 48 weeks prior to entry. One of 
the HIV-1 RNA values must be the screening visit value, and the other value 
obtained between 24 and 48 weeks prior to entry. 
 
NOTE:  All values must have been reported from a US laboratory that has a 
Clinical Laboratory Improvement Amendments (CLIA) certification or its 
equivalent, or at any network-approved non-US laboratory that is Virology Quality 
Assurance (VQA) certified. 
 
4.1.3 No change in ART in the 24 weeks prior to entry.  
 
NOTE A: Modifications of ART formulation (e.g., from standard formulation to 
fixed dose combination or single tablet regimen) will be permitted.  
 
NOTE B: Within-class substitutions are not permitted. 
 
4.1.4 No plan to change ART for the study duration.  
 
4.1.5 Within 30 days prior to pre-entry, a minimum WC measurement of ≥95 cm for 
individuals assigned male sex at birth or ≥94 cm for individuals assigned female 
sex at birth. 
 
NOTE: For transgender study participants, sites should use the parameter that 
matches sex assigned at birth. 
 
4.1.6 At least one of the following drawn within 30 days prior to pre-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: 
• 
Fasting plasma glucose 100-125 mg/dL (refer to section 6.3 for a definition of 
fasting). 
• 
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• 
HOMA-IR >3.0 (Refer to calculator: https://www.mdcalc.com/homa-ir-
homeostatic-model-assessment-insulin-resistance) 
 
4.1.7 Documentation of negative hepatitis A virus (HAV) immunoglobulin M (IgM) 
or HAV vaccination prior to study entry. 
 
NOTE: If documentation is not available prior to screening, this should be 
obtained through routine clinical care within 30 days prior to entry.  
 
4.1.8 Hepatic fat content (i.e., IHTG) ≥5%, as determined by liver MRI-PDFF within 14 
days prior to entry (and between 1-30 days after screening). 
 
NOTE: Refer to section 6.2.1 for more details. 
 
4.1.9 CD4+ T-cell count ≥200 cells/mm3 within 30 days prior to pre-entry (may be from 
standard of care) at any US laboratory that has a CLIA certification or its 
equivalent, or at any network-approved non-US laboratory that is Immunology 
Quality Assurance (IQA) certified. 
 
4.1.10 The following laboratory values obtained within 30 days prior to pre-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 individuals assigned male at birth and >9 g/dL for 
individuals assigned female at birth 
• 
Creatinine clearance (CrCl) ≥50 mL/min, as calculated by the CKD-Epi 
equation.  
NOTE: Please refer to A5371 PSWP for the website link to calculate CrCl 
using the CKD-Epi calculator. 
 
NOTE: Calculations will be done without using cystatin C. Please refer to the 
A5371 MOPS for further details. 
 
• 
Aspartate aminotransferase (AST) (SGOT) ≤3 x ULN on at least two 
measurements, with at least one within 30 days prior to pre-entry.  
Participants must also have no evidence of AST >3 x ULN within the 3 
months prior to entry, from routine clinical monitoring, if available. If no 
additional monitoring is available in the 3 months prior to entry, 
additional testing should be obtained within the screening interval (2-4 
weeks apart) to ensure stability. 
• 
Alanine aminotransferase (ALT) (SGPT) ≤3 x ULN on at least two 
measurements, with at least one within 30 days prior to pre-entry. 
Participants must also have no evidence of ALT >3 x ULN within the 3 
months prior to entry, from routine clinical monitoring, if available. If no 
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additional testing should be obtained within the screening interval (2-4 
weeks apart) to ensure stability. 
• 
Fasting triglyceride level ≤500 mg/dL. 
 
NOTE A: See section 6.3 for a definition of fasting. 
 
NOTE B: If level is >500 mg/dL, level may be rechecked within the screening 
window. 
 
4.1.11 For individuals taking daily medications with anti-inflammatory properties, 
including but not limited to, statins and chronic corticosteroids (inhaled 
corticosteroids exempt), the doses must be stable as determined by the site 
investigator for ≥3 months prior to study entry, and the individual should have no 
active plans to change dosing during the study period. 
 
4.1.12 For individuals taking daily lipid-lowering medications (such as statins, fibrates, 
niacin, fish oil), the doses must be stable as determined by the site investigator 
for ≥3 months prior to study entry, and the individual should have no active plans 
to change dosing during the study period. 
 
NOTE: Lipid-lowering equivalents for niacin and fish oil are ≥1 g and ≥3 g daily, 
respectively. 
 
4.1.13 Ability and willingness of participant to provide informed consent. 
 
4.1.14 Willingness and ability to use auto-inject pen weekly for 24 weeks. 
 
4.1.15 Willingness and ability to undergo MRI scans. 
 
NOTE: Anxiolytics will not be provided through the study but may be provided at 
site expense. 
 
4.1.16 For persons able to become pregnant, a negative serum or urine pregnancy 
test (urine test must have a sensitivity of <25 mIU/mL) both 1) at screening 
(within 30 days prior to pre-entry MRI) and 2) within 3 days before or at entry 
(prior to registration into study) 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 Good Clinical Laboratory Practices (GCLP) and participates in 
appropriate external quality assurance programs.   
 
NOTE:  Individuals able to become pregnant are defined as individuals who 
have reached menarche and who have not been post-menopausal for at least 24 
consecutive months (i.e., have had menses within the preceding 24 months), and 
have not undergone surgical sterilization such as hysterectomy, bilateral 
oophorectomy, tubal ligation, or salpingectomy.  
 


 
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4.1.17 If participating in sexual activity that could lead to the participant becoming 
pregnant, the participant must agree to use contraception while on study drug (24 
weeks) and for 2 months following the last dose of study drug. At least one of the 
following must be used: 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
• 
Partner sterilization (i.e., vasectomy) and is the sole partner for the 
participant. 
  
NOTE: Participant self-report of partner sterilization is acceptable.  
 
4.1.18 For individuals taking Vitamin E (any dose), the dose must be stable as 
determined by the site investigator for more than 1 year prior to entry. 
 
4.1.19 Adults age ≥18 years. 
 
4.1.20 Willingness to be contacted by telephone or e-mail by study staff throughout the 
study. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Known active hepatitis C virus (HCV) infection, defined as a detectable HCV 
RNA within 24 weeks prior to study entry. 
  
NOTE A: Individuals with HCV RNA below the limit of quantitation for >24 weeks 
prior to study entry are eligible, i.e., individuals who have been treated 
for hepatitis C are eligible if they have completed therapy >24 weeks 
prior to study entry, and/or individuals who spontaneously cleared 
hepatitis C virus are eligible as long as they have had undetectable 
HCV RNA for >24 weeks. HCV RNA testing is not provided by the 
study. 
  
NOTE B: If HCV antibody testing has not been performed in the 5 years prior to 
screening and the participant does not have history of cured HCV 
infection, HCV antibody testing should be repeated at screening. If 
screening HCV antibody is positive or reactive, the individual is 
not eligible and should be referred for clinical evaluation through 
routine care. 
 
4.2.2 Active/chronic hepatitis B (HBV), defined as a positive hepatitis B surface antigen 
(HBsAg) at screening.  
 
NOTE A: HBsAg testing is only required at screening if HBV laboratory results 
are not available within the last 5 years prior to screening and 
individual does not have documented immunity.  
 


 
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NOTE B: If HBsAg positive, individual is not eligible and should be referred for 
clinical evaluation through routine care. 
 
4.2.3 Known active severe delayed gastric emptying, as determined by the site 
investigator. 
 
4.2.4 Gain or loss of >5% body weight within 12 weeks prior to study entry. 
 
NOTE: Self-report recall is acceptable. 
 
4.2.5 Any plans to change diet or exercise regimen significantly, except for the 
adoption of study provided suggestions for diet and exercise, within the study 
period. 
 
NOTE: “Significantly” refers to intent to join a weight-loss program such as 
Weight Watchers, or start a specific diet (such as ketogenic or very low 
carbohydrate). 
 
4.2.6 Known acute or chronic liver disease with cirrhosis or portal hypertension. 
 
4.2.7 History of liver transplant. 
 
4.2.8 Breastfeeding or plans to become pregnant. 
 
4.2.9 Current diagnosis of diabetes mellitus or current use of diabetes medications, or 
a laboratory measurement of hemoglobin A1c ≥6.5% at screening. 
 
NOTE: Stable use of metformin (i.e., for ≥12 weeks) for indication other than 
diabetes (e.g., polycystic ovarian syndrome or pre-diabetes/impaired fasting 
glucose) may be permitted with approval of the Clinical Management Committee 
(CMC). 
 
4.2.10 Known retinopathy (excluding remote history of cotton wool spots). 
 
4.2.11 Personal or family (first-degree relative) history of medullary thyroid carcinoma or 
multiple endocrine neoplasia type 2 (MEN2). 
 
4.2.12 Untreated, poorly controlled, or previously undiagnosed thyroid disease 
defined as the presence of abnormal thyroid-stimulating hormone (TSH) at 
screening with no clear explanation. 
 
4.2.13 Unexplained hypercalcemia corrected for albumin that is >10.5 mg/dL at 
screening. Please refer to the A5371 MOPS for the calculation.  
 
4.2.14 Use of any immunomodulatory (including prednisone equivalent of ≥10 mg), HIV 
vaccine, investigational therapy, or TNF-α therapy within 3 months prior to study 
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4.2.15 Use of human growth hormone, tesamorelin, supraphysiologic testosterone to 
achieve therapeutic blood levels, or any use of other anabolic steroids within 3 
months prior to study entry or plans to start these while on study.  
 
NOTE: Chronic, stable hormone replacement therapy ≥3 months prior to entry in 
men with diagnosed hypogonadism or transgender person on masculinizing 
hormonal therapy is permitted.  
 
4.2.16 Use of estrogens or progesterones at supraphysiologic doses within 3 months 
prior to study entry. 
 
NOTE: Stable doses used for contraception, post-menopausal hormone 
replacement or feminizing hormone therapy for transgender persons ≥3 months 
prior to entry is permitted. 
 
4.2.17 Known allergy/sensitivity or any hypersensitivity to components of study drug or 
its formulation. 
 
4.2.18 Current serious illness requiring systemic treatment and/or hospitalization. 
 
NOTE: The individual can be rescreened when they complete therapy or are 
clinically stable as determined by the site investigator.  
 
4.2.19 Use of GLP-1 agonists within 24 weeks prior to study entry. 
 
4.2.20 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.21 Excessive consumption of alcohol of ≥3 months within 90 days prior to screening, 
defined as:  
 
• 
Consuming ≥5 alcoholic drinks for men or consuming ≥4 alcoholic drinks for 
women during a single occasion (i.e., at the same time or within a couple of 
hours of each other), or  
• 
≥3 drinks on 4 or more days of the week on average for men or ≥2 drinks on 
4 or more days of the week on average for women. 
 
NOTE: For transgender study participants, sites should use the parameter that 
matches sex assigned at birth. 
 
4.2.22 Known chronic pancreatitis or more than one episode of pancreatitis ever in the 
past. 
 
4.2.23 Inability to keep study product at 36°F to 46°F (2°C to 8°C) prior to first use, or to 
maintain the study product at a controlled room temperature between 59°F and 
86°F (15°C to 30°C) following first use. 


 
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4.2.24 Intent to use any medication likely to cause significant changes in weight during 
the study period. 
 
NOTE: Refer to section 5.4.2 for a list of medications in this category.  
 
4.2.25 Use of stavudine within 12 months prior to study entry. 
 
4.2.26 Prior bariatric surgery (e.g., lap band, gastric sleeve, or Roux-en-Y bypass 
surgery) or major gastric surgery or plans to undergo weight reduction surgery 
while on study. 
 
4.2.27 Individuals with any metal, implantable devices (e.g., pacemakers, prosthetics), 
or shrapnel, per standard MRI exclusion criteria. 
 
4.2.28 Any condition that the site investigator believes would make the individual 
unsuitable for participation. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by the institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE) responsible for 
oversight of the study. Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS Protocol Registration 
Office (DAIDS PRO) at the Regulatory Support Center (RSC). The DAIDS PRO 
will review the submitted protocol registration packet to ensure that all of the 
required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s)  
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 


 
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For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant or legal representative will be 
asked to read and sign the approved protocol consent form.  
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC 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 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 form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
• 
US sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Co-enrollment in A5128 does not require permission from the 
A5371 protocol chairs.  
• 
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 A5371 protocol chairs.  
• 
Participants from the A5332 REPRIEVE study may co-enroll in A5371. 
• 
Participants from the A5322 HAILO study may co-enroll in A5371. 
• 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the CMC via e-mail as described in the Study 
Management section. 
 


 
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5.0 
STUDY TREATMENT 
 
Study treatment is defined as study-provided semaglutide (Ozempic). 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimen 
 
Beginning at entry, participants will receive open-label semaglutide 
subcutaneously once weekly, dosed as per section 5.1.2. 
 
NOTE: Participants must remain on their non-study-provided ART throughout the 
study. 
 
5.1.2 Administration and Duration 
 
Semaglutide will be administered subcutaneously weekly into the abdomen, thigh 
or upper arm, and will be initiated at study entry at a dose of 0.25 mg once 
weekly, increased at week 2 to 0.5 mg once weekly, and finally increased to 1.0 
mg once weekly at week 4 for continuation through week 24. The dose may be 
reduced or dose escalation held for intolerability, if necessary, in discussion 
with the CMC (refer to section 8.1.1). 
 
The drug should be administered on the same day each week at any time of the 
day without regard to meals. Refer to the A5371 MOPS for more details. 
 
Participants must insert a new needle prior to each injection and safely discard 
the needle after each injection. Sites will instruct participants how to appropriately 
dispose of the needles. Participants will rotate injection sites weekly if injecting in 
the same body area. To ensure that participants are using the appropriate 
technique, they will receive training in titrating the injection pen and will be 
observed injecting semaglutide at study entry, with retraining and observation 
conducted as needed. 
 
Study treatment will be 24 weeks in duration. Durability of medication effects will 
be assessed at 24 weeks after study treatment discontinuation (study week 48). 
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1  Semaglutide 
 
Semaglutide is a clear, colorless solution that will be supplied as pre-filled, 
multidose, disposable, single-participant-use pens that deliver doses of 0.25 mg, 
0.5 mg, or 1.0 mg. Each pen contains a total of 1.5 mL of semaglutide solution at 
a concentration of 1.34 mg/mL. 
 


 
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Prior to initial use, semaglutide should be stored between 2°C and 8°C (36ºF to 
46ºF). Do not store in the freezer or directly adjacent to the refrigerator cooling 
element. Do not freeze semaglutide and do not use semaglutide if it has been 
frozen. After initial use, the semaglutide pen can be stored for 56 days at 
controlled room temperature (15°C to 30°C; 59°F to 86°F) or in a refrigerator 
(2°C to 8°C; 36°F to 46°F). Semaglutide should be protected from excessive heat 
and sunlight. Do not freeze. When not in use, the semaglutide pen should be 
stored without an injection needle attached and with the cap on.  
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Semaglutide (Ozempic®) manufactured by Novo Nordisk®, sharps container(s), 
and alcohol swabs will be purchased for the study and available through the 
NIAID Clinical Research Products Management Center (CRPMC). The site 
pharmacist should obtain the semaglutide, sharps container(s), and alcohol 
swabs 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 study products 
received from the NIAID CRPMC and subsequently dispensed. At US CRSs, all 
unused study products must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are provided in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks. At non-US CRSs, the site 
pharmacist must follow the instructions in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks for the destruction of unused 
study products. 
 
5.4 
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/. 
 
5.4.1 Required Medications 
 
All participants will be required to continue their ongoing ART regimen for the 
duration of the study. Changes in ART are discouraged during the study, but may 
be allowed if clinical need arises as determined by sites. If possible, sites should 


 
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consult the A5371 CMC via email (actg.cmca5371@fstrf.org) prior to any ART 
changes. ART will not be provided by the study. 
 
5.4.2 Prohibited Medications 
 
Medications prohibited while on study treatment are: (1) stavudine; (2) GLP-1 
agonists; (3) estrogens or progesterones at supraphysiologic doses, with the 
exception of doses used for contraception, post-menopausal hormone 
replacement or feminizing hormone therapy (for transgender persons) that have 
been stable for ≥3 months prior to study entry; (4) use of any immunomodulatory 
therapy HIV vaccine, investigational therapy, or TNF-α therapy; (5) use of human 
growth hormone, tesamorelin, supraphysiologic testosterone to achieve 
therapeutic blood levels (with the exception of stable doses for ≥3 months prior to 
entry in men with diagnosed hypogonadism or transgender persons on 
masculinizing hormonal therapy), or use of other anabolic steroids; and (6) 
diabetes medications other than metformin use for non-diabetes indications (see 
4.2.8). Medications likely to cause significant changes in weight are prohibited: 
glucocorticoids (e.g., prednisone, at doses ≥10mg), typical and atypical 
antipsychotics (e.g., olanzapine, haloperidol), dronabinol, megestrol 
acetate, and mirtazapine if prescribed for weight management (usually with 
diagnosis of AIDS wasting; other indications not related to weight okay if 
stable dosing), GLP-1 agonists, bupropion-naltrexone, orlistat, lorcaserin, 
phentermine-topiramate, and commercial over-the-counter weight loss 
supplements such as Hydroxycut. 
 
5.4.3 Precautionary Medications 
 
None. 
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Schedule of Evaluations 
Evaluation 
Screening 
Pre-Entry 
Entry 
On-treatment weeks 
Study 
Completion 
1 
2 
3 
4 
8 
12 
16 
20 
Week 24 or 
Premature 
Treatment/Study D/C 
(see section 6.2.4) 
48 
Visit windows 
Within 30 
days prior 
to pre-entry 
≥1 day after 
screening and within 
14 days prior to entry 
±3 days 
-3 and 
 +7 days 
±7 days 
±14 days 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of demographic 
information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical assessment  
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Liver function tests 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Chemistry 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
X 
Hemoglobin A1c 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Insulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HOMA-IR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel and LDL measurement  
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
X 
 
 
 
As 
indicated 
 
As 
indicated 
 
 
X 
 
CD4+/CD8+ 
X 
 
 
 
 
 
 
 
 
 
 
X 
 


 
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Evaluation 
Screening 
Pre-Entry 
Entry 
On-treatment weeks 
Study 
Completion 
1 
2 
3 
4 
8 
12 
16 
20 
Week 24 or 
Premature 
Treatment/Study D/C 
(see section 6.2.4) 
48 
Visit windows 
Within 30 
days prior 
to pre-entry 
≥1 day after 
screening and within 
14 days prior to entry 
±3 days 
-3 and 
 +7 days 
±7 days 
±14 days 
HCV antibody, HBsAg, HAV IgG 
and/or HAV IgM tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
 
Stored plasma/PBMC/serum 
 
 
X 
 
 
 
 
 
X 
(plasma 
and serum 
only) 
 
 
X 
X 
(plasma and 
serum only) 
Stool kit  
(D=distribute, C= collect) 
 
XD 
XC 
 
 
 
 
 
XD 
 
 
XC 
 
MRI-PDFF 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
3-day food diary  
(D=distribute, C= collect) 
 
XD 
XC 
 
 
 
 
 
XD 
 
 
XC 
 
Hypoglycemia questionnaire 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
Quality of life questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Physical activity and diet  
questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
ART adherence self-report 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Study treatment adherence  
assessment 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
Acceptability and tolerability   
self-report 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
Physical function assessments 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Study product dispensation 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 


 
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Evaluation 
Screening 
Pre-Entry 
Entry 
On-treatment weeks 
Study 
Completion 
1 
2 
3 
4 
8 
12 
16 
20 
Week 24 or 
Premature 
Treatment/Study D/C 
(see section 6.2.4) 
48 
Visit windows 
Within 30 
days prior 
to pre-entry 
≥1 day after 
screening and within 
14 days prior to entry 
±3 days 
-3 and 
 +7 days 
±7 days 
±14 days 
Injection training/ 
retraining/observation 
 
 
X 
 
 
 
As needed 
 
As needed 
 
 
 
 
Study drug cartridge count 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
Exercise and diet education 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia and hydration 
education 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Telephone or email contact 
 
 
 
X 
X 
X 
 
X  
 
X 
X 
 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening and Pre-Entry Evaluations  
 
Screening and pre-entry evaluations must occur prior to the participant starting 
any study medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 30 days 
prior to pre-entry unless otherwise indicated. 
 
Participants must arrive fasting (refer to section 6.3 for a definition of fasting) for 
the screening visit. If the participant is not fasting, the visit will be rescheduled. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
on participants who do not enroll in a Screening Failure form and entered into the 
ACTG database.  
 
Pre-Entry  
Pre-entry evaluations must be completed after screening and within 14 days prior 
to entry evaluations unless otherwise specified. Screening blood work should be 
completed and reviewed, and all other entry criteria must be met, prior to 
performance of MRI-PDFF. MRI-PDFF should only proceed once screening 
evaluations are completed. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations will occur only after the site has received confirmation from the 
MRI reading center that the pre-entry MRI-PDFF scan is of acceptable quality 
and that the participant has ≥5% IHTG (and is otherwise eligible). Participants 
must arrive fasting for the entry visit. If the study participant is not fasting, the 
entry visit should be rescheduled (see section 6.3 for a definition of fasting) within 
7 days. 
 
6.2.3 Post-Entry Evaluations 
 
Participants must arrive fasting (see section 6.3 for a definition of fasting) for the 
weeks 12, 24, and 48 visits or a premature discontinuation visit. If the study 
participant is not fasting, the participant should return to the clinic for fasting 
evaluations within the visit window per Table 6.1-1, Schedule of Evaluations 
(SOE).  
 
If a participant experiences an acute inflammatory condition within 14 days prior 
to a scheduled visit, any scheduled blood collection should be postponed for 7 
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collection 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 A5371 CMC via email 
(actg.cmcA5371@fstrf.org) with any questions regarding whether a specific 
situation would require a delay in blood collection. 
 
Because of diurnal variations in values that may be measured on stored 
samples, all blood collections should be collected prior to 11AM local time. If this 
is not possible, then each participant’s 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 visit. Evaluations at weeks 
12, 24, and 48 must occur ±14 days of the visit. 
 
Telephone or e-mail contact during weeks 1 through 3 must occur ±3 days. Week 
8 contact must occur ±7 days. For weeks 16 and 20, contact must occur ±14 
days.  
 
Study Treatment Completion Evaluations 
The week 24 evaluations will be the participant’s final visit on treatment. The 
participant should be on study drug at the time of all week 24 evaluations (visit to 
occur within 7 days of the last study drug dose). If there are scheduling issues, 
additional study drug can be provided, if needed, to ensure continued 
administration. If a participant does not bring in their stool sample at week 24, the 
participant can bring the stool sample to the study clinic within 14 days. 
 
Study Completion Evaluations 
Participants will have the week 48 evaluations per the SOE.  
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the entry visit. 
 
Premature Treatment Discontinuation Evaluations 
Participants who discontinue study treatment early and have received at least 12 
weeks of study treatment will have the week 24/premature discontinuation 
evaluations performed at the time study treatment has stopped. In contrast, 
participants who prematurely discontinue study treatment before receiving 12 
weeks will not complete a discontinuation visit but should be followed to 
resolution of any applicable adverse event before being taken off-study, per 
section 8.0. 
 
Participants who discontinue treatment because of an adverse event should be 
followed on study, off study treatment until resolution of the adverse event, per 
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performed as determined by the severity of the AE, as recommended by the 
CMC and local principal investigators, until the resolution of the adverse event.   
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue from the study and have received at 
least 12 weeks of study treatment will have the premature discontinuation 
evaluations performed as indicated in the SOE as soon as possible.  
 
No premature study discontinuation evaluations need to be completed for 
participants who received less than 12 weeks of study treatment.   
 
6.3 
Instructions for Evaluations 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy 
on Requirements for Laboratories Performing Testing for DAIDS-Supported and/or 
Sponsored Clinical Trials, which is available at: 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.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 Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table) and AE reporting of 
adverse events requirements. 
 
Fasting Instructions 
Fasting is required at screening, entry, and weeks 12, 24, and 48 or a premature 
discontinuation visit. Fasting is defined as nothing to eat or drink, except for prescription 
medications or water, for at least 8 hours before the evaluations. If participants are in a 
non-fasting state, they should return to the clinic for fasting evaluations within the visit 
window identified in the SOE. 
 
6.3.1 Documentation of HIV 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Collection of Demographic Information 
 
Per the SOE, demographic information will be recorded on the screening 
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6.3.3 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Bone fractures as an adult (≥18 years) (verbal history accepted) 
• 
Coronary heart disease or other cardiovascular disease  
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes  
• 
Tuberculosis 
• 
Hepatitis C, with documentation of undetectable HCV RNA for ≥24 weeks  
• 
Hepatitis B 
• 
History of hepatitis A infection or HAV immunization immunoglobulin G 
(IgG)  
• 
Pancreatitis 
• 
Renal impairment 
• 
Cholecystitis 
 
Any allergies to any medications or their formulations must also be documented.  
 
6.3.4 Medication History 
 
A medication history must be taken, including start and stop dates. Table 6.3.4-1 
below lists the medications that must be included in the history. 
 
The medication history evaluation will be assessed at the screening and entry 
visits and recorded on the eCRFs at the entry visit. 
 
Table 6.3.4-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
Complete ART history, as available 
Immune-based therapy, including 
corticosteroids 
Within 2 years prior to entry 
Blinded study treatment 
Within 1 year prior to study entry 
HIV-1-related vaccines 
Complete history 
HAV vaccine 
Within 30 days prior to study entry 
Prescription drugs for treatment of 
opportunistic infections 
Within 30 days prior to study entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 30 days prior to study entry 
Prescription drugs (other) 
Within 30 days prior to study entry 
Alternative therapies 
Within 30 days prior to study entry 
Dietary supplements 
Within 30 days prior to study entry 


 
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Medication Category 
Complete History or Timeframe 
Diet or weight loss therapy, either 
prescribed or over the counter 
Within 12 months prior to study entry 
Sex-hormone medications or sex-
hormone analogues or antagonists* 
Within 12 months prior to study entry 
except as noted below 
Growth hormones 
Within 12 months prior to study entry 
 
*Includes: hormone-releasing IUDs (e.g., current Mirena use); 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 
(including aldactone/spironolactone).  
 
6.3.5 Clinical Assessments  
 
Complete Physical Examination 
A physical examination will be performed at screening and is to include 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 physical examination will also include signs and 
symptoms, diagnoses, and vital signs (height, weight, minimum WC [refer to the 
A5371 MOPS for minimum waist definition and measurement instruction], 
temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Examination 
A targeted physical examination is to be conducted per the SOE, beginning at 
entry. The examination at each in-person visit will include vision assessment if 
participant has vision complaints (blurred vision, sudden loss of vision, 
black spots, flashing lights, and difficulty reading or seeing small details) 
and vital signs (weight, temperature, pulse, respiration rate, and blood pressure); 
additional examination components will be driven by any previously identified or 
new adverse event/targeted condition (as described in below bullets), that the 
participant has experienced since the last visit. 
 
Minimum WC measurement will occur at entry and then again at weeks 12, 24, 
and 48 (or Premature Study or Treatment Discontinuation for participants 
receiving at least 12 weeks of study drug).  
 
Post entry, see section 8.3 for collection requirements for pregnancy.  
 
At screening and entry, refer to section 6.3.3 medical history for reporting 
requirements. Post-entry, refer to section 7.2 for AE collection requirements. 
Starting at entry and during the study, the following targeted events must be 
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• 
AIDS-defining conditions (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease)  
• 
Bone fractures as an adult (verbal history accepted) 
• 
Coronary heart disease or other cardiovascular disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes mellitus 
• 
Tuberculosis 
• 
Hepatitis C virus infection 
• 
Hepatitis B virus infection 
• 
Hepatitis A virus infection 
• 
Hypertension  
• 
Hypotension  
• 
Hypoglycemia 
• 
Vision changes 
• 
Renal impairment 
• 
Liver disease 
• 
Pancreatitis 
• 
Cholecystitis 
• 
Bleeding or coagulation disorders 
• 
Any inflammatory condition, including, but not limited to; 
o Systemic illness or genital infections requiring antimicrobial therapy 
o Immune reconstitution inflammatory syndrome 
o Lupus 
o Rheumatoid arthritis 
o Inflammatory bowel disease 
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded: 
• 
Any new medication 
• 
Sex-hormone medications or sex-hormone analogues or antagonists (see 
section 6.3.4 for examples) 
• 
Growth hormone or growth hormone-releasing analogs 
• 
Any drugs with anti-inflammatory properties 
• 
Any weight loss drugs 
• 
Any drugs expected to increase weight 
 
Study Treatment Modifications 
At each visit beginning at entry, record all study drug modifications, including 
initial doses, participant-initiated and/or protocol-mandated modifications, any 
inadvertent or deliberate delays of 3 or more days past due date (10 days since 
last dose) of any injection since the last visit. Record any permanent 
discontinuation of treatment. 
 


 
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ART Modifications 
Beginning at entry, record all ART modifications, including any temporary 
interruptions, and document the reason for the modifications and interruptions. 
“Temporary ART interruption” is defined as inadvertent or deliberate interruption 
of any ART component for at least 3 consecutive days but fewer than 14 days at 
any time during the study; “ART discontinuation” is defined as inadvertent or 
deliberate interruption of any ART component for at least 14 days prior to week 
48. Sites should inform the A5371 CMC via email (actg.cmca5371@fstrf.org) of 
any ART interruptions or discontinuations to obtain participant management 
instructions. 
 
6.3.6 Laboratory Evaluations 
 
At screening and entry, all laboratory values must be recorded. For post-entry 
assessments, all hemoglobin, hemoglobin A1c, WBC with differential, creatinine, 
AST, ALT, alkaline phosphatase, total bilirubin, albumin, total protein, glucose, 
platelets, and lipid profile values should be recorded regardless of grade. For all 
other labs, record all Grade ≥2 values and any laboratory toxicity leading to a 
change in study treatment. Refer to section 7.2 for AE reporting requirements for 
abnormal laboratory findings. Refer to section 6.2.3 for rescheduling fasting 
evaluations.  
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), WBC differential, 
absolute neutrophil count (ANC), platelets. 
 
Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, indirect 
bilirubin, total protein, albumin. Refer to section 4.1.10 regarding additional 
testing that may be needed within the screening interval (2-4 weeks apart). 
 
Chemistry 
Glucose, CrCl, electrolytes (e.g., sodium, potassium, chloride, phosphate, 
bicarbonate), calcium, blood urea nitrogen (BUN). 
 
Hemoglobin A1c  
Performed per the SOE. 
 
Insulin  
Insulin (performed in real time at screening only, afterwards insulin will be 
measured at the end of the study from batched stored samples collected at 
weeks 0, 24, and 48).  
 
HOMA-IR 
HOMA-IR is calculated by site at screening only. Refer to calculator at 
https://www.mdcalc.com/homa-ir-homeostatic-model-assessment-insulin-


 
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resistance. Post-screening, HOMA-IR is calculated by the Statistical Data 
Analysis Center (SDAC). 
 
Lipid Panel and LDL Measurement  
Triglycerides, high-density lipoprotein (HDL) cholesterol, calculated or direct 
LDL cholesterol, total cholesterol. 
 
TSH 
A TSH will be ordered to screen for overt thyroid disease. If the TSH is abnormal 
and the individual has not undergone testing for causes, the individual will need 
to undergo evaluation through routine clinical care prior to enrollment (refer to 
exclusion criterion 4.2.12). 
 
Pregnancy Test 
A pregnancy test will be performed per the SOE. At week 24, the pregnancy test 
will be performed prior to the MRI. For individuals able to become pregnant: 
Serum or urine β-HCG. (Urine test must have a sensitivity of <25 mIU/mL). 
Record pregnancy and pregnancy outcome per section 8.3.  
 
6.3.7 Immunologic Studies 
 
CD4+/CD8+  
Absolute CD4+ and CD8+ T cell count and percentages must be obtained within 
30 days prior to pre-entry (may be standard of care) at a laboratory that 
possesses a CLIA certification or equivalent (US sites) or IQA certification (non-
US sites). 
 
All CD4+ and CD8+ T cell count and percentage values should be recorded; 
refer to section 7.2 for AE reporting requirements for abnormal laboratory 
findings. 
 
HCV Antibody, HBsAg, HAV IgG and/or HAV IgM Tests 
HCV antibody, HBsAg, HAV IgG, and/or HAV IgM tests may be performed, if 
needed by the site’s local laboratory per the SOE. Refer to sections 4.1.7, 4.2.1 
and 4.2.2. 
 
6.3.8 Virologic Studies 
 
HIV-1 RNA 
Screening HIV-1 RNA must be performed within 30 days prior to pre-entry at a 
laboratory that possesses a CLIA certification or equivalent (US sites) or VQA 
certification (non-US sites). Eligibility will be determined based on the screening 
value. The two values for eCRF documentation (values in inclusion criterion 
4.1.2) must include the screening value and one measurement obtained 24-48 
weeks prior to entry. Documentation of all other HIV-1 RNA values performed in 
the 48 weeks prior to entry will not be required on the eCRFs. 
 


 
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For US sites, post-entry evaluations will be performed at the protocol-designated 
laboratory and values will be keyed. In addition, results will be reported back to 
sites. For non-US sites, record HIV-1 RNA values on the eCRF. 
 
6.3.9 Stored Plasma/PBMC/Serum 
 
Blood will be collected as indicated on the SOE for metabolic, adherence, and 
circulating inflammatory biomarker profiles. Insulin will be measured at the end of 
the study from batched stored samples collected at weeks 0, 24, and 48. At 
weeks 12 and 48, plasma and serum only will be collected and stored; PBMC 
will not be collected. For immunogenicity studies, plasma and serum will 
be collected and stored at entry, and weeks 12 and 24. Testing will be 
performed at a central laboratory. Collection, processing, and shipping 
instructions are provided in the current A5371 LPC that is posted on the PSWP.  
 
If a participant arrives for a visit in a non-fasting state, the fasting evaluations 
should be re-scheduled within the visit window noted in the SOE. 
 
Samples will be stored according to the LPC and are expected to be used for 
sCD14, hs-IL-6, sCD163, hs-CRP, IP-10, adiponectin, and MCP-1 measurement, 
although final determination will occur at study end.  
 
Phenotyping of Immune Cell Subsets and Activation Markers  
PBMCs will be stored according to the A5371 laboratory processing chart (LPC) 
and are expected to be used for the following advanced flow assays: 
• 
Activated (HLA-DR+/CD38+) CD4+ and CD8+ T lymphocytes 
• 
Monocyte (CD14/CD16/CCR2/CX3CR1/CD36/CD11c) subsets 
• 
Invariant natural killer (6B11/CD69) and mucosal associated invariant 
(Vα7.2/CD161) T lymphocytes  
 
NOTE: Advanced flow analysis requires a CD4+/CD8+ and WBC with differential 
from a sample obtained at the same time. 
 
6.3.10 Stool Kit 
 
Stool collection kits will be distributed to each participant per the SOE. Stool 
samples will be self-collected within 2 days before the study visits noted in the 
SOE. Instructions for collection (stool-collection instructions that can be 
given to the participant), storage, and transport of samples are included in the 
A5371 MOPS.  
 
6.3.11 MRI-PDFF 
 
MRI-PDFF can be performed on a modern (1.5T or 3.0T field strength) MR 
scanner equipped with a phased array surface coil for signal reception and the 
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• 
IDEAL-IQ (GE)/M-Dixon (Philips) or q-Dixon (Siemens) or 
• 
Multi-echo (6 or more) spoiled gradient echo technique 
The sites will be required to send test data sets to ensure that the acquisition 
meets imaging requirements before participation begins. 
 
MRI-PDFF will be performed at the time points indicated in the SOE for IHTG, 
VAT, and SAT density and area, and areas of psoas and other trunk 
musculature. The pre-entry scans will be read centrally for IHTG within five 
business days of receipt, and the site will be notified whether the participant has 
≥5% IHTG, to determine whether the individual is eligible to participate in the 
study. No clinical report will be provided to the site. Sites will do a local clinical 
read and refer as needed if an incidental finding is identified. Instructions for 
shipping/transfer of the MRI-PDFF images will be site-specific and 
communicated individually with each site. 
 
MRI-PDFF scanning will also be performed at the premature study/treatment 
discontinuation visit if the participant has received ≥12 weeks of study drug. 
 
6.3.12 Food Diary and Questionnaires 
 
The food diary and questionnaires are posted on the DMC Portal in the Forms 
Management Utility. 
 
3-Day Food Diary  
Participants will be distributed a food diary per the SOE. All participants will 
complete a food diary for the 3 days preceding stool collection. The completed 
food diary will be collected at the stool collection visit noted in the SOE. These 
diaries will be analyzed centrally for macronutrients and estimated caloric 
content. See A5371 MOPS for additional instructions for sharing 3-Day Food 
Diary results. 
 
Hypoglycemia Questionnaire  
A hypoglycemia questionnaire will be administered as indicated in the 
SOE. 
 
Quality of Life Questionnaire 
Standardized quality of life questionnaire will be administered as indicated in the 
SOE. 
 
Physical Activity and Diet Questionnaire  
Information about physical activity and diet will be collected from all participants 
as indicated in the SOE. 
 
ART Adherence Self-Report 
At the time points indicated in the SOE, participants will be asked to report on 
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Study Treatment Adherence Assessment 
A self-reported study treatment adherence assessment will be performed for 
each participant as indicated in the SOE. 
 
Acceptability and Tolerability Self-Report 
At the time points indicated in the SOE, participants will be asked to report on 
study drug acceptability and tolerability.  
 
6.3.13 Physical Function Assessments 
 
At the time points indicated in the SOE, participants will be asked to rise from a 
standard height chair that does not have wheels or arms 10 times from a seated 
position. Time to complete 5 and 10 rises from the chair will be captured. Gait 
speed will be assessed by the average of two measurements walking at usual 
pace (see the A5371 MOPS for further details).   
 
6.3.14 Study Product Dispensation 
 
At the time points indicated in the SOE, study product will be dispensed.  
 
6.3.15 Injection Training, Retraining, and Observation 
 
At the time points indicated in the SOE, to ensure that participants are using the 
appropriate technique, participants will receive training in titrating the injection 
pen and will be observed injecting semaglutide, with retraining and observation 
conducted as needed (see the A5371 MOPS for further details). 
 
6.3.16 Study Drug Cartridge Count 
 
Participants will be instructed to bring the cartridges to the in-person study 
visits. At the time points indicated in the SOE, cartridge counts will be performed 
for each participant. 
 
6.3.17 Exercise and Diet Education 
 
At the time point indicated in the SOE, participants will receive diet and exercise 
recommendations. Education materials are posted on the PSWP. 
 
6.3.18 Hypoglycemia and Hydration Education 
 
At entry, participants will receive hypoglycemia and hydration education. 
Education materials are posted on the A5371 PSWP. 
 
6.3.19 Telephone or Email Contact 
 
At the time points indicated in the SOE, participants will be contacted by 
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changes in signs/symptoms, including symptoms of hypotension, dizziness, 
hypoglycemia, and vision changes (such as blurred vision, sudden loss of 
vision, black spots, flashing lights, and difficulty reading or seeing small 
details). Record signs/symptoms on the clinical events log unless they 
meet AE reporting requirements. At week 20, participants will be reminded 
about stool collection and to complete the food diary. Contact is recorded on the 
eCRF. Refer to the A5371 MOPS for guidance. 
 
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 
(study entry) condition.  
 
7.2 
Adverse Event Collection Reporting 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  
• 
Grade ≥2 laboratory values 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
 
Post-entry the following must be recorded on the eCRFs within 48 hours, and the 
CMC must be notified within 48 hours by e-mail (actg.cmca5371@fstrf.org) if the 
following occur: 
• 
Grade ≥3 AEs attributable to study product; 
• 
“Liver” events leading to treatment being held or permanent treatment 
discontinuation, as defined in section 8.2.1. 
• 
Any occurrence of symptoms of hypoglycemia with fasting glucose 
measurement <60mg/dL (see section 8.2.2) 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System DAERS system as indicated. 
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: 
• 
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• 
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 Adverse Events to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited 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 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are: 
semaglutide. 
 
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 
 
• 
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• 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the DAIDS EAE Manual, will be reported to DAIDS if the study 
staff become aware of the events on a passive basis (from publicly available 
information). 
 
7.4 
Study Monitoring 
 
The protocol monitoring team will monitor the conduct of the study via regular 
summaries of accrual, baseline characteristics, data completeness, and study status; 
study status summaries will include details on premature study and/or treatment 
discontinuations, which will enable the team to monitor the discontinuation rates.  
 
The DAIDS clinical representative will review and assess select EAE reports for potential 
impact on the study participant safety and protocol conduct as per DAIDS policies, 
guidance documents, and SOPs as applicable. Additionally, the DAIDS clinical 
representative and the protocol monitoring team will review AE summaries, cumulative 
and new AEs (since last report), prepared quarterly by the SDAC. 
 
The study will undergo interim review at least annually by an independent ACTG-
appointed Study Monitoring Committee (SMC). The SMC will review summaries of 
accrual, baseline characteristics, conduct of the study (including premature treatment 
and study discontinuations), and AEs. The first interim review will occur no more than 1 
year after the first participant enters the study. An interim review may also be convened 
if a concern (e.g., higher than anticipated treatment discontinuation rate) is identified by 
the DAIDS clinical representative, the study chairs, or study statisticians in consultation 
with the team. See section 10.5 for statistical and other considerations related to interim 
monitoring. 
 
Study enrollment will be held and the SMC will convene an emergency meeting to 
review all study AEs, in collaboration with the DAIDS clinical representative, if any 
of the following is observed: (1) three participants with the same Grade 3 events 
attributable to study product, (2) two participants with Grade 4 events attributable 
to study product, (3) two participants with hepatoxicity events leading to 
treatment being held or permanent treatment discontinuation (see section 8.2.1.1), 
or (4) death. After reviewing the types of AEs and relatedness to the study 
product, the SMC will make recommendations as to whether to stop the study, 
alter monitoring/drug dosing, or other changes as required to the protocol and 
participant management.  
 
Detailed plans for study monitoring will be outlined in a Study Progress, Data, and Safety 
Study Monitoring Plan (SPDSMP) developed by the Statistical and Data Management 
Center (SDMC) prior to enrollment of the first participant. 
 


 
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8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
8.1.1 Following consultation with and approval by the A5371 CMC 
(actg.cmca5371@fstrf.org), study treatment dose may be reduced or dose 
escalation held for intolerability, with initial dose reduction to 0.5 mg, and further 
dose reduction to 0.25 mg/week permitted. Participants who cannot tolerate at 
least 0.25 mg/week will be discontinued from the study.  
 
NOTE: Most treatment-emergent nausea is mild-to-moderate and resolves with 
continued use (see section 8.2.4). 
 
8.1.2 For decline in CrCl to <40 mL/min or 50% decline from entry value, see section 
8.2.3 for management and additional monitoring instructions.  
 
Grade 1 or 2 
There will be no dose interruptions, modification, or discontinuations for any 
Grade 1 or 2 toxicity except as specified below.  
 
For participants experiencing Grade 1 or 2 AEs who have received at least 12 
weeks of study drug and choose to discontinue study treatment, the premature 
treatment discontinuation evaluations should be completed (per section 6.2.4) 
and the site should contact the A5371 CMC (actg.cmcA5371@fstrf.org). 
 
NOTE: If participants discontinue study treatment due to experiencing Grade 1 or 
2 AEs, this should be noted as the reason for discontinuation.   
 
Grade ≥3 
Study treatment may be held for all drug-related toxicities Grade ≥3 (with the 
exception of liver enzyme elevation, as described below in section 8.2.1) until the 
toxicity returns to Grade ≤2 or to the level at the time of study entry.  
 
Study treatment may be restarted when the toxicity grade returns to Grade ≤2 or 
to the level at the time of study entry, but the CMC should be notified prior to re-
challenge. Upon re-challenge, if Grade ≥3 toxicities recur, then study treatment 
should be permanently discontinued (with the exception of liver enzyme 
elevation, as described below in section 8.2.1).  
 
All Grade ≥3 hypersensitivity reactions will result in permanent discontinuation of 
study treatment.  
 
NOTE: Participants who permanently discontinue study treatment due to toxicity 
reasons should be followed until symptoms resolve to Grade ≤2. See sections 
6.1 and 6.2 for evaluations for participants not completing treatment. 
 


 
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8.2  
Other Conditions  
 
8.2.1 Hepatotoxicity – LFTs 
 
8.2.1.1 If participants with abnormal entry liver indices develop elevations 
of AST or ALT >2x entry values or total bilirubin >1.5x entry values 
during the study, repeat testing should be performed within 48-72 
hours. If there are persistent elevations (AST or ALT >2x baseline 
or total bilirubin >1.5x entry values) upon repeat testing, then 
close observation (testing and physical examination 2-3 times per 
week) should be implemented. 
Study treatment should be held for the following reasons:  
• 
If either entry measurements is <2 x ULN, temporarily hold 
study treatment if the respective value of ALT or AST increases 
to >5x entry values. 
• 
If either entry measurement is 2 x ULN or greater, temporarily 
hold study treatment if either ALT or AST increases to 3x entry 
values. 
• 
If ALT or AST increases to >2x entry values and the increase is 
accompanied by a concomitant increase in total bilirubin to >2x 
entry values.  
• 
Signs and symptoms of acute liver toxicity including fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%). 
 
NOTE: If study treatment is held, the CMC must be notified within 48 
hours by e-mail (actg.cmca5371@fstrf.org). 
 
Close observation includes: 
• 
Repeating liver enzyme and serum bilirubin tests two or three 
times weekly. Frequency of retesting can decrease to once a 
week or less if abnormalities stabilize or the trial drug has been 
discontinued and the participant is asymptomatic. 
• 
Obtaining a more detailed history of symptoms and prior or 
concurrent diseases. 
• 
Excluding acute viral hepatitis A, B, C, D, and E; autoimmune 
hepatitis; or alcoholic hepatitis; hypoxic/ischemic hepatopathy; 
and biliary tract disease. 
• 
Obtaining a history of exposure to environmental chemical 
agents. 
• 
Obtaining additional tests to evaluate liver function, as 
appropriate (e.g., INR, direct bilirubin). 
• 
Consideration for obtaining gastroenterology or hepatology 
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• 
Locally performed laboratory testing with results promptly 
communicated to the site investigator for participants living in 
a remote area. 
 
8.2.1.2 Study treatment can be resumed when symptoms have resolved 
and AST/ALT return to ≤2x the entry value. If an elevation in AST or 
ALT of ≥3x the entry value recurs following reintroduction of study 
treatment and the cause is possibly or definitely related to study drug, 
semaglutide should be permanently discontinued. The site should notify 
the CMC within 48 hours by e-mail (actg.cmca5371@fstrf.org) if this 
occurs.  
 
8.2.2 Hypoglycemia 
 
Hypoglycemia appears to be a risk primarily when people with diabetes are 
treated with semaglutide in combination with insulin or other antidiabetic 
medications, including insulin secretagogues (i.e., not with semaglutide alone). 
As people with diabetes are excluded from this study, the risk of hypoglycemia 
is expected to be very low.  
 
All participants must receive education on monitoring and management of 
hypoglycemia at study entry. If participants report symptoms of 
hypoglycemia on routine assessments and/or the hypoglycemia 
questionnaires during telephone/e-mail contact or study visits, they will 
first be provided instructions to ensure adequate fluid and food intake. If 
the symptoms persist over the subsequent 24 hours, participants should 
be instructed to come to the clinic in fasting state for assessment of blood 
pressure, electrolytes, fasting glucose, and a clinical assessment. If fasting 
blood glucose is <60 mg/dL, the CMC should be notified via e-mail 
(actg.cmca5371@fstrf.org) within 48 hours. If the participant rapidly 
responds to treatment with no recurrence of symptoms, they will have 
weekly glucose assessments in clinic while the dose is titrating up. If 
symptoms persist, study treatment will be discontinued.  
 
If symptoms of documented, clinically significant, severe hypoglycemia occur and 
are believed to be possibly or definitely related to study treatment, the CMC 
should be notified, study treatment should be temporarily held, and the 
participant should be closely observed. Re-challenge may occur at the discretion 
of the CMC, in consultation with the site investigator. 
 
Because symptoms of hypoglycemia are non-specific and often due to other 
causes, it is very important to attempt to document measured blood glucose at 
the time of occurrence of symptoms. If participant has symptoms of 
hypoglycemia (e.g., sweating, palpitations, and tremulousness), hold semaglutide 
and measure glucose as soon as feasible (does not require fasting). Take care 
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and glucose measurement. Sites may choose to provide a home glucose-
monitoring device for this purpose, at their own discretion and as a supplement to 
glucose measurements performed in the clinic, but these will not be provided by 
the study. If a participant experiences hypoglycemic symptoms, they should be 
instructed to consume 15-20 grams glucose or simple carbohydrates. Examples 
include:  
• 
4 ounces (0.5 cup) of juice or regular soda (e.g., Coke [Coca-Cola®]) 
• 
8 ounces of non-fat or 1% milk 
• 
1 tablespoon sugar, honey, or corn syrup 
• 
2 tablespoons of raisins 
• 
15-20 grams sugar from hard candy, jellybeans, and gumdrops. 
 
8.2.2.1 Fasting Blood glucose 55-64 mg/dL (Grade 1) 
 
Continue study treatment and monitor for symptoms of hypoglycemia. 
 
8.2.2.2 Fasting Blood glucose 40-54 mg/dL (Grade 2) 
 
• 
Temporarily hold study treatment and evaluate for other potential 
causes of hypoglycemia.  
• 
Repeat fasting blood glucose within 1 week. If repeat is ≥55 mg/dL, 
study treatment can be resumed. 
• 
If symptoms of hypoglycemia recur and blood glucose is again 40-55 
mg/dL, discontinue study treatment permanently.  
 
8.2.2.3 Fasting Blood glucose <40 mg/dL (Grade 3 or 4) 
 
• 
Temporarily hold study treatment and evaluate for other potential 
causes of hypoglycemia.  
• 
Repeat fasting blood glucose within 1 week. If repeat is ≥55 mg/dL, 
and no other potential causes of hypoglycemia are identified, re-
challenge can be attempted, after discussion with the CMC, if the 
low blood glucose is believed to be secondary to alternative causes.  
• 
If the low blood glucose is believed to be due to study treatment, 
discontinue study treatment permanently. 
 
8.2.3 Calculated CrCl 
 
Consideration of potential causes of reduced renal function should be made, if 
any participant experiences a calculated CrCl <40 mL/min or 50% decline from 
study entry. The calculated CrCl should be repeated within 7 days and recorded 
on the eCRF. As semaglutide does not require renal dosing, and is not expected 
to cause renal dysfunction, specific clinical circumstances should be discussed 
with the A5371 CMC (actg.cmca5371@fstrf.org) prior to modification of study 
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8.2.4 Nausea/Vomiting 
 
Development of Grade ≥2 nausea or vomiting should lead to evaluation for 
causes other than study treatment, e.g., new medication, pancreatitis, viral 
illness, etc. If nausea and vomiting are suspected secondary to study treatment, 
study treatment can be held until symptoms are Grade <2 or to baseline. 
Symptoms will be re-assessed every 2-4 days. For participants with Grade 
≥2 symptoms of nausea or vomiting, a weekly clinical assessment will 
include measurement of blood pressure and pulse, and ascertainment of 
fasting glucose, complete metabolic panel, and magnesium. If Grade ≥3 
nausea or vomiting return following re-challenge and are suspected to be due to 
study treatment, study treatment should be permanently discontinued and 
premature treatment discontinuation evaluations should be performed at the time 
of study treatment discontinuation, where applicable. Use of antiemetic agents is 
encouraged for Grade ≤2 nausea and vomiting but are not provided by the study. 
In clinical trials thus far, discontinuation for nausea and vomiting has been 
infrequent, with most nausea being manageable and resolving within a few 
weeks. If persistent nausea occurs during dose titration, the dose titration 
schedule may be altered, in discussion with the CMC.    
 
8.2.5 Diarrhea 
 
Development of Grade ≥3 diarrhea should lead to evaluation for causes other 
than study treatment. If diarrhea is suspected to be secondary to study treatment, 
study drug can be held until diarrhea is Grade ≤2 or to baseline (study entry). If 
diarrhea Grade ≥3 returns following re-challenge and is suspected to be due to 
study treatment, study treatment should be permanently discontinued and 
premature treatment discontinuation evaluations should be performed at the time 
of study treatment discontinuation. Participants who develop Grade ≤2 diarrhea 
are encouraged to use antidiarrheal agents (e.g., Imodium or Lomotil), although 
these will not be provided by the study. 
 
8.2.6  Pancreatitis 
 
8.2.6.1 Pancreatitis is defined as the presence of nausea, vomiting, and 
abdominal pain associated with any elevation in serum lipase. 
 
8.2.6.2 If a diagnosis of symptomatic Grade ≥2 pancreatitis is made and is 
believed to be secondary to study treatment, study treatment will be 
permanently discontinued and premature treatment discontinuation 
evaluations should be performed, where applicable. If the diagnosis is 
believed to be secondary to other causes, those should be managed per 
local standard of care, with study treatment held until pancreatitis is 
Grade <2.   
 
For symptomatic Grade <2 pancreatitis, conservative management with 
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pancreatitis recurs following re-challenge and is believed to be 
secondary to study treatment, study treatment should be discontinued. 
 
For asymptomatic lipase elevations, administration of study treatment 
may continue. 
 
8.2.7 Fatigue and Headache Symptoms 
 
If participant has new onset or Grade ≥2 fatigue or headache symptoms for >14 
days, work-up for causes other than study product should be initiated. Also: 
• 
Consult the A5371 CMC via email (actg.cmcA5371@fstrf.org) before 
discontinuation of study treatment. 
• 
Consider temporarily holding study treatment. 
 
8.2.8 Allergic Reactions 
 
If a participant develops a skin reaction, rash, angioedema, or other symptoms 
felt to represent an allergic reaction potentially related to study treatment, 
temporarily hold the study treatment and instruct participant to return to the CRS 
or emergency health center immediately for care. If the reaction is determined to 
be related to study treatment, permanently discontinue the study treatment and 
perform premature treatment evaluations, where applicable. 
 
8.2.9 Study Drug Injection Site Reactions 
 
If a participant develops a Grade 1 or 2 injection site reaction, it should be 
managed at the discretion of the site investigator. If the injection site reaction is 
Grade 3 or 4, the site should contact the A5371 CMC via email 
(actg.cmcA5371@fstrf.org). 
 
8.3 
Pregnancy  
 
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. Telephone 1-800-258-
4263 or fax: 800-800-1052. For studies conducted at sites outside the United States, 
report to The Antiretroviral Pregnancy Registry—Telephone: 910-679-1598; Fax: 44-
1628-789-666 or 910-256-0637. 
 
Pregnancy Outcomes and Reporting 
Pregnant individuals must discontinue study treatment and study evaluations, but will be 
encouraged to remain in contact with the study team to provide pregnancy outcome 
data. Individuals who become pregnant should complete the premature study 
discontinuation assessments (except MRI) within 14 days of the site becoming aware of 
the pregnancy/stopping study medication (whichever is earlier), but the off-study eCRF 
will be completed at the end of the pregnancy. Birth outcomes will be recorded on an 
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If an individual discontinues from the study before the end of the pregnancy, the site staff 
should request permission to contact the participant regarding pregnancy outcomes at 
the end of pregnancy. If the information is obtained, pregnancy outcomes will be 
submitted on an eCRF at the end of the pregnancy.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity if no improvement per instructions (see section 8.1 Toxicity 
and section 8.2 Other Conditions).  
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Request by participant to terminate treatment (refer to section 6.2.4). 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
 
9.2 
Premature Study Discontinuation 
 
• 
Failure by the participant to attend ≥2 consecutive study visits. 
• 
Participant repeatedly noncompliant (i.e., missed ≥6 injections as prescribed). The 
study team should be consulted on specific circumstances before a participant is 
discontinued for noncompliance. 
• 
Participant’s inability to tolerate at least 0.25 mg/week of study treatment. 
• 
Participant’s inability complete study procedures, including the MRIs, as required. 
• 
Participant changes diet or exercise regimen significantly (refer to section 
4.2.5). 
• 
Participant’s inability to keep study product at 36°F to 46°F (2°C to 8°C) prior to 
first use, or to maintain the study product at a controlled room temperature 
between 59°F and 86°F (15°C to 30°C) following first use (refer to section 
4.2.23). 
• 
Request by participant to terminate study (refer to section 6.2.4). 
• 
Request by the participant to withdraw. 
• 
Pregnancy or breastfeeding. 
• 
At the discretion of the IRB/EC, ACTG, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, or 
investigator. 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5371 is a phase II, single-arm, open-label, clinical trial designed to study the effects of 
semaglutide on MRI-PDFF-quantified IHTG in persons with HIV on suppressive ART. 
Eligible participants will receive semaglutide; all participants will be followed on-


 
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treatment for 24 weeks and on-study for 48 weeks. The total sample size is 50 
participants.   
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publications are listed under “Other Outcome 
Measures.” 
 
10.2.1 Primary Outcome Measure 
 
Change (absolute) in IHTG (%) (from pre-entry to week 24). 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 Change (percent) in IHTG (%) (from pre-entry to week 24). 
 
10.2.2.2 Change (absolute) in BMI, body weight, and minimum WC from week 
0 to weeks 12 and 24. 
 
10.2.2.3 Level of IHTG (%) at pre-entry and week 24. 
 
10.2.2.4 Occurrence of premature discontinuation of study treatment, including 
reasons for discontinuation.  
 
10.2.2.5 Occurrence of Grade ≥3 adverse event that are related to study 
treatment.    
 
10.2.2.6 Changes in insulin resistance (HOMA-IR) and glucose from week 0 to 
weeks 12 and 24. 
 
10.2.2.7 Change (absolute) in lipid profiles (triglycerides, HDL cholesterol, LDL 
cholesterol, total cholesterol) from week 0 to weeks 12 and 24. 
 
10.2.2.8 Presence of metabolic syndrome at weeks 0, 12, and 24. Metabolic 
syndrome is defined as having ≥3 of the following: increased minimum 
WC, high triglyceride level, reduced HDL cholesterol, increased blood 
pressure, and elevated fasting blood glucose, based on current 
guidelines. 
 
10.2.3 Other Outcome Measures 
 
10.2.3.1 Cartridge counts of adherence at weeks 4, 12, and 24. 
 


 
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10.2.3.2 Changes in physical function (gait speed defined as <1 m/sec or ≥1 
m/sec, chair rise rate defined as time in seconds to rise 5 times and 10 
times) from week 0 to weeks 24 and 48. 
 
10.2.3.3 Change (absolute) in muscle fat area and density as measured by MRI 
from pre-entry to week 24. 
 
10.2.3.4 Quality of life measures at weeks 0 and 24. 
 
10.2.3.5 Change (absolute) in adipose tissue (VAT and SAT) area and density 
as measured by MRI from pre-entry to week 24. 
 
10.2.3.6 Change in inflammatory and metabolic biomarkers from week 0 to 
week 24. 
 
10.2.3.7 Gastrointestinal microbial taxonomy, abundance, diversity and function 
from fecal samples at weeks 0 and 24 and change from week 0 to 24 
(pending additional funding). 
 
10.2.3.8 Proportions of immune cells at weeks 0 and 24 and change from week 
0 to 24.  
 
10.2.3.9 Change (absolute) in body weight, BMI, minimum WC, lipid profiles, 
glucose, HOMA-IR, and select inflammatory and metabolic biomarker 
from week 24 to week 48. 
10.2.3.10 Physical activity and dietary changes between weeks 24 and 48. 
 
10.3 
Randomization and Stratification 
 
There is no randomization or stratification in this study. Eligible participants will be 
registered at study entry and will receive study treatment.   
 
Participant enrollment targets are at least 40% persons currently identifying as cisgender 
or transgender women and 50% non-white. Each site will be guaranteed three slots, 
one of which must be filled with a woman (cisgender or transgender), and two of 
which must be filled with non-white participants (of course, the woman could be 
non-white and fulfill both requirements). If after 60% of enrollment is completed and 
enrollment of women is <40%, additional restrictions to enhance enrollment of 
women may occur to ensure ≥40% enrollment of women. The remaining 
participant slots will be available by competitive enrollment. If after 50% of 
enrollment is completed the enrollment of non-Hispanic Caucasians is >70%, restrictions 
will be placed on their enrollment. Sites will be encouraged to enroll transgender 
participants. 
 


 
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10.4 
Sample Size and Accrual 
 
The planned total sample size is 50 participants. Allowing for 25% loss to follow-up, the 
anticipated evaluable sample size is 37 participants. It is anticipated that participants will 
accrue to the study at a rate of 6-7 participants per month; at this rate, the study should 
fully accrue in approximately 7-8 months.  
 
This study’s primary objective is to evaluate whether 24 weeks of semaglutide will 
improve IHTG in ART-treated, adults with HIV, hepatic steatosis, central obesity, and 
insulin resistance or pre-diabetes. The primary comparison will examine the absolute 
change in IHTG from pre-entry to week 24. 
 
The sample size is based on a two-sided, one-sample t-test with 5% significance level 
and 90% statistical power, and assumes, based on published literature, that semaglutide 
will reduced (improve) IHTG. A range of effect sizes and corresponding standard 
deviations (SDs) were considered to determine the sample size for this study.  There is 
limited literature on the SD of the change in MRI-PDFF-quantified IHTG; one study of a 
different intervention showed an estimate of 4.6% for the intervention arm and 9.9% for 
the placebo arm. Considering this range of reported SDs, possible scenarios considering 
different SDs and mean differences are shown below (see Table 10.4-1).   
 
Assuming a 9% SD, with 37 participants, there is 90% statistical power to identify a 
significant change in IHTG, under the assumption that the true change is 5% over 24 
weeks. Inflating the sample size to account for 25% loss to follow-up and premature 
treatment discontinuation, yields a total sample size of 50 participants. With a short 
intervention, regular telephone/email contract, and once weekly dosing, we anticipate 
<25% loss to follow-up. 
 
Table 10.4-1: Sample Sizes under Different Scenarios Assuming: One-sample T-test 
with Two-sided 5% Alpha (significance level) and ≥90% Power  
N Inflated by 25% for LTFU 
Total N 
Enrolled 
N Evaluable 
Mean Change from Pre-
entry to Week 24 (%) 
Standard Deviation of 
Change in IHTG (%) 
8 
6 
-9 
5 
12 
9 
-9 
7 
18 
13 
-9 
9 
11 
8 
-7 
5 
18 
13 
-7 
7 
27 
20 
-7 
9 
18 
13 
-5 
5 
31 
23 
-5 
7 
50 
37 
-5 
9 
43 
32 
-3 
5 
80 
60 
-3 
7 
130 
97 
-3 
9 


 
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Table 10.4-2: Statistical Power under Different Scenarios Assuming: N=37  
Evaluable per Arm 
One-sample T-test with Two-sided 5% Alpha 
N Enrolled Included by 25% for LTFU 
Power 
Mean Change from Pre-
entry to Week 24 (%) 
Standard Deviation of 
Change in IHTG (%) 
94% 
-3 
5 
72% 
-3 
7 
51% 
-3 
9 
100% 
-5 
5 
99% 
-5 
7 
91% 
-5 
9 
77% 
-5 
11 
100% 
-7 
5 
100% 
-7 
7 
100% 
-7 
9 
96% 
-7 
11 
 
10.5 
Data and Safety Monitoring  
 
At SMC reviews, data will be considered as detailed in section 7.4. There are no pre-
specified stopping guidelines. 
 
10.6 
Analyses 
 
10.6.1 Primary Analysis 
 
The primary analysis will be limited to participants who remain on treatment 
through week 24.  
 
Absolute change from pre-entry to week 24 in IHTG (%) will be summarized with 
the mean and a 95% confidence interval (CI) for the mean change, and will be 
assessed, with a two-sided t-test with 5% alpha. In addition, a supplemental 
analysis will consider all participants with an on-treatment IHTG assessment, 
regardless if they prematurely discontinued treatment. 
 
10.6.2 Secondary Analyses 
 
The percent change in IHTG (%) from pre-entry to week 24 will be summarized in 
a similar manner as the primary analysis. The mean percent change and 
corresponding 95% CI for the mean change will be summarized, and assessed 
with a two-sided t-test with 5% alpha. Additional supplemental analyses of 
percent change in IHTG will be considered to account for participants who 


 
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prematurely discontinue treatment. Level of IHTG will be summarized with 
descriptive summary statistics.  
 
Safety will be evaluated by estimating the proportion of participants who 
experience any Grade ≥3 AE, or, for AST/ALT, elevation ≥3x higher than entry or 
≥500 U/L (whichever value is lower), that are related to study treatment. In 
addition, tabular summaries of all protocol-defined AEs will be included to 
evaluate the nature and rate of AEs. Participant-level listings of premature 
treatment discontinuations, with reasons for discontinuations, will be provided. 
No formal statistical tests will be provided for safety or tolerability analyses.  
 
Levels of insulin resistance, lipid profiles, BMI, body weight, minimum WC, and 
the presence of metabolic syndrome will be summarized with descriptive 
summary statistics by study week. Absolute changes in BMI, insulin resistance, 
lipid profiles, weight, and minimum WC will also be summarized at each time 
point with means and 95% confidence intervals. The comparison of change in the 
presence of metabolic syndrome will use GEE for binary data to provide an 
estimate of decreased risk within arm, corresponding p-values and 95% CIs will 
be also provided. To evaluate the relationships between changes in IHTG and 
changes in metabolic parameters (insulin resistance, lipid profiles, number of 
metabolic syndrome components), correlation analysis will be used. 
 
Durability of treatment efficacy will be measured by summarizing the change in 
body weight, BMI, minimal WC, lipid profiles, glucose, HOMA-IR, and select 
circulating inflammatory and metabolic biomarkers between weeks 24 and 48. 
 
11.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
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 registration. 
 
12.2 
Role of Data Management 
 
12.2.1 Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
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12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, eCRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, participants’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
12.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the ACTG, IRB/EC, the site monitors, the FDA, the 
NIAID, the OHRP, other local, US, and international regulatory entities for 
confirmation of the study data.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix II) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study. A signed consent form will be obtained from the participant. 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. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or other government agencies as part of their duties to ensure that research participants 
are protected. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies.  
 


 
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15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
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16.0 
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Morse CG, McLaughlin M, Matthews L, et al. Nonalcoholic steatohepatitis and hepatic 
fibrosis in HIV-1-monoinfected adults with elevated aminotransferase levels on antiretroviral 
therapy. Clin Infect Dis 2015;60:1569-78. 
Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the 
treatment of nonalcoholic fatty liver disease. Hepatology 2010;52:79-104. 
Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-
alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver 
disease severity. Ann Med 2011;43:617-49. 
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic 
steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 
2010;52:774-88. 
O'Brien KK, Tynan AM, Nixon SA, Glazier RH. Effectiveness of progressive resistive 
exercise (PRE) in the context of HIV: systematic review and meta-analysis using the 
Cochrane Collaboration protocol. BMC Infect Dis 2017;17:268. 
O’Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared 
with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-
blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 2018;392:637-49. 
doi: 10.1016/S0140-6736(18)31773-2. Epub 2018 Aug 16. 
Patel J, Bettencourt R, Cui J, et al. Association of noninvasive quantitative decline in liver fat 
content on MRI with histologic response in nonalcoholic steatohepatitis. Therap Adv 
Gastroenterol 2016;9:692-701. doi: 10.1177/1756283X16656735. 
Perera S, Patel KV, Rosano C, et al. Gait speed predicts incident disability: a pooled 
analysis. J Gerontol A Biol Sci Med Sci 2016;71:63-71. 
Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide 
in weight management. N Engl J Med 2015;373:11-22. 
Post WS, Budoff M, Kingsley L, et al. Associations between HIV infection and subclinical 
coronary atherosclerosis. Ann Intern Med 2014;160:458-67. 
Pratley R, Nauck M, Bailey T, et al. One year of liraglutide treatment offers sustained and 
more effective glycaemic control and weight reduction compared with sitagliptin, both in 
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open-label trial. Int J Clin Pract 2011;65:397-407. 
Qu Y, Li M, Hamilton G, Zhang YN, Song B. Diagnostic accuracy of hepatic proton density 
fat fraction measured by magnetic resonance imaging for the evaluation of liver steatosis 
with histology as reference standard: a meta-analysis. Eur Radiol 2019;29:5180-9.  


 
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Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. 
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Rakipovski G, Rolin B, Nøhr J, et al. The GLP-1 analogs liraglutide and semaglutide reduce 
atherosclerosis in ApoE-/- and LDLr-/- mice by a mechanism that includes inflammatory 
pathways. JACC Basic Transl Sci 2018;3:844-57.  
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associated with insulin-resistant glucose metabolism than visceral adiposity in HIV, and is 
improved with tauroursodeoxycholic acid treatment. [Abstract 023]. In: 19th International 
Workshop on Co-morbidities and Adverse Drug Reactions in HIV; October 23-25, 2017; 
Milan, Italy.  
Schuppan D, Schattenberg JM. Non-alcoholic steatohepatitis: pathogenesis and novel 
therapeutic approaches. J Gastroenterol Hepatol 2013;28(Suppl 1):68-76. 
Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid 
atherosclerosis: a systematic review. J Hepatol 2008;49:600-7. 
Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 
2011;305:50-8. 
Tang W, Xu Q, Hong T, et al. Comparative efficacy of anti-diabetic agents on nonalcoholic 
fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-
analysis of randomized and non-randomized studies. Diabetes Metab Res Rev 
2016;32:200-16. 
Targher G, Bertolini L, Poli F, et al. Nonalcoholic fatty liver disease and risk of future 
cardiovascular events among type 2 diabetic patients. Diabetes 2005;54:3541-6. 
Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently 
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Diabetes Care 2007;30:2119-21. 
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic 
fatty liver disease. N Engl J Med 2010;363:1341-50. 
Tashiro Y, Sato K, Watanabe T, et al. A glucagon-like peptide-1 analog liraglutide 
suppresses macrophage foam cell formation and atherosclerosis. Peptides 2014;54:19-26. 
doi: 10.1016/j.peptides.2013.12.015. Epub 2014 Jan 10. 
Vallet-Pichard A, Mallet V, Pol S. Nonalcoholic fatty liver disease and HIV infection. 
Seminars in liver disease 2012;32:158-66. 
Vodkin I, Loomba R. Editorial: NAFLD in HIV infection--call for action. Authors' reply. Aliment 
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Vodkin I, Valasek MA, Bettencourt R, et al. Clinical, biochemical and histological differences 
between HIV-associated NAFLD and primary NAFLD: a case-control study. Aliment 
Pharmacol Ther 2015;41:368-78. 
Yusta B, Baggio LL, Koelher J, et al. GLP-1R agonists modulate enteric immune responses 
through the intestinal intraepithelial lymphocyte GLP-1R. Diabetes 2015;64:2537-49. 
Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr 
Res 2015;77:245-51. doi: 10.1038/pr.2014.157. Epub 2014 Oct 13. 


 
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APPENDIX I: PROTOCOL SYNOPSIS 
 
A5371 
 
A Single-Arm, Open-Label, Pilot Study of Semaglutide for Non-Alcoholic Fatty 
Liver Disease (NAFLD), a Metabolic Syndrome with Insulin Resistance, Increased 
Hepatic Lipids, and Increased Cardiovascular Disease Risk 
(The SLIM LIVER Study) 
 
DESIGN 
A5371 is a phase II, single-arm, open-label pilot study of the effects 
of semaglutide on intra-hepatic triglyceride (IHTG) content in people 
living with HIV, central adiposity, insulin resistance or pre-diabetes, 
and hepatic steatosis. Participants will complete seven study visits 
(screening, pre-entry, entry, and weeks 4, 12, 24, and 48) and be 
contacted by telephone or e-mail six times (between study visits). 
IHTG will be quantified by magnetic resonance imaging-proton 
density fat fraction (MRI-PDFF) at two time points. Stool and blood 
samples (for hematology, liver function tests, chemistry, lipid panel 
and LDL measurement, CD4, and HIV-RNA) will be collected at 
several visits. Participants will also complete food diaries, a 
hypoglycemia questionnaire, adherence and strength assessments, 
and report on physical activity, diet, quality of life, and acceptability 
of study drug.  
 
OBJECTIVES 
Primary Objective 
 
To evaluate whether semaglutide will reduce IHTG content, as 
quantified by MRI-PDFF, among ART-treated adults with HIV, hepatic 
steatosis, central adiposity, and insulin resistance or pre-diabetes.  
 
Secondary Objectives 
 
1. To evaluate the safety and tolerability of semaglutide in adults 
with HIV, hepatic steatosis, central adiposity, and insulin 
resistance or pre-diabetes.  
2. To evaluate the effects of semaglutide on weight, minimum waist 
circumference (WC), and body mass index (BMI). 
3. To evaluate the effects of semaglutide on insulin resistance or 
pre-diabetes, lipid profiles, and the prevalence of metabolic 
syndrome. 
4. To evaluate relationships between observed changes in IHTG 
and changes in metabolic parameters. 


 
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OUTCOME 
MEASURES 
Primary Outcome Measure 
 
 
Change (absolute) in IHTG (%)  
[Time Frame: Measured from pre-entry to Week 24]  
 
Secondary Outcome Measures 
 
Change (percent) in IHTG (%)  
[Time Frame: Measured from pre-entry to Week 24]  
 
Change (absolute) in body mass index (BMI)  
[Time Frame: Measured from Week 0 to Weeks 12 and 24] 
 
1. Change (absolute) in body weight  
[Time Frame: Measured from Week 0 to Weeks 12 and 24]  
 
2. Change (absolute) in minimum waist circumference (WC)  
[Time Frame: Measured from Week 0 to Weeks 12 and 24] 
 
3. Level of IHTG (%)  
[Time Frame: Measured at pre-entry and Week 24] 
 
4. Occurrence of premature discontinuation of study treatment, 
including reasons for discontinuation. 
[Time Frame: Measured through Week 24]  
 
5. Occurrence of Grade ≥3 adverse event that are related to study 
treatment  
 
6. Change (absolute) in insulin resistance (HOMA-IR)  
[Time Frame: Measured from Week 0 to Weeks 12 and 24]  
 
7. Change (absolute) in glucose  
[Time Frame: Measured from Week 0 to Weeks 12 and 24]  
 
8. Change (absolute) in lipid profiles (triglycerides, HDL 
cholesterol, LDL cholesterol, and total cholesterol)  
[Time Frame: Measured from Week 0 to Weeks 12 and 24]  
 
9. Presence of metabolic syndrome  
 
10. Metabolic syndrome is defined as having ≥3 of the following: 
increased minimum WC, high triglyceride level, reduced HDL 
cholesterol, increased blood pressure, and elevated fasting 
blood glucose, based on current guidelines. 
[Time Frame: Measured at Weeks 0, 12, and 24] 


 
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DURATION 
Approximately 48 weeks.  
 
SAMPLE SIZE 
50 participants. 
 
KEY ELIGIBILITY  
CRITERIA 
Inclusion Criteria 
 
1. Adults ≥18 years of age with HIV. 
 
2. Two separate reports of HIV-1 RNA measurements <50 
copies/mL, and no HIV-1 RNA measurement >500 copies/mL, 
during the 48 weeks prior to entry. 
 
3. No change in ART in 24 weeks prior to entry or plans to change 
during study. 
 
4. Not meeting criteria for diabetes but with central adiposity (i.e., 
minimum waist circumference of ≥95 cm for individuals assigned 
male sex at birth or ≥94 cm for individuals assigned female sex 
at birth), ≥5% IHTG content, plus at least one of the following 
indicators of insulin resistance or pre-diabetes: fasting plasma 
glucose 100-125 mg/dL, HbA1c between 5.7% and <6.5%, or 
HOMA-IR >3.0.  
 
5. Documented evidence of immunity to hepatitis A virus (HAV) or 
documented history of HAV vaccination within 30 days prior to 
entry. 
 
6. CD4+ T-cell count ≥200 cells/mm3 within 30 days prior to pre-
entry. 
 
7. The following laboratory values obtained within 30 days prior to 
pre-entry: 
a. Absolute neutrophil count (ANC) >750 cells/mm3. 
b. Hemoglobin >10 g/dL for individuals assigned male sex at 
birth and >9 g/dL for individuals assigned female sex at birth. 
c. Creatinine clearance (CrCl) ≥50 mL/min, as calculated by the 
CKD-Epi equation.  
d. Aspartate aminotransferase (AST) (SGOT) ≤3 x ULN on at 
least two measures. 
e. Alanine aminotransferase (ALT) (SGPT) ≤3 x ULN on at least 
two measures. 
f. Fasting triglyceride level ≤500 mg/dL. 
 
8. For individuals prescribed daily medications with anti-
inflammatory properties, the doses must be stable. 


 
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9. For individuals taking daily lipid-lowering medications, the doses 
must be stable.  
 
10. Agree to use contraception if able to become pregnant. 
 
11. For individuals taking vitamin E (any dose), the dose must be 
stable. 
 
Exclusion Criteria 
 
1. Pregnant, breastfeeding, or plans to become pregnant. 
 
2. Known active hepatitis C virus (HCV) infection. 
 
3. Active/chronic hepatitis B virus (HBV). 
 
4. Known retinopathy (excluding remote history of cotton wool 
spots). 
 
5. Known active severe delayed gastric emptying. 
 
6. Gain or loss of >5% body weight within 12 weeks prior to study 
entry. 
 
7. Any plans to change diet or exercise regimen significantly, 
except for the adoption of study-provided suggestions for diet 
and exercise, within the study period. 
 
8. Known acute or chronic liver disease with cirrhosis or portal 
hypertension. 
 
9. History of liver transplant.  
 
10. Current diagnosis of diabetes mellitus or current use of diabetes 
medications, or a laboratory measurement of hemoglobin A1c 
≥6.5% at screening. 
 
11. Personal or family history of medullary thyroid carcinoma or 
multiple endocrine neoplasia type 2 (MEN2). 
 
12. History of unexplained hypercalcemia corrected for albumin that 
is >10.5 mg/dL. 
 
 


 
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13. Use of any immunomodulatory (including prednisone equivalent 
of ≥10 mg), HIV vaccine, investigational therapy, or TNF-α 
therapy within 3 months prior to study entry. 
 
14. Use of human growth hormone, tesamorelin, supraphysiologic 
testosterone to achieve therapeutic blood levels, or any use of 
other anabolic steroids within 3 months prior to study entry or 
plans to start these while on study. 
 
15. Use of estrogens or progesterones at supraphysiologic doses 
within 3 months prior to study entry. 
 
16. Known allergy/sensitivity or any hypersensitivity to components 
of study drug or its formulation. 
 
17. Current serious illness requiring systemic treatment and/or 
hospitalization. 
 
18. Use of GLP-1 agonists within 24 weeks prior to study entry. 
 
19. Active drug or alcohol use or dependence that, in the opinion of 
the site investigator, would interfere with adherence to study 
requirements. 
 
20. Excessive consumption of alcohol of ≥3 months within 90 days 
prior to screening. 
 
21. Known chronic pancreatitis or more than one episode of 
pancreatitis ever in the past. 
 
22. Intent to use any medication likely to cause significant changes 
in weight during the study period. 
 
23. Use of stavudine within 12 months prior to study entry. 
 
24. Prior bariatric surgery (e.g., lap band, gastric sleeve, or Roux-en-Y 
bypass surgery) or major gastric surgery or plans to undergo 
weight reduction surgery while on study. 
 
25. Individuals with any metal, implantable devices (e.g., 
pacemakers, prosthetics), or shrapnel, per standard MRI 
exclusion criteria. 
 
REGIMEN 
Participants will receive semaglutide subcutaneously once weekly 
for 24 weeks. Participants will receive a dose of 0.25 mg weekly 
starting at entry, followed by 0.5 mg weekly starting at week 2, and 


 
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then 1.0 mg weekly from weeks 4 through 24. During weeks 25-48, 
all participants will be off study drug. 
 
SITES 
This is a limited-center study being conducted at both US and non-
US ACTG clinical research sites (CRSs) with the ability to perform 
MRI-PDFF. 
 


 
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APPENDIX II: SAMPLE INFORMED CONSENT 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
For Protocol: A5371 
A Single-Arm, Open-Label Pilot Study of Semaglutide for Non-Alcoholic Fatty Liver 
Disease (NAFLD), a Metabolic Syndrome with Insulin Resistance, Increased Hepatic 
Lipids, and Increased Cardiovascular Disease Risk  
(The SLIM LIVER Study) 
FINAL Version 2.0, dated 06/22/20 
 
SHORT TITLE FOR THE STUDY: The SLIM LIVER Study 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate the safety and tolerability of a 
drug called semaglutide and to see whether it can reduce fat in the liver 
(also called intra-hepatic triglycerides, IHTG). 
 
STUDY  
TREATMENT 
Semaglutide, a liquid that is given once a week using a pre-filled 
self-injection (or “auto-inject”) pen, will be provided to you through 
this study. Semaglutide (brand name Ozempic) is a drug that is used 
to treat people who have diabetes; it also causes weight loss and 
may provide some protection against cardiovascular disease and 
diabetes. In people living with HIV, the use of semaglutide to reduce 
weight and the level of IHTG are experimental. You will continue 
taking your anti-HIV medications that are prescribed by your doctor 
while you are in this study. The anti-HIV medications will not be 
provided to you in this study. 
 
NUMBER OF  
PARTICIPANTS 
About 50 participants will take part in this study.  
 
LENGTH OF  
STUDY  
The study treatment will last for 24 weeks (about 6 months). Participants 
will be followed for an extra 24 weeks after stopping medication. The total 
time on study will be 48 weeks (about 12 months). 
 
REQUIRED  
ACTIVITIES 
 
Blood and stool collections 
• 
At all visits, some blood will be collected from a vein in your arm.  
• 
At two visits, you will be asked to provide a stool sample. 
  


 
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Special Procedures  
• 
You will use an auto-inject pen weekly for 24 weeks to deliver study 
product to yourself. 
• 
At a two visits, a magnetic resonance imaging (MRI) scan will be 
performed.  
• 
At three visits, you will be asked to perform some tests of physical 
function.  
• 
The study staff will contact you by telephone or e-mail several 
times during the study. 
 
 
RISKS  
 
The following are possible while taking study treatment: 
Nausea, vomiting, diarrhea, abdominal pain, constipation, thyroid tumor, 
inflammation of the pancreas, low blood sugar, low blood pressure, 
kidney problems, eye problems, liver damage, allergic reaction, risks 
related to injections, discomfort when collecting stool, and risks related to 
MRI scans. 
 
 
BENEFITS 
There may be a direct benefit to you, but no guarantee can be made. It is 
also possible that you will not receive any benefit from being in this 
study. 
 
 
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 are at risk for having non-
alcoholic fatty liver disease (also known as NAFLD [excess fat in the liver]), you are not diabetic, 
and because you have been taking anti-HIV medications that have controlled your HIV for at 
least 1 year. 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. 
 
 


 
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WHY IS THIS STUDY BEING DONE? 
 
Up to 40% of people living with HIV (PLWH) have NAFLD. In people with controlled HIV, most 
illnesses and deaths that are associated with NAFLD are due to cardiovascular disease (any 
disease of the heart or blood vessels that, for example, can lead to a stroke or heart attack). 
This is not surprising, because most people with NAFLD also have what are called metabolic 
complications (such as high cholesterol, obesity, increased belly fat, or type 2 diabetes) that can 
lead to cardiovascular disease. People with higher levels of intra-hepatic triglycerides (IHTG, a 
type of fat stored in the liver) often have metabolic complications. A drug that can lower the level 
of IHTG in PLWH might treat NAFLD and reduce the risk of cardiovascular disease.  
 
The purpose of this study is to evaluate the safety and tolerability of a drug called semaglutide 
and to see whether it can reduce IHTG. IHTG will be measured by magnetic resonance imaging 
(MRI; an MRI machine contains a powerful magnet that uses simple radio waves to take 
pictures of organs). Semaglutide (brand name Ozempic®) is a drug that is used to treat people 
who have diabetes; it also causes weight loss and may provide some protection against  
cardiovascular disease and diabetes. In PLWH, the use of semaglutide to reduce weight and 
the level of IHTG are experimental. The study will enroll about 50 people. You will be on the 
study for 48 weeks (about 12 months). 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you are interested in joining this study, you will have a screening visit. You will arrive fasting 
for this visit. At this visit, the study staff will:  
• 
perform a physical exam 
• 
ask you questions about how you are feeling and the medications that you are taking 
• 
measure your weight, height, waist size, blood pressure, and temperature 
• 
draw blood for some routine laboratory tests 
• 
test for hepatitis A, B, or C virus, if needed 
 
All of these activities and tests will be used to see if you are eligible to enter the study. 
 
If you appear to be eligible for the study, you will have an MRI of your liver as part of a pre-entry 
visit.  
 
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, assigned sex at birth, current 
gender, race), clinical (for example, disease condition, diagnosis), and laboratory (for example, 
CD4 cell count, HIV viral load) information will be collected from you. We also collect information 
on whether you use (or have used) IV drugs. 
  
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may determine whether there are patterns and/or common 
reasons why people do not join a study. 


 
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If you enroll into the study 
At study entry, you will receive exercise, diet, hypoglycemia (low levels of blood sugar), and 
hydration education and be asked about any problems you are having with taking your anti-HIV 
medications. If you have any vision issues, you will have a vision assessment. You will 
also receive semaglutide, a liquid that is given once a week using a pre-filled self-injection (or 
“auto-inject”) pen. Semaglutide and the auto-inject pens will be provided by the study at no cost 
to you. The injection is into the skin using a very small needle, similar to insulin injections, and 
not a deep injection like most vaccines. You will be given information and some training on the 
use of the auto-inject pen. At one study visit, the clinic staff will watch you use the auto-inject 
pen. If needed, retraining and observation will occur. You may ask for and receive additional 
instructions any time you feel you need it.  
 
You must be able to:  
• 
Keep the auto-inject pens that are given to you between 36°F and 46°F (2°C and 8°C) 
prior to first use.  
• 
Maintain the auto-inject pens at a room temperature between 59°F and 86°F (15°C to 30°C) 
or in a refrigerator (2°C to 8°C; 36°F to 46°F) following first use.  
• 
Protect the auto-inject pens from extreme cold. If an auto-inject pen has been frozen, 
do not use it. 
• 
Protect auto-inject pens from excessive heat and sunlight. 
 
After the study entry visit, you will be seen in the clinic about 4 times. The study staff will tell you 
how long each visit could be. You may need to come to the clinic for additional visits if you 
develop side effects. As part of the study, if you agree, the clinic staff will contact you by phone 
or by e-mail several times between clinic visits to check on how you are doing. 
 
You will have a brief physical exam at all visits. If you have any vision issues, the brief 
physical exam will include a vision assessment. 
 
The samples of your blood and stool that are collected as part of this study may be used 
for additional research tests including liver function, thyroid disease, cholesterol and blood sugar 
tests (tests for diabetes), your HIV viral load (a measure of the amount of HIV in your blood), 
and your CD4 and CD8 T cell count (a measure of the strength of your immune system, the 
system that helps your body fight infections). Details of the study visits and procedures are 
explained in ATTACHMENT A.  
 
You will have another MRI of your liver at the end of study treatment (week 24). 
 
You will continue to take your anti-HIV medications throughout the study. You will receive 
semaglutide.  
 
You will be provided the results of blood tests when they are available. At most visits, blood 
samples will be collected from you and stored for later research tests. You will not receive the 
results of these tests because they will be done in the future. No more than about 5 tablespoons 
of blood will be collected from you at any single visit. 


 
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You will be asked to arrive fasting at four study visits at entry and weeks 12, 24, and 48. This 
means that you will not eat or drink anything other than water and your prescribed medications 
for at least 8 hours before the visit. The study staff will remind you when you need to fast. If you 
are not fasting for any of these visits, the visits will be rescheduled, and you will need to return 
to the clinic on a different day. 
 
At two visits, you will be given a food diary to complete over 3 days. The study staff will give you 
instructions for completing and returning this diary. 
 
At some visits, you will have one or more questionnaires to complete. The questionnaires ask 
about your physical activity, what you eat and drink, your quality of life, and how you feel about 
taking the study treatment.  
 
At three visits, you will be asked to perform physical function tests (chair stands, or standing up 
from a seated position multiple times and a timed walk test). These are tests of muscle strength. 
 
At two visits, you will be asked to provide a stool sample. You will collect this sample yourself 
between study visits, using instructions and a kit provided to you by the clinic staff. Stool 
samples will be tested to evaluate the health of your gut microbiome (a collection of the 
microorganisms in your body); changes in your microbiome are linked to NAFLD. Researchers 
may be able to evaluate whether either of the study treatments affect the gut microbiome. 
Results from these tests will not be shared with you because they will be used for research only. 
 
If you must stop study treatment before you complete the 24 weeks (close to 6 months) and you 
have received at least 12 weeks of study treatment, you will need to have one final visit before 
you leave the study.  
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood and stool will be stored and used for study-required metabolic and 
immunologic testing.  
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you. If you are enrolling in this study at 
a site outside the US you must know that samples collected from you may be shipped and 
stored outside of the country from which they are collected. 
 
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.  
 
ATTACHMENT B describes how your stored samples might be used in other studies. 
Please read that document and then decide if you want to give your consent to the use of 
any of your samples in other studies. 


 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 50 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for 48 weeks (about 12 months).  
 
 
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 
• 
You are not able to complete the study procedures, including the MRIs, as required 
• 
You are not able to continue taking study treatment 
• 
You become pregnant or you are breastfeeding 
• 
You change diet or exercise regimen significantly 
• 
You are unable to keep study product at 36°F to 46°F (2°C to 8°C) prior to first use, or 
to maintain the study product at a controlled room temperature between 59°F and 
86°F (15°C to 30°C) following first use  
 
The study doctor may also need to take you off your study treatment without your permission if: 
 
• 
Continuing the study treatment may be harmful to you.  
• 
If you are experiencing symptoms with the study treatment, the study doctor may 
reduce the study treatment dose, hold the study treatment dose where it is, or stop 
the study treatment. The study treatment may be started again if the symptoms go 
away. 
• 
You need a treatment that you may not take while on the study 
• 
You are not able to take the study treatment as required by the study 
 
If you must stop taking study treatment before the study is over but you have taken the study 
treatment for at least 12 weeks, the study doctor will ask you to return for one final visit. If you 
have not taken the study treatment for at least 12 weeks, you will not return for a final visit. 
 
If you developed a side effect that is still ongoing when you decide to leave the study, the 
study staff and study doctor will explain to you if you need an additional visit and the side effect 
that has to be checked, the evaluations that will be done, and answer any questions you may 
have. 
 


 
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What if I have to permanently stop taking the study-provided semaglutide after I start taking it? 
 
During the study: 
If you must permanently stop taking the study-provided semaglutide before your study 
participation is over, the study staff will discuss other options that may be available to you, 
including no additional medication. 
 
After the study: 
After you have completed your study participation, the study will not provide you with the 
semaglutide you received on the study. In the opinion of your physician, if continuing to take this 
or a similar product would be of benefit to you, the study staff will discuss how you may be able 
to obtain it. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Semaglutide may have side effects, some of which are listed below. Please note that these lists 
include only the more serious or common side effects with a known or possible relationship. If 
you have questions concerning the additional study treatment side effects please ask the 
medical staff at your site. 
 
Semaglutide  
The following side effects have been associated with the use of semaglutide: 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Abdominal pain 
• 
Constipation 
• 
Fatigue 
• 
Headache 
• 
Thyroid tumor, including cancer, which was seen when the drug was tested in rodents, but 
we do not know if this happens in people. Symptoms of this may include:  
o Lump or swelling in the neck 
o Hoarseness 
o Trouble swallowing or  
o Shortness of breath  
• 
Inflammation of the pancreas.  Symptoms of this may include:  
o Abdominal pain with or without vomiting.  
• 
Low blood sugar; signs and symptoms of low blood sugar may include: 
o Headache 
o Drowsiness 
o Weakness 
o Dizziness 
o Confusion 
o Irritability 
o Hunger 


 
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o Fast heart beat 
o Sweating 
o Feeling jittery 
• 
Low blood pressure 
• 
Kidney problems (if you become dehydrated) 
• 
Eye problems 
• 
Among people that took semaglutide, a small number of people with both type 2 
diabetes and a high risk for heart problems had eye disease develop or it 
worsened. If you have had eye problems, it is possible that you may be at 
increased risk for complications while taking semaglutide. 
• 
Hepatotoxicity (liver damage) 
• 
Allergic reaction. Symptoms of this may include:  
o Itching  
o Rash 
o Difficulty breathing 
o Swelling 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with study treatment. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study team before enrolling in any other 
clinical trials while on this study. 
 
Risks of Injection 
The following side effects have been associated with the use of semaglutide: 
• 
Rash, redness, itching at injection site 
 
Risks of MRI Scan 
Some things may interfere with MRI and some can be potentially dangerous. You should inform 
the study team if you have any of the following: 
• 
Heart problems 
• 
Pacemaker 
• 
Metal implanted under your skin, such as an insulin pump 
• 
Hearing aid or cochlear implant 
• 
Surgical clips or staples 
• 
Any metal prosthesis. A prosthesis is an artificial body part, like an artificial leg. 
• 
Shrapnel  
• 
Tattooed eyeliner 
• 
Metal dental items 
• 
Braces 
• 
Pregnancy 
 
Metal in or on the body 
The MRI scanner functions like a magnet and any metals in your body can be pulled off by the 
machine. If you have metal implants (under the skin) such as a pacemaker or metal pins or 
rods, you may be at risk when you are close to the machine. To minimize this risk, we will ask 


 
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you a series of questions about metal exposure over the course of your lifetime from work 
experiences and medical procedures. 
 
Claustrophobia (fear of small spaces) 
When you have the MRI, you will lie on a small bed and the bed will be inserted inside a large 
tube. The opening of the tube is narrow, and some people may experience claustrophobia 
(anxiety or nervousness while inside small spaces) when in the scanner. If you think that you 
may experience excessive anxiety or nervousness while inside the scanner, you should not 
participate in this study. If you decide to participate in the study and begin to experience 
claustrophobia while inside the scanner, the procedure will be stopped at your request. If you 
are unable to complete the MRI, you will not be able to participate in this study. 
 
Other  
There is a possibility that a serious abnormality, not as a result of your study participation but an 
incidental finding, may be discovered in the MRI picture of your liver. If this is the case, you will 
be notified by the site. You will be referred to your primary care physician for clinical follow up. 
Clinical follow-up will not be provided or paid for by the study. 
 
Risks of Stool Collection  
You may have mild discomfort when collecting the stool samples, particularly if you have sores 
or hemorrhoids. In some cases, a very small amount of bleeding may occur. If you are already 
having pain in the rectal area, be sure to let the study team know. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The MRI scans may harm an unborn baby. 
 
It is not known if the study treatment, semaglutide, harms unborn babies. If you are having sex 
that could lead to pregnancy, you must agree not to become pregnant while taking semaglutide 
in the study. If you want to become pregnant, you should wait 2 months after your last dose of 
semaglutide before you try to become pregnant.  
 
If you can become pregnant and are sexually active, you must use one reliable form of birth 
control that you can discuss with the study staff. One of the following methods MUST be used 
while taking semaglutide and for 2 months following your last dose of semaglutide: 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
 
If your partner has had a vasectomy and you do not have any other partners, you do not need to 
use one of the forms of birth control listed above. 
 
If you are having sex that could lead to pregnancy, you must have a pregnancy test before 
you enter this study and at a few other visits. These tests must show that you are not pregnant. 
If you think you may be pregnant at any other time during the study, tell your study staff right 
away. The study staff will talk to you about your choices.   
 


 
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If you become pregnant while on study, you will have to stop study treatment and discontinue 
the study. You will complete premature study discontinuation evaluations except for an MRI 
scan. The study staff would like to stay in contact with you 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 anti-HIV drugs when you become pregnant, your pregnancy will be reported to an 
international database that collects information about pregnancies in individuals taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you will not receive any benefit from being in this study. 
Information learned from this study may help others who have HIV and NAFLD. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Regular and consistent diet and exercise are the first treatment that doctors usually prescribe 
for NAFLD, and would be the care recommended to you outside of the study. Study-provided 
drugs, laboratory tests to monitor how well these drugs are working, and quality medical care 
may or may not be available to you outside the study. The clinic staff will discuss with you other 
treatment choices in your area and the risks and the benefits of all the 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, this research is covered by a Certificate of 
Confidentiality from the U.S. Federal Government. This certificate means that researchers 
cannot be forced to tell people who are not connected with this study, such as the court system, 
about your participation. Also, any publication of this study will not use your name or identify you 
personally.   
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, and their designees. The Certificate of Confidentiality 
does not prevent you from releasing information about yourself and your participation in the 
study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 


 
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A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
For Sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. In 
addition to the efforts of the study staff to help keep your personal information private, this 
research is covered by a Certificate of Confidentiality from the US Federal Government. The 
Certificate of Confidentiality may not provide protections for the participant’s data in your 
country. Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, and their designees. The 
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 ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for study-related visits, physical examinations, laboratory tests, 
study medications or other procedures. You, your insurance company, or your health care 
system may need to assume the cost of drugs not provided by the study (delete references to 
insurance company or health care system if not applicable at site). In some cases, it is possible 
that your insurance company or health care system will not pay for these costs because you are 
taking part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
(Sites should insert a statement about any participant compensation for MRIs and study visits.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of your being in this study, you will be given immediate treatment 
for injuries and be referred for further treatment, if necessary.  
 


 
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[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.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  
• 
The cost for this treatment will be charged to you or your insurance company. There is no 
program for compensation either through this institution or the NIH.  
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part. 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. 
 
 
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 subject, contact: 
• 
Name or title of person on the Institutional Review Board or Ethics Committee (IRB or EC) 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 
 
 
 
____________________________ 
_________________________________________ 
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: A5371 STUDY VISITS AND PROCEDURES 
 
Section A: Study Visits 
 
 Attachment A Table 1: Expected Study Visit Schedule 
Procedure 
Screening 
Pre-entry 
Study entry 
(Day 0) 
On-study 
Week 24 or if 
stopping 
treatment early* 
Week 48 
Physical exam 
 
 
 
At all visits 
 
 
Blood collected 
 
 
 
At all visits 
 
 
Pregnancy test 
 
 
 
Possibly 
 
 
MRI performed 
 
 
 
 
 
 
Stool kit and 3-day food diary 
provided 
 
 
 
At one visit 
 
 
Stool kit and 3-day food diary 
collected 
 
 
 
 
 
 
Questionnaires 
 
 
 
At all visits 
 
 
Adherence checked 
 
 
 
 
 
 
Exercise and diet education 
 
 
 
 
 
 
Low blood sugar and 
hydration education 
 
 
 
 
 
 
Physical function tests 
 
 
 
 
 
 
Study drug provided 
 
 
 
At two visits 
 
 
Injection training, retraining, and 
observed injection 
 
 
 
As needed 
 
 
Telephone or email contact 
 
 
 
Between some 
clinic visits 
 
 
*If you have taken at least 12 weeks of study treatment, you will have these evaluations performed. 


 
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Section B: Explanation of Visit Schedule 
 
Screening: This visit will take place within 30 days before the pre-entry visit. 
 
Pre-entry: This visit will take place within 2 weeks before you enter the study. 
 
Study Entry/Day 0: This is the day that you will start your study treatment. This visit 
will take place within 2 weeks after you have the first magnetic resonance imaging 
(MRI) scan of the study. 
 
On-study: You will continue to take your anti-HIV medications, which are not 
provided by the study. After study entry, you will have about 3 study visits while you 
are taking study treatment (semaglutide). Your last visit while you are taking 
semaglutide will be at week 24. If you stop semaglutide early but have taken at least 
12 weeks of it, you will have a visit that is similar to the week 24 visit.  
 
Week 48 will be your final study visit. 
 
Section C: Explanation of Procedures 
 
Physical exam: You will have a complete physical exam at screening and then only a 
brief physical exam at all other visits. You will be asked about feeling light-headed 
and if you have experienced any problems with your eyes or vision. If you have 
experienced any problems with your eyes or vision including blurred vision, 
sudden loss of vision, black spots, flashing lights, and difficulty reading or 
seeing small details, you will have a vision assessment.  
 
Blood collected: Blood will be collected from a vein in your arm at all visits for 
research tests, which may include liver function, thyroid disease, cholesterol and 
blood sugar tests (tests for diabetes), your HIV viral load (a measure of the amount 
of HIV in your blood), and your CD4 and CD8 T cell count (a measure of the strength 
of your immune system, the system that helps your body fight infections). You may 
be tested to see if you have or previously had hepatitis A, B, or C infections. 
 
Pregnancy test: If you are able to become pregnant, you will have a pregnancy test, 
using either a blood sample or a urine sample. A pregnancy test will be done at 
screening, entry, and week 24, and any time you think you may be pregnant. 
 
Exercise and diet education: You will receive diet and exercise recommendations at 
the beginning of the study. 
 
Low blood sugar and hydration education: At the beginning of the study, you 
will receive education about very low levels of blood sugar and how to stay 
hydrated when feeling nauseated. 
 


 
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MRI performed: An MRI machine contains a powerful magnet that uses simple radio 
waves to take pictures of organs. An MRI will be performed two times during the 
study. The clinic staff will give you any information you might need to prepare for this 
procedure. There is no pain associated with this procedure. You will be positioned on 
your back on a small bed and made to feel as comfortable as possible. You will be 
inserted inside a large tube. Once the scan starts, you will need to lie still for about 
30 minutes. You will be able to ask the technician to end the scan at any time if you 
feel uncomfortable. 
 
Stool kit: You will be asked to provide a stool sample twice during the study using 
a test kit and instructions that the clinic staff gives you. The stool sample will be self-
collected at home within 2 days before a study visit. 
 
3-day food diary: The study includes a 3-day food diary that you will be asked to 
complete twice during the study. 
 
Questionnaires: At all visits, you will have one or more questionnaires to complete. 
The study includes questionnaires about your physical activity, what you eat and 
drink, your quality of life, and how you feel about taking the study treatment.  
 
Adherence checks: At some visits, you may be asked about any problems you are 
having with taking your anti-HIV medications, your study treatment, or both.  
 
Physical function tests: You will be asked to stand up multiple times from a seated 
position, and be timed on how long it takes you to walk a short distance. 
 
Injection training, retraining, and observation: You will receive training on how to use 
the auto-inject pen. You will also be observed using the auto-inject pen when you 
start study treatment. If needed, you will be retrained and possibly observed again 
during the study. You may ask for help with the auto-inject pen at any time. 
 
Telephone or email contact: Between entry and week 24, you will be contacted by 
study staff by telephone or email up to six times.


 
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ATTACHMENT B: CONSENT FOR USE OF SAMPLES IN OTHER STUDIES 
 
When samples are no longer needed for this study, the ACTG may want to use them in 
other studies and share them with other researchers. These samples are called “extra 
samples.” The ACTG will only allow your extra samples to be used in other studies if 
you agree to this. If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has 
been collected about you. This means that no one looking at the labels or at other 
information will be able to know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples 
will be stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored.  
[Site: Revise the previous sentence to insert limits if your regulatory authority imposes 
them.] 
 
When a researcher wants to use your samples and information, their research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or 
ethics committee (EC) will review the researcher’s 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. 


 
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____ (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  
Your extra samples will not be used for human genetic testing.  
 
The ACTG has two different studies that collect samples for genetic testing. 
 
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. 
 

SAP_001.pdf: 
Approvals 


 
 
 
 
ACTG A5371 (SLIM LIVER) 
Primary Statistical Analysis Plan 
Version 2.0  
June 23, 2023  
 
A Single-Arm, Open-Label, Pilot Study of Semaglutide for Non-
Alcoholic Fatty Liver Disease (NAFLD), a Metabolic Syndrome 
with Insulin Resistance, Increased Hepatic Lipids, and Increased 
Cardiovascular Disease Risk 
ClinicalTrials.gov Identifier: NCT04216589 
 
A5371 Version 2.0 (CM #1, CM #2, LOA #1)  
 
This is the ACTG A5371 SAP Version 2.0 with names of authors, names of publication 
writing team members and analysis timeline redacted. 
 
 
Created by: 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 


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Page 1 of 18 
 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
VERSION HISTORY ........................................................................................................................ 2 
1 
INTRODUCTION ........................................................................................................................ 3 
1.1 
Purpose ............................................................................................................................ 3 
1.2 
Version History ............................................................................................................... 3 
2 
STUDY OVERVIEW ................................................................................................................... 3 
2.1 
Overview of Study Design .............................................................................................. 3 
2.2 
Hypotheses ...................................................................................................................... 4 
2.2.1 
Primary Hypothesis .............................................................................................. 4 
2.2.2 
Secondary Hypotheses ........................................................................................ 4 
2.3 
Study Objectives ............................................................................................................. 4 
2.3.1 
Primary Objective ................................................................................................. 4 
2.3.2 
Secondary Objectives .......................................................................................... 4 
2.3.3 
Exploratory Objectives ......................................................................................... 5 
2.4 
Overview of Sample Size Considerations .................................................................... 5 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 6 
3 
OUTCOME MEASURES ........................................................................................................... 6 
3.1 
Primary Outcome Measure ............................................................................................ 6 
3.2 
Secondary Outcome Measures ..................................................................................... 6 
3.3 
Other Outcome Measures .............................................................................................. 7 
4 
GENERAL CONSIDERATIONS ................................................................................................ 8 
4.1 
Definitions........................................................................................................................ 9 
5 
ESTIMANDS AND ANALYSIS ................................................................................................ 10 
5.1 
Primary Estimand and Analysis .................................................................................. 10 
5.2 
Secondary Estimands and Analyses .......................................................................... 11 
5.2.1 
First Secondary Estimand .................................................................................. 11 
5.2.2 
Second Secondary Estimand ............................................................................. 11 
5.2.3 
Third Secondary Estimand ................................................................................. 12 
6 
ANALYSIS OF OBJECTIVES ................................................................................................. 13 
6.1 
Primary Analysis ........................................................................................................... 13 
6.2 
Secondary and Exploratory Analyses ........................................................................ 13 
7 
REPORT CONTENTS ............................................................................................................. 16 
 
 


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Version History 
 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
11/10/2020 
1.1 
A review occurred for LOA #1 with no changes needed.  The SAP 
authors and the document header were updated. 
06/14/2022 
2.0 
Added all protocol-specified primary, secondary and exploratory 
objectives and associated analyses. 
Added primary and secondary estimands. 
Adjusted analysis visit windows. 
Finalized subgroup analyses and metabolic syndrome definition. 
Removed analysis timelines as these will be tracked and 
maintained by the CTS. 
06/23/2023 
 
 
 


A5371 Version 2.0 (CM #1, CM #2, LOA #1) 
 
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Page 3 of 18 
 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary estimand and secondary and 
other outcome measures that will address specific study objectives of the A5371 study. The 
Primary SAP includes general analytic approaches for the estimand and outcome measures in 
the primary manuscript 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 and secondary analysis reports. 
The Analysis Implementation Plan (AIP) provides outlines of tables, figures, and possibly coding 
descriptions. 
1.2 
Version History 
Version 2.0 of the SAP contains all analyses associated with protocol-specified primary, 
secondary and exploratory objectives.  
Major modifications include the addition al primary and secondary estimands and specific 
outcome measures for all objectives.  
2 
Study Overview 
2.1 
Overview of Study Design 
A5371 is a single-arm, open-label, pilot study of the effects of semaglutide on intra-hepatic 
triglyceride (IHTG) content in adults living with HIV, central adiposity, insulin resistance or pre-
diabetes, and hepatic steatosis.  Eligible participants will receive semaglutide subcutaneously 
once weekly for 24 weeks; IHTG will quantified by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) prior to starting treatment (pre-entry) and at week 24.   
The study aims to enroll 50 participants, targeting at least 40% persons currently identifying as 
cisgender or transgender women and 50% non-white. 
The study population consists of adults (≥ 18 years of age) with HIV not meeting criteria for 
diabetes who: 
- 
Have central adiposity (minimum waist circumference ≥ 95cm for individual assigned 
male sex at birth or ≥ 94 cm for individuals assigned female sex at birth) 
- 
Have ≥ 5% IHTG content 
- 
Have at least one of the following insulin resistance or pre-diabetes indicators: fasting 
plasma glucose 100-125 mg/dL, HbA1c between 5.7 and <6.5%, or HOMA-IR > 3.0 
- 
Have had stable body weight (no gains or losses of >5%) within 12 weeks prior to entry 
- 
Have CD4+ T-cell count ≥ 200 cells/mm3 within 30 days prior to pre-entry 
- 
Have no changed ART in the 24 weeks prior to entry 


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- 
Have two separate reports of HIV-1 RNA < 50 copies/mL, and no > 500 copies/mL during 
48 weeks prior to entry 
The primary analysis will commence once all primary outcome measures have been read and 
recorded in the central database. This analysis will also address all secondary and exploratory 
objectives through study week 24. All secondary and exploratory objectives through study week 
48 will be included in a secondary analysis. 
2.2 
Hypotheses 
2.2.1 
Primary Hypothesis 
Among antiretroviral therapy (ART)-treated, virologically suppressed adults with HIV, 
hepatic steatosis, central adiposity, and insulin resistance, 24 weeks of semaglutide will 
result in reductions in intra-hepatic triglyceride (IHTG) content, as quantified by magnetic 
resonance imaging-proton density fat fraction (MRI-PDFF). 
2.2.2 
Secondary Hypotheses 
1) Semaglutide will be safe and well tolerated. 
 
2) Semaglutide will improve cardiometabolic parameters central to the pathogenesis of 
atherosclerosis and increased cardiovascular risks. 
2.3 
Study Objectives 
This Primary SAP addresses the following primary, secondary and exploratory objectives in the 
study protocol with the corresponding protocol numbering shown in brackets. 
Analysis of the study objectives below will be analyzed under an “any effect” framework (i.e., 
identify effects different than zero). These analyses will be finalized once the last participant has 
completed the Week 24 (for primary analysis report) or Week 48 (for secondary analysis report) 
study visit, all queries have been resolved, and the study database closure/data lock has been 
completed (applicable to secondary analysis report only).  
2.3.1 
Primary Objective 
To evaluate whether semaglutide will reduce IHTG content, as quantified by MRI-PDFF, 
among ART-treated adults with HIV, hepatic steatosis, central adiposity, and insulin 
resistance or pre-diabetes [Protocol Objective 1.2]. 
2.3.2 
Secondary Objectives 
1) To evaluate the safety and tolerability of semaglutide in adults with HIV, hepatic 
steatosis, central adiposity, and insulin resistance or pre-diabetes [Protocol Objective 
1.3.1]. 
 


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2) To evaluate the effects of semaglutide on weight, minimum waist circumference (WC), 
and body mass index (BMI) [Protocol Objective 1.3.2]. 
 
3) To evaluate the effects of semaglutide on insulin resistance or pre-diabetes, lipid profiles, 
and the prevalence of metabolic syndrome [Protocol Objective 1.3.3]. 
 
4) To evaluate relationships between observed changes in IHTG and changes in metabolic 
parameters. [Protocol Objective 1.3.4]. 
2.3.3 
Exploratory Objectives 
1) To evaluate the durability of semaglutide on weight, minimum WC, and BMI after 
cessation of study therapy [Protocol Objective 1.4.1].  
 
2) To evaluate the relationships between systemic measures of carbohydrate and lipid 
metabolism and a) IHTG and b) visceral adipose tissue (VAT) area in participants treated 
with semaglutide [protocol Objective 1.4.2]. 
 
3) To evaluate the effects of semaglutide on MRI-quantified VAT and abdominal 
subcutaneous adipose tissue (SAT) area and density [Protocol Objective 1.4.3]. 
 
4) To evaluate the effects of semaglutide on circulating inflammatory biomarker and 
adipocytokine levels [Protocol Objective 1.4.4]. 
 
5) To evaluate the effects of semaglutide on muscle function and muscle fat [Protocol 
Objective 1.4.5]. 
 
6) To evaluate the effects of semaglutide adherence on primary and secondary outcomes 
[Protocol Objective 1.4.6]. 
 
7) To evaluate the effects of semaglutide on self-reported quality of life [Protocol Objective 
1.4.7]. 
 
8) To evaluate the effects of semaglutide on the gut microbiome [Protocol Objective 1.4.8]. 
 
9) To evaluate relationships between changes in IHTG content and changes in VAT and 
SAT area and muscle fat quantity [Protocol Objective 1.4.9]. 
 
10) To evaluate the effects of semaglutide on circulating immune cell profiles [Protocol 
Objective 1.4.10]. 


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2.4 
Overview of Sample Size Considerations 
The study is designed to evaluate whether 24 weeks of semaglutide will improve IHTG in ART-
treated, adults with HIV, hepatic steatosis, central obesity, and insulin resistance or pre-diabetes. 
The primary comparison will examine the absolute change in IHTG from pre-entry to week 24.   
The sample size is based on a two-sided, one-sample t-test with 5% significance level and 90% 
statistical power, and assumes, based on published literature, that semaglutide will reduce 
(improve) IHTG. Assuming a 9% SD, with 37 participants, there is 90% statistical power to 
identify a significant change in IHTG, under the assumption that the true change is 5% over 24 
weeks. Inflating the sample size to account for 25% loss to follow-up and premature treatment 
discontinuation, yields a total sample size of 50 participants. 
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 
approximately 6 months (and no later than 1 year) after the first participant enrolls; interim 
reviews may also be convened if a concern is identified. The SMC will review summaries of 
accrual, baseline characteristics, study conduct (including premature treatment and study 
discontinuations), and adverse events.  Summaries of primary efficacy will not be provided during 
interim reviews and there are no pre-specified stopping guidelines.  
Study enrollment will be paused and the SMC will convene an emergency meeting to review all 
study AEs, in collaboration with the DAIDS clinical representative, in the event any of the 
following are observed:  
(1) Three participants with the same Grade 3 (or higher) events attributable to 
semaglutide; 
(2) Two participants with Grade 4 events attributable to semaglutide; 
(3) Two participants with hepatoxicity events leading to semaglutide being held or 
permanently discontinued (see protocol section 8); 
(4) Death. 
3 
Outcome Measures 
Only outcome measures addressed in this SAP are included below, see protocol section 10.2 for 
additional measures. Other Outcome Measures, defined in the protocol, which address changes 
in biomarkers, the microbiome, physical activity/diet, or outcomes listed below through week 48, 
will be outlined in future SAPs.  
3.1 
Primary Outcome Measure 
1) Change (absolute) in IHTG (%) from pre-entry to week 24.   
[For Primary Objective, Secondary Objective 4, and Exploratory Objectives 2 and 9] 


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3.2 
Secondary Outcome Measures 
1) Change (percent) in IHTG (%) from pre-entry to week 24.  
[For Primary Objective, Secondary Objective 4, and Exploratory Objectives 2 and 9] 
 
2) Level of IHTG (%) at week 24.  
[For Primary Objective] 
 
3) Occurrence of premature discontinuation of study treatment, including reasons for 
discontinuation. 
[For Secondary Objective 1] 
 
4) Occurrence of new Grade ≥3 adverse event that are related to study treatment.  
[For Secondary Objective 1] 
 
5) Change (absolute) in body mass index (BMI), body weight, and minimum waist 
circumference (WC) from week 0 to weeks 12 and 24.  
[For Secondary Objectives 2 and 4] 
 
6) Changes (absolute) in insulin resistance (HOMA-IR), HbA1c and glucose from week 0 to 
week 24.  
[For Secondary Objectives 3 and 4, and Exploratory Objective 2] 
 
7) Change (absolute) in lipid profiles (triglycerides, HDL cholesterol, LDL cholesterol, total 
cholesterol) from week 0 to weeks 12 and 24.  
[For Secondary Objectives 3 and 4, and Exploratory Objective 2] 
 
8) Presence of metabolic syndrome at weeks 0, 12, and 24.   
[For Secondary Objective 3] 
3.3 
Other Outcome Measures 
1) Number of empty cartridge pen counts at weeks 4, 12, and 24. 
[For Exploratory Objective 6] 
 
2) Self-reported adherence of semaglutide injections at weeks 4, 12, and 24. 
[For Exploratory Objective 6] 
 
3) Changes (absolute) in chair rise rate from week 0 to week 24 defined as time in seconds 
to rise 5 times and 10 times.  
[For Exploratory Objective 5] 
 
4) Change in presence of slow gait speed from week 0 to week 24, defined as ≥1 m/sec. 
[For Exploratory Objective 5] 
 


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5) Change (absolute) in gait speed (m/sec) from week 0 to week 24  
[For Exploratory Objective 5] 
 
6) Change (absolute) in total psoas muscle fat percent as measured by MRI from pre-entry 
to week 24.  
[For Exploratory Objectives 5 and 9] 
 
7) Quality of life measures (general health, poor physical health, poor mental health, 
impairment) at weeks 0 and 24.  
[For Exploratory Objective 7] 
 
8) Change (absolute) in adipose tissue (VAT and SAT) volume as measured by MRI from 
pre-entry to week 24.  
[For Exploratory Objectives 2, 3, and 9] 
 
9) Change (absolute) in BMI, body weight, and WC from week 24 to week 48.  
[For Exploratory Objective 1] 
 
10) Change (absolute) in circulating inflammatory biomarkers (sCD14, IL-6, sCD163, CRP, 
IP-10, MCP-1, CD40L, oxidized LDL, and FABP-4) and adipocytokine levels (adiponectin 
and GLP-1) from week 0 to weeks 12, 24 and 48. [For Exploratory Objective 4] 
 
11) Change (absolute) in gut microbiome from week 0 to week 24. [For Exploratory Objective 
8, analyzed outside of SDAC] 
 
12) Change (absolute) in circulating immune cell profiles (Activated (HLA-DR+/CD38+) CD4+ 
and CD8+ T lymphocytes; Monocyte (CD14/CD16/CCR2/CX3CR1/CD36/CD11c) 
subsets; Invariant natural killer (6B11/CD69) and mucosal associated invariant 
(Vα7.2/CD161) T lymphocytes) from week 0 to week 24. [For Exploratory Objective 10] 
4 
General Considerations 
The following analysis populations are defined for A5371: 
- 
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 study  
treatment (this is a modified ITT population or “Safety 
Set”). 
 
- 
Evaluable Population: 
 
All participants who remained on study treatment 


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until 28 days prior to the Week 24 MRI, who did not have 
any eligibility violations, and who did not start prohibited 
medications known to cause changes in weight prior to 
the Week 24 MRI (this is a per protocol [PP] population 
or “Efficacy Set”). 
Note:  All concomitant medications will be reviewed by the study chairs in a blinded fashion prior 
to final analysis to flag prohibited medications known to cause changes in weight.  
Study week windows are as defined in the protocol.   
For all analyses, the following visit windows will be used (based on days from study entry): 
• 
Screening: evaluations completed within 30 days of pre-entry. 
• 
Pre-Entry: ≥1 day after screening and within 14 days prior to entry. 
• 
Entry (week 0): entry evaluations must occur on/after randomization and on/prior to 
treatment initiation. 
• 
On-treatment evaluations: 
o 
Week 4: weeks [2, 6] / days [14, 42] 
o 
Week 12: weeks [8, 16] / days [56, 112] 
o 
Week 24: weeks [20, 29] / days [140, 203] 
• 
Week 48: post-treatment evaluation scheduled within a week [44, 52] / day [308, 364] 
window. 
If multiple results are available within a visit window priority will first be given to data collected 
while on treatment and second to data closest to the scheduled visit. 
If participants start prohibited medications known to cause changes in weight after the Week 24 
MRI, data collected after this initiation will be excluded from analyses. 
Key study visits occur at pre-entry, entry, week 24 and week 48.  
Pre-entry: 
Occurs after screening, but within 14 days of study entry (week 0).  First 
MRI-PDFF to measure IHTG. 
Entry (week 0): First dose of study treatment occurs. 
Week 24: 
Last on-treatment study visit; second MRI-PDFF to measure IHTG. 
Week 48: 
Last on-study visit. 
Analysis of primary and secondary outcomes will not adjust for multiple comparisons.  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. Non-normal continuous data will be log-transformed to the log-
10 scale for analysis; it is anticipated that biomarkers such as HOMA-IR will be log-transformed.  
All statistical tests will be evaluated using a 5% alpha.  


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4.1 
Definitions 
New Grade 3 or higher AE is defined as Grade 3 or higher event that was new in onset or 
aggravated in severity from the baseline condition (i.e., Grade 1 or 2 at baseline escalates to 
Grade 3 or higher, or Grade 3 at baseline escalates to Grade 4 or higher), following the start of 
study treatment. 
Metabolic syndrome is defined as having 3 or more of the following:  increased minimum WC 
(≥40 inches men, ≥35 inches women), high triglyceride level (>150 mg/dL or taking lipid-lowering 
medication), reduced HDL cholesterol (<40 mg/dL men, <50 mg/dL women), increased blood 
pressure (≥130/85 mm Hg or taking blood pressure medication), and elevated fasting blood 
glucose (>100 mg/dL or taking glucose-lowering medication), based on current guidelines.  
Factors for subgroup analyses: 
1. Sex at birth (male sex at birth, female sex at birth) 
2. Gender (cisgender or transgender female, cisgender or transgender male) 
3. Race/ethnicity (White non-Hispanic and Other, White Hispanic, Black [regardless 
of ethnicity]) 
4. Age (<40, 40-60, >60) 
5. IHTG % at pre-entry (<5%, 5%-<15%, 15%-<25%, ≥25%) 
6. VAT at pre-entry (<sex-specific median, ≥sex-specific median) 
7. Semaglutide doses received (100%, <100%) 
5 
Estimands and Analysis 
5.1 
Primary Estimand and Analysis 
Primary Objective 1: To evaluate whether semaglutide will reduce IHTG content, as 
quantified by MRI-PDFF, among ART-treated adults with HIV, hepatic steatosis, central 
adiposity, and insulin resistance or pre-diabetes 
Estimand  
Absolute change in IHTG (%) 24 weeks after initiating semaglutide, among HIV-
infected adults with NAFLD who remain on study treatment without use of prohibited 
medications.   
 
Treatment 
Semaglutide 
Target population  
Analysis set  
Adults ≥18 years of age with HIV, central adiposity, 
insulin resistance or pre-diabetes, and hepatic steatosis, 
with HIV RNA suppression for at least the prior 48 
weeks on ART. 
 
Efficacy set (Participants who remained on 
study treatment for 24 weeks and did not 
receive prohibited medications during this 
time period) 
Variable(s) 
Outcome measure(s)  
Change in IHTG 24 weeks after initiating semaglutide. 
Absolute change from pre-entry to Week 24 in 
IHTG (%). 
Handling of intercurrent events  
Handling of missing data 


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The following intercurrent events are relevant to the 
estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: ignored 
(treatment policy) 
3. Use of prohibited medications: excluded 
(principal stratum) 
4. Treatment discontinuation prior to week 24: 
excluded (principal stratum) 
5. Pregnancy: excluded (principal stratum) 
 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 
 
Sensitivity analysis: If >10% of participants in 
the efficacy set are missing outcomes the 
analysis will be repeated using multiple 
imputation for the missing values.  
 
Population-level summary measure 
Analysis approach 
 
The average absolute change in IHTG (%) 24 weeks 
after initiating semaglutide. 
 
Linear regression of absolute IHTG change 
(%) on treatment arm without a model 
intercept. The estimated treatment arm effect, 
95% CI and associated p-value will be 
provided. 
 
 
5.2 
Secondary Estimands and Analyses 
5.2.1 
First Secondary Estimand 
Secondary Objective 1: To evaluate the safety and tolerability of semaglutide in adults with 
HIV, hepatic steatosis, central adiposity, and insulin resistance or pre-diabetes 
Estimand  
Probability of new Grade ≥3 adverse events related to study treatment among HIV-
infected adults with NAFLD who initiated study treatment. 
 
Treatment 
Semaglutide 
Target population  
Analysis set  
Adults ≥18 years of age with HIV, central adiposity, 
insulin resistance or pre-diabetes, and hepatic 
steatosis, with HIV RNA suppression for at least the 
prior 48 weeks on ART. 
 
Safety set (Participants who received at least 
one dose of study treatment) 
Variable(s) 
Outcome measure(s)  
Occurrence of new Grade ≥3 adverse event related to 
study treatment.after initiating semaglutide. 
Outcome measure as defined by the Variable. 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand:  
1. Non-treatment-related death: ignored 
(treatment policy) 
2. Change in background ART regimen: ignored 
(treatment policy) 
3. Use of prohibited medications: excluded 
ignored (treatment policy) 
4. Treatment discontinuation prior to week 24: 
ignored (treatment policy) 
 
Participants who discontinue follow-up before 
prematurely will have their outcome 
determined based on data available until the 
time of discontinuation (i.e., a participant who 
discontinued follow-up without a prior AE is 
assumed not to have an AE had they been 
observed for the intended duration [48 
weeks]). 
 
Sensitivity analysis: If >10% of participants in 
the safety set are prematurely discontinued, 
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5. Pregnancy: ignored (treatment policy) 
Grade ≥3 treatment-related AE with 
participants censored at the time of study 
discontinuation will be estimated. 
 
Population-level summary measure 
Analysis approach 
 
The probability of a Grade ≥3 adverse event related to 
semaglutide. 
 
 
The observed proportion will be provided. 
 
5.2.2 
Second Secondary Estimand 
Secondary Objective 2: To evaluate the effects of semaglutide on weight, minimum waist 
circumference (WC), and body mass index (BMI) 
Estimand  
Absolute change in metabolic parameters (weight, WC, BMI) 24 weeks after initiating 
semaglutide, among HIV-infected adults with NAFLD who remain on study treatment 
without use of prohibited medications.   
 
Treatment 
Semaglutide 
Target population  
Analysis set  
Adults ≥18 years of age with HIV, central adiposity, 
insulin resistance or pre-diabetes, and hepatic steatosis, 
with HIV RNA suppression for at least the prior 48 
weeks on ART. 
 
Efficacy set (Participants who remained on 
study treatment for 24 weeks and did not 
receive prohibited medications during this 
time period) 
Variable(s) 
Outcome measure(s)  
Change in metabolic parameters (weight, WC, BMI) 24 
weeks after initiating semaglutide. 
Absolute change from entry to Week 24 in 
metabolic parameters (weight, WC, BMI). 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: ignored 
(treatment policy) 
3. Use of prohibited medications: excluded 
(principal stratum) 
4. Treatment discontinuation prior to week 24: 
excluded (principal stratum) 
5. Pregnancy: excluded (principal stratum) 
 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 
 
Sensitivity analysis: Sensitivity analysis: If 
>10% of participants in the efficacy set are 
missing outcomes the analysis will be 
repeated using multiple imputation for the 
missing values.  
 
Population-level summary measure 
Analysis approach 
 
The average absolute change in metabolic parameters 
(weight, WC, BMI) 24 weeks after initiating semaglutide. 
 
Linear regression of absolute metabolic 
parameter (weight, WC, BMI) change on 
treatment arm without a model intercept. The 
estimated treatment arm effect, 95% CI and 
associated p-value will be provided. 
 


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5.2.3 
Third Secondary Estimand 
Secondary Objective 2: To evaluate the effects of semaglutide on insulin resistance or pre-
diabetes, lipid profiles, and the prevalence of metabolic syndrome 
Estimand  
Absolute change in HOMA-IR 24 weeks after initiating semaglutide, among HIV-
infected adults with NAFLD who remain on study treatment without use of prohibited 
medications.   
 
Treatment 
Semaglutide 
Target population  
Analysis set  
Adults ≥18 years of age with HIV, central adiposity, 
insulin resistance or pre-diabetes, and hepatic steatosis, 
with HIV RNA suppression for at least the prior 48 
weeks on ART. 
 
Efficacy set (Participants who remained on 
study treatment for 24 weeks and did not 
receive prohibited medications during this 
time period) 
Variable(s) 
Outcome measure(s)  
Change in HOMA-IR 24 weeks after initiating 
semaglutide. 
Absolute change from entry to Week 24 in 
HOMA-IR. 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the 
estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: ignored 
(treatment policy) 
3. Use of prohibited medications: excluded 
(principal stratum) 
4. Treatment discontinuation prior to week 24: 
excluded (principal stratum) 
5. Pregnancy: excluded (principal stratum) 
 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 
 
Sensitivity analysis: Sensitivity analysis: If 
>10% of participants in the efficacy set are 
missing outcomes the analysis will be 
repeated using multiple imputation for the 
missing values.  
  
Population-level summary measure 
Analysis approach 
 
The average absolute change in HOMA-IR 24 weeks 
after initiating semaglutide. 
 
Linear regression of absolute HOMA-IR 
change on treatment arm without a model 
intercept. The estimated treatment arm effect, 
95% CI and associated p-value will be 
provided. 
 
6 
Analysis of Objectives 
6.1 
Primary Analysis 
1. IHTG (%)  
a. Using the PP population, the average absolute change in IHTG (%) from Pre-
Entry to Week 24 will be estimated by a linear regression model without an 
intercept term (as this is a single arm study). Each participant will have a single 
outcome measure of IHTG (%) absolute change from pre-entry to Week 24. 
Study arm will be the only covariate in the model.  


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b. Using the PP population, the above analysis (a) will be repeated with the model 
being adjusted for baseline covariates found to differ between participants with 
and without IHTG (%) change outcomes. 
c. Using the mITT population, the average absolute change in IHTG (%) from Pre-
Entry to final MRI will be estimated by a linear regression model without an 
intercept term (as this is a single arm study). Each participant will have a single 
outcome measure of IHTG (%) absolute change from pre-entry to final MRI. 
Study arm will be the only covariate in the model. [NOTE: this analysis will only 
be conducted if >10% of the mITT population is excluded from the PP population] 
d. Using the PP population, differential semaglutide effects will be assessed for the 
subgroups listed in Section 4.1 by linear regression models without an intercept 
term. Each participant will have a single outcome measure of IHTG (%) absolute 
change from Pre-Entry to Week 24. Study arm and the subgroup of interest will 
be covariates in the model. 
6.2 
Secondary and Exploratory Analyses 
1. IHTG (%)  
a. The IHTG (%) analyses outlined in 6.1 will be repeated using percent change in 
IHTG (%) from pre-entry to Week 24. 
 
2. Safety and Tolerability  
a. No formal statistical testing will be performed for safety (Grade 3 or higher AEs 
related to treatment) or tolerability (premature treatment discontinuation). Data 
summaries are outlined in the AIP. 
 
3. Metabolic Parameters   
a. BMI, Body Weight and Minimum Waist Circumference 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). Absolute changes in these outcomes from 
Week 0 to 12 will only use analysis a) from 6.1.  
ii. Absolute changes in these outcomes from Week 24 to 48 will only use 
analysis a) from 6.1. 
iii. Using the PP population, absolute changes from Week 0 to 24 will be 
correlated with both absolute and percent change from Pre-Entry to 
Week 24 in IHTG (%). 
b. HOMA-IR, HbA1c and Glucose 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). Absolute changes in HbA1c and glucose 
from Week 0 to 12 will only use analysis a) from 6.1. 
ii. Absolute changes in these HbA1c and glucose from Week 24 to 48 will 
only use analysis a) from 6.1. 
iii. Using the PP population, absolute changes from Week 0 to 24 will be 
correlated with both absolute and percent change from Pre-Entry to 
Week 24 in IHTG (%). 


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c. Lipids (total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride) 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). Absolute changes in these outcomes from 
Week 0 to 12 will only use analysis a) from 6.1. 
ii. Using the PP population, absolute changes from Week 0 to 24 will be 
correlated with both absolute and percent change from Pre-Entry to 
Week 24 in IHTG (%). 
d. Metabolic Syndrome 
i. Using the PP population, the prevalence of metabolic syndrome at 
Weeks 0, 12 and 24 will be estimated by a generalized estimating 
equation (GEE) model for binary data without an intercept term. Each 
participant will have up to three metabolic syndrome outcomes (Yes/No) 
from Weeks 0, 12 and 24. Study arm and time (study visit) will be the 
only covariates in the model.  
ii. The above analysis (i) will be repeated using the modified ITT 
population. 
4. Adherence 
a. No formal statistical testing will be performed for adherence (assessed by 
participant treatment log information and self-reported adherence at Weeks 4, 12 
and 24). Data summaries are outlined in the AIP. 
5. Physical Function 
a. Chair Rise Rate (5 Rises and 10 Rises) 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). 
ii. Absolute changes from Week 24 to 48 will only use analysis a) from 6.1. 
b. Gait Speed 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). 
ii. Absolute changes from Week 24 to 48 will only use analysis a) from 6.1. 
c. Presence of Slow Gait Speed 
i. The prevalence of slow gait speed at Weeks 0 and 24 will use the 
analysis approaches outline for Metabolic Syndrome above. 
ii. Using the PP population, the prevalence of slow gait speed at Weeks 0 
and 24 will be estimated by a GEE model for binary data without an 
intercept term. Each participant will have up to two slow gait speed 
outcomes (Yes/No) from Weeks 0 and 24. Study arm and time (study 
visit) will be the only covariates in the model.  
1. This analysis will be repeated with Week 0, 24 and 48 data. 
iii. The above analysis (i) will be repeated using the modified ITT 
population. 
1. This analysis will be repeated with Week 0, 24 and 48 data. 
6. Muscle and Fat 
a. Total Psoas Muscle Fat Percent 


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i. Absolute changes from Pre-Entry to Week 24 will use the analysis 
approaches outlined in 6.1 for IHTG (%). 
ii. Percent changes from Pre-Entry to Week 24 will use the analysis 
approaches outlined in 6.1 for IHTG (%). 
iii. Using the PP population, absolute changes from Pre-Entry to Week 24 
will be correlated with both absolute and percent change from Pre-Entry 
to Week 24 in IHTG (%) as well as absolute change from Week 0 to 24 
in BMI, body weight, minimum WC, HOMA-IR, HbA1c, glucose and 
lipids. 
b. Total Psoas Muscle Volume 
i. Absolute changes from Pre-Entry to Week 24 will use the analysis 
approaches outlined in 6.1 for IHTG (%). 
ii. Percent changes from Pre-Entry to Week 24 will use the analysis 
approaches outlined in 6.1 for IHTG (%). 
c. VAT Volume and SAT Volume 
i. Absolute changes from Pre-Entry to Week 24 will use the analysis 
approaches outlined in 6.1 for IHTG (%). 
ii. Using the PP population, absolute changes from Pre-Entry to Week 24 
will be correlated with both absolute and percent change from Pre-Entry 
to Week 24 in IHTG (%) as well as absolute change from Week 0 to 24 
in BMI, body weight, minimum WC, HOMA-IR, HbA1c, glucose and 
lipids. 
7. Quality of Life 
a. General Health 
i. Responses will be scored (Excellent=5, Very Good=4, Good=3, Fair=2, 
Poor=1) at Weeks 0 and 24. Using the mITT population, the distribution 
of self-reported general health will be compared between Week 0 and 
Week 24 by calculating the absolute change and applying the Wilcoxon 
Signed Rank test. 
b. Poor Physical Health, Poor Mental Health and Impairment 
i. Using the mITT population, the average absolute change in self-reported 
days with each condition from Week 0 to 24 will be estimated by a linear 
regression model without an intercept term. Each participant will have a 
single outcome measure of absolute change from Week 0 to 24. Study 
arm will be the only covariate in the model.  
8. Inflammatory Biomarkers 
a. sCD14, IL-6, sCD163, CRP, IP-10, MCP-1 and CD40L 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). Absolute changes in these outcomes from 
Week 0 to 12 will only use analysis a) from 6.1.  
ii. Absolute changes in these outcomes from Week 24 to 48 will only use 
analysis a) from 6.1. 
9. Adipocytokine Levels 
a. Adiponectin and GLP-1 


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i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). Absolute changes in these outcomes from 
Week 0 to 12 will only use analysis a) from 6.1.  
ii. Absolute changes in these outcomes from Week 24 to 48 will only use 
analysis a) from 6.1. 
10. Immune Cell Profiles 
a. Activated (HLA-DR+/CD38+) CD4+ and CD8+ T lymphocytes; Monocyte 
(CD14/CD16/CCR2/CX3CR1/CD36/CD11c) subsets; Invariant natural killer 
(6B11/CD69) and mucosal associated invariant (Vα7.2/CD161) T lymphocytes 
i. Absolute changes from Week 0 to 24 will use the analysis approaches 
outlined in 6.1 for IHTG (%). 
 
7 
Report Contents 
The following elements will be included in the primary analysis report or secondary analysis 
report, as noted. Detailed descriptions of these elements are provided in the AIP. 
1. Study History (primary and secondary analysis reports) 
2. Screen Failures (primary analysis report) 
3. Accrual (primary analysis report) 
4. Eligibility Violations (primary and secondary analysis reports) 
5. Study Status (primary and secondary analysis reports; reported to ClinicalTrials.gov) 
6. Treatment Status (primary analysis report; reported to ClinicalTrials.gov) 
7. ART Adherence (primary and secondary analysis reports) 
8. Treatment Adherence (primary analysis report) 
9. Concomitant Medication Use (primary and secondary analysis reports) 
10. Prohibited Medication Use (primary and secondary analysis reports) 
11. Deaths (primary and secondary analysis reports) 
12. Pregnancies (primary and secondary analysis reports) 
13. Baseline Characteristics (primary analysis report; reported to ClinicalTrials.gov) 
14. Adverse Events (primary [through Week 24] and secondary [all follow-up] analysis 
reports; reported to ClinicalTrials.gov) 
15. Targeted Clinical Events (primary [through Week 24] and secondary [all follow-up] 
analysis reports) 
16. IHTG (%) Summaries and Analyses (primary analysis report; reported to 
ClinicalTrials.gov) 
17. BMI, Body Weight and Minimum Weight Circumference Summaries and Analyses 
(primary [through Week 24; reported to ClinicalTrials.gov] and secondary [Week 24 to 48] 
analysis reports) 
18. HOMA-IR, HbA1c and Glucose Summaries and Analyses (primary analysis report; 
reported to ClinicalTrials.gov) 
19. Lipid Summaries and Analyses (primary analysis report; reported to ClinicalTrials.gov) 


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20. Metabolic Syndrome Summaries and Analyses (secondary analysis report) 
21. Physical Function Summaries and Analyses (primary [through Week 24] and secondary 
[Week 24 to 48] analysis reports) 
22. Muscle and Fat Summaries and Analyses (primary analysis report [psoas muscle fat and 
volume] and secondary analysis report [VAT and SAT]) 
23. Quality of Life Summaries and Analyses (secondary analysis report) 
24. Inflammatory Biomarker Summaries and Analyses (secondary analysis report) 
25. Adipocytokine Summaries and Analyses (secondary analysis report) 
26. Immune Cell Profile Summaries and Analyses (secondary analysis report)