Clinical trial NCT05630885
Conditions: HIV-1-infection Elevated Cardiovascular Risk
Keywords: HIV Vascular Inflammation
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2023-05-30; Completion date: 2024-06-19
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was conducted to determine if cenicriviroc mesylate (CVC) would decrease vascular inflammation as measured by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging of the aorta and carotid arteries.

Detailed description:
This was a double-blind, placebo-controlled phase II clinical trial comparing the intervention of CVC versus placebo for a duration of 24 weeks on arterial inflammation evaluated by FDG-PET/CT imaging.

A total of 110 participants were randomized 2:1 to the CVC arm (Arm A) or placebo for CVC arm (Arm B). Stratification by statin use at randomization ensured even distribution of statin use between the treatment groups.

Analyses were based on the efficacy population: all enrolled participants who completed at least 22 weeks of study treatment and remained on the same ART drug class throughout the study without use of prohibited medications.

Analysis of the primary outcome utilized multiple imputation by regression to impute missing data.

Arms: arm 1: Participants with pre-existing ART regimen of efavirenz (EFV) took CVC 300 mg. Participants with all other pre-existing ART regimens took CVC 150 mg. arm 2: Participants with pre-existing ART regimen of efavirenz (EFV) took placebo for CVC 300 mg. Participants with all other pre-existing ART regimens took placebo for CVC 150 mg.
Interventions: intervention 1: CVC 150 mg intervention 2: CVC 300 mg intervention 3: Placebo for CVC 150 mg intervention 4: Placebo for CVC 300 mg
Intervention descriptions: intervention 1: Administered as one 150-mg tablet by mouth once a day with food. intervention 2: Administered as two 150-mg tablets by mouth once a day with food. intervention 3: Administered as one 150-mg matching placebo tablets by mouth once a day with food. intervention 4: Administered as two 150-mg matching placebo tablets by mouth once a day with food.

Protocol documents:
Prot_ICF_000.pdf: 
 
A5415 
 
 
A Limited-Center, Prospective, Double-Blind, Placebo-Controlled Study to 
Evaluate the Effects of Cenicriviroc Mesylate on Arterial Inflammation in People 
Living with HIV 
 
 
A Limited-Center Trial of the ACTG (Advancing Clinical Therapeutics Globally for 
HIV/AIDS and Other Infections) 
 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
 
AbbVie 
 
 
 
IND #163626 
 
 
 
The ACTG Comorbidities 
Transformative Science Group: 
Netanya Utay, MD, Chair 
 
Protocol Chair: 
Janet Lo, MD, MMSc 
 
Protocol Vice Chairs: 
Judith S. Currier, MD 
 
Ahmed Tawakol, MD 
 
DAIDS Clinical Representative: 
Beverly Alston-Smith, MD 
 
Clinical Trials Specialist: 
Jhoanna C. Roa, MD 
 
 
FINAL Version 2.0 
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A5415 
FINAL Version 2.0 
22Mar2024 
 
 
A Limited-Center, Prospective, Double-Blind, Placebo-Controlled Study to Evaluate the Effects 
of Cenicriviroc Mesylate on Arterial Inflammation in People Living with HIV 
 
SIGNATURE PAGE 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 
 
 
 


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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 ................................................................... 16 
1.1 
Hypothesis ......................................................................................................... 16 
1.2 
Primary Objective ............................................................................................... 16 
1.3 
Secondary Objectives ........................................................................................ 16 
1.4 
Exploratory Objectives ....................................................................................... 16 
2.0 
INTRODUCTION ........................................................................................................... 17 
2.1 
Background and Rationale ................................................................................. 17 
3.0 
STUDY DESIGN ........................................................................................................... 30 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 31 
4.1 
Inclusion Criteria ................................................................................................ 31 
4.2 
Exclusion Criteria ............................................................................................... 34 
4.3 
Study Enrollment Procedures............................................................................. 36 
4.4 
Coenrollment Guidelines .................................................................................... 38 
5.0 
STUDY TREATMENT ................................................................................................... 38 
5.1 
Regimens, Administration, and Duration ............................................................ 38 
5.2 
Study Product Formulation and Preparation ....................................................... 39 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 39 
5.4 
Concomitant Medications ................................................................................... 39 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 44 
6.1 
Schedule of Evaluations..................................................................................... 44 
6.2 
Timing of Evaluations ......................................................................................... 47 
6.3 
Instructions for Evaluations ................................................................................ 50 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 59 
7.1 
Definition of Adverse Events .............................................................................. 59 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 59 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 60 
7.4 
Study Monitoring ................................................................................................ 61 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 61 
8.1 
Toxicity .............................................................................................................. 61 
8.2 
Specific Management of Toxicities Related to Study-Provided Treatment .......... 63 
8.3 
Adverse Event Related to FDG-PET/CT Imaging ............................................... 65 


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CONTENTS (Cont’d) 
Page 
 
 
8.4 
FDG-PET/CT Imaging Findings ......................................................................... 65 
8.5 
Pregnancy.......................................................................................................... 65 
8.6 
Breastfeeding ..................................................................................................... 66 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 66 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 66 
9.2 
Premature Study Discontinuation ....................................................................... 66 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 67 
10.1 
General Design Issues ....................................................................................... 67 
10.2 
Outcome Measures ............................................................................................ 67 
10.3 
Randomization and Stratification ........................................................................ 68 
10.4 
Sample Size and Accrual ................................................................................... 69 
10.5 
Data and Safety Monitoring ................................................................................ 70 
10.6 
Analyses ............................................................................................................ 70 
10.7 
Unblinding .......................................................................................................... 71 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 72 
11.1 
Pharmacology Objectives .................................................................................. 72 
11.2 
Pharmacology Study Design .............................................................................. 72 
11.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 73 
11.4 
Anticipated Outcomes ........................................................................................ 74 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 74 
12.1 
Records to Be Kept ............................................................................................ 74 
12.2 
Role of Data Management ................................................................................. 74 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 74 
12.4 
Reporting Protocol Deviations ............................................................................ 74 
13.0 
PARTICIPANTS ............................................................................................................ 75 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 75 
13.2 
Participant Confidentiality ................................................................................... 75 
13.3 
Study Discontinuation ........................................................................................ 75 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 75 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 75 
16.0 
REFERENCES .............................................................................................................. 77 
APPENDIX I: RESULTS OF CENICRIVIROC MESYLATE (CVC) STUDIES ............................ 80 
INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION ........................................................................ 94 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION .......... 113 
ATTACHMENT A: OPTIONAL CONSENT FOR USE OF SAMPLES IN OTHER 
STUDIES ..................................................................................................................... 115 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5415 is a limited-center study open to US and non-US ACTG clinical research sites (CRSs) 
with the capacity to perform the 18F-fluorodeoxyglucose (FDG)-positron emission tomography 
(PET)/computed tomography (CT) imaging. 
 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Janet Lo, MD, MMSc 
Massachusetts General Hospital LON-207 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-3425 
Email: jlo@mgh.harvard.edu 
 
Vice Chairs 
Judith S. Currier, MD 
University of California at Los Angeles 
Division of Infectious Diseases 
Clinical AIDS Research and Education 
(CARE) Center 
911 Broxton Avenue 
Los Angeles, CA 90024 
Phone: 310-825-6689 
Email: JSCurrier@mednet.ucla.edu 
 
Ahmed Tawakol, MD 
Massachusetts General Hospital 
Cardiovascular Imaging, Suite 400 
165 Cambridge Street 
Boston, MA 02114 
Phone: 617-726-0791 
Email: atawakol@mgh.harvard.edu 
 
DAIDS Clinical Representative 
Beverly Alston-Smith, MD 
DAIDS/NIAID/NIH 
Complications and Co-Infections 
Research Branch 
5601 Fishers Lane, Room 9F50 
Rockville, MD 20852 
Phone: 301-435-3773 
Email: balston@niaid.nih.gov 
 
Clinical Trials Specialist 
Jhoanna C. Roa, MD 
ACTG Network Coordinating Center 
DLH 
6720B Rockledge Drive, Suite 777 
Bethesda, MD 20817 
Phone: 301-628-3196 
Email: jhoanna.roa@dlhcorp.com 
Statisticians 
Heather J. Ribaudo, PhD 
Harvard TH Chan School of Public Health 
FXB Building, Room 519 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-2897 
Email: ribaudo@sdac.harvard.edu 
 
Kevin Wongsodirdjo 
Harvard TH Chan School of Public Health 
FXB Building, Room 535 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-2424 
Email: kwongsod@sdac.harvard.edu 
 
Data Managers 
Kristine Coughlin, BA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7239 
Email: coughlin@frontierscience.org 
 
Jenna Meldrum, BA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
Email: meldrum@frontierscience.org 
 
Anna Yoder, MS 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 
Email: yoder@frontierscience.org 
 


 
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PROTOCOL TEAM ROSTER (Cont’d) 
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DAIDS Pharmacist 
Oladapo Alli, PharmD 
Pharmaceutical Affairs Branch 
Division of AIDS/OCSO/NIAID/NIH 
5601 Fishers Lane 
Room Hoteling MSC 9831 
Rockville, MD 20852 
Phone: 240-627-3593 
Email: oladapo.alli@nih.gov 
 
Immunologist 
Michael Lederman, MD 
Case Western Reserve University CRS 
The Foley Building, Room 401-A 
2061 Cornell Road 
Cleveland, OH 44106-5083 
Phone: 216-844-8786 
Email: MXL6@case.edu 
 
Virologist 
Daniel R. Kuritzkes, MD 
Brigham and Women’s Hospital 
Therapeutics CRS 
Section of Retroviral Therapeutics 
Harvard Medical School 
65 Landsdowne Street, Room 447 
Cambridge, MA 02139 
Phone: 617-768-8371 
Email: dkuritzkes@partners.org 
 
Pharmacologist 
Amelia Deitchman, PharmD, PhD 
University of California, San Francisco 
HIV/AIDS CRS 
UCSF Drug Research Unit Lab 192 
1001 Potrero Avenue 
Building 100, Room 157 
San Francisco, CA 94110 
Phone: 415-476-1148 
Email: amelia.deitchman@ucsf.edu 
 
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 
Email: anchalee.a@hivnat.org 
 
Noel Kayange, MBBS, MMED 
Blantyre CRS 
Johns Hopkins Research Project 
Chiptala Avenue 
P.O. Box 1131 
Blantyre 25, MALAWI 
Phone: 265-1874885 
Email: noelkay@yahoo.co.uk 
 
Jordan E. Lake, MD, MSc 
McGovern Medical School 
UT Health Science Center at Houston 
6431 Fannin Street, MSB 2.112 
Houston, TX 77057 
Phone: 713-500-6759 
Email: Jordan.E.Lake@uth.tmc.edu 
 
Field Representative 
Sofia Lupo, MD 
Houston AIDS Research Team CRS (31473) 
6431 Fannin Street 
Houston, TX 77030 
Phone: 713-500-6718 
Email: sofia.lupo@uth.tmc.edu 
 
Laboratory Technologist 
Brian Clagett, BA 
Case CRS 
BRB, Room 1048A, 2109 Adelbert Road 
Cleveland, OH 44106 
Phone: 216-368-4853 
E-mail: bmc@case.edu 
 


 
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Community Scientific Subcommittee (CSS) 
Representative 
Lionel Hillard 
Trinity Health and Wellness Center CRS 
219 Sunset Avenue, Suite 116A 
Dallas, TX 75208 
Phone: 972-632-9124 
Email: hillardlionel@gmail.com 
 
Laboratory Data Manager 
David Vlieg, BA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 Ext. 7333 
Email: vlieg@frontierscience.org 
 
Laboratory Specialists 
Emma Duffy 
ACTG Laboratory Center at UCLA 
IMPAACT Laboratory Center 
University of California Los Angeles 
10990 Wilshire Boulevard, Suite 260 
Los Angeles, CA 90024 
Phone: 617-407-8713 
Email: eduffy@milabcentral.org 
 
Kathie Ferbas, PhD 
ACTG Laboratory Center at UCLA 
University of California, Los Angeles 
675 Charles E. Young Drive South 
MacDonald Research Laboratory 
(MRL), 4-629 310 825 7708 
Los Angeles CA 90095 
Phone: 310-780-3639 
E-mail: kferbas@milabcentral.org 
 
Source Document Specialist 
Josie M. Marshall, BS 
ACTG Network Coordinating Center 
DLH 
6720B Rockledge Drive, Suite 777 
Bethesda, MD 20817 
Phone: 303-724-0803 
Email: josie.marshall@dlhcorp.com 
 
Industry Representative 
Patrick Dorr, PhD 
Scientific Director 
Precision Medicine - Specialty 
AbbVie R & D 
Abbott Park, 1 N. Waukegan Road 
North Chicago, IL 60064 
Phone: +447818428106 
Email: patrick.dorr@abbvie.com 
 
Network Coordinating Center (NCC) 
Project Managers 
Bridget Makhlouf, MS 
ACTG Network Coordinating Center 
4505 Emperor Blvd. Suite 400 
Durham, NC 27703 
Phone: 919-287-4549 
Email: bridget.makhlouf@dlhcorp.com 
 
Sara McCurdy Murphy, BA 
ACTG Network Coordinating Center 
DLH 
6720B Rockledge Drive, Suite 777 
Bethesda, MD 20817 
Phone: 301-628-3464 
Email: sara.mccurdy@dlhcorp.com 
 
 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5415@fstrf.org via 
email. The appropriate team member will generally respond within 1 working day. 
 
When sending messages to individual team members by role (e.g., Protocol Data 
Manager, Clinical Trials Specialist), sites should check the current roster on the ACTG 
Member Website. 
 
Protocol Email 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.protA5415 email group. 
Include the protocol number in the email subject line. 
• 
Send an email message to actg.user.support@fstrf.org. 
 
In order to remove site personnel from the actg.protoA5415 email group, contact the 
User Support Group at the DMC. Include the protocol number in the email subject line. 
• 
Send an email message to actg.user.support@fstrf.org. 
 
Clinical Management 
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the Clinical Management Committee (CMC). 
• 
Send an email message to actg.cmcA5415@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to laboratory element of the study (e.g., immunology, 
pharmacology, virology), contact the protocol team. 
• 
Send an email message to actg.teamA5415@fstrf.org (ATTN: Michael Lederman / Daniel 
Kuritzkes / Amelia Deitchman). 
• 
Include the study number and “laboratory question” in the email subject line. 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
study’s protocol data manager. Electronic CRFs (eCRFs) completion guidelines and 
participant completed CRFs can be downloaded from the Frontier Science & Technology 
Research Foundation (FSTRF) website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP 119, and contact Kristine 
Coughlin and Jenna Meldrum directly. 
• 
For other questions, send an email message to actg.teamA5415@fstrf.org (ATTN: Kristine 
Coughlin, Jenna Meldrum and Anna Yoder). 
• 
Include the protocol number, PID, and “Data Management Question” in the subject line. 
 


 
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DMC Portal and Medidata Rave Problems 
Contact DMC User Support: 
• 
Send an email message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
Randomization 
For randomization questions or problems and study identification number SID lists, contact the 
Randomization Desk at the Frontier Science Data Management Center (DMC). 
• 
Send an email message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900 x7301. 
 
DMC Portal and Medidata Rave Problems 
For questions about the DMC portal or Medidata Rave, contact DMC User Support. 
• 
Send an email message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. 
• 
Send an email message to actg.teamA5415@fstrf.org (ATTN: Jhoanna Roa). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@dlhcorp.com. Electronic 
copies can be downloaded from the protocol-specific web page (PSWP) on the ACTG 
Member Website (https://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, contact DAIDS Protocol Registration. 
• 
Send an email message to Protocol@tech-res.com or call 301-897-1707. 
 
Protocol Activation 
For questions related to protocol activation at US sites, contact the Clinical Trials Specialist 
(CTS). 
• 
Send an email message to the study’s CTS with a cc to actg.teamA5415@fstrf.org. 
 
For questions related to protocol activation at non-US sites, contact the ACTG Site Coordination 
Group. 
• 
Send an email message to actgsitecoordination@dlhcorp.com with a cc to the study’s 
CTS. 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Dapo Alli, Protocol Pharmacist, at 301-761-7269. 
 


 
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Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741 between 
8 AM and 5 PM Eastern Time (ET). Outside of this timeframe, sites may use other 
contact information found in the CRPMC Online Site Management and Ordering System 
(COSMOS). 
 
IND (Investigational New Drug) Number or Questions 
The IND number will be available on the PSWP approximately 30 days after the submission of 
the final protocol version to the FDA. 
 
For any questions related to the IND submission, contact the DAIDS RSC. 
• 
Send an email message to Regulatory@tech-res.com 
or 
• 
Call 1-800-537-9979 or 301-897-1709 
or 
• 
Fax 1-800-275-7619 or 301-897-1710. 
 
Expedited Adverse Event (EAE) Reporting/Questions 
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710. 
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5415 team members. 
• 
Send an email to actg.teamA5415@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the PSWP on the 
ACTG Member Website. 
 
 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ADR/ADRs 
adverse drug reaction/adverse drug reactions 
ALT 
alanine aminotransferase 
APRI 
AST to Platelet Ratio Index 
AST 
aspartate aminotransferase 
CAC 
coronary artery calcification 
CAD 
coronary artery disease 
CCL2/CCL3/CCL4 
chemokine ligand 2/chemokine ligand 3/chemokine ligand 4 
CCR2/CCR5/CCR7 
chemokine receptor 2/chemokine receptor 5/chemokine receptor 7 
CKD-Epi 
Chronic Kidney Disease Epidemiology Collaboration 
CMC 
Clinical Management Committee 
COBI 
cobicistat 
CPK 
creatine phosphokinase 
CT 
computed tomography 
CVC 
cenicriviroc mesylate 
CVD 
cardiovascular disease 
DILI 
drug-induced liver injury 
DM 
diabetes mellitus 
FDG-PET 
18F-fluorodeoxyglucose-positron emission tomography 
FIB-4 
Fibrosis-4 
GFR 
glomerular filtration rate 
HLA-DR 
human leukocyte antigen-DR 
HOMA-IR 
homeostasis model assessment-estimated insulin resistance 
hsCRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IL-6/hsIL-6 
interleukin-6/high sensitivity interleukin 6 
INR 
international normalized ratio 
INSTI 
integrase strand transfer inhibitor 
IUD 
intrauterine device 
MCP-1 
monocyte chemoattractant protein-1 
MDS 
most diseased segment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
mSv 
milliSieverts 


 
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NASH 
non-alcoholic steatohepatitis 
PPI 
proton pump inhibitor 
RTV 
ritonavir 
sCD14/sCD163 
soluble CD14/soluble CD163 
SUV 
standardized uptake value 
TBR 
target-to-background ratio 
TEAE/TEAEs 
treatment-emergent adverse event/treatment-emergent adverse 
events 
ULN 
upper limit of normal 
 
 


 
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SCHEMA 
 
A5415 
 
A Limited-Center, Prospective, Double-Blind, Placebo-Controlled Study to Evaluate the Effects 
of Cenicriviroc Mesylate on Arterial Inflammation in People Living with HIV 
 
 
DESIGN 
Double-blind, placebo-controlled phase II clinical trial comparing the 
intervention of cenicriviroc mesylate (CVC) versus placebo for arterial 
inflammation. 
 
DURATION 
Approximately 24 weeks 
 
SAMPLE SIZE 
Target Accrual= 93 participants 
(62 in the CVC arm [Arm A], 31 in the placebo for CVC arm [Arm B]) 
 
Actual Accrual= 110 participants 
 
On October 27, 2023, the study closed to screening, and participants 
who were in screening prior to that point were permitted to enroll if 
eligible. All screenings that were ongoing at the time of screening 
closure were completed on January 5, 2024, and the study closed to 
accrual. This resulted in over-enrollment of 110/93 participants. 
 
POPULATION 
Individuals living with HIV 
• 
≥45 years of age 
• 
On stable non-nucleoside reverse transcriptase inhibitor (NNRTI)-
based or unboosted integrase strand transfer inhibitor (INSTI)-based 
antiretroviral therapy (ART) regimen, defined as no within-class 
changes in ART regimen within 12 weeks prior to entry and no 
between-class changes for 24 weeks prior to entry 
• 
With suppressed HIV-1 RNA for ≥48 weeks prior to entry 
• 
With at least one of the following cardiovascular risk factors (current 
diagnosis or receiving treatment): 
o Clinical atherosclerotic disease 
o Subclinical atherosclerotic disease 
o Diabetes mellitus (DM) or prediabetes or impaired fasting glucose 
or insulin resistance 
o Obesity or enlarged iliac waist circumference 
o History of hypertension or blood pressure ≥130/80 mmHg 
o Elevated low-density lipoprotein (LDL) cholesterol 
o Low high-density lipoprotein (HDL) cholesterol 
o Smoking (any current tobacco smoking) 


 
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o Family history of premature coronary artery disease (CAD; first 
degree relative with CAD prior to age 55 for male relative and 65 
for female relative) 
o High sensitivity C-reactive protein (hsCRP) >2.0 mg/L 
 
STRATIFICATION 
Randomization will be stratified by current use of statins (defined as statin 
use within the past 90 days prior to study entry versus none) to ensure 
even distribution of statin use between the treatment arms. 
 
REGIMEN 
Participants will be randomized 2:1 to either the CVC arm (Arm A) or 
placebo for CVC arm (Arm B). CVC 150 mg or placebo for CVC by mouth 
once a day for at least 24 weeks will be added to the participants’ pre-
existing antiretroviral (ARV) regimens. 
 
For participants who are on an efavirenz (EFV)-based regimen, dosing 
will be 300 mg once a day. 
 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
Cenicriviroc mesylate (CVC) will decrease vascular inflammation as measured by 18F-
fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography 
(CT) imaging of the aorta. 
 
1.2 
Primary Objective 
 
To assess whether CVC treatment results in reduced arterial inflammation by comparing 
the changes in arterial target-to-background ratio (TBR) in the carotid arteries and aorta 
after treatment with CVC versus placebo. 
 
1.3 
Secondary Objectives 
 
1.3.1 To assess changes in metabolic parameters including fasting glucose, fasting 
insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), 
inflammatory markers including high sensitivity interleukin 6 (hsIL-6) and hsCRP, 
and markers of monocyte/macrophage activation including soluble CD14 
(sCD14), soluble CD163 (sCD163), and monocyte chemoattractant protein-1 
(MCP-1) after treatment with CVC compared to placebo. 
 
1.3.2 To assess changes in plasma chemokine receptor 5 (CCR5) and CCL2 
(previously known as MCP-1) levels (MIP-1α, MIP-1β and RANTES for CCR5; 
MCP-1 for CCR2) after treatment with CVC compared to placebo. 
 
1.3.3 To evaluate the safety of CVC in virally suppressed antiretroviral therapy (ART)-
treated, individuals living with HIV. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To measure the effects of CVC on adipocytokines including adiponectin and on 
noninvasive assessments of liver fibrosis, including AST to Platelet Ratio Index 
(APRI) and Fibrosis-4 (FIB-4). 
 
1.4.2 To assess changes in FDG uptake in visceral fat and to quantify changes in 
visceral adipose tissue area and volume, subcutaneous adipose tissue area and 
volume, fat density, and liver to spleen attenuation ratio (as a noninvasive 
measure of hepatosteatosis) by noncontrast CT, after treatment with CVC 
compared to placebo. 
 
1.4.3 To determine the association between CVC trough exposure and the primary 
treatment outcome (i.e., reduced arterial inflammation). 
 


 
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1.4.4 To evaluate the effects of CVC on markers of monocyte and T cell homing and 
activation as well as on myeloid cells. 
 
1.4.5 To assess changes in occupancy of the CCR5 and CCR2 receptors on T cells 
and monocytes after treatment with CVC compared to placebo. 
 
1.4.6 To evaluate the effects of CVC on fibrinogen and other coagulation markers. 
 
1.4.7 To evaluate potential drug interactions by a) investigating the impact of INSTI- 
and NNRTI-based ART on CVC trough estimates and to compare these 
estimates across regimens and b) investigating the impact of CVC treatment 
versus no treatment on the trough exposure of ART. 
 
2.0 
INTRODUCTION 
 
2.1 
Background and Rationale 
 
The incidence of cardiovascular disease (CVD) and mortality from CVD are increased 
among people living with HIV [1, 2, 3]. Traditional risk factors for atherosclerosis 
including dyslipidemia, diabetes mellitus, abdominal adiposity, and smoking are very 
common among people living with HIV. Furthermore, activation of the innate immune 
system and increased inflammation are likely to contribute to increased cardiovascular 
risk in individuals with chronic HIV [4]. Chemokines are important in the recruitment of 
leukocytes and their adhesion and migration, leading to the formation of atherosclerotic 
plaque [5]. CCR2 and CCR5 both are posited to have roles in the pathogenesis of 
atherosclerosis development [6, 7]. CVC is an orally active and potent inhibitor of CCR5 
that was previously being developed as a therapeutic agent for HIV. In addition to CCR5 
antagonistic activity, CVC is also a CCR2 antagonist. CVC was initially developed as an 
anti-HIV drug by Takeda and then Tobira, prior to acquisition by Allergan for 
investigation in liver disease, namely liver fibrosis with NASH. (Allergan subsequently 
acquired by AbbVie.) CVC displays potent, selective anti-HIV-1 activity via binding to 
CCR5 as a coreceptor of HIV-1 to prevent virus entry into the cell [8, 9]. CVC showed 
efficacy in treating HIV infection with HIV-suppressive activity at doses associated with a 
highly favorable safety profile as demonstrated in a comprehensive Phase 2b clinical 
study compared with the then standard of care (SoC) comparator efavirenz [8]. High-
level dual-receptor blockade was demonstrated as highlighted by the high levels of viral 
suppression (not achievable without complete CCR5 occupancy [10] and dose-
dependent increases of CCL2 [8]. Elevation of CD4 count was numerically greater in the 
CVC arms than SoC comparator arms (no statistical analysis reported), and the myeloid 
inflammatory marker sCD14 was reduced in the CVC arms, but elevated in the SoC 
arms, with this difference being statistically significant. Despite this encouraging profile 
as a direct-acting, antiviral candidate agent for HIV infection, it was not further developed 
as an HIV clinical candidate following its acquisition by Allergan, but investigated instead 
for potential therapy of NASH with liver fibrosis, due to the pharmacologies associated 
with CCR2 and CCR5 in this disease [11, 12]. In a Phase 2b study, CVC showed an 
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safety profiles between both CVC and placebo groups. It was also associated with 
reduced levels of markers of cardiovascular outcomes such as C-reactive protein and 
fibrinogen and biomarkers of inflammation such as IL-6 and IL-1β [13, 14]. Despite 
mechanistically associated evidence of efficacy, the AURORA Phase 3 study was 
terminated early due to lack of efficacy based on the results of the planned interim 
analysis of Part 1 data. Therefore, we propose to investigate the effects of CCR2 and 
CCR5 antagonism on arterial inflammation using CVC in a prospectively recruited cohort 
of individuals living with HIV on stable suppressive ART. We will further investigate the 
changes in insulin resistance, adipocytokines, altered adipose tissue distribution, 
monocyte activation, and chemokine receptor occupancy in response to CVC. 
 
Atherosclerosis is an inflammatory disease where immune mechanisms interact with 
metabolic factors [15-18]. Chronic HIV is associated with a state of systemic 
inflammation and immune activation. HIV causes alterations in the monocyte repertoire 
[19] with expansion of the CD14+CD16+ monocyte subset. Tilton and colleagues found 
individuals living with HIV, with or without ART, have elevated monocyte production of 
inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), 
and IL-6 when compared to findings among controls without HIV, and that individuals 
living with HIV on ART with effective viral suppression still have markedly elevated 
frequency of monocytes producing inflammatory cytokines [20]. We propose a 
physiologic interventional study using CVC, a CCR5 and CCR2 inhibitor, to investigate 
its effects on arterial inflammation as well as its immunomodulatory effects on monocyte 
activation in individuals living with HIV. 
 
The ligand for CCR2, MCP-1, is important in monocyte migration into the vascular intima 
during the development of atherogenesis [21]. Participants living with HIV with MCP-1 
2518G allele were found to have an associated 5-fold increased risk for atherosclerosis, and 
individuals with atherosclerosis had higher plasma concentrations of MCP-1 than individuals 
without atherosclerosis [22]. This same polymorphism has also been associated with 
severity of coronary artery disease (CAD) in individuals without HIV [23]. Prior reports have 
suggested that the HIV-1 Tat protein, an early viral protein critical in HIV-1 replication, may 
promote MCP-1 secretion, leading to increased transmigration of monocytes across the 
vascular endothelium [24] and may cause endothelial dysfunction in porcine coronary 
arteries [25]; however, the clinical implication of these published data is not fully clear, as 
monocyte infection with HIV is rare and we do not yet have evidence of Tat protein being 
present in abundance in extracellular space to stimulate monocytes. MCP-1’s receptor, 
CCR2, is also one of the co-receptors that could be used by HIV to enter CD4 lymphocytes 
[26]. Polymorphisms of CCR2 have been associated with increased risk of acute coronary 
events and interestingly, polymorphisms in CCR2 have also been associated with 
differences in HIV disease progression [27-35]. Signaling via CCR2 and CCR5 also drives 
recruitment of myeloid-derived suppressor cells, which are profoundly immune-suppressive, 
elevated in HIV+ and in acute coronary syndrome [33-35]. 
 


 
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Figure 2.1-1: Relationship between CVC levels and MCP-1 concentrations. 
 
MCP-1 is a chemokine that is produced by adipocytes and is overexpressed in obesity 
and hyperinsulinemic states [36]. In mice with obesity, treatment with an antagonist of 
CCR2 reduced adipose tissue macrophage content and improved insulin sensitivity [37]. 
As visceral obesity and insulin resistance is highly prevalent in individuals living with HIV 
on chronic ART treatment, the potential beneficial effects of blocking MCP-1 actions at 
the CCR2 receptor in ameliorating insulin resistance and visceral adiposity as well as 
decreasing inflammation within visceral adipose tissue will also be investigated in this 
study. In a clinical study conducted by Allergan, plc. (Study 202), higher CVC plasma 
concentration levels were associated with greater increases from baseline to week 48 in 
bound plasma MCP-1 levels, suggesting concentration-dependent CCR2 blockade by 
CVC. Using peripheral blood mononuclear cells from participants treated with CVC, T 
cells from these participants were unable to bind MCP-1, indicating receptor occupancy 
(unpublished data from A5415 Protocol Immunologist, Dr. Michael Lederman). 
 
To investigate the effects of CVC on arterial inflammation, we propose to use FDG-PET. 
In contrast to imaging approaches that assess structural components of atherosclerosis, 
FDG-PET allows functional imaging of macrophage activity in vivo. FDG competes with 
glucose for uptake into metabolically active cells, including macrophages in 
atherosclerotic plaques, and is trapped inside cells after phosphorylation. FDG-PET can 
image metabolic activity (as a marker of plaque inflammation) quantitatively in 
atherosclerotic plaques [38, 39], has been shown to have high reproducibility [40], and 
correlates with histologic macrophage accumulation [39]. Macrophages play a key role in 
plaque destabilization and thrombus formation [41], thus, measurement of its activity 
may help to identify risk for cardiovascular events [13]. Furthermore, individuals living 
with HIV have been shown to have increased FDG uptake in the aorta compared to 
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sCD163, a marker of monocyte/macrophage activation [14] among individuals living with 
HIV. FDG-PET can also be used to image macrophage activity within adipose tissue 
depots [42]. Preliminary data from a clinical trial investigating effects of statin therapy on 
arterial inflammation at Massachusetts General Hospital (MGH) in participants living with 
chronic HIV on ART demonstrate that 49 out of 50 (98%) participants living with HIV 
have aortic target-to-background ratio (TBR) >1.6 and 46 out of 50 (92%) have TBR 
>1.8 at baseline prior to randomization. Thus, a very significant proportion of persons 
living with chronic HIV have a high degree of vascular inflammation. TBR ≥1.6 has 
previously been considered to define inflamed and active atheroma [39, 42]. 
 
Monocyte subpopulations will be characterized by expression of CD14 and CD16 as 
described previously [43]. Within each population, expression of the CVC binding 
chemokine receptors, CCR5 and CCR2, will be examined, as will their occupancy by 
CVC. In each monocyte subpopulation, we will also monitor the expression of the 
fractalkine binding receptor CX3CR1 that promotes binding to endothelial fractalkine. 
Monocyte activation will be monitored by measuring density of human leukocyte antigen-
DR (HLA-DR) and CD69. Further characterizations of the myeloid population may be 
undertaken with collected or archived frozen samples to include investigation into MDSC 
population effects. MDSCs are classified as CD14+HLA-DR-/lo, in contrast to the 
monocyte subsets, which are HLA-DR+, and are increased in the blood of patients with 
acute coronary syndrome [33]. 
 
Lymphocyte populations (CD4+ and CD8+ T cells, B cells, and NK [natural killer] cell 
numbers) will also be monitored by flow cytometry as will T cell maturation subsets 
(determined by expression of CCR7 and CD45RA). In these populations, the expression of 
the CVC-binding chemokine receptors CCR5 and CCR2 will be monitored. Among the 
circulating CD4+ and CD8+ T cells, occupancy of these receptors by CVC will be monitored 
by assays we have developed that identify occupied receptors that are recognized by their 
inability to bind CCR5 ligands (RANTES analogues) and CCL2 that each block binding of 
co-receptor binding monoclonal antibodies. An effect of CVC on T cell activation will be 
explored by monitoring expression of CD38 and HLA-DR on T cell maturation subsets and 
on T cell subsets that express CCR5 and CCR2. 
 
Rationale for 150 mg Dose 
CVC is a well-tolerated oral formulation with most adverse events considered mild or 
moderate; the most common side effects reported are nausea, headache, and diarrhea 
[14, 40]. CVC should be administered with food for optimal absorption. There were no 
major safety signals in over 2,000 patients exposed to CVC, including vulnerable patient 
populations, such as patients with HIV-1 or patients with liver cirrhosis, in CVC clinical 
trials. Optimal responses on CCR2 blockade (as evidenced by increase in MCP-1 
[chemokine ligand 2 {CCL2}] level) were seen with a 150 mg dose of CVC in Phase IIa 
study (Study 652-2-201) in participants living with HIV [44]. Furthermore, in participants 
with nonalcoholic steatohepatitis (NASH), CVC at a 150 mg dose significantly increased 
MCP-1 (CCL2), CCL3, and CCL4 (consistent with CCR2 and CCR5 blockade), and 
reduced sCD14, IL-6, hsCRP, and fibrinogen compared to placebo [45]. Due to the 
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dose could be effective in reducing arterial inflammation, which is reflective of macrophage 
infiltration and metabolism in the arterial wall. 
 
Furthermore, this dose (150 mg) was evaluated in the CENTAUR (phase 2) and 
AURORA (Phase 3) studies (Study 652-2-203 and 3152-301-002, respectively) and 
selected based on the clinical activity, pharmacokinetics (PK), pharmacodynamics (PD), 
and safety data from prior studies (652-1-110, 652-1-111, 652-120, 652-1-121, 652-1-
122, 652-123, 652-124, 652-2-202, and 652-2-201), which together support: 
• 
Evidence of meaningful clinical efficacy of CVC 150 mg in participants with NASH 
and liver fibrosis in the CENTAUR study (Study 652-2-203) 
• 
Evidence that CVC 150 mg is safe and well tolerated in participants with NASH and 
liver fibrosis in the CENTAUR study (Study 652-2-203) 
• 
CVC dose of 150 mg provides an expectation of effective primary pharmacology (i.e., 
CCR2 and CCR5 antagonism) 
• 
Evidence of improvement in systemic inflammation biomarkers support underlying 
CVC pharmacology 
 
In CENTAUR, the CVC dose of 150 mg daily exposed >77% of participants to minimum 
plasma concentration (Cmin) values that exceed the ECmin50 (Cmin associated with 
half-maximal response; using most conservative ECmin50 of 50 ng/mL, based on data 
from the HIV Phase II program), providing an expectation of substantial and near 
maximal antagonism of CCR2/CCR5 in most participants at this dose. When using the 
ECmin50 of 40 ng/mL, which was based on changes in CCL2 and CCL4 levels (i.e., 
reciprocal increases in CCL2 and CCL4 levels observed due to effective CCR2 and 
CCR5 blockade by CVC) observed in the CENTAUR study, >84% of CVC-treated 
participants achieved this target drug concentration. Results from a drug interaction 
study (Study 652-123) have shown that administration of a proton pump inhibitor (PPI) 
90 minutes prior to CVC, dosed at 150 mg, resulted in significantly decreased CVC 
concentrations. In the CENTAUR study, PPIs were allowed with specific dosing 
instructions (i.e., dosing of PPIs at least 2 hours after CVC 150 mg daily dose) and were 
used in 44% of all participants. Although fewer participants achieved an ECmin50 of 40 
ng/mL when using PPIs (84.5%) compared to those who did not (94.3%), a similar 
proportion of participants in both groups achieved the key efficacy endpoint of 
improvement in fibrosis by at least 1 stage and no worsening of steatohepatitis: 21.0% 
for PPI users versus 25.0% for nonusers, respectively (mITT). Therefore, the dose of 
150 mg appears sufficient when managing coadministration of CVC with commonly used 
concomitant medications, such as PPIs. Taken together, prior PK/PD analyses further 
support that the CVC 150 mg dose was able to maximize CCR2/CCR5 blockade in most 
participants and support its evaluation in the current study. 
 
This is also supported by data from the Phase 3, two-part AURORA study (3152-301-
002), which aimed to confirm the antifibrotic benefit of CVC as compared with placebo in 
adults with NASH and Stage 2 or 3 fibrosis. Part 1 of the study was designed to 
demonstrate the superiority of CVC compared with placebo on liver histology at Month 
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NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system), as confirmed by an 
independent central pathologist. Part 1 assessed the proportion of participants with 
improvement in fibrosis by at least 1 stage (NASH CRN system), and no worsening of 
steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning grade) 
on liver histology at Month 12 relative to the screening biopsy. Upon interim analysis of 
the data from Part 1 completion, the study was terminated early, as no meaningful 
numerical or statistical difference was observed between CVC 150 mg once daily and 
placebo, with respect to the key efficacy endpoints regarding liver histology at Month 12 
relative to the screening biopsy in adult participants with a liver biopsy diagnosis of 
NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system). CVC 150 mg once daily 
was, in general, well tolerated in this study, and there were no treatment-related TEAEs 
that were fatal or life-threatening. 
 
Allergan also conducted a Phase 2 clinical study “Rollover” (3152-201-002) to provide 
open-label treatment and to assess the long-term safety of continued treatment with 
CVC for eligible participants who have previously participated in CVC studies 
(CENTAUR 652-2-203 and AURORA 3152-301-002). Following the analysis of the data 
from Part 1 of the AURORA study, the sponsor decided not to develop this product 
further for the treatment of NASH due to not achieving the primary efficacy endpoint, and 
the AURORA and Rollover studies were prematurely terminated. The CVC program was 
not terminated due to safety concerns. CVC 150 mg once daily was well tolerated in this 
study. No clinically significant safety information was identified. In overall terms coupling 
the mechanistic data generated and safety profile, the totality of information further 
support that the CVC 150 mg dose was able to maximize CCR2/CCR5 blockade in most 
participants and support its evaluation in the current study. 
 
Rationale for CVC Dose with ART Regimen 
Clinical drug-drug interaction studies have been performed by Allergan, plc, in healthy 
adult volunteers. To summarize, CVC exposure was increased when co-administered 
with protease inhibitors (ritonavir [RTV], darunavir/ritonavir [DRV/r], or 
atazanavir/ritonavir [ATV/r]). Although the PK profile of CVC in combination with 
cobicistat (COBI) has not been studied, it is assumed that there will be significant 
increase in CVC concentration when co-administered with regimens boosted with COBI 
since COBI is a potent CYP3A inhibitor. CVC exposure was decreased when co-
administered with efavirenz (EFV) and dolutegravir (DTG), but not changed with 
tenofovir (TFV). Co-administration with CVC increased TFV and ATV/r exposure, and 
had no effect on EFV, DRV/r, or DTG exposure. For EFV specifically, there was a 23% 
reduction in CVC Cmax, a 43% reduction in AUC0-24, and a 48% reduction in Cmin with 
EFV co-administration, which is a large enough reduction in CVC exposure to warrant a 
CVC dosage adjustment when given with EFV. (See Cenicriviroc mesylate [CVC] 
Investigator’s Brochure [IB], Version 8.0, dated 04/2022) 
 
Based on these data, dosing will be 150 mg once a day for participants who are on an 
INSTI- or rilpivirine (RPV)-based regimen, and 300 mg once a day in the morning with 
food for participants who are on an EFV-based regimen at bedtime. Although co-
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expected to be clinically significant (CVC IB, Version 8.0, dated 04/2022), and thus does 
not warrant dose adjustment. As RPV is not a potent inducer of CYP3A, we believe it is 
unlikely to accelerate metabolism of CVC; therefore, no dose adjustment is proposed for 
participants who may be receiving an RPV-based ART regimen. At this time, we will 
exclude participants who are on protease inhibitors or on regimens boosted by RTV or 
COBI. 
 
Rationale for 2:1 Randomization 
At study entry, participants will be randomized at a 2:1 ratio (CVC arm:placebo arm). 
The 2:1 allocation is chosen so that more participants may potentially benefit from CVC 
(as opposed to no benefit from placebo). This is felt to be particularly important in the 
context of a placebo controlled study in which participants are being asked to undergo 
multiple imaging studies. This approach will also give us more statistical power to assess 
within group changes for the CVC arm. 
 
Rationale for Per-protocol Analyses 
The per-protocol analysis approach will be used in primary and key secondary analyses 
since the primary focus of the study is to determine the biological activity of CVC on 
vascular inflammation rather than clinical efficacy. 
 
Rationale for Duration of 24 Weeks 
In another study in participants living with HIV, Study 652-2-202, a Phase IIb study, CVC 
led to significant increases in MCP-1 (CCL2) at week 24 compared to EFV and CVC led 
to significant decreases in the monocyte activation marker sCD14 by 12 weeks that were 
sustained at week 24 and later. Prior studies examining arterial inflammation have 
shown that arterial inflammation can be reduced by 12 weeks using other interventions 
such as statin therapy and thus, we believe at least 12 weeks duration would be needed. 
Extending the intervention to 24 weeks will allow us to safely prolong exposure to CVC, 
which might produce a greater effect, and also examine the duration of the effect if 
maximum activity that is demonstrable at 12 weeks. 
 
Rationale for Pharmacology Study 
The majority of the prior PK information on drug-drug interactions (DDIs) was generated 
in healthy volunteers. Therefore, to provide information for CVC PK in individuals living 
with HIV on select ART regimens and to provide ART PK in the context of CVC, 
specifically in individuals living with HIV, a sparse PK design is included in the protocol. 
 
CVC Safety Data 
All safety data and information described here is taken from the Cenicriviroc 
Investigator’s Brochure (CVC IB version 8.0 04/2022 – AbbVie Data on file) and has 
been selected in light of the dosing regimen similarity with this study. 
 
Overall, to date, 1361 participants have been exposed to either single or multiple doses 
of CVC in AbbVie-Sponsored completed clinical studies. The overall safety experience 
of CVC is based on data from all the studies (including healthy participants, adult 
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HIV, and participants with COVID-19). CVC doses range from 25 mg to 900 mg across 
all CVC studies. 
 
Adverse drug reactions (ADRs) included in this section were identified by the Sponsor, 
based on the nature and frequency of observed events (from all clinical studies) and 
reasonable evidence of causal association with CVC. The ADRs described in this 
section are considered non-serious. 
 
CENTAUR (Study 652-2-203) 
Safety in adult participants with liver fibrosis was evaluated in the CENTAUR Phase 2 
study, “A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Multinational, 2-
year Study” (Study 652-2-203). The 150 mg dose in the CENTAUR study was well 
tolerated. Overall, the safety profile of CVC (150 mg QD) was comparable to that in 
participants treated with placebo and was well tolerated over 2 years. The overall 
incidence of treatment-emergent adverse events (TEAEs) during the study was similar 
across the treatment groups (≥95.0% of participants in each group). No deaths occurred 
during the study. (See CVC IB, 8.0, dated 04/2022) 
 
The adverse drug reactions (ADRs) for CVC in participants with NASH are listed by 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class and 
Preferred Term in Table 2.1-1. The overall frequency of the ADR represents the 
frequency for all ADRs regardless of seriousness. The information includes the nature of 
the ADR, including serious, life threatening, or fatal outcomes. For all events in the table, 
non-serious events are expected. Frequency categories are defined using the following 
convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to 
<1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000) (See CVC IB, 8.0, 
dated 04/2022). 
 
Table 2.1-1: Expected Adverse Drug Reactions in Participants with NASH Treated with 
CVC in Clinical Studies (CVC IB, 8.0, dated 04/2022) 
System Organ Class 
Preferred Term 
Centaur Year 1 
Centaur Year 1 + Year 2 
CVC 150 mg 
N=144 
Placebo 
N=144 
CVC/CVC 
N=121 
Placebo/ 
Placebo 
N=60 
Adverse Reactions 
Gastrointestinal disorders 
Abdominal distention 
Diarrhea 
Flatulence 
Nausea 
Vomiting 
10 (6.9%) 
2 (1.4%) 
11 (9.1%) 
0 (0.0%) 
30 (20.8%) 
21 (14.6%) 
25 (20.7%) 
14 (23.3%) 
9 (6.3%) 
5 (3.5%) 
9 (7.4%) 
1 (1.7%) 
25 (17.4%) 
13 (9.0%) 
23 (19.0%) 
8 (13.3%) 
14 (9.7%) 
6 (4.2%) 
14 (11.6%) 
5 (8.3%) 
General disorders and administration site conditions 
Asthenia 
Pyrexia 
6 (4.2%) 
3 (2.1%) 
6 (5.0%) 
1 (1.7%) 
8 (5.6%) 
3 (2.1%) 
6 (5.0%) 
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System Organ Class 
Preferred Term 
Centaur Year 1 
Centaur Year 1 + Year 2 
CVC 150 mg 
N=144 
Placebo 
N=144 
CVC/CVC 
N=121 
Placebo/ 
Placebo 
N=60 
Musculoskeletal and connective tissue disorders 
Arthralgia 
Joint swelling 
18 (12.5%) 
6 (4.2%) 
20 (16.5%) 
4 (6.7%) 
5 (3.5%) 
0 (0.0%) 
5 (4.1%) 
0 (0.0%) 
Skin and subcutaneous tissue disorders 
Dermatitis contact 
Rash* 
5 (3.5%) 
0 (0.0%) 
6 (5.0%) 
0 (0.0%) 
16 (11.1%) 
8 (5.6%) 
16 (13.2%) 
7 (11.7%) 
* Rash, rash macular, rash maculopapular, rash erythematous, rash pustular, rash pruritic and 
rash generalized. 
 
The frequency and types of TEAEs reported were comparable between treatment 
groups during Year 1 and Year 2 (Table 2.1-2 and Table 2.1-3). 
 
Table 2.1-2: Summary of Treatment Emergent Adverse Events (≥10% of Participants in 
any Treatment Arm) by System Organ Class and Preferred Term – Safety 
Analysis Set Year 1 (CVC IB, 8.0, dated 04/2022) 
System Organ Class 
Preferred Term 
Placeboa 
(Arm B + C) 
(N = 144) 
n (%) 
CVC 150 mg 
(Arm A) 
(N = 144) 
n (%) 
 
Total 
(N = 288) 
n (%) 
Any TEAEb 
133 (92.4) 
134 (93.1) 
267 (92.7) 
Gastrointestinal disorders 
Diarrhea 
Nausea 
Abdominal pain upper 
Abdominal pain 
73 (50.7) 
77 (53.5) 
150 (52.1) 
21 (14.6) 
30 (20.8) 
51 (17.7) 
13 (9.0) 
25 (17.4) 
38 (13.2) 
19 (13.2) 
14 (9.7) 
33 (11.5) 
13 (9.0) 
15 (10.4) 
28 (9.7) 
Musculoskeletal and connective tissue disorders 
Back pain 
Arthralgia 
51 (35.4) 
57 (39.6) 
108 (37.5) 
17 (11.8) 
11 (7.6) 
28 (9.7) 
6 (4.2) 
18 (12.5) 
24 (8.3) 
General disorders and administration site conditions 
Fatigue 
34 (23.6) 
47 (32.6) 
81 (28.1) 
20 (13.9) 
18 (12.5) 
38 (13.2) 
Nervous system disorders 
Headache 
33 (22.9) 
41 (28.5) 
74 (25.7) 
24 (16.7) 
19 (13.2) 
43 (14.9) 
a The Placebo column includes all participants randomized to placebo during Treatment Period 1. 
b TEAEs include all events with a start date/time after the date of first dose of study medication 
during the treatment period. 
 


 
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Table 2.1-3: Summary of Treatment Emergent Adverse Events (≥5% of Participants in 
any Treatment Arm) by System Organ Class and Preferred Term – Year 2 
– Safety Analysis Set Year 2 (CVC IB, 8.0, dated 04/2022) 
System Organ Class 
Preferred Term 
Placebo/ 
Placebo 
(Arm C) 
(N=60) 
n (%) 
CVC 150 mg/ 
CVC 150 mg 
(Arm A) 
(N=121) 
n (%) 
Placebo/ 
CVC 150 
mg 
(Arm B) 
(N=61) 
n (%) 
 
 
Total 
(N=242) 
n (%) 
Any TEAE* 
50 (83.3) 
105 (86.8) 
46 (75.4) 
201 (83.1) 
Infections and infestations 
Nasopharyngitis 
Upper respiratory tract infection 
Urinary tract infection 
Sinusitis 
Bronchitis 
Ear infection 
18 (30.0) 
62 (51.2) 
22 (36.1) 
102 (42.1) 
2 (3.3) 
11 (9.1) 
5 (8.2) 
18 (7.4) 
3 (5.0) 
8 (6.6) 
5 (8.2) 
16 (6.6) 
0 (0.0) 
9 (7.4) 
3 (4.9) 
12 (5.0) 
4 (6.7) 
6 (5.0) 
1 (1.6) 
11 (4.5) 
3 (5.0) 
4 (3.3) 
0 (0.0) 
7 (2.9) 
3 (5.0) 
1 (0.8) 
1 (1.6) 
5 (2.1) 
Gastrointestinal disorders 
Abdominal pain 
Abdominal pain upper 
Diarrhea 
Nausea 
18 (30.0) 
31 (25.6) 
12 (19.7) 
61 (25.2) 
4 (6.7) 
4 (3.3) 
2 (3.3) 
10 (4.1) 
3 (5.0) 
4 (3.3) 
3 (4.9) 
10 (4.1) 
5 (8.3) 
2 (1.7) 
3 (4.9) 
10 (4.1) 
2 (3.3) 
7 (5.8) 
0 (0.0) 
9 (3.7) 
Musculoskeletal and connective tissue 
disorders 
Arthralgia 
Back pain 
Pain in extremity 
11 (18.3) 
28 (23.1) 
8 (13.1) 
47 (19.4) 
2 (3.3) 
6 (5.0) 
0 (0.0) 
8 (3.3) 
3 (5.0) 
0 (0.0) 
4 (6.6) 
7 (2.9) 
0 (0.0) 
7 (5.8) 
0 (0.0) 
7 (2.9) 
Injury, poisoning and procedural 
complications 
Procedural pain 
10 (16.7) 
20 (16.5) 
8 (13.1) 
38 (15.7) 
4 (6.7) 
4 (3.3) 
2 (3.3) 
10 (4.1) 
General disorders and administration site 
conditions 
Fatigue 
11 (18.3) 
18 (14.9) 
5 (8.2) 
34 (14.0) 
3 (5.0) 
11 (9.1) 
2 (3.3) 
16 (6.6) 
Skin and subcutaneous tissue disorders 
Rash 
Pruritus 
11 (18.3) 
15 (12.4) 
8 (13.1) 
34 (14.0) 
4 (6.7) 
6 (5.0) 
1 (1.6) 
11 (4.5) 
3 (5.0) 
3 (2.5) 
1 (1.6) 
7 (2.9) 
Investigations 
Alanine aminotransferase increased 
6 (10.0) 
15 (12.4) 
7 (11.5) 
28 (11.6) 
2 (3.3) 
6 (5.0) 
2 (3.3) 
10 (4.1) 
Respiratory, thoracic and mediastinal 
disorders 
Cough 
8 (13.3) 
14 (11.6) 
1 (1.6) 
23 (9.5) 
0 (0.0) 
6 (5.0) 
1 (1.6) 
7 (2.9) 
* TEAEs include all events with a start date/time after the date of first dose of study medication 
during the treatment period. 
 
CVC in Participants Living with HIV 
In participants living with HIV in Study 652-2-201, CVC was generally well tolerated at 
the doses studied and no safety concerns were identified. There were no SAEs, deaths, 


 
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or other significant AEs, and there were no discontinuations because of an AE. Most 
TEAEs were mild or moderate in severity. Participants who received 150 mg of CVC 
(i.e., the highest dose studied) had more AEs compared with participants in the other 
dose groups, although the severity of AEs was comparable across all dose groups. The 
most common (>2 participants) TEAEs reported on CVC were diarrhea (n=9), nausea 
(n=8), headache (n=6), fatigue (n=6), flatulence (n=3), vomiting (n=3), cough (n=3), and 
pyrexia (n=3). (See CVC IB, 8.0, dated 04/2022) 
 
In participants living with HIV in Study 652-2-202, doses of 100 mg and 200 mg of CVC 
were generally well tolerated during the entire study period (up to 48 weeks of treatment 
followed by a 4-week follow-up period). No participants died. One participant in each 
treatment arm experienced SAEs, all unrelated to study drug. AEs leading to 
discontinuation of study medication occurred in one participant (2%) in the CVC 200 mg 
arm and in six participants (21%) in the EFV arm. Most AEs were mild or moderate 
(Grade 1 or Grade 2) in severity. The percentage of participants who experienced a 
Grade ≥3 AE was lower in the CVC arms (total of 4%) than in the EFV arm (15%). No 
Grade 4 AEs were reported in CVC-treated participants. The percentage of participants 
with AEs that were at least Grade 2 and at least possibly related to study medication 
was lower in the CVC arms (9% in both CVC arms) than in the EFV arm (36%). 
Headache, fatigue, and upper respiratory tract infection were reported more frequently in 
the CVC arms than in the EFV arm (Table 2.1-4). The most frequently reported study 
drug-related clinical TEAEs of at least moderate (Grade 2) severity occurring in ≥2% of 
participants in any treatment group were nausea (2%) in the CVC groups combined, and 
abnormal dreams (11%), insomnia (11%), nausea (7%), and rash (7%) in the EFV 
group. Most laboratory abnormalities were Grade 1 or Grade 2 in severity. Except for 
abnormalities in creatine phosphokinase (CPK) that were observed more frequently in 
the CVC 200 mg arm, there were no differences in percentages of participants with 
Grade 3 or Grade 4 laboratory abnormalities between the treatment arms. All cases of 
CPK elevations were transient and were not associated with clinical symptoms. No 
Grade 4 ALT or AST elevations were observed. A decrease was observed during CVC 
treatment in total cholesterol, mainly due to decreases in low density lipoprotein 
cholesterol. No clinically relevant changes in ECG or vital sign parameters were 
observed during the treatment period in any of the treatment arms [8]. (See CVC IB, 8.0, 
dated 04/2022) 
 
Table 2.1-4: Treatment-Emergent Adverse Events Occurring in ≥10% of 
Participants in CVC or EFV Arms - Study 652-2-202 (CVC IB, 8.0, 
dated 04/2022) 
Preferred Term 
n (%) 
CVC 
100 mg 
CVC 
200 mg 
All 
CVC 
EFV 
(N = 58) 
(N = 57) 
(N = 115) 
(N = 28) 
Mean (SE) duration of intake 
study medication (weeks)a 
41.2 (1.89) 
40.9 (1.88) 
41.1 (1.33) 
36.2 (3.64) 
Any AE 
51 (88%) 
48 (84%) 
99 (86%) 
27 (96%) 
Nausea 
10 (17%) 
8 (14%) 
18 (16%) 
6 (21%) 


 
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Preferred Term 
n (%) 
CVC 
100 mg 
CVC 
200 mg 
All 
CVC 
EFV 
(N = 58) 
(N = 57) 
(N = 115) 
(N = 28) 
Upper respiratory tract infection 
9 (16%) 
9 (16%) 
18 (16%) 
2 (7%) 
Diarrhea 
7 (12%) 
10 (18%) 
17 (15%) 
3 (11%) 
Headache 
9 (16%) 
7 (12%) 
16 (14%) 
0 
Rashb 
7 (12%) 
7 (12%) 
14 (12%) 
5 (18%) 
Fatigue 
6 (10%) 
8 (14%) 
14 (12%) 
1 (4%) 
Dizziness 
5 (9%) 
6 (11%) 
11 (10%) 
8 (29%) 
Nasopharyngitis 
2 (3%) 
8 (14%) 
10 (9%) 
1 (4%) 
Abnormal dreams 
6 (10%) 
3 (5%) 
9 (8%) 
6 (21%) 
Insomnia 
0 
7 (12%) 
7 (6%) 
4 (14%) 
Lymphadenopathy 
3 (5%) 
4 (7%) 
7 (6%) 
4 (14%) 
Depression 
2 (3%) 
1 (2%) 
3 (3%) 
3 (11%) 
Syphilis 
1 (2%) 
0 
1 (1%) 
3 (11%) 
a Note that exposure is based on ITT population. 
b Included rash, rash maculopapular, rash pruritic, rash generalized, and rash papular. 
 
Safety data originating from the four studies completed in 2021 (Aurora, Rollover, 
Tandem, and CLJC242A2101) are aligned with the current knowledge of the safety 
profile of CVC and are summarized below. 
 
AURORA (Study 3152-301-002) 
Full Cohort 
TEAEs reported by 22% participants in the CVC group and that occurred at an incidence rate 
of 22% greater than in the placebo group were nausea (104 [8.8%] participants in the CVC 
group versus 39 [6.6%] participants in the placebo group), alanine aminotransferase increase 
(45 [3.8%] participants in the CVC group versus 9 [1.5%] participants in the placebo group), 
aspartate aminotransferase increase (38 [3.2%] participants in the CVC group versus 6 [1.0%] 
participants in the placebo group), and nephrolithiasis (25 [2.1%] participants in the CVC 
group versus 0 participants in the placebo group). CVC 150 mg once daily was, in general, 
well tolerated in this study, there were no treatment-related TEAEs that were fatal or life-
threatening. The nature and incidence rates of AEs observed with CVC were similar to those 
observed with placebo, except for nausea, elevation in transaminases, and nephrolithiasis, the 
latter, a finding inconsistent with previous safety data. The proportion of participants who 
experienced DILI (cases adjudicated as possible or probable DILI) was higher in the CVC 
group (4 participants [0.3%]) compared to placebo group (0 participants [0%]), suggesting a 
possible causal relationship between CVC and DILI. Nevertheless, all these cases were non-
serious, non-clinically significant, and reversible after CVC discontinuation. 
 
ROLLOVER (Study 3152-201-002) 
The incidence of all Treatment-emergent Adverse Events (TEAEs) reported during the 
study was 140 of 167 participants (83.8%). Treatment-related TEAEs, as determined by 


 
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the investigator, were reported for 28 participants (16.8%). The majority of TEAEs were 
mild in intensity. Severe TEAEs were reported for 40 participants (24.0%). There were 
no clinically meaningful findings regarding clinical laboratory. The most common events 
reported in ≥10% of participants were arthralgia (13.2%), diarrhea (12.0%), and 
nasopharyngitis (10.2%). 
 
TANDEM (Study CLJC242A2201J) 
The safety profiles of the combination therapies of tropifexor 140 mcg + CVC 150 mg 
and tropifexor 90 mcg + CVC 150 mg were similar to those of each monotherapy, with 
no additional emergent safety signals compared to those identified and reported in 
previous monotherapy studies. Overall, pruritus, nausea, and fatigue were the most 
frequently experienced AEs. The proportion of participants who experienced pruritus 
was highest in the tropifexor 140 mcg alone group and notably lower with tropifexor 140 
mcg + CVC 150 mg combination treatment. Similar patterns are noted for fatigue and 
urinary tract infection, and this pattern may be explained by the DDI by which CVC 
treatment reduces tropifexor levels. 
 
No deaths were reported in the study. Most SAEs were single occurrences. The AEs 
most frequently leading to discontinuation from study treatment were pruritus (tropifexor 
140 mcg group: 4, 8.0%; tropifexor 140 mcg + CVC 150 mg group: 2, 4.3%) and 
flatulence (tropifexor 140 mcg + CVC 150 mg group: 2, 4.3%); all other AEs leading to 
discontinuation were single occurrences. 
 
Study CLJC242A2101 
There were no deaths reported during this study, and one SAE (unrelated ovarian 
torsion) was reported after the cut-off date for TEAEs in the clinical database. One 
participant who received tropifexor + CVC discontinued from the study due to a TEAE 
(rash), which was suspected to be definitely related to the study drugs. None of the 4 
TEAEs reported for tropifexor alone or the 10 TEAEs reported for CVC alone were 
considered related to the study drugs. The most commonly reported PTs were 
abdominal pain reported for two (14.3%) participants after receiving tropifexor alone, and 
dermatitis contact and headache each reported for two (14.3%) participants, after 
receiving CVC alone. 
 
Radiation Safety Considerations 
The FDG-PET/CT imaging will be associated with radiation exposure of ~19 to 21 
milliSieverts (mSv). This exposure is similar amount of radiation that a person is 
exposed to when undergoing a single exercise stress test with myocardial perfusion 
imaging (~15 mSv for technetium studies, and ~21 to 24 mSv for thallium studies), and 
is substantially below the 50 mSv limit that is established by Institutional Review Boards 
(IRBs) in the United States (the annual limit established for radiation workers). To further 
limit the radiation risks to participants, anyone who reports any significant radiation 
exposure over the course of the year prior to study entry (defined in the exclusion 
criteria) or who has a history of radiation therapy will be excluded. There may be rare 
instances when imaging has to be repeated because the initial image obtained was 
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Biomarkers 
As CVC binds and inhibits function of CCR2 and CCR5, interference with binding and 
clearance of CCL2 and MIP-1a, MIP-1b, and RANTES (CCR5 ligands) might be 
anticipated. As we hypothesize that monocyte/macrophage activation may be attenuated 
by CVC administration, we also plan to monitor levels of sCD14 and sCD163, indices of 
monocyte/macrophage activation. 
 
Supporting Pharmacokinetic Data from Allergan/AbbVie 
In Study 104, there was a 2.39-fold increase in CVC Cmax, a 3.55-fold increase in CVC 
AUC from time 0 to 24 hours post dose (AUC0-24), and a 5.24-fold increase in CVC 
Cmin with RTV co-administration. 
 
In Study 105, there was no evidence of a drug-drug interaction on CVC by tenofovir 
disoproxil fumarate (TDF); however, co-administration with CVC increased plasma TDF 
exposure by approximately 28%-36%. 
 
In Study 107, there was a 2.17-fold increase in CVC Cmax, a 3.13-fold increase in CVC 
AUC0-24, and a 4.17-fold increase in Cmin with DRV/r co-administration, which is 
comparable to the effect seen with co-administration of RTV alone in Study 104. In 
Study 113, there was no meaningful effect of CVC on plasma darunavir (DRV) or RTV 
exposure. 
 
In Study 108, there was a 2.55-fold increase in CVC Cmax, a 3.89-fold increase in 
AUC0-24, and a 5.75-fold increase in Cmin with ATV/r co-administration, which is 
comparable to the effect seen with co-administration of RTV alone in Study 104. In 
Study 112, there were modest effects of CVC on RTV Cmin (1.50-fold increase) and on 
atazanavir (ATV) Cmax (1.19-fold increase), AUC0-24 (1.33-fold increase), and Cmin 
(1.55-fold increase). There were no statistically significant effects of CVC on RTV Cmax 
or AUC0-24. 
 
In Study 109, there was a 23% reduction in CVC Cmax, a 43% reduction in AUC0-24, 
and a 48% reduction in Cmin with EFV co-administration. CVC did not result in a 
meaningful change in plasma EFV exposure. 
 
In Study 110, there was a 28% reduction in CVC Cmax, a 29% reduction in AUC0-24, 
and a 23% reduction in Cmin with DTG co-administration. CVC did not result in a 
meaningful change in plasma DTG exposure. 
 
A summary of detailed results of these studies performed is shown in Appendix I. 
 
3.0 
STUDY DESIGN 
 
This is a double-blind, placebo-controlled phase II clinical trial comparing the intervention 
of CVC versus placebo for a duration of 24 weeks on arterial inflammation evaluated by 
FDG-PET/CT imaging. Image analysis will be performed by imaging specialists at the 


 
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central imaging core laboratory at the Massachusetts General Hospital (MGH) Imaging 
Trials Center (MITC). The imaging specialists at the core laboratory are blinded to the 
clinical history and treatment group classification of the participant. 
 
A total of 93 participants will be randomized 2:1 to the CVC arm (Arm A) or placebo for 
CVC arm (Arm B). Stratification by statin use at randomization will ensure even 
distribution of statin use between the treatment groups. 
 
Blood samples will be collected per the SOE. 
 
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 one of the following: 
• 
A licensed Western blot  
• 
A second antibody test by a method other than the initial rapid HIV and/or 
E/CIA 
• 
HIV-1 antigen, plasma HIV-1 RNA viral load, or 
• 
Two HIV-1 RNA >1,000 copies/mL. 
 
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 Currently on a stable, continuous NNRTI-based or unboosted INSTI-based ART 
regimen for ≥48 weeks prior to study entry with no ART interruption longer than 7 
consecutive days and with no plans to change ART during the course of the study. 
 


 
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NOTE A: Stable is defined as no within-class changes in ART regimen within 12 
weeks prior to study entry and no between-class changes for 24 weeks prior to 
study entry. 
 
NOTE B: Unboosted ART is defined as an ART regimen that does not include 
the pharmacologic booster COBI or RTV. 
 
NOTE C: Modifications of ART formulation within 12 weeks prior to study entry 
(e.g., from standard formulation to fixed-dose combination of the same drugs), 
are permitted. 
 
4.1.3 Screening HIV-1 RNA level below the limit of quantification (e.g., <20, <40, <50, or 
<75 copies/mL, depending on the assay) using an FDA-approved assay with a 
quantification limit of 75 copies/mL or lower performed by any US laboratory that 
has a Clinical Laboratory Improvement Amendments (CLIA) certification or its 
equivalent, or at any network-approved non-US laboratory that operates in 
accordance with Good Clinical Laboratory Practices (GCLP) and participates in 
appropriate external quality assurance programs within 90 days prior to study entry. 
 
4.1.4 All HIV-1 RNA levels within 48 weeks prior to study entry below the limit of 
quantification (e.g., <20, <40, <50, or <75 copies/mL, depending on the assay) 
using an FDA-approved assay with a quantification limit of 75 copies/mL or lower 
performed 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. 
 
NOTE A: Up to two HIV-1 RNA determinations that are between the assay 
quantification limit and 500 copies/mL (i.e., “blips”) are allowed as long as the 
preceding and subsequent determinations are below the level of quantification. 
 
NOTE B: The screening value may serve as the subsequent undetectable value 
following a blip. 
 
4.1.5 CD4+ cell count >200 cells/mm3 obtained within 90 days prior to study entry at 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that is IQA certified. 
 
4.1.6 At least one of the following cardiovascular risk factors (current diagnosis or 
receiving treatment, except where a time period is specified): 
• 
Clinical atherosclerotic disease (symptomatic atherosclerotic lesions in any 
vessel) 
• 
Subclinical atherosclerotic disease (coronary artery calcification [CAC] >10 or 
presence of non-obstructive plaques) 
• 
DM or prediabetes (hemoglobin A1c [HbA1c] ≥5.7%) or impaired fasting 
glucose (documented fasting glucose of >100 mg/dL within 6 months prior to 
study entry) or insulin resistance (HOMA-IR ≥2.6) or any one of these 


 
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laboratory values within 6 months prior to study entry 
• 
Obesity (body mass index [BMI] ≥30 kg/m2) or enlarged iliac waist 
circumference (>40 inches in males, >35 inches in females) 
 
NOTE A: BMI calculator is available at the Data Management Center (DMC) 
website: https://www.fstrf.org/ACTG/ccc.html. 
 
• 
History of hypertension or blood pressure ≥130/80 mmHg measured during 
screening 
NOTE: See the A5415 Manual of Procedures (MOPS) for blood pressure 
measurement guidance. 
• 
Elevated LDL cholesterol (fasting LDL of >160 mg/dL; result from sample 
taken within 90 days prior to study entry can be used) 
• 
Low HDL cholesterol (<40 mg/dL; result from sample taken within 90 days 
prior to study entry can be used) 
• 
Smoking (any current tobacco smoking) 
• 
Family history of premature CAD (first degree relative with CAD prior to age 
55 for male relative and 65 for female relative; participant report is 
acceptable) 
• 
hsCRP >2.0 mg/L within 90 days prior to study entry without an active 
infection or acute illness at the time the sample was obtained 
 
4.1.7 The following laboratory values obtained within 90 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent, or at any 
network-approved non-US laboratory that operates in accordance with Good 
Clinical Laboratory Practices (GCLP) and participates in appropriate external 
quality assurance programs. 
• 
Absolute neutrophil count (ANC) >750/mm3 
• 
Platelet count >100,000/mm3 
• 
Aspartate aminotransferase (AST) (SGOT) ≤5x upper limit of normal (ULN) 
• 
Alanine aminotransferase (ALT) (SGPT) ≤5x ULN 
• 
Alkaline phosphatase ≤5x ULN 
• 
Estimated glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 as calculated using 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation 
 
NOTE: See the A5415 MOPS for further information and a link to the CKD-Epi 
equation and calculator. 
 
4.1.8 Pre-entry FDG-PET/CT imaging (within 60 days prior to study entry) that has 
been deemed: 
• 
Interpretable as assessed by the central imaging core laboratory 
AND 
• 
Without incidental findings that will preclude participation in the study at the 
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4.1.9 No plans to receive immunizations 7 days prior to the week 24 study visit. 
 
4.1.10 For study candidates of child-bearing potential, negative serum or urine 
pregnancy test within 90 days prior to study entry and prior to starting study 
treatment at study entry by any 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: Reproductive potential is defined as individuals who have reached 
menarche and individuals who have not been post-menopausal for at least 12 
consecutive months with follicle-stimulating hormone (FSH) ≥40 IU/mL or 24 
consecutive months if an FSH is not available, or have not undergone surgical 
sterilization (e.g., hysterectomy, bilateral oophorectomy, tubal ligation or 
salpingectomy). 
 
4.1.11 If participating in sexual activity that could lead to pregnancy, willingness of 
person of childbearing potential to use two forms of contraception while receiving 
study medication and for 3 months after stopping study medication as required. 
 
NOTE A: Acceptable forms of contraception include: 
• 
Barrier methods (condoms [male or female] with or without a spermicidal 
agent, diaphragm, or cervical cap [with spermicide]) 
• 
Hormone-based contraception (oral, patch, parenteral, implants, or vaginal 
ring) 
• 
Intrauterine device (IUD) 
 
NOTE B: If the participant is not of reproductive potential (individuals who are 
post-menopausal as defined above, or individuals who have undergone surgical 
sterilization [e.g., hysterectomy, bilateral oophorectomy, tubal ligation or 
salpingectomy]), they are eligible without requiring the use of a contraceptive 
method. Acceptable documentation of surgical sterilization and menopause is by 
participant-reported history. 
 
4.1.12 Individuals ≥45 years of age. 
 
4.1.13 Ability and willingness of participant or legal guardian/representative to provide 
informed consent. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Acute coronary syndrome, defined as myocardial infarction (MI) or unstable 
angina, within 90 days prior to study entry. 
 


 
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4.2.2 A current diagnosis of latent or active tuberculosis (TB) infection, any prior 
untreated TB infection, inadequate treatment of active TB, or inadequate 
treatment of latent TB. 
 
NOTE A: Individuals with cases of active infection and latent TB infection with a 
history of adequate treatment may be considered for enrollment provided the 
individual has a negative chest X-ray following treatment and within 1 year prior 
to study entry. 
 
NOTE B: Written documentation of prior TB treatment and negative chest x-ray is 
required. 
 
4.2.3 Current diagnosis with other intracellular pathogens (Mycobacterium avium 
complex, Listeria monocytogenes, Toxoplasma gondii, and Cryptococcus 
neoformans) within 90 days prior to study entry. 
 
4.2.4 Untreated hepatitis B virus (HBV) infection with detectable HBV DNA within 6 
months prior to study entry. 
 
4.2.5 Current hepatitis C virus (HCV) infection (i.e., detectable HCV RNA within 6 
months prior to study entry). 
 
NOTE: Individuals with successfully treated HCV, and are at least 6 months post 
treatment completion, are not excluded. 
 
4.2.6 Acute or clinically significant infection or illness requiring IV antibiotics or 
hospitalization within 90 days prior to study entry. 
 
4.2.7 History of cirrhosis with severe hepatic impairment and/or hepatic 
decompensation including ascites, hepatic encephalopathy, or variceal bleeding. 
 
4.2.8 Active malignancy, except squamous cell skin cancer. 
 
4.2.9 Hemoglobin A1c >8% within 90 days prior to study entry by any laboratory that 
has a CLIA certification or its equivalent, 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. 
 
4.2.10 Initiation of statin therapy or change in statin dose within 90 days prior to study 
entry. 
 
4.2.11 Current use of any of the statins at the doses indicated: 
• 
Atorvastatin, >40 mg/day dose 
• 
Rosuvastatin, ≥20 mg/day dose 
 


 
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4.2.12 Anticipated addition of any lipid lowering medication during the course of the 
study. 
 
4.2.13 Concurrent use of drugs with potential drug-drug interactions with CVC within 90 
days prior to study entry (refer to the prohibited medications list in section 5.4.2). 
 
4.2.14 Known allergy/sensitivity or any hypersensitivity to components of study drug(s) 
or their formulation. 
 
4.2.15 Treatment within 30 days prior to study entry or anticipated treatment with 
immunomodulating agents (such as systemic corticosteroids, interleukins, 
interferons, cyclosporine, and tacrolimus). 
 
4.2.16 Immunization within 7 days prior to the pre-entry FDG-PET/CT imaging (refer to 
section 6.3.9). 
 
4.2.17 History of radiation therapy. 
 
4.2.18 High radiation exposure within one year prior to entry, defined as having 
undergone more than two of any of the procedures below (includes having 
undergone the same procedure twice within one year prior to study entry): 
• 
Coronary artery catheterization with or without percutaneous coronary 
intervention (PCI) 
• 
Myocardial perfusion stress test 
• 
Coronary CT angiography 
• 
CT of the chest and abdomen 
• 
Barium enema 
 
4.2.19 Currently pregnant, breastfeeding, or planning to become pregnant during the 
length of the study and three months after completing the study. 
 
4.2.20 Body weight >300 pounds or >136 kilograms. 
 
4.2.21 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
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 


 
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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 the required 
documents have been received. Site-specific ICF(s) WILL NOT be reviewed and 
approved by the DAIDS PRO. Sites will receive an Amendment Registration Notification 
when the DAIDS PRO receives a complete registration packet. A copy of the 
Amendment Registration Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully discussed. 
The participant (or, when necessary, the legal representative if the participant is under 
guardianship) will be asked to read and sign the approved protocol consent form. 
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Participant Enrollment System. 
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment. 
 
4.3.3 Randomization 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the protocol, an ACTG Screening 
Failure Results form must be completed and keyed into the database. 
 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures. 
 


 
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4.4 
Coenrollment Guidelines 
 
• 
US sites are encouraged to coenroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Coenrollment in A5128 does not require permission from the 
A5415 protocol chair. 
• 
Coenrollment is not allowed for participants in A5332, “Randomized Trial to Prevent 
Vascular Events in HIV – REPRIEVE.” 
• 
For specific questions and approval for coenrollment in other studies, sites should 
first check the PSWP or contact the protocol team via email as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as CVC or placebo for CVC, both of which will be provided by 
the study. 
 
The study treatment will be added to the current NNRTI-based or unboosted INSTI-based 
antiretroviral (ARV) regimen. The background ART will not be provided by the study. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
At study entry, participants will be randomized 2:1 to oral CVC (Arm A) or oral 
placebo for CVC (Arm B) once a day. The study treatment will be added to the 
participants’ pre-existing ARV regimens. 
 
Table 5.1.1-1: Pre-existing ART Regimen and CVC or Placebo for CVC Dose 
Pre-existing ART regimen 
Arm A 
Arm B 
EFV 
CVC 300 mg 
Placebo for CVC 300 mg 
All other ARTs 
CVC 150 mg 
Placebo for CVC 150 mg 
 
5.1.2 Administration 
 
CVC 150 mg or Placebo: Administered as one 150-mg tablet/placebo. 
 
CVC 300 mg or Placebo: Administered as two 150-mg tablets/placebo. 
 
The appropriate dose of CVC or placebo for CVC will be administered by mouth 
once a day with food. The dose should be taken as close to the same time of day 
as possible. 
 
For participants who are on EFV-based regimen, CVC or placebo for CVC will be 
administered in the morning with food. 


 
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5.1.3 Treatment Duration 
 
Study participants will remain on study treatment for at least 24 weeks. Study 
treatment may be extended if needed to ensure that treatment is not discontinued 
before the end of study evaluations at week 24 are completed (see section 6.2.3). 
 
5.2 
Study Product Formulation and Preparation 
 
CVC and placebo for CVC are available as 150 mg yellow-coated, immediate-release 
tablets for oral administration, and packaged in high-density polypropylene (HDPE) 
bottles with child-resistant screw caps. 
 
CVC and placebo for CVC should be stored at 15°C to 30°C (59°F to 86°F) with 
transient excursions permitted between -20°C (-4°F) and 60°C (140°F). 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
CVC and placebo for CVC will be manufactured and provided by AbbVie and will 
be available through the NIAID Clinical Research Products Management Center 
(CRPMC). The clinical research site (CRS) pharmacist should obtain the study 
products for this protocol by following the instructions in the manual Pharmacy 
Guidelines and Instructions for Division of AIDS (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. 
Investigators must also review the study agent’s prohibited and precautionary 
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Additional drug information may be found on the Precautionary and Prohibited 
Medications Database located at: https://www.ppmdb.org/PPMD. 
 
5.4.1 Required Medications 
 
NNRTI-based or unboosted INSTI-based ART. 
 
NOTE: Refer to section 4.1.2 for the definition of unboosted ART. 
 
5.4.2 Prohibited Medications 
 
Caution should always be exercised when administering concomitant 
medications based on the individual medication profile and clinical risk-benefit 
assessment. 
 
The participant should not take the following prohibited medications at any time 
during the study. 
 
• 
Immunomodulating agents (such as systemic corticosteroids*, interleukins, 
interferons, cyclosporine, and tacrolimus) 
 
*If there are plans to start a participant on systemic corticosteroids while on 
study, contact the A5415 Clinical Management Committee (CMC) 
(actg.cmca5415@fstrf.org) for additional guidance. 
 
• 
Immunizations 7 days prior to the week 24 study visit. 
 
• 
High-dose statins (see Table 5.4.2-1) 
 
Table 5.4.2-1: Prohibited High-Dose Statins 
Statin 
Prohibited Dose 
Atorvastatin 
>40 mg/day 
Rosuvastatin 
≥20 mg/day 
 
Contact the A5415 CMC (actg.cmca5415@fstrf.org) for any question 
regarding allowed statin doses. 
 
• 
Drugs with potential drug-drug interactions with CVC (see Table 5.4.2-2) 
 


 
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Table 5.4.2-2: Drugs with Potential Drug-Drug Interactions with CVC 
Antibacterial 
rifampin 
nafcillin 
clarithromycin 
erythromycin 
telithromycin 
Anticonvulsant 
carbamazepine 
phenytoin 
Antidiabetic 
pioglitazone 
Antidepressant 
nefazodone 
Antifungal 
voriconazole 
itraconazole 
ketoconazole 
posaconazole 
Antihistamine 
astemizole 
Anti-inflammatory 
sulfasalazine 
Antimetabolite 
methotrexate 
Antipsychotic 
pimozide 
Antiviral 
all antivirals for treatment of HCV 
HIV protease inhibitors 
Cobicistat 
Maraviroc 
Nirmatrelvir/ritonavir usage ≥10 days is considered 
prohibited, and participants should be permanently 
discontinued from study treatment, per section 6.2.4. 
Short term (<10 days) use of nirmatrelvir/ritonavir is 
considered precautionary. See section 5.4.3. 
Ergot alkaloid 
dihydroergotamine 
ergonovine 
ergotamine 
methylergonovine 
Immunosuppressant 
cyclosporine 
tacrolimus 
Lipid-lowering agent 
gemfibrozil 
Opioid 
fentanyl 
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Sedative/hypnotic 
midazolam* 
triazolam 
*Midazolam is allowed for sedation for surgical 
procedures; however, the lowest dose possible should be 
used and titrated according to the desired clinical 
response. Contact the A5415 CMC 
(actg.cmca5415@fstrf.org) for any questions. 
Other 
cisapride 
obeticholic acid 
high-dose (i.e., >400 IU/day) vitamin E 
 
5.4.3 Precautionary Medications 
 
Table 5.4.3-1: Precautionary Medications 
Medicinal Product 
Class 
Drugs that are Allowed but Must be Taken with Precaution 
During Intake of CVC 
(Mechanism) 
Acid-reducing agents 
(H2 receptor 
antagonists, antacids, 
and PPIs) 
When required, acid-reducing agents should be administered 
at least 2 hours after the CVC dose to ensure that adequate 
CVC concentrations are maintained. When possible, use of an 
H2 receptor antagonist (except cimetidine) or antacids is 
preferred over a PPI. It is recommended to start with the lowest 
dose of these agents and titrate according to clinical response. 
• H2 receptor antagonists (e.g., famotidine or ranitidine) 
should preferably be given from 2 to 12 hours after 
administration of CVC at a dose that does not exceed doses 
comparable to famotidine 40 mg daily. 
• Antacids (e.g., aluminum hydroxide, calcium carbonate, 
magnesium carbonate, magnesium hydroxide, or bismuth 
subsalicylate) should preferably be given at least 4 hours 
after administration of CVC due to their immediate effect in 
increasing gastric pH. 
• PPIs (e.g., omeprazole, lansoprazole, esomeprazole, 
pantoprazole, rabeprazole, or dexlansoprazole) should 
preferably be given approximately 3 hours after 
administration of CVC at a dose that does not exceed doses 
comparable to omeprazole 20 mg daily. Due to the 
prolonged acid-reducing effect of PPIs (~16 to 24 hours), it 
is advised to follow these dosing recommendations to 
reduce their potential impact on CVC absorption at 
subsequent dosing. 
Lipid-lowering agents 
Refer to Table 5.4.2-1 for the statin doses that are not allowed. 
Contact the A5415 CMC (actg.cmca5415@fstrf.org) for any 
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Medicinal Product 
Class 
Drugs that are Allowed but Must be Taken with Precaution 
During Intake of CVC 
(Mechanism) 
PDE5 enzyme 
inhibitors 
sildenafil, tadalafil, vardenafil (CYP3A4 substrates) 
The recommended starting doses for these medications are as 
follows: 
− sildenafil 25 mg 
− tadalafil 2.5 mg 
− vardenafil 2.5 mg 
Short term (<10 
days) use of 
nirmatrelvir/ritonavir 
 
When required, the study treatment should be stopped 
during the time the participant is receiving the medication 
and can be restarted after it is stopped. The participant 
should remain off study treatment for at least 5 days after 
stopping nirmatrelvir/ritonavir. The participant should 
remain on study and complete all protocol evaluations. 
Please consult with the CMC regarding study treatment 
hold, restarting study treatment, and the timing of key study 
evaluations. 
 
 


 
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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 
Post-Entry Evaluations 
(weeks, see section 6.2.3 for visit 
windows) 
Confirmation 
of 
Suspected 
Virologic 
Failure 
Confirmation of  
Grade ≥3 
Toxicity 
Premature 
Treatment 
Discontinuation 
Premature 
Study 
Discontinuation 
4 
8 
12 
16 
22 
24 
Documentation of 
HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
  
Targeted Physical 
Exam 
 
 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
(see section 
6.3.4) 
X 
X 
Weight 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Waist 
Circumference 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Concomitant 
Medications 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Treatment 
Modifications 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Hematology 
X 
X 
X 
 
 
X 
 
X 
X 
 
(X) 
(see section 
8.1) 
X 
(X) 
(see section 
6.2.4) 


 
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Evaluation 
Screening 
Pre-
Entry 
Entry 
Post-Entry Evaluations 
(weeks, see section 6.2.3 for visit 
windows) 
Confirmation 
of 
Suspected 
Virologic 
Failure 
Confirmation of  
Grade ≥3 
Toxicity 
Premature 
Treatment 
Discontinuation 
Premature 
Study 
Discontinuation 
4 
8 
12 
16 
22 
24 
Blood Chemistries 
X 
 
X 
X 
 
X 
 
 
X 
 
(X) 
(see section 
8.1) 
X 
(X) 
(see section 
6.2.4) 
Glucose (fasting) 
X 
 
X 
 
 
X 
 
 
X 
 
(X) 
(see section 
8.1) 
X 
(X) 
(see section 
6.2.4) 
Insulin (fasting, real-
time) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel (fasting) 
X 
 
 
 
 
 
 
 
X 
 
(X) 
(see section 
8.1) 
X 
(X) 
(see section 
6.2.4) 
Liver Function Tests 
X 
 
X 
X 
 
X 
 
 
X 
 
(X) 
(see section 
8.2.1) 
X 
(X) 
(see section 
6.2.4) 
HbA1C (real-time) 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Prothrombin Time 
and International 
Normalized Ratio 
 
 
X 
 
 
 
 
 
 
 
(X) 
(see section 
8.2.1) 
 
(X) 
(see section 
6.2.4) 
hsCRP 
(real-time) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated GFR 
X 
 
X 
X 
 
X 
 
 
X 
 
(X) 
(see section 
8.2.2) 
X 
(X) 
(see section 
6.2.4) 
Pregnancy Testing 
X 
 
X 
(see 
section 
6.3.5) 
If suspected 
 
 
If suspected 
 
CD4+/CD8+ 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 


 
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Evaluation 
Screening 
Pre-
Entry 
Entry 
Post-Entry Evaluations 
(weeks, see section 6.2.3 for visit 
windows) 
Confirmation 
of 
Suspected 
Virologic 
Failure 
Confirmation of  
Grade ≥3 
Toxicity 
Premature 
Treatment 
Discontinuation 
Premature 
Study 
Discontinuation 
4 
8 
12 
16 
22 
24 
Plasma HIV-1 RNA 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
Stored Plasma 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
Stored Serum 
(fasting) 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Stored PBMC 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
FDG-PET with CT 
 
X 
 
 
 
 
 
 
X 
 
 
(X) 
(see section 6.2.4) 
 
Pharmacokinetic 
Studies 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
Adherence 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Food Diary 
(D=distribute, 
C=collect) 
 
XD 
XC 
 
 
 
 
XD 
XC 
 
 
 
 
Perceived Stress 
Scale-10 
 
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 participants starting any 
study medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed within 90 days 
prior to study entry unless otherwise specified. Screening evaluations must be 
completed, and the results confirmed as meeting eligibility requirements based 
on screening evaluations, before the FDG-PET/CT imaging at pre-entry is 
performed. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on participants who do not enroll will 
be captured in a Screening Failure Results form and entered into the ACTG 
database. 
 
Pre-Entry 
Pre-entry evaluations must be performed after all screening evaluations have 
been completed and within 60 days prior to entry evaluations unless otherwise 
specified. The FDG-PET/CT imaging must be performed only after it is confirmed 
that a candidate meets eligibility requirements based on the screening 
evaluations. It is encouraged that all pre-entry evaluations occur on the same 
day. If evaluations cannot occur on the same day as the FDG-PET/CT imaging, 
evaluations must occur ±7 days of imaging. 
 
6.2.2 Entry Evaluations 
 
Entry evaluations must occur within 60 days from the date of the pre-entry FDG-
PET/CT imaging unless otherwise specified. Participant must begin treatment 
within 72 hours after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations 
All post-entry evaluations must be scheduled as per section 6.1. 
 
Weeks 4 through 22 have a visit window of ±7 days. Week 24 has a visit window 
of -7 and +14 days. 
 
Study Completion Evaluations 
The week 24 evaluations will be the participant’s final on-study visit. Participants 
must continue taking the study treatment until all week 24 evaluations are 
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evaluations are completed. It is encouraged that all week 24 evaluations occur 
on the same day. If evaluations cannot occur on the same day as the FDG-
PET/CT imaging, evaluations must occur ±7 days of imaging. Site personnel 
should notify the A5415 CMC via email (actg.cmca5415@fstrf.org) if study 
treatment is anticipated to require extension past the week 24 visit window to 
complete the required evaluations. 
 
Event-Driven Evaluations 
Evaluations must be scheduled as per section 8.0. 
 
Confirmation of Suspected Virologic Failure 
Virologic failure is defined as two consecutive plasma HIV-1 RNA levels ≥200 
copies/mL at any visit. 
 
If the HIV-1 RNA level is ≥200 copies/mL at any visit, a repeat HIV-1 RNA will be 
performed (per section 6.1) within 2 weeks of receipt of the result. If the 
Confirmation of Suspected Virologic Failure visit coincides with a regularly 
scheduled visit, the evaluations should be combined. If the repeat HIV-1 RNA 
level is ≥200 copies/mL, the participant will be considered to have confirmed 
virologic failure and the A5415 CMC must be notified via email CMC 
(actg.cmca5415@fstrf.org) within 48 hours. 
 
If a participant is confirmed to have virologic failure, the participant must return to 
the clinic to complete the premature treatment discontinuation evaluations as 
described in section 6.2.4 and then taken off study treatment. If an evaluation is 
not completed at the premature treatment discontinuation visit, effort should be 
made to obtain the evaluation as soon as possible and within the evaluation 
window. The participant will be followed on study/off study treatment through 
completion of the study. 
 
Confirmation of Grade ≥3 Toxicity 
Toxicities are defined in section 8.0. Evaluation of Grade ≥3 laboratory toxicity 
must follow instructions outlined in sections 8.1 and 8.2. Only the evaluations 
required to assess the toxicity are required at this visit. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All eCRFs must be keyed for the period up to and including the Entry visit. 
 
No follow-up evaluations are required for randomized participants who do not 
start the study treatment. 
 
Premature Treatment Discontinuation Evaluations 
The premature treatment discontinuation evaluations, as noted in section 6.1, will 
be performed in the following situations: 


 
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• 
Combined premature treatment and study discontinuation 
• 
Premature treatment discontinuation (see section 9.1) but continuing with 
study follow-up (i.e., on study/off study treatment). 
 
Site personnel should notify the A5415 CMC via email CMC 
(actg.cmca5415@fstrf.org) within 48 hours of learning of any participant who 
prematurely discontinues study treatment. 
 
Stored samples must be drawn as soon as possible, preferably within 7 days 
after the last study treatment dose. All other evaluations must be performed as 
soon as possible, preferably within 14 days after the last study treatment dose. 
 
The FDG-PET/CT imaging is not required if the participant prematurely 
discontinues study treatment before week 12. If premature treatment 
discontinuation is at or after week 12 and before week 24, the FDG-PET/CT 
imaging must be performed as soon as possible, preferably within 7 days after 
the last study treatment dose. The participant should be instructed to return to 
clinic in a fasting state. Refer to the A5415 MOPS for the pre-imaging dietary 
instructions and section 6.3.5 for the fasting instructions. If premature treatment 
discontinuation is not due to pregnancy, refer to section 6.3.5 for the pregnancy 
test guidelines and section 6.3.9 for pregnancy testing prior to conducting the 
FDG-PET/CT imaging. A participant who is found to be pregnant at the 
premature treatment discontinuation visit will not have the FDG-PET/CT imaging 
performed. 
 
A participant who prematurely discontinues study treatment because of 
pregnancy will NOT have the FDG-PET/CT imaging performed and is NOT 
required to fast prior to the discontinuation visit. 
 
Participants should be encouraged to continue to attend all study visits and 
receive study evaluations as per section 6.1, with the exception of the FDG-
PET/CT imaging at week 24 and the PK evaluation. They will be followed on 
study/off study treatment through completion of the study. 
 
Participants who prematurely discontinue treatment and the study at the same 
time will have no further visits other than follow-up of ongoing adverse events 
and toxicities until resolution to Grade ≤2 (refer to section 8.0). 
 
Evaluations for Premature Study Discontinuation during On Study/Off Study 
Treatment Follow-up 
A participant who prematurely discontinues from the study (i.e., prior to 
completing the week 24 visit) during on study/off study treatment follow-up will 
have no additional evaluations performed other than follow-up of ongoing 
adverse events and toxicities (see section 8.0). 
 


 
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Site personnel should notify the A5415 CMC via email CMC 
(actg.cmca5415@fstrf.org) within 48 hours of any participant who prematurely 
discontinues from the study during on study/off study treatment follow-up. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/score-source-documentation-
requirements.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and adverse event (AE) 
reporting of AE requirements. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per protocol 
should be entered into eCRFs so that the data can be used for analysis or to otherwise 
assist with interpretation of study findings. In such cases, sites will be officially instructed 
to enter the additional data into eCRFs from available source documentation. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history will be recorded per the SOE unless otherwise specified. 
 
At screening, all signs and symptoms regardless of grade within the past 30 days 
must be documented, however only Grade ≥2 signs and symptoms must be 
recorded. At entry, all new signs and symptoms regardless of grade that 
occurred since the screening visit must be documented, however only Grade ≥2 
signs and symptoms must be recorded. 
 
At screening, all diagnoses identified by the ACTG criteria for clinical events and 
other diagnoses regardless of grade within the past 30 days must be recorded. In 
addition, the following diagnoses must be recorded regardless of the date when 
they occurred: 
• 
AIDS-defining conditions (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease) 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease or stroke 


 
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• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Tuberculosis 
• 
Chronic hepatitis C virus infection 
• 
Chronic hepatitis B virus infection 
• 
Lowest known CD4 cell count (participant report accepted) 
• 
Clinical or subclinical atherosclerotic disease 
• 
DM or prediabetes or impaired fasting glucose or insulin resistance 
• 
Obesity 
• 
Hypertension 
• 
Dyslipidemia 
• 
Smoking and vaping (tobacco), current and in past three years 
 
At entry, all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade that occurred since the screening visit must be 
recorded. 
 
Any allergies to any medications and their formulations must also be documented 
but are not recorded on the eCRF. 
 
A family history of premature CAD (first degree relative with CAD prior to age 55 
for male relative and 65 for female relative) must be recorded on the eCRF. 
 
6.3.3 Medication History 
 
A medication history must be present and recorded on the eCRF, including start 
and stop dates. Table 6.3.3-1 below lists the medications that must be included 
in the history. 
 
Table 6.3.3-1: Medication History 
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
Within 12 months prior to entry 
Statins and other lipid-lowering agents 
Complete History 
Immune-based therapy 
Complete History 
Immunizations 
60 days prior to entry 
Prescription drugs for treatment of 
opportunistic infections 
Within 12 months prior to entry 
Prescription drugs for prophylaxis of 
opportunistic infections 
Within 12 months prior to entry 
Sex-hormone medications or sex-hormone 
analogues or antagonists* 
Within 12 months prior to entry, except 
for hormone-releasing IUDs 
Prescription drugs (other) 
Current 
Non-prescription drugs† 
Within 90 days prior to entry 


 
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Medication Category 
Complete History or Timeframe 
Alternative therapies 
Current 
Dietary supplements 
Current 
* Includes hormone-releasing IUDs (e.g., Mirena) inserted in the last 5 years; oral, 
injectable, implanted, or patch contraceptives; vaginal ring, creams, or inserts; estrogen, 
progesterone, or testosterone therapy; leuprolide or other synthetic gonadotropin-
releasing hormone; tamoxifen, raloxifene, aromatase inhibitors, or any other androgen, 
estrogen, or progesterone analogue or antagonist therapy. 
† Includes over-the-counter (OTC) and complementary medicines. 
 
6.3.4 Clinical Assessments 
 
At screening and entry, refer to section 6.3.2 Medical History for reporting 
requirements. Post-entry, refer to section 7.2 for AE collection requirements and 
section 8.5 for collection requirements for pregnancy. 
 
Complete Physical Exam 
A complete physical examination will be performed per the SOE and is to 
include, at a minimum: 
• 
Examination of the skin, head, mouth, and neck 
• 
Auscultation of the chest 
• 
Cardiac exam  
• 
Abdominal exam 
• 
Examination of the lower extremities for edema 
• 
Signs and symptoms 
• 
Diagnoses 
• 
Vital signs (temperature, pulse, respiration rate, and blood pressure). Blood 
pressure should be measured following the procedure in the A5415 MOPS. 
 
Targeted Physical Exam 
A targeted physical examination includes vital signs (temperature, pulse, 
respiration rate, and blood pressure) and is to be driven by any previously 
identified or new signs or symptoms and diagnoses. Blood pressure should be 
measured following the procedure in the A5415 MOPS. 
 
For confirmation of Grade ≥3 toxicity, perform a targeted physical examination if 
the investigator feels it is clinically indicated. 
 
Height, Weight, and Waist Circumference 
Record height, weight, and waist circumference per the SOE. 
 
Height and weight should be measured using the ACTG Metabolic Study Group 
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circumference should be measured following the procedure in the A5415 
MOPS. 
 
Concomitant Medications 
Post-entry, any new and discontinued prescription and non-prescription 
medications including immunizations and ARVs taken/received since the last 
study visit must be recorded. 
 
Study Treatment Modifications 
Record all study drug modifications, including initial doses and treatment 
interruptions (inadvertent and deliberate) since the last visit. Record any 
permanent discontinuation of treatment. 
 
6.3.5 Laboratory Evaluations 
 
At screening, pre-entry, and entry, all protocol-required laboratory values must be 
recorded regardless of grade. 
 
For post-entry assessments, record all of the following values regardless of grade: 
• 
Hemoglobin 
• 
White blood cell (WBC) count with differential 
• 
Platelet count 
• 
Creatinine 
• 
Fasting glucose 
• 
HbA1c 
• 
Total cholesterol (fasting) 
• 
HDL cholesterol (fasting) 
• 
LDL cholesterol (fasting) 
• 
Triglycerides (fasting) 
• 
AST 
• 
ALT 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Prothrombin Time (PT) 
• 
International Normalized Ratio (INR) 
• 
Estimated GFR 
 
NOTE: Refer to the A5415 MOPS for the link to the CKD-Epi equation and 
calculator. 
 
Refer to section 7.2 for AE reporting requirements for post-entry abnormal 
laboratory findings. 
 
Refer to the current A5415 Laboratory Processing Chart (LPC) for the collection 
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Fasting Instructions 
Fasting is defined as nothing to eat or drink except prescription medications and 
water for at least 8 hours, preferably 10 hours. If participants are in a non-fasting 
state, they should be instructed to return to the clinic within 3 days of the original 
scheduled visit for fasting evaluations (as indicated in section 6.1). 
 
Fasting is NOT required for pregnant participants. 
 
For the fasting requirements for the FDG-PET/CT imaging: See section 6.3.9. 
 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBCs), WBCs with differential, absolute 
neutrophil count (ANC), and platelets 
 
Blood Chemistries 
Serum electrolytes (sodium, potassium, and chloride), BUN, creatinine, and 
amylase. 
 
Fasting Glucose 
Fasting blood sample for glucose will be collected per section 6.1. All glucose 
collections should be collected in a gray top tube (sodium fluoride). Refer to the 
current A5415 LPC for the collection and processing instructions. 
 
Insulin 
At screening, fasting blood sample for insulin will be collected and insulin testing 
will be performed in real time. 
 
After screening, insulin testing will be performed on stored serum (see sections 
3.0 and 6.3.8). 
 
Fasting Lipid Panel 
Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides 
 
Liver Function Tests (LFTs) 
AST (SGOT), ALT (SGPT), alkaline phosphatase (ALP), total bilirubin, and direct 
bilirubin 
 
HbA1C 
HbA1c will be done in real-time per section 6.1. 
 
Prothrombin Time (PT) and International Normalized Ratio (INR) 
PT will be performed to support calculation of the INR when needed to confirm 
elevated liver enzymes that occur on study (see section 8.2.1). 
 


 
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hsCRP 
At screening, hsCRP will be performed in real-time. 
 
After screening, hsCRP will be performed on stored plasma (see sections 3.0 
and 6.3.8). 
 
Estimated GFR 
GFR will be estimated using the CKD-Epi equation per section 6.1. Refer to the 
A5415 MOPS for further information and a link to the CKD-Epi equation and 
calculator. 
 
Pregnancy Testing 
For people of childbearing potential: Serum or urine β-HCG at screening and 
entry. Urine test must have a sensitivity of <25 mIU/mL. The pregnancy test at 
entry must be performed within 15 days of the visit and the result must be 
available at the site at the time of entry. 
 
At all other visits, perform as indicated in section 6.1 and if pregnancy is 
suspected. 
 
In the event of a positive pregnancy test result, refer to section 8.5 for pregnancy 
and pregnancy outcome reporting requirements. 
 
For pregnancy testing prior to conducting the FDG-PET/CT imaging: See section 6.3.9. 
 
6.3.6 Immunologic Studies 
 
NOTE: Because of the diurnal variation in biomarkers that may be measured as 
part of the study (e.g., CD4+ and CD8+ T cell counts and other biomarkers that 
may be measured on stored samples), blood draws for individual participants 
should be performed consistently in either the morning or the afternoon 
throughout the study, if possible. 
 
CD4+/CD8+ 
At pre-entry, obtain absolute CD4+/CD8+ count and percentages from a 
laboratory that possesses a CLIA certification or equivalent (US sites) or IQA 
certification (non-US sites). 
 
For entry and post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent or equivalent (US sites) or IQA certification (non-US 
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6.3.7 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 90 days prior to study 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. 
 
At the entry and post-entry visits, HIV-1 RNA testing must be performed at the 
protocol-designated laboratory. Refer to the A5415 LPC. 
 
6.3.8 Stored Plasma/Serum and PBMC 
 
For collection, processing and shipping instructions, refer to the A5415 LPC. 
 
Stored Plasma 
Plasma will be collected per section 6.1 and stored. The stored plasma will be 
used for the following batched assays: inflammatory markers, adiponectin, 
fibrinogen, and other coagulation markers. 
 
If a participant experiences an acute inflammatory condition (including colds and 
sexually transmitted diseases [STDs]), receives a vaccine, or experiences a 
severe concurrent illness during the study, plasma must be collected with as 
much interval as possible between the illness or vaccination and blood draw 
while staying within the visit window. Sites should contact the A5415 CMC 
(actg.cmca5415@fstrf.org) with any questions regarding whether an interval 
between a specific situation and plasma collection is required. 
 
Stored Serum (fasting) 
Fasting blood sample will be collected for serum per section 6.1 and stored. 
Refer to the fasting instructions in section 6.3.5 if a participant arrives in clinic in 
the non-fasting state. The stored serum will be used for batched insulin assay. 
 
Stored PBMC 
PBMC will be collected per section 6.1 and stored. The stored samples will be 
used for batched advanced flow analysis. 
 
Advanced Flow 
Advanced flow analysis requires a CD4+/CD8+ and WBC with differential from a 
sample obtained at the same time (see section 6.1). 
 
6.3.9 18F-Fluorodeoxyglucose (FDG)-positron Emission Tomography (PET) / 
Computed Tomography (CT) 
 
FDG-PET/CT imaging will be performed per section 6.1 following the FDG-PET/CT 
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local IRB requirement for pregnancy testing prior to the imaging. Participants will 
be asked not to exercise for 24 hours before the scan and must fast for at least 8 
hours, preferably 10 hours, before the procedure. If the procedure will be 
performed in the afternoon, participants are allowed to have a low-carbohydrate 
breakfast in the morning (after fasting overnight for at least 8 hours, preferably 10 
hours) and then must fast for at least 4 hours before the procedure. Fasting blood 
glucose will be obtained prior to the imaging following the local imaging center 
procedure. The results of the pregnancy and fasting blood glucose tests are not 
reported on an eCRF. Refer to the A5415 MOPS for the pre-imaging dietary 
instructions for participants, and the image acquisition protocol for pre-imaging 
preparation and safety tests, imaging procedure, and submission guidelines. 
 
The imaging at pre-entry must be performed only after confirming that the 
participant meets all screening eligibility requirements. If participants have 
received any immunizations prior to the pre-entry (baseline) FDG-PET/CT 
imaging, the imaging must be performed at least 7 days after the 
immunization(s). For participants receiving any immunizations during the study, 
the imaging must be performed at least 7 days after the immunization(s). The site 
must notify the A5415 CMC (actg.cmca5415@fstrf.org) if the imaging may have 
to be performed outside the visit window to achieve the required separation 
between an immunization and the imaging. If participants interrupted their ART 
for ≥5 days prior to the pre-entry FDG-PET/CT or their ART or study drug for ≥5 
days prior to the week 24 FDG-PET/CT, sites must notify and consult the A5415 
CMC (actg.cmca5415@fstrf.org) prior to performing the FDG-PET/CT. 
 
The pre-entry FDG-PET/CT imaging is valid for 60 days prior to study entry. All 
imaging at pre-entry and on study must be evaluated by the local radiologist for 
incidental findings and the central reading laboratory for overall completeness 
and image quality. Any incidental findings in the pre-entry imaging must be 
reviewed by the site investigator to determine if it is safe for the participant to 
proceed with entry into the study. Refer to section 8.4 for additional guidance 
regarding the management of any clinically relevant incidental findings in the pre-
entry and on study imaging. The site investigator should contact the CMC via 
email (actg.cmca5415@fstrf.org) if there are any concerns. 
 
The imaging at pre-entry or week 24 may be repeated once and only once if the 
image is deemed not interpretable. The site must have permission from the 
A5415 CMC (actg.cmca5415@fstrf.org) before the repeat imaging is scheduled 
and performed. 
 
Refer to section 6.2.4 for the instructions for performing FDG-PET/CT imaging at 
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6.3.10 Pharmacokinetic Studies 
 
At each visit indicated in section 6.1, a single PK sample will be drawn and stored. 
 
Participants should be stable on ART for at least 10 days (i.e., no ART regimen 
change for 10 days) prior to PK draws. The ART dose prior to the PK evaluations 
should be given as close to 12 hours prior to the PK evaluation as is feasible. 
Blood should be drawn before the morning dose of CVC/CVC placebo (as 
applicable) and ART. In the case where a morning CVC/CVC placebo or ART 
dose is taken prior to the trough measurements or if any of the four preceding 
doses have been missed, the PK sampling should be rescheduled during the 
same week, if possible. If this is not possible, contact the A5415 CMC 
(actg.cmca5415@fstrf.org) for guidance. Dates and times of the last four doses 
of ART and CVC will be recorded. 
 
For processing and shipping instructions, refer to the A5415 LPC. Refer to 
section 11.0 for assay details. 
 
6.3.11 Adherence Assessment 
 
Adherence to ART by self-report will be assessed at entry, all post entry visits, 
and at premature treatment discontinuation. Adherence to CVC by self-report 
and pill count will be assessed at all post entry visits and at premature treatment 
discontinuation. Sites will provide adherence reinforcement, according to 
standard practice, throughout the study. Participants with poor adherence will be 
provided counseling by the site. 
 
The adherence eCRF is posted on the DMC Portal in the Forms Management 
Utility. 
 
6.3.12 Food Diary 
 
A 4-day food record (3 weekdays and 1 weekend day) will be collected per 
section 6.1. The food diary does not have to be collected on consecutive days 
and should represent the participant’s usual diet. Refer to the A5415 MOPS for 
the instructions for completing the food diary. The date the food diary was 
collected will be recorded. 
 
6.3.13 Perceived Stress Scale-10 
 
The Perceived Stress Scale-10 will be completed by participants within 7 days of 
the FDG-PET with CT scan at pre-entry and at week 24. If the participant has not 
completed the scale prior to the FDG-PET with CT scan, the participant may 
complete it during the FDG-PET with CT scan visit. 
 


 
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The Perceived Stress Scale-10 is posted on the DMC Portal in the Forms 
Management Utility. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition. 
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
• 
All new Grade ≥2 diagnoses and the following targeted events regardless of grade: 
o AIDS-defining conditions (refer to the CDC HIV Classification and the WHO 
Staging System for HIV Infection and Disease) 
o Bone fractures (verbal history accepted) 
o Coronary heart disease 
o Cancer (exclusive of basal/squamous cell skin cancer) 
o Diabetes 
o Tuberculosis, active or latent 
o Hepatitis C virus infection 
o Hepatitis B virus infection 
o SARS-CoV-2 infection 
o Any infection 
• 
All Grade ≥3 signs and symptoms, except fever and chills, which should be reported 
regardless of grade 
• 
All Grade ≥2 laboratory findings 
o NOTE: Creatinine and eGFR should be graded using the categorical mL/min 
values from the DAIDS AE Grading Table. The percent change criteria from 
baseline will not apply to A5415. 
• 
Any Grade ≥3 AE that occurs due to or during the FDG-PET/CT imaging 
• 
All AEs that led to a change in study treatment regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
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found on the DAIDS RSC Web site: https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Result 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 participant 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 DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. 
 
DAERS, an internet-based reporting system, must be used for expedited EAE 
reporting to DAIDS. In the event of system outages or technical difficulties, EAEs 
may be submitted via 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 Clinical Research 
Management System (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: cenicriviroc 
(CVC) and placebo for cenicriviroc (CVC). 
 


 
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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 Web site at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables. 
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as per the DAIDS EAE manual. 
• 
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 team will monitor the conduct and safety of the study via monthly 
summaries of accrual and reportable AEs. This summary will be pooled over the 
treatment arms. In addition, baseline characteristics, early study treatment and study 
discontinuations, and virologic failures, pooled over arms, will be reviewed regularly by 
the leadership team, at a minimum of once a month. 
 
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. 
 
The study will undergo interim review yearly by the CTSG Study Monitoring Committee 
(SMC). The first interim review will occur approximately 8 months after enrollment of the 
first participant. An interim review may also be convened if a concern is identified by the 
DAIDS Clinical Representative, the study chairs, or study statistician in consultation with 
the team. See section 10.5 for statistical considerations related to interim monitoring. 
 
Detailed plans for study monitoring will be outlined in a Study Progress, Data, and Safety 
Monitoring Plan developed by the Statistical and Data Management Center (SDMC) 
prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity 
 
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8.1.1 Grades 1 and 2 Toxicity 
 
Participants who develop a Grade 1 or 2 laboratory abnormality or AE may 
continue the study treatment at the discretion of the site investigator and 
managed according to local guidelines. 
 
8.1.2 Grade 3 Toxicity 
 
If a participant develops a Grade 3 laboratory abnormality, a confirmatory 
measurement should be obtained within 5 days after the laboratory result 
becomes available. 
 
A Grade 3 laboratory abnormality that is not confirmed upon repeat testing will 
be managed according to the toxicity management guidance for the new toxicity 
grade. 
 
If the Grade 3 laboratory abnormality is confirmed or the participant has a 
Grade 3 clinical AE, the study treatment may be continued if the laboratory 
abnormality or clinical AE is considered to be unrelated to study drug after 
discussion with the A5415 CMC (actg.cmca5415@fstrf.org). 
 
If a confirmed Grade 3 laboratory abnormality or an AE is considered to be 
related to study treatment, the study treatment should be interrupted. The AE 
should be monitored and/or the laboratory test repeated regularly as clinically 
indicated. The study treatment may be resumed once the toxicity returns to 
Grade ≤2. 
 
If a laboratory abnormality or AE recurs to Grade ≥3 following rechallenge with 
study drug and is considered related to study treatment, the study treatment will 
be permanently discontinued and the participant managed according to local 
practice. The decision to continue a participant on study/off study treatment until 
completion of all other study visits for assessment of clinical outcomes must be 
agreed upon by the site investigator and the A5415 CMC. Refer to section 6.2.4 
for the instructions for following participants on study/off study treatment. 
 
Recurrence of a laboratory abnormality or AE considered unrelated to study 
treatment may not require permanent treatment discontinuation. Continuing the 
study drug after a recurrent Grade 3 laboratory abnormality or AE considered 
not related to study treatment should be discussed with the A5415 CMC 
(actg.cmca5415@fstrf.org) prior to continuing the study drug. 
 
The study treatment may be continued without dose interruption for a clinically 
nonsignificant Grade 3 laboratory abnormality (e.g., glucose elevation in 
participants with pre-existing diabetes; glucose, cholesterol or triglyceride 
elevation that is non-fasting or that can be medically managed). 
 


 
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8.1.3 Grade 4 Toxicity 
 
If a participant develops a Grade 4 laboratory abnormality, a confirmatory 
measurement should be obtained within 5 days after the laboratory result 
becomes available. 
 
The study treatment may be continued without dose interruption for a 
clinically nonsignificant Grade 4 laboratory abnormality (e.g., glucose 
elevation in participants with pre-existing diabetes; glucose, 
cholesterol, or triglyceride elevation that is non-fasting or that can be 
medically managed). 
 
A Grade 4 laboratory abnormality that is not confirmed upon repeat testing will 
be managed according to the toxicity management guidance for the new 
toxicity grade. 
 
If the Grade 4 laboratory abnormality is confirmed or the participant has a 
Grade 4 clinical AE, the study treatment may be continued if the laboratory 
abnormality or clinical AE is considered to be unrelated to study treatment after 
discussion with the A5415 CMC (actg.cmca5415@fstrf.org). 
 
If a confirmed Grade 4 laboratory abnormality or an AE is considered to be 
related to study treatment, the study treatment should be permanently 
discontinued and the participant managed according to local guidelines. The 
participant should be followed as clinically indicated until the AE or laboratory 
abnormality returns to Grade ≤2, if applicable, or is otherwise explained, 
whichever occurs first. 
 
The decision to continue on study/off study treatment until completion 
of all other study visits for assessment of clinical outcomes must be 
agreed upon by the site investigator and the A5415 CMC. Refer to 
section 6.2.4 for the instructions for following participants on study/off 
study treatment. 
 
8.2 
Specific Management of Toxicities Related to Study-Provided Treatment 
 
8.2.1 Elevated Liver Enzymes 
 
Site personnel must report treatment-emergent (i.e., not present at screening or 
baseline) and confirmed ALT and/or AST elevations meeting any of the following 
criteria for suspected drug-induced liver injury (DILI), with special consideration 
given to baseline transaminase values: 
• 
When the baseline ALT or AST values are <2 x ULN, and the ALT and/or 
AST increases to >3 × ULN and >5 x the baseline value (confirmed upon 
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• 
When the baseline ALT or AST values are <2 x ULN, and ALT and/or AST 
increases to >3 x ULN but ≤5 x the baseline value (confirmed upon repeat 
testing) AND the increase is accompanied by total bilirubin >2 x ULN (in 
participants with Gilbert’s syndrome use direct bilirubin >2 x baseline) 
AND/OR if the participant also has symptoms consistent with clinical hepatitis 
(for example, fatigue, nausea/vomiting, right upper quadrant [RUQ] 
abdominal pain or tenderness, fever, rash, or eosinophilia) without an 
alternative explanation for the event as judged by the site investigator. 
• 
When the baseline values are ≥2 x ULN but <5 x ULN, and the ALT and/or 
AST increases to >3 x the baseline value (confirmed upon repeat testing). 
• 
When the baseline values are ≥2 x ULN but <5 x ULN, and the ALT and/or 
AST increases to >2 x the baseline but ≤3 x baseline value (confirmed upon 
repeat testing) AND the increase is accompanied by total bilirubin >2 x ULN 
(in participants with Gilbert’s syndrome use direct bilirubin >2 x baseline) 
AND/OR if the participant also has symptoms consistent with clinical hepatitis 
(e.g., fatigue, nausea/vomiting, RUQ abdominal pain or tenderness, fever, 
rash, eosinophilia) without an alternative explanation for the event as judged 
by the site investigator. 
• 
When baseline values are ≥5 × ULN and ALT and/or AST increases to >2 × 
the baseline value (confirmed upon repeat testing). 
• 
When the ALT and/or AST increases to >3 x ULN and >2 x baseline 
(confirmed upon repeat testing) AND the increase is accompanied by either 
total bilirubin increase to >2 x the baseline value OR INR increase by >0.3 
from baseline to a value >1.5. 
 
The participant must return to the CRS for re-evaluation within 5 days after the 
treatment-emergent AST and/or ALT elevation for confirmatory testing that will 
include an ALT or AST, AND total bilirubin or INR. A comprehensive clinical 
evaluation, including evaluations for causes other than study treatment, and 
close clinical monitoring must be performed. The A5415 CMC should be 
informed via email (actg.cmca5415@fstrf.org) within 48 hours of receipt of the 
treatment-emergent AST and/or ALT elevation. 
 
After the confirmation that the ALT or AST elevations and other laboratory tests 
meet the criteria for suspected DILI, the A5415 CMC should be informed via 
email (actg.cmca5415@fstrf.org) within 48 hours. Study treatment should be 
interrupted upon confirmation. After consultation with the CMC, a decision 
regarding temporary or permanent discontinuation will be made. The 
participant should continue to be followed for close monitoring, which will 
include repeat liver enzyme and serum bilirubin tests at least once a week, and 
INR as clinically indicated, until abnormalities stabilize and the participant is 
asymptomatic. Refer to the A5415 MOPS for additional guidance on evaluating 
participants with suspected DILI. 
 


 
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Site investigators may involve the CMC in the clinical management of LFT 
abnormality or clinical hepatitis without other explanation whenever there is 
concern that the event is study treatment-related, regardless of whether specific 
DILI criteria are met, to discuss study drug management. 
 
8.2.2 GFR 
 
GFR will be monitored as scheduled in section 6.1. 
 
A participant experiencing an estimated GFR <50 mL/min/1.73 m2 should have 
the value confirmed within 14 days. 
 
A participant who has confirmed two consecutive reductions in estimated GFR to 
<60 mL/min/1.73 m2 may continue to participate, however the site investigator 
should consider dose adjustment or discontinuation of TDF and inform the 
participant’s primary physician. 
 
8.3 
Adverse Event Related to FDG-PET/CT Imaging 
 
Any Grade ≥3 AE that occurs due to or during the FDG-PET/CT imaging must be 
reported to the A5415 CMC (actg.cmca5415@fstrf.org) within 48-72 hours after the 
occurrence of the AE and monitored for resolution. 
 
8.4 
FDG-PET/CT Imaging Findings 
 
Any incidental findings in the imaging must be reviewed by the site investigator, and 
consult with the local radiologist designated by the site to read for incidental findings 
should be considered. Refer to section 6.3.9 for the details regarding the requirement for 
a local radiologist to review all imaging. The site investigator should inform the 
participant and the participant’s primary physician of any clinically relevant incidental 
finding and discuss the need for further evaluations. 
 
8.5 
Pregnancy 
 
Participants who become pregnant after study entry must discontinue study treatment 
immediately. These participants should be seen for premature treatment discontinuation 
evaluations as per section 6.2.4. These participants will also be followed on study, off 
study treatment through completion of the study with evaluations per section 6.1, except 
they will not be required to fast and will not have the FDG-PET/CT imaging performed 
and PK samples drawn. The only safety laboratory tests that will be performed are 
hematology (except ANC) and LFTs. The A5415 CMC (actg.cmca5415@fstrf.org) must 
be notified of any pregnancies that occur in participants on study. Management of the 
background ART is at the discretion of the site investigator. 
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. Pregnancies that 
occur on study should be reported prospectively to The Antiretroviral Pregnancy 


 
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Registry. More information is available at www.apregistry.com. Phone: 800-258-4263; 
Fax: 800-800-1052. (For studies conducted at sites outside the United States, report to 
The Antiretroviral Pregnancy Registry—Telephone: 910-679-1598; Fax: 44-1628-789-
666 or 910-256-0637.) 
 
Pregnancy Outcomes and Reporting 
If an individual chooses to discontinue from the study before the end of the pregnancy, 
site staff should request permission to contact them regarding pregnancy outcomes at 
the end of pregnancy. Once the information is obtained, pregnancy outcomes will be 
submitted on an eCRF at the end of the pregnancy and EAE reporting, if appropriate. 
 
8.6 
Breastfeeding 
 
Breastfeeding is exclusionary and not allowed during the study. If a participant begins 
breastfeeding during the study, they will be discontinued from study treatment. The 
participant will continue to be followed on study, off study treatment through the end of 
the study period with evaluations per section 6.1, except they will not be required to fast 
and will not have the FDG-PET/CT imaging performed and PK samples drawn. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see sections 8.1 and 8.2). 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Confirmed virologic failure (see section 6.2.3). 
• 
Pregnancy or breast-feeding. 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the Toxicity section of the protocol. 
 
9.2 
Premature Study Discontinuation 
 
• 
Participant repeatedly noncompliant (missing eight consecutive doses or more) with 
study medications as prescribed. 
• 
Failure to start study treatment. 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
• 
At the discretion of the IRB/Ethics Committee, ACTG, Food and Drug Administration 
(FDA), NIAID, Office for Human Research Protections (OHRP), other government 
agencies as part of their duties, investigator, or industry supporter. 
 


 
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10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
A5415 is a double-blind, randomized, placebo-controlled, phase II trial to evaluate 24 
weeks of CVC on TBR in the carotid arteries and aorta among individuals living with 
chronic HIV on ART with viral suppression. CVC or placebo for CVC will be administered 
for 24 weeks to participants. The total sample size will be 93 participants (62 in the CVC 
arm and 31 in the placebo arm). 
 
10.2 
Outcome Measures 
 
Primary and secondary outcomes listed below will be addressed in the study’s primary 
Statistical Analysis Plan, which will define the content of the primary statistical analysis 
report. This report will form the basis for the primary study manuscript(s) and results 
reporting to https://ClinicalTrials.gov. Outcomes of interest for secondary and exploratory 
objectives intended for subsequent publications are listed as other outcome measures. 
 
10.2.1 Primary Outcome Measures 
 
Change in arterial most diseased segment (MDS) 18-FDG-PET target-to-background 
ratio (TBR), measured in the carotid arteries and aorta, from baseline to week 24. 
 
The standardized uptake value (SUV) of FDG will be measured in the carotid 
arteries, aortic root, and the left main coronary artery. The SUV is the decay-
corrected tissue concentration of FDG (in kBq/mL) divided by the injected dose 
per body weight (kBq/g). TBR will be calculated for each vascular segment as the 
segment SUV divided by mean venous blood SUV. 
 
NOTE: The MDS has been preferred as the primary outcome measure at the 
time of the study design. However, since this choice of endpoint is guided by 
studies in populations with chronic atherosclerotic disease that typically excluded 
individuals with active inflammatory diseases or HIV, the study team intends to 
re-evaluate this choice of primary outcome measure closer to the time of the 
analysis (prior to review of the arterial inflammation data) based on contemporary 
data at that time. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 
Change in aortic TBR (and other TBRs) from baseline to week 24 
 
10.2.2.2 
Change in SUV measured in the carotid arteries and aorta from 
baseline to week 24 
 
10.2.2.3 
Change in fasting glucose from baseline to week 24 
 


 
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10.2.2.4 
Change in HOMA-IR from baseline to week 24 
 
10.2.2.5 
Change in biomarkers from baseline to week 22/24 
 
10.2.3 Other Outcome Measures 
 
10.2.3.1 
Change in FDG uptake in visceral fat and lymph nodes from baseline 
to week 24 
 
10.2.3.2 
Change in adipocytokines (such as adiponectin) from baseline to 
week 24 
 
10.2.3.3 
Change in plasma CCR5 and CCL2 levels from baseline to week 
22/24 
 
10.2.3.4 
Changes in myeloid derived suppressor cell (MDSC) frequencies as 
well as monocyte subsets (as defined by expression of CD14 AND 
CD16, expression of homing receptors: CX3CR1, CCR5, CCR2, and 
activation as determined by HLA-DR density and CD69 expression) 
from baseline to week 22/24 
 
10.2.3.5 
Changes in CD4 and CD8 T cell expression of CX3CR1, CCR2, 
CCR5, and activation as determined by expression of CD38 and HLA-
DR from baseline to week 22/24 
 
10.2.3.6 
Change in fasting insulin from baseline to week 24 
 
10.2.3.7 
Change in fibrinogen and other coagulation markers from baseline to 
week 24 
 
10.2.3.8 
Changes in visceral adipose tissue area and volume, subcutaneous 
adipose tissue area and volume, fat density, and liver to spleen 
attenuation ratio (as a noninvasive measure of hepatosteatosis) by 
noncontrast CT from baseline to week 24 
 
10.3 
Randomization and Stratification 
 
At study entry, participants will be randomized at a 2:1 ratio (CVC arm: placebo arm), 
using permuted blocks stratified by statin use. Institutional balance will not be used at 
randomization. 
 
While enrollment is ongoing, enrollment limits will be increased to replace participants 
who are randomized but do not start treatment. 
 


 
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10.4 
Sample Size and Accrual 
 
The target sample size is 75 participants (50 in the CVC arm and 25 in the placebo arm) 
with baseline and follow-up PET/CT. To allow for some loss to follow-up and participants 
unwilling or unable to complete 2 scans, we plan to enroll 93 participants (62 in the CVC 
arm and 31 in the placebo arm) in this trial. 
 
The primary analysis will focus on between-treatment arm differences in the within-
participant changes in arterial MDS TBR (the measure of arterial inflammation by 
PET/CT). Based on a superiority trial design with two-sided α=0.05, assuming a 
standard deviation (SD) of 0.065 log10 TBR for change in MDS TBR, a total of 75 
participants providing complete, evaluable data sets will ensure 80% power to detect a 
between-groups difference of 0.046 log10 MDS TBR (which is a 10% reduction from 
baseline). 
 
The assumptions underlying the power calculation are as follows: 
1) The target effect size for the change in MDS TBR on therapy of 10% is based on the 
observation of a statin intensification study [46]. 
2) The assumed SD for change in (log10) MDS TBR of 0.065 is derived from the 
placebo arm of ACTG A5314. 
3) The use of a two-sided, two-sample T-test with type-I error rate of 5%. 
 
The assumption that 93 enrolled participants will provide 75 participants with evaluable 
data is derived by 20% total data loss due to drop-out after randomization (including 
premature discontinuation of study treatment and change in background ART drug 
class). 
 
If the variability in the change in MDS TBR is lower than assumed (smaller SD) or the 
total data loss is lower than assumed, the statistical power to detect the targeted effect 
size for our primary analysis will be higher (see Table 10.4-1). 
 
Table 10.4-1: Sample Sizes and Power Corresponding to Various Total Data Loss and 
Assumed SD 
Total sample 
size 
Total data 
loss 
Evaluable 
sample size 
Power 
Assumed SD for 
change in MDS 
TBR (in log10) 
93 (62 + 31) 
20% 
75 (50 + 25) 
80% 
0.065 
108 (72 + 36) 
20% 
87 (58 + 29) 
80% 
0.071 
93 (62 + 31) 
20% 
75 (50 + 25) 
85% 
0.061 
93 (62 + 31) 
17% 
78 (52 + 26) 
83% 
0.065 
 
For secondary outcome measures (excluding the secondary imaging measures), the 
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assumes a 15% total data loss (lower since there will be no loss due to image 
scheduling or quality related issues). 
 
We expect to have slow accrual completed over a period of 2 years. Full details of the 
accrual plan will be outlined in the Study Progress, Data, and Safety Monitoring Plan 
(SPDSMP). Participants who do not start study treatment will be replaced unless 
enrollment has been completed. 
 
10.5 
Data and Safety Monitoring 
 
The ACTG CTSG SMC will review study conduct and adverse events over time, broken 
by treatment arms. Efficacy review or treatment arm comparisons will not be included in 
the SMC interim reviews. There is no other formal stopping guideline for this study. See 
section 7.4 for study monitoring timelines and other details. 
 
10.6 
Analyses 
 
All statistical tests will be two-sided with a nominal alpha level of 0.05. No adjustment for 
multiple testing will be performed. Stratification will be taken into account in all analyses 
unless stated otherwise. 
 
Since the goal of the study is to determine the biological activity of CVC on vascular 
inflammation, the primary analytic approach will be per protocol and limited to 
participants who remain on study treatment without change in background ART drug 
class per the study design. 
 
Baseline is defined as pre-entry for TBR and SUV, average of entry and pre-entry for 
immunology markers, and entry for all other outcome measures. 
 
10.6.1 Analysis Sets 
 
Per-protocol population is defined as all participants who receive study treatment 
over 22 weeks and remain on the same ART drug class during the entire study 
period. 
 
Safety analysis population is defined as all participants who initiated study 
treatment. 
 
10.6.2 Primary Analyses 
 
The primary analysis of efficacy will be limited to the per-protocol population. 
 
TBR will be transformed for analyses on the log10 scale and back transformed to 
percentage change for interpretation and presentation. Change in TBR will be 
summarized by mean and 95% confidence interval for percentage for each 
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use. A 95% confidence interval for the relative between-arm shift will also be 
estimated. 
 
10.6.3 Secondary Analyses 
 
A sensitivity analysis for the primary analysis will include participants in the per-
protocol analysis described in the primary analysis above as well as participants 
with data available for evaluation completed at premature treatment or study 
discontinuation that is after week 12 as long as they are on treatment within 7 
days of the evaluation. 
 
Supplementary analyses for the primary analysis will exclude participants with 
confirmed HIV-1 RNA >200 copies/mL at any time during the course of the study 
and extensive periods of ART interruption (see SAP for more detail). 
 
Key secondary endpoints (section 10.2.2) will be analyzed in the same manner 
(also per-protocol) as in the primary analysis. 
 
For immunology markers, two blood draws will be performed at baseline (pre-
entry and entry) and week 22/24 (week 22 and week 24) and the measurements 
will be the average of two values in order to reduce intra-participant variability. 
Outcome measurements may be transformed for analyses on the log10 scale, as 
appropriate. 
 
Safety will be evaluated by summarizing the nature and rate of AEs (signs and 
symptoms, laboratory values, SAEs) for the safety analysis population. 
 
10.6.4 Handling of Missing Data and Sensitivity Analyses 
 
Multiple imputation will be used to account for missing data due to unreadable or 
missed scans. 
 
A sensitivity analysis for the primary analysis will include a complete case 
analysis. 
 
10.7 
Unblinding 
 
Planned Unblinding 
Participants will be unblinded at completion of the study. Please refer to ACTG SOP-123 
Unblinding Participants for details. 
 
Sudden/Unplanned Unblinding 
• 
The decision to unblind one or more arms of an ongoing study is made by the team 
in conjunction with the relevant Scientific Committee and the Executive Committee. 
This can occur based on a recommendation from the SMC or the results of another 
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• 
If the decision is made to unblind, participants should be unblinded as soon as 
possible. Unblinding is conducted through the DMC, which sends treatment 
assignments to the sites soon after the unblinding decision. Every effort should be 
made by the sites to contact participants who have completed follow-up in order to 
explain the study results. 
• 
When a treatment comparison is unblinded based on an interim analysis, the results 
of that interim analysis must be reported in publications. Data from visits that 
occurred before the interim review but that were not in the database at the data 
cutoff date have little potential for bias and may be reported with a comment. Data 
from visits that occurred after unblinding are potentially biased and must not be used 
if the intent is to claim that all the data are from a blinded study. In unblinding due to 
both “interim analysis” and the “other trial results” situations, if analyses are reported 
on clinical data or samples taken after the unblinding date, the conditions under 
which these data were gathered must be made clear in any publication. 
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
11.1.1 To determine the impact of INSTI and NNRTI-based ART on CVC trough 
estimates. 
 
11.1.2 To determine the impact of CVC treatment on the trough exposure of ART. 
 
11.1.3 To determine the association between CVC trough exposure and the primary 
treatment outcome (i.e., reduced arterial inflammation). 
 
11.2 
Pharmacology Study Design 
 
Participants will be enrolled who are stabilized on an NNRTI-based or unboosted INSTI-
based ART regimen for ≥48 weeks prior to study entry. PK data available to date is 
specified in section 2.1 (“Supporting Pharmacokinetic Data from Allergan/AbbVie”). 
Appropriate dosage adjustments will be made for participants on EFV-based ART based 
on these prior data. Data for those on INSTI-based ART is limited to DTG where modest 
reduction in CVC exposure (28% and 29% reduction in CVC Cmax and AUC 0-24 hr, 
respectively) was detected. Therefore, to provide information for CVC PK in individuals 
living with HIV on these regimens and to provide ART PK in the context of CVC 
specifically in individuals living with HIV, a sparse PK design will be completed. Since 
CVC should be taken with meals, information about whether or not dosing is done with 
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11.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
11.3.1 Outcome Measures 
 
Blood for PK sampling will be collected at select study visits, and before the 
morning dose of CVC/placebo, as per protocol for CVC and ART. Trough ART 
levels will be determined for all participants at pre-entry and weeks 4, 8, 12, and 
24. For those randomized to active drug, trough levels for CVC will be 
determined at weeks 4, 8, 12, and 24. 
 
Only drug concentration levels determined from samples obtained at steady state 
(no missed doses within the preceding 4 days) and no more than 14 hours post 
last EFV-based ART or 26 hours post last non-EFV based ART and 
CVC/placebo for CVC dose will be used in analyses. 
 
11.3.2 Data Analysis 
 
Pharmacokinetics 
CVC Exposure: An average steady-state CVC trough concentration will be 
estimated by ART regimen (INSTI- or NNRTI-based ART) and compared 
between ART regimens and with historical data for CVC. 
 
ART exposure: An average steady-state ART trough concentration will be 
estimated pre- and post-CVC/placebo for CVC dosing. Average steady state ART 
trough concentrations during CVC/placebo for CVC co-administration will be 
compared a) between those on CVC and those on placebo for CVC (inter-
participant comparison) and b) with pre-CVC levels (intra-participant comparison). 
 
Analyses will use time-adjusted linear mixed effect models with measured 
concentration log-transformed. 
 
Pharmacodynamics 
Correlation of CVC exposure to outcomes: A composite time-adjusted CVC 
exposure estimate over the 24-week study period will be obtained for each 
participant from the mixed effect modelling based on their measured 
concentrations at weeks 4, 8, 12, and 24. Associations of these empirical Bayes 
estimates and the following arterial inflammation outcomes measured will be 
estimated via Spearman’s rank-based correlation. 
• 
Change in most diseased vessel TBR from baseline to week 24 
• 
Change in aortic TBR from baseline to week 24 
• 
Change in carotid artery TBR from baseline to week 24 
• 
Week 24 aortic TBR 
• 
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11.4 
Anticipated Outcomes 
 
Average trough estimates for CVC and each ART will be calculated for comparisons 
outlined above. Trough estimates for CVC at weeks 4, 8, 12, and 24 will be time 
adjusted to provide a composite exposure estimate as described above. 
 
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 randomization. 
 
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 ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include 
remote source document verification using methods specified for this purpose by NIAID. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to 
ensure the safety of study participants and data integrity [47]. The site must make 
available study documents for site monitors to review utilizing a secure platform that is 
HIPAA and 21 CFR Part 11 compliant. The Data Management Center will configure 
Medidata Remote Source Review (RSR) and make it available to all sites. We 
encourage Sites to use the the DMC provided Medidata RSR platform but other 
potential platform options include: Veeva SiteVault, site-controlled SharePoint or cloud-
based portal, and direct access to Electronic Medical Record (EMR). Other secure 
platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS 
Office of Clinical Site Oversight (OCSO). 
 
12.4 
Reporting Protocol Deviations 
 
The site principal investigator and staff are responsible for identifying and reporting 
deviations. If protocol deviations are identified, corrective actions are to be developed by 
the site and implemented promptly. Protocol deviations must be reported to the IRB/EC 
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Refer to the MOPS for the definition of protocol deviation and instructions for completing 
the study protocol deviation eCRF. 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the Informed Consent document and any subsequent modifications 
will be reviewed and approved by the IRB or EC responsible for oversight of the study. A 
signed consent form will be obtained from the participant (or legal guardian or person 
with power of attorney for participants who cannot consent for themselves). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the participant or 
legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory authorities as part of their duties, or 
the industry supporter or designee. 
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other country-specific government agencies as part of their duties to ensure that 
research participants are protected, or the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission. 
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 


 
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All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 
 
 


 
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16.0 
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41. Virmani R, Kolodgie FD, Burke AP, et al. Atherosclerotic plaque progression and 
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Thromb Vasc Biol 2005;25:2054-61. 
42. Elkhawad M, Rudd JHF, Sarov-Blat L, et al. Effects of p38 mitogen-activated protein kinase 
inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC 
Cardiovasc Imaging 2012;5:911-22. 
43. Funderburg NT, Mayne E, Sieg SF, et al. Increased tissue factor expression on circulating 
monocytes in chronic HIV infection: relationship to in vivo coagulation and immune 
activation. Blood 2010;115:161-7. 
44. Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and 
pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral 
treatment-experienced, CCR5 antagonist-naïve patients. Antimicrob Agents Chemother 
2011;55:2768-74. 
45. Sanyal A, Ratziu V, Harrison S, et al. Cenicriviroc versus placebo for the treatment of non-
alcoholic steatohepatitis with liver fibrosis: results from the year 1 primary analysis of the 
phase 2b CENTAUR Study. In: Program and Abstracts of the American Academy for the 
Study of Liver Diseases (AASLD) Annual Meeting (the Liver Meeting®); November 11-15, 
2016; Boston, MA. 
46. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid 
reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-
positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol 
2013;62:909-17. 
47. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards. March 2020; Updated on January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download. 


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APPENDIX I: RESULTS OF CENICRIVIROC MESYLATE (CVC) STUDIES 
 
Appendix I Table 1 
Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
104 
Phase 1 
A phase 1 multiple-dose, 
cross-over study to assess 
the potential interaction 
between TBR-652 and RTV 
in healthy volunteers 
20 healthy adults 
50 mg CVC po × 10 days, then 50 mg 
CVC + 100 mg RTV po × 10 days 
(CVC administered as 2×25 mg 
tablets after a standardized meal) 
[Standardized meal contained 
approximately 500-700 kcal and <15-
20 g fat] 
DP3_25 
formulation, 
manufactured by 
Emerson 
Resources 
1. Plasma PK of CVC 
with/without RTV 
2. Safety, tolerability 
Noteworthy Findings: 
RTV significantly increased exposure to CVC (based on ratios of LS geometric means: 2.39-fold increase in Cmax and a 3.55-fold increase in AUC0-24) and 
reduced exposure to CVC metabolites. There were no clinically important safety findings. 
Allergan Study 652-1-
105 
Phase 1 
A phase 1, open-label, 
single-dose, randomized, 
cross-over study to assess 
the potential interaction 
between TDF and TBR-652 
in healthy volunteers 
21 healthy adults 
150 mg CVC po, 300 mg TDF, 150 
mg CVC po + 300 mg TDF (CVC 
administered as 6×25 mg tablets after 
a standardized breakfast) 
[Standardized breakfast contained 
approximately 500-700 kcal and <15-
20 g fat] 14-day washout between 
regimens 
DP3_25 
formulation, 
manufactured by 
Emerson 
Resources 
1. Plasma PK of CVC 
with/without TDF 
2. Plasma PK of TDF 
with/without CVC 
3. Safety, tolerability 
Noteworthy Findings: 
TDF had no effect on CVC exposure. Co-administration of CVC and TDF did not affect the AUC0-t and AUC0-∞ of TDF, based on the protocol-defined equivalence 
range of 0.70-1.43. However, co-administration with CVC increased the AUC and Cmax of TDF by approximately 28%-36%, with the 90% CI for the Cmax of TDF 
falling outside the 0.80-1.25 “no effect” range. There were no clinically important safety findings. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
107 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of DRV/r 
on the PK of CVC 
20 healthy adults 
Period 1: CVC 50 mg QD po × 10 
days after a standardized breakfast 
Period 2: CVC 50 mg QD po + DRV/r 
800/100 mg QD po × 10 days after a 
standardized breakfast 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. Plasma PK of CVC 
2. Safety and 
tolerability 
Noteworthy Findings: 
Co-administration of DRV/r 800/100 mg with CVC 50 mg daily for 10 days resulted in an approximately 2.17-fold increase in plasma CVC Cmax, a 4.17-fold increase 
in Cmin, and a 3.13-fold increase in AUC0–24. 
Allergan Study 652-1-
108 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of ATV/r 
on the PK of CVC 
20 healthy adults 
Period 1: CVC 50 mg QD po × 10 
days after a standardized breakfast 
Period 2: CVC 50 mg QD po + ATV/r 
300/100 mg QD po × 10 days after a 
standardized breakfast 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. Plasma PK of CVC 
2. Safety and 
tolerability 
Noteworthy Findings: 
Co-administration of ATV/r 300/100 mg with CVC 50 mg daily for 10 days resulted in an approximately 2.55-fold increase in plasma CVC Cmax, a 5.75-fold increase 
in Cmin, and a 3.89-fold increase in AUC0-24. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
109 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of EFV on 
the PK of CVC and to 
assess the effect of CVC on 
the PK of EFV 
40 healthy adults 
(20 in Group 1 and 
20 in Group 2) 
Group 1 (effect of EFV on CVC):  
Period 1: CVC 200 mg QD po after 
dinner* × 10 days 
Period 2: CVC 200 mg QD po after 
dinner* + EFV 600 mg QD po at 
bedtime × 10 days 
Period 3: CVC 400 mg QD po after 
dinner* + EFV 600 mg QD po at 
bedtime × 10 days 
(14-day washout between Periods 2 
and 3) 
Group 2 (effect of CVC on EFV): 
Period 1: EFV 600 mg QD po at 
bedtime × 10 days 
Period 2: EFV 600 mg QD po at 
bedtime + CVC 400 mg QD po after 
dinner* × 10 days 
 
 
[*Standardized dinner contained 725 
kcal, 26 g fat, 89 g carbohydrates, 26 
g protein] 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. Plasma PK of CVC 
(Group 1) 
2. Plasma PK of EFV 
(Group 2) 
3. Safety and 
tolerability 
Noteworthy Findings: 
In Group 1, co-administration of EFV 600 mg with CVC 200 mg daily for 10 days during Period 2 resulted in a significant decrease in CVC exposure compared to 
CVC alone, with Cmax, Cmin, and AUC0–24 being 23%, 48%, and 43% lower, respectively, for EFV + CVC co-administration compared to CVC alone. Dose 
adjustment of CVC to 400 mg daily in Period 3 offset the drug interacting effect of EFV 600 mg co-administration with CVC; for Cmax, Cmin, and AUC0–24, the 
ratios of the LS geometric means (90% CI) were 1.23 (1.12, 1.35), 0.85 (0.71, 1.01), and 0.98 (0.85, 1.12), respectively (i.e., with the 90% CIs including 1.00 for 
Cmin, and AUC0–24 and within the 0.80–1.25 “no-effect” range for AUC0–τ and within the 0.70–1.43 “equivalence” range for Cmax and Cmin). In Group 2, plasma 
EFV exposure remained essentially unchanged in the presence of CVC 400 mg daily. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
110 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of DTG on 
the PK of CVC and the 
effect of CVC on the PK of 
DTG and on a single dose of 
midazolam 
40 healthy 
participants (20 in 
Group 1 and 20 in 
Group 2) 
Group 1: 
Period 1: Single dose of midazolam 5 
mg po on Day –1 and Day 9 + CVC 
150 mg QD po after a standardized 
breakfast × 10 days (Days 1 to 10) 
Period 2: CVC 150 mg QD po + DTG 
50 mg po QD after a standardized 
breakfast × 10 days 
Group 2: 
Period 1: DTG 50 mg QD po after a 
standardized breakfast × 10 days 
Period 2: DTG 50 mg QD po + CVC 
150 mg QD po after a standardized 
breakfast × 10 days 
DP7_150 
formulation, 
manufactured by 
QS Pharma 
1. Plasma PK of CVC 
(Group 1) 
2. Plasma PK of DTG 
administered with 
and without CVC 
3. PK of midazolam 
and α-hydroxy 
midazolam 
4. Safety and 
tolerability 
Noteworthy Findings: 
In Group 1, co-administration of DTG 50 mg with CVC 150 mg once daily for 10 days during Period 2 resulted in a significant reduction in plasma CVC exposure (by 
28% for Cmax, 23% for Cmin, and 29% for AUC0–24). In Group 2, co-administration of CVC 150 mg with DTG 50 mg once daily for 10 days during Period 2 had no 
effect on plasma DTG exposure. CVC increased plasma midazolam Cmax and AUC0-∞ by approximately 49% and 84%, respectively, indicating it is a mild inhibitor 
of CYP3A4. CVC did not result in a meaningful change in plasma α-hydroxymidazolam exposures: there was a 7% decrease in Cmax and an 18% increase in 
AUC0-∞. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
111 
Phase 1 
A Phase 1, open-label, 
single-dose, crossover study 
in healthy participants to 
assess the bioavailability of 
a new oral tablet formulation 
of CVC when administered 
fasting and after food 
relative to the current 
formulation 
42 healthy adult 
participants (14 
participants per 
group) 
Group 1: 50 mg CVC: DP6 fed, DP7 
fed, DP7 fasting 
Group 2: 150 mg CVC DP6 fed, DP7 
fed, DP7 fasting 
Group 3: 200 mg CVC DP6 fed, DP7 
bedtime 
Single oral dose of the current CVC 
formulation (DP6) or the new 
formulation (DP7) in each of 2 or 3 
periods after a standardized breakfast 
(“fed”), fasting, or ≥3 h post dinner 
(“bedtime”), separated by a washout 
period of ≥10 days.  
DP6_50 
formulation, 
manufactured by 
Bend Research 
DP7 formulation 
(DP7_25, 150), 
manufactured by 
QS Pharma 
1. Relative 
bioavailability of 
plasma CVC (current 
and new 
formulations) 
2. Safety and 
tolerability 
3. Effect of intragastric 
pH on PK of CVC 
Noteworthy Findings: 
For comparison of the 50 mg CVC dose administered under fed conditions in the morning, the ratios of LS geometric means for plasma CVC Cmax, AUC0-t, and 
AUC0-∞ for the DP7 formulation (Treatment B) relative to the DP6 formulation (Treatment A) were 0.83, 0.72, and 0.79, respectively, with 90% CIs including 1.0. For 
comparison of the 150 mg CVC dose administered under fed conditions in the morning, the ratios of LS geometric means for plasma CVC Cmax, AUC0-t, and 
AUC0-∞ for the DP7 formulation (Treatment E) relative to the DP6 formulation (Treatment D) were 1.22, 0.98, and 1.05, respectively, with 90% CIs including 1.0. 
The DP7 formulation was significantly better absorbed in the fed than fasting state, particularly at the 150 mg dose. The DP7 formulation administered as a single 
oral dose of 200 mg at bedtime (Treatment H: DP7 200 mg HS) had an approximately 2-fold higher exposure compared to the DP6 formulation administered as a 
single oral dose of 200 mg in the morning following a standard breakfast (Treatment G: DP6 200 mg Fed AM); the ratios of LS geometric means for plasma CVC 
Cmax, AUC0-t, and AUC0-∞ for the DP7 formulation administered at bedtime (Treatment H) compared to the DP6 formulation after a standardized breakfast 
(Treatment G) were 1.49, 2.08 and 2.06, respectively. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-1-
112 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of CVC on 
the PK of ATV and RTV 
20 healthy adults 
Period 1: ATV/r 300/100 mg QD po 
after a standardized breakfast × 10 
days (Days 1-10) 
Period 2: ATV/r 300/100 mg QD po + 
CVC 50 mg QD po after a 
standardized breakfast × 10 days 
(Days 11-20) 
Period 1 was immediately followed by 
Period 2 without washout. 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. PK of ATV and RTV 
with/without CVC 
2. Safety and 
tolerability of CVC 
with ATV and RTV 
Noteworthy Findings: 
CVC had no effect on RTV Cmax or AUC0–24, although significantly increased exposure to ATV (1.2-fold increase in Cmax, 1.6-fold increase in Cmin, and a 1.3-
fold increase in AUC0–24) and RTV Cmin (1.5-fold increase in RTV Cmin). 
Allergan Study 652-1-
113 
Phase 1 
A Phase 1, multiple-dose, 
open-label, crossover study 
in healthy participants to 
assess the effect of CVC on 
the PK of DRV and RTV 
20 healthy adults 
Period 1: DRV/r 800/100 mg QD po 
after a standardized breakfast × 10 
days 
Period 2: DRV/r 800/100 mg QD po + 
CVC 50 mg QD po after a 
standardized breakfast × 10 days 
Period 1 was immediately followed by 
Period 2 without washout. 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. PK of DRV and RTV 
with/without CVC 
2. Safety and 
tolerability of CVC 
with DRV and RTV 
Noteworthy Findings: 
Co-administration of CVC 50 mg with DRV/r 800/100 mg daily for 10 days during Period 2 resulted in no meaningful effects of CVC on plasma DRV or RTV 
exposure. The ratios of LS geometric means for DRV Cmax, Cmin, and AUC0–24 for CVC+DRV/r co-administration compared to DRV alone were 1.02, 0.94, and 
0.98, respectively, with 90% CIs including 1.0 and being well within the 0.80–1.25 “no effect” range for all 3 plasma DRV PK parameters. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-2-
201 
Phase 2a 
A double-blind, randomized, 
placebo-controlled, proof of 
concept, multiple dose-
escalating study to evaluate 
the antiviral activity, safety, 
and PK of the CCR5 
antagonist CVC in HIV-1-
infected, antiretroviral 
treatment-experienced, 
CCR5 antagonist-naïve 
participants 
54 adults with R5-
tropic HIV-1 8/dose 
level on CVC 
2/dose level on 
placebo 
25 mg (1×25 mg DP3 tablet) 50 mg 
(2×25 mg DP3 tablets) 75 mg (3×25 
mg DP3 tablets) 100 mg (1×100 mg 
DP4 tablet) 150 mg (6×25 mg DP3 
tablets) 
All administered orally once daily and 
all provided with a meal. 
Participants knew to which dose 
group they were assigned, but were 
blind to treatment assignment (CVC 
or placebo) 
DP3_25 
formulation, 
manufactured by 
Emerson 
Resources 
DP4_100 
formulation, 
manufactured by 
Emerson 
Resources 
1. Antiviral activity 
2. Safety, tolerability 
3. Plasma PK 
4. PD 
5. Biomarkers of 
inflammation 
Noteworthy Findings: 
CVC significantly reduced HIV-1 RNA. The median nadir changes from Baseline for the 25, 50, 75, and 150 mg dose groups were −0.7, −1.6, −1.8, and −1.7 log10 
copies/mL, respectively (note that the efficacy and PK results with CVC 100 mg [administered as an alternative formulation] are not shown). CVC significantly 
increased MCP-1 by up to 340 pg/mL at the 150 mg dose level. Treatment was well tolerated with no dose-limiting AEs. 


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Study Number/Phase 
Study Title 
Participant 
Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-2-
202 
Phase 2b 
A Phase 2b randomized, 
double-blind, double-dummy 
trial of 100 or 200 mg once-
daily doses of CVC or once-
daily EFV, each with open-
label FTC/TDF, in HIV-1-
infected, antiretroviral 
treatment-naïve, adult 
participants with only CCR5-
tropic virus 
143 adults living 
with HIV, 
treatment-naïve 
participants with 
CCR5-tropic virus 
Participants were 
randomized in a 
2:2:1 ratio to: CVC 
100 mg, CVC 200 
mg, or EFV 600 mg 
(all administered 
orally QD, but not 
at the same time, in 
combination with 
FTC/TDF). 
CVC 100 mg (Phase 2b formulation; 
administered as 2×50 mg tablets + 2× 
CVC matching placebo tablets) and 
EFV placebo 
CVC 200 mg (Phase 2b formulation; 
administered as 4×50 mg tablets) and 
EFV placebo 
EFV 600 mg and 4 × CVC matching 
placebo tablets 
CVC/placebo administered following a 
low-fat breakfast; EFV/placebo on an 
empty stomach at bedtime 
DP6_50 
formulation, 
manufactured by 
Bend Research 
1. Efficacy 
2. Safety, tolerability 
3. Plasma PK 
4. PD 
5. Biomarkers of 
inflammation and 
immune function 
6. Metabolic 
parameters 
Noteworthy Findings: 
CVC when administered as either 100 mg + FTC/TDF or 200 mg + FTC/TDF was effective and well tolerated over 48 weeks in participants living with HIV, 
antiretroviral treatment-naïve adult participants with only CCR5-tropic virus. A greater proportion of CVC- than EFV-treated participants completed the study, 42 
(71%), 41 (73%), and 17 (61%) for the CVC 100 mg, CVC 200 mg, and EFV treatment arm, respectively. The percentage of participants with virologic success, 
defined as HIV-1 RNA <50 copies/mL (using the FDA Snapshot analysis and the ITT population), was comparable among the 3 treatment arms at Week 24 (the 
primary efficacy endpoint: 76% with CVC 100 mg, 73% with CVC 200 mg, and 71% with EFV) and higher in the CVC arms than in the EFV arm at Week 48 (68% 
with CVC 100 mg, 64% with CVC 200 mg, and 50% with EFV). 
A dose-response was observed with CVC in increases over time of MCP-1, the ligand of CCR2, which is a chemokine receptor found on monocytes, suggesting 
potent CCR2 blockade. Additionally, a decrease over the first 48 weeks was observed for sCD14, an established biomarker of monocyte activation, in both CVC 
treatment arms, while an increase was observed for sCD14 in the EFV arm during the same observation period. 
CVC showed a favorable safety profile with fewer treatment-related AEs, fewer AEs of at least Grade 3 in severity, and fewer AEs leading to discontinuations 
compared to EFV. Both doses of CVC (100 mg and 200 mg) were well tolerated and no apparent dose-relationship based on safety data or dose-limiting toxicities 
were observed. 
 


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Study Number/Phase 
Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Allergan Study 652-2-203 
Phase 2b 
CENTAUR: Efficacy and 
Safety Study of Cenicriviroc 
for the Treatment of 
Nonalcoholic Steatohepatitis 
(NASH) in Adult Participants 
with Liver Fibrosis 
289 adults with NASH with liver 
fibrosis (biopsy-diagnosed 
NASH with NAS ≥4 and liver 
fibrosis (Stage 1 to 3 [NASH 
CRN system]), who are at 
increased risk of disease 
progression. 
Randomization 1:1 stratified by 
NAS at Screening (4 or ≥5) and 
fibrosis stage (≤2 or >2). 
150 mg tablets and 
matching placebo tablets 
DP7_150 
formulation 
Manufactured by 
QS Pharma 
The primary efficacy 
endpoint: Hepatic 
histological 
improvement as 
measured by the 
NAFLD Activity 
Score (NAS) at Year 
1 relative to the 
Screening biopsy. 
Noteworthy Findings: 
Year 1: Twenty-three (15.9%) participants in the CVC group met the primary efficacy endpoint compared to 27 (18.8%) participants in the placebo group. The difference 
between the treatment groups was not statistically significant in the ITT population (p=0.5194). 
In the ITT population, 11 participants (7.6%) in the CVC group compared with 8 participants (5.6%) in the placebo group had complete resolution of steatohepatitis and 
no concurrent worsening of fibrosis stage at Year 1 relative to the Screening biopsy (p=0.4941). These results did not change after prespecified sensitivity analyses. 
Importantly, in the Year 1 analysis, 29 participants (20.0%) in the CVC group compared with 15 participants (10.4%) in the placebo group had improvement in fibrosis 
by at least 1 stage and no worsening of steatohepatitis at Year 1 relative to the Screening biopsy in the ITT population set (p=0.0234). A higher proportion of 
participants in the CVC group (29%) compared with the combined placebo group (19%) had an improvement of at least 1 stage at Year 1 per the NASH CRN staging 
system. Furthermore, at Year 1, the proportion of participants achieving the more stringent endpoint of ≥2-stage improvement in fibrosis AND no worsening of 
steatohepatitis for CVC or placebo = 8.2% (8/98) and 3.1% (3/96), respectively, in the ITT population excluding participants with baseline NASH CRN fibrosis Stage 1. 
Year 2: At the end of the first year of treatment, a total of 242 participants remained in the study and entered Year 2 according to their treatment assignment at 
randomization (121, 61, and 60 participants in the CVC/CVC, placebo/CVC, and placebo/placebo groups, respectively). Given the lack of apparent effect of CVC 
treatment on the NAS or resolution of steatohepatitis at Year 1, the results presented below describe findings from prespecified analyses focused on the endpoint of 
improvement in fibrosis stage (by ≥1 stage or by ≥2 stages) AND no worsening of steatohepatitis in the ITT population. 
Overall, the results from the final Year 2 analysis confirmed the clinically meaningful antifibrotic effect of CVC treatment observed in the Year 1 primary analysis. Twice 
as many CVC-treated participants achieving ≥1-stage improvement in fibrosis at Year 1 (CVC/CVC group) maintained this benefit at Year 2 compared to placebo (60% 
vs 30%, respectively). A higher proportion of Year 1 placebo nonresponder participants who received CVC (placebo/CVC group) experienced an improvement in 
fibrosis by ≥1 stage AND no worsening of steatohepatitis compared with participants who remained on placebo (placebo/placebo group) from Year 1 to Year 2 (24.4% 
vs 17.1%, respectively). In this analysis, improvement in fibrosis by ≥1 stage regardless of effect on steatohepatitis was reported in 39.0% of placebo/CVC participants 
versus 28.6% of placebo/placebo participants. 
A similar and consistent antifibrotic response was observed in the pooled analysis of participants treated with CVC for 1 year (participants in the CVC/CVC group who 
received CVC during Year 1 and the placebo/CVC group who received CVC during Year 2) compared with participants treated with placebo for 1 year (placebo/placebo 


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Study Number/Phase 
Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
group; data from Year 1): improvement in fibrosis by ≥1 stage AND no worsening of steatohepatitis (19.9% vs 11.1%); improvement in fibrosis by ≥1 stage regardless of 
effect on steatohepatitis (27.7% vs 16.7%). Furthermore, consistent with observation at Year 1, a higher proportion of participants receiving CVC relative to participants 
receiving placebo (9.3% [7/75] in the CVC/CVC group versus 2.7% [1/37] in the placebo/placebo group) achieved ≥2-stage improvement in fibrosis AND no worsening 
of steatohepatitis at Year 2. 
Tobira Study 652-2-
204-  
 
Phase 2a 
ORION: Effect of CCR2 and 
CCR5 Antagonism by 
Cenicriviroc on Peripheral 
and Adipose Tissue Insulin 
Sensitivity in Adult Obese 
Participants with 
Prediabetes or Type 2 
Diabetes Mellitus and 
Suspected Non-Alcoholic 
Fatty Liver Disease (NAFLD) 
45 adult obese participants 
(BMI ≥ 30 kg/m2) with 
prediabetes or T2DM and 
suspected NAFLD; 
randomized 1:1 to active drug 
or placebo 
(50 participants planned, 45 
enrolled) 
150 mg tablets and 
matching 
placebo tablets 
once daily for 24 weeks 
DP7_150 
formulation 
Manufactured by 
QS Pharma 
1. Efficacy 
2. Safety, tolerability 
3. Plasma PK 
4. PD 
5. Biomarkers of 
inflammation and 
immune function 
Metabolic parameters 
Noteworthy Findings: 
There was no observed therapeutic effect of CVC on peripheral and adipose tissue insulin sensitivity as compared to placebo. CVC was well tolerated and resulted in a 
lower incidence of AEs compared with placebo. No new safety signals were observed. 
Tobira Study 652-205 
Phase 2 
PERSEUS: A Phase 2 Proof 
of Concept Study 
Investigating the Preliminary 
Efficacy and Safety of 
Cenicriviroc in Adult 
Participants with Primary 
Sclerosing Cholangitis 
(PSC) 
24 adult participants with PSC 
150 mg tablets 
once daily for 24 weeks 
DP7_150 
formulation 
Manufactured by 
QS Pharma 
1. Efficacy 
3. Safety, tolerability 
Noteworthy findings: In adults with PSC, treatment with CVC 150 mg QD for 24 weeks resulted in a modest (median of 18%) decrease in the surrogate endpoint of 
ALP. No new safety signals were observed 
 
 


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Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
3152-201-002 Rollover 
Phase 2 
Open-label Rollover Study of 
Cenicriviroc for the 
Treatment of Liver Fibrosis 
in Adult Subjects with 
Nonalcoholic Steatohepatitis 
(NASH 
167 Adult participants with 
NASH enrolled in the study who 
completed both Treatment 
Period 1 and Treatment Period 
2 in the CENTAUR study, or 
who completed the AURORA 
study because of progression to 
cirrhosis or reaching an 
adjudicated liver-related clinical 
outcome in either Part 1 or Part 
2 of the study; all 167 received 
CVC 
 
Cenicriviroc mesylate 150 
mg immediate release 
oral tablet daily for 
duration of trial 
 
The CVC drug 
product was 
formulated with 
fumaric acid (160 
mg) and other 
excipients, 
including 
microcrystalline 
cellulose, 
croscarmellose 
sodium, colloidal 
silicon dioxide, 
magnesium 
stearate, and 
Opadry® II yellow 
(film coating). The 
CVC drug 
product was 
provided as 150-
mg yellow-
coated, 
immediate 
release tablets for 
oral 
administration. 
 
Safety; incidence of 
adverse events 
 
Noteworthy findings: CVC 150 mg once daily was well tolerated in this study. No clinically significant safety findings were identified. The study was terminated early for 
administrative reasons 
 


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Study Number/Phase 
Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
3152-301-002  
 
Phase 3 
AURORA: A Phase 3, 
Multicenter, Randomized, 
Double-Blind, Placebo-
Controlled Study to Evaluate 
the Efficacy and Safety of 
Cenicriviroc for the 
Treatment of Liver Fibrosis in 
Adult Subjects with 
Nonalcoholic Steatohepatitis 
Part 1: 
A total of 1288 participants with 
NASH were analyzed in Part 1 
(859 participants in Arm A; and 
429 participants in Arm B) 
[1293 participants were 
randomized (861 to the CVC 
group and 432 to the placebo 
group)] 
Part 2: 
A total of 1769 participants 
with NASH were analyzed in 
the full study cohort (1180 
participants in Arm A, and 589 
participants in Arm B) [A total 
of 1778 participants were 
enrolled in the full study 
cohort. Of these, 1185 
participants were randomized 
to the CVC group and 593 
participants were randomized 
to the placebo group.] 
 
Cenicriviroc mesylate 
150 mg immediate 
release oral tablet (Arm 
A) or placebo (Arm B) 
once daily (2:1) 
 
Cenicriviroc 
mesylate 
150 mg 
immediate 
release oral 
tablet (Arm A) or 
placebo (Arm B) 
once daily (2:1) 
 
Part 1: 
Proportion of 
participants with 
improvement in fibrosis 
by at least 1 stage 
(NASH CRN system) 
AND no worsening of 
steatohepatitis (no 
worsening of lobular 
inflammation or 
hepatocellular 
ballooning grade) 
Safety and tolerability 
Part 2: 
Composite endpoint of 
histopathologic 
progression to cirrhosis 
(defined by NASH CRN 
Fibrosis Stage 4), liver-
related clinical 
outcomes, and all-cause 
mortality, as measured 
by the time to first 
occurrence of any of the 
listed adjudicated 
events (clinical 
outcomes composite 
endpoint) 
Safety and tolerability 
 


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Study Number/Phase 
Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
Noteworthy findings: The primary endpoint was not met for Part 1, leading to early termination of the study. No meaningful numerical or statistical difference was 
observed between CVC 150 mg once daily and placebo with respect to the key efficacy endpoints regarding liver histology at Month 12 relative to the screening biopsy 
in adult participants with a liver biopsy diagnosis of NASH and Stage 2 or 3 liver fibrosis (by NASH CRN system). CVC 150 mg once daily was, in general, well tolerated 
in this study, and there were no treatment-related AEs that were fatal or life-threatening.  
CLJC242A2201J 
Phase 2 
TANDEM: A randomized, 
double-blind multicenter 
study to assess the safety, 
tolerability, and efficacy of 
CVC with tropifexor in adults 
with NASH and LF 
40 healthy participants (20 in 
Group 1 and 20 in Group 2) 
193 adults with NSH and 
LF 
150mg tablets 
immediate 
release 
Occurrence of AEs, 
SAEs and AESIs. 
AEs resulting in d/c. 
Effect on vital signs 
over 48w. Proportion 
of patients with at 
least 1 point 
improvement in 
fibrosis and 
proportion with 
resolution of 
steatohepatitis 
Noteworthy findings: Neither of the combination therapies, tropifexor 140 mcg + CVC 150 mg or tropifexor 90 mcg + CVC 150 mg, increased the likelihood of response 
compared with either tropifexor 140 mcg alone or CVC 150 mg alone. The safety profiles of the combination therapies of tropifexor 140 mcg + CVC 150 mg and 
tropifexor 90 mcg + CVC 150 mg were similar to those of each monotherapy, with no additional emergent safety signals compared to those identified and reported in 
previous monotherapy studies. Overall, pruritus, nausea, and fatigue were the most frequently experienced AEs. The proportion of participants who experienced 
pruritus was highest in the tropifexor 140 mcg alone group and notably lower with tropifexor 140 mcg + CVC 150 mg combination treatment. Similar patterns are noted 
for fatigue and urinary tract infection, and this pattern may be explained by the DDI by which CVC treatment reduces tropifexor levels. No deaths were reported in the 
study. Most SAEs were single occurrences. There were few AESI of liver injury. Elevations in ALT and AST were higher in the tropifexor-containing groups, with most 
elevations transient and reversible. There was no drug-induced serious hepatotoxicity detected, and no participant met Hy’s law criteria (total bilirubin >2 × ULN and 
ALT ≥ 3 × ULN) at any time after start of study treatment. 


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Study Number/Phase 
Study Title 
Participant Description 
Dose & Administration 
CVC Formulation 
Endpoints 
CLJC242A2101  
Phase 1 
A randomized, parallel 
group, 3-arm, double-blind, 
double-dummy study to 
investigate the drug-drug 
interaction potential between 
tropifexor (LJN452) and 
cenicriviroc (CVC) in healthy 
and healthy but overweight 
to obese subjects 
42 healthy and healthy but 
overweight to obese 
participants with BMI of up to 
32 kg/m2 
Arm 1: 60 μg 
tropifexor + CVC placebo 
daily (n=14) 
Arm 2: 150 mg CVC + 
tropifexor placebo daily 
(n=14) 
Arm 3: 60 μg tropifexor + 
150 mg CVC daily (n=14) 
CVC is 
available as 
150 mg 
yellow-
coated 
immediate-
release 
tablets for 
oral admin. 
 
PK of tropifexor, CVC, 
and their metabolites 
Safety assessments 
and measurements 
(including physical 
examination, vital 
signs, ECG, clinical 
laboratory evaluations 
and AEs) up to and 
including the end of 
study visit 
Noteworthy findings: When tropifexor is used in combination with CVC, an increase in the dose of tropifexor may be considered to compensate for the lower 
exposure seen when co-administered with CVC. Overall, administration of tropifexor alone, CVC alone, and tropifexor + CVC was considered to be well tolerated 
by the participants in the study. Co-administration of tropifexor and CVC did not increase the safety and tolerability profiles when compared to administration of 
each drug independently. All reported TEAEs were of mild severity. There were no deaths reported during this study, and 1 SAE (unrelated ovarian torsion) was 
reported after the clinical database cut-off date. One participant who received tropifexor + CVC discontinued from the study due to a TEAE (rash), which was 
suspected to be definitely related to the study drugs. No clinically significant changes were noted in laboratory parameters, vital signs, or ECG parameters. 
 


 
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INFORMED CONSENT AND AUTHORIZATION TO USE AND DISCLOSE PROTECTED 
HEALTH INFORMATION 
 
SHORT TITLE FOR THE STUDY: Cenicriviroc for Arterial Inflammation in HIV 
 
Sponsor / Study Title: 
 
National Institute of Allergy and Infectious Diseases (NIAID / “A 
Limited-Center, Prospective, Double-Blind, Placebo-Controlled 
Study to Evaluate the Effects of Cenicriviroc Mesylate on 
Arterial Inflammation in People Living with HIV” 
 
Protocol Number: 
 
A5415 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
SUMMARY 
 
PURPOSE 
The purpose of this study is to see if cenicriviroc mesylate (or CVC) can reduce inflammation of 
the arteries (the blood vessels that carry blood from the heart through the body) in people living 
with HIV (human immunodeficiency virus) (the virus that causes acquired immune deficiency 
syndrome [AIDS]). This study will also look at how safe CVC is when it is taken by people living 
with HIV who are taking anti-HIV medications. You are being asked to participate in this study 
because you are a person living with HIV and have one or more cardiovascular (heart and/or 
blood vessel) risk factors. 
 
NUMBER OF PARTICIPANTS 
There will be at least 93 participants in this study. 
 
LENGTH OF STUDY 
This study will last about 24 weeks (about 6 months). You will have about 7 visits (including the 
entry visit) over this time period. If needed, you may have to be in this study longer to complete 
all the required tests. 
 
STUDY TREATMENT 
Study drug and placebo (inactive substance) provided and required in this study. 
• 
You will be randomly assigned (as if by flipping a coin) to receive study drug or placebo, and 
you will have twice the chance of getting CVC versus placebo. Study drug that will be 
provided is CVC, a drug that reduces inflammation (a reaction of the body to injury or 
infection) and fibrosis (thickening or scarring of tissue, usually as a result of injury). It is 


 
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taken by mouth. It is an experimental drug that is not yet approved by the United States 
(U.S.) Food and Drug Administration (FDA). This study will also provide a placebo, a pill that 
looks like the study treatment (CVC) but does not have any active drug in it. 
• 
This study also requires you to continue the anti-HIV medications that you are currently 
taking. However, this study will not provide you with the anti-HIV medications. 
 
REQUIRED ACTIVITIES 
Blood and urine collections 
At most visits, some blood will be collected from a vein in your arm. If you are able to become 
pregnant, you may also be asked to provide a urine sample for a pregnancy test. 
 
Special procedures 
You will have a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan and 
computed tomography (CT) scan of your head, neck, chest, and abdomen. A PET scan is a 
medical imaging technique that produces a 3-D image of processes in the body. A small amount 
of radiotracer (a drug that emits radioactivity), called fluorodeoxyglucose or FDG, will be injected 
into a vein to show differences between healthy tissue and diseased tissue. A CT scan or 
computerized axial tomography (CAT) scan is a diagnostic medical test that produces multiple 
images or pictures of the inside of the body. You will be asked to lie down for about 2 hours 
after the FDG injection before the scans are performed. The scans will take about 45 minutes. 
 
RISKS 
Because CVC is an investigational drug (an experimental drug being tested in a research study 
that involves people), all of its possible side effects may not be known. The most common side 
effects reported in studies of CVC were the following: 
• 
Diarrhea (watery stools) 
• 
Nausea (feeling of sickness with an urge to vomit) 
• 
Joint pain 
• 
Rash 
• 
Itchy skin 
• 
Vomiting 
• 
Flatulence (passing gas) and abdominal distension (abdominal bloating due to gas in the intestine) 
• 
Fever 
• 
Joint swelling 
• 
Asthenia (abnormal physical weakness or lack of energy) 
• 
Contact dermatitis (skin irritation or rash caused by touching something) 
• 
Headache 
• 
Urinary tract infection 
• 
Pain in extremity (limbs, such as arms or legs) 
 
You may also experience an increase in liver enzymes, a blood test that can be a sign of liver 
damage. If you have liver disease, there is a chance that you may develop autoimmune 
hepatitis, a disease in which the body’s immune system attacks liver cells, but this is very rare. 
 


 
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You will also be exposed to radiation from the FDG-PET and CT scans. The total amount of 
radiation exposure you will receive from participation in this research study is about the same as 
you would normally receive in approximately 5.4 years from background radiation sources. A 
possible effect that could occur at the exposure associated with this study is a slight increase in 
the risk of developing cancer later in life. If you have taken part in other studies or tests in the past 
12 months that have involved radiation exposure, please inform the study doctor or study staff. 
 
There is a rare risk of a major allergic reaction to FDG, the radioactive substance that is used 
for the FDG-PET scan. FDG may also expose the fetus of a pregnant individual or the infant of 
an individual who is breastfeeding to radiation. Because of this, pregnant people and people 
breastfeeding cannot join this study. 
 
BENEFITS 
No direct benefits should be expected from participating in this study. Taking medication to 
reduce inflammation in arteries is not part of standard of care, even for individuals with HIV and 
with cardiovascular risk factors; however, it is being evaluated to see if it may provide benefit in 
this study. 
 
OTHER CHOICES 
This project is research with voluntary participation. Instead of being in this study, you have the 
following options: 
• 
Receiving treatment to reduce cardiovascular risk with a prescription medication under the 
care of your regular doctor or other health care provider 
• 
Starting a new treatment with another investigational drug, if you qualify for a research study 
• 
No treatment 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are living with human 
immunodeficiency virus (HIV), the virus that causes AIDS, your HIV viral load (the amount of 
HIV in your blood) is under control on your anti-HIV medicines for at least 48 weeks (almost 1 
year), and you are at risk for cardiovascular disease. This study is sponsored by the National 
Institutes of Health (NIH). The study doctor is in charge of this study at this site. 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 and date this consent form. You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
Cardiovascular disease or heart disease, is a disease of the heart and blood vessels, which can 
include heart attacks, strokes, coronary artery disease (when arteries that supply blood to heart 
muscle become hardened and narrowed), congestive heart failure (when the heart muscle doesn't 


 
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pump blood as well as it should), and hypertension (high blood pressure). Studies have shown 
that individuals living with HIV are more likely to develop heart disease than individuals without 
HIV because HIV itself and some anti-HIV medications increase the risk for heart disease. Also, 
the traditional risk factors for heart disease, such as abnormally elevated cholesterol or fats in the 
blood, diabetes, excessive abdominal fat, and smoking, are very common in people living with 
HIV. HIV is also associated with increased arterial inflammation (inflammation of the blood 
vessels), which may also contribute to the increased risk for heart disease. 
 
The study drug being evaluated in this study is oral cenicriviroc mesylate (or CVC), which is a drug 
that reduces inflammation (a reaction of the body to injury or infection) and fibrosis (thickening or 
scarring of tissue, usually as a result of injury). CVC is still being studied for this and other 
purposes but is not approved by the U.S. Food and Drug Administration (FDA) for any purpose. 
 
We are doing this study to see if CVC can reduce inflammation of the arteries (the blood vessels 
that carry blood from the heart through the body) in people with HIV. We will also evaluate how 
safe CVC is when it is taken by people with HIV who are taking anti-HIV medications. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study, you will be asked to sign and date this consent form. After you 
have signed and dated the form, you will be asked some questions and will undergo some tests 
at the screening visit to see if it is safe for you to join the study. You may have as little as ¼ 
tablespoon (around 3.5 mL) to as much as 8 tablespoons (around 118 mL) of blood collected at 
any one visit. Over the course of the study, the amount of blood collected from you will be within 
approved limits. 
 
During the study, you will receive results, when they are available, from any routine tests, blood 
sugar tests, HIV tests, tests to evaluate risk of heart disease, and pregnancy tests that are done 
during the study. Any important medical problems on the FDG-PET scan and CT scan of your 
head, neck, chest, and abdomen will be shared with your regular doctor when the results of the 
scans are available. 
 
Information Collected at Screening 
There is some information that we collect on everyone who is screened for an ACTG (AIDS 
Clinical Trials Group) study. As part of your screening visit, some demographic (for example, 
age, gender, race), clinical (for example, disease condition, diagnosis), and laboratory (for 
example, CD4 cell count, viral load) information will be collected from you. We also collect 
information on whether you use (or have used) IV drugs. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that ACTG researchers may help determine whether there are patterns or common 
reasons why people do not join a study. 
 


 
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Screening Visit 
The screening visit will take about 1-2 hours. You will be asked to come to clinic having fasted 
(no food or drink, except water and your medicines, for the 8 to 10 hours just before the visit). 
• 
You will be asked about your medical history, including your HIV history, and any conditions 
or habits that raise your risk of coronary artery disease. 
• 
An HIV test may be required to document your HIV status. The study doctor may be 
required by law to report the result of the test to the local health authority. 
• 
You will also be asked about any medicines you have ever taken and are taking, including 
any anti-HIV drugs. 
• 
You will have a brief physical exam. The study staff will check your vital signs, such as 
temperature, blood pressure, breathing, and pulse. Your height, weight, and waist 
circumference will also be measured. 
• 
You will have blood drawn for routine blood tests, blood sugar, insulin (a hormone that helps 
keep your blood sugar from getting too high or too low), average blood sugar level over the 
last 2-3 months, HIV viral load, and tests to evaluate risk of heart disease. 
• 
If you are able to become pregnant, you will have a pregnancy test. Pregnant individuals 
cannot enter the study. If you plan to become pregnant any time during the length of the 
study and three months after completing the study, which is a period of about 9 months, you 
also cannot enter the study. 
 
Pre-entry Visit 
If you are eligible for this study, based on the screening visit, you will come in for a pre-entry 
visit. The visit will take about 3-4 hours. 
• 
Within 7 days of the FDG-PET scan and CT scan, you will complete the Perceived Stress 
Scale-10. The scale asks 10 questions about stress. 
• 
You will have blood drawn to measure your red and white blood cell counts and CD4+/CD8+ 
count (infection-fighting cells in the blood). Some of the blood will also be stored for future 
tests that will evaluate metabolism (processes in the body that turn food into energy) and 
inflammation and measure the levels of anti-HIV drugs you are taking. 
• 
You will be given a food diary to record everything that you eat and drink for a 4-day period. 
The study staff will tell you when to start and stop recording in the food diary. 
• 
You will have an FDG-PET scan and CT scan of your head, neck, chest, and abdomen. A 
PET scan is a type of medical imaging technique that produces a 3-D image of processes in 
the body. A small amount of radiotracer (a drug that emits radioactivity) called 
fluorodeoxyglucose or FDG will be used to show differences between healthy tissue and 
diseased tissue. FDG is injected into a vein. A CT scan or CAT scan is a diagnostic medical 
test that, like traditional x-rays, produces multiple images or pictures of the inside of the 
body. The FDG-PET and CT scans are being done to evaluate the effects of CVC on 
inflammation of the arteries. The image will also be used to assess physical appearance and 
tracer accumulation. The scans at the pre-entry visit will be used to confirm that you can join 
this study. You may not be able to join this study based on the findings of the scans. If you 
enter the study, the scans at pre-entry will also be compared with the scans at week 24 to 
evaluate the effects of CVC on inflammation of the arteries. 
o You will be asked to follow a low-carbohydrate diet for your meal the night before the 
scan. The study staff will provide you with dietary instructions to follow for this meal. 


 
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o You will be asked not to exercise for 24 hours before the scan. 
o If your scan is scheduled in the morning, you will be asked to come to clinic fasting (no 
food or drink, except water, for at least 8 to 10 hours just before the visit). 
o If your scan is scheduled in the afternoon, you will be asked to fast (no food or drink, 
except water) for at least 8 to 10 hours the previous night. You may have a low-
carbohydrate meal for breakfast. The study staff will provide you with dietary instructions 
for your breakfast. However, you will have to come to the clinic fasting for at least 4 
hours before your scheduled scan in the afternoon. 
o If you are able to become pregnant, you may have a pregnancy test before the scans 
are performed if it is required by the Institutional Review Board (IRB; a committee that 
protects the rights and safety of participants in research) of this study site. 
o Your blood sugar level will be measured before the FDG injection following the local 
imaging center procedure. 
o You will be asked to lie down for about 2 hours after the FDG injection so the drug can 
distribute throughout your body. You will have the scans after this time. The scans will 
take about 30-45 minutes to complete. 
o The study staff and study doctor will give you detailed instructions on how to prepare for 
the scans and can answer any questions you have. 
• 
The FDG-PET and CT scans will be reviewed to confirm that you qualify for this study. 
 
Entry Visit 
Within 90 days after your screening visit, you will come to clinic for entry evaluations. This visit 
will last about 1-2 hours. You will be asked to come to clinic having fasted (no food or drink, 
except water and your medicines, for the 8 to 10 hours just before the visit). 
• 
You will have a brief physical exam and will be asked questions about your health and about 
any medicine changes you have had since your screening visit. 
• 
You will have blood drawn for routine blood tests, blood sugar test, CD4+/CD8+ count, and 
HIV viral load. Some of the blood will also be stored for future tests that will evaluate 
metabolism, inflammation, and coagulation (the process by which blood changes from liquid 
to a gel to form a clot to stop bleeding). 
• 
If you are able to become pregnant, you will have a pregnancy test. You cannot enter the 
study if you are pregnant. 
• 
You will be asked to fill out a questionnaire to see how well you are taking your anti-HIV drugs. 
• 
You will be asked to bring your food diary with a record of everything that you ate and drank 
during a 4-day period before your entry visit. 
 
If you qualify to participate in this study, you will be randomly assigned (like “flipping a coin”) to 
one of two groups (Group A or Group B). However, because of the way the study is designed, 
there will be twice the chance of your being assigned in Group A, compared to Group B. 
• 
Group A: CVC (one pill once a day; the dose of CVC will depend on the HIV medications 
you are taking) 
• 
Group B: placebo for CVC (one pill once a day) – A placebo is a pill that looks exactly like 
the experimental drug but contains no active study drug. 
 


 
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This study is a double-blind study. This means that you, the study staff, and the study doctor will 
not know which group you are assigned to. You will not be able to choose which group you will be 
in. However, your study doctor can find out which group you are in if there is an emergency. Upon 
completion of the study, participants will be unblinded. 
 
You will continue taking the anti-HIV drugs that you are currently taking. You will also be given 
the study drug based on the group that you are randomly assigned to. You must start the study 
drug within 72 hours after you are randomized. 
 
On Study Visits after Entry 
Regardless of which group you are assigned to, you will come to clinic every 4 weeks for 16 
weeks (at weeks 4, 8, 12, and 16, about 4 months) and then at week 22 (about 5 months) and 
week 24 (about 6 months). The visits will take about 1 hour except week 24, which will take 
about 3-4 hours. You will be asked to come to clinic fasting (no food or drink, except water and 
your medicines, for the 8 to 10 hours just before the visit) for the week 12 and week 24 visits. 
During these visits: 
• 
You will have a brief physical exam, and will be asked questions about your health and 
about any medicine changes you have had, at every visit. 
• 
Your weight and waist circumference will be measured at weeks 12 and 24. 
• 
You will have blood drawn for: 
o Routine blood tests at weeks 4, 12, 22, and 24 
o HIV viral load at weeks 4, 12, and 24 
o Measurement of CD4+/CD8+ count and storage for future tests that will evaluate 
metabolism, inflammation, and coagulation at weeks 12, 22, and 24 
o Blood sugar test at weeks 12 and 24 
o Average blood sugar level over the last 2-3 months at week 24 
o A test to evaluate risk of heart disease 
o Levels of study drug and/or anti-HIV drugs at weeks 4, 8, 12, and 24 
• 
If you are able to become pregnant, you will have a pregnancy test if it is suspected that you 
may be pregnant. 
• 
You will be asked to fill out a questionnaire to see how well you are taking your anti-HIV 
drugs and the study drug. You will also be asked to bring the bottle of your study drug so the 
number of pills you took between visits can be counted. 
• 
You will be given a food diary at your week 22 visit and will be asked to record everything 
that you eat and drink for a 4-day period before your week 24 visit. You will be asked to 
bring your food diary at your week 24 visit. 
• 
Within 7 days of the FDG-PET scan and CT scan, you will complete the Perceived Stress 
Scale-10. You will have an FDG-PET scan and CT scan of your head, neck, chest, and 
abdomen at week 24. You will be asked to follow the same instructions to prepare for the 
scans and you will have the same tests that were done for the scans before you entered the 
study. If you are able to become pregnant, you may have a pregnancy test before the scans 
are performed if it is required by the IRB of this study site. Your blood sugar level will be 
measured before the FDG injection following the local imaging center procedure. You will be 
asked to lie down for about 2 hours after the FDG injection so the drug can distribute 
throughout your body. You will have the scans after this time and the scans will take about 


 
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30-45 minutes to complete. The study staff and study doctor will give you the detailed 
instructions on how to prepare for the scans and can answer any questions you have. 
 
Virologic Failure 
Virologic failure is when your anti-HIV drugs are not keeping HIV at a very low level. If the study 
staff sees that your HIV viral load has gone up, you will be asked to have another test done 
within 2 weeks. You will have blood drawn for the HIV viral load test. If your viral load is still up 
and you are still taking study drug, you will be asked to stop the study drug and come to the 
clinic within 7 days to have the evaluations for stopping the study early. 
 
Confirming Toxicity 
You may develop a side effect (such as a new symptom you report to the study staff, an 
abnormality found during physical examination, or an abnormal laboratory result) while 
participating in this study. If this occurs, you will be asked to return to the clinic within 5 days for 
evaluation. You will have a brief physical exam. You may also have blood drawn for a repeat 
test and any other test that may be required to confirm the abnormal laboratory result. The study 
staff and study doctor will explain to you the side effects that have to be checked, the 
evaluations that will be done, and answer any questions you may have. 
 
If You Have to Stop Taking the Study Drug Early 
If you have to stop taking the study drug early, you will come to the clinic for an additional visit. 
This visit will last about 1-4 hours. If you are not pregnant, you will be asked to come to clinic 
fasting (no food or drink, except water and your medicines, for the 8 to 10 hours just before the 
visit). If you are pregnant, you will not be asked to fast. At this visit: 
• 
You will have a brief physical exam, and will be asked questions about your health and 
about any medicine changes you have had. Your weight and waist circumference will also 
be measured. 
• 
You will have blood drawn for routine blood tests, blood sugar, average blood sugar level 
over the last 2-3 months, test to evaluate risk of heart disease, CD4+/CD8+ count, HIV viral 
load, and storage for future tests that will evaluate metabolism, inflammation, and 
coagulation. 
• 
You will be asked to fill out a questionnaire to see how well you are taking your anti-HIV 
drugs and the study drug. You will also be asked to bring the bottle of your study drug so the 
number of pills you took since your last visit can be counted. 
• 
If you stop taking the study drug at, or after you complete, the week 12 visit but before week 
24, you will have an FDG-PET scan and CT scan of your head, neck, chest, and abdomen 
within 7 days after stopping the study drug. You will be asked to follow the same instructions 
to prepare for the scans and you will have the same tests that were done for the scans 
before you entered the study. If you are able to become pregnant, you may have a 
pregnancy test before the scans are performed. Your blood sugar level will be measured 
before the FDG injection following the local imaging center procedure. You will be asked to 
lie down for about 2 hours after the FDG injection so the drug can distribute throughout your 
body. You will have the scans after this time and the scans will take about 30-45 minutes to 
complete. The study staff and study doctor will give you detailed instructions on how to 
prepare for the scans and can answer any questions you have. 


 
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• 
If you stop taking the study drug before you complete the week 12 visit, or because you 
become pregnant, you will not have the FDG-PET scan and CT scan. 
• 
You may be asked to continue to be part of the study and return for some study visits and 
procedures until you complete the rest of the study visits. 
 
If You Stop Taking the Study Drug and Stop the Study Early 
If you stop taking the study drug early, and at the same time you also stop the study, you will not 
have any more study visits unless you developed a side effect that is still ongoing. 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. 
 
If You Have to Stop the Study Before You Complete All the Study Visits 
If you continued in the study after stopping the study drug early, and then later stop the study 
before completing the rest of the study visits, you may need to have an additional visit if you 
developed a side effect that is not yet resolved at the time you stop. 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. 
 
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood will be stored and used for study-required (metabolic, inflammatory, and 
coagulation) testing. 
 
Your samples and any private information that is collected about you will be coded. This 
means that no one looking at the labels or at other information will be able to know that the 
samples or information came from you. 
 
The tests described above are required by this study. If you do not agree to the storage or 
testing that has been described above, you should not join this study. 
 
More information about the storage of extra samples and use in other studies are provided in 
Attachment A. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
At least 93 people (age 45 years and older) will take part in this study. On October 27, 2023, 
the study closed to screening, and participants who were in screening prior to that point 
were allowed to enroll, if eligible. All screenings that were ongoing at the time of 
screening closure were completed on January 5, 2024, and the study closed to accrual. 
This resulted in over-enrollment of 110/93 participants. 
 
 


 
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HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 24 weeks (about 6 months). It is possible that you will have to 
be in this study longer so that all the required tests can be completed. You will be informed if 
this occurs. 
 
 
WHY WOULD THE STUDY DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
You are unable to follow the requirements of the study 
• 
You request to stop participating 
• 
Your study doctor or regular doctor believes that remaining on the study is no longer what is 
best for you 
• 
The study is stopped or cancelled 
• 
You never start study treatment 
 
The study doctor may also need to take you off the study drug without your permission if: 
• 
Continuing the study drug may be harmful to you 
• 
You need a treatment that you may not take while on the study 
• 
Your HIV viral load tests show that the anti-HIV drugs you are taking are no longer working 
well for you; this is known as having virologic failure 
• 
You become pregnant or are breastfeeding 
• 
You are not able to take the study drug as required by the study 
 
If you must stop taking the study drug before the study is over, the study doctor may ask you to 
continue to be part of the study and return for some study visits and procedures. 
 
If I have to permanently stop taking study-provided CVC, or once I leave the study, how would 
CVC be provided? 
During the study: 
If you must permanently stop taking study-provided CVC before your study participation is over, 
the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
After you have completed you study participation, the study will not be able to continue to 
provide you with CVC. If continuing to take this or a similar drug would be of benefit to you, the 
study staff will discuss how you may be able to obtain it. 
 
 


 
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WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with this study drug. These lists include 
the more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects, please ask the study staff at your 
study site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or study 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 doctor or study nurse before 
enrolling in any other clinical trials while on this study. 
 
Because CVC is an investigational drug (an experimental drug being tested in a research study 
that involves people), all of its possible side effects may not be known. There may be rare and 
unknown side effects. Some of these may be life-threatening. You must tell the study doctor or 
study staff about all side effects that you have. Please see below the list of reported adverse 
events (medical conditions occurring during participation in clinical studies that may or may not 
be side effects) seen to date. 
 
The common side effects reported in studies, after unique and multiple doses of CVC were the 
following: 
• 
Diarrhea (watery stools) 
• 
Nausea (feeling of sickness with an urge to vomit) 
• 
Joint pain 
• 
Rash 
• 
Itchy skin 
• 
Vomiting 
• 
Flatulence (passing gas) and abdominal distension (abdominal bloating due to gas in the 
intestine) 
• 
Fever 
• 
Joint swelling 
• 
Asthenia (abnormal physical weakness or lack of energy) 
• 
Contact dermatitis (skin irritation or rash caused by touching something) 
• 
Headaches 
• 
Urinary tract infection 
• 
Pain in extremity  
 
Because in previous studies some participants experienced increases in enzymes that are 
found in the liver, you will be monitored for this throughout this study. Such elevation in liver 
function tests in the blood can be early signs of liver injury. Because of this possibility, some of 
the blood drawn while you are in the study will be used to measure liver tests. You will be asked 
to return for confirmatory tests, and additional blood draws may be required within 3‐5 days after 
your laboratory data are available that show abnormality requiring close monitoring. 


 
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To date, rare cases of possible autoimmune hepatitis have been observed in clinical studies of 
CVC. Autoimmune Hepatitis is a serious condition involving inflammation of the liver that occurs 
when your body's immune system turns against liver cells. Possible cases of autoimmune 
hepatitis have been observed in people with liver disease treated with both CVC and placebo in 
previous studies. Signs and symptoms of autoimmune hepatitis can range from minor to severe, 
may come on suddenly and may include: 
• 
Fatigue (tiredness) 
• 
Abdominal discomfort 
• 
Yellowing of the skin and whites of the eyes (jaundice) 
• 
Enlarged liver 
• 
Abnormal blood vessels on the skin (spider angiomas) 
• 
Skin rashes 
• 
Joint pains 
• 
Loss of menstruation 
 
Contact your study doctor or study staff if you experience any of these or if you experience: 
• 
Loss of appetite for food 
• 
Nausea 
• 
Rash 
• 
Vomiting 
• 
Diarrhea 
• 
Itchiness 
• 
Fever 
 
It is unknown whether these reported side effects are directly related to study drug, CVC. Because 
CVC is still being studied, information on possible side effects of the drug is not complete. 
 
It is unknown whether reported adverse events are directly related to the study drug, CVC. 
 
Risks of Radiation 
As a result of your participation in this study, you will be exposed to radiation from FDG-PET/CT 
scans at the pre-entry and week 24 visits. There is also a very small possibility that the scan 
may be repeated if one of these two scans could not be evaluated. At most the scan will only be 
repeated one extra time. Please note that this radiation is not necessary for your medical care 
and is for research purposes only. 
 
The total amount of radiation exposure you will receive from participation in this study is equal to 
a whole body exposure of up to approximately 19 to 21 milliSieverts (mSv) from two scans and 
up to 28 to 32 mSv if an extra scan is needed. The dose that you will receive from participation 
in this research study is about the same as you would normally receive in approximately 5.4 
years from background radiation sources. 
 


 
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Scientists disagree on whether radiation doses at these low levels are harmful. A possible effect 
that could occur at doses associated with this study is a slight increase in the risk of developing 
cancer later in life. 
 
Since the effects of radiation can be cumulative, it is important to know of your past radiation 
exposure. If you have taken part in other studies or tests in the past 12 months, which have 
involved radiation exposure, please inform the study doctor or study staff. If it is determined that 
your past radiation exposure exceeds this study’s guidelines, it is possible that you will not be 
allowed to take part in this study. 
 
Potential Risks with Fluorodeoxyglucose (FDG) 
FDG is a radioactive drug with glucose (a type of sugar) that shows differences between healthy 
tissue and diseased tissue. This radioactive substance is taken up by your cells and remains in 
your body for a short time. This radioactive substance may expose the fetus of a pregnant 
individual or the infant of an individual who is breastfeeding to radiation. Pregnant and 
breastfeeding individuals cannot participate in this study. There is a rare risk of a major allergic 
reaction to FDG. 
 
Risk of Findings on Non-Clinical Radiological Procedures 
We are doing the FDG-PET/CT scan in this study to answer research questions, not as part of 
your medical care. The information created by this study will not usually become part of your 
hospital record. This FDG-PET/CT scan is not the same as one that your own doctor would 
order. It may or may not show problems that would be found on a standard FDG-PET/CT scan. 
 
If we do see something that looks like a medical problem, we will ask a radiologist (a doctor who 
specializes in x-rays/scans/test results of this sort) to review the results. 
 
If the radiologist thinks there might be a problem, we will tell you and help you get follow-up 
care. If the radiologist thinks that you might have a medical problem, but it turns out that you 
don’t, we may have caused you to worry needlessly about your health. 
 
Other Risks with the Radiological Procedures 
• 
Pain at the site of injection/IV catheter – You may have pain or discomfort where we place 
the IV catheter and give you the injection of FDG. You may also get a bruise, have an 
allergic reaction, or get an infection. 
• 
Discomfort during the scan – During the FDG-PET/CT scan, you will be asked to lie on your 
back for about 60 minutes. You may experience back pain, fatigue, and/or anxiety while the 
scan is taking place. 
 
Risks of Fasting 
You will be asked to not eat or drink anything for a number of hours before some study visits 
because of the FDG-PET scan or some blood tests that will be done at those visits. Fasting may 
cause hunger, weakness, fatigue (tiredness), anxiety, difficulty concentrating, and/or dizziness. 
 


 
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Risks of Blood Draws 
A needle will be used to take blood from a vein in your arm. This may lead to brief pain from the 
needle stick, bruising, and rarely, infection. Some people become light-headed. The risk of 
taking blood includes low red blood cell counts, which can make you feel tired, weak, and dizzy. 
If the study staff feel you are at risk for low blood counts, the amount of blood taken will be 
lowered and your blood counts will be checked. 
 
Allergic Reaction Risks 
All drugs have a possible risk of an allergic reaction, which, if not treated right away, could 
become life-threatening. If you have a serious allergic reaction, you may be at risk of death. 
Some symptoms of allergic reactions are: 
• 
Rash 
• 
Wheezing and difficulty breathing 
• 
Dizziness and fainting 
• 
Swelling around the mouth, throat, or eyes 
• 
A fast pulse 
• 
Sweating 
 
Please seek treatment immediately and tell the study doctor and study staff if you have any of 
these symptoms. 
 
Unknown Risks 
Other side effects that are not known at this time could happen during the study. During the study, 
you will be told about any new information that may affect your decision to stay in the study. If you 
decide to stay in the study, you will be asked to sign and date an updated consent form. If you 
decide to leave the study early, the study staff will talk with you about your treatment options. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The effects of CVC on an embryo/fetus are unknown at this time. It is also unknown if CVC 
passes through breast milk and whether it can produce adverse effects in the infant. If you are 
breastfeeding, pregnant, think you may be pregnant, or are trying to get pregnant, you may not 
join this study. 
 
If you are having sex that could lead to pregnancy, you must agree not to become pregnant. 
Because of the risk involved, you and your partner must use at least two methods of birth 
control. You must continue to use birth control until 3 months after stopping CVC. You must 
choose two of the birth control methods listed below: 
• 
A condom (male or female) with or without a spermicide 
• 
Diaphragm or cervical cap with spermicide 
• 
Hormone-based contraceptive 
• 
An intrauterine device 
 


 
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If you become pregnant while on study, you will stay on study but come off the study drug, CVC. 
When you come off the study drug, study staff will get blood tests required for all participants 
who stop study drugs. After that, you will have minimal blood draws for safety tests only. The 
study staff would like to obtain information from you about the outcome of the pregnancy (even 
if it is after your participation in the study ends). If you are taking 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? 
 
Since there is limited information about the effect of CVC in people with HIV, it is not known if 
there is a direct benefit from this study drug. It is also possible that you could be assigned to 
placebo. It is possible that you may receive no benefit from being in this study: your condition 
may not get better, and it may even get worse. Information learned from this study may help 
others who have HIV and are at higher risk for heart disease. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you 
• 
Treatment with other experimental drugs, if you qualify 
• 
No treatment 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
For sites in the US 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff to 
help keep your personal information private, we have gotten a Certificate of Confidentiality from 
the U.S. Federal Government. This certificate means that researchers cannot be forced to tell 
people who are not connected with this study, such as the court system, about your participation. 
Also, any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the U.S. Food and Drug Administration (FDA), the ACTG, the 
U.S. Office for Human Research Protections (OHRP), or other local, U.S., and international 
regulatory entities as part of their duties, Advarra IRB (a committee that protects the rights and 
safety of participants in research), National Institutes of Health (NIH), study staff, study monitors, 
the drug company supporting this study, and their designees. Having a Certificate of Confidentiality 
does not prevent you from releasing information about yourself and your participation in the study. 
 


 
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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 https://ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Identifiers might be removed from your identifiable private information or identifiable 
biospecimens collected during this study and could then be used for future research studies or 
distributed to another investigator for future research studies without additional informed consent. 
 
For sites outside the US 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. Any 
publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) institutional review board (IRB) or 
Ethics Committee (a committee that protects the rights and safety of participants in research), 
National Institutes of Health (NIH), study staff, study monitors, drug companies supporting this 
study, and their designees. 
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with information from 
other study participants and statistical analysis of study results. Your name and other personal 
identifiers will not be sent. Your research site is responsible for sending your information in 
accordance with the laws, regulations and policies of your country and research site. 
 
A description of this clinical trial will be available on https://ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. 
 
Taking part in this study may lead to added costs to you and your insurance company if we 
learn of any medical problems that need extra testing or follow-up. In some cases, it is possible 
that your insurance company will not pay for these costs because you are taking part in a 
research study. 
 


 
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WILL I RECEIVE ANY PAYMENT? 
 
«Compensation» 
 
Your biospecimens collected during this study will never be used for commercial profit (even if 
identifiers are removed). 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment could be charged to you or your insurance company. 
 
• 
There is no program for compensation through the NIH, but this site has clinical trials 
insurance. This insurance will allow the site to provide you with monetary compensation if 
you suffer harm as a result of participating in this research study. 
OR 
• 
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 and dating this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study such as: 
• 
Whom to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a research participant; 
• 
Eligibility to participate in the study; 
• 
The study doctor’s or study site’s decision to exclude you from participation; 
• 
Results of tests and/or procedures; 


 
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Please contact the study doctor at the telephone number listed on the first page of this consent 
document. 
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• 
Or call toll free:    877-992-4724 
• 
Or by email:         adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00065562. 
 
 
 


 
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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)  
 
 
 
 


 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED 
HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and study staff will use and share health data 
about you to conduct the study. Health data may include: 
• 
Your name 
• 
Address 
• 
Phone number 
• 
Date of birth 
• 
Medical history 
• 
Information from your study visits, including all test results 
 
Health data may come from your study records or from existing records kept by your regular 
doctor or other health care workers. 
 
For this study, the study staff may share health data about you with authorized users. 
Authorized users may include: 
• 
Representatives of National Institute of Allergy and Infectious Diseases (NIAID) 
• 
Representatives of the AIDS Clinical Trials Group (ACTG) 
• 
Representatives of AbbVie (the industry sponsor) 
• 
Representatives of Advarra IRB (an Institutional Review Board that reviews this study) 
• 
The Food and Drug Administration (FDA) and other US federal and state agencies 
• 
Government agencies to whom certain diseases (such as HIV, hepatitis, and STDs) must be 
reported 
• 
Governmental agencies of other countries 
• 
Other local, US, and international regulatory entities 
• 
Outside individuals and companies, such as laboratories and data storage companies, that 
work with the researchers and sponsor and need to access your information to conduct this 
study 
• 
Other research doctors and medical centers participating in this study, if applicable 
• 
A data and safety monitoring board that oversees this study, if applicable 
 
Your health data will be used to conduct and oversee the research, including, for instance: 
• 
To see if the study drug works and is safe 
• 
To compare the study drug to other drugs 
• 
For other research activities related to the study drug 
 
Once your health data has been shared with authorized users, it may no longer be protected by 
federal privacy law and could possibly be used or disclosed in ways other than those listed here. 
Your permission to use and share health data about you will end in 50 years unless you revoke it 
(take it back) sooner. 
 
You may revoke (take back) your permission to use and share health data about you at any 
time by writing to the study doctor at the address listed on the first page of this form. If you do 


 
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this, you will not be able to stay in this study. No new health data that identifies you will be 
gathered after your written request is received. However, health data about you that has already 
been gathered may still be used and given to others as described in this form. 
 
Your right to access your health data in the study records will be suspended during the study to 
keep from changing the study results. When the study is over, you can access your study health 
data. 
 
If you decide not to sign and date this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form, and its contents were explained. My questions have been answered. I 
voluntarily agree to allow study staff to collect, use, and share my health data as specified in this 
form. I will receive a signed and dated copy of this form for my records. I am not giving up any of 
my legal rights by signing and dating this form. 
 
__________________________________ 
Printed Name of Participant 
 
 
__________________________________  
 
__________ 
Signature of Participant 
 
 
 
 
Date 
 
 
 


 
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ATTACHMENT A: OPTIONAL 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. 
 
Your samples and any private information that is collected about you will be coded. 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. 
 
When a researcher wants to use your samples and information, their research plan must be 
approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review their plan 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 study staff 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 
samples will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the study staff any questions that you have before you indicate your 
selection. 
 
Research without Human Genetic Testing 
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved HIV-related research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples 
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples 
 
 
 


 
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Research with Human Genetic Testing 
The ACTG has a study that collects samples for genetic testing. 
 
This study is called ACTG A5128, Plan for Obtaining Informed Consent to Use Stored Human 
Biological Materials (HBM) for Currently Unspecified Analyses. 
 
Your site might ask you if you would like to participate in this study if it is being done where you 
live. If you would like to participate, you will sign and date a separate consent form. 
 
Your extra samples will not be used for human genetic testing unless you sign and date a 
consent form for A5128. 
 

SAP_001.pdf: 
  
Approvals 


A5415 
Primary Statistical Analysis Plan 
Version 2.0  
 
July 18, 2024 
 
A Limited-Center, Prospective, Double-Blind, Placebo-Controlled 
Study to Evaluate the Effects of Cenicriviroc Mesylate on Arterial 
Inflammation in People Living with HIV  
 
ClinicalTrials.gov Identifier: NCT05630885  
Protocol Version 2.0 
 
 
 
 
This is ACTG A5415 SAP Version 2.0 with names of authors, names of publication writing team 
members, and analysis timeline redacted. 
 


A5415 
July 18, 2024 
Primary Statistical Analysis Plan, Version 2.0 
 
Page 1 of 17 
Table of Contents 
 
TABLE OF CONTENTS ............................................................................................................................... 1 
VERSION HISTORY TABLE ........................................................................................................................ 3 
1 
INTRODUCTION .................................................................................................................................... 4 
1.1 
Purpose ........................................................................................................................................ 4 
1.2 
Version History ............................................................................................................................ 4 
2 
STUDY OVERVIEW ............................................................................................................................... 4 
2.1 
Study Design ................................................................................................................................ 4 
2.2 
Hypotheses .................................................................................................................................. 4 
2.3 
Study Objectives ......................................................................................................................... 4 
2.3.1 
Primary Objective and Estimand ....................................................................................... 5 
2.3.2 
Secondary Objectives ........................................................................................................ 6 
2.3.3 
Exploratory Objectives ....................................................................................................... 6 
2.4 
Overview of Sample Size Considerations ................................................................................. 6 
2.5 
Timing of Final Analyses ............................................................................................................ 7 
3 
OUTCOME MEASURES ........................................................................................................................ 7 
3.1 
Key Definitions Related to FDG-PET Imaging .......................................................................... 7 
3.2 
Primary Outcome Measure ......................................................................................................... 8 
3.3 
Secondary and Other Outcome Measures ................................................................................ 8 
4 
STATISTICAL PRINCIPLES .................................................................................................................. 9 
4.1 
General Considerations .............................................................................................................. 9 
4.1.1 
Data for Analysis ................................................................................................................ 9 
4.1.2 
Participant Exclusions ........................................................................................................ 9 
4.1.3 
Analysis Windows ............................................................................................................ 10 
4.1.4 
Analysis Sets ................................................................................................................... 10 
4.2 
Analysis Approaches ................................................................................................................ 10 
REPORT CONTENTS ................................................................................................................................ 11 
5 
PARTICIPANT CHARACTERISTICS AND DISPOSITION ................................................................. 11 
5.1 
Screening ................................................................................................................................... 11 
5.2 
Accrual ....................................................................................................................................... 11 
5.3 
CONSORT diagram .................................................................................................................... 11 
5.4 
Protocol Deviations ................................................................................................................... 11 
5.5 
Baseline characteristics ........................................................................................................... 11 
5.6 
Study status ............................................................................................................................... 12 
5.7 
Treatment status ........................................................................................................................ 12 
6 
ADVERSE AND TARGETED EVENTS (AE) ....................................................................................... 13 
6.1 
Adverse Events .......................................................................................................................... 13 
6.2 
Pregnancies ............................................................................................................................... 13 
6.3 
Mortality ...................................................................................................................................... 13 
6.4 
Virologic failures ....................................................................................................................... 13 
7 
ARTERIAL INFLAMMATION ............................................................................................................... 13 


A5415 
July 18, 2024 
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7.1 
Inclusion/Exclusion for Efficacy Analyses ............................................................................. 13 
7.2 
TBR-related Outcomes.............................................................................................................. 14 
7.2.1 
Descriptive Statistics for TBR Outcomes ......................................................................... 14 
7.2.2 
Figure of changes in TBR from Baseline to Week 24 versus participants ...................... 14 
7.2.3 
Regression Analysis of Difference in Change in TBR between Treatment Arms ........... 14 
7.2.4 
Modification of CVC effect by Sex and Race................................................................... 15 
7.3 
Correlates of MDS TBR of the Index Vessel ........................................................................... 15 
7.4 
SUV Outcomes ........................................................................................................................... 16 
8 
SOLUBLE AND CELLULAR BIOMARKERS ..................................................................................... 16 
8.1.1 
Distribution Plot of Biomarkers by Visit Week ................................................................. 16 
9 
PHARMACOKINETIC (PK) / PHARMACODYNAMIC (PD) OUTCOMES .......................................... 16 
9.1.1 
Descriptive Statistics of CVC Trough Estimates by ART Class ...................................... 17 
9.1.2 
Change in ART Trough Estimates ................................................................................... 17 
9.1.3 
Correlation between CVC Trough Exposure versus Index Vessel MDS TBR ................ 17 
 
 
 


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Version History Table 
 
Version 
Changes Made 
Date Finalized 
1.0 
Original Version per Protocol Version 1.0 
Apr 5, 2023 
1.1 
Reviewed for Protocol version 2.0 with no changes needed. 
Apr 15, 2024 
2.0 
Section 2: 
• 
Removed details on Interim monitoring 
• 
In Section 2.3.1, clarified outcome measure description (most diseased 
vessel) and revised analysis approach to use linear regression instead of t-
test. 
• 
Added Section 2.3.3: exploratory analyses. 
• 
Added Section 2.6: regarding timing of final analyses. 
Section 3: 
• 
Added Section 3.1: Key definitions section. 
• 
Revised Section 3.1 for clarity, updated to Section 3.2. 
• 
Revised Section 3.2 to include other outcome measures and to update 
presentation structure into table-list. Updated to Section 3.3 
Section 4.1:  
• 
Added Section 4.1.1 and 4.1.2: key dates and data inclusion/exclusion for 
data to be analyzed. 
• 
Revised Section 4.1.3 (previously 4.1): updated Day 1, week 4, and week 22 
definition/range. Updated baseline definitions for outcomes to be based on 
entry instead of pre-entry/entry. 
• 
In Section 4.1.4 (previously 4.2.1): added complete-case set definition. 
• 
Revised Section 4.2: cleaned up sentences and moved details to be in 
Section 5. 
Section 5: 
• 
Added protocol deviation table to be reported. 
• 
Modified components of baseline characteristics summary. 
• 
Updated summary measures for baseline characteristics, study status, and 
treatment status from continuous to categorical. 
• 
Added analysis set to be used, groups, statistical tests, and other details 
relevant to each table to be generated. 
• 
Added sections on all listed outcomes and associated details. 
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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary, secondary, and other outcome 
measures that will address specific study objectives and interim monitoring of the A5415 study. The 
Primary SAP includes general analytic approaches for all primary, secondary, and other outcome 
measures that will be included in the primary manuscript(s), Conference on Retroviruses and 
Opportunistic Infections (CROI) submission, or submitted to ClinicalTrials.gov (regardless of the reporting 
timeline). The Primary SAP facilitates discussion of the statistical analysis components among the writing 
team and statisticians, helping them agree on the statistical analyses to be performed and presented in 
the final analysis report.  
An Analysis Implementation Plan (AIP) will also be prepared to provide more detailed outlines of tables, 
figures, and coding descriptions.  
1.2 
Version History 
Version 1.0: Original version based on Protocol Version 1.0 dated August 22, 2022. 
Version 2.0: Prepared leading up to the final analysis. 
• 
The study team revised baseline and week 24 testing for immunological outcomes from averaging 
pre-entry/entry and week 22/24 to only using entry and week 24 samples due to budget constraints. 
• 
Other changes include updates to visit window definitions, adds more details and clarifications to 
analytic plans for the primary and secondary objectives, as well as providing analysis plans for 
exploratory objectives that will be included in the Primary Statistical Report. See Version History 
Table for more details. 
2 
Study Overview 
2.1 
Study Design 
A5415 is a double-blind, randomized, placebo-controlled, phase II trial to evaluate 24 weeks of 
Cenicriviroc mesylate (CVC) to reduce arterial inflammation among individuals living with chronic HIV on 
ART with viral suppression. CVC or placebo for CVC will be administered for 24 weeks to participants. 
The target sample size was 93 participants (62 in the CVC arm and 31 in the placebo arm). The study 
enrolled between May 2023 and January 2024 with a final sample size of 110 participants. 
2.2 
Hypotheses 
Cenicriviroc mesylate (CVC) will decrease vascular inflammation as measured by 18F-
fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) cardiac 
imaging. 
2.3 
Study Objectives 
This Primary SAP addresses the following primary and secondary objectives listed in the study protocol 
as well as other study objectives in the protocol that will be analyzed for the primary statistical report.  


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2.3.1 
Primary Objective and Estimand 
See Section 3.1 for details about TBR-related terms. 
Primary Objective 1:  To assess whether CVC treatment results in reduced arterial inflammation by 
comparing the changes in arterial target-to-background ratio (TBR) in the carotid arteries and aorta after 
treatment with CVC versus placebo.  
Estimand description 
Percentage change in the arterial 18-FDG-PET TBR in the most diseased segment 
(MDS) of the carotid arteries and aorta following 24 weeks of CVC therapy among 
virally suppressed people living with HIV with at least one cardiovascular risk factor.   
Treatment 
Addition of CVC to background ART compared to ART alone. 
Target population    
Analysis set  
Individuals living with HIV who are ≥45 years old, have at least 
one cardiovascular risk factor, and are on stable NNRTI-based 
or unboosted INSTI-based ART regimen, with suppressed HIV-1 
RNA for ≥48 weeks prior to CVC start and who remain on the 
same ART drug class over an additional 24 weeks of CVC. 
Participants who remain on study treatment for 
at least 22 weeks, and remain on the same 
ART drug class during the study. 
Variable(s) 
Outcome measure(s)  
Fold change in 18-FDG-PET TBR, measured in the MDS of the 
most diseased vessel between the left and right carotid arteries 
and aorta over 24 weeks of CVC treatment 
Fold change from baseline to week 24 in 18-
FDG-PET TBR of the MDS of the most 
diseased vessel between the left and right 
carotid arteries and aorta. 
MDS TBR will be log10 transformed 
(log10[week 24] – log10[pre-entry]) for analysis 
and back transformed for a fold change 
interpretation. 
Handling of intercurrent events  
Handling of missing data 
The following intercurrent events are relevant to the estimand:  
- Change in background ART regimen not within the same drug 
class: excluded (principal stratum) 
- Change in background ART regimen within the same drug 
class: ignored (treatment policy) 
- Treatment interruption or missed doses: ignored (treatment 
policy) 
- Permanent discontinuation of treatment or background ART: 
Excluded (principal stratum) 
- Death – excluded (principal stratum) 
- Prohibited medications – excluded (principal stratum) 
- Pregnancy or breast-feeding – excluded (principal stratum) 
Missing data due to unreadable or missed 
scans will be handled by using multiple 
imputation.  
A sensitivity analysis for the primary analysis 
will include complete case analysis.  
Population-level summary statistic 
Analysis approach 
Geometric mean fold change (expressed as a percentage) in 
arterial MDS TBR after 24 weeks of treatment with and without 
CVC. 
Fold change in TBR (1 - the geometric mean 
change) will be summarized by treatment 
groups with a 95% confidence interval. 
The relative treatment difference will be 
described as a geometric mean difference 
(active compared to placebo) and compared 
with a linear regression, stratified by statin use.  
A supplementary analysis to the primary analysis will include participants who remain on treatment for at least 12 
weeks and remain on the same ART drug class. A second supplementary analysis will exclude participants with 
confirmed HIV-1 RNA > 200 copies/mL or ART interruption for 14 or more consecutive days at any time during the 
course of the study. 


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2.3.2 
Secondary Objectives 
1) To assess changes in metabolic parameters including fasting glucose, fasting insulin, homeostasis 
model assessment-estimated insulin resistance (HOMA-IR), inflammatory markers including high 
sensitivity interleukin 6 (hsIL-6) and hsCRP, and markers of monocyte/macrophage activation 
including soluble CD14 (sCD14), soluble CD163 (sCD163), and monocyte chemoattractant protein-1 
(MCP-1) after treatment with CVC compared to placebo. 
2) To assess changes in cellular chemokine receptor 5 (CCR5) and CCR2 levels and changes in their 
plasma ligands (MIP-1α, MIP-1β and RANTES for CCR5; MCP-1 [CCL2] for CCR2) after treatment 
with CVC compared to placebo. 
3) To evaluate the safety of CVC in virally suppressed antiretroviral therapy (ART)-treated, HIV-infected 
individuals. 
2.3.3 
Exploratory Objectives 
1) To measure the effects of CVC on adipocytokines (adiponectin) and on noninvasive assessments of 
liver fibrosis, including AST to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4). 
2) To assess changes in FDG uptake in visceral fat and to quantify changes in visceral adipose tissue 
area and volume, subcutaneous adipose tissue area and volume, fat density, and liver to spleen 
attenuation ratio (as a noninvasive measure of hepatosteatosis) by noncontrast CT after treatment 
with CVC compared to placebo. 
3) [PK/PD] To determine the association between CVC trough exposure and the primary treatment 
outcome (i.e., reduced arterial inflammation). 
4) To evaluate the effects of CVC on markers of monocyte and T cell homing and activation as well as 
on myeloid cells. 
5) To assess changes in occupancy of the CCR5 and CCR2 receptors on T cells and monocytes after 
treatment with CVC compared to placebo.  
6) [PK/PD] To evaluate potential drug interactions by a) investigating the impact of INSTI- and NNRTI-
based ART on CVC trough estimates and to compare these estimates across regimens and b) 
investigating the impact of CVC treatment versus no treatment on the trough exposure of ART. 
Note: The Study Pharmacologist is evaluating currently available data on the effects of CVC on ART 
exposures to determine ARTs would be of interest for part b) of this objective.  
2.4 
Overview of Sample Size Considerations 
The target sample size is 75 participants (50 in the CVC arm and 25 in the placebo arm) with baseline 
and follow-up PET/CT. To allow for some loss to follow-up and participants unwilling or unable to 
complete 2 scans, the study planned to enroll 93 participants (62 in the CVC arm and 31 in the placebo 
arm). Final enrollment was 110 participants. 
The primary analysis will focus on between-treatment arm differences in the within-participant changes in 
arterial MDS TBR (the measure of arterial inflammation by PET/CT). Based on a superiority trial design 
with two-sided α=0.05, assuming a standard deviation (SD) of 0.065 log10 TBR for change in MDS TBR, a 
total of 75 participants providing complete, evaluable data sets will ensure 80% power to detect a 
between-groups difference of 0.046 log10 MDS TBR (which is a 10% reduction from baseline). 
The assumptions underlying the power calculation are as follows: 
1) The target effect size for the change in MDS TBR on therapy of 10% is based on the observation of a 
statin intensification study. 
2) The assumed SD for change in (log10) MDS TBR of 0.065 is derived from the placebo arm of ACTG 
A5314. 


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3) The use of a two-sided, two-sample T-test with type-I error rate of 5%. 
The assumption that 93 enrolled participants will provide 75 participants with evaluable data is derived by 
20% total data loss due to drop-out after randomization (including premature discontinuation of study 
treatment and change in background ART drug class). 
2.5 
Timing of Final Analyses 
Last participant visit occurred June 19, 2024. If final data for the coronary artery PET/CTs are submitted 
to the Data Management Center (DMC) by the end of August, we aim to have a preliminary result for a 
CROI 2025 submission (due September 2024) that would include the primary and secondary PET/CT and 
limited biomarker results. To achieve this goal, the team has developed a schedule for data submission 
for preliminary reads of the PET/CT and phased testing of limited biomarkers in July and August 2024 on 
which analysis programming can be based.  
The comprehensive final primary analysis report is expected to be distributed to the team no later than 
mid-late December 2024 following the database lock. Outcomes that are expected to be included as part 
of Preliminary report for CROI versus the Final Primary report are labelled accordingly in Section 3 below. 
NOTE: The inclusion of secondary and exploratory outcomes in the report are highly contingent on the 
timeliness of submission of laboratory data to the DMC and associated processing. If all data are 
available in time, they will be included. 
3 
Outcome Measures 
3.1 
Key Definitions Related to FDG-PET Imaging 
Term(s) 
Definitions at a Participant Level 
Target vessel 
Specific arterial vessels of interest: R carotid, L carotid, and aorta. 
Background vessel 
Internal jugular vein (JV) for carotids and superior vena cava (SVC) for 
aorta.  
Standardized Uptake Value (SUV): 
Decay-corrected tissue concentration of FDG (in kBq/mL) divided by the 
injected dose per body weight (kBq/g). SUV is unitless. 
1. 
Target SUV 
1. 
Target SUV is the maxSUV measured for each of 10 slices of the target 
vessel. 
2. 
Background SUV 
2. 
Background SUV is the meanSUV measured for each of 10 slices of 
the background vessel. 
3. 
Average background SUV 
3. 
Average background SUV is calculated as the average of the 
meanSUVs of the respective background vessel. 
Most diseased segment (MDS) 
2-3 slices of arterial segment, centered on the slice of the target vessel with 
the highest SUV at baseline. 
Index Vessel 
Vessel with the highest vessel TBR (see definition below) at baseline (i.e., 
most diseased vessel). 
Target-to-Background Ratio (TBR): 
Measure of FDG uptake, calculated as a ratio between the target and 
background SUV. 
1. 
Vessel TBR 
1. 
Vessel TBR is calculated as the ratio of the average target SUV (over 
10 slices) and its associated average background SUV. 
2. 
Vessel MDS TBR 
2. 
Vessel MDS TBR is calculated as the ratio of the average target SUV of 
the MDS of the vessel (over 2-3 slices) and its associated average 
background SUV. 
3. 
Index vessel MDS TBR 
3. 
Index vessel MDS TBR is defined as the vessel MDS TBR of the index 
vessel (i.e., the vessel with the highest vessel TBR). 


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3.2 
Primary Outcome Measure 
Primary Outcome Measure 
 
Expected 
Reporting 
Timeline 
Outcome Measure(s) 
Associated 
Objective(s) 
1 
CROI 
Change in the Index vessel MDS TBR of the index vessel from baseline to 
week 24 
Primary 
3.3 
Secondary and Other Outcome Measures 
Secondary Outcome Measures 
 
Expected 
Reporting 
Timeline 
Outcome Measure(s) 
Associated 
Objective(s) 
1 
CROI 
Change in vessel TBR  of the bilateral carotid artery and aorta from baseline 
to week 24 from baseline to week 24 
For the bilateral carotid, the mean of the maxSUV for both the right and left 
carotid arteries will be combined. 
Further 
investigation of 
Primary 
2 
CROI 
Change in average vessel SUV of the bilateral carotid artery and aorta from 
baseline to week 24 
For the bilateral carotid, the mean of the maxSUV for both the right and left 
carotid arteries will be combined. 
3 
CROI 
Change in fasting glucose from baseline to week 24 
Secondary 1 
4 
FINAL 
Change in fasting insulin and HOMA-IR from baseline to week 24 
Secondary 1 
5 
CROI 
Change from baseline to week 24 in  
• 
IL-6, hsCRP, MCP-1 (inflammatory biomarkers) 
• 
sCD14, sCD163 (markers of monocyte/macrophage activation) 
Secondary 1 
6 
FINAL 
Change from baseline to week 24 in: 
• 
Cellular levels of CCR5 and CCR2  
• 
Plasma levels of RANTES, MIP-1α, MIP-1β (CCR5 plasma ligands) 
• 
Plasma levels of MCP-1 (CCR2 plasma ligand) 
Note: MCP-1 is the same outcome measure described above, it is 
retained here as it will be repeated in tabular summaries related to CVC 
effects on CCR5 and CCR2. 
Secondary 2 
7 
CROI 
• 
Occurrence of at least one SAE 
• 
Occurrence of at least one treatment related AE 
• 
Occurrence of at least one treatment limiting AE 
Secondary 3 
Other Outcome Measures 
 
Expected 
Reporting 
Timeline 
Outcome Measure(s) 
Associated 
Objective(s) 
1 
FINAL 
Change in FDG uptake in visceral fat and lymph nodes from baseline to week 
24. 
Exploratory 2 
2 
FINAL 
Change in adipocytokines (such as adiponectin) from baseline to week 24. 
Exploratory 1 


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3 
FINAL 
Change from baseline to week 24 in myeloid derived suppressor cell (MDSC) 
frequencies 
Change from baseline to week 24 in monocyte subsets: 
• 
% CD14+, CD16- (Classical); % CD14+, CD16+ (Inflammatory); % CD14-
, CD16+ (Non-classical) where % is % of total monocytes  
• 
Expression of CX3CR1, CCR5, CCR2 (homing receptors) on total 
monocytes and on monocyte subsets. 
• 
HLA-DR density and CD69 expression (monocyte activation) on total 
monocytes and on monocyte subsets. 
Exploratory 4, 5 
4 
FINAL 
Changes from baseline to week 24 in CD4 and CD8 T cell expression of 
CX3CR1, CCR2, CCR5 
Changes from baseline to week 24 in CD4 and CD8 T cell expression CD38 
and HLA-DR 
Exploratory 5 
5 
FINAL 
[PK/PD] CVC trough concentration measured at weeks 4, 8, 12, and 24. 
Exploratory 3, 6 
6 
FINAL 
[PK/PD] ART trough concentration measured at pre-entry, weeks 4, 8, 12, 
and 24. 
Measured only in participants randomized to CVC.  
Exploratory 6 
4 
Statistical Principles 
4.1 
General Considerations 
4.1.1 
Data for Analysis 
Key Timepoints 
Date 
Timepoint 
Jun 21, 2024 
Anticipated Primary Completion Date 
Aug 31, 2024 
Final PET/CT scan data and all other outcome data received by the DMC. 
Note: If this date cannot be met for the PET/CT results, CROI abstract submission will be 
deferred to the late-breaker deadline. 
Sep 10, 2024 
Preliminary data cut for CROI 
Oct 4, 2024 
Clinical database closure / data freeze 
Nov 25, 2024 
Final database lock 
Nov 26, 2024 
Data push for final analysis 
4.1.2 
Participant Exclusions 
Participants who had any events below will be excluded from efficacy data to be analyzed, per handling of 
intercurrent events (Section 2.3.1): 
• 
Never started treatment 
• 
Deemed clinically ineligible for the study 
• 
Took prohibited medication(s) during the study 
• 
Died 
• 
Became pregnant 


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4.1.3 
Analysis Windows 
Defined as follows: 
• 
Day 1 = study treatment initiation date 
• 
Week 4: -21 / +14 days 
• 
Weeks 8, 12, 16: +/- 14 days 
• 
Week 22: -14 / +7 days 
• 
Week 24: -7 days up to maximum days observed 
Baseline refers to study evaluation closest to Week 0 prior to initiation of study treatment unless 
otherwise stated. 
In the event of multiple results within a study window, the result closest to the scheduled evaluation week 
based on the time since study treatment initiation date will be used. Exceptions may include repeat visits 
for confirmation of events such as virologic failures. 
4.1.4 
Analysis Sets 
Efficacy set (per-protocol set): All eligible participants who remain on study treatment for at least 22 
weeks and remain on the same ART drug class during their entire study period. 
Complete-case set: Efficacy set participants who have baseline-week 24 pair of PET/CT scan data. 
Supplementary efficacy set one: All eligible participants in the efficacy set as well as participants who 
remained on study treatment for at least 12 weeks and remained on the same ART drug class during their 
entire study period. 
Supplementary efficacy set two: All eligible participants in the efficacy set excluding participants with 
confirmed HIV-1 RNA > 200 copies/mL or ≥ 14 consecutive days of ART interruption at any time during 
the course of the study. 
Safety set: All enrolled participants who initiate study treatment. 
4.2 
Analysis Approaches 
• 
Descriptive summaries in Section 5 will be presented for both the Safety set and Efficacy set, unless 
otherwise specified. 
• 
Summary statistics for discrete and continuous outcomes will be detailed under each report-content in 
Sections 5 - 9.  
• 
All statistical tests will be two-sided with a nominal alpha level of 0.05.  
o 
No adjustment for multiple testing will be performed.  
• 
Stratification will be taken into account in efficacy outcome analyses unless stated otherwise. 
• 
No statistical comparisons across groups for baseline characteristics are planned. 
• 
Missing data for TBR analyses will be handled using multiple imputation; sensitivity analyses will be 
complete case where missing data are ignored. 
• 
Missing data for biomarker analyses will be ignored (i.e., all analyses will be complete case). 


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Report Contents 
5 
Participant Characteristics and Disposition 
5.1 
Screening 
1) Table of N (%) of participants screened. 
2) Table of N (%) of participants failed screening, with reasons for failed screening. 
5.2 
Accrual 
1) Figure: Bar chart of number of accrual by month 
o 
By sex  
o 
By treatment arm 
2) Table of N (%) accrual by site  
5.3 
CONSORT diagram 
Flowchart of number of participants from screening up to analyses by treatment arms, including 
information on exclusions from each step. 
5.4 
Protocol Deviations 
  
Cenicriviroc Mesylate (CVC) 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
Overall Deviation 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Deviation Reason Category 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Reason 1 
xx 
xx 
xx 
Reason 2 
xx 
xx 
xx 
… 
… 
… 
… 
 
 [All contents below will be by treatment groups, unless otherwise mentioned] 
5.5 
Baseline characteristics  
Analysis set(s): Safety set, Efficacy set 
Table 1a 
Demographics 
Characteristic 
Summary Statistic(s) 
Age 
Median (Q1, Q3), and P10, P90 
N (%): 45-54, 55-64, 65-74, 75+ 
Sex at Birth 
N (%): Male, female 
Gender Identity 
N (%): Cisgender, transgender spectrum 
Race 
N (%): White, Black or African American, unknown 
Ethnicity 
N (%): Hispanic or Latino, Not Hispanic or Latino 
BMI 
Median (Q1, Q3), and P10, P90 
N (%): Underweight (< 18.5), normal (18.5 – 24.9), overweight (25 
– 29.9), obese (30+) 


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Current-use of statins at entry 
N (%): Current use of statins, no current use of statins. 
Statin agents 
N (%): statins 
eGFR 
Median (Q1, Q3), and P10, P90 
Table 1b 
HIV Characteristics 
Characteristic 
Summary Statistic(s) 
CD4 Count 
Median (Q1, Q3), and P10, P90 
CD4 % 
Median (Q1, Q3), and P10, P90 
HIV-1 RNA 
Median (Q1, Q3), and P10, P90 
N (%): < LLQ, > LLQ (lower limit of quantification) 
ART Class at entry 
N (%): INSTI and NNRTI-based, INSTI-based, NNRTI-based 
ART Regimens 
N (%): ARV regimens at entry 
Table 1c 
Cardiovascular Risk Factors 
Characteristic 
Summary Statistic(s) 
Participants’ number of cardiovascular 
risk factors 
N (%): 1, 2, 3, 4+ CV risk factors 
High-risk cardiovascular risk factors (see 
Protocol Section 4.1.6 for the list) 
For each CV risk factor: 
N (%): With, without 
5.6 
Study status   
Table 
Study Status 
Characteristic 
Summary Statistic(s) 
Study Status 
N (%): completed study, prematurely discontinued study 
Last Clinic Visit 
N (%): No follow-up, < 12 weeks, 12 - < 24 weeks, 24+ weeks 
Study Discontinuation Reasons 
N (%): Reasons 
5.7 
Treatment status 
Table 1 
Treatment Status 
Characteristic 
Summary Statistic(s) 
Treatment Status 
N (%): Completed, did not start, prematurely discontinued 
Days from Entry to First Dose of Treatment 
N (%): 0, 1, 2, 3, 4+ days 
Reasons for Treatment Discontinuation 
N (%): Reasons 
Week of Treatment Discontinuation 
N (%): Did not start, < 12 weeks, 12 - < 24 weeks, 24+ weeks 
Treatment Interruption Reason 
N (%): Reason 
Week of Initial Interruption 
N (%): Did not start, < 12 weeks, 12 - < 24 weeks, 24+ weeks 
Total Interruption Duration 
N (%): 1-7, 8-14, 15+ days 


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6 
Adverse and Targeted events (AE) 
6.1 
Adverse Events 
Analysis set(s): Safety set 
Statistics: N (%) 
Listing: Public ID, AE start day, AE term, Grade, Action taken with treatment, Relationship to treatment. 
1) Table of all new, post-entry AEs by MedDRA PT grouped by SOC (reported in ClinicalTrials.gov) 
2) Listing of longitudinal creatinine and eGFR with creatinine-related AEs 
3) Table/listing of SAEs by MedDRA PT grouped by SOC, excluding those related to PET/CT 
4) Listing of all AEs related to study treatment by MedDRA PT grouped by SOC, excluding those related 
to PET/CT 
5) Table/listing of all AEs related to PET/CT scan by MedDRA PT grouped by SOC 
6.2 
Pregnancies 
Listing of participants who become pregnant while on study, with public ID, treatment arm, weeks of 
positive pregnancy test, weeks of study treatment discontinuation, and pregnancy outcomes 
6.3 
Mortality 
Listing of participants who died, with public ID, treatment arm, primary cause of death, and weeks of 
death, and relationship to study treatment 
6.4 
Virologic failures 
Table of N (%) of participants with virologic failure. If N is small, listing of virologic failures with public ID, 
treatment arm, weeks of initial and confirmed virologic failure, and HIV-1 RNA copies/mL at initial and 
confirmed virologic failure may be provided in lieu of summary table. 
7 
Arterial Inflammation 
7.1 
Inclusion/Exclusion for Efficacy Analyses 
1) Table of N (%) of participants included or excluded, by reasons and treatment arm, in: 
a. Efficacy set 
b. Complete-case set 
c. Supplementary set 1 
d. Supplementary set 2 
 
Inclusion/Exclusion for xxx Analysis Set 
CVC 
(N=xxx) 
Placebo 
(N=xxx) 
Total 
(N=xxx) 
Safety 
Population 
Flag 
On-treatment 
for at least 12 
weeks 
Per-Protocol 
Population 
Flag 
On-treatment for at 
least 22 weeks 
No change in ART 
class from baseline 
xx (xx%) 
Included 
Included 
Included 
Included 
Included 
xx (xx%) xx (xx%) 
Excluded 
Excluded 
Included 
xx (xx%) xx (xx%) xx (xx%) 
Excluded 
xx (xx%) xx (xx%) xx (xx%) 
Excluded 
Excluded 
Excluded 
Included 
xx (xx%) xx (xx%) xx (xx%) 
 


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7.2 
TBR-related Outcomes 
• 
TBRs will be log10-transformed for analyses and back-transformed to fold-change for interpretation 
and presentation.  
• 
Missing data due to unreadable or missed week 24 scans will be handled using multiple imputation 
(MI) with regression (details will be provided in the AIP). 
7.2.1 
Descriptive Statistics for TBR Outcomes 
Analysis set(s): Efficacy set 
Stratification: Overall, by statin-use 
Grouped by: Baseline, Week 24, Change 
Analysis method: (change-outcomes only) stratified, within-arm paired two-sample t-test between 
baseline and week 24 with null hypothesis of no difference between baseline and week 24 TBRs. 
Table  
Columns for each group: Total (baseline group only), Cenicriviroc, Placebo 
Characteristic 
Baseline, Week 24 Statistic(s) 
Change Statistic 
Index vessel MDS TBR 
Mean (st.dev.), Median (Q1, Q3), and P10, P90 
Mean, 95% confidence interval 
Index vessel 
N (%): Aorta, R Carotid, L Carotid 
 
Aortic Vessel TBR 
Mean (st.dev.), Median (Q1, Q3), and P10, P90 
Mean, 95% confidence interval 
Bilateral Carotid Vessel 
TBR 
Mean (st.dev.), Median (Q1, Q3), and P10, P90 
Mean, 95% confidence interval 
7.2.2 
Figure of changes in TBR from Baseline to Week 24 versus participants 
Analysis set(s): Efficacy set 
Grouped by: by statin-use and treatment arm 
7.2.3 
Regression Analysis of Difference in Change in TBR between Treatment Arms 
• Analysis set(s):  
1. 
Outcome: Efficacy set  
2. 
(Primary only) Sensitivity analysis: Complete-case set 
3. 
(Primary only) Supplementary analysis 1: Supplementary set 1 
4. 
(Primary only) Supplementary analysis 2: Supplementary set 2 


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• Analysis method:  
a) 
Linear regression of change in TBR on treatment arm, adjusted by statin-use. 
b) 
Linear regression above with interaction between treatment arm and statin-use. 
NOTE: Linear regression with interaction (b) for secondary outcomes will be done only if linear regression 
with interaction of primary outcome shows that change in MDS TBR is different by statin-use. 
 
7.2.4 
Modification of CVC effect by Sex and Race 
Analyses 1b above will be repeated replacing statin-use with a) sex assigned at birth b) race (Black 
versus non-black). 
7.3 
Correlates of MDS TBR of the Index Vessel 
These analyses are planned for the Final Report. 
• Analysis set(s): Efficacy set 
• Outcomes: 1) Baseline MDS TBR of the index vessel 2) Change in MDS TBR of the index vessel 
• Covariates: Age, sex, race, BMI, use of statins at entry, ART (INSTI vs NNRTI), perceived stress 
scale, diet, average CVC trough (analysis of change only) 
With the exception of average CVC trough, all measures are at entry. In the event of a positive effect 
of CVC, analyses of change will be limited to participants in the CVC arm. 
• Analysis method:  
a) Descriptive graphic displays of the distribution TBR by each of the covariates of interest 
b) Linear regression of TBR adjusted for each covariate in turn (i.e., unadjusted analyses). 
Analyses of change in MDS TBR will also adjust for baseline MDS TBR. 
c) Linear regression of TBR adjusted for each covariate with evidence of association with TBR in 
unadjusted analyses. Given the relatively small sample size, evidence of association will be judged 
with either relaxed type 1 error or clinically meaningful effect sizes. 
• 
Presentation of results: Forest plot for each outcome showing parameter estimates and 95% 
confidence interval. 
Table 
Regression Analysis Results 
Outcome 
Characteristic 
Summary 
Statistic(s) 
Statistical Test 
PRIMARY 
Change in Index vessel MDS 
TBR (a) 
Treatment 
parameter estimate 
95% confidence interval, p-value 
Change in Index vessel MDS 
TBR given statin-use (b) 
Treatment 
parameter estimate 
95% confidence interval, p-value of 
interaction effect of statin-use 
Change in Index vessel MDS 
TBR given no statin-use (b) 
Treatment 
parameter estimate 
Outcome 
Characteristic 
Summary 
Statistic(s) 
Statistical Test 
Secondary 
Change in aortic vessel TBR (a) 
Treatment 
parameter estimate 
95% confidence interval, p-value 
Change in bilateral carotid vessel 
TBR (a) 
Treatment 
parameter estimate 
95% confidence interval, p-value 


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7.4 
SUV Outcomes 
Analysis set(s): Efficacy set 
Same analyses as Primary outcome (Section 7.2) on aorta, carotid arteries. 
8 
Soluble and Cellular Biomarkers  
Analysis set(s): Efficacy set, Supplementary analysis set 1. 
• 
All change-from-baseline-to-week-24 outcomes described in Section 3.3 will be analyzed in the same 
manner as the Primary outcome (Section 7.2). 
• 
Soluble biomarkers may be transformed for analyses on the log10 scale and back transformed to fold 
change for interpretation and presentation, as appropriate. 
• 
Missing data will be ignored; all analyses will be complete case including only participants with paired 
values of each given biomarker available. 
8.1.1 
Distribution Plot of Biomarkers by Visit Week 
Analysis set(s): Efficacy set 
Stratification: Overall, by statin-use 
Grouped by: Baseline, Week 24, Change 
• 
Figure: Jitter and boxplot of biomarkers at baseline and week 24 by treatment arms (with a 3rd group 
of boxplots showing the within-participant change) 
 
9 
Pharmacokinetic (PK) / Pharmacodynamic (PD) Outcomes 
Analyses in this section are subject to change based on pending review of current literature of CVC and 
ART drug-drug interactions. Based on review of participant regimens, only bictegravir (BIC), dolutegravir 
(DTG), rilpivirine (RPV), tenofovir alafenamide (TAF), emtricitibine (FTC), and lamiviudine (3TC) have 
exposure by at least 10 participants. 
All PK outcomes are limited to participants in the CVC arm. 


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9.1.1 
Descriptive Statistics of CVC Trough Estimates by ART Class 
Analysis set(s): Complete case set (cenicriviroc arm only) 
Grouped by: a) ART Class (INSTI, NNRTI, both); b) ART Agent  
 
 
 
 
 
9.1.2 
Change in ART Trough Estimates 
Analysis set(s): Complete case set 
Grouped by: Specific ART Bictegravir, Dolutegravir, Rilpivirine 
Stratification: None 
Analysis method: paired t-test of pre-study treatment and participant-level average post-study treatment 
ART trough estimates with null hypothesis of no difference between pre- and post- study measures. 
 
Table  
Columns for each group: Pre, Post, Change 
Characteristic 
Pre-, Post- Treatment Statistic(s) 
Change Statistic 
Average <DRUG> 
trough concentration 
Mean (st.dev.), Median (Q1, Q3), and P10, 
P90 
Mean, 95% confidence interval, p-value 
 
9.1.3 
Correlation between CVC Trough Exposure versus Index Vessel MDS TBR 
Analysis set(s): Complete case set 
Stratification: Overall, by statin-use 
Analysis method: Spearman’s rank-based correlation 
• 
Figure: Scatterplot of Index Vessel MDS TBR vs CVC trough exposure 
o 
CVC exposure is based on composite time-adjusted CVC exposure estimate over the 24-week 
study period obtained from mixed-effect modelling based on measured concentrations at weeks 4, 
8, 12, and 24 (see Protocol Section 11.3.2). 
 
 
 
Table 
CVC Trough Estimates by ART Class / Agent 
Characteristic 
Summary Statistic(s) 
Participant-level average CVC trough concentration 
Median (Q1, Q3), and P10, P90 
CVC trough concentration by week 
Median (Q1, Q3), and P10, P90