Clinical trial NCT01933594
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2014-05-05; Completion date: 2018-04-16
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Antiretroviral therapy (ART) can reduce HIV to very low levels in the blood, but it cannot cure HIV infection because a small amount of virus remains in cells as a hidden (latent) form. The purpose of this study was to evaluate the safety and efficacy of single dose and multiple dose administration of romidepsin (RMD) in HIV-infected adults.

Detailed description:
A major challenge in eradicating HIV-1 infection is the persistence of virus in long-lived cells, such as latently infected memory CD4 T cells. One approach for eliminating the HIV-1 reservoir is to activate viral replication in these latently infected CD4 T cells by targeting cellular mechanisms that repress proviral transcription. Histone deacetylase inhibitors (HDACis), such as RMD, induce HIV-1 expression by increasing acetylation and facilitating transcriptional activation of HIV-1. RMD administered in combination with ART may serve as an important component of a strategy to eradicate the HIV-1 latent reservoir. The purpose of this study was to evaluate the safety and efficacy of single dose and multiple dose administration of RMD in HIV-infected adults.

Participants were sequentially enrolled into four cohorts and randomly assigned to receive either RMD or placebo. The cohorts differed in the dose of RMD given. Participants in Cohorts 1, 2, and 3 had one intravenous (IV) infusion of RMD or placebo at Day 0. Participants in Cohort 4 had four IV infusions of RMD or placebo at Days 0, 14, 28, and 42.

For participants in Cohorts 1, 2, and 3, study duration was 4 weeks. For participants in Cohort 4, study duration was a minimum of 24 weeks and a maximum of 48 weeks.

Participants attended several study visits, which could include a physical examination, blood and urine collection, pharmacokinetic (PK) sampling, and an electrocardiogram (ECG).

Arms: arm 1: Participants in Cohort 1, Arm 1A received Romidepsin intravenously (IV) over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 0.5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 2: Participants in Cohort 1, Arm 1B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 0.5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 3: Participants in Cohort 2, Arm 2A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 2 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 4: Participants in Cohort 2, Arm 2B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 2 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 5: Participants in Cohort 3, Arm 3A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of Romidepsin was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 6: Participants in Cohort 3, Arm 3B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0 study visit. Dose of sodium chloride for injection placebo was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 7: Participants in Cohort 4, Arm 4A received Romidepsin IV over 4 hours (beginning at Hour 0) at the Day 0, 14, 28, and 42 study visits. Dose of Romidepsin was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight). arm 8: Participants in Cohort 4, Arm 4B received 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 0, 14, 28, and 42 study visits. Dose of sodium chloride for injection placebo was 5 mg/m\^2, with total dose based on the participant's body surface area (determined by participant's height and weight).
Interventions: intervention 1: Romidepsin intervention 2: Placebo for Romidepsin
Intervention descriptions: intervention 1: RMD administered over 4 hours via an intravenous (IV) catheter. intervention 2: Placebo for RMD administered over 4 hours via an IV catheter.

Protocol documents:
Prot_001.pdf: 
 
 
 
 
A5315 
 
A Phase I/II Study of Romidepsin in HIV-Infected Adults with Suppressed Viremia 
on Antiretroviral Therapy to Assess Safety, Tolerability, and Activation of HIV-1 
Expression 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
In collaboration with 
Gilead Sciences 
 
 
IND #119,069 
 
 
The ACTG HIV Reservoirs and Viral Eradication 
Transformative Science Group: 
Rajesh Gandhi, MD, Chair 
 
Protocol Co-Chairs: 
Deborah McMahon, MD 
 
John Mellors, MD 
 
Protocol Vice Chairs: 
Rajesh Gandhi, MD 
 
Michael Para, MD 
 
DAIDS Clinical Representative: 
Catherine Godfrey, MD 
 
Clinical Trials Specialists: 
Lara Hosey, MA, CCRP 
 
Parita Rathod, BS, RAC 
 
 
 
FINAL Version 4.0 
June 7, 2018 
 


 
 
A5315 
FINAL Version 4.0 
 
 
06/07/18 
 
 
A Phase I/II Study of Romidepsin in HIV-Infected Adults with Suppressed Viremia on 
Antiretroviral Therapy to Assess Safety, Tolerability, and Activation of HIV-1 Expression 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
Name/Title 


 
 
A5315 
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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 .....................................................................11 
SCHEMA ..................................................................................................................................12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 14 
1.1 
Hypothesis ......................................................................................................... 14 
1.2 
Primary Objectives ............................................................................................. 14 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Exploratory Objectives ....................................................................................... 15 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale ........................................................................................................... 16 
3.0 
STUDY DESIGN ........................................................................................................... 24 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 25 
4.1 
Inclusion Criteria – Cohorts 1, 2, and 3 .............................................................. 25 
4.2 
Exclusion Criteria – Cohorts 1, 2, and 3 ............................................................. 28 
4.3 
Inclusion Criteria – Cohort 4, Step 1................................................................... 30 
4.4 
Exclusion Criteria – Cohort 4, Step 1 ................................................................. 33 
4.5 
Inclusion Criteria – Cohort 4, Step 2................................................................... 35 
4.6 
Exclusion Criteria – Cohort 4, Step 2 ................................................................. 35 
4.7 
Inclusion Criteria – Cohort 4, Step 3................................................................... 35 
4.8 
Exclusion Criteria – Cohort 4, Step 3 ................................................................. 36 
4.9 
Inclusion Criteria – Cohort 4, Step 4................................................................... 36 
4.10 
Exclusion Criteria – Cohort 4, Step 4 ................................................................. 37 
4.11 
Study Enrollment Procedures............................................................................. 37 
4.12 
Coenrollment Guidelines .................................................................................... 38 
5.0 
STUDY TREATMENT ................................................................................................... 38 
5.1 
Regimens, Administration, and Duration ............................................................ 38 
5.2 
Study Product Formulation and Preparation ....................................................... 42 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 46 
5.4 
RMD Pharmacokinetic Samples ......................................................................... 47 
5.5 
Concomitant Medications ................................................................................... 47 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 48 
6.1 
Schedules of Evaluations ................................................................................. 48 
6.2 
Timing of Evaluations ......................................................................................... 67 
6.3 
Instructions for Evaluations ................................................................................ 71 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 81 


A5315 
 
 
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CONTENTS (Cont’d) 
Page 
 
7.1 
Toxicity .............................................................................................................. 82 
7.2 
Pregnancy.......................................................................................................... 83 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 84 
8.1 
Permanent and Premature Treatment Discontinuation ....................................... 84 
8.2 
Premature Study Discontinuation ....................................................................... 85 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 85 
9.1 
General Design Issues ....................................................................................... 85 
9.2 
Outcome Measures ............................................................................................ 86 
9.3 
Randomization and Stratification ........................................................................ 88 
9.4 
Sample Size and Accrual ................................................................................... 88 
9.5 
Monitoring .......................................................................................................... 93 
9.6 
Analyses ............................................................................................................ 94 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 95 
10.1 
Pharmacology Objectives .................................................................................. 95 
10.2 
Pharmacology Study Design .............................................................................. 95 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis .............................. 96 
10.4 
Anticipated Outcomes ........................................................................................ 96 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 97 
11.1 
Records to Be Kept ............................................................................................ 97 
11.2 
Role of Data Management ................................................................................. 97 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 97 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 97 
12.0 
HUMAN PARTICIPANTS .............................................................................................. 99 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 99 
12.2 
Participant Confidentiality ................................................................................... 99 
12.3 
Study Discontinuation ........................................................................................ 99 
13.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................ 100 
14.0 
BIOHAZARD CONTAINMENT .................................................................................... 100 
15.0 
REFERENCES ............................................................................................................ 101 
APPENDIX I: A5315 STUDY VISITS – COHORT 3 ................................................................ 104 
APPENDIX II: A5315 STUDY VISITS – COHORT 4 ............................................................... 107 
APPENDIX III: A5315 BENEFITS AND RISKS ....................................................................... 111 
APPENDIX IV: SAMPLE INFORMED CONSENT, COHORTS 1 & 2 ...................................... 113 
APPENDIX V: SAMPLE INFORMED CONSENT, COHORT 3 ................................................ 122 
APPENDIX VI: SAMPLE INFORMED CONSENT, COHORT 4 ............................................... 131 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5315 is open to US ACTG clinical research sites (CRSs) that have a research unit (eg, a 
GCRC-type unit) to perform chemotherapy infusion followed by pharmacokinetic (PK) blood 
collections. Other requirements are noted in the A5315 site implementation plan (SIP) found on 
the Protocol Specific Webpage (PSWP).   
 
 


 
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PROTOCOL TEAM ROSTER 
 
Co-Chair 
Deborah McMahon, MD 
University of Pittsburgh 
3520 Fifth Avenue 
Keystone Building, Suite 510 
Pittsburgh, PA  15213 
Phone:  412-383-1717 
FAX:  412-383-2900 
E-Mail: mcmahond@pitt.edu 
 
Co-Chair/Virologist  
John Mellors, MD   
University of Pittsburgh 
3550 Terrace Street 
Scaife Hall, Suite 818 
Pittsburgh, PA  15261 
Phone:  412-624-8512 
FAX:  412-383-7982 
E-Mail: jwm1@pitt.edu 
 
Vice Chairs 
Rajesh Gandhi, MD 
Cox 5th Floor 
55 Fruit Street 
Boston MA 02114 
Phone: 617-724-9690 
FAX: 617-726-7653 
E-Mail: rgandhi@partners.org 
 
Michael Para, MD 
Division of Infectious Diseases 
Ohio State University Medical Center 
410 West 10th Avenue, Room N1147 
Columbus OH 43210-1228 
Phone: 614-293-5666 
FAX: 614-293-4556 
E-Mail: michael.para@osumc.edu 
 
DAIDS Clinical Representative 
Catherine Godfrey, MD 
HIV Research Branch 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane 
Room 9E49 
Rockville MD 20852 
Phone: 240-627-3074 
FAX: 301-432-9282 
E-Mail: cgodfrey@niaid.nih.gov 
 
Clinical Trials Specialists 
Lara Hosey, MA, CCRP 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3395 
FAX: 301-628-3302 
E-Mail: lhosey@s-3.com 
 
Parita Rathod, BS, RAC 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3378 
E-Mail: prathod@s-3.com 
 
Statisticians 
Evgenia Aga, MS 
Harvard TH Chan School of Public Health 
FXB Building, Room 504 
651 Huntington Avenue 
Boston MA 02115-6017 
Phone: 617-432-3029 
FAX: 617-432-3163 
E-Mail: eaga@sdac.harvard.edu 
 


 
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Statisticians (Cont’d) 
Summer Zheng, PhD 
Harvard TH Chan School of Public Health 
FXB Building, Room 613 
651 Huntington Avenue 
Boston MA 02115-6017 
Phone: 617-432-3021 
FAX: 617-432-2843 
E-Mail: szheng@sdac.harvard.edu 
 
Data Managers 
Jennifer Janik, MS  
Frontier Science and Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst NY 14226-1056 
Phone: 716-834-0900 Ext. 7287 
FAX: 716-834-8432  
E-Mail: janik@fstrf.org 
 
Apsara Nair, MS 
Frontier Science and Technology 
Research Foundation, Inc. 
4033 Maple Road 
Amherst NY 14226-1056 
Phone: 716-834-0900 Ext. 7293 
FAX: 716-834-8432  
E-Mail: anair@fstrf.org 
 
DAIDS Pharmacist 
Katherine Shin, PharmD 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
5601 Fishers Lane Room 9D30B 
Rockville MD 20852 
Phone: 240-627-3047 
FAX: 240-627-3112 
E-Mail: kashin@niaid.nih.gov 
 
Immunologist  
Bernard JC Macatangay, MD 
University of Pittsburgh 
3520 Fifth Ave 
Keystone Building, Suite 510 
Pittsburgh, PA 15213 
Phone: 412-383-1272 
FAX: 412-383-2900 
E-Mail: macatangaybj@upmc.edu 
 
Pharmacologist  
Edward Acosta, PharmD 
Division of Clinical Pharmacology 
Department of Pharmacology and 
Toxicology 
University of Alabama 
1670 University Boulevard, VH 258 
Birmingham AL 35294-0019 
Phone: 205-934-2655 
FAX: 205-934-6201 
E-Mail: eacosta@uab.edu 
 
Investigators 
Joshua Cyktor, PhD 
University of Pittsburgh VSL 
Division of Infectious Diseases 
S825 Scaife Hall 
3550 Terrace Street 
Pittsburgh, PA 15261 
Phone: 412-648-8198 
E-Mail: jcc114@pitt.edu 
  
Ronald Mitsuyasu, MD 
UCLA CARE Center  
9911 West Pico Boulevard, Suite 980 
Los Angeles CA 90035 
Phone: 310-557-1893 
FAX: 310-557-1899 
E-Mail: rmitsuya@mednet.ucla.edu 
 


 
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PROTCOL TEAM ROSTER (Cont'd) 
06/07/18 
 
 
 
Field Representative 
Kathy Watson, RN 
The Ohio State University AIDS CRS 
McCampbell Hall 
1581 Dodd Drive 
Room 423 
Columbus OH 43210-1228 
Phone: 614-293-5856 
Fax: 614-293-5240 
E-Mail: kathy.watson@osumc.edu 
 
Co-Laboratory Technologists 
Joan Dragavon, MLM 
Virology Specialty Laboratory 
University of Washington 
Research & Training Building 
300 9th Avenue, Room 725 
Seattle WA 98104-2499 
Phone: 206-897-5210 
FAX: 206-897-5237 
E-Mail: dragavon@u.washington.edu 
 
Carmen Irizarry, MT, (ASCP) 
Medical Science Campus 
University of Puerto Rico 
Pathology 606-A 
San Juan PR 00935 
Phone: 787-758-5815 
FAX: 787-751-9210 
E-Mail: lab053.rcm@upr.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Liz Barr, MS 
E-Mail: barrlizbarr@gmail.com 
 
Industry Representatives 
Joseph S. Camardo, MD 
Celgene Corporation 
86 Morris Avenue 
Summit NJ 07901 
Phone: 908-673-9982  
E-Mail: jcamardo@celgene.com 
 
Industry Representatives (Cont'd) 
Romas Geleziunas, PhD 
Gilead Sciences 
333 Lakeside Drive 
Foster City, CA 94404 
Phone: 650-652-6241 
E-Mail: romas.geleziunas@gilead.com 
 
James Rooney, MD 
Gilead Sciences 
333 Lakeside Drive 
Foster City, CA 94404 
Phone: 650-522-5708 
FAX: 650-522-5854 
E-Mail: Jim.Rooney@gilead.com 
 
Joseph Hesselgesser, PhD 
Gilead Sciences, Inc. 
333 Lakeside Dr. 
Foster City, CA  94404 
Phone: 650-522-6327 
E-Mail: Joe.Hesselgesser@gilead.com 
  
Laboratory Data Manager 
Laura Hovind, BS, MS 
Frontier Science and Technology Research 
Foundation  
4033 Maple Rd  
Amherst, NY 14226  
Phone: 716-834-0900 Ext. 7468  
E-Mail: lhovind@fstrf.org 
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.corea5315@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.corea5315@fstrf.org.  A response 
should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5315 e-mail group. 
Include the protocol number in the e-mail subject line.  
 
 
Send an e-mail message to actg.user.support@fstrf.org  
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol team. Send an e-mail message to actg.corea5315@fstrf.org. 
Include the protocol number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to immunologic, virologic, or pharmacologic laboratory tests, 
contact the protocol immunologist, virologist, or pharmacologist. Send an e-mail message to 
actg.corea5315@fstrf.org (ATTN: Bernard Macatangay/John Mellors/Edward Acosta). 
 
Data Management 
CRFs can be downloaded from the FSTRF website at www.fstrf.org. 
 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events, randomization/registration, delinquencies, and other data 
management issues, contact the data managers, Jennifer Janik, at janik@fstrf.org and Apsara 
Nair, at anair@fstrf.org.  
 
For transfers, reference the Study Participant Transfer SOP 119, and contact Jennifer Janik 
directly (janik@fstrf.org).  
 
 
For other questions, send an e-mail message to Jennifer Janik (janik@fstrf.org) and Apsara 
Nair (anair@fstrf.org), with a cc to: actg.corea5315@fstrf.org.   
 
Include the protocol number in the subject line. In the body of the message, include the PID 
and any relevant details. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification number 
SID lists.  
 
Send an e-mail message to rando.support@fstrf.org. Call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at 716-898-7301.    
 


 
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Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
 
Send an e-mail message to actg.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialists, Lara 
Hosey and Parita Rathod. Send an e-mail message to lhosey@s-3.com and prathod@s-3.com 
with a cc to: actg.corea5315@fstrf.org. 
 
Copies of the Protocol 
Electronic copies can be downloaded from the ACTG Web site (https://www.actgnetwork.org). 
 
To request a hard copy of the protocol, send a message to ACTGNCC@s-3.com.  
 
Product Package Inserts  
To request copies of product package inserts, contact the DAIDS Regulatory Support Center 
(RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Katherine Shin, protocol pharmacist, at 240-627-3047.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
The IND number is 119,069. For any questions related to the IND submission, contact the 
DAIDS RSC at Regulatory@tech-res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5315 team members by 
sending an e-mail to actg.corea5315@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ANA  
antinuclear antibody 
ANC 
absolute neutrophil count 
ART 
antiretroviral therapy 
AUC 
area under curve 
BSA 
body surface area 
CTCL  
cutaneous T-cell lymphoma 
DTG  
dolutegravir 
EFV 
efavirenz 
FACS 
fluorescence activated cell sorting  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDACi 
histone deacetylase inhibitors  
HLA-DR 
human leukocyte antigen disease resistance 
LTR 
long terminal repeat 
MS 
milliseconds 
MTD  
maximum tolerated dose 
PBMC 
peripheral blood mononuclear cell 
PMA 
phorbol 12-myristate 13-acetate  
PTEF-b 
positive transcription elongation factor b 
qVOA 
quantitative viral outgrowth assay 
RAL 
raltegravir 
RMD 
romidepsin 
SAHA 
suberoylanilide hydroxamic acid (Vorinostat or Zolinza®) 
SCA 
single copy assay of HIV-1 RNA in plasma 
TVR 
total virus recovery (assay) 
 


 
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SCHEMA 
 
A5315 
A Phase I/II Study of Romidepsin in HIV-Infected Adults with Suppressed Viremia on 
Antiretroviral Therapy to Assess Safety, Tolerability, and  
Activation of HIV-1 Expression 
 
DESIGN 
A5315 is a phase I/II, double-blinded, randomized, placebo-controlled, 
dose-escalation study to evaluate the safety and efficacy of single dose 
and multiple dose administration of romidepsin (RMD). Four cohorts (1-4) 
of 15 participants each will be sequentially enrolled into the study 
(depending on safety outcomes, which will determine whether to dose 
escalate or not). Toxicity related to the administration of RMD will be 
evaluated systematically in all cohorts. The effect of RMD on HIV 
expression will be evaluated in all cohorts. Samples will also be collected 
for pharmacokinetic (PK) evaluation of antiretroviral drugs (ARVs) and 
RMD. 
 
DURATION 
For participants in Cohorts 1 – 3, study duration is 4 weeks. For 
participants in Cohort 4, study duration is a minimum of 24 weeks; study 
duration will be increased if any of the infusions after the first one must be 
delayed. The maximum study duration for Cohort 4 participants will be 48 
weeks. 
 
SAMPLE SIZE 
60 evaluable participants (approximately 15 evaluable participants in 
each cohort)  
 
POPULATION 
HIV- infected adults at least 18 years of age with CD4+ counts 
≥300 cells/mm3 who have suppressed viremia on a raltegravir (RAL), 
dolutegravir (DTG), or efavirenz (EFV)-based regimen or, for Cohort 4, 
on a RAL- or DTG-based regimen (plasma HIV-1 RNA levels 
<50 copies/mL and no blips >50 copies/mL on standard commercial 
assays) and, for Cohorts 1-3 only, who have ≥0.4 HIV-1 RNA copies/mL 
by single-copy assay (SCA) at screening. Plasma HIV-1 RNA ≥0.4 HIV-1 
RNA copies/mL by SCA is not required as part of eligibility for Cohort 4. 
 
REGIMEN  
Participants will be sequentially enrolled to cohorts and randomized 4:1 to 
receive RMD or placebo as shown below.  
 
Cohort 1: 
12 participants will receive 0.5 mg/m2 RMD in 0.9% saline 3 
participants will receive placebo in 0.9% saline  
 
Cohort 2:  12 participants will receive 2 mg/m2 RMD in 0.9% saline 3 
participants will receive placebo in 0.9% saline  
 
Cohort 3:  12 participants will receive 5 mg/m2 RMD in 0.9% saline 3 
participants will receive placebo in 0.9% saline  


 
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Cohort 4: 
12 participants will receive a total of 20 mg/m2 RMD in 0.9% 
saline (5 mg/m2 RMD at each of four dosing time points) 3 
participants will receive placebo in 0.9% saline (at each of 
four dosing time points) 
 
Accrual of the first five participants in any cohort will be limited to one 
participant in a 3-day period. Participants who do not receive or who do 
not complete any of the scheduled infusions of study treatment (RMD or 
placebo) will be replaced. 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
We hypothesize that adjunctive therapy with the potent histone deacetylase inhibitor 
(HDACi) romidepsin (RMD) administered at doses well below the maximum tolerated 
dose (MTD), will be well tolerated and lead to activation of proviral HIV-1 expression in 
latently-infected cells in HIV-infected participants receiving suppressive antiretroviral 
therapy (ART).   
 
NOTE: Due to insufficient numbers of resting CD4+ T-cells available from some 
Cohort 4 participants to perform all the planned assays (e.g., cell-associated HIV-1 
RNA, total HIV-1 DNA, histone acetylation, PTEF-b activation), those assays will be 
performed using peripheral blood mononuclear cells (PBMCs). The team carefully 
reassessed the priorities for the use of these cells based on advances in the field 
since the prior protocol version. Accordingly, the relevant objectives and 
outcomes measures sections have been updated. 
 
1.2 
Primary Objectives 
 
1.2.1 To determine the safety and tolerability of the intravenous administration of a 
single dose of RMD to HIV-infected participants with HIV-1 RNA levels <50 
copies/mL on a stable ART regimen in Cohorts 1-3, and of multiple doses of 
RMD in Cohort 4.  
 
1.2.2 To assess the induction of HIV-1 expression in HIV-infected participants with 
suppressed viremia by measuring plasma viremia using a single copy HIV-1 RNA 
assay prior to and following a single dose of RMD in Cohorts 1-3 and prior to 
and following each of multiple doses of RMD in Cohort 4. 
 
1.2.3 To assess changes in cell-associated HIV-1 RNA levels in resting CD4+ T-cells 
obtained prior to and following a single dose of RMD in Cohorts 1-3 and in 
PBMCs prior to and following each of multiple RMD doses in Cohort 4. 
 
NOTE: Due to insufficient numbers of resting CD4+ T-cells available from 
some Cohort 4 participants to perform all the planned assays (e.g., 
cell-associated HIV-1 RNA, total HIV-1 DNA, histone acetylation, 
PTEF-b activation), those assays will be performed using peripheral 
blood mononuclear cells (PBMCs). The team carefully reassessed 
the priorities for the use of these cells based on advances in the 
field since the prior protocol version. Accordingly, the relevant 
objectives and outcomes measures sections have been updated. 
 


 
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1.3 
Secondary Objectives 
 
1.3.1 To assess changes in histone acetylation levels and P-TEFb activation in CD4+ 
and CD8+ T-cells prior to and following a single dose of RMD in Cohorts 1-3 and 
in PBMCs prior to and following each of multiple RMD doses in Cohort 4. 
 
1.3.2 To assess changes in total HIV-1 DNA in resting and total CD4+ T-cells prior to 
and following a single dose of RMD in Cohorts 1-3 and in PBMCs prior to and 
following each of multiple RMD doses in Cohort 4.  
 
1.3.3 To obtain pharmacokinetic (PK) data for RMD and coadministered antiretroviral 
drugs prior to and following a single dose of RMD in Cohorts 1-3 and following 
the third and fourth doses in Cohort 4 to assess potential drug-drug interactions. 
 
1.3.4 To assess changes in the levels of cellular immune activation by evaluating 
the proportion of CD4+ and CD8+ T-cells co-expressing CD38/HLA-DR or 
CD69/CD25 on CD4+ and CD8+ T cells prior to and following a single dose 
or multiple doses of RMD. 
 
1.3.5 To assess apoptosis by evaluating the proportion of total lymphocytes 
staining with annexin V alone (early apoptosis) or both annexin V 
(apoptotic) and 7-amino-actinomycin D (7-AAD) (dead cells) prior to and 
following a single dose or multiple doses of RMD. 
 
1.4 
Exploratory Objectives 
 
1.4.1 To examine the efficacy of multiple doses of RMD for reducing the latent, 
inducible HIV-1 reservoir, as measured by the quantitative viral outgrowth 
assay (qVOA) assay in Cohort 4. 
 
1.4.2 To assess changes in the proportion of cycling CD4+ and CD8+ T-cells by 
evaluating Ki67 expression prior to and following a single dose or multiple doses 
of RMD. 
 
1.4.3 To assess changes in systemic inflammation by evaluating the levels of soluble 
biomarkers such as IL-6, C-reactive protein (CRP), and D-dimer prior to and 
following a single dose or multiple doses of RMD. 
 
1.4.4 In Cohort 4, to assess HIV-specific immune responses following the first and 
fourth doses of RMD.  
 
1.4.5  In Cohort 4, to assess host RNA expression profiles by RNAseq of PBMC 
prior to the first dose of RMD and following the first and fourth doses of 
RMD.  
 
1.4.6 In Cohort 4, to assess the impact of multiple doses of RMD on the 
proportion of CD4+ T-cells with intact proviral DNA. 


 
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2.0 
INTRODUCTION 
 
2.1 
Background 
 
A major obstacle to eradicating HIV-1 infection is the persistence of virus in long-lived 
cells, such as latently-infected memory CD4+ T-cells. It has been estimated that the 
decay half-life of these cells exceeds 40 months and that more than 70 years of 
suppressive ART would be required to eliminate this viral reservoir [1-3]. A current 
estimate of the size of the latent HIV-1 reservoir is that approximately one in a million 
memory CD4+ T-cells contains integrated replication-competent HIV-1 provirus [4]. In 
addition, recent studies have shown that the majority of patients on ART with viremia 
suppressed to <50 HIV-1 RNA copies/mL have residual viremia that can be detected by 
assays with single copy sensitivity [5]. Studies of ART intensification [6-8] that involve 
the addition of a potent antiretroviral drug to a suppressive regimen have failed to show 
any effect of this approach on the level of residual viremia. These results are consistent 
with viremia arising from stable reservoirs of long-lived, chronically infected cells and not 
from ongoing, complete cycles of viral replication, underscoring the need for new 
therapeutic approaches to eliminate these HIV-1 reservoirs.  
 
Because viral replication in activated CD4+ T-cells usually results in the death of the 
host cell, one approach for eliminating the HIV-1 reservoir is to specifically activate viral 
replication in latently-infected CD4+ T-cells. If induction of HIV-1 expression kills the 
infected cell and ART prevents infection of new cells, there may be depletion of the HIV-
1 reservoir. Alternatively, based on recent in vitro work, induction of HIV-1 from latency 
with vorinostat may not be sufficient to eliminate infected cells, and additional measures, 
such as stimulation of cytotoxic T lymphocytes, may be necessary to deplete cells that 
have been induced to express HIV-1 [9]. Nevertheless, activation of virus from latency is 
likely to be required in any strategy that seeks to eliminate HIV-1 infection. 
 
Multiple agents have the potential to activate HIV-1 from latency, but to be optimally 
useful these drugs need to target the subset of CD4+ T-cells which harbor the virus.  
Immune activation with anti-CD3 and recombinant human interleukin (IL)-2 in HIV-1-
infected patients on potent ART was studied a number of years ago with limited success 
and, in some cases, substantial toxicity [10, 11]. More recently, IL-7 has been shown to 
induce expression of latent HIV in vitro and in the SCID-hu mouse model of HIV-1 
infection [12]. IL-7 induces expression of latent HIV-1 with minimal effects on T-cell 
phenotype but may also expand latent virus reservoirs by promoting T-cell proliferation 
[13 -14].  The effect of IL-7 on HIV-1 reservoirs is currently being tested in clinical trials 
such as ERAMUNE [15]. 
 
Another approach to inducing HIV-1 expression in latently-infected cells is to target 
cellular mechanisms that repress proviral transcription. Perhaps the most promising of 
these approaches is modulation of the activity of histone deacetylases, a family of 
chromatin remodeling enzymes that control gene expression, through the use of specific 
inhibitors of these enzymes. 
 
2.2 
Rationale 


 
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Studies of Histone Deacetylase Inhibitors to Reverse HIV-1 Latency 
Histone deacetylase inhibitors (HDACi) induce HIV-1 expression by increasing histone 
acetylation and facilitating transcriptional activation of HIV-1. Several HDACi have been 
studied in vitro as inducers of HIV-1 expression, of which two, valproic acid and 
vorinostat, have been studied in HIV-infected participants [16-23]. 
 
Valproic Acid 
Valproic acid is used clinically as an anticonvulsant. In addition to blocking voltage gated 
sodium channels and Type-T calcium channels, valproic acid is a weak HDACi. 
Ylisastiqui et al. [16] demonstrated that valproic acid induced outgrowth of HIV from 
resting memory CD4+ cells of aviremic HIV-1 infected participants. Lehrman et al. [17] 
dosed patients with valproic acid and also intensified the suppressive ART regimen with 
enfuvirtide. In three of four participants studied, they observed a reduction in the 
frequency of resting memory T-cells from which infectious virus could be recovered.  
Other studies of valproic acid were not able to confirm that finding [18]. Of note, valproic 
acid is a nonspecific and weak HDACi. Therefore, the Food and Drug Administration 
(FDA)-approved doses of valproic acid are not likely to result in HIV-1 activation in vivo 
[19], and doses that may be required to exert a significant effect on virus activation may 
have unacceptable long-term toxicities. 
 
Vorinostat  
Vorinostat (suberoylanilide hydroxamic acid [SAHA] or Zolinza®) is the other HDACi that 
is currently being evaluated as an inducer of latent HIV-1 [20-22]. Vorinostat is a class I 
and class II HDACi that is FDA-approved for the treatment of cutaneous T-cell 
lymphoma (CTCL). Archin [23] and Contreras [22] found that vorinostat induced HIV-1 
production from resting CD4+ T-cells of HIV-1 infected patients with suppressed viremia 
on ART. These findings provided in vitro data supportive of two ongoing phase I/II 
clinical trials of vorinostat in HIV-infected people. In a recent report from an ongoing trial, 
eight participants who received a single 400 mg dose of oral vorinostat had a mean 
4.8-fold (range 1.5-10) induction of cell-associated RNA levels in resting CD4+ cells [23]. 
The single dose of vorinostat was well-tolerated. It should be noted, however, that 
vorinostat scores positive in the AMES test indicating that it is mutagenic. This presents 
a potential barrier to multiple dose administration of vorinostat to otherwise healthy HIV-
infected patients on suppressive ART. Nevertheless, a clinical trial of vorinostat 
administered daily for 14 days in HIV-infected participants with suppressed viremia in 
Australia has concluded and demonstrated an increase in HIV transcription from latency 
in the majority of the trial participants [40]. 
 


 
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Romidepsin 
 
 
 
\Romidepsin (Istodax® package insert October 2014) is a cyclic peptide HDACi (Figure 
1) that was FDA-approved in 2009 for the treatment of CTCL.  Romidepsin (RMD) is a 
substantially more potent HDACi (1000 to 20,000-fold) than vorinostat. RMD inhibits 
HDACs 1, 2, and 3 (IC50 ~30 pM vs. 100 - 500 nM for SAHA), HDAC 5 (IC50 = 12 pM vs. 
~200 nM for SAHA) and HDACs 9, 10, 11 (IC50 ~100 – 400 pM vs. 300 – 500 nM). In 
patients with CTCL, RMD is administered as a 4-hour intravenous infusion at a dose of 
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on days 1, 8, and 15 of a 28-day cycle, usually for multiple cycles. Following a 4-hour 
intravenous administration of RMD at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle in 
patients with T-cell lymphomas, the terminal half-life (t1/2) was approximately 3 hours. 
No accumulation of RMD was observed after repeated dosing. Early clinical trials of 
RMD in CTCL patients revealed a potentially increased risk of QTc prolongation. As a 
result, the package insert for this drug indicates that it should not be given to a patient 
with a prolonged QTc. Side effects of RMD at the MTD include nausea, fatigue, 
vomiting, and anorexia. Common first cycle toxicities reported include bone marrow 
suppression and transient elevations of liver function tests [24-25, 32]. In clinical trials of 
RMD for T-cell lymphoma, bone marrow suppression has been associated with fatal and 
serious infections as well as reactivation of EBV and hepatitis B virus. RMD is 
predominantly metabolized by the cytochrome P450 enzyme CYP3A4. RMD is highly 
protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 
1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. 
Although there are no formal drug interaction studies for RMD, strong CYP3A4 inhibitors 
may increase plasma concentrations of RMD. RMD is also a substrate of the efflux 
transporter P-gp (ABSB1); hence drugs that inhibit P-gp may increase plasma 
concentrations of RMD. Finally, RMD competes with beta estradiol for binding to 
estrogen receptors, which inhibits their function (RMD Investigators Brochure v 10.0 May 
2012). 
 
Table 2.2-1:  Induction of HIV-1 RNA ex vivo 
 
HIV-infected  
donor 
Fold increase  
over no drug control 
p value  
vs. control 
1 
4.8 
0.03 
2 
5.6 
0.006 
3 
14.0 
0.0008 
4 
3.0 
0.0005 
5 
5.9 
0.02 
6 
14.0 
0.02 
7 
5.2 
0.00002 
8 
2.8 
0.01 
9 
16.0 
0.00003 
10 
20.1 
0.0003 
11 
1.8 
0.4 
12 
5.8 
0.005 
13 
12.3 
0.001 
 
Avg = 8.6 
 
HIV-1 RNA levels were measured by Roche Taqman v2.0 
at day 6 in culture supernatants of CD4+ memory T-cells 
from patients on suppressive ART. Intracellular HIV RNA 
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In laboratory studies, Gilead Sciences has found that RMD is approximately 1000-fold 
more potent than vorinostat for inducing latent HIV-1 expression, using both a modified 
version of the primary cell latency model described by Bosque and Planelles [26] (Figure 
2) and memory T-cells from HIV-infected participants on suppressive ART (Table 2.2-1). 
When tested at 5 nM [approximately 6% of the free fraction at the peak plasma 
concentration (Cmax) after a 4 hour IV infusion of 14mg/m2], RMD induced HIV-1 
expression in cells from 12 of 13 HIV-infected participants (92% response rate; Table 
2.2-1) with an average induction over the no drug control of 8.6-fold. Of note, when 
vorinostat was tested at a concentration of 2.5 M (approximately 5 times the free 
fraction at Cmax after a 400 mg dose) in a similar assay, HIV-1 expression was induced in 
only 3 of 25 participants (17%) [27].  
 
We have also found that a 4-hour in vitro pulse of 5 nM RMD, which mimics the 4-hour 
IV infusion administered to CTCL patients, is sufficient to induce HIV-1 expression ex 
vivo in cells from HIV-infected participants on suppressive ART. When tested at higher 
levels (20 nM, 40nM, and 80 nM) in cells from HIV-infected participants on suppressive 
ART, a 4-hour pulse of RMD increased HIV-1 RNA expression in culture supernatants 
by 6-, 8- and 10-fold, respectively (Unpublished observations, Gilead Sciences, Inc.). 
 
Of note, the free fraction of RMD at Cmax after a 14 mg/m2 dose is well in excess (16-fold 
greater) of the EC50 required to induce latent HIV. This same ratio for vorinostat after a 
400 mg oral dose is 0.15-fold (ie, only 15% of the EC50 for HIV-1 induction in vitro). 
Collectively, these data suggest that RMD may be a more robust inducer of HIV-1 
expression in vivo than vorinostat. The in vitro potency of RMD for HIV-1 induction 
suggests that a much lower dose than that used to treat CTCL patients will be able to 
induce latent HIV-1 in vivo. A dose of RMD that corresponds to only 4% of the MTD 
should produce a plasma concentration that is approximately equivalent to the EC50 for 
induction of latent HIV-1 in vitro. A summary of the Cmax values derived from five human 
PK studies (26a, 26b, 26c, 26d, 26e) following 4-hour intravenous infusions of RMD is 
presented in Table 2.2-2. 
 
Table 2.2-2: RMD Human Pharmacokinetics (units for doses = mg/m2; n = number of 
participants dosed) 
 
Dose
1
1
1.7
2
2.5
3.25
3.5
5
6.5
7.5
n=
3
3
3
4
3
4
1
2
3
1
Mean Cmax (ng/mL)
35.6
90
40.8
17
49.5
230
129.9
420
211.8
690
SD
22.2
10
20.9
6
31.7
110
NA
NA
77.1
NA
Dose
9.1
10
12.7
13.3
17.7
17.8
18
23.5
24.9
n=
4
2
3
6
2
11
12
1
8
Mean Cmax (ng/mL)
162.6
740
224.7
540
370
553.8
800
210
478.2
SD
53.8
NA
241
680
NA
299.5
700
NA
316.6
Dose
10
13
17
22
n=
3
4
3
2
Median Cmax (ng/mL)
1364
1017
2414
3103
Range
318-6865
610-2192 1069-4850
1570-4636
 
 


 
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Based on the preclinical work presented in this protocol, three dose levels of RMD will 
be studied in HIV-infected participants on suppressive ART: 0.5 mg/m2 (0.6 times EC50, 
4% of the MTD of 14 mg/ m2); 2 mg/m2 (2.3 times EC50, 14% of the MTD), and 5 mg/m2 
(6 times EC50, 35% of the MTD). As described above, the MTD for RMD was determined 
following three sequential 14 mg/m2 doses (on days 1, 8, 15), but only a single dose will 
be administered in the current study. Thus, the percent of the MTD that will be given in 
this study will be 3-fold lower than the 4%, 14%, and 35% noted. Finally, in contrast to 
vorinostat, RMD is AMES negative (and therefore not expected to be mutagenic); as a 
result, multiple doses could be investigated in HIV-infected populations if single doses 
are safe and well tolerated. 
 
In addition to the preclinical results summarized above, RMD has been studied in a 
single-arm trial of 6 HIV-infected participants on long-term ART.  Each participant 
received 3 weekly infusions of RMD at 5 mg/m2.  Following the RMD infusions, cell-
associated HIV-1 RNA and, in five of 6 cases, plasma HIV-1 RNA increased modestly 
(range 46-103 copies/ml, p=0.04)) following the second infusion, suggesting the drug 
may be activating virus expression.  However, HIV-1 DNA and virus outgrowth levels did 
not decrease.  RMD was well tolerated with no Grade 3 or 4 study-related adverse 
events (AE) [35]. T cell function was not reduced by RMD, allaying a concern raised by 
an in vitro study [36]. In a second single-arm trial, 17 participants received a therapeutic 
vaccine (Vacc-4x) followed by RMD 5 mg/m2 once a week for 3 weeks.  There was a 
decline in HIV-1 DNA after RMD treatment.  In terms of adverse events, 95% were 
Grade 1 and there were no grade 4 events [37]. 
 
The ACTG is committed to studying novel therapies to potentially reduce and eradicate 
the HIV-1 latent reservoir. As a potent HDACi, RMD administered in combination with 
ART may serve as an important component of an eradication strategy. It is 
acknowledged, however, that activation of viral expression may not kill HIV-infected cells 
[28], and that additional interventions, including the stimulation of cytotoxic T 
lymphocytes, may be required to deplete HIV-1 reservoirs [29]. 
 
Total Virus Recovery Assay 
In Cohorts 1 and 2, changes in the inducible HIV-1 reservoir were assessed using the 
total virus recovery (TVR) assay. Samples for this assay were obtained from 
leukapheresis products. However, because leukapheresis was a major logistical barrier 
to study enrollment, it was removed beginning in Cohort 3. Following optimization of a 
revised version of the assay, it will be feasible in Cohort 4 for the TVR assay to be 
performed without requiring leukapheresis. Modification of the TVR assay for blood 
samples has been accomplished at the Pitt Virology Laboratory and Monogram, with 
support from Gilead.  
 
TVR was chosen as the measure of the inducible HIV-1 reservoir for this study in 
Cohorts 1-2 because it is capable of detecting a quantitative and significant reduction in 
the total inducible HIV-1 reservoir. TVR is less variable than the quantitative viral 
outgrowth assay (qVOA): 2-3 fold variation with TVR compared to 6-fold with qVOA [38]. 
The TVR assay is also more efficient, more sensitive (rare censoring), and 5-fold less 
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inducible HIV-1 reservoir and although TVR does not distinguish infectious from 
defective virus,  developmental work at the Pitt Virology Laboratory shows that TVR from 
resting CD4+ cells (Fig 1) and total CD4+ cells (Fig 2) are highly correlated with qVOA 
(Cillo et al, preliminary unpublished data). These data show that TVR can be a 
reasonable surrogate in studies where full qVOA is not feasible. The expected lower limit 
of detection using the TVR assay is 40 copies of HIV-1 RNA produced by 1 million 
resting CD4+ T cells. 
 
 
 
 


 
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Monogram TVR Development 
For Cohorts 1 and 2, Monogram Biosciences used leukopaks collected pre- and post-
treatment from participants. Standard Ficoll separation of the blood components in a 
partial leukopak/RPMI mixture yielded 2-5 billion PBMCs.  Resting CD4+ T cells were 
isolated using a Stem Cell Easy SepTM negative selection procedure.   
 
Summary of Cohorts 1 – 3  
Fifteen participants enrolled into Cohort 1 and received a single infusion of 0.5 mg/m2 of 
RMD or placebo for RMD. This dose was well tolerated: no AEs or serious AEs (SAEs) 
definitely related to RMD were reported. Accordingly, following an SMC review, Cohort 2 
was opened to accrual. Fourteen participants enrolled into this cohort and received a 
single dose of 2 mg/m2 of RMD or placebo for RMD. Again, this dose was well-tolerated: 
no AEs or SAEs definitely related to RMD were reported. Note that self-reported low-
grade AEs that were deemed possibly related to study treatment in both Cohorts 1 and 2 
included, but were limited to, fatigue, headache, and diarrhea.  
 
Following the second SMC review, Cohort 3, was opened to accrual. Starting with this 
cohort, leukapheresis was replaced by blood collections. As noted previously, this 
change was made based on the strong correlation of virologic measures in total and 
resting CD4+ T cells isolated from blood and from leukopaks. Twelve to fifteen 
participants will enroll into Cohort 3 and receive a single infusion of 5 mg/m2 of RMD or 
placebo for RMD. As with the previous cohorts, safety and tolerability data will be 
reviewed by the SMC before enrollment to Cohort 4 is permitted. Safety data from at 
least 12 evaluable Cohort 3 participants should be sufficient to determine if it is safe to 
proceed with Cohort 4 enrollment. In addition, since the study was originally designed, 
published safety data regarding dosing of RMD in HIV-infected individuals is now 
available from other studies of RMD (REDUC A and B) that support administering 
multiple doses of RMD at 5 mg/m2 [35, 37]. 
 
Data from Cohorts 1, 2, and 3 will be analyzed collectively once available.  
 
Rationale for Cohort 4 
In Version 3.0 of the study, a new cohort (Cohort 4) is being added to evaluate the safety 
and tolerability of multiple doses of RMD and study its effect on HIV reactivation and 
reduction in the latent HIV reservoir. Fifteen participants will be randomized to receive 
4 infusions of 5 mg/m2 RMD or placebo for RMD, every 2 weeks, over a 6-week period. 
As in the three earlier cohorts, the randomization will be 4:1 (12 participants randomized 
to receive RMD and 3 to receive placebo infusions). Three RMD infusions of 5 mg/m2 
have been found to be well tolerated thus far in REDUC-A and REDUC-B studies [35, 
37]. The safety and tolerability of a single dose of RMD 5 mg/m2 in HIV-infected 
individuals will also be evaluated in Cohort 3 of this study.  
 
Data from RMD studies conducted to date are insufficient to address whether RMD can 
reduce HIV reservoirs. A modest reduction in the inducible HIV reservoir was noted in 
the REDUC-B study that combined 3 doses of RMD (5 mg/m2) with immunization with a 
Vacc-4x peptide, but there was extensive censoring of the viral outgrowth data below the 


 
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limit of detection, making it difficult to draw firm conclusions. The question of reservoir 
reduction will be addressed in Cohort 4. 
 
For Cohort 4, a quantitative viral outgrowth assay (qVOA) will be performed 
instead of the modified TVR assay [41]. The team opted to perform the qVOA since 
it is the current gold-standard assay for quantifying the latent reservoir.  
 
Testing Plan for Study Samples 
Study endpoint assessments to be performed include plasma HIV-1 RNA monitoring (by 
standard ultrasensitive and single copy assays) and cell-associated HIV-1 RNA analyses 
to determine whether RMD activates HIV-1 expression in vivo [33]. In addition, ex vivo 
HIV-1 induction from study participants’ resting CD4+ T-cells by RMD and 
PMA/ionomycin will be performed to determine the size of the RMD and PMA/ionomycin 
inducible HIV-1 reservoirs, before and 14 days after in vivo RMD dosing. Histone 
acetylation will be measured in total CD4+ T-cells to determine if RMD modulates HDAC 
activity in vivo. P-TEFb upregulation and phosphorylation status will be assessed since 
activation of this kinase complex is essential for HIV transcriptional elongation.  
Measurements of CycT1 levels provide an estimate of the total amount of P-TEFb in the 
cells, while measurements of the CDK9 Ser-175 phosphorylation provides an estimate of 
the amount of P-TEFb that is actively engaged in transcription. Since P-TEFb is 
minimally expressed in resting memory T-cells but becomes activated within 30 minutes 
after T-cell receptor stimulation, this assay provides a biologically-relevant early marker 
that may be correlated with extent of HIV expression. HIV-specific immune responses 
will be assessed on samples collected in Cohort 4 prior to the first RMD or placebo 
infusion and following the fourth infusion (two separate collections at each of these time 
points). 
 
Much of this testing plan was developed at the time that PBMCs were to be collected via 
leukapheresis. Starting in Cohort 3, leukapheresis has been replaced with a blood 
collection.  
 
3.0 
STUDY DESIGN 
 
This is a multicenter, phase I/II safety, dose-escalation, and preliminary efficacy study. 
The study will be conducted in two stages. Stage 1 is a placebo-controlled, double-
blinded, randomized, single administration with inter-group dose escalations in three 
distinct dosing cohorts, followed by Stage 2, a placebo-controlled, double-blinded, 
randomized, multi-dose administration in a single cohort. Because safety is a primary 
objective, and there are limited data on longitudinal changes in cell-associated HIV-1 
RNA levels, a placebo-controlled cohort is considered necessary to accurately assess 
treatment-related toxicity and efficacy. Accrual of the first five participants in any cohort 
will be limited to one participant in a 3-day period. 
 
The overall goal of the Stage 1 cohorts (Cohorts 1-3) in this exploratory study is to 
identify single doses of RMD that are safe and well-tolerated in HIV-infected patients on 
ART, and that induce HIV-1 expression. If safety is established in Cohort 3 (i.e., dose-
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with the goal of assessing safety, tolerability, induction of HIV-1 expression, and 
depletion of latent reservoirs, as assessed by infectious virus recovery from resting 
CD4+T-cells [30,31]. Toxicity related to the infusion of a single dose and of multiple 
doses of RMD or placebo will be evaluated systematically. Dose escalation will be based 
on safety outcomes. Efficacy and response data from lower dose cohorts will not be 
available prior to the enrollment of the subsequent dose cohorts. 
 
In all cohorts, RMD or placebo infusion will occur over 4 hours. An electrocardiogram 
(ECG) will be performed prior to and following RMD administration. In Cohorts 1 – 3, 
pharmacokinetic (PK) sampling will be performed prior to and following RMD infusion to 
measure ARV (RAL, DTG, and EFV) and RMD plasma concentrations and to evaluate 
any drug-drug interactions. In Cohort 4, similar PK testing will be performed before and 
after the third and fourth RMD infusions.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria – Cohorts 1, 2, and 3 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 
RNA. 
 
Note: The term “licensed” refers to a US FDA-approved kit, which is required for 
all 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 (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 
RNA assay. 
 
4.1.2 Receiving two (or more) nucleoside or nucleotide reverse transcriptase inhibitors 
with raltegravir, dolutegravir, or efavirenz for at least 90 days prior to study entry 
with no intention to change for the duration of the study.  
 
NOTE: Candidates receiving PI-based regimens or regimens containing 
rilpivirine, maraviroc, etravirine, or cobicistat will be excluded to avoid drug-drug-
interactions. RMD is metabolized by CYP3A4, and co-administration of PIs or 
other agents that inhibit CYP3A4 could significantly increase RMD 
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4.1.3 Documentation of at least two historical HIV-1 RNA measurements 
<50 copies/mL while on ART obtained by standard ultrasensitive assay. 
Documentation of the first measurement must be from a result obtained between 
365 days and 91 days, inclusive, prior to study entry. Documentation of the 
second measurement must be from a result obtained between 730 days and 
366 days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA 
values ≥50 copies/mL for at least 365 days prior to study entry. 
 
4.1.4 CD4+ cell count ≥300 cells/mm3 obtained within 90 to 50 days prior to study entry 
at any US laboratory that has a CLIA certification or its equivalent. 
 
4.1.5 HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay 
within 90 to 50 days prior to study entry. 
 
4.1.6 HIV-1 RNA level ≥0.4 copies/mL obtained by single copy assay (SCA) within 90 
to 50 days prior to study entry.  
 
NOTE: This result must be available prior to the pre-entry visit.   
 
4.1.7 The following laboratory values obtained within 21 to 0 days prior to study entry 
by any laboratory that has a CLIA certification or its equivalent. 
 
Absolute neutrophil count (ANC) ≥1500 cells/mm3 
 
Hemoglobin ≥12.0 g/dL for men and >11.0 g/dL for women 
 
Platelet count  ≥120,000/mm3 
 
4.1.8 The following laboratory values obtained within 21 to 7 days prior to study entry 
by any laboratory that has a CLIA certification or its equivalent. 
 
Creatinine clearance (CrCl) ≥60 mL/min  
 
Potassium and magnesium within normal limits (see section 6.3.7 for details)  
 
Aspartate aminotransferase (AST) (SGOT) <2.0 x upper limit of normal (ULN) 
 
Alanine aminotransferase (ALT) (SGPT) <2.0 x ULN 
 
Alkaline phosphatase <2.0 x ULN 
 
Total bilirubin <2.5 x ULN 
 
4.1.9 HCV antibody negative result within 90 to 50 days prior to study entry or, for 
study candidates who are HCV antibody positive (based on testing performed at 
any time prior to study entry), a negative HCV RNA result obtained within 90 to 
50 days prior to study entry. 
 
4.1.10 Negative HBsAg result obtained within 90 to 50 days prior to study entry or a 
positive HBsAb result at any time prior to study entry.  
 
4.1.11 For females of reproductive potential, negative serum or urine pregnancy test 
(latter with a sensitivity of ≤25 mIU/mL) at the screening visit, pre-entry visit 
within 21 to 7 days prior to study entry, and at entry prior to romidepsin infusion, 
by any US laboratory that has a CLIA certification or its equivalent. 


 
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Note A: Reproductive potential is defined as: 
 
Girls who have reached menarche or 
 
Women who have had menses within the past 12 months and who do not 
have an FSH >40 IU/L or 
 
Women who have had menses within the past 24 consecutive months if an 
FSH measurement is not available 
 
Women who have not undergone surgical sterilization (eg, hysterectomy, or 
bilateral oophorectomy, or bilateral salpingectomy).  
 
Note B:  Confirmation of the lack of reproductive potential is required.  
Written documentation or oral communication from a clinician or 
clinician’s staff documented in source documents of one of the following 
must be provided: Physician report/letter, operative report or other 
source documentation in the patient record, discharge summary, 
laboratory report of azoospermia (required to document successful 
vasectomy), FSH measurement elevated into the menopausal range (as 
established by the reporting laboratory). 
 
Note C:  If the female candidate cannot provide written proof of a male partner’s 
vasectomy status, the oral report of her partner’s status should be 
written into the source documents. 
 
4.1.12 Female candidates of reproductive potential must refrain from participating in 
active attempts to become pregnant, and, if participating in sexual activity that 
could lead to pregnancy, must agree to use at least two reliable forms of 
contraception that are non-estrogen based. All female participants of 
reproductive potential (as defined in section 4.1.11) must be instructed to use 
contraceptives for 6 months/180 days after completing RMD/placebo infusion. 
 
Acceptable forms of contraception include: 
 
Condoms (male or female) with or without spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Non-hormonal or progestin-only containing intrauterine device (IUD) (eg, 
Mirena, Implanon, Nuva Ring) 
 
Tubal ligation 
 
Non-estrogen containing formulations of hormonal birth control drugs, 
given by pills, shots, or placed on or under the skin, for at least 90 days 
prior to study entry 
 
NOTE: Providers and candidates/participants should be advised that not all 
contraceptive choices listed above can prevent HIV transmission and that some 
may actually increase the risk of HIV acquisition. Participants who are sexually 
active with HIV negative or unknown HIV serostatus partners should be advised 
that they need to consider effective strategies for reducing the risk of HIV 
transmission, as well as meeting the requirement for effective contraception 


 
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during their participation in the study. Participants should discuss contraceptive 
choices and HIV risk reduction methods with their health care provider. 
 
Females who are not of reproductive potential are not required to practice 
contraception.  
 
4.1.13 Karnofsky performance score  80 within 21 to 7 days prior to study entry.  
 
4.1.14 Men and women age  18 years  
 
4.1.15 Ability and willingness to provide written informed consent.  
 
4.1.16 Site investigator anticipates that a fully active alternative ART regimen could be 
constructed in the event of virologic failure on the current ART regimen. 
 
4.2 
Exclusion Criteria – Cohorts 1, 2, and 3 
 
4.2.1 History of or current malignancy requiring cytotoxic therapy. 
 
4.2.2 Bacterial, fungal or viral infection (other than HIV) requiring systemic therapy 
within 30 days prior to entry.  
 
4.2.3  History of or current cytomegalovirus (CMV) end organ disease (e.g., retinitis). 
 
4.2.4 History of or current AIDS-related syndromes or symptoms that pose a perceived 
excessive risk for study drug-related morbidity, as determined by the site 
investigator. 
 
4.2.5 Chronic, acute, or recurrent infections that are current and serious, in the opinion 
of the site investigator, for which the participant has not completed at least 14 
consecutive days of therapy within 30 days prior to study entry and/or is not 
clinically stable.   
 
4.2.6 Active autoimmune disorders including but not limited to inflammatory bowel 
diseases, scleroderma, severe psoriasis as determined by the site investigator, 
systemic lupus erythematosus, rheumatoid arthritis, and optic neuritis.   
  
4.2.7 History of seizure disorders.  
 
4.2.8 History of anticonvulsant use within 60 days prior to study entry. 
 
4.2.9 History of myocardial infarction (MI) within 6 months prior to study entry, history 
of QTc prolongation (defined as ECG with QTc intervals > 450 ms) at any time 
prior to study entry, New York Heart Association (NYHA) class III or IV heart 
failure at any time prior to study entry, or family history of prolonged QTc 
syndrome. 
 


 
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NOTE: See section 6.3.8 for information about calculating QTc. 
 
4.2.10 Breastfeeding 
 
4.2.11 Use of immunomodulators (eg, interleukins, interferons, cyclosporine), HIV 
vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 
days prior to study entry.  
 
NOTE: Study candidates receiving stable physiologic glucocorticoid doses, 
defined as prednisone ≤10 mg/day, will not be excluded. Study candidates 
receiving inhaled or topical corticosteroids will not be excluded. 
 
4.2.12 Any vaccination within 30 days prior to entry or intent to receive an elective 
vaccination (e.g., flu shot, hepatitis A or B vaccine) during the course of the 
study.  
 
4.2.13 Intent to use cytokines (e.g., IL-2 or IL-12) during the course of the study.  
 
NOTE: Prior administration of cytokines is not an exclusion criterion; however, at 
least 60 days between the most recent cycle of any cytokine and study 
entry is required. 
 
4.2.14 Within 60 days prior to study entry, use of systemic azole antifungals 
(voriconazole, itraconazole, ketoconazole), dexamethasone, macrolide antibiotics 
(azithromycin, clarithromycin, erythromycin), antiretrovirals that are inhibitors of, 
or are metabolized by CYP3A4 (atazanavir, ritonavir, nelfinavir, indinavir, 
saquinavir, darunavir, lopinavir, rilpivirine, maraviroc), cobicistat, warfarin, 
nefazodone, rifamycins (rifabutin, rifampin, rifapentine), St. John's Wort, 
carbamazepine, phenytoin, phenobarbital, amiodarone, dofetilide, pimozide, 
procainamide, quinidine, sotalol, and birth control products containing estrogen, 
drugs that are p-glycoprotein inhibitors, and drugs that prolong the QTc interval 
with a risk of Torsades de Pointes [see the A5315 Manual of Procedures (MOPS) 
on the PSWP for a complete list of drugs related to this criterion]. 
 
NOTE: The use of fluconazole is permitted. 
 
4.2.15 Known allergy/sensitivity or any hypersensitivity to components of RMD or its 
formulation. 
 
4.2.16 Use of histone deacetylase inhibitors (e.g., vorinostat, valproic acid) at any time 
prior to study entry.  
 
4.2.17 Active illicit drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.18 Acute or serious illness requiring systemic treatment and/or hospitalization that is 
not resolved within 30 days prior to entry. 


 
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4.2.19 Psychosocial conditions that would prevent study compliance and follow-up, as 
determined by the site investigator. 
 
4.2.20 Documented opportunistic infections within 60 days prior to entry. 
 
4.3 
Inclusion Criteria – Cohort 4, Step 1 
 
4.3.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 
RNA. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies. 
 
WHO and CDC guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. A reactive 
initial rapid test should 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 assay. 
 
4.3.2 Receiving two or more nucleoside or nucleotide reverse transcriptase inhibitors 
with raltegravir or dolutegravir for at least 90 days prior to study entry with no 
intention to change for the duration of the study.  
 
NOTE A: The use of other ART regimens for ≤7 days within 90 days prior to 
study entry will be permitted.  
 
NOTE B: Candidates receiving PI-based regimens or regimens containing 
efavirenz, rilpivirine, maraviroc, etravirine, or cobicistat will be excluded 
to avoid drug-drug-interactions. RMD is metabolized by CYP3A4, and 
co-administration of PIs or other agents that inhibit CYP3A4 could 
significantly increase RMD concentrations.  
 
NOTE C: Candidates who switch from a tenofovir disoproxil fumarate to a 
tenofovir alafenamide formulation will be considered as being on a 
stable regimen because this change in formulation is not regarded as a 
regimen change.  
 
4.3.3 Documentation of at least two historical HIV-1 RNA measurements <50 
copies/mL while on ART obtained by standard ultrasensitive assay. 
Documentation of the first measurement must be from a result obtained between 
365 days and 61 days, inclusive, prior to study entry. Documentation of the  


 
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second measurement must be from a result obtained between 730 days and 366 
days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA 
values ≥50 copies/mL for at least 365 days prior to study entry. 
 
4.3.4 CD4+ cell count ≥300 cells/mm3 obtained between 36 and 60 days prior to study 
entry (screening visit) at any US laboratory that has a CLIA certification or its 
equivalent. 
 
4.3.5 HIV-1 RNA level of <50 copies/mL obtained by standard ultrasensitive assay at 
screening (between 36 and 60 days prior to study entry). 
 
4.3.6 The following laboratory values obtained at pre-entry (between 3 and 14 days 
prior to study entry) by any laboratory that has a CLIA certification or its 
equivalent. 
 
Absolute neutrophil count (ANC) ≥1500 cells/mm3 
 
Hemoglobin ≥12.0 g/dL for men and >11.0 g/dL for women 
 
Platelet count  ≥120,000/mm3 
 
Creatinine clearance (CrCl) ≥60 mL/min  
NOTE: A calculator for estimating the CrCl can be found at 
www.fstrf.org/ACTG/ccc.html 
 
Potassium and magnesium within normal limits (see section 6.3.7 for 
details.)  
 
Aspartate aminotransferase (AST) (SGOT) <2.0 x upper limit of normal 
(ULN) 
 
Alanine aminotransferase (ALT) (SGPT) <2.0 x ULN 
 
Alkaline phosphatase <2.0 x ULN 
 
Total bilirubin <2.5 x ULN 
 
4.3.7 HCV antibody negative result at screening (between 36 and 60 days prior to 
study entry) or, for study candidates who are HCV antibody positive (based on 
testing performed at any time prior to study entry), a negative HCV RNA result 
obtained at screening. 
 
4.3.8 Negative HBsAg result obtained at screening (between 36 and 60 days prior to 
study entry) or a positive HBsAb result at any time prior to study entry.  
 
4.3.9 For females of reproductive potential, negative urine pregnancy test (with a 
sensitivity of ≤25 mIU/mL) at screening (between 36 and 60 days prior to study 
entry), at pre-entry (between 3 and 14 days prior to study entry), and at entry 
prior to infusion, by any US laboratory that has a CLIA certification or its 
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NOTE A: Reproductive potential is defined as: 
 Girls who have reached menarche or 
 Women who have had menses within the past 12 months and who 
do not have an FSH >40 IU/L or 
 Women who have had menses within the past 24 consecutive 
months if an FSH measurement is not available 
 Women who have not undergone surgical sterilization (eg, 
hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy).  
 
NOTE B:  Confirmation of the lack of reproductive potential is required.  
Written documentation or oral communication from a clinician or 
clinician’s staff documented in source documents of one of the 
following must be provided: Physician report/letter, operative report or 
other source documentation in the patient record, discharge summary, 
laboratory report of azoospermia (required to document successful 
vasectomy), FSH measurement elevated into the menopausal range 
(as established by the reporting laboratory). 
 
NOTE C:  If the female candidate cannot provide written proof of a male partner’s 
vasectomy status, the oral report of her partner’s status should be 
written into the source documents. 
 
4.3.10 Female candidates of reproductive potential must refrain from participating in 
active attempts to become pregnant, and, if participating in sexual activity that 
could lead to pregnancy, must agree to use at least two reliable forms of 
contraception that are non-estrogen based. All participants of reproductive 
potential will be instructed to use contraceptives for 6 months or 180 days after 
completing RMD/placebo infusion. 
 
Acceptable forms of contraception include: 
 
Condoms (male or female) with or without spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Non-hormonal or progestin-only containing intrauterine device (IUD) (e.g., 
Mirena, Implanon, Nuva Ring) 
 
Tubal ligation 
 
Non-estrogen containing formulations of hormonal birth control drugs, 
given by pills, shots, or placed on or under the skin, for at least 90 days 
prior to study entry 
 
NOTE: Providers and candidates/participants should be advised that not all 
contraceptive choices listed above can prevent HIV transmission and that some 
may actually increase the risk of HIV acquisition. Participants who are sexually 
active with HIV negative or unknown HIV serostatus partners should be advised  


 
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that they need to consider effective strategies for reducing the risk of HIV 
transmission, as well as meeting the requirement for effective contraception 
during their participation in the study. Participants should discuss contraceptive 
choices and HIV risk reduction methods with their health care provider. 
 
Females who are not of reproductive potential are not required to practice 
contraception.  
 
4.3.11 Karnofsky performance score  80 at pre-entry (between 3 and 14 days prior to 
study entry)  
 
4.3.12 Men and women age 18 years  
 
4.3.13 Ability and willingness to provide written informed consent.  
 
4.3.14  Site investigator anticipates that a fully active alternative ART regimen could be 
constructed in the event of virologic failure on the current ART regimen. 
 
4.4 
Exclusion Criteria – Cohort 4, Step 1 
 
4.4.1 History of or current malignancy requiring cytotoxic therapy. 
 
4.4.2 Bacterial, fungal or viral infection (other than HIV) requiring systemic therapy 
within 30 days prior to entry.  
 
4.4.3  History of or current cytomegalovirus (CMV) end organ disease (e.g., retinitis). 
 
4.4.4 History of or current AIDS-related syndromes or symptoms that pose a perceived 
excessive risk for study drug-related morbidity, as determined by the site 
investigator. 
 
4.4.5 Chronic, acute, or recurrent infections that are current and serious, in the opinion 
of the site investigator, for which the participant has not completed at least 14 
consecutive days of therapy within 30 days prior to study entry and/or is not 
clinically stable.   
 
4.4.6 Active autoimmune disorders including but not limited to inflammatory bowel 
diseases, scleroderma, severe psoriasis as determined by the site investigator, 
systemic lupus erythematosus, rheumatoid arthritis, and optic neuritis.   
  
4.4.7 History of seizure disorders.  
 
4.4.8 History of anticonvulsant use within 60 days prior to study entry. 
 
4.4.9 History of myocardial infarction (MI) within 6 months prior to study entry, history 
of QTc prolongation (defined as ECG with QTc intervals > 450 ms) at any time 
prior to study entry, New York Heart Association (NYHA) class III or IV heart 


 
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failure at any time prior to study entry, or family history of prolonged QTc 
syndrome. 
 
NOTE: The correction formula expected to be used is the Fridericia correction 
(available on the DMC website: https://www.fstrf.org).  
 
4.4.10 Breastfeeding 
 
4.4.11 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV 
vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 
days prior to study entry.  
 
NOTE: Study candidates receiving stable physiologic glucocorticoid doses, 
defined as prednisone ≤10 mg/day, will not be excluded. Study 
candidates receiving inhaled or topical corticosteroids will not be 
excluded. 
 
4.4.12 Any vaccination within 30 days prior to entry or intent to receive an elective 
vaccination (e.g., flu shot, hepatitis A or B vaccine) during the course of the 
study.  
 
4.4.13 Intent to use cytokines (e.g., IL-2 or IL-12) during the course of the study.  
 
NOTE: Prior administration of cytokines is not an exclusion criterion; however, at 
least 60 days between the most recent cycle of any cytokine and study 
entry is required. 
 
4.4.14 Within 60 days prior to study entry, use of systemic azole antifungals 
(voriconazole, itraconazole, ketoconazole), dexamethasone, macrolide antibiotics 
(azithromycin, clarithromycin, erythromycin), antiretrovirals that are inhibitors of, 
or are metabolized by CYP3A4 (atazanavir, ritonavir, nelfinavir, indinavir, 
saquinavir, darunavir, lopinavir, rilpivirine, maraviroc), cobicistat, warfarin, 
nefazodone, rifamycins (rifabutin, rifampin, rifapentine), St. John's Wort, 
carbamazepine, phenytoin, phenobarbital, amiodarone, dofetilide, pimozide, 
procainamide, quinidine, sotalol, and birth control products containing estrogen, 
drugs that are p-glycoprotein inhibitors, and drugs that prolong the QTc interval 
with a risk of Torsades de Pointes (see the A5315 Manual of Procedures [MOPS] 
on the PSWP for a complete list of drugs related to this criterion). 
 
NOTE: The use of fluconazole is permitted. 
 
4.4.15 Known allergy/sensitivity or any hypersensitivity to components of RMD or its 
formulation. 
 
4.4.16 Use of histone deacetylase inhibitors (e.g., vorinostat, valproic acid) at any time 
prior to study entry.  
 


 
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4.4.17 Active illicit drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.4.18 Acute or serious illness requiring systemic treatment and/or hospitalization that is 
not resolved within 30 days prior to entry. 
 
4.4.19 Psychosocial conditions that would prevent study compliance and follow-up, as 
determined by the site investigator. 
 
4.4.20 Documented opportunistic infections within 60 days prior to entry. 
 
4.4.21 Use of any of the medications listed in the Prohibited Medications table in the 
current A5315 MOPS, within the timeframes listed in that table. 
 
4.5 
Inclusion Criteria – Cohort 4, Step 2 
 
4.5.1 HIV-1 RNA level of <50 copies/mL obtained by TaqMan v2.0 assay within 
14 days prior to Step 2 registration. 
 
4.5.2 For females of reproductive potential, negative urine pregnancy test (with 
sensitivity of ≤25 mlU/mL) obtained within 2 days prior to Step 2 registration by 
any US laboratory that has a CLIA certification or its equivalent. 
 
4.5.3 Potassium and magnesium values within normal limits obtained within 
7 days prior to Step 2 registration by any laboratory that has a CLIA 
certification or its equivalent (see section 6.3.7 for details). 
 
4.5.4 The following laboratory values obtained within 7 days prior to Step 2 registration 
by any laboratory that has a CLIA certification or its equivalent. 
 Absolute neutrophil count (ANC) ≥1500 cells/mm3 
 Hemoglobin ≥12.0 g/dL for men and >11.0 g/dL for women 
 Platelet count ≥120,000/mm3 
 
4.6 
Exclusion Criteria – Cohort 4, Step 2 
 
4.6.1  Acute or serious illness requiring systemic treatment and/or hospitalization and 
that is not resolved by 7 days prior to Step 2 registration. 
 
4.6.2 Receipt of any vaccination within 14 days prior to Step 2 registration. 
 
NOTE: The infusion must not be performed within 14 days following any 
vaccination. 
 
4.7 
Inclusion Criteria – Cohort 4, Step 3 
 
4.7.1 HIV-1 RNA level of <50 copies/mL obtained by TaqMan v2.0 assay within 
14 days prior to Step 3 registration. 


 
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4.7.2 For females of reproductive potential, negative urine pregnancy test (with 
sensitivity of ≤25 mlU/mL) obtained within 2 days prior to Step 3 registration by 
any US laboratory that has a CLIA certification or its equivalent. 
 
4.7.3 Potassium and magnesium values within normal limits obtained within 7 days 
prior to Step 3 registration by any laboratory that has a CLIA certification or 
its equivalent (see section 6.3.7 for details). 
 
4.7.4 The following laboratory values obtained within 7 days prior to Step 3 registration 
by any laboratory that has a CLIA certification or its equivalent. 
 Absolute neutrophil count (ANC) ≥1500 cells/mm3 
 Hemoglobin ≥12.0 g/dL for men and >11.0 g/dL for women 
 Platelet count ≥120,000/mm3 
 
4.8 
Exclusion Criteria – Cohort 4, Step 3 
 
4.8.1  Acute or serious illness requiring systemic treatment and/or hospitalization and 
that is not resolved by 7 days prior to Step 3 registration. 
 
4.8.2 Receipt of any vaccination within 14 days prior to Step 3 registration. 
 
NOTE: The infusion must not be performed within 14 days following any 
vaccination. 
 
4.9 
Inclusion Criteria – Cohort 4, Step 4 
 
4.9.1 HIV-1 RNA level of <50 copies/mL obtained by TaqMan v2.0 assay within 14 
days prior to Step 4 registration. 
 
4.9.2 For females of reproductive potential, negative urine pregnancy test (with 
sensitivity of ≤25 mlU/mL) obtained within 2 days prior to Step 4 registration by 
any US laboratory that has a CLIA certification or its equivalent. 
 
4.9.3 Potassium and magnesium values within normal limits obtained within 7 
days prior to Step 4 registration by any laboratory that has a CLIA 
certification or its equivalent (see section 6.3.7 for details). 
 
4.9.4 The following laboratory values obtained within 7 days prior to Step 4 
registration by any laboratory that has a CLIA certification or its equivalent. 
 Absolute neutrophil count (ANC) ≥1500 cells/mm3 
 Hemoglobin ≥12.0 g/dL for men and >11.0 g/dL for women 
 Platelet count ≥120,000/mm3 
 


 
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4.10 
Exclusion Criteria – Cohort 4, Step 4 
 
4.10.1  Acute or serious illness requiring systemic treatment and/or hospitalization and 
that is not resolved by 7 days prior to Step 4 registration. 
 
4.10.2 Receipt of any vaccination within 14 days prior to Step 4 registration. 
 
NOTE: The infusion must not be performed within 14 days following any 
vaccination. 
 
4.11 
Study Enrollment Procedures 
 
4.11.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form 
approved, as appropriate, by its local institutional review board (IRB) and any 
other applicable regulatory entity (RE). Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS Protocol 
Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that 
all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for any 
subsequent full version amendments, 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 ICFs will not be reviewed and approved by the DAIDS PRO and 
sites will receive an Amendment Registration Notification when the DAIDS PRO 
receives a complete registration packet. A copy of the final amendment 
Registration Notification issued by the DAIDS PRO should be retained in the 
site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the candidate. The candidate (or, when necessary, the legal 
representative if the candidate is under guardianship) will be asked to read and 
sign the approved protocol consent form.  
 


 
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For candidates from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System.  
 
4.11.2 Protocol Activation 
 
Following initial registration to the protocol, sites must complete the Protocol 
Activation Checklist found on the ACTG Member website. The completed 
checklist must be approved before screening of study candidates can begin.  
 
4.11.3 Randomization/Participant Registration 
 
At entry, candidates will be enrolled according to standard ACTG DMC 
procedures. For candidates from whom informed consent has been obtained, but 
who are deemed ineligible or who do not enroll into the initial protocol step, an 
ACTG Screening Failure Results form must be completed and keyed into the 
database.  
 
4.12 
Coenrollment Guidelines  
 
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 protocol chairs 
of either study. Because of blood volume limitations in A5315, sites must NOT collect a 
separate blood sample during the A5315 study follow up period from participants who 
coenroll in A5128.  
 
For specific questions and approval for coenrollment into other studies, sites should 
check the PSWP or contact the core team via e-mail (actg.corea5315@fstrf.org). 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as Romidepsin (RMD) or Placebo for RMD.  ART is required 
but it will not be provided by the study. 
 
5.1 
Regimens, Administration, and Duration 
 
At entry, participants will be randomized (4:1) to receive blinded RMD or Placebo for 
RMD. The first fifteen study participants enrolled in Cohort 1 and received one dose of 
blinded RMD or Placebo for RMD by intravenous (IV) infusion over 4 hours on Day 0. 
Additional participants are enrolled, approximately 15 per cohort, into different cohorts as 
these are opened to accrual.  
 
Participants in Cohorts 2 and 3 received one dose of blinded RMD, at increased 
dosages, or placebo for RMD by IV infusion over 4 hours on Day 0. Participants in 
Cohort 4 will receive a dose of blinded RMD or placebo for RMD by IV infusion over 4 


 
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hours on Days 0, 14, 28, and 42, for a total of four doses. Each Cohort 4 participant will 
receive four doses of either RMD or placebo for RMD. 
 
After Cohort 1, Cohorts 2 and 3 were opened sequentially, based on safety outcomes as 
defined in section 9.0. The decisions to open these two subsequent cohorts were made 
after two separate reviews of available safety data by the A5315 core team and SMC. 
 
Body Surface Area (BSA) Calculation 
The dose of RMD to be administered will be calculated based on body surface area 
(BSA) expressed in square meters (m2), which will be determined by weight and height 
measurement. Measured height and weight obtained during the complete physical exam 
at pre-entry is to be used for calculating the BSA for the first infusion. For Cohort 4, the 
weight and height recorded at the first pre-entry visit will be used for calculating the 
BSA for Step 1. Weight recorded at Days 7, 21, and 35 and height recorded at the 
first pre-entry visit will be used for calculating the BSA for Cohort 4 Steps 2, 3, 
and 4, respectively. 
 
The BSA should be calculated using the BSA calculator available on the FSTRF portal.   
 
BSA (m2) = ([Height (cm) x Weight (kg)] / 3600)1/2 
 
5.1.1 Cohort 1 
 
Upon randomization, the participant PID and SID will be provided to the site clinic 
for the clinic to send a prescription to the pharmacy. 
 
o Arm 1A (RMD) 
RMD intravenously (IV) over 4-hours starting at Hour 0 on Day 0. The mg 
dose and corresponding volume of RMD to be added to 500 mL 0.9% 
Sodium Chloride for Injection, USP IV bag for infusion is based on 
participant’s BSA per Table 5.1.1-1.  
 
OR 
 
o Arm 1B (Placebo for Romidepsin) 
0.9% Sodium Chloride (NaCl) for Injection USP, IV over 4 hours starting at 
Hour 0 on Day 0. The volume of 0.9% NaCl for injection, USP to be added to 
500 mL 0.9% Sodium Chloride for Injection, USP IV bag for infusion is based 
on participant’s BSA per Table 5.1.1-1. 
 


 
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Table 5.1.1-1: RMD and Placebo for RMD Dosing at 0.5 mg/m2 Dose Level in Cohort 1 
 
5.1.2 Cohort 2 
 
Upon randomization, the participant PID and SID will be provided to the site clinic 
for the clinic to send a prescription to the pharmacy. 
 
o 
Arm 2A (RMD) 
RMD intravenously (IV) over 4-hours starting at Hour 0 on Day 0. The mg 
dose and corresponding volume of RMD to be added to 500 mL 0.9% 
Sodium Chloride for Injection, USP IV bag for infusion is based on 
participant’s BSA per Table 5.1.2-1.  
 
OR 
 
o 
Arm 2B (Placebo for RMD) 
0.9% Sodium Chloride for Injection, USP IV over 4 hours starting at Hour 0 
on Day 0. The volume of 0.9% NaCl for injection, USP to be added to 500 
mL 0.9% Sodium Chloride for Injection, USP IV bag for infusion is based on 
participant’s BSA per Table 5.1.2-1.  
 
Table 5.1.2-1: RMD and Placebo for RMD Dosing at 2 mg/m2 Dose Level in Cohort 2 
 
BSA Range  
Arm 1A: RMD 
Arm 1B: Placebo for RMD 
Dose of 
RMD 
(mg) 
Volume of RMD to add to 
500 mL 0.9% Sodium 
Chloride for Injection, 
USP IV Bag in Arm 1A 
Volume of 0.9%  NaCl for 
Injection, USP to add to 500 mL 
0.9% Sodium Chloride for 
Injection USP IV Bag in Arm 1B 
1.35 - 1.74 
0.75 mg 
0.15 mL 
0.15 mL 
1.75 - 2.24 
1 mg 
0.2 mL 
0.2mL  
2.25 - 2.54 
1.25 mg 
0.25 mL 
0.25 mL 
2.55 - 3 
1.5 mg 
0.3 mL 
0.3 mL 
BSA Range 
Arm 2A: RMD 
Arm 2B: Placebo for RMD 
Dose of 
RMD 
(mg) 
Volume of RMD to add to 
500 mL 0.9% Sodium 
Chloride for Injection USP 
IV Bag in Arm 2A 
Volume of 0.9% NaCl for 
Injection, USP to add to 500 mL 
0.9% Sodium Chloride for 
Injection USP IV Bag in Arm 2B 
1.35 - 1.74 
3 mg 
0.6 mL 
0.6 mL 
1.75 - 2.24 
4 mg 
0.8 mL 
0.8 mL  
2.25 - 2.54 
5 mg 
1    mL 
1    mL 
2.55 - 3 
6 mg 
1.2 mL 
1.2 mL 


 
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5.1.3 Cohort 3 
 
Upon randomization, the participant PID and SID will be provided to the site 
clinic for the clinic to send a prescription to the pharmacy. 
 
o 
Arm 3A (RMD) 
RMD intravenously (IV) over 4-hours starting at Hour 0 on Day 0. The mg 
dose and corresponding volume of RMD to be added to 500 mL 0.9% 
Sodium Chloride for Injection, USP IV bag for infusion is based on 
participant’s BSA per  Table 5.1.3-1..  
 
OR 
 
o 
Arm 3B (Placebo for RMD) 
0.9% Sodium Chloride for Injection, USP IV over 4 hours starting at Hour 0 
on Day 0. The volume of 0.9% NaCl for injection, USP to be added to 500 
mL 0.9% Sodium Chloride for Injection, USP IV bag for infusion is based on 
participant’s BSA per Table 5.1.3-1. 
 
Table 5.1.3-1: RMD and Placebo for RMD Dosing at 5 mg/m2 Dose Level in Cohort 3 
BSA Range  
Arm 3A: 
RMD 
Arm 3B: 
Placebo for RMD 
Dose of 
RMD 
(mg) 
Volume of RMD to add 
to 500 mL 0.9% Sodium 
Chloride for Injection, 
USP IV Bag in Arm 3A 
Volume of 0.9% NaCl for 
Injection, USP to add to 500 mL 
0.9% Sodium Chloride for 
Injection, USP IV Bag in Arm 3B 
1.35 - 1.74 
8 mg 
1.6 mL 
1.6 mL 
1.75 - 2.24 
10 mg 
2 mL 
2L  
2.25 - 2.54 
12 mg 
2.4 mL 
2.4 mL 
2.55 - 3 
14 mg 
2.8 mL 
2.8 mL 
 
5.1.4 Cohort 4 
 
Upon randomization to each step, the participant’s PID and SID will be provided 
to the site clinic for the clinic to send a prescription to the pharmacy. A new 
prescription that includes the participant’s most recent BSA must be provided to 
the pharmacy at least 5 days prior to each subsequent infusion. 
 
Arm 4A (RMD) 
RMD intravenously (IV) over 4 hours starting at Hour 0 on Day 0 and at Hour 0 on 
Days 14, 28, and 42, for a total of four doses. The mg dose and corresponding 
volume of RMD to be added to 500 mL 0.9% Sodium Chloride for Injection, USP 
IV bag for infusion is based on the participant’s BSA per Table 5.1.4-1.  
 
OR 
 


 
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Arm 4B (Placebo for RMD) 
0.9% Sodium Chloride for Injection, USP IV over 4 hours starting at Hour 0 on 
Day 0 and at Hour 0 on Days 14, 28, and 42, for a total of four doses. The 
volume of 0.9% NaCl for injection, USP, to be added to 500 mL 0.9% Sodium 
Chloride for Injection, USP IV bag for infusion is based on the participant’s BSA 
per Table 5.1.4-1. 
 
Table 5.1.4-1: RMD and Placebo for RMD Dosing at 5 mg/m2 Dose Level in Cohort 4 
 
BSA 
Range  
Arm 4A: 
RMD 
Arm 4B: 
Placebo for RMD 
Dose of 
RMD 
(mg) 
Volume of  RMD  to add 
to 500 mL 0.9% Sodium 
Chloride for Injection, 
USP IV Bag in Arm 4A 
Volume of 0.9% NaCl for 
Injection, USP to add to 500 mL 
0.9% Sodium Chloride for 
Injection, USP IV Bag in Arm 4B 
1.35 - 1.74 
8 mg 
1.6 mL 
1.6 mL 
1.75 - 2.24 
10 mg 
2 mL 
2 mL  
2.25 - 2.54 
12 mg 
2.4 mL 
2.4 mL 
2.55 - 3 
14 mg 
2.8 mL 
2.8 mL 
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Study Product Formulation 
 
RMD 
RMD (Istodax®) is supplied as a kit in a single carton that includes a sterile, 
lyophilized powder in a single-use vial containing 10 mg of RMD and 20 mg of 
the bulking agent, povidone, USP. In addition, each kit includes 1 sterile vial 
containing 2 mL (deliverable volume) of the Diluent composed of 80% propylene 
glycol, USP, and 20% dehydrated alcohol, USP.  RMD for injection vial and 
diluent vial in a single carton must be stored at 20° to 25°C, excursions permitted 
between 15° to 30°C. (See USP Controlled Room Temperature.) 
 
Placebo for RMD 
0.9% Sodium Chloride for Injection, USP in single use vial will be used as the 
Placebo for RMD and must be stored as directed by the manufacturer. 
 
5.2.2 Study Product Preparation and IV Administration 
 
5.2.2.1 RMD Preparation 
One vial of RMD 10 mg and one vial containing 2 mL of diluent included 
in the RMD kit in a single carton will be needed to prepare RMD dose. 
 
RMD should be handled in a manner consistent with recommended safe 
procedures for handling cytotoxic drugs. Caution should be exercised in 
handling RMD. The use of gloves and gown is recommended. If RMD 


 
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comes in contact with the skin or mucosa, immediately wash thoroughly 
with soap and water. 
 
The pharmacist will prepare RMD dose in a biological safety cabinet or 
an isolator using aseptic technique.  
 
RMD must be reconstituted with the supplied Diluent and further diluted 
with 0.9% Sodium Chloride for Injection, USP before intravenous 
infusion. 
 
Using aseptic technique, reconstitute RMD 10 mg vial with supplied 
Diluent. Using a 3 mL or 5 ml size syringe, withdraw 2 mL from the 
supplied Diluent vial and slowly inject it into the 10 mg RMD for injection 
vial.   
 
Swirl the contents of the RMD vial until there are no visible particles in 
the resulting solution. The reconstituted solution will contain RMD 
5 mg/mL. 
 
The reconstituted RMD solution in the vial is chemically stable for 
8 hours at room temperature. 
 
Withdraw the specified amount of participant’s dose of RMD in mL from 
the reconstituted RMD vial. Refer to the RMD and Placebo for RMD 
dosing Tables for the specified amount of participant’s dose for each 
dosing cohort and BSA for each participant.   
 
If the participant’s specified dose volume of RMD is less than 1 mL, then 
use a 1 mL size syringe to withdraw the participant’s dose from the 
reconstituted RMD vial. 
 
If the participant’s specified dose volume of RMD is equal to 1 mL, then 
use a 3 mL size syringe to withdraw the participant’s dose volume (mL) 
from the reconstituted RMD vial. 
 
If the participant’s dose volume of RMD is greater than 1 mL and less 
than 2 mL, then use a 3 mL size syringe to withdraw 1 mL of 
reconstituted RMD solution and a 1 mL size syringe to withdraw less 
than 1 mL volume of reconstituted RMD solution from the vial. 
 
If the participant’s specified dose volume of RMD is equal to 2 mL, then 
use a 3 mL size syringe to withdraw the participant’s dose volume (mL) 
from the reconstituted RMD vial. 
 
If the participant’s specified dose volume of RMD is greater than 2 mL 
and less than 3 mL, then use a 3 mL size syringe to withdraw 2 mL of 


 
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reconstituted RMD solution and a 1 mL size syringe to withdraw less 
than 1 mL volume of reconstituted RMD solution from the vial. 
 
Inject the participant’s specified RMD dose volume (mL) into a 500 mL 
0.9% Sodium Chloride for injection, USP IV bag for infusion. 
 
Label the participant’s prepared blinded RMD study drug for infusion in 
500 mL 0.9% NaCl IV bag as “Romidepsin ___mg or Placebo for 
Romidepsin” study product.   
 
The RMD mg amount to state on the blinded label is the participant’s 
specified RMD total dose in mg that was withdrawn into the syringe(s) 
and injected into a 500 mL 0.9% NaCl injection, USP IV bag for infusion.  
 
The solution for infusion prepared as above is stable for up to 24 hours 
when stored at room temperature. The infusion must be completed 
within 24 hours from the time the RMD vial is reconstituted to the end of 
infusion of the prepared IV solution. 
 
Discard any unused RMD solution according to proper handling and 
disposal procedures for cytotoxic drugs. 
 
5.2.2.2 Placebo for RMD Preparation 
0.9% Sodium Chloride for Injection, USP in a single use vial will be 
needed to prepare Placebo for RMD dose. 
 
The pharmacist will prepare Placebo for RMD dose in a biological safety 
cabinet or an isolator using aseptic technique.  
 
Withdraw the specified amount of participant’s Placebo for RMD dose 
volume in mL from 0.9% Sodium Chloride for Injection, USP single use 
vial. Refer to the RMD and Placebo for RMD Dosing Tables for the 
specified amount of participant’s dose for each dosing cohort and BSA 
for each participant and corresponding mL volume of 0.9%, NaCl for 
injection, USP to withdraw into the syringe(s) to prepare Placebo for 
RMD dose.   
 
If the participant’s specified dose volume of Placebo for RMD is less 
than 1 mL, then use a 1 mL size syringe to withdraw the participant’s 
dose from 0.9% NaCl for injection, USP vial. 
 
If the participant’s specified dose volume of Placebo for RMD is equal to 
1 mL, then use a 3 mL size syringe to withdraw the participant’s dose 
volume (mL) from 0.9% NaCl for injection, USP vial. 
 
If the participant’s dose volume of Placebo for RMD is greater than 1 mL 
and less than 2 mL, then use a 3 mL size syringe to withdraw 1 mL from 


 
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0.9% NaCl for injection, USP vial and a 1 mL size syringe to withdraw 
less than 1 mL volume from 0.9% NaCl for injection, USP vial. 
 
If the participant’s specified dose volume of Placebo for RMD is equal to 
2 mL, then use a 3 mL size syringe to withdraw the participant’s dose 
volume (mL) from 0.9% NaCl for injection, USP vial. 
 
If the participant’s specified dose volume of Placebo for RMD is greater 
than 2 mL and less than 3 mL, then use a 3 mL size syringe to withdraw 
2 mL from 0.9% NaCl for injection, USP vial and a 1 mL size syringe to 
withdraw less than 1 mL volume from 0.9% NaCl for injection, USP vial. 
 
Inject the participant’s specified Placebo for RMD dose (0.9% NaCl for 
injection, USP) volume (mL) into a 500 mL IV bag of 0.9% Sodium 
Chloride for injection, USP for infusion. 
 
Label the participant’s prepared blinded Placebo for RMD study product 
for infusion in 500 mL 0.9% NaCl, USP IV bag as “Romidepsin___mg or 
Placebo for Romidepsin” study product.   
 
The RMD mg amount to state on the blinded label is the mg amount that 
is appropriate for that participant’s BSA and dose cohort as listed in the 
RMD and Placebo for RMD Dosing Table that corresponds to the 
volume (mL) of 0.9% NaCl for injection, USP injected into a 500 mL 
NaCl 0.9% injection, USP IV bag for infusion. 
 
The solution for infusion prepared as above is stable for up to 24 hours 
when stored at room temperature. The infusion must be completed 
within 24 hours from the time the Placebo for RMD IV solution is 
prepared to the end of infusion of the prepared IV solution. 
 
5.2.2.3 RMD or Placebo for RMD IV Administration 
RMD or Placebo for RMD blinded study product for infusion should be 
handled in a manner consistent with recommended safe procedures for 
handling cytotoxic drugs. 
 
Inspect the prepared study product for infusion visually for particulate 
matter and discoloration before administration. Do not administer if the 
prepared solution for infusion has particulate matter or discoloration is 
present. 
 
Infuse over 4 hours. 
 
The prepared study product solution for infusion is compatible with 
polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene 
(PE) infusion bags as well as glass bottles. 
 


 
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The prepared study product solution for infusion is stable for 24 hours 
when stored at room temperature. However, it should be administered 
as soon as possible. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Supply 
 
Romidepsin (Istodax®) manufactured by Ben Venue Laboratories, Inc. for 
Celgene Corporation will be supplied through the study for Cohorts 1-3 by the 
ACTG with funding support from Gilead Sciences.  
 
Romidepsin (Istodax®) manufactured by Ben Venue Laboratories, Inc. for 
Celgene Corporation will be supplied through the study for Cohort 4 by Celgene. 
 
Clinical Research Sites are responsible for locally obtaining the 500 mL 0.9% 
Sodium Chloride Injection, USP IV bag, 0.9% Sodium Chloride Injection, USP in 
single use vial, sterile syringes and other supplies required for preparation of 
RMD and Placebo for RMD study product infusion. 
 
5.3.2 Study Product Acquisition/Distribution 
 
RMD (Istodax®) will be available through the NIAID Clinical Research Products 
Management Center (CRPMC). The ACTG site pharmacist can obtain the study 
product for this protocol by following the instructions in the manual, Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks, in the section 
entitled Study Product Control.  
 
After the pre-entry visit is completed, the site investigator must provide the site 
pharmacist with the participant’s PID number and BSA. The site pharmacist must 
include the PID number and BSA when ordering study product from the CRPMC.   
 
5.3.3 Study Product Accountability 
 
The ACTG pharmacist is required to maintain complete records of RMD study 
product received from the NIAID CRPMC and subsequently dispensed. As the 
0.9% Sodium Chloride for Injection, USP will be obtained locally by the site, the 
continuous inventory is not required, but all other information must be completed 
(including the lot number for the vial and IV solution used).  All unused RMD 
study product must be returned to the NIAID CRPMC after the study is 
completed or terminated. The procedures to be followed are in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks, in the 
section entitled, Study Product Management Responsibilities. 
 


 
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5.4 
RMD Pharmacokinetic Samples 
 
Per section 10.2, post-infusion whole blood samples will be collected from the opposite 
side of the body (e.g., infuse in right arm, draw PK or other samples from left arm).  
 
5.5 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the updated ACTG Drug Interactions 
Database located at: http://tdm.pharm.buffalo.edu/home/di_search/Search. 
 
5.5.1 Required Medications 
 
In Cohorts 1 – 3, two or more nucleoside or nucleotide reverse transcriptase 
inhibitors with raltegravir, dolutegravir, or efavirenz. In Cohort 4, two or more 
nucleoside or nucleotide reverse transcriptase inhibitors with raltegravir or 
dolutegravir. None of these will be supplied through the study. 
 
5.5.2 Prohibited Medications 
 
A table of prohibited medications can be found in the A5315 MOPS. Note that the 
table includes the duration of time prior to study entry that use of these 
medications is also prohibited. 
 
5.5.3 Precautionary Medications 
 
There are no precautionary medications listed for this protocol.   
 
NOTE: RMD is a competitive inhibitor of estradiol and thus inhibits estrogen 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedules of Evaluations 
 
6.1.1 Table 6.1.1-.1:  Cohorts 1 and 2 
Valuation 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA ≥ 200 
copies/ml 
Discontinuation 
Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infusion 
Infusion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 
to -
30 
Days 
-21 
to 
 -7 
Days  
-7 
Days 
to 0 
hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
Documentation of 
HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Complete Physical 
Exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Exam 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology  
X 
 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Liver Function 
Tests  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Blood Chemistries 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Valuation 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA ≥ 200 
copies/ml 
Discontinuation 
Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infusion 
Infusion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 
to -
30 
Days 
-21 
to 
 -7 
Days  
-7 
Days 
to 0 
hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
Pregnancy Testing  
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Hepatitis Screen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
X 
 
 
 
 
X 
 
 
 
 
if 
indicated 
X 
if indicated 
 
 
CD4+/CD8+  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma/PBMC 
for Immunology 
Studies  
 
 
 
 
X 
 
 
 
 
 
 
 
X* 
X* 
 
X* 
 
 
 
D-dimer 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X* 
 
X* 
 
 
 
Plasma HIV-1 RNA 
Real-Time  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(see 
6.2.4) 
 
 
X 
X 
 
Plasma HIV-1 RNA 
by SCA 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
X 
Resting CD4+T-Cells 
for Cell-associated 
Total HIV-1 DNA and 
RNA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X* 
 
 
 
 
Histone Acetylation 
Assay 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
 
Stored PBMC for 
Virology Studies  
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
X 


 
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Valuation 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA ≥ 200 
copies/ml 
Discontinuation 
Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infusion 
Infusion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 
to -
30 
Days 
-21 
to 
 -7 
Days  
-7 
Days 
to 0 
hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
Resting CD4+T-Cells 
for Ex Vivo 
PMA/Ionomycin & 
RMD Inducible HIV-1 
RNA Expression, i.e., 
TVR assay  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
 
 
Leukapheresis  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X* 
 
 
 
 
PK for RMD, RAL, 
EFV, DTG  
 
 
 
 
X 
-15 mins 
to RMD 
(see 
10.2) 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
RMD/Placebo 
Infusion 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
* These evaluations are not required if participant does not undergo the Hour 24 leukapheresis. 


 
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6.1.2 Table 6.1.2-1:  Cohort 3 
Evaluation 
(Cohort 3) 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA > 200 
copies/ml
Discontinuation Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infus
ion 
Infus
ion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 to 
-30 
Days 
-21 to 
-7 
Days  
-7 
Days 
to 0 hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
Documentation of 
HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Complete Physical 
Exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical 
Exam 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hematology  
X 
 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Liver Function Tests  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Blood Chemistries 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing  
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Hepatitis Screen  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
X 
 
 
 
 
X 
 
 
 
 
if clinically 
indicated 
X 
if indicated 
 
 


 
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Evaluation 
(Cohort 3) 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA > 200 
copies/ml
Discontinuation Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infus
ion 
Infus
ion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 to 
-30 
Days 
-21 to 
-7 
Days  
-7 
Days 
to 0 hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
CD4+/CD8+  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored 
Plasma/PBMC for 
Immunology Studies  
 
 
 
 
X 
 
 
 
 
 
 
 
X* 
X* 
 
X* 
 
 
 
D-dimer 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X* 
 
X* 
 
 
 
Plasma HIV-1 RNA 
Real-Time  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
(see 
6.2.
4) 
 
 
X 
X 
 
Plasma HIV-1 RNA 
by SCA 
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
X 
Resting CD4+T-Cells 
for Cell-associated 
Total HIV-1 DNA and 
RNA  
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X* 
 
 
 
 
Histone Acetylation 
Assay 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
 
Stored PBMC for 
Virology Studies  
X 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X* 
X* 
X* 
X* 
 
 
X 


 
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Evaluation 
(Cohort 3) 
Screen 
(see 
section 
6.2.1 for 
rescreen) 
Pre-Entry 
Entry 
Post-Entry Evaluations 
Confirmation of HIV-1 RNA > 200 
copies/ml
Discontinuation Evaluations 
Week 1 
Wk 2 
Wk 4 
Wk 8 
Day 1 
Day 
2 
Day 
7 
Day 
14 
Day 
28 
Day 
56 
(see 
6.2.4) 
Hour 
Hour 0 
2 
4 
6 
8 
12 
24 
48 
Pre-
Infus
ion 
Infus
ion 
Start 
Window 
-90 to -50 
Days 
unless 
otherwise 
specified 
-35 to 
-30 
Days 
-21 to 
-7 
Days  
-7 
Days 
to 0 hr 
±15 minutes for blood draws and  
+60 minutes for ECG 
±2 
hrs 
±4 
hrs 
±2 Days 
-1 to 
+2 
Days 
±4 
Days 
Resting CD4+T-Cells 
for Ex Vivo 
PMA/Ionomycin & 
RMD Inducible HIV-1 
RNA Expression, i.e., 
TVR assay  
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X* 
 
 
 
 
PK for RMD, RAL, 
EFV, DTG  
 
 
 
 
X 
-15 
mins 
to 
RMD 
(see 
10.2) 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
RMD/Placebo 
Infusion 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
*These evaluations are not required if participant does not undergo the Hour 24 blood collection.


 
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6.1.3 Table 6.1.3-1:  Cohort 4 Screening through Step 2 
Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screening 
Pre-Entry 
Pre-Entry 
Step 1  
Step 2 
Prem. Tx and Study D/C 
Step 
2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-infusion) 
Week 1/ Day 3 
(72 hr post-infusion) 
Week 1 / Day 7   
(7 days post-
infusion)
Weeks 2 to 9 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-infusion) 
Week 3 / Day 17 
(72 hr post-infusion) 
Week 3 / Day 21  
(7 days post-
infusion)
Weeks 4 to 11 
(conditional) 1 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Medication 
History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
Once 
each week 
X 
X 
X 
X 
Once each 
week 
X 
Complete Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky Performance 
Score 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
X 
 
X 
X 
X 
X 
X 
Once 
each week 
X 
X 
X 
X 
Once each 
week 
X 
Hematology 
 
 
X 
 
X 
X 
X 
Wk 4, 8 
(Weekly – 
see 6.2.3) 
 
X 
X 
X 
Wk 6, 10 
(Weekly – 
see 6.2.3) 
X 


 
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Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screening 
Pre-Entry 
Pre-Entry 
Step 1  
Step 2 
Prem. Tx and Study D/C 
Step 
2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-infusion) 
Week 1/ Day 3 
(72 hr post-infusion) 
Week 1 / Day 7   
(7 days post-
infusion)
Weeks 2 to 9 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-infusion) 
Week 3 / Day 17 
(72 hr post-infusion) 
Week 3 / Day 21  
(7 days post-
infusion)
Weeks 4 to 11 
(conditional) 1 
Potassium and 
Magnesium (see section 
6.3.7 for timing at Pre-
entry) 
 
 
X 
 
 
 
X 
Wk 4, 8 
(Weekly – 
see 6.2.3) 
 
 
 
X 
Wk 6, 10 
(Weekly – 
see 6.2.3) 
 
LFTs/Blood Chemistries 
(see section 6.3.7) 
 
 
X 
 
 
 
X 
Wk 
2, 6 
 
 
 
X 
Wk 
6, 10 
X 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step. (See section 6.2.3). If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testing 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
CD4+ cell count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV/HCV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
X  
Hr 4 
As clinically indicated 
X  
Hr 4 
As clinically indicated 
 


 
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Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screening 
Pre-Entry 
Pre-Entry 
Step 1  
Step 2 
Prem. Tx and Study D/C 
Step 
2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-infusion) 
Week 1/ Day 3 
(72 hr post-infusion) 
Week 1 / Day 7   
(7 days post-
infusion)
Weeks 2 to 9 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-infusion) 
Week 3 / Day 17 
(72 hr post-infusion) 
Week 3 / Day 21  
(7 days post-
infusion)
Weeks 4 to 11 
(conditional) 1 
CD4% 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Stored Plasma and 
PBMC for immunology 
testing (see section 6.3.9) 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
Plasma HIV-1 RNA real 
time 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
 
 
 
X 
Wk 4, 8 
(Weekly – 
see 6.2.3) 
 
 
 
X 
Wk 6, 10 
(Weekly – 
(see 6.2.3) 
 
Plasma HIV-1 RNA by 
SCA 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
PBMCs (see section 
6.3.10) 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 


 
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Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screening 
Pre-Entry 
Pre-Entry 
Step 1  
Step 2 
Prem. Tx and Study D/C 
Step 
2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-infusion) 
Week 1/ Day 3 
(72 hr post-infusion) 
Week 1 / Day 7   
(7 days post-
infusion)
Weeks 2 to 9 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-infusion) 
Week 3 / Day 17 
(72 hr post-infusion) 
Week 3 / Day 21  
(7 days post-
infusion)
Weeks 4 to 11 
(conditional) 1 
Stored PBMC for virology 
testing (see section 
6.3.10) 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Histone Acetylation 
 
 
 
Hr 0 
X 
X 
 
 
Hr 0 
X 
X 
 
 
 
Stored PBMC for qVOA 
(see section 6.3.10) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RMD/Placebo Infusion 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
 


 
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Table 6.1.3-2:  Cohort 4 Screening through Steps 3 and 4 
Evaluation 
(Cohort 4, Steps 3 
and 4; standard) 
Step 3 
Step 4 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 
4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion)
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
Clinical Assessments 
X 
X 
X 
X 
Once each 
week 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
 
X 
X 
X 
Wk 8, 12 
(Weekly – 
see 6.2.3) 
 
X 
X 
 
X 
X 
X 
X 
X 
Potassium and 
Magnesium (see 
section 6.3.7 for 
timing at Pre-entry) 
 
 
 
X 
Wk 8, 12 
(Weekly – 
see 6.2.3) 
 
 
 
X 
 
 
 
 
 
LFTs/Blood 
Chemistries (see 
section 6.3.7) 
 
 
 
X 
Wk 8, 12 
 
 
 
X 
 
 
 
X 
X 
Urine Pregnancy 
Testing 
X 
 
 
 
 
X 
 
 
 
As clinically 
indicated 
 


 
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Evaluation 
(Cohort 4, Steps 3 
and 4; standard) 
Step 3 
Step 4 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 
4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion)
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
ECG 
X 
Hr 4 
As clinically indicated 
X 
Hr 4 
As clinically indicated 
X 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 
6.2.3).  If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
CD4% 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored Plasma and 
PBMC for 
immunology testing 
(see section 6.3.9) 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA 
real time 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
X 
Wk 8, 12 
(Weekly – 
see 6.2.3) 
 
 
 
 
 
X 
 
 
 
Plasma HIV-1 RNA 
by SCA 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 


 
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Evaluation 
(Cohort 4, Steps 3 
and 4; standard) 
Step 3 
Step 4 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 
4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion)
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
PBMCs (see section 
6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored PBMC for 
virology testing (see 
section 6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Histone Acetylation 
Hr 0 
X 
X 
 
 
Hr 0 
X 
X 
 
 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step. (See section 
6.2.3). If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
Stored PBMC for 
qVOA (see section 
6.3.10) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
RMD/Placebo 
Infusion 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ART Adherence 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 


 
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Evaluation 
(Cohort 4, Steps 3 
and 4; standard) 
Step 3 
Step 4 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 
4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion)
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
Assessment 
PK RMD 
(Collection times are 
from the start of the 
infusion) 
X 
Hr 0 
&  
Hr 4 
 
 
 
 
X 
Hr 0 
& 
Hr 4 
 
 
 
 
 
 
 
 
PK ARVs 
(Collection time is 
from the start of the 
infusion) 
X 
Hr 0 
X 
 
 
 
X 
Hr 0 
X 
 
 
 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 
6.2.3).  If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
 
 


 
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6.1.4 Table 6.1.4-1: Cohort 4 Delayed Infusion SOE, Steps 2 and 3 
Evaluation 
(Cohort 4, Steps 2 and 3; 
delayed infusion) 
Step 2  
Infusion 2 
Step 3  
Infusion 3 
Prem. Tx and/or Study   D/C 
Reg. to Step 2 1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
 Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional)  
(See section 6.2.3) 
Reg. to Step 3  1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional) 
(See section 6.2.3) 
 
Clinical  
Assessments 
X 
X 
X 
X 
Once 
each week 
X 
X 
X 
X 
Once 
each week 
X 
Targeted Physical Exam 
X 
X 
X 
X 
Once 
each week 
X 
X 
X 
X 
Once 
each week 
x 
Hematology 
X 
X 
X 
 
R+4 & 
R+8 
(Weekly) 
X 
X 
X 
 
R+4 & 
R+8 
(Weekly) 
X 
Potassium and Magnesium 
(see section 6.3.7 for timing 
at Pre-entry) 
 
 
 
X 
R+4 & 
R+8 
(Weekly) 
 
 
 
X 
R+4 & 
R+8 
(Weekly) 
 
LFTs/Blood Chemistries 
(see section 6.3.7) 
 
 
 
X 
R+2 & 
R+6 
 
 
 
X 
R+2 & 
R+6 
X 
Urine Pregnancy Testing 
X 
 
 
 
 
X 
 
 
 
 
 
ECG 
X 
Hr 4 
As clinically indicated 
X  
Hr 4 
As clinically indicated 
 
CD4% 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
1 Registration to step week (R) is defined as one week past the week of the last visit on the previous step. 


 
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Evaluation 
(Cohort 4, Steps 2 and 3; 
delayed infusion) 
Step 2  
Infusion 2 
Step 3  
Infusion 3 
Prem. Tx and/or Study   D/C 
Reg. to Step 2 1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
 Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional)  
(See section 6.2.3) 
Reg. to Step 3  1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional) 
(See section 6.2.3) 
 
Stored Plasma and PBMC 
for immunology testing (see 
section 6.3.9) 
 
X 
 
 
 
 
X 
 
 
 
X 
Plasma HIV-1 RNA real 
time 
 
 
 
 
 
 
 
 
 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
X 
R+4 & 
R+8 
(Weekly) 
 
 
 
X 
R+4 & 
R+8 
(Weekly) 
 
Plasma HIV-1 RNA by SCA 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
PBMCs (see section 
6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Stored PBMC for virology 
testing (see section 6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Histone Acetylation 
X 
Hr 0 
X 
X 
 
 
X 
Hr 0 
X 
X 
 
 
 
RMD / Placebo Infusion 
X 
 
 
 
 
X 
 
 
 
 
 


 
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Evaluation 
(Cohort 4, Steps 2 and 3; 
delayed infusion) 
Step 2  
Infusion 2 
Step 3  
Infusion 3 
Prem. Tx and/or Study   D/C 
Reg. to Step 2 1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
 Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional)  
(See section 6.2.3) 
Reg. to Step 3  1 
R + 1 day  
(24 hr post-infusion) 
R + 3 days  
(72 hr post-infusion) 
Week R + 1  
(7 days post-
infusion)  
Weeks R+2 to R+ 9  
(conditional) 
(See section 6.2.3) 
 
ART Adherence 
Assessment 
X 
 
 
 
 
X 
 
 
 
 
X 
1 Registration to step week (R) is defined as one week past the week of the last visit on the previous step. 
PK RMD 
(Collection times are from 
the start of the infusion) 
 
 
 
 
 
X 
Hr 0 & 
Hr 4 
 
 
 
 
 
PK ARVs 
(Collection time is from the 
start of the infusion) 
 
 
 
 
 
X 
Hr 0 
X 
 
 
 
 
1 Registration to step week (R) is defined as one week past the week of the last visit on the previous step. 
 
 


 
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Table 6.1.4-2:  Cohort 4 Delayed Infusion SOE, Step 4 
Evaluation 
(Cohort 4, Step 4; delayed 
infusion) 
Step 4 
Prem. Tx or Study   
D/C 
Infusion 4 
Post-Infusion 4 Follow Up  
Reg. to 
Step 4 1 
R + 1 day 
(24 hr post-
infusion) 
R + 3 days 
(72 hr post-
infusion) 
Week R + 1  
(7 days post-
infusion) 
Week 
R + 2 
Week
R + 5 
WeekR 
+ 10 
Week R 
+ 18 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
x 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LFTs/Blood Chemistries 
(see section 6.3.7) 
 
 
 
 
 
 
 
X 
X 
Urine Pregnancy Testing 
X 
 
 
 
As clinically indicated 
 
ECG 
X 
Hr 4 
As clinically indicated 
X 
 
 
 
 
CD4% 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored Plasma and PBMC 
for immunology testing 
(see section 6.3.9) 
 
X 
 
 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA real 
time 
 
 
 
 
X 
X 
X 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
X 
 
 
 
 
 
1 Registration to step week (R) is defined as one week past the week of the last visit on the previous step. 


 
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Evaluation 
(Cohort 4, Step 4; delayed 
infusion) 
Step 4 
Prem. Tx or Study   
D/C 
Infusion 4 
Post-Infusion 4 Follow Up  
Reg. to 
Step 4 1 
R + 1 day 
(24 hr post-
infusion) 
R + 3 days 
(72 hr post-
infusion) 
Week R + 1  
(7 days post-
infusion) 
Week 
R + 2 
Week
R + 5 
WeekR 
+ 10 
Week R 
+ 18 
Plasma HIV-1 RNA by SCA 
X 
X 
X 
 
X 
X 
X 
X 
X 
CD4+ T cells (see section 
6.3.10) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored PBMC for virology 
testing (see section 6.3.10) 
X 
X 
X 
 
X 
X 
X 
X 
X 
Histone Acetylation 
X 
Hr 0 
X 
X 
 
 
 
 
 
 
Stored PBMC for qVOA 
(see section 6.3.10) 
 
 
 
 
 
X 
 
X 
 
RMD/ Placebo Infusion 
X 
 
 
 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
 
 
 
 
X 
X 
X 
PK RMD 
(Collection times are from 
the start of the infusion) 
Hr 0 &  
Hr 4 
 
 
 
 
 
 
 
 
PK ARVs 
(Collection time is from the 
start of the infusion) 
Hr 0 
X 
 
 
 
 
 
 
 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening and Pre-Entry Evaluations  
 
Screening and pre-entry evaluations must occur prior to the participant’s starting 
any study medications, treatments, or interventions. 
 
Screening, Cohorts 1-3 
Screening evaluations to determine eligibility must be completed between 50 and 
90 days prior to study entry unless otherwise specified.  
 
The screening Plasma HIV-1 RNA by Single Copy Assay (SCA) will be collected 
between 50 and 90 days prior to entry and shipped for real-time testing. See 
section 6.3.10. 
 
In addition to data being collected on candidates who enroll into the study, 
demographic, clinical, and laboratory data on candidates who do not enroll will be 
captured in a Screening Failure Results form and entered into the ACTG 
database. Due to blood volume restrictions, candidates who fail screening can 
only be rescreened 60 days after their previous screening visit.  
 
The following data will also be collected on an additional CRF from candidates 
who do not enroll in the study: screening CD4+ cell count, screening HIV-1 RNA 
level, pre-ART HIV-1 RNA level, pre ART nadir CD4 (if documentation is not 
available participant recall can be used),  date of first undetectable HIV-1 RNA 
level prior to sustained viral load suppression (may be estimated if exact date not 
available), antiretroviral regimen at the time of screening and the start date of this 
regimen, the start date of the first antiretroviral regimen and the date(s) of any 
previous virologic failure on ART (if known) as determined by the investigator. 
 
Pre-Entry, Cohorts 1 – 3   
The timing for each pre-entry evaluation is noted in the SOE. The window ranges 
for their completion are: between 30 and 35 days, between 7 and 21 days, or 
between 7 days prior to study entry and hour 0 of the study entry day. Sites must 
ensure that each evaluation occurs within the appropriate pre-entry window of 
time. 
 
Screening, Cohort 4 
Screening evaluations to determine eligibility must be completed between 36 and 
60 days prior to study entry unless otherwise specified.  
 
In addition to data being collected on candidates who enroll into the study, 
demographic, clinical, and laboratory data on candidates who do not enroll will be 
captured in a Screening Failure Results form and entered into the ACTG 
database.  
 


 
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The following data will also be collected on an additional CRF from candidates 
who do not enroll in the study: screening CD4+ cell count, screening HIV-1 RNA 
level, pre-ART HIV-1 RNA level, pre-ART nadir CD4 (if documentation is not 
available participant recall can be used),  date of first undetectable HIV-1 RNA 
level prior to sustained viral load suppression (may be estimated if exact date not 
available), antiretroviral regimen at the time of screening and the start date of this 
regimen, the start date of the first antiretroviral regimen and the date(s) of any 
previous virologic failure on ART (if known) as determined by the investigator. 
 
Pre-Entry, Cohort 4  
Pre-entry evaluations must be performed per SOE section 6.1.3, between 35 
and 28 days or between 14 and 3 days prior to entry. 
 
6.2.2 Entry Evaluations 
 
Cohorts 1 – 3  
Entry/Hour 0 evaluations must occur within 24 hours after randomization and at 
least 7 days after the second pre-entry visit (-21 to -7 days) evaluations, unless 
otherwise specified.  
 
All entry/Hour 0 specimens must be obtained and pregnancy test reported before 
initiating RMD or placebo infusion. 
 
Cohort 4 
Entry evaluations must occur within 24 hours after randomization. 
 
All entry/Hour 0 specimens must be obtained and pregnancy test reported before 
initiating the first RMD or placebo infusion. 
 
6.2.3 Post-Entry Evaluations 
 
The RMD/placebo infusion should be completed in 4 hours. In the event that the 
infusion requires more than 4 hours, the time of infusion completion is still to be 
considered Hour 4.  
 
Post-Treatment Evaluations, Cohorts 1 – 3   
Hour 4 evaluations begin immediately following completion of RMD/placebo 
infusion. All subsequent evaluation time points are to be calculated from the 
infusion completion time which is considered Hour 4 regardless of whether the 
actual time from infusion start to completion took less or more time than 4 hours 
(ie, Hour 6 is 2 hours after the infusion has finished, Hour 8 is 4 hours after the 
infusion has finished, etc.). 
 
Post-Treatment Visit Schedule, Cohorts 1 – 3  
Study visits and collection time points must be scheduled as indicated in the 
Schedule of Events (SOE) ± 15 minutes for Hour 2, 4 (except for ECG which has 
a window of +0-60 minutes), 6, 8, 12; ± 2 hours for Hour 24; ± 4 hours for Hour 


 
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48/Day 2; ± 2 days for Day 7 and Week 2/Day 14, and -1 day to +2 days for 
Week 4/Day 28.  Per sections 6.2.4 and 7.1, participants may be required to 
return for a Week 8/Day 56 visit ± 4 days. 
 
Study Completion Evaluations, Cohorts 1 – 3   
Week 4/Day 28 evaluations will serve as the study completion evaluations for 
participants who have maintained an HIV-1 RNA level of < 200 copies/mL by 
standard ultrasensitive assay since the Day 7 visit. See section 6.2.4 for 
participants who have an HIV-1 RNA level of >200 copies/mL at the Day 7 visit. 
 
Also, these evaluations will be the study completion evaluations for participants 
who did not experience any >Grade 3 AE or clinical event (per section 7.1).  
 
Post-Entry Visit Schedule, Cohort 4 
Study visits and collection time points must be scheduled as indicated in the 
Cohort 4 SOE, section 6.1.3. The windows are ±6 hours for day 1 (24 hours 
post-infusion), ±1 day for day 3 (72 hours post-infusion), and ±1 day for day 
7 (7 days post infusion). For participants whose second, third, and/or fourth 
infusion must be delayed for any reason, the Delayed Infusion SOE,  
section 6.1.4, must be followed until the end of the study follow-up for that 
participant. Participants’ visits will be scheduled per this SOE beginning with the 
first delayed infusion.  
 
Sites should notify the A5315 core team if any infusion will be delayed 
(actg.corea5315@fstrf.org). 
 
Conditional Evaluation Weeks, Cohort 4 
Conditional evaluation weeks are only for participants whose next infusion will be 
delayed. The evaluations are performed weekly, unless otherwise specified, until 
the participant meets the criteria for the next infusion. If the participant does not 
meet the criterial for the next infusion by the last conditional evaluation week 
visit, then the participant will have the premature discontinuation evaluations 
performed per the SOE and then be taken off study. 
 
Evaluations for hematology, potassium, magnesium, and/or plasma HIV-1 
RNA expedited must be performed weekly as needed to meet the eligibility 
criteria for the next infusion. Otherwise, these evaluations should only be 
performed at the specific weeks indicated on the SOE.  
 
6.2.4 Event-Driven Evaluations  
 
Cohorts 1 – 3  
Participants with HIV-1 RNA levels > 200 copies/mL detected at the Day 7 visit 
(real-time HIV-1 RNA level) should be contacted immediately upon receipt of the 
Day 7 HIV-1 RNA results and asked to return as soon as possible (preferably 
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PCR level after Day 7 is >200 copies/mL, the participant will complete both the 
Week 4/Day 28 and Week 8/Day 56 visits per section 6.1.1 or 6.1.2 
 
Also, per section 7.1, participants who experience any >Grade 3 AE or clinical 
event, regardless of their Day 7 HIV-1 RNA level, will be seen at Week 8/Day 56.  
 
Cohort 4 
Participants with plasma HIV-1 RNA levels >50 copies/mL detected 7 days after 
any of the first three infusions should be contacted immediately upon receipt of 
the results by site staff and asked to return as soon as possible (preferably within 
72 hours) for additional real-time testing. While this testing is being performed, 
the next infusion should be postponed. The participant should have weekly HIV-1 
RNA levels tested, in addition to the other evaluations per the SOE, until the HIV-
1 RNA level is <50 copies/mL, after which infusions and/or blood collections can 
continue per the Delayed Infusion SOE, section 6.1.4. Sites must promptly 
advise the A5315 core team upon initial receipt of any elevated HIV-1 RNA level 
(actg.corea5315@fstrf.org). 
 
Also, per section 7.1, participants who experience any ≥ Grade 3 AE or 
clinical event during an infusion will be followed as indicated in section 
6.2.5. 
 
6.2.5 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
No further evaluations are required for participants who do not initiate 
RMD/placebo infusion.  
 
Cohorts 1 – 3  
All CRFs must be completed and keyed for the period up to and including 
entry/Hour 0. 
 
Cohort 4 
All CRFs must be completed and keyed for the period up to and including 
Entry/Hour 0. 
 
Premature Treatment and Study Discontinuation Evaluations  
Cohorts 1 – 3  
Participants who receive RMD/placebo infusion but from whom blood is not 
collected at the 24-hour time point should remain on study for safety monitoring 
through Day 28.  
 
Participants who prematurely discontinue study participation after receiving 
RMD/placebo or prior to the completion of RMD/placebo infusion, will have the 
premature study discontinuation evaluations performed per the SOE and 
recorded on CRFs. 
 


 
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Cohort 4 
Participants who prematurely discontinue study treatment due to a ≥ Grade 3 
AE or clinical event or for any other reason will not have any further infusions 
but will be followed on study/off study treatment. Participants will remain on 
their current step and complete the following visits: 24-hour post-infusion, 
72-hour post-infusion, 7-day (1 week) post-infusion, and premature 
treatment/study discontinuation evaluations 4 weeks post-infusion and will 
then be taken off study. 
 
Participants from whom the blood collection is not performed at more than 
one of the 24-hour time points after a RMD/placebo infusion will not have 
any further infusions but will be followed on study/off study treatment. 
Participants will remain on their current step and complete the following 
visits: 72-hour post-infusion, 7-day (1 week) post-infusion, and premature 
treatment/study discontinuation evaluations 4 weeks post-infusion and 
then will be taken off study. 
 
Participants who prematurely discontinue study participation after receiving four 
RMD/placebo infusions or prior to the completion of four RMD/placebo infusions, 
will have the premature study discontinuation evaluations performed per the SOE 
and then will be taken off study. A replacement participant may be enrolled for 
each participant who prematurely discontinues the study, including participants 
who receive all four infusions but discontinue study participation prior to the week 
11 visit. 
 
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 
Web site for information about what must be included in the source document: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
definitions for a serious adverse event. 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Congenital anomaly/birth defect 
 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above).   
 


 
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To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC Web site: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting. 
 
6.3.1 Documentation of HIV-1 
 
Sections 4.1.1 and 4.3.1 specify assay requirements for HIV-1 documentation. 
HIV-1 documentation is not recorded on the CRF. 
 
6.3.2 Medical History 
 
In addition to recording all diagnoses that occurred within 30 days prior to study 
entry, the following diagnoses should be recorded and keyed within 2 business 
days, regardless of when the diagnosis was made: 
 
 Immunologic including AIDS-defining conditions and HIV- associated 
opportunistic infection (OI) 
 Bone fractures (verbal history accepted) 
 Cardiovascular including coronary heart disease 
 Cancer (exclusive of basal/squamous cell skin cancer) 
 Diabetes 
 Tuberculosis (TB) 
 Chronic hepatitis C 
 Chronic hepatitis B 
 Gastrointestinal including cholecystectomy, peptic ulceration, and 
inflammatory bowel disease 
 Allergies to any medications and their formulations  
 
Document the pre-ART HIV-1 RNA level and nadir CD4 count if available. If nadir 
documentation is not available, then collect and record participant recall. Record 
the date of the first undetectable HIV-1 RNA level prior to sustained viral load 
suppression (may be estimated if exact date not available). Record date(s) of any 
previous virologic failure on ART (if known) as determined by the investigator. 
 
6.3.3 Medication History 
 
At study entry, record in source documentation only, the treating physician’s 
confirmation that a viable alternate ART regimen can be constructed for the 
participant, should a single dose of RMD lead to virologic failure (ie, 2 
consecutive HIV-1 RNA levels > 200 copies/mL) and resistance to the current 
ART regimen. 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 


 
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Table 6.3.3-1: Medication History  
Medication Category 
Complete History or Timeframe 
Antiretroviral therapy 
Complete history 
Immune-based therapy 
Complete history 
Blinded study treatment 
Complete history 
HIV-1-related vaccines 
Complete history 
Prescription drugs (other) 
Current use  
(within 30 days prior to entry) 
Potassium & Magnesium 
Supplements 
Current use  
(within 21 days prior to entry) 
 
6.3.4 Clinical Assessments 
 
Height  
Height (cm) will be measured and recorded at the pre-entry visit only.  
 
Weight  
Cohorts 1 – 3   
Weight in kilograms (kg) should be assessed at the screening, pre-entry, entry, 
and Days 7, 14, and 28 study visits.  
 
Cohort 4  
Weight (in kg) should be assessed at screening, the first pre-entry visit, entry, at 
Days 7, 21, and 35, and at Days 14, 28, and 42. For participants following the 
Delayed Infusion SOE, weight will be assessed at the following visits: 
Registration to Step 2, Registration to Step 3, and Registration to Step 4. If at 
least 8 weeks have elapsed since the dose of study treatment (RMD or placebo 
for RMD) was calculated, then the site pharmacist must recalculate the dose 
using the participant’s most recently documented weight. 
 
Signs and Symptoms 
At entry, all grades of signs and symptoms that occurred 30 days prior to study 
entry must be recorded and keyed within 2 business days. Post-entry, all signs 
and symptoms Grade  2 must be recorded and keyed within two business days. 
Further evaluation will be required for signs and symptoms, regardless of grade, 
that led to a change in study treatment and/or Grade ≥ 3 and/or meet EAE or ICH 
reporting requirements, which must also be recorded and keyed within 2 
business days. 
 
Diagnoses 
Record all diagnoses identified by the ACTG criteria for clinical events and other 
diseases since the last visit and key within 2 business days.  


 
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Concomitant Medications 
Record, all new or discontinued prescription medications, and potassium and 
magnesium supplements, since the last visit.  
 
Antiretroviral Medications 
During the study, all modifications to the participant’s ARV regimen, including any 
ARV interruptions (there is no minimum number of days of interruption needed 
for report), dose modifications, formulation modifications, starts, and permanent 
discontinuations since the last study visit or at the study visit must be recorded.   
 
If the site decides to have the participant stay overnight at a Clinical and 
Translational Research Center or similar facility, they should remind participant to 
bring his/her own antiretroviral medications for the inpatient stay or overnight stay 
elsewhere.  
 
Study Treatment Modifications 
Record and key within 2 business days, the RMD/placebo infusion, including 
dose administered, whether administration was temporarily halted for any 
reason, duration of infusion, and whether the full dose was administered. If the 
infusion is temporarily halted, the schedule of evaluations should resume 
following completion of the RMD/placebo infusion (referred to as Hour 4, 
regardless of whether the actual time from infusion start to completion took more 
time than 4 hours). See sections 6.2.3 and 6.3.11. Record any unscheduled 
discontinuation of RMD or placebo for RMD. 
 
6.3.5 Complete Physical Exam 
 
A complete physical examination will be conducted at the pre-entry visit indicated 
on the appropriate SOE and is to include at a minimum an examination of the 
skin, head, mouth, and neck; auscultation of the chest; cardiac exam; abdominal 
exam; examination of the lower extremities for edema; and calculation of 
Karnofsky performance score. The complete physical exam will also include 
signs and symptoms, diagnoses, and vital signs (temperature, pulse, respiration 
rate, and blood pressure). 
 
Note: For Cohort 4, a Complete Physical Exam will be performed at the first 
pre-entry visit (Day -35 to Day -28) with the exception of the calculation for 
the Karnofsky performance score, which will be performed at the second 
pre-entry visit (Day -14 to Day -3). 
 
6.3.6 Targeted Physical Exam 
 
A targeted physical examination will be performed at the visits indicated in the 
SOE; at a minimum, it will include vital signs (temperature, pulse, respiration rate, 
and blood pressure) and, beginning at entry, is to be driven by any previously 


 
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identified or new signs or symptoms and diagnoses that the participant has 
experienced since the last study visit. 
 
Vital signs must be obtained prior to the RMD/placebo infusion, at Hour 2 (+/- 15 
minutes) during the RMD/placebo infusion, at any time during the RMD/placebo 
infusion if clinically indicated, and following completion of the RMD/placebo 
infusion. 
 
6.3.7 Laboratory Evaluations 
 
Refer to the A5315 MOPS and lab processing chart (LPC), located on the A5315 
PSWP, for the specific procedures for the collection, preparation, and storage of 
specimens.  
 
NOTE: All post-infusion blood collections must be performed on the opposite side 
of the body from the infusion. 
 
At screening, pre-entry, and entry, all laboratory values, regardless of grade, 
must be recorded and keyed within 2 business days of study enrollment. 
The entry laboratory values must be obtained and reviewed prior to initiating 
RMD/placebo infusion. For post-entry assessments, record and key all Grade >2 
laboratory values within 2 business days.  
 
Further evaluation will be required for laboratory values and toxicities, regardless 
of grade, that led to a change in RMD or placebo for RMD infusion and/or Grade 
≥ 3 and/or meet EAE or ICH reporting requirements and must be recorded within 
2 business days.  
 
Hematology 
Cohorts 1 – 3   
Hemoglobin, hematocrit, red blood cells [RBC], mean corpuscular volume [MCV], 
white blood cell count [WBC], differential WBC, absolute neutrophil count (ANC), 
and platelets will be evaluated.  
 
The pre-entry window for hematology testing is -21 days to 0 hour on Day 0.  
 
Cohort 4  
Hemoglobin, hematocrit, RBC, MCV, WBC, ANC, and platelets.  
 
NOTE:  On the days that infusions are scheduled, the results from the previous 
visit must be available before the infusion begins and must meet the step’s 
eligibility criteria (refer to sections 4.5.4, 4.7.4, 4.9.4) for the infusion to 
proceed. Notify the study’s core team (actg.corea5315@fstrf.org) if an 
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Liver Function Tests 
Cohorts 1 – 3 
Total bilirubin, AST [SGOT], ALT [SGPT], alkaline phosphatase, indirect bilirubin, 
and -glutamyl transaminase [GGT] will be evaluated. 
 
Cohort 4 
Total bilirubin, AST [SGOT], ALT [SGPT], alkaline phosphatase, indirect bilirubin, 
and GGT will be evaluated. 
 
The pre-entry window for blood chemistries and liver function tests is -14 days to 
-3 days (i.e., day -14 to day -3 pre-entry visit). 
 
Potassium and Magnesium 
Prior to the Step 1 infusion, potassium and magnesium levels will be 
assessed at the day -14 to day -3 pre-entry visit, as indicated in the SOE. 
 
Potassium and magnesium levels will be assessed 7 days prior to the Steps 2, 
3, and 4 infusions. Blood potassium and magnesium values must be within 
normal limits.  If the potassium and/or magnesium value is below the site's 
clinical laboratory’s limit of normal, the participant should be supplemented as 
medically indicated, retested, and evaluated again within 3 days prior to the 
infusion. The repeated potassium and/or magnesium values must be within 
normal range for the site’s limit of normal for the infusion to take place.  
 
Given blood volume constraints in this study, sites should use pediatric volume 
tubes for checking potassium and magnesium levels whenever feasible.  
 
Prior to the Steps 2, 3, and 4 infusions, if the potassium and magnesium 
levels are still out of range after retest, consultation with the core team is 
required before a decision about discontinuation is made 
(actg.corea5315@fstrf.org). 
 
Blood Chemistries 
All Cohorts  
Electrolytes [sodium, potassium, chloride, phosphate, bicarbonate], calcium, 
magnesium, creatinine, blood urea nitrogen (BUN), and uric acid will be 
evaluated. 
 
Calculated creatinine clearance estimated by the Cockcroft-Gault equation will be 
evaluated.  
 
NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault 
method is available on www.fstrf.org. 
 
Urinalysis 
Urinalysis with microscopic exam will be done at screening only. 
 


 
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Pregnancy Test 
Pregnancy testing will be done per the SOE. For women of reproductive 
potential: Serum or urine -HCG (urine test must have a sensitivity of < 25 
mIU/mL).  
 
For Cohort 4, only urine pregnancy testing is permitted.  
 
Refer to section 7.2 for details on pregnancy and pregnancy outcome reporting.  
 
Hepatitis Screen 
HBsAg and HCV antibody testing will be done per the SOE. HCV RNA testing is 
required if HCV antibody positive. See sections 4.1.9, 4.1.10, 4.3.7, and 4.3.8 for 
details. 
 
6.3.8 ECG 
 
Resting ECG results, including heart rate and measured QTc interval, must be 
recorded per the SOE.  For the ECG done during pre-entry, the QTc interval 
must be read by a cardiologist and signed off by the site investigator prior to the 
start of the RMD/placebo infusion and should ideally be taken from limb lead II.   
 
For the ECGs that are performed at the completion of the RMD/placebo infusion 
(Hour 4) and 2 weeks later, the QTc interval must be read by a cardiologist but 
this reading may be done at a later time and QTc interval will be recorded. See 
section 7.1.5 for clinical management directions for participants with a prolonged 
QTc interval on study.  
 
NOTE: Should ECGs be performed for any reason at visits after entry, the site is 
responsible for recording any change in QTc interval relative to the 
baseline value. 
 
A program for calculating QTc by Fridericia’s correction is available on the DMC 
website at www.fstrf.org.  
 
6.3.9 Immunologic Studies 
 
CD4+/CD8+ (Cohorts 1 – 3 only) 
For Cohorts 1-3 only, obtain absolute CD4+/CD8+ T cell count and percentages 
within 90 days prior to entry from a laboratory that possesses a CLIA (Clinical 
Laboratory Improvement Amendments) certification or equivalent.  
 
CD4+ (Cohort 4 only) 
At screening, obtain absolute CD4+ cell count between 36 and 60 days 
prior to study entry performed at a laboratory that possess CLIA 
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CD4+ percentages 
At the time points indicated in the SOE, obtain CD4 percentages only 
performed at a laboratory that possess CLIA certification or equivalent. 
 
During the study, all laboratories must possess a CLIA certification or equivalent 
and must be qualified for protocol testing by the DAIDS Immunology Quality 
Assurance (IQA) Program. 
 
Stored Plasma/PBMC for Immunology Studies 
Cryopreserved PBMC obtained by blood draw will be stored for T cell analysis 
per the SOE. Specific lymphocyte marker testing will include the following: 
- Proportion of CD4+ and CD8+ T cells co-expressing CD38/HLA-DR or 
CD25/CD69  
- Percentage of CD3+  lymphocytes that are CD4+ and CD8+ 
- Proportion of CD4+ and CD8+ T cells that are in cell cycle (Ki-67+) 
- Percent of total lymphocytes expressing Annexin V alone and those 
expressing both Annexin V and 7-AAD 
 
Plasma samples will be obtained to test for the levels of soluble markers of 
inflammation including IL-6 and hsCRP. 
 
D-dimer (Cohorts 1 – 3 only) 
Citrated plasma samples will be obtained per the SOE to test for the levels of D-
dimer. 
 
6.3.10 Virologic Studies 
 
See the LPC for processing, shipping, and storage information. 
 
Plasma HIV-1 RNA Real-Time  
Screening, Cohorts 1 – 3 
Screening HIV-1 RNA (real-time) by standard ultrasensitive assay must be 
obtained between 50 and 90 days prior to study entry.  
 
Screening, Cohort 4  
Screening HIV-1 RNA (real-time) by standard ultrasensitive assay must be 
obtained between 36 and 60 days prior to entry.  
 
Pre-entry and post-entry, all cohorts  
After the screening visit, plasma HIV-1 RNA will be performed real time per the 
SOE at the protocol-designated laboratory. See section 6.2.4. See the LPC for 
processing, shipping, and storage information. 
 
Day 7 post-infusion, Cohorts 1 – 3  
The HIV-1 RNA level sample obtained at the Day 7 visit must be processed and 
shipped in real-time, preferably on the day the sample is obtained to ensure 
results are available prior to the Week 4/Day 28 visit. 


 
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Plasma HIV-1 RNA Expedited 
Day 7 post-infusion, Cohort 4 
The HIV-1 RNA level plasma sample obtained 7 days after each infusion must be 
processed and shipped overnight. See the LPC for overnight shipping 
instructions. 
 
Conditional Evaluation Weeks, Cohort 4 
HIV-1 RNA level plasma samples obtained at conditional evaluation weeks per 
the SOE must be processed and shipped overnight per the LPC. Refer to section 
6.2.4, Event-Driven Evaluations for Cohort 4.  
 
Plasma HIV-1 RNA by SCA 
Screening, entry, and post-entry, Cohorts 1 – 3   
The plasma samples for the screening SCA will be collected between 50 and 90 
days prior to entry and shipped to a central laboratory for real-time testing. Pre-
entry SCA must be obtained between 30 and 35 days prior to entry. Other 
plasma for SCA will be obtained per the SOE and stored for batched analyses. 
 
Entry and post-entry SCA evaluations will be performed by the designated ACTG 
Virology Specialty Laboratory on stored plasma samples collected per SOE. 
 
Pre-entry, entry, and post-entry, Cohort 4 
Plasma for HIV-1 RNA by SCA will be collected per the SOE and stored for 
batched analysis by the designated ACTG Virology Specialty Laboratory.  
 
PMBC (Cohort 4) 
In Cohort 4, histone acetylation assay will be performed real-time in total CD4+ 
cells isolated from PBMC per the SOE. 
 
Resting CD4+T-Cells for Cell-associated HIV-1 DNA and HIV-1 RNA  
Cohorts 1 – 3   
Cell-associated HIV-1 RNA will be measured in resting CD4+ cells from blood 
collected on Day 0 prior to RMD/placebo infusion and then about 24 hours after 
the start of the infusion and about 14 days following infusion.  
 
Cell-associated HIV-1 DNA will be measured in resting CD4+ cells from blood 
collected within 7 days prior to RMD/placebo infusion and then about 24 hours 
after the start of the infusion and about 14 days following infusion; see section 
6.2.3 for timing.  
 
Cohort 4 
Cell-associated total HIV-1 RNA will be measured in PBMCs cells from blood 
collected at pre-entry visits, on Day 0 prior to RMD/placebo infusion, and then 
about 24 and 72 hours after the start of each infusion. 
 


 
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Cell-associated HIV-1 DNA will be measured in PBMCs from blood collected 
prior to RMD/placebo infusion and then about 24 and 72 hours after the start of 
each infusion. 
 
Stored PBMC for Virology Studies 
Stored PBMCs will be used for: 
 Future virology studies 
 Total CD4+ T-cells for Histone Acetylation and PTEF-b Phosphorylation 
Assays: Positive transcription elongation factor-b (PTEF-b) phosphorylation 
will be assessed in total CD4+ cells isolated from cryopreserved stored 
PBMC per the SOE. 
 
Stored PBMC for qVOA (Cohort 4 only) 
At the time points indicated in section 6.1.3 SOE, a separate blood collection will 
be made and PBMCs will be stored for a quantitative viral outgrowth assay. 
 
Resting CD4+ T-cells for Ex vivo PMA/Ionomycin and RMD Inducible HIV-1 RNA 
Expression  
Cohorts 1 – 3  
Resting CD4+ T cells will be isolated from blood collected per the SOE. Cells will 
be cultured in the presence of RMD or PMA/Ionomycin.  At various times post-
stimulation, HIV-1 RNA levels will be measured in culture supernatants by Abbott 
real-time assay.  
 
6.3.11 Pharmacokinetic (PK) Studies (Refer to Section 10.0) 
 
NOTE: For PK collections, blood must be drawn from the opposite side of the 
body from that used for the RMD infusion. 
 
Refer to the LPC for collection, processing, storage, and shipping details. 
 
Cohorts 1 – 3   
Blood will be drawn following completion of the RMD infusion for determination of 
RMD and ARV (RAL, EFV, or DTG) plasma levels per the SOE and section 10.2. 
The date and time of the last three doses of ARV taken immediately prior to the 
pre-infusion blood sample must be recorded. 
 
Cohort 4  
Blood will be collected immediately prior to the third and fourth infusions and then 
again at Hour 4 (for RMD PK) and at Hour 24 (for ARV PK) after the third and 
fourth infusions. The date and time of the last three doses of ARV taken 
immediately prior to the pre-infusion blood sample must be recorded. 
 
6.3.12 RMD or Placebo for RMD Infusion 
 
For correct RMD dosing calculate BSA per section 5.1. See section 6.3.4, 
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Cohorts 1 – 3  
RMD will be administered as a single 4-hour intravenous infusion starting at 
entry/Hour 0. Potassium and magnesium levels will be assessed prior to infusion 
at the pre-entry visit (day -21 to -7). Blood potassium and magnesium values 
must be within normal limits. If the pre-entry potassium and/or magnesium 
value(s) is below the site's clinical laboratory’s limit of normal, the participant 
should be supplemented as medically indicated, retested, and evaluated prior to 
study entry. If the pre-entry potassium and/or magnesium value(s) is high, the 
value(s) should be retested, and evaluated prior to study entry. The repeated 
pre-entry potassium and/or magnesium values must be within normal range for 
the site’s limit of normal for study entry. Given blood volume constraints in this 
study, sites should use pediatric volume tubes whenever feasible.  
 
Cohort 4 
RMD will be administered as a 4-hour intravenous infusion at four time points, as 
indicated in the Cohort 4 SOE, section 6.1.3 or, as warranted, in the Cohort 4 - 
Delayed Infusion SOE, section 6.1.4, . See section 6.3.7 for pre-infusion safety 
testing. 
 
6.3.13 ART Adherence Assessment  
 
Participants will be asked to complete a brief ART adherence questionnaire per 
the SOE.  
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
Criteria for participant management, dose interruption and discontinuation changes in 
drug treatment will be mandated only for toxicities attributed to RMD. Toxicities due to 
drugs in the antiretroviral regimen should be managed according to standard clinical 
practice, with the goal of maintaining continuous therapy, if possible.  
 
The grading system for drug toxicities is located in the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 
2004 (Clarification, August 2009), which can be found on the DAIDS RSC Web site: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting.   
 
NOTE: The core team must be notified within 24 hours by email at 
actg.corea5315@fstrf.org regarding toxicities thought to be associated with RMD that 
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7.1 
Toxicity  
 
7.1.1 Grade 1 or 2 Toxicity (All Cohorts) 
 
Participants who develop a Grade 1 or 2 AE or toxicity during infusion may 
complete the infusion at the discretion of the site investigator, and will be 
followed carefully. If a participant chooses to discontinue the infusion, the site 
should notify the A5315 Core Team at actg.corea5315@fstrf.org and encourage 
the participant to complete safety visits for the study. Grade 1 or 2 AEs that may 
be related to RMD should be handled according to standard clinical practice and 
documented.  
 
7.1.2 Grade 3 Toxicity 
 
Cohorts 1 – 3 
Participants who develop a Grade 3 AE or toxicity during infusion should have 
the infusion discontinued and the A5315 Core Team should be notified. Grade 3 
AEs or toxicities that occur following infusion should be handled according to 
standard clinical practice and the A5315 Core Team should be notified. 
Participants who experience a Grade 3 AE or clinical event must return for a 
Week 8/Day 56 visit. 
 
Cohort 4 
Participants who develop a Grade 3 AE or toxicity during infusion should 
have the infusion discontinued. The A5315 Core Team should be notified 
within 48 hours (preferably within 24 hours). No further infusions will be 
performed. Refer to section 6.2.5 for required evaluations. 
 
Grade 3 AEs or toxicities that occur following an infusion should be handled 
according to standard clinical practice, and the A5315 Core Team should be 
notified. 
 
7.1.3 Grade 4 Toxicity 
 
Cohorts 1 – 3 
Participants who develop a Grade 4 AE or toxicity during infusion will have the 
infusion discontinued.  Participants experiencing Grade 4 AEs should be followed 
closely until the resolution of the AE to < Grade 2 and the A5315 Core Team 
must be consulted within 72 hours (preferably within 24 hours). Participants who 
experience a Grade 4 AE or clinical event must return for a Week 8/Day 56 visit. 
 
Cohort 4 
Participants who develop a Grade 4 AE or toxicity during infusion should 
have the infusion discontinued. The A5315 Core Team should be notified 
within 48 hours (preferably within 24 hours). No further infusions will be 
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Grade 4 AEs or toxicities that occur following an infusion should be handled 
according to standard clinical practice, and the A5315 Core Team should be 
notified. 
 
7.1.4 Nausea/Vomiting 
 
Nausea/vomiting may be treated symptomatically with oral antiemetics or 
antiemetic suppositories per standard clinical practice.  
 
7.1.5 Cardiac Toxicity 
 
Refer to the A5315 MOPS for the DAIDS Toxicity Table to grade QTc 
prolongation. 
 
Grade 1: 
Infusion should continue without interruption, at the discretion of 
the site investigator.  
 
Grade 2:  
Infusion should continue without interruption, at the discretion of 
the site investigator. A repeat ECG should be performed at the 7 
and 14 days following the infusion.  
 
Grade 3 and 4:   The infusion should be interrupted. If the Grade 3 QTc 
prolongation is considered to be most likely due to concomitant 
illness or medication, standard management, including 
discontinuation of the likely causative agent, should be 
undertaken. A repeat ECG should be performed 7 and 14 days 
after the infusion. 
 
Several treatment-emergent changes in ECGs (including T-wave and ST-
segment changes) have been reported in clinical studies of RMD. The clinical 
significance of these changes is unknown. In this study, electrolytes and ECGs 
are monitored at Pre-Entry and then again after each infusion. The use of strong 
CYP3A4 inhibitors that may increase RMD concentrations is prohibited during 
the study. ECG changes observed in participants may be multifactorial. Clinicians 
should evaluate participants with ECG changes for other possible contributing 
factors and address any that are identified. Sites should contact the core team 
(actg.corea5315@fstrf.org) to help determine whether additional infusions should 
be cancelled.  
 
7.2 
Pregnancy  
 
If a female participant becomes pregnant during study follow-up, the site staff should 
request permission to contact her regarding pregnancy outcomes at the end of 
pregnancy. A visit 6 months following the end of pregnancy will be conducted to assess 
for evidence of adverse events (AEs) in the participant and infant and an outcome case 
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pregnancy complications and outcome for all pregnancies that occur during study follow-
up and within 180 days after an infusion. 
 
Intrapartum complications and/or pregnancy outcome will be recorded on the CRFs. 
Pregnancies that occur on study must be reported prospectively to The Antiretroviral 
Pregnancy Registry which collects information about ART exposure and adverse 
pregnancy outcomes. More information is available at www.apregistry.com. Phone: 800-
258-4263; Fax: 800-800-1052.  
 
Pregnancy Outcomes 
Pregnant women will be asked to provide pregnancy outcome data. The outcome and 
the AEs for the participant and infant will be recorded on an outcome CRF. Site staff 
must request permission to contact her regarding pregnancy and infant outcomes at the 
end of pregnancy. Pregnancy outcomes for the participant and infant will be submitted 
on a CRF at the end of the pregnancy. 
 
Procedures in the Event of Contraceptive Failure 
In the event of contraceptive failure, the use of an emergency contraceptive is an option. 
A levonorgestrel-only emergency contraceptive (ie, Plan B) is preferred to minimize the 
occurrence of nausea. The use of EFV with an emergency contraceptive containing both 
ethinyl estradiol and levonorgestrel may cause significantly increased ethinyl estradiol 
levels (Stocrin package insert, 2014), thereby increasing the incidence of nausea and 
vomiting. Combined ethinyl estradiol/levonorgestrel emergency contraceptive is, 
however, an acceptable option if a levonorgestrel-only emergency contraceptive is 
unavailable. 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent and Premature Treatment Discontinuation 
 
 
Grade 3 or higher drug-related toxicity (see section 7.1 Toxicity).  
 
Requirement for prohibited concomitant medications (see section 5.5). 
 
Request by participant to terminate treatment. 
 
Clinical reasons believed to be serious or life-threatening by the physician, even if 
not addressed in the toxicity section of the protocol. 
 
Temperature >101.5 degrees Fahrenheit during an infusion.   
 
Development of an allergic reaction (such as difficulty breathing, wheezing, 
symptomatic hypotension, hives) which is thought by the site investigator to be 
related to the study drug. 
 
Development of a symptomatic cardiac arrhythmia. 
 


 
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8.2 
Premature Study Discontinuation 
 
 
Participant does not receive any RMD or placebo. 
 
Participant lacks adequate venous access. 
 
In Cohort 4, participant does not receive all four infusions of RMD or placebo for 
RMD. 
 
In Cohort 4, participant misses more than one of the 24-hour post-infusion blood 
collections. 
 
In Cohort 4, participant does not complete the week 11 visit. 
 
Pregnancy or breastfeeding. 
 
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. 
 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
 
At the discretion of the ACTG, IRB, Food and Drug Administration (FDA), NIAID, 
Office for Human Research Protections (OHRP), other government agency as part of 
their duties, investigator, or industry supporter.  
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
This is a dose-escalation study in which cohorts will open sequentially based on the 
safety of the previous cohort. Up to three dose levels of single-dose RMD (0.5 mg/m2, 2 
mg/m2, 5 mg/m2) may be assessed in the first three cohorts. Multiple doses of RMD (at 
5mg/m2) may be assessed in Cohort 4 if safety is established in Cohort 3, ie, if dose-
escalation criteria are met. Each cohort of 15 participants consists of 12 evaluable 
participants receiving RMD and 3 receiving placebo (single dose in Cohorts 1 – 3, and 
multiple doses in Cohort 4).  
 
The study is double-blinded, placebo-controlled and randomized. There are three 
participants receiving placebo at each dose cohort. Inclusion of a placebo group in each 
cohort, albeit small, may help assess treatment-related events by allowing blinded 
assessment of events in relation to treatment. Also, the efficacy of RMD among those 
receiving RMD in Cohorts 1 – 3 can be compared to those of placebo participants 
pooled from Cohorts 1 – 3.  
 
Accrual of the first five participants in any cohort will be limited to one participant in a 3-
day period.  
 
Analyses and dissemination of study results from Cohorts 1 – 3 will commence after 
Cohort 3 follow-up is completed. Analyses and dissemination of Cohort 4 results will 
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9.2 
Outcome Measures 
 
NOTE: Due to insufficient numbers of resting CD4+ T-cells available from some 
Cohort 4 participants to perform all the planned assays (e.g., cell-associated HIV-1 
RNA, total HIV-1 DNA, histone acetylation, PTEF-b activation), those assays will be 
performed using peripheral blood mononuclear cells (PBMCs). The team carefully 
reassessed the priorities for the use of these cells based on advances in the field 
since the prior protocol version. Accordingly, the relevant objectives and 
outcomes measures sections have been updated. 
 
9.2.1 Primary Endpoints  
 
9.2.1.1 Safety 
 
Occurrence of Grade ≥ 3 AE including signs/symptoms, lab toxicities, 
and /or clinical events that is probably, possibly or definitely related to 
study treatment (as judged by the core team, blinded to treatment arm) 
any time from the time of study treatment administration until 28 days 
after the administration. 
 
9.2.1.2 Efficacy 
 
9.2.1.2.1 Change in plasma HIV-1 RNA levels from baseline (average 
of pre-entry and entry values) as detected by single copy 
assay at 24 and 48 hours (average) after the single 
administration of RMD or placebo in Cohorts 1 – 3. 
 
9.2.1.2.2 Change in plasma HIV-1 RNA levels from baseline 
(average of pre-entry and entry values) as detected by 
single copy assay before and 24 hours after each 
administration of RMD or placebo in Cohort 4. 
 
9.2.1.2.3 Change in cell-associated HIV-1 RNA levels in resting CD4+ 
T-cells from baseline to 24 hours after the single 
administration of RMD or placebo in Cohorts 1 – 3. 
 
9.2.1.2.4 Change in cell-associated HIV-1 RNA levels in PBMCs 
before and 24 hours after each administration of RMD or 
placebo in Cohort 4. 
 
9.2.2 Secondary Outcome Measures 
 
9.2.2.1 Changes in plasma HIV-1 RNA levels as detected by single copy assay 
from baseline to after the single administration of RMD or placebo in 
Cohorts 1 – 3 and after each administration of RMD or placebo in 
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9.2.2.2 Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells 
from baseline to 14 days after the administration of RMD or placebo in 
Cohorts 1-3, and in PBMCs after each administration of RMD or 
placebo in Cohort 4. 
 
9.2.2.3 Changes in histone acetylation in CD4+ and CD8+ T-cells from baseline 
to after the single administration of RMD or placebo in Cohorts 1-3 and 
after each administration of RMD or placebo in Cohort 4. 
 
9.2.2.4 Changes in total HIV-1 DNA in resting or total CD4+ T-cells from 
baseline to after the single administration of RMD or placebo in Cohorts 
1 – 3 and in PBMCs after each administration of RMD or placebo in 
Cohort 4. 
 
9.2.2.5 Pharmacokinetic parameters for RMD and co-administered antiretroviral 
drugs (EFV, DTG, or RAL). 
 
9.2.2.6 Number/percent of participants in Cohorts 1 – 3 with HIV-1 RNA levels 
≥200 copies at the Day 7 visit 
 
9.2.2.7 Number/percent of participants in Cohort 4 with HIV-1 RNA levels ≥200 
copies/mL at scheduled post-infusion 4 visits. 
 
9.2.2.8 All reported Grade 2-4 AEs. 
 
9.2.2.9 Change in CD4+ T cell percent from baseline to after each 
administration of RMD or placebo in Cohort 4. 
 
9.2.2.10 Change in CD4+ and CD8+ T cell percent from baseline to after the 
single administration of RMD or placebo in Cohorts 1 – 3 and after 
each administration of RMD or placebo in Cohort 4. 
 
9.2.2.11 Changes in the percentage of CD3+ CD4+ and CD3+ CD8+ 
lymphocytes and cellular markers of immune activation 
(CD38/HLA-DR or CD69/CD25 expression on CD4+ and CD8+ T-
cells) from baseline to after the single administration of RMD or 
placebo in Cohorts 1 – 3 and after each administration of RMD or 
placebo in Cohort 4.  
 
9.2.2.12 Change in percentage of total lymphocytes expressing annexin V 
and/or 7 amino-actinomycin D (7-AAD) from baseline to after the 
single administration of RMD or placebo in Cohorts 1 – 3 and after 
each administration of RMD or placebo in Cohort 4. 
 
9.2.2.13 Changes in P-TEFb and HIV-1 expression; changes in PTEF-b 
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the single administration of RMD or placebo in Cohorts 1 – 3 and 
after each administration of RMD or placebo in Cohort 4. 
 
9.2.3 Exploratory Outcome Measures 
 
9.2.3.1 Change in quantitative viral outgrowth assay (qVOA) from baseline 
to after administration of all doses of RMD or placebo in Cohort 4. 
 
9.2.3.2 Changes in proportion of cycling CD4+ and CD8+ T-cells (Ki67 
expression) from baseline to after the single administration of RMD or 
placebo in Cohorts 1 – 3 and after each administration of RMD or 
placebo in Cohort 4. 
 
9.2.3.3 Changes in the levels of soluble markers IL-6, C-reactive protein (CRP), 
and D-dimer from baseline to after the single administration of RMD or 
placebo in Cohorts 1 – 3 and after each administration of RMD or 
placebo in Cohort 4. 
 
9.2.3.4 Changes in HIV-specific immune responses from baseline to after 
the first and fourth administration of RMD or placebo in Cohort 4. 
 
9.2.3.5 Changes in host RNA expression profiles by RNAseq of PBMC 
from after the first and fourth administration of RMD or placebo in 
Cohort 4. 
 
9.3 
Randomization and Stratification 
 
Each cohort will open sequentially. Within each cohort, 15 participants will be 
randomized to receive RMD (12 participants) or placebo (3 participants). Randomization 
will use a permuted block method without institutional balancing or stratification. After 
each cohort enrollment is complete, study enrollment will be suspended until a decision 
on the subsequent cohort is made, based on the dose escalation criteria.  
 
9.4 
Sample Size and Accrual 
 
The total sample size of this study will be 60 evaluable participants (12 evaluable active 
plus 3 evaluable placebo controls, per dosing cohort) if all four cohorts are enrolled.  For 
Cohorts 1 – 3, participants who do not receive study drug (RMD or placebo) and/or 
complete the pre-infusion blood collection and/or the 24-hour blood collection will be 
replaced. For Cohort 4, participants who do not complete all 4 doses of study drug (RMD 
or placebo) and/or who miss more than one of the 24-hour post-infusion blood 
collections or the week 11 blood collection will be replaced.  
 
9.4.1 Safety 
 
Dose escalation criteria for consideration by the SMC are defined as: 
 


 
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a) No more than three participants have experienced a Grade 3 AE that is 
probably or possibly related to study treatment (as judged by the core team, 
blinded to treatment arm) prior to or on Day 14 after the treatment 
administration; and 
 
b) None of the participants has experienced a Grade ≥ 3 AE that is definitely 
related to study treatment or that is Grade ≥ 4 and probably or possibly 
related to study treatment (as judged by the core team, blinded to treatment 
arm) prior to or on Day 14 after the treatment administration.  
 
Note: The occurrence of a Grade 3 infusion site pain or tenderness that is 
sustained for less than 48 hours will be excluded from the dose escalation 
evaluation. 
 
The tables below show the probabilities of dose escalation under various 
assumed true rates for two types of AEs as described above and under various 
enrollment projections (i.e., if at least 12 but fewer than 15 participants are 
enrolled into a cohort).  
 
In the tables, the column “True rate of Grade 3 AE probably or possibly related to 
study Rx” is the probability conditional on not having the “Grade 3 or higher AE 
definitely related or Grade 4 or higher AE probably or possibly related to study 
Rx”. The column “True rate of Grade 3 or higher AE definitely related or Grade 4 
or higher AE probably or possibly related to study Rx” is the unconditional 
probability of the event. The calculations in these tables assume there is 
negligible probability that a participant in the placebo arm will experience a Grade 
≥ 3 AE.  
 
The proposed sample size provides a reasonably high probability of dose 
escalation when the true event rates are, in fact, acceptable. For example, if the 
probability of a participant in the active treatment arm of a given dose cohort 
experiencing a Grade 3 AE as described above that is possibly or probably due 
to study treatment is 0.012 (ie, 1.2%), and the corresponding probability of 
experiencing such an AE that is definitely due to study treatment is 0.10 (ie, 1%), 
then the probability that the study will dose escalate to the next higher dose is 
0.89 (ie, 89%). Given that this is an acceptable safety profile, this means that the 
probability of incorrectly concluding the current dose unsafe is 11%. On the other 
hand, the proposed sample size provides a low probability of dose escalation 
when the true event rates are unacceptable. For example, if the true rate of 
Grade 3 AE that is probably or possibly related to study treatment is 0.180 (ie, 
18%), and the true rate of Grade 3 AE that is definitely related or Grade 4 or 
higher AE that is probably or possibly related to study treatment is 0.150 (ie, 
15%), then the probability of dose escalation is only 0.12 (ie, 12%), and the 
corresponding probability of not dose escalating and correctly concluding the 
dose unsafe is high at 0.88 (1-0.12). 
 


 
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Table 9.4.1-1:  Probabilities of dose escalation under various assumed true rates 
(n=12 on RMD). 
True rate of Grade 3 AE 
probably or possibly related 
to study Rx 
True rate of Grade 3 or higher 
AE definitely related or Grade 
4 or higher AE probably or 
possibly related to study Rx 
Probability of Dose 
Escalation 
0.006 
0.005 
0.94 
0.012 
0.010 
0.89 
0.024 
0.020 
0.78 
0.036 
0.030 
0.69 
0.048 
0.040 
0.61 
0.060 
0.050 
0.54 
0.120 
0.100 
0.27 
0.180 
0.150 
0.12 
0.240 
0.200 
0.05 
0.360 
0.300 
<0.01 
The randomization of study participants to either RMD or placebo uses a 
permuted block design. With a ratio of 4:1, a block size of 5 has been used. 
Based on this method, with a total of 12 participants enrolled in Cohort 3, there 
will be 9 or 10 participants randomized to receive RMD. The following 
calculations of probabilities of dose escalation using the same criteria are based 
on N=9 or 10 on RMD.  
 
Table 9.4.1-2: Probability of dose escalation under various assumed true rates 
(n=10 on RMD) 
True rate of Grade 3 
AE probably or 
possibly related to 
study Rx 
True rate of Grade 3 or 
higher AE definitely related 
or Grade 4 or higher AE 
probably or possibly related 
to study Rx 
Probability 
of Dose 
Escalation 
0.006 
0.005 
0.95 
0.012 
0.010 
0.90 
0.024 
0.020 
0.82 
0.036 
0.030 
0.74 
0.048 
0.040 
0.66 
0.060 
0.050 
0.60 
0.120 
0.100 
0.34 
0.180 
0.150 
0.18 
0.240 
0.200 
0.09 
0.360 
0.300 
0.01 


 
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With N=10, the study still provides a low probability (although higher than with 
N=12) of dose escalation when the true event rates are unacceptable. For 
example, for the same assumed rates as above, the probability of dose 
escalation is 0.18 (ie, 18%) vs. 0.12 with N=12, and the corresponding probability 
of not dose escalating and correctly concluding the dose unsafe is high at 0.82 
(1-0.18) vs. 0.88. 
 
Table 9.4.1-3:  Probability of dose escalation under various assumed true rates 
(n=9 on RMD) 
True rate of Grade 3 
AE probably or 
possibly related to 
study Rx 
True rate of Grade 3 or 
higher AE definitely related 
or Grade 4 or higher AE 
probably or possibly 
related to study Rx 
Probability of Dose 
Escalation 
0.006 
0.005 
0.96 
0.012 
0.010 
0.91 
0.024 
0.020 
0.83 
0.036 
0.030 
0.76 
0.048 
0.040 
0.69 
0.060 
0.050 
0.63 
0.120 
0.100 
0.38 
0.180 
0.150 
0.22 
0.240 
0.200 
0.11 
0.360 
0.300 
0.02 
 
With N=9, the probabilities of dose escalation are larger than in the setting with 
N=12 as expected. For example, for the same assumed rates as above, the 
probability of dose escalation is 0.22 (ie, 22%) vs. 0.12 with N=12, and the 
corresponding probability of not dose escalating and correctly concluding the 
dose unsafe is high at 0.78 (1-0.22) vs. 0.88. 
 
9.4.2 Efficacy 
 
For evaluating primary efficacy endpoints in Cohorts 1 – 3, the study will use the 
results from the placebo arms combined across Cohorts 1 – 3 as a control. If all 
three cohorts are fully enrolled and treated and followed per protocol, there will 
be n=9 participants in the combined placebo control group and n=36 participants 
in the combined RMD group.  
 


 
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The study is powered on the change of HIV-1 RNA by SCA from baseline 
(average of pre-entry and entry values) to the 24 and 48 hour measurements 
(averaged) after RMD administration. Under the assumptions that the standard 
deviation of log10 change is 0.32 (derived from A5244 SCA measurements) and 
there will be no change in HIV-1 RNA in the placebo group, with a sample size of 
n=36 in the combined RMD group and n=9 in the combined placebo group, the 
study will have 80% power to detect a 0.42 log10 increase in HIV-1 RNA by SCA 
using a two-sided Wilcoxon rank sum test at 5% level.  
 
For the secondary comparison of a given RMD dose group (n=12) with the 
combined placebo group (n=9), the study will have 80% power to detect a 0.52 
log10 increase in RNA by SCA.  
 
The sample size estimation includes an adjustment of 15% for the potential loss 
of efficiency due to left censoring of SCA results below assay limit.  
 
The following table presents the detectable effect size based on various sample 
sizes and standard deviations: 
 
Table 9.4.2-1: Detectable effect sizes based on various sample sizes and assumed standard 
deviations. 
Estimated 
standard 
deviation of 
log10 change 
Sample size per 
cohort: RMD/ 
placebo 
Detectable Effect size 
(log10) with 80% power for 
comparison between 
combined RMD group and 
combined placebo group 
Detectable Effect size 
(log10) with 80% power for 
comparison between a 
given RMD dose group 
and combined placebo 
group 
SD=0.29 
15/5 
0.29 
0.37 
12/3 
0.38 
0.47 
SD=0.32 
15/5 
0.32 
0.41 
12/3 
0.42 
0.52 
SD=0.35 
15/5 
0.35 
0.44 
12/3 
0.46 
0.56 
 
For comparison of the change of cell-associated viral RNA in resting CD4+ T-
cells from baseline, assuming that the standard deviation (SD) of log10 change is 
0.33 [39] and there will be no change in HIV-1 RNA in the placebo group, with 36 
active and 9 placebos combined in Cohorts 1 – 3, the study will have 80% power 
to detect a difference of 0.38 log10 copies/million CD4 cells in the cell-associated 
viral RNA between the two combined groups, using a two-sided 5% level 
Wilcoxon rank sum test. For Cohort 4, with 12 in the RMD group and 3 in the 
placebo group, the study will have 80% power to detect a difference of 0.79 log10 
copies/million CD4 cells.   
 
For Cohort 4, a quantitative viral outgrowth assay (qVOA) will be performed 
instead of the modified TVR assay [41]. The team opted to perform the qVOA 


 
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since it is the current gold-standard assay for quantifying the latent 
reservoir.  
 
9.4.3 Accrual 
 
Accrual and screening will be suspended when the current cohort is fully enrolled 
and until the cohort is evaluated. Screening will reopen for enrollment once the 
decision to open the next cohort is made.  
 
Participants who do not receive study treatment or complete the pre-infusion and 
hour 24 blood collection will be replaced in Cohorts 1 – 3; in Cohort 4, any 
participant who misses an infusion, more than one of the 24-hour post-infusion 
blood collections, or the week 11 blood collection will be replaced. Any 
participant who prematurely discontinues the 4 hour study treatment infusion for 
reasons other than the study treatment-attributed Grade ≥ 3 events will be 
replaced with a participant assigned to the same dose cohort and the same arm.  
 
Expected accrual per month is 2 to 4 participants. 
 
In the unlikely event that dose escalation to all three doses is not undertaken due 
to the stopping rules noted in section 9.5, the enrollment will be expanded in the 
lower dose cohort(s) to maintain power for efficacy comparisons. Details and 
implementation of the enrollment expansion plan will be discussed in consultation 
with the SMC. 
 
9.5 
Monitoring 
 
Accrual, baseline characteristics, conduct of the study, all toxicities, and AEs will be 
monitored during the trial with reports pooled over treatment arms and broken down by 
dose cohort sent to the core team on a regular basis. The protocol core safety team will 
review the individual safety data frequently to assess relation of all reported toxicities 
and AEs to the study treatment in blinded assessments, incorporating the site 
investigator’s opinion on their relation to the treatment reported on the CRFs.  
 
It will be the responsibility of the core safety team to interpret the toxicity data, make 
decisions needed to protect participants from undue risk, and determine whether or not 
participant replacements are needed. 
 
If at any time within a given dose cohort, 
 
a) four or more participants experience a primary safety endpoint (section 9.2.1.1) that 
is possibly or probably related to study treatment (as judged by the core safety 
team, blinded to treatment arm); or  
 
b) one or more participants experience a primary safety endpoint (section 9.2.1.1) that 
is definitely related to study treatment or that is Grade 4 or death and possibly or 
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treatment arm) then enrollment into the study will be temporarily suspended and an 
independent SMC, unblinded to treatment assignment, will be asked to review all 
safety data; review the relation to study treatment of the event(s) thought by the 
blinded core safety team to be a primary safety endpoint; and recommend how the 
study should proceed with respect to resuming enrollment, continuing study 
treatment and dose escalation.  
 
After the last enrolled participant in a given cohort completes 14 days after the study 
treatment and the blinded data become available for review, all safety data, including the 
decisions on the relationships between AEs and study treatment, will be reviewed by the 
SMC to determine whether to dose escalate or modify the study. In addition, the SMC 
will review the study at least yearly while the study is ongoing. Furthermore, the core 
safety team, at any time it thinks appropriate, may ask for the SMC to independently 
review all available safety data (unblinded to treatment arms) and make a 
recommendation to the HIV Reservoirs and Eradication Transformative Science Group 
on whether to modify or stop the study.  
 
The DAIDS clinical representative will receive the standard toxicity summary report 
according to the schedule for phase I/II studies.  
 
9.6 
Analyses 
 
For the primary safety analysis, Grade ≥ 3 AEs attributed to the study treatment will be 
described separately for the treatment arm of each dose cohort, and for the combined 
placebo arms. All participants who have been exposed to the study treatment/placebo 
will be included in this analysis. As secondary analyses, all reported Grade ≥ 2 AEs on 
all enrolled participants will be summarized for the treatment arm of each dose cohort, 
and combined placebo arms. 
 
For the primary efficacy outcome measures of changes in plasma HIV-1 RNA level and 
cell-associated viral RNA levels in resting memory CD4+ T-cells in Cohorts 1-3, the 
analyses will be “as-treated” based only on participants who completed study 
treatment/placebo administration. Changes from baseline to scheduled study visits will 
be summarized with appropriate median plots, separately for the combined RMD and the 
combined placebo groups. A Wilcoxon rank sum test will be used for the comparison 
between the two combined groups for Cohorts 1 – 3. Analysis for the primary efficacy 
outcome measures in Cohort 4 will use the same approach between RMD and placebo. 
 
Secondary outcome measures will be explored in a similar fashion. Additionally, a 
generalized Wilcoxon test will be used to compare the changes in plasma HIV-1 RNA by 
SCA in Cohort 4 between RMD and placebo to account for potential censoring due to 
undetectable SCA value at baseline. If proportions of undetectable SCA values are high, 
changes in SCA levels may also be analyzed as categorical data (increase from 
baseline vs. decrease from baseline vs. undetermined). Furthermore, longitudinal SCA 
levels per participant will be plotted. 
  


 
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As exploratory secondary analyses, the comparison of a given RMD dose group with the 
combined placebo group will be made using the same approach. Furthermore, the 
relationship between dose level and changes in plasma HIV-1 RNA level and cell-
associated viral RNA levels will be explored using a Wilcoxon rank sum test (comparison 
between two dose levels) or Jonckheere-Terpstra test (comparison among three dose 
levels), depending on the actual study cohorts that open. In addition, comparisons will be 
made with non-parametric repeated measures test (Wei-Johnson test with Xu-Tian-Wei 
method with a Wilcoxon-type kernel function) between the combined RMD and placebo 
groups for Cohorts 1 – 3 and between RMD and placebo for Cohort 4. Each test will be a 
2-sided with a type I error rate of 5%. As exploratory analyses, no adjustment for 
multiple tests will be made in the type I error rate. 
 
10.0 
PHARMACOLOGY PLAN 
 
The pharmacology plan described in this section applies primarily to Cohorts 1-3. In 
Cohort 4, similar PK testing will be performed before and after the third and fourth RMD 
infusion from samples collected at appropriate time points. 
 
10.1 
Pharmacology Objectives 
 
The primary objective is to evaluate RMD pharmacokinetics in HIV-infected participants 
on ART at three different single dose levels in Cohorts 1 – 3 and at a single dose level 
after multiple administrations in Cohort 4. The secondary objective is to assess the effect 
of efavirenz, dolutegravir, or raltegravir on RMD exposure in Cohorts 1 – 3 and of 
dolutegravir or raltegravir on RMD exposure in Cohort 4. The third objective is to 
determine whether there is an association between RMD PK parameters (AUC, Cmin, 
Cmax, etc.) and induction of HIV-1 transcription in CD4+ T-cells of HIV-infected 
participants receiving suppressive ART. 
 
10.2 
Pharmacology Study Design 
 
This is a dose-finding trial of RMD at dose levels of 0.5, 2.0, and 5.0 mg/m2. Participants 
in Cohorts 1 – 3 will be receiving an EFV-, DTG-, or RAL-based regimen that includes 
two N(t)RTIs. In Cohort 4, participants will be receiving a DTG- or RAL-based regimen 
that includes twp N(t)RTIs. PIs are not permitted in any cohort nor are other ARVs that 
are eliminated by or induce CYP3A4 (e.g., maraviroc, etravirine, rilpivirine).  
 


 
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Cohorts 1 – 3  
The last ARV dosing taken prior to infusion will be recorded as a part of the entry/Hour 0 
evaluation. A baseline whole blood sample (4 mL) will be drawn at pre-infusion 
entry/Hour 0 (within 15 minutes prior to RMD administration). RMD/placebo will be 
administered intravenously over a 4 hour infusion. Post infusion whole blood samples 
will be collected following completion of the RMD-infusion from the opposite side of the 
body, at 4, 6, 12, and 24 hours after initiation of RMD dosing. RAL, EFV, or DTG plasma 
levels will also be quantitated from these samples.  
 
Cohort 4 
The last ARV dosing taken prior to infusion will be recorded as a part of the Hour 0 
evaluation for Steps 3 and 4. In each of these two steps, a whole blood sample will be 
drawn at pre-infusion /Hour 0 (within 15 minutes prior to RMD/placebo administration). 
RMD/placebo will be administered intravenously over a 4-hour infusion. Post-infusion 
whole blood samples will be collected from the opposite side of the body, at 4 and 24 
hours after initiation of the infusion. RMD plasma levels will be quantified from the 
4-hours post-infusion sample and DTG or RAL plasma levels will be quantitated from 
the 24-hours post-infusion sample.  
 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis 
 
The primary analysis will be non-compartmental (WinNonlin 5.3, Pharsight). The area 
under the plasma concentration time curve (AUC) will be calculated using the linear-
up/log-down trapezoidal rule. Maximum plasma concentration (Cmax) and time to 
maximum concentration (Tmax) will be taken directly from the observed concentration-
time data. Clearance (CL/F) is calculated as dose/AUC. Terminal apparent distribution 
volume (Vz/F) is calculated as dose divided by the product of the elimination rate 
constant (z) and AUC. The elimination rate constant will be determined by linear 
regression of the terminal elimination phase concentration-time points; elimination half-
life (t1/2) is calculated as ln(2)/z.  
 
RMD PK parameters will be compared across participants receiving RAL, DTG, or EFV 
to determine the magnitude of any interactions. Relationships between RMD PK 
parameters and biomarkers of HIV-1 reactivation will be explored using maximum effect 
models. These biomarkers include, but are not limited to, plasma viremia using a single 
copy HIV-1 RNA assay, changes in cell-associated viral RNA levels in resting memory 
CD4+ T-cells, changes in total HIV-1 DNA, and other immunologic and inflammatory 
biomarkers.  
 
10.4 
Anticipated Outcomes 
 
We anticipate full description of RMD pharmacokinetic parameters in this patient 
population. Since this drug is metabolized by CYP3A4, we also anticipate a potential 
interaction with EFV (a CYP3A4 inducer) (for Cohorts 1 – 3), but not RAL or DTG. The 
RMD concentration range should be large enough to establish relationships with 
biomarkers, but these analyses will be exploratory.  


 
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11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon (randomization/registration). 
 
11.2 
Role of Data Management 
 
11.2.1 
Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely 
fashion. 
 
11.2.2 
It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 
Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, 
CRFs, supporting data, laboratory specimen records, and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to 
ensure protection of study participants, compliance with the protocol, and 
accuracy and completeness of records. The monitors also will inspect sites’ 
regulatory files to ensure that regulatory requirements are being followed and 
sites’ pharmacies to review product storage and management. 
 
11.3.2 
The site investigator will make study documents (eg, consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the NIAID, 
the OHRP, other local, US, and international regulatory entities, and the 
industry supporter(s) or designee for confirmation of the study data.  
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting. 
 


 
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The DAIDS Adverse Events Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS.  In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please 
contact NIAID CRMS Support at CRMSSupport@niaid.nih.gov. Site queries 
may also be sent from within the DAERS application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting. For questions about expedited reporting, please 
contact DAIDS RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
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 relationship assessments are required: Romidepsin 
or Placebo for Romidepsin. 
 
The Division of AIDS Table for Grading the Severity of Adult and Adverse 
Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, 
August 2009), must be used and is available on the DAIDS at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables. 
 
The protocol-defined expedited event reporting period for this protocol is 3 
months for an individual participant in Cohorts 1, 2, or 3 (beginning at study 
enrollment) and 6 months for an individual participant in Cohort 4 (beginning at 
study enrollment). If the site becomes aware of an event after the reporting 
period, it should be reported in a timely fashion.   
 
After the end of the protocol-defined EAE Reporting Period stated above, sites 
must report serious, unexpected, clinical suspected adverse drug reactions if 
the study site staff becomes aware of the event on a passive basis, ie, from 
publicly available information. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is  
available on the RSC website: http://rsc.tech-res.com/clinical-research-
sites/safety-reporting. For questions about EAE reporting, please contact the 
RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 
(Clarification, August 2009), must be used and is available on the DAIDS RSC 
Web site at http://rsc.tech-res.com/clinical-research-sites/safety-reporting. 


 
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11.4.3 
Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is 3 months for an 
individual participant in Cohorts 1, 2, or 3 (beginning at study enrollment) 
and 6 months for an individual participant in Cohort 4 (beginning at study 
enrollment). 
 
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
SAEs, as defined in Version 2.0 of the EAE Manual, will be reported to 
DAIDS if the study staff become aware of the events on a passive basis 
(from publicly available information). 
 
12.0 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendices IV, V, and VI) and any 
subsequent modifications will be reviewed and approved by the IRB responsible for 
oversight of the study. A signed consent form will be obtained from the participant (or 
parent, legal representative, or person with power of attorney for participants who cannot 
consent for themselves, such as those below the legal age of consent). 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, 
parent, or legal representative, and this fact will be documented in the participant’s 
record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or 
the industry supporter or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
or the industry supporter, or other government agencies as part of their duties to ensure 
that research participants are protected.  
 


 
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13.0 
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.  
 
14.0 
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. 
 
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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15.0 
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39. Hong F, Aga E, Cillo A, et al. Novel assays to measure total cell-associated HIV-1 DNA 
and RNA. J Clin Microbiol. 2016 Apr;54(4):902-11.  
40. Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-
course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS 
Pathogens. 2014;10(10):e1004473. 
41. Wang Z, Simonetti FR, Siliciano RF, et al. Measuring replication competent HIV-1: 
advances and challenges in defining the latent reservoir. Retrovirology. 
2018:15:21. 


 
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APPENDIX I: A5315 STUDY VISITS – COHORT 3 
 
The study staff can answer any questions you have about individual study visits, the evaluations that will occur, or how long each 
visit will be. The table below can be used as a quick reference for you, along with the explanations that follow. 
 
Appendix I, Table 1: Study Schedule 
 
Evaluation 
Screen1 
Pre-Entry2 
Entry3 
On Study Visits4 
HIV-1 RNA >200 
Early Disc5 
-90 to  
-50 
Days 
-35  
to  
-30  
Days 
-21 to  
-7 
Days 
-7 Days to -0 Hours 
Hour 
Day 
0 
2 
4 
6 
8 
12 
1 
2 
7 
14 
28 
56 
Consent Signed  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Confirmed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood Collected  
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Collected 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test  
X 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Electrocardiogram (ECG) 
 
 
X 
 
 
 
X 
 
 
 
 
if required 
X 
if required 
 
 
Study Drug Infusion 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 


 
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1 Screening Visit: Between 50 and 90 days before entry and after you have read and signed the 
consent form, you will have several evaluations done to make sure that you meet the 
requirements for joining the study. These evaluations may be scheduled in more than one visit. 
2 Pre-Entry Visits: You will come to the clinic for about three pre-entry visit evaluations. The first pre-
entry evaluations will be done between 30 and 35 days before the entry visit. The second pre-
entry evaluations will be done between 7 and 21 days before the entry visit. The third pre-entry 
evaluations will be done at any time between 7 days before the entry visit and up to the same day 
as the entry visit. 
3 Entry Visit: If you are eligible to join the study, you will be admitted to the clinic in the morning. You 
will have blood collected for some study-specific tests either on the day of study entry or up to 7 
days before. On the day of entry, the study treatment (RMD or placebo) will be given to you via an 
infusion. This should take about 4 hours. Then, over the next 24 hours, you will have blood 
collected about five times. You may be asked to stay overnight at a clinic in the hospital or another 
facility close by. You will return to the clinic the next morning for one more blood collection. 
4 On Study Visits: You will have study visits at days 7, 14, and 28. If your viral load at day 7 is less 
than 200 copies/mL by the standard test, day 28 will be your final study visit. If your viral load at 
day 7 is more than 200 copies/mL, you will be asked to return for an additional visit before day 28;  
if the repeat HIV-1 RNA PCR level (viral load) after day 7 is more than 200 copies/mL, you will be 
asked to return for a day 56 (+/- 4 days) visit. 
5 Early Discontinuation: If you stop participating in this study before completing the study drug 
infusion or after receiving the study drug infusion before the end of the study, you will be asked to 
come in for a special visit. 
 
II. Explanation of Evaluations  
 
Consent signed and contact information collected 
After you read the consent and have had a chance to ask questions about the study, you will 
sign the consent form if you want to continue to be evaluated for study participation. You will 
also be asked how to be contacted in case you miss a visit or there are problems with your 
tests, and whether you give the study team permission to contact you. 
 
HIV infection confirmed 
If an HIV test has to be done, you may have to sign a separate consent form. You will be told 
the results of the HIV test as soon as it is available.   
 
Medical/medication history 
You will be asked about the medications you have taken and your medical history.  
 
Physical examination 
You will have a physical exam which will include being weighed and you will be asked questions 
about your health and about any medicines you have taken or are taking now. 
 
Blood collected 
Blood will be collected from you for various tests during the study. These include routine safety 
lab tests to check your red and white blood cell counts and the health of your liver and kidneys, 
to test for hepatitis B and hepatitis C, measure levels of study drug, measure CD4+/CD8+ cell 
counts (cells that fight infection), and measure HIV viral load. In addition, some of your blood will 


 
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be stored for future tests of the immune system and HIV virus. The total amount of blood 
collected at any one visit and across multiple visits is within clinical guidelines. (Sites may insert 
total volumes by study visit using information from the LPC.) (Sites to use this next sentence 
only if applicable: If the hepatitis B or hepatitis C test is positive, the results may be reported to 
the local or state department of health per local standards.) 
 
Urine collected 
To check the health of your kidneys 
 
Pregnancy test 
If you are a woman who is able to become pregnant, you will be asked to give a small urine or 
blood sample for a pregnancy test.  
 
Electrocardiogram (ECG) 
An ECG is a test to measure heart activity. Small adhesive pads connected to wires from 
the ECG machine will be painlessly placed on your chest and arms. You will be asked to 
lie down, remain still, and breathe normally during the test.  
 
Study drug infusion 
A small thin tube called an indwelling catheter will be placed into a vein in your arm. The 
catheter will be connected with a long tube to the bag of study drug solution, and then the study 
drug solution will be infused over 4 hours.   
 
ART adherence assessment 
You will be asked to complete a brief questionnaire about how you are taking your HIV drugs. 


 
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APPENDIX II: A5315 STUDY VISITS – COHORT 4 
 
The study staff can answer any questions you have about individual study visits, the evaluations 
that will occur, or how long each visit will be. The table below can be used as a quick reference 
for you, along with the explanations that follow. 
 
I. Appendix II, Table 1: Study Schedule, Part 1 
 
Evaluation 
Screening 
Visit1 
Pre-Entry/Entry Visits2 
36-60 
days 
before 
entry 
28-35 
days 
before 
entry 
3-14 
days 
before 
entry 
Entry, Pre-
Infusion 
Consent Signed  
X 
 
 
 
HIV Confirmed 
X 
 
 
 
Physical Exam 
X 
X 
X 
X 
Blood Collected  
X 
X 
X 
X 
Urine Collected 
X 
 
 
 
Pregnancy Test  
(females able to 
become pregnant) 
X 
X 
X 
X 
Electrocardiogram 
(ECG) 
 
X 
 
 
ART Adherence 
Assessment 
X 
 
X 
X 
 
1Screening Visit: Between 36 and 60 days before entry and after you have read and signed the 
consent form, you will have several evaluations done to make sure that you meet the 
requirements for joining the study. These evaluations may be scheduled in more than one visit. 
 
2Pre-Entry/Entry Visits: You will come to the clinic for two pre-entry visits. The first pre-entry 
evaluations will be done between 28 and 35 days before the entry visit. The second pre-entry 
evaluations will be done between 3 and 14 days before the entry visit. If you are eligible to join 
the study, you will be admitted to the clinic in the morning. You will have blood collected for 
some study-specific tests either on the day of study entry or up to 7 days before. 
 


 
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Appendix II, Table 2: Study Schedule, Part 2 
 
Evaluation 
Day of 
infusion1 
Days after each 
infusion1 
Weeks after the last 
infusion2 
Extra 
Visits3 
Early 
Disc4 
0 
1 
3 
7 
2 
5 
10 
18 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Collected  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
if required 
 
 
Electrocardiogram 
(ECG) 
X 
if required 
X 
if required 
if required 
Study Drug 
Infusion 
X 
 
 
 
 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
 
 
 
 
X 
X 
 
X 
 
1Days of the infusion and days after each infusion:  
You will have four infusions in this study. For every infusion, there will be a visit on the day of 
the infusion (day 0, in the table above), and then a visit 1 day, 3 days, and 7 days later. Then 
there will be 1 week with no visits before the next infusion or, in the case of the fourth infusion, 
before the next study visit.  
 
 
2Weeks after the last infusion:  
There will be visits 2, 5, 10, and 18 weeks after your last infusion.  
 
3Extra Visits:  
If your viral load (VL) increases or if you are not eligible for the next infusion, you will be asked 
to return to the clinic for more testing. The study staff can tell you how your schedule will be 
adjusted if this happens.  
 
4Early Discontinuation:  
If you want or are asked to stop participating in this study before completing any or all four of the 
infusions, you will be asked to come in for 24-hour post-infusion, 72-hour post-infusion, 7 
day (1 week) post-infusion, and 4-weeks post-infusion premature treatment/study 
discontinuation visits. If you want or are asked to stop participating in this study after 
receiving all of the infusions but before the end of the study, you will be asked to come in for 
one more study visit.  
 


 
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II. Explanation of Evaluations  
 
Consent signed  
After you read the consent and have had a chance to ask questions about the study, you will 
sign the consent form if you want to continue to be evaluated for study participation. You will 
also be asked how to be contacted in case you miss a visit or there are problems with your 
tests, and whether you give the study team permission to contact you. 
 
HIV infection confirmed 
If an HIV test has to be done, you may have to sign a separate consent form before this is done. 
You will be told the results of the HIV test as soon as it is available.   
 
Physical examination 
You will have a physical exam which will include being weighed and asked questions about your 
health and about any medicines you have taken or are taking now. At the screening and entry 
visits, you will also be asked about the medications you have taken and your medical history.  
 
Blood collected 
Blood will be collected from you for various tests during the study. These include routine safety 
lab tests to check your blood cell counts and the health of your liver and kidneys, test for 
hepatitis, measure levels of study drug, measure CD4+/CD8+ cell counts (cells that fight 
infection), and measure HIV viral load. In addition, some of your blood will be stored for future 
tests of the immune system, HIV virus, and drug levels.  
 
The total amount of blood collected at any one visit and across multiple visits is within clinical 
guidelines. (Sites may insert total volumes by study visit using information from the LPC.) (Sites 
to use this next sentence only if applicable: If the hepatitis B or hepatitis C test is positive, the 
results may be reported to the local or state department of health per local standards.) 
 
Urine collected 
You will be asked to provide a small amount of urine during the study visit to check the health of 
your kidneys. 
 
Pregnancy test 
If you are a woman who is able to become pregnant, you will be asked to provide a small 
amount of urine for a pregnancy test.  
 
Electrocardiogram (ECG) 
An ECG is a test to measure heart activity. Small adhesive pads connected to wires from 
the ECG machine will be placed on your chest and arms. You will be asked to lie down, 
remain still, and breathe normally during the test. The study staff will tell you about how 
long each ECG might take. 
 


 
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Study drug infusion 
A small thin tube called an indwelling catheter will be placed into a vein in your arm. The 
catheter will be connected with a long tube to the bag of study drug solution, and then the study 
drug solution will be infused (or delivered directly into your vein) over 4 hours.   
 
ART adherence assessment 
You will be asked to complete a brief questionnaire about how you are taking your anti-HIV 
drugs. 


 
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APPENDIX III: A5315 BENEFITS AND RISKS 
 
A. 
Benefits 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can 
be made. It is also possible that you may receive no benefit from being in this study. 
Information learned from this study may help others who have HIV. 
 
B. 
Risks of Study Drug 
 
Listed below are the most common side effects experienced when taking romidepsin, as 
well as the more serious side effects. The staff will be able to tell you which are the most 
serious side effects. They will also be able to tell you what to do if you have any of these 
side effects.  
 
Romidepsin (Istodax) 
The most common side effects associated with the use of RMD are 
 
Nausea  
 
Fatigue (tiredness)  
 
Vomiting  
 
Anorexia (loss of appetite) 
 
Infection 
 
Other serious side effects that are associated with higher doses of RMD include: 
 
Thrombocytopenia (a drop in platelets that help blood to clot) 
 
Leukopenia (a drop in blood white cells that fight infection)  
 
Anemia (low red blood cell count) 
 
Electrocardiographic (ECG) changes in heart rate and rhythm 
 
Serious infections and fatal infections: 
o These have been reported rarely in clinical trials of RMD in people who 
were not infected with HIV. 
o These infections can occur at the time of treatment and up to 30 days after 
treatment. 
o The infections have included the following: 
 
Pneumonia 
 
Sepsis (a severe illness caused by a bacterial infection of the 
bloodstream) 
 
Reactivation (recurrence) of viruses in people who previously had an 
Epstein Barr virus infection or a hepatitis B infection. 
o Life-threatening infections have also been reported in people who were 
treated with RMD for bone marrow disease. 
 
Some of these side effects are potentially serious. The study staff will discuss them 
with you and will tell you what to do if you have any of them. 
 


 
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C. 
Risks Associated with Procedures 
 
Intravenous infusion and indwelling catheter 
Rarely, sepsis (a severe illness caused by a bacterial infection of the bloodstream), 
blood clots, and localized infection may occur. Common risks that may occur include 
discomfort, bleeding, or bruising at the catheter site. 
 
Blood draw 
Taking blood may cause some discomfort, lightheadedness, bleeding, swelling, or 
bruising where the needle enters the body, and in rare cases, fainting or infection. At 
some visits, the amount of blood collected is very close to the maximum amount under 
these guidelines. You should not plan to have blood collected for other testing while you 
are on this study without first discussing the collection with the study staff. If you must 
have blood collected between study visits, you should tell the study staff.  
 
Electrocardiogram (ECG) 
You may have local skin irritation and redness where the adhesive patches are placed 
on your skin.  


 
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APPENDIX IV: SAMPLE INFORMED CONSENT, COHORTS 1 & 2 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For Cohorts 1 and 2 in protocol A5315 Final Version 4.0, dated 06/07/18 
 
A Phase I/II Study of Romidepsin in HIV-Infected Adults  
with Suppressed Viremia on Antiretroviral Therapy to Assess  
Safety, Tolerability, and Activation of HIV-1 Expression 
 
NOTE: Cohorts 1 and 2 are closed. No further enrollment will be possible into either  
of these cohorts.  
 
Cohort 3 and Cohort 4 have separate sample informed consent forms 
 (APPENDICES V and VI, respectively) 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with human 
immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome 
(AIDS) and: 
1) You have been taking a combination of antiretroviral drugs that does not include a 
protease inhibitor for at least the past 3 months; and   
2) Your HIV-1 RNA level (viral load, the amount of HIV in your blood) has been less than 
50 copies/mL plasma, or below the limit of detection, for the past 24 months.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
HIV medications can reduce HIV virus to very low levels in the blood and partially repair the 
immune system. However, these medications do not cure (remove) the HIV infection and a 
small amount of the virus continues to live in the body even when the viral load is measured 
below the limit of detection. This explains why the virus levels rebound or come back when 
these medications are stopped. The source of this rebounding HIV is likely coming from cells 
that live for a long time after becoming infected with HIV. These cells are thought to carry the 
HIV virus in a latent or hidden form (like they are “asleep”).  As long as the virus exists in this 
sleeping state, HIV medications, that block only multiplying (awake) virus, cannot eliminate the 
HIV, and infected persons cannot be cured.  
 
Romidepsin [RMD] (Istodax) is a drug approved by the Food and Drug Administration (FDA) for 
the treatment of cutaneous T-cell lymphoma, a serious type of skin cancer. In laboratory studies 
with HIV-infected cells, RMD can awaken HIV from its sleeping state and this is thought to be an 


 
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important step in getting rid of the virus that remains in your body. But RMD’s ability to do this in 
people with HIV has not been studied.  
 
This study is being done to see if RMD is safe in HIV-infected persons and whether it can 
awaken the latent (sleeping) HIV. Once the virus is awakened it should reproduce, and the new 
HIV that is produced will hopefully kill the cell that is hiding it. If any of the awakened virus 
escapes the cell, no other cells should become infected because you will be continuing to take  
your HIV medications.  The overall goal of this exploratory study is to identify single doses of 
RMD that are safe and well-tolerated in HIV-infected persons on antiretroviral therapy (ART), 
and that can awaken the latent or sleeping HIV allowing it to be targeted by your HIV 
medications.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Study Visits 
If you join this study, you will be seen in the clinic approximately 8 times; most people will 
complete the study in 1 month; some people may need to come back for a visit 2 months after 
starting the study. The study staff will tell you about how long each visit could be. You may need 
to come to the clinic for additional visits if you develop side effects. The study drug, all tests, and 
strategies are for research purposes; antiretroviral medications are part of routine clinical care 
and not covered by the study. Details of the study visits and procedures are in Attachment A.  
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this 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 is being collected from you so that ACTG 
researchers may help determine whether there are patterns or common reasons why people do 
not join a study. 
 
Study medication 
If you qualify to be in this study, you will be randomized (by chance, like the flip of a coin) to 
receive either the study medication, RMD or the placebo (a salt solution that does not contain 
RMD).  
 
At study entry, RMD or placebo will be given as a single intravenous (IV) infusion over 4 hours 
through a small plastic flexible tube placed into a vein in your arm.  
 
Depending on when you enter this study, you will be placed in one of three groups. Each group 
will have a total of 15 participants: 12 will receive RMD and 3 will receive the placebo salt 
solution that does not contain RMD. You cannot choose which group you are in.  
 
 
The first 15 study participants will be in Group 1. They will receive 0.5 mg/m2 of RMD or 
placebo. By chance, 12 participants will receive RMD and 3 will receive placebo. If this 
amount of RMD solution is found to be safe, then the next 15 participants will enter into 
Group 2. 


 
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 
The 15 participants in Group 2 will receive 2 mg/m2 of RMD or placebo. By chance, 12 
participants will receive RMD and 3 will receive placebo. If this amount of RMD solution is 
found to be safe, then the next 15 participants will enter into Group 3. 
 
The 15 participants in Group 3 will receive 5 mg/m2 of RMD or placebo. By chance, 12 
participants will receive RMD and 3 will receive placebo. 
 
Neither you nor the study staff will know whether you will receive RMD or the placebo. You will 
be notified if you received RMD or placebo once the entire study is completed and all of the 
information from the study has been reviewed. 
 
Blood will be drawn before the infusion, during the infusion, and 4, 6, 12, 24, and 48 hours 
afterward and on Days 7, 14, and 28 in order to measure the amount of study drug in your blood 
and/or to measure your viral load using a new investigational test called a single copy assay, or 
SCA, that can measure viral load down to 1 copy/mL. The SCA is not approved by the FDA for 
routine medical care, and you will not be given the results of this test. You will be given the 
results of other study tests as soon as they are available, including all standard viral loads, 
safety blood tests, and pregnancy tests. If required, blood will also be drawn on Day 56 to 
measure your viral load. 
 
Even the highest dose of RMD used in this study is only 35% of the dose used for cancer 
treatment.  Also, only one infusion will be given in this study instead of three infusions over a 28 
day period usually given for cancer treatment. Furthermore, participants will first receive the 
lowest doses being tested and only when safety is assured will the next higher dose be given. 
RMD has not been shown to cause mutations or changes in the genetic material in cells like 
some other cancer drugs.   
 
RMD does not persist for a long time in the body; it has a half-life of about 3 hours (half of the 
drug remaining in the blood is removed or broken down over this time period). 
 
If the RMD does awaken the inactive HIV, it may become detectable in the blood. Since the 
effect of one dose of RMD is short-lived and because you will continue to receive your HIV 
therapies, this viral load increase is expected to last a brief time if it should occur. Nevertheless, 
your viral load will be monitored repeatedly, and if it does not become undetectable quickly you 
could possibly require an addition of another anti-HIV medication. The chance of this being 
necessary is thought to be highly unlikely.  
 
What if I have to permanently stop the study-provided infusion before completion? 
During the study: 
 
If you must permanently stop the study-provided infusion before completion, the study doctor 
may ask you to return for a study visit and some procedures, and the study staff will discuss 
other options that may be available to you. 
 
After the study: 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with RMD you received on the study. 


 
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Use of Your Samples for this Study 
Some of your blood samples will be stored and used for testing that is required for this study. No 
one will know just from looking at the labels of your stored samples that they came from you. 
 
Use of Your Stored Samples 
If you agree, some of your blood samples that are left over after all required study testing is 
done may be stored for future research that is not yet planned, including future ACTG-approved 
HIV-related research. No one will know just from looking at the labels of your stored samples 
that they came from you.  Although researchers will not be given your name or any other 
personally identifying information about you, some information about your medical condition, 
your race, ethnicity, gender, and age may be shared.  
 
These samples will be kept frozen for an indefinite length of time. We cannot ensure that you 
will be told of the results of the research done on these samples.  
Allowing your samples to be stored for this use is optional.  Please indicate below if you agree 
to this storage for later use. No matter what you decide, it will not affect your participation in the 
study.  
 
 
________ (initials) YES, I agree               ________ (initials) NO, I do not agree 
 
If you decide now that your samples can be stored for research to be done at a later date, you 
may change your mind at any time. If you change your mind, you must contact your study 
doctor or nurse and let them know that you do not want your samples used for research to be 
done at a later date. Every effort will then be made to destroy your left-over samples. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 45 men and women 18 years of age and older will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 4 to 8 weeks. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
you are not able to attend the study visits as required by the study 
 
you become pregnant or are breast-feeding 


 
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 
the study is stopped or cancelled  
 
A study monitoring committee (SMC) of the ACTG, or the IRB/EC, FDA, NIAID, the Office 
for Human Research Protections (OHRP), or another government agency with the duty to 
ensure that research participants are protected, or Gilead Sciences (the industry supporter), 
recommends that the study be stopped early. A SMC is an outside group of experts who 
monitor the study. An IRB is a committee that watches over the safety and rights of research 
participants. 
 
The study doctor may also need to take you off the study drug without your permission if: 
 
 
continuing the study drug infusion may be harmful to you 
 
you need a treatment that you may not take while on the study 
 
you are not able to receive the study drug infusion as required by the study 
 
If you must stop participating in this study before completing the study drug infusion or after 
receiving the study drug before the study is over, the study doctor may ask you to return for a 
study visit and some procedures. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study may have side effects, some of which are listed in Attachment B. 
These lists include only the more serious or common side effects with a known or possible 
relationship. If you have questions concerning the additional study drug side effects please ask 
the medical staff at your site. Safety data from the lower dose level will be carefully reviewed 
before higher doses are administered. If needed, side effects will be treated with use of anti-
nausea medication and electrolyte supplements. An ECG (electrocardiogram) will be performed 
before and following RMD administration. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drug in this study may be unsafe for unborn babies. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant or make a woman pregnant while 
participating in this study. Because of the risk involved, we will ask for written or oral 
documentation if you report you are not able to become pregnant. If you can possibly get 
pregnant, you must use two non-estrogen methods of birth control that you discuss with the 
study staff for 180 days (6 months) after receiving the RMD infusion. You may choose two of the 
birth control methods listed below although not all contraceptives recommended can prevent 
HIV transmission. 


 
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• Non-estrogen containing formulations of hormonal birth control drugs that prevent pregnancy 
given by pills, shots, or placed under the skin, for at least 90 days prior to study entry 
• Condoms (male or female) with or without a spermicide (cream or gel that kills sperm) 
• Diaphragm or cervical cap with spermicide 
• Plan B or emergency contraceptive may be used in case of contraceptive failure 
• Intrauterine device (IUD) 
• Tubal ligation 
 
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. Pregnancy tests will also be performed at most study 
visits. If you think you may be pregnant at any time during the study or up to 180 days of 
receiving the study medication, tell your study staff right away. The study staff will talk to you 
about your choices. You will be followed on study until study completion. You will be asked to 
return to the clinic 6 months after the end of your or your partner’s pregnancy to follow up on 
any side effects. Pregnancies will be reported to the Antiretroviral Pregnancy Registry. 
 
Based on long-term studies in animals (rats), male and female fertility may be compromised by 
treatment with RMD.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
This is the first use of RMD in humans to awaken latent HIV in an attempt to decrease the HIV 
reservoir, and no guarantee of any benefit can be made. It is possible that you may receive no 
benefit from being in this study. Information learned from this study may help others who have 
HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
continuing the antiretrovirals you are currently prescribed by your HIV provider or changing 
to other FDA- approved antiretroviral drugs  
 
talking with your doctor about other studies for which you may be eligible 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
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 


 
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personally. A description of this clinical trial will be available on ClinicalTrials.gov, as required by 
U.S. law. This website will not include information that can identify you. At most, the web site will 
include a summary of the results. You can search this website at any time. 
 
People who may review your records include the ACTG, OHRP, FDA, (insert name of site) 
IRB/EC, National Institutes of Health (NIH), your country’s national health agency, or other 
local, US, and international regulatory entities with the duty to ensure that research 
participants are protected, study staff, study monitors, Gilead Sciences, 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. 
 
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. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drug, RMD or placebo, study-related visits, physical 
examinations, required laboratory tests or other procedures. This study will not provide you with 
antiretroviral drugs. You, your insurance company, or your health care system may need to 
assume the cost of drugs not provided by the study. In some cases, it is possible that your 
insurance company or health care system will not pay for these costs because you are taking 
part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Insert site-specific information on compensation to study participants.] 
 
 
WHAT IF I AM INJURED? 
 
If you are injured as a result of your being in this study, you will be given immediate treatment 
for injuries and be referred for further treatment, if necessary. However, you may/may not (per 
site/country policy) have to pay for this care. There is no program for compensation either 
through (this institution) or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT HAPPENS IF I BECOME PREGNANT, MY BABY IS INJURED? 
 
If you or your baby is injured as a result of your being in this study, you or your baby will be 
given immediate treatment for injuries and be referred for further treatment, if necessary. 
However, you may/may not (per site/country policy) have to pay for this care. There is no 
program for compensation either through (this institution) or the NIH.  You will not be giving up 
any of your legal rights by signing this consent form. 
 


 
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WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part.  Your decision will not have any impact on your participation in other 
studies conducted by NIH and will not result in any penalty or loss of benefits to which you are 
otherwise entitled.  
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
name of the investigator or other study staff 
 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
 
telephone number of above 
 


 
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SIGNATURE PAGE ACTG Study A5315, Cohorts 1 or 2 only  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 


 
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APPENDIX V: SAMPLE INFORMED CONSENT, COHORT 3 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
 
For Cohort 3 in protocol A5315 Final Version 4.0, dated 06/07/18 
 
A Phase I/II Study of Romidepsin in HIV-Infected Adults  
with Suppressed Viremia on Antiretroviral Therapy to Assess  
Safety, Tolerability, and Activation of HIV-1 Expression 
 
NOTE:  A separate consent form, APPENDIX IV, was used for Cohorts 1 and 2. The consent 
form for Cohort 4 is APPENDIX VI.  
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with human 
immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome 
(AIDS) and: 
 
1) You have been taking a combination of antiretroviral drugs that does not include a 
protease inhibitor for at least the past 3 months; and   
2) Your HIV-1 RNA level (viral load, the amount of HIV in your blood) has been less than 
50 copies/mL plasma, or below the limit of detection, for the past 24 months.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
HIV medications can reduce HIV virus to very low levels in the blood and partially repair the 
immune system. However, these medications do not cure (remove) the HIV infection and a 
small amount of the virus continues to live in the body even when the viral load is measured 
below the limit of detection. This explains why the virus levels rebound or come back when 
these medications are stopped. The source of this rebounding HIV is likely coming from cells 
that live for a long time after becoming infected with HIV. These cells are thought to carry the 
HIV virus in a latent or hidden form (like they are “asleep”).  As long as the virus exists in this 
sleeping state, HIV medications, which block only multiplying (awake) virus, cannot eliminate 
the HIV, and infected persons cannot be cured.  
 
Romidepsin [RMD] (Istodax) is a drug approved by the Food and Drug Administration (FDA) for 
the treatment of cutaneous T-cell lymphoma, a serious type of skin cancer. In laboratory studies 
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important step in getting rid of the virus that remains in your body. But RMD’s ability to do this in 
people with HIV has not been studied.  
 
This study is being done to see if RMD is safe in HIV-infected persons and whether it can 
awaken the latent (sleeping) HIV. Once the virus is awakened it should reproduce, and the new 
HIV that is produced will hopefully kill the cell that is hiding it. If any of the awakened virus 
escapes the cell, no other cells should become infected because you will be continuing to take  
your HIV medications.  The overall goal of this exploratory study is to identify single doses of 
RMD that are safe and well-tolerated in HIV-infected persons on antiretroviral therapy (ART), 
and that can awaken the latent or sleeping HIV allowing it to be targeted by your HIV 
medications.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Study Visits 
If you join this study, you will be seen in the clinic approximately 8 times; most people will 
complete the study in 1 month; some people may need to come back for a visit 2 months after 
starting the study. The study staff will tell you about how long each visit could be. You may need 
to come to the clinic for additional visits if you develop side effects. The study drug, all tests, and 
strategies are for research purposes; antiretroviral medications are part of routine clinical care 
and not covered by the study. Details of the study visits and procedures may be provided in a 
separate document.  
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this 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 is being collected from you so that ACTG 
researchers may help determine whether there are patterns or common reasons why people do 
not join a study. 
 
Study medication 
If you qualify to be in this study, you will be randomized (by chance, like the flip of a coin) to 
receive either the study medication, RMD or the placebo (a salt solution that does not contain 
RMD).  
 
At study entry, RMD or placebo will be given as a single intravenous (IV) infusion (putting the 
drug slowly into your blood) over 4 hours through a small plastic flexible tube placed into a vein 
in your arm.  
 
Depending on when you enter this study, you will be placed in one of three groups. Each group 
will have a total of 15 participants: 12 will receive RMD and 3 will receive the placebo salt 
solution that does not contain RMD. You cannot choose which group you are in.  
 
 
The first 15 study participants will be in Group 1. They will receive 0.5 mg/m2 of RMD or 
placebo. By chance, 12 participants will receive RMD and 3 will receive placebo. If this 


 
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amount of RMD solution is found to be safe, then the next 15 participants will enter into 
Group 2. 
 
The 15 participants in Group 2 will receive 2 mg/m2 of RMD or placebo. By chance, 12 
participants will receive RMD and 3 will receive placebo. If this amount of RMD solution is 
found to be safe, then the next 15 participants will enter into Group 3. 
 
The 15 participants in Group 3 will receive 5 mg/m2 of RMD or placebo. By chance, 12 
participants will receive RMD and 3 will receive placebo. 
 
Neither you nor the study staff will know whether you will receive RMD or the placebo. You will 
be notified if you received RMD or placebo once the entire study is completed and all of the 
information from the study has been reviewed. 
 
Blood will be drawn before the infusion, during the infusion, and 4, 6, 12, 24, and 48 hours 
afterward and on days 7, 14, and 28 in order to measure the amount of study drug in your blood 
and/or to measure your viral load using a new investigational test called a single copy assay, or 
SCA, that can measure viral load down to 1 copy/mL. The SCA is not approved by the FDA for 
routine medical care, and you will not be given the results of this test. You will be given the 
results of other study tests as soon as they are available, including all standard viral loads, 
safety blood tests, and pregnancy tests. If required, blood will also be drawn on day 56 to 
measure your viral load. 
 
Even the highest dose of RMD used in this study is only 35% of the dose used for cancer 
treatment.  Also, only one infusion will be given in this study instead of three infusions over a 28 
day period usually given for cancer treatment. Furthermore, participants will first receive the 
lowest doses being tested and only when safety is assured will the next higher dose be given. 
RMD has not been shown to cause mutations or changes in the genetic material in cells like 
some other cancer drugs.   
 
RMD does not persist for a long time in the body; it has a half-life of about 3 hours (half of the 
drug remaining in the blood is removed or broken down over this time period). 
 
If the RMD does awaken the inactive HIV, it may become detectable in the blood. Since the 
effect of one dose of RMD is short-lived and because you will continue to receive your HIV 
therapies, this viral load increase is expected to last a brief time if it should occur. Nevertheless, 
your viral load will be monitored repeatedly, and if it does not become undetectable quickly you 
could possibly require an addition of another anti-HIV medication. The chance of this being 
necessary is thought to be highly unlikely.  
 
What if I have to permanently stop the study-provided infusion before completion? 
During the study: 
 
If you must permanently stop the study-provided infusion before completion, the study doctor 
may ask you to return for a study visit and some procedures, and the study staff will discuss 
other options that may be available to you. 
 


 
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After the study: 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with RMD you received on the study. 
 
Use of your samples for this study 
Some of your blood samples will be stored and used for testing that is required for this study. No 
one will know just from looking at the labels of your stored samples that they came from you. 
 
Use of your stored samples 
If you agree, some of your blood samples that are left over after all required study testing is 
done may be stored for future research that is not yet planned, including future ACTG-approved 
HIV-related research. No one will know just from looking at the labels of your stored samples 
that they came from you.  Although researchers will not be given your name or any other 
personally identifying information about you, some information about your medical condition, 
your race, ethnicity, gender, and age may be shared.  
 
These samples will be kept frozen for an indefinite length of time. We cannot ensure that you 
will be told of the results of the research done on these samples.  
Allowing your samples to be stored for this use is optional.  Please indicate below if you agree 
to this storage for later use. No matter what you decide, it will not affect your participation in the 
study.  
 
 
________ (initials) YES, I agree               ________ (initials) NO, I do not agree 
 
If you decide now that your samples can be stored for research to be done at a later date, you 
may change your mind at any time. If you change your mind, you must contact your study 
doctor or nurse and let them know that you do not want your samples used for research to be 
done at a later date. Every effort will then be made to destroy your left-over samples. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 60 men and women 18 years of age and older will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 4 to 8 weeks. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
 
You are not able to attend the study visits as required by the study 


 
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 
You become pregnant or are breast-feeding. 
 
The study is stopped or cancelled.  
 
A study monitoring committee (SMC) of the ACTG, or the IRB/EC, FDA, NIAID, the Office 
for Human Research Protections (OHRP), or another government agency with the duty to 
ensure that research participants are protected, or Gilead Sciences (the industry supporter), 
recommends that the study be stopped early. A SMC is an outside group of experts who 
monitor the study. An IRB is a committee that watches over the safety and rights of research 
participants. 
 
The study doctor may also need to take you off the study drug without your permission if: 
 
 
Continuing the study drug infusion may be harmful to you. 
 
You need a treatment that you may not take while on the study. 
 
You are not able to receive the study drug infusion as required by the study. 
 
If you must stop participating in this study before completing the study drug infusion or after 
receiving the study drug before the study is over, the study doctor may ask you to return for a 
study visit and some procedures. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study may have side effects, some of which are listed in a separate 
document. These lists include only the more serious or common side effects with a known or 
possible relationship. If you have questions concerning the additional study drug side effects 
please ask the medical staff at your site. Safety data from the lower dose level will be carefully 
reviewed before higher doses are administered. If needed, side effects will be treated with use 
of anti-nausea medication and electrolyte supplements. An ECG (electrocardiogram) will be 
performed before and following RMD administration. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
The drug in this study may be unsafe for unborn babies. If you are having sex that could lead to 
pregnancy, you must agree not to become pregnant or make a woman pregnant while 
participating in this study. Because of the risk involved, we will ask for written or oral 
documentation if you report you are not able to become pregnant. If you can possibly get 
pregnant, you must use two non-estrogen methods of birth control that you discuss with the 
study staff for 180 days (6 months) after receiving the RMD infusion. You may choose two of the 
birth control methods listed below although not all contraceptives recommended can prevent 


 
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HIV transmission. 
 
Non-estrogen containing formulations of hormonal birth control drugs that prevent 
pregnancy given by pills, shots, or placed under the skin, for at least 90 days prior to 
study entry 
 
Condoms (male or female) with or without a spermicide (cream or gel that kills sperm) 
 
Diaphragm or cervical cap with spermicide 
 
Plan B or emergency contraceptive may be used in case of contraceptive failure 
 
Intrauterine device (IUD) 
 
Tubal ligation 
 
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. Pregnancy tests will also be performed at most study 
visits. If you think you may be pregnant at any time during the study or up to 180 days of 
receiving the study medication, tell your study staff right away. The study staff will talk to you 
about your choices. You will be followed on study until study completion. Pregnancies will be 
reported to The Antiretroviral Pregnancy Registry. 
 
Based on long-term studies in animals (rats), male and female fertility may be compromised by 
treatment with RMD.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
This is the first use of RMD in humans to awaken latent HIV; there should be no expectation of 
any benefit. Information learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
 
Not being in a study. 
 
Talking with your doctor about other studies for which you may be eligible. 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
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. A description of this clinical trial will be available on ClinicalTrials.gov, as required by 


 
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U.S. law. This website will not include information that can identify you. At most, the web site will 
include a summary of the results. You can search this website at any time. 
 
People who may review your records include the ACTG, OHRP, FDA, (insert name of site) 
institutional review board (IRB)/ethics committee (EC), National Institutes of Health (NIH), or 
other local, US, and international regulatory entities with the duty to ensure that research 
participants are protected, study staff, study monitors, the pharmaceutical companies supporting 
this study, and their designees. Having a Certificate of Confidentiality does not prevent you from 
releasing information about you and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to you or others, we will be required to tell the proper authorities. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drug, RMD or placebo, study-related visits, physical 
examinations, required laboratory tests or other procedures. This study will not provide you with 
anti-HIV medications. You, your insurance company, or your health care system may need to 
assume the cost of drugs not provided by the study. In some cases, it is possible that your 
insurance company or health care system will not pay for these costs because you are taking 
part in a research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
(Insert site-specific information on compensation to study participants.) 
 
 
WHAT IF I AM INJURED? 
 
If you are injured as a result of your being in this study, you will be given immediate treatment 
for injuries and be referred for further treatment, if necessary. However, you may/may not (per 
site/country policy) have to pay for this care. There is no program for compensation either 
through (this institution) or the NIH. You will not be giving up any of your legal rights by signing 
this consent form. 
 
 
WHAT HAPPENS IF I BECOME PREGNANT, MY BABY IS INJURED? 
 
If you or your baby is injured as a result of your being in this study, you or your baby will be 
given immediate treatment for injuries and be referred for further treatment, if necessary. 
However, you may/may not (per site/country policy) have to pay for this care. There is no 
program for compensation either through (this institution) or the NIH. You will not be giving up 
any of your legal rights by signing this consent form. 
 
 


 
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WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part.  Your decision will not have any impact on your participation in other 
studies conducted by NIH and will not result in any penalty or loss of benefits to which you are 
otherwise entitled.  
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, tell the study 
staff. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
Name of the investigator or other study staff 
 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
 
Name or title of person on the IRB/EC or other organization appropriate for the site 
 
Telephone number of above 
 


 
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SIGNATURE PAGE for Cohort 3, ACTG Study A5315  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Representative (print) 
Legal Representative’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 


 
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APPENDIX VI: SAMPLE INFORMED CONSENT, COHORT 4 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT 
 
For Cohort 4 of protocol A5315 Final Version 4.0, dated 06/07/18 
 
A Phase I/II Study of Romidepsin in HIV-Infected Adults with Suppressed Viremia on 
Antiretroviral Therapy to Assess Safety, Tolerability, and Activation of HIV-1 Expression 
 
Short title: Romidepsin to Awaken HIV 
 
INTRODUCTION 
 
This study involves research. Research is not the same as medical care. Research answers 
scientific questions. These answers can help find new medicines, treatments, vaccines, and 
even knowledge on how the human body works. Only people who want to participate will be part 
of this study. You can discuss the study with others before deciding to join. No matter what your 
decision is, any other care that you get at this clinic will not change. 
 
You are being asked to take part in this research study because: 
 
1) you are infected with human immunodeficiency virus (HIV), the virus that causes 
acquired immune deficiency syndrome (AIDS),  
2) you have been taking a combination of anti-HIV drugs that does not include a protease 
inhibitor for at least the past 3 months, and   
3) your HIV-1 RNA level (viral load, the amount of HIV in your blood) has been less than 50 
copies/mL, or below the limit of detection, for the past 24 months.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of site Principal Investigator). Before you decide if you want to 
be a part of this study, we want you to know about the study. This is a consent form; it provides 
you with information about the study. This consent form is for the second part of this two-part 
study.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
Anti-HIV drugs can reduce HIV virus to very low levels in the blood of an HIV-infected person. 
But these drugs do not cure (or completely remove) the HIV infection. A small amount of HIV 
can still be in a person’s body even though it cannot be measured in their blood. Some cells that 
are infected with HIV can live for a long time, and they are able to keep the virus latent (as if it 
were asleep). As long as the virus is in this sleeping state, anti-HIV drugs, which attack only 
active (awake) virus, cannot completely remove HIV.  
 


 
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In laboratory studies with HIV-infected cells, romidepsin [RMD] (Istodax) can “awaken” latent 
HIV. This is thought to be an important step in completely removing HIV from an infected 
person’s body. RMD is a drug approved by the Food and Drug Administration (FDA) for the 
treatment of cutaneous T-cell lymphoma, a serious type of skin cancer. RMD’s ability to awaken 
HIV has only been studied in a very small number of people, and the results of these studies are 
not available. 
  
This study is being done to see if there is a safe and well-tolerated dose of RMD that can 
awaken latent HIV in HIV-infected persons who are taking anti-HIV drugs.  
 
Once the virus is awakened, it should reproduce, and the new HIV that is produced should kill 
the cell that is hiding it. If any of the awakened virus escapes the cell, the anti-HIV drugs that a 
person is taking should kill it. 
 
 
WHY IS THIS PART OF THIS STUDY BEING DONE? 
 
In the first part of this study, we tested three doses of RMD in each of three groups of 12-15 
people. These people received a one-time infusion of one of three doses of RMD or a placebo 
(a solution that does not contain any medicine). An infusion is a way of slowly delivering liquid 
(in this case, RMD or placebo) into a person’s bloodstream through a thin tube that is placed 
into a vein in the arm. In this study, the infusion takes about 4 hours.   
 
The doses that have been tested so far appear safe. This second part is being added to this 
study to see if multiple doses of RMD are safe and to test whether multiple doses are able to 
awaken latent HIV better than a single dose. If this is the case, then the study might be able to 
see if awakening these cells can lower the number of them in your body.   
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Study Visits 
If you join this study, you will be seen in the clinic at least 3 times before the study starts; these 
visits will be for screening and pre-entry tests to see if it is safe and appropriate for you to be in 
this study. Once you enter the study, you will be seen in the clinic approximately 16-20 times 
over 24 weeks (or about 6 months.)  
 
The study staff will tell you about how long each study visit could be. You may need to come to 
the clinic for additional visits if you develop side effects. Details of the study visits and 
procedures are in a separate document (Appendix II). If you have to come for extra visits, then 
you could be in the study for up to 48 weeks (or almost 1 year) 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, we 
will still use some of your information. As part of this screening visit, some demographic (for 
example, age, sex, race), clinical (for example, disease condition, diagnosis), and laboratory (for 
example, CD4 cell count, viral load) information is being collected from you so that ACTG 


 
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researchers can help determine whether there are patterns or common reasons why people do 
not join a study. 
 
Study treatment 
If you meet all the requirements to be in this study, you will be randomized (assigned by chance, 
as if by the flip of a coin) to receive either the study medication, RMD, or the placebo.  
 
Fifteen people will enter this part of the study: 12 will receive RMD and 3 will receive the 
placebo. You cannot choose which product you receive and neither you nor the clinic staff will 
know which product you are receiving. You will be told whether you received RMD or placebo 
once the entire study is completed and all of the information from the study has been reviewed. 
 
At study entry, and again every 2 weeks for a total of four times, RMD or placebo will be given 
as an infusion over about 4 hours through a small plastic flexible tube placed into a vein in your 
arm. An ECG (electrocardiogram) will be performed immediately following each infusion. 
 
You must continue to take your anti-HIV drugs throughout the study.  
 
Study tests 
Blood will be collected from you before each infusion, and then 1 day and 3 days and then 1 
week after each infusion. This blood will be used for safety tests, viral load, drug levels, and 
study-specific testing. You will be given the results of some tests, including all standard viral 
loads, safety blood tests, and pregnancy tests, as soon as they are available. Blood will also be 
collected from you 2, 5, 10, and 18 weeks after the last infusion. 
 
If the RMD does awaken latent HIV, then HIV may become detectable in your blood (your viral 
load will become measurable). Because you will continue taking your anti-HIV drugs while on 
this study, this increase in your viral load is only expected to last a brief time. Your viral load will 
be monitored frequently; if it does not become undetectable within a few weeks you might need 
another anti-HIV drug. The chance of this being necessary is thought to be very small.  
 
What if I have to permanently stop the infusion before completion? 
During the study: 
 
If you are unable to complete all four infusions, you will be asked to complete the follow-
up visits for any infusion that was interrupted and to return for premature 
treatment/discontinuation evaluations 4 weeks after the infusion.  
 
After the study: 
 
After you have completed your study participation, the study will not provide you with RMD or 
placebo. 
 
Use of your blood for this study 
Some of your blood will be stored and used for testing that is required for this study. No one will 
know just from looking at the labels of your stored blood that it came from you. 
 


 
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Use of your stored blood 
If you agree, some of your blood that is left over after all required study testing is done may be 
stored for future research that is not yet planned, including future ACTG-approved HIV-related 
research. No one will know just from looking at the labels of your stored blood that it came from 
you.  Although researchers will not be given your name or any other personally identifying 
information about you, some information about your medical condition, your race, ethnicity, sex, 
and age may be shared.  
 
Stored blood will be kept frozen for an indefinite length of time. We cannot ensure that you will 
be told of the results of the research that is done on this blood.  
 
Allowing your blood to be stored for this use is optional. Please indicate below if you agree to 
this storage for later use. No matter what you decide, it will not affect your participation in the 
study.  
 
 
________ (initials) YES, I agree               ________ (initials) NO, I do not agree 
 
If you decide now that your blood can be stored for research to be done at a later date, you may 
change your mind at any time. If you change your mind, you must contact your study doctor or 
nurse and let them know that you do not want your blood used for research to be done at a later 
date. Every effort will then be made to destroy your left-over blood. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 60 men and women 18 years of age and older will take part in this study: about 45 in the 
first part and 15 in the part of the study that you are now reading about. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 24 weeks (almost 6 months). If one of your infusions has to be 
delayed for any reason, you could be on the study for an extra 6 weeks. If more than one of 
your infusions has to be delayed for any reason, then you could be on the study for an extra 6 
weeks each time. The maximum length of time that you could be on the study would be 48 
weeks (about 11 months). 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
 
You are not able to attend the study visits as required by the study. 
 
The staff is not able to start one of your infusions because there is trouble finding a vein in 
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 
You are not able to complete one of the infusions. 
 
You are not able to have blood collected 24 hours after one of the infusions. 
 
You are not able to complete the study visit that is about 5 weeks after the 4th infusion. 
 
You become pregnant or are breast-feeding. 
 
The study is stopped or cancelled.  
 
A study monitoring committee (SMC) of the ACTG, or your site’s institutional review board 
(IRB)/ethics committee (EC), FDA, NIAID, the Office for Human Research Protections 
(OHRP), or another government agency with the duty to ensure that research participants 
are protected, or an industry supporter recommends that the study be stopped early. A SMC 
is an outside group of experts who monitor the study. An IRB or EC is a committee that 
watches over the safety and rights of research participants. 
 
The study doctor may also need to take you off the study treatment without your permission if: 
 
 
Continuing the treatment may be harmful to you. 
 
You need a treatment that you may not take while on the study. 
 
You are not able to receive the infusion as required by the study. 
 
If you must stop participating in this study before completing the infusion or before the study is 
over, the study doctor may ask you to return for a study visit and some procedures. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study may have side effects, some of which are listed below (and in a 
separate document - Appendix III). These lists include only the more serious or common side 
effects with a known or possible relationship. If you have questions concerning the additional 
study drug side effects please ask the medical staff at your site.  
 
Safety data from the lower dose levels and from a single infusion of the dose level to be used in 
this part of the study have been carefully reviewed. If needed, side effects will be treated with 
use of anti-nausea medication and electrolyte supplements.  
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
 
IS THERE OTHER INFORMATION I SHOULD KNOW ABOUT? 
 
In earlier groups or cohorts of this study, three different single dose levels of RMD were studied 
to see if they were safe and well-tolerated in HIV-infected persons receiving HIV treatment.  
Based on information from these cohorts, a safe and well-tolerated dose was chosen to be used 
in this cohort.  


 
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It may be that a single dose of RMD cannot activate or ‘wake up’ all the HIV in the HIV reservoir. 
In this part of the study, we will test how much HIV is activated after each infusion and after all 
infusions have been completed. This study will provide important information regarding the role 
that drugs like RMD may have in awakening HIV.   
 
 
The dose of RMD being used in this part of the study is about one-third of the dose used for 
cancer treatment. The dosing schedule in this study (one infusion every 2 weeks over a 6-week 
period) is different from what is followed for cancer treatment: one infusion a week for 3 weeks, 
followed by a 1-week pause and then a repeat of one infusion per week for 3 weeks.  
 
RMD will not stay in your blood system for a long time; it has a half-life of about 3 hours (this 
means that half of the drug that entered your blood will have been broken down or otherwise 
removed within 3 hours; every 3 hours, another half of what is remaining is removed until none 
is left). 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
RMD may be unsafe for unborn babies. If you are having sex that could lead to pregnancy, you 
must agree not to become pregnant or make a woman pregnant while participating in this study.  
 
Because of the risk involved, we will ask for written or oral documentation if you report you are 
not able to become pregnant.  
 
If you can possibly get pregnant, you must use two non-estrogen methods of birth control that 
you discuss with the study staff for 180 days (6 months) after your last RMD infusion. You may 
choose two of the birth control methods listed below. 
 
• Non-estrogen containing formulations of hormonal birth control drugs that prevent pregnancy 
given by pills, shots, or placed under the skin, for at least 90 days prior to study entry 
• Condoms (male or female) with or without a spermicide (cream or gel that kills sperm) 
• Diaphragm or cervical cap with spermicide 
• Plan B or emergency contraceptive may be used in case of contraceptive failure 
• Intrauterine device (IUD) 
• Tubal ligation 
 
Note that some but not all of these contraceptive methods can also prevent HIV transmission. 
 
If you can become pregnant, you must have a pregnancy test before you enter this study. The 
test must show that you are not pregnant. Pregnancy tests will also be performed at most study 
visits. If you think you may be pregnant at any time during the study or up to 180 days (about 6 
months) after the last time that you received the study medication, tell your study staff right 
away. The study staff will talk to you about your choices. You will be followed on study until 
study completion. Pregnancies will be reported to The Antiretroviral Pregnancy Registry. 
 


 
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Based on long-term studies in animals (rats), male and female fertility may be compromised by 
treatment with RMD.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
There is no expectation of any benefit to you. Information learned from this study may help 
others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
 
Not entering a study 
 
Talking with your doctor about other studies for which you may be eligible 
 
Your doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
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 a Certificate of Confidentiality from the 
US Federal Government. This certificate means that researchers cannot be forced to tell people 
who are not connected with this study, such as the court system, about your participation. Also, 
any publication of this study will not use your name or identify you personally. A description of 
this clinical trial will be available on ClinicalTrials.gov, as required by US law. This website will 
not include information that can identify you. At most, the web site will include a summary of the 
results. You can search this website at any time. 
 
People who may review your records include employees of the ACTG, OHRP, FDA, (insert 
name of site) IRB/EC, National Institutes of Health (NIH), or other local, US, and international 
regulatory entities with the duty with the duty to ensure that research participants are 
protected, as well as study staff, study monitors, employees of the pharmaceutical and 
laboratory testing companies supporting this study, or their designees. Having a Certificate of 
Confidentiality does not prevent you from releasing information about yourself and your 
participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to you or others, they will be required to tell the proper authorities. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drug, RMD or placebo, study-related visits, physical 
examinations, required laboratory tests or other procedures. This study will not provide you with 


 
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anti-HIV drugs. You, your insurance company, or your health care system may need to assume 
the cost of drugs not provided by the study. In some cases, it is possible that your insurance 
company or health care system will not pay for these costs because you are taking part in a 
research study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
(Insert site-specific information on compensation to study participants.) 
 
 
WHAT IF I AM INJURED? 
 
If you are injured as a result of your being in this study, you will be given immediate treatment 
for injuries and be referred for further treatment, if necessary. However, you may/may not (per 
site policy) have to pay for this care. There is no program for compensation either through (this 
institution) or the NIH. You will not be giving up any of your legal rights by signing this consent 
form. 
 
 
WHAT HAPPENS IF I BECOME PREGNANT AND MY BABY IS INJURED? 
 
If you or your baby is injured as a result of your being in this study, you or your baby will be 
given immediate treatment for injuries and be referred for further treatment, if necessary. 
However, you may/may not (per site policy) have to pay for this care. There is no program for 
compensation either through (this institution) or the NIH.  You will not be giving up any of your 
legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. The care that you would normally receive will not be affected if 
you decide not to take part.  Your decision will not have any impact on your participation in other 
studies conducted by the 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, tell the study 
staff. 
 
 


 
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WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
 
Name of the investigator or other study staff 
 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
 
Name or title of person on the IRB/EC or other organization appropriate for the site 
 
Telephone number of above 


 
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SIGNATURE PAGE ACTG Study A5315, Cohort 4  
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Representative 
Legal Representative’s Signature and Date 
(As appropriate) (print) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’ Name (print) 
Witness’ Signature and Date 
(As appropriate) 

SAP_000.pdf: 
Filename: M:\documentation\AnalysisPlan\A5315_analysis_plan_v3.0_clinicaltrialsgov.docx 
Directory mapping: E:\ maps to /home/actg/A5315 
Printed on: March 7, 2019 
This is the Statistical Analysis Plan Version 3.0 for A5315 with names of authors, names of publication 
writing team members and analysis timeline redacted.  
 
 
A5315 
A Phase I/II Study of Single Dose Romidepsin in HIV-Infected Adults with Suppressed Viremia on 
Antiretroviral Therapy to Assess Safety, Tolerability, and Activation of HIV-1 Expression 
 
ClinicalTrials.gov Identifier: NCT01933594 
 
Statistical Analysis Plan 
 
 
 
Version 3.0 - May 7, 2018 
 
 
 
 
 
 


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Page 2 of 28 
Table of Contents 
TABLE OF CONTENTS ................................................................................................................................ 2 
TABLE OF TABLES ..................................................................................................................................... 4 
TABLE OF FIGURES .................................................................................................................................... 4 
1 
INTRODUCTION ..................................................................................................................................... 5 
2 
CORE TEAM ROSTER........................................................................................................................... 5 
3 
STUDY SCHEMA ................................................................................................................................... 6 
4 
HYPOTHESES AND OBJECTIVES ....................................................................................................... 7 
4.1 
Hypothesis .................................................................................................................................... 7 
4.2 
Primary Objectives ...................................................................................................................... 7 
4.3 
Secondary Objectives ................................................................................................................. 7 
5 
ANALYSIS REPORTS............................................................................................................................ 9 
5.1 
SMC (interim) review ................................................................................................................... 9 
5.1.1 
SMC report for annual reviews ........................................................................................... 9 
5.1.2 
SMC report for dose escalation .......................................................................................... 9 
5.2 
Final Analysis report ................................................................................................................... 9 
6 
GENERAL ANALYSIS CONSIDERATIONS .......................................................................................10 
6.1 
Lists of Data in Reports .............................................................................................................10 
6.2 
Study Treatment .........................................................................................................................10 
6.3 
Analysis Populations .................................................................................................................10 
6.4 
Definition of “Day 0” and “baseline” .......................................................................................10 
6.5 
Period of follow-up ....................................................................................................................10 
6.6 
Visit schedule and definition of “Day” and “Week” for analysis purposes ........................11 
6.7 
Validation of programs ..............................................................................................................11 
7 
ANALYSES ...........................................................................................................................................11 
7.1 
Accrual ........................................................................................................................................11 
7.2 
Eligibility Violations ...................................................................................................................11 
7.3 
Participant Replacement ...........................................................................................................12 
7.4 
Baseline Characteristics ...........................................................................................................12 
7.5 
Study Status ...............................................................................................................................12 
7.6 
Treatment Status ........................................................................................................................13 
7.7 
HIV-1 RNA level at day 7............................................................................................................13 
7.8 
Data and stored sample completeness (interim analysis only) ............................................13 
7.9 
Safety data ..................................................................................................................................14 
7.9.1 
List of events ....................................................................................................................14 
7.9.2 
Dose escalation criteria (protocol Section 9.4.1, for dose escalation review only) ..........14 
7.9.3 
Primary safety outcome (protocol Section 9.2.1.1) ..........................................................15 


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7.10 Primary efficacy outcomes (protocol Section 9.2.1.2) ...........................................................15 
7.10.1 
Change in plasma HIV-1 RNA levels from baseline (average of pre-entry and entry values) as 
detected by single copy assay (SCA) at 24 and 48 hours (average) after the administration of 
RMD or placebo. ........................................................................................................15 
7.10.2 
Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells from baseline to 24 hours after 
the administration of RMD or placebo. ......................................................................16 
7.11 Secondary outcomes .................................................................................................................16 
7.11.1 
Changes in plasma HIV-1 RNA levels as detected by single copy assay from baseline to 6 and 12 
hours, and 7, 14, and 28 days after the administration of RMD or placebo. .............16 
7.11.2 
Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells from baseline to 14 days after 
the administration of RMD or placebo. ......................................................................16 
7.11.3 
Changes in cell-associated HIV-1 RNA levels in total CD4+ T-cells from baseline to 6, 12, 24 and 48 
hours, and 7, 14, and 28 days after completion of RMD or placebo. ........................16 
7.11.4 
Changes in histone acetylation in total CD4+ T-cells by flow cytometry from baseline to 12, 24, 48 
hours and 7 and 14 days after the administration of RMD or placebo. .....................16 
7.11.5 
Changes in total HIV-1 DNA and 2-LTR circles in resting or total CD4+ T-cells from baseline to 6, 12, 
24, and 48 hours and 7, 14, and 28 days after the administration of RMD or placebo.17 
7.11.6 
Pharmacokinetic parameters (AUC, Cmax, Cmin) for RMD and co-administered antiretroviral drugs 
(EFV, DTG, or RAL)...................................................................................................17 
7.11.7 
Number/percent of subjects with HIV-1 RNA levels > 200 copies at the Day 7 visit .......17 
7.11.8 
All reported Grade 2-4 AEs. .............................................................................................17 
7.12 Exploratory outcomes ...............................................................................................................17 
7.12.1 
Change in CD4+ and CD8+ T cell percent from baseline to 48 hours, 7, and 28 days after the 
administration of RMD or placebo. ............................................................................18 
7.12.2 
Changes in the percentage of CD3+ CD4+ and CD3+ CD8+ lymphocytes and cellular markers of 
immune activation (CD38/HLA-DR or CD69/CD25 expression on CD4+ and CD8+ T-cells) from 
baseline to 48 hours, and 7 and 28 days after the administration of RMD or placebo.18 
7.12.3 
Changes in proportion of cycling CD4+ and CD8+ T-cells (Ki67 expression) from baseline to 48 
hours, 7, and 28 days after the administration of RMD or placebo. ..........................18 
7.12.4 
Changes in the levels of soluble markers IL-6, C-reactive protein (CRP), and D-dimer from baseline to 
7 and 28 days after the administration of RMD or placebo. ......................................18 
7.12.5 
Percentage of total lymphocytes expressing annexin V and 7 amino-actinomycin D (7-AAD) at 
baseline, 48 hours, 7 and 28 days after the administration of RMD or placebo........18 
7.12.6 
Changes in ex vivo PMA/Ionomycin and RMD inducible HIV-1 RNA expression in resting CD4+ T-
cells from baseline to 14 days after RMD dosing. .....................................................18 
7.12.7 
Changes in P-TEFb and HIV-1 expression; changes in PTEF-b phosphorylation in total CD4+ T-cells 
by flow cytometry from baseline to 12, 24, 48 hours and 7 and 14 days after the administration of 
RMD or placebo. ........................................................................................................19 
APPENDICES .............................................................................................................................................23 
Appendix 1 Schedule of Events (protocol Section 6) .....................................................................23 
 


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Table of Tables 
No table of figures entries found. 
 
Table of Figures 
No table of figures entries found. 


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1 
INTRODUCTION 
This document describes the content proposed for the primary statistical analysis of ACTG 5315. The focus is on 
analyses that address the key safety, tolerability and efficacy outcome measures, including those needed to address 
the study’s primary and major secondary objectives. A subset of these analyses (as described herein) will form the 
basis of reports provided to the Study Monitoring Committee (SMC) while the study is ongoing. This analysis plan 
therefore includes the key analyses which might lead to modification or termination of the study, and hence also form 
the core of any presentation or publication used to disseminate the primary conclusions of the study. It is, however, 
recognized that this analysis plan may be modified by the study team as new information becomes available outside of 
the study, or to reflect recommendations made by the SMC or changes in the study design. In addition, some 
analyses, tables, or figures may be omitted at interim analyses if there are insufficient data to warrant analysis or at the 
request of the SMC. 
 
2 
CORE TEAM ROSTER 
Information redacted 
 
 
 


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3 
STUDY SCHEMA 
Note: The following material is extracted from the study protocol version 2.0 
DESIGN 
A5315 is a phase I/II, double-blinded, randomized, placebo-controlled, dose-escalation study to 
evaluate the safety and efficacy of single dose and multiple dose administration of romidepsin 
(RMD). Four cohorts (1-4) of 15 participants each will be sequentially enrolled into the study 
(depending on safety outcomes, which will determine whether to dose escalate or not). Toxicity 
related to the administration of RMD will be evaluated systematically in all cohorts. The effect of 
RMD on HIV expression will be evaluated in all cohorts. The effect of RMD on total virus recovery 
(TVR) will be assessed in most cohorts. Samples will also be collected before and after most 
infusions for pharmacokinetic (PK) evaluation of antiretroviral drugs (ARVs) and RMD. 
DURATION 
For participants in Cohorts 1 – 3, study duration is 4 weeks. For participants in Cohort 4, study 
duration is a minimum of 24 weeks; study duration will be increased if any of the infusions after the 
first one must be delayed. The maximum study duration for Cohort 4 participants will be 48 weeks. 
SAMPLE SIZE 
60 evaluable participants (approximately 15 evaluable participants in each cohort) 
POPULATION 
HIV- infected adults at least 18 years of age with CD4+ counts >300 cells/mm3 who have 
suppressed viremia on a raltegravir (RAL), dolutegravir (DTG), or efavirenz (EFV)-based regimen 
(plasma HIV-1 RNA levels <50 copies/mL and no blips >50 copies/mL on standard commercial 
assays) and, for Cohorts 1-3 only, who have ≥0.4 HIV-1 RNA copies/mL by single-copy assay 
(SCA) at screening. Plasma HIV-1 RNA ≥0.4 HIV-1 RNA copies/mL by SCA is not required as part 
of eligibility for Cohort 4.  
REGIMEN 
Participants will be sequentially enrolled to cohorts and randomized 4:1 to receive RMD or 
placebo as shown below.  
 
 
 
 
Cohort 1: 12 participants will receive 0.5 mg/m2 RMD in 0.9% saline  
     3 participants will receive placebo in 0.9% saline 
 
 
 
Cohort 2: 12 participants will receive 2 mg/m2 RMD in 0.9% saline  
     3 participants will receive placebo in 0.9% saline 
 
 
 
Cohort 3: 12 participants will receive 5 mg/m2 RMD in 0.9% saline  
     3 participants will receive placebo in 0.9% saline 
Cohort 4: 12 participants will receive a total of 20 mg/m2 RMD in 0.9% saline  
     (5 mg/m2 RMD at each of four dosing time points) 
    3 participants will receive placebo in 0.9% saline (at each of four 
      dosing time points) 
 
 


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4 
HYPOTHESES AND OBJECTIVES 
4.1 Hypothesis  
We hypothesize that adjunctive therapy with the potent histone deacetylase inhibitor (HDACi) romidepsin (RMD) 
administered at doses well below the maximum tolerated dose (MTD), will be well tolerated and lead to activation of 
proviral HIV-1 expression in latently-infected cells in HIV-infected participants receiving suppressive antiretroviral 
therapy (ART). 
 
 
 
4.2 Primary Objectives 
 
To determine the safety and tolerability of the intravenous administration of a single dose of RMD to HIV-
infected participants with HIV-1 RNA levels <50 copies/mL on a stable ART regimen in Cohorts 1-3, and of 
multiple doses of RMD in Cohort 4.  
 
To assess the induction of HIV-1 expression in HIV-infected participants with suppressed viremia by 
measuring plasma viremia using a single copy HIV-1 RNA assay prior to and following a single dose of RMD 
in Cohorts 1-3. 
 
To assess the induction of HIV-1 expression in HIV-infected participants with suppressed viremia by 
measuring plasma viremia using a single copy HIV-1 RNA assay prior to and following each of multiple doses 
of RMD in Cohort 4. 
 
To assess changes in cell-associated HIV-1 RNA levels in resting CD4+ T-cells obtained prior to and 
following a single dose of RMD in Cohorts 1-3 and prior to and following each of multiple RMD doses in 
Cohort 4. 
 
To examine the efficacy of multiple doses of RMD for reducing the latent, inducible HIV-1 reservoir, as 
measured by the total virus recovery (TVR) assay in Cohort 4.   
4.3 Secondary Objectives 
 
To assess changes in cell-associated HIV-1 RNA levels in total CD4+ T-cells obtained prior to and following a 
single dose of RMD in Cohorts 1-3 and prior to and following each of multiple RMD doses in Cohort 4.  
 
To assess changes in histone acetylation levels and P-TEFb expression in total CD4+ T-cells prior to and 
following a single dose of RMD in Cohorts 1-3 and prior to and following each of multiple RMD doses in 
Cohort 4. 
 
To assess changes in total HIV-1 DNA and 2-LTR circles in resting and total CD4+ T-cells prior to and 
following a single dose of RMD in Cohorts 1-3 and prior to and following each of multiple RMD doses in 
Cohort 4.  


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 
To assess the induction of HIV-1 expression in HIV-infected participants with suppressed viremia by 
measuring plasma viremia using single copy HIV-1 RNA assay prior to and following each of multiple RMD 
doses in Cohort 4. 
 
To obtain pharmacokinetic (PK) data for RMD and coadministered antiretroviral drugs prior to and following a 
single dose of RMD in Cohorts 1-3 and at and following the third and fourth doses in Cohort 4 to assess 
potential drug-drug interactions. 
 
 
 


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5 
ANALYSIS REPORTS 
This section describes the various analysis reports that will be created for this study. 
 
5.1 SMC (interim) review 
5.1.1 
SMC report for annual reviews 
As outlined in the A5315 monitoring plan, an analysis report will be prepared and distributed to the SMC members for 
each SMC review. The report will include analyses from the following subsections of Section 7 broken down by 
treatment arm and dose cohort: 
 
Accrual 
 
Baseline characteristics 
 
Study status 
 
Treatment status 
 
HIV-1 RNA level at day 7 
 
Primary safety endpoint 
 
List of events 
and a pooled (over treatment arm) summary of: 
 
Data and stored sample completeness 
Note: Only a closed report will be generated. 
 
5.1.2 
SMC report for dose escalation 
For the SMC review after completion of each cohort, to assess whether dose escalation can occur, an abbreviated 
analysis report will be prepared in order to expedite the dose escalation review. This report will include the following 
subsections of Section 7 broken down by treatment arm and dose cohort: 
 
Accrual 
 
Baseline characteristics 
 
Study status 
 
Treatment status 
 
HIV-1 RNA level at day 7 
 
List of events  
Note: Only a closed report will be generated. 
 
5.2 Final Analysis report 
Unless otherwise noted, the final analysis report will include all subsections of Section 7. 


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6 
GENERAL ANALYSIS CONSIDERATIONS 
6.1 Lists of Data in Reports 
Listings of data by individual study participants are described below to facilitate the interpretation of the study results.  
To help protect confidentiality of data, the content of these lists will be limited and will not include dates, participants’ 
ACTG identifier numbers or other combinations of information that might identify an individual participant (except that 
these may be included in the confidential closed reports prepared for SMC review). 
6.2 Study Treatment  
The study treatment is Romidepsin (RMD) or Placebo for RMD (placebo).   
6.3 Analysis Populations 
Safety: All participants who have been exposed to study treatment/placebo will be included in the safety analyses. 
Efficacy: For Cohorts 1-3, all participants who completed the study treatment infusion at Day 0 and with available 
outcome data will be included in the as-treated efficacy analyses.  
For Cohort 4, all participants who completed all study treatment infusions and with available outcome data will be 
included in the as-treated efficacy analyses. 
6.4 Definition of “Day 0” and “baseline” 
“Day 0” is defined as the day of study registration (variable ONSTDT from ADM0020). In the study protocol, this is 
often referred to as entry date. “Baseline” is defined as the last evaluation on or before Day 0.  
6.5 Period of follow-up 
For Cohorts 1-3: 
Per protocol Section 6.2.3, Week 4/Day 28 evaluations will serve as the study completion evaluations for participants 
who have maintained an HIV-1 RNA level of < 200 copies/mL by standard ultrasensitive assay at the Day 7 visit. Also, 
these evaluations will be the study completion evaluations for participants who did not experience a Grade ≥ 3 AE or 
clinical event (per protocol Section 7.1).  
Participants who experience a Grade ≥ 3 AE or clinical event must return for a Week 8/Day 56 visit (per protocol 
Section 7.1.2). 
Per protocol Section 6.2.4, participants with an HIV-1 RNA level of > 200 copies/ml at the Day 7 visit will be contacted 
immediately and asked to return as soon as possible (preferably within 72 hours) for a repeat HIV-1 RNA PCR. If the 
repeat HIV-1 RNA PCR level after Day 7 is > 200 copies/ml, the participant will complete both Week 4 /Day 28 and 
Week 8 /Day 56 visits.  
 
 


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For Cohort 4: 
Per protocol Section 6.1, participants will be followed for 18 weeks after the 4th infusion. Note: infusions can be 
delayed per protocol.  
6.6 Visit schedule and definition of “Day” and “Week” for analysis purposes 
Days and Weeks on study will be based on the study treatment administration dates (i.e., will be “ 
anchored” on the infusion timing) and will use the protocol-specified windows. The protocol schedule of events for 
Cohort 4 is provided in Appendix 1.  
6.7 Validation of programs 
All programs creating treatment codes, derived datasets, formats, and primary analysis programs will be validated in 
accordance with SOP PROG.10066 and PROG.10067 (or PROG.10083, as applicable). All user options files will be 
validated in accordance with SOP PROG.10071.  
The primary analyses (safety and efficacy) will be additionally validated through independent coding.  
 
7 
ANALYSES 
Analysis summaries will be presented for each dose cohort active arm, for the pooled dose cohort arms (if applicable), 
the pooled placebo arms (if applicable), and overall. Separate analyses may be performed by cohort in which 
summaries will be by active dose cohort, placebo arm and overall. 
For SMC reports all summaries will be presented by randomized treatment, and overall, separately by dose cohort.  
Lists will be indexed by the alternate participant identifier (PUBLICID variable), and visit week/date as needed. 
 
7.1 Accrual 
a. Table: number (%) of participants enrolled by month/year 
b. Table: number (%) of participants enrolled by site 
[STATUS dataset] 
 
7.2 Eligibility Violations 
a. Table: violations of eligibility criteria by site (if any) 
b. List: details of exclusions from analyses (if any) 
 


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7.3 Participant Replacement 
Table: reasons for replaced participants (if any), as described in protocol Section 9.4. 
 
7.4 Baseline Characteristics 
a. Table (demographic information): 
 
Age at randomization date (years): N, median, 25th and 75th percentiles, min, max; number (%) by category 
(18-34, 35-49, ≥50) 
 
Sex: number (%) 
 
Self-reported race/ethnicity: number (%) 
 
IV drug use: number (%) by category (never used, previously used, currently used) 
 
BMI (kg/m2): N, median, 25th and 75th percentiles, min, max 
 
Background ART regimen: number (%) by category (raltegravir, dolutegravir, efavirenz)  
[STATUS dataset, PKW0348 form, ANSTAB table (for background regimen)] 
b. Table (health status information): 
 
Time since first HIV-1 RNA below the detection limit: N, median, 25th and 75th percentiles, min, max and 
number (%) by category (1-3, 3-5, 5-10, 10-15, 15-20, 20+) 
 
History of VF on an ART regimen: number (%) 
 
Nadir CD4 count: N, median, 25th and 75th percentiles, min, max 
 
Screening CD4 count (cells/mm3): N, median, 25th and 75th percentiles, min, max 
 
Screening HIV-1 RNA level by SCA (copies/mL): N, median, 25th and 75th percentiles, min, max 
 
Screening negative HCV antibody: number (%) by category (Yes, No) 
 
Pre-entry ECG result: QTC interval (msec): N, median, 25th and 75th percentiles, min, max 
[HXW182 form, HXW183 form, F1015 form, ANSTAB table, F0875 form] 
 
7.5 Study Status 
a. Table: 
 
Number (%) of participants who completed the protocol 
 
Number (%) of participants who did not complete the protocol 
o 
Number (%) of participants off study due to death 
o 
Number (%) of participants off study prior to completion of protocol for reasons  
other than death 
b. List of lost-to follow-up participants (if any) with follow-up duration and reason off study 
c. List of deaths (if any) including study week of death and cause of death information 
[STATUS dataset] 


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7.6 Treatment Status 
For Cohorts 1-3: 
a. Table: 
 
Number (%) of participants who completed RMD/placebo infusion 
 
Number (%) of participants who discontinued prematurely RMD/placebo infusion 
c. List: details (including reasons and % infused) for participants with incomplete treatment, if any 
For Cohort 4: 
a. Table: 
 
Number (%) of participants who completed all 4 RMD/placebo infusions  
 
Number (%) of participants who did not complete all 4 RMD/placebo infusions 
o 
Reasons why not all 4 RMD/placebo infusions were not completed 
b. List: details (including reasons and % infused) for participants with incomplete treatment, if any 
NOTE: For final analysis the duration of infusion (hours) will also be summarized (N, median, 25th and 75th percentiles, 
min, and max) 
[TXW0279 form, STATUS dataset] 
 
7.7 HIV-1 RNA level at day 7 after each infusion 
a. Table: HIV-1 RNA level (copies/mL) at day 7 after each infusion: number (%) by category (<40 (G), <40 (J), 40-199, 
≥200)  
NOTE: The table will have a footnote listing all the HIV-1 RNA levels at day 7 that are ≥40 copies/mL 
[RNALDMS dataset] 
 
7.8 Data and stored sample completeness (interim analysis only) 
Tables summarizing completeness of selected data and stored sample (using the CBAR macro %DAR): 
 
BLD/DPE/CEL/DMS or BLD/EDT/CEL/DMS PBMC (for virology/immunology studies) 
 
BLD/EDT/PLH or BLD/DPE/PLH aliquots (for SCA testing) 
 
LPK/SCI/CEL/DMS or LPK/ACD/CEL/DMS (Leukopak) 
 
LPK/SCI/LPK/RPM or LPK/ACD/LPK/RPM (Monogram) 
 
BLD/SCI/PL2 (D-dimer) 
 
BLD/DPE/PL1 (PK for raltegravir, dolutegravir, efavirenz)  
NOTE: The completeness of the stored samples will be based on the LPC-required number of aliquots and a lower 
number (depending on the sample). 
[ALIQ dataset, TXW0279 form] 


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7.9 Safety data  
7.9.1 
List of events 
List showing all the grade > 0 safety events for each study participant. The list will include the following: 
 
public ID 
 
treatment dispensation days 
 
core team assigned code (regarding the relatedness to study treatment) 
 
visit week 
 
onset day 
 
resolution day 
 
event description 
 
value and units (for laboratory results) 
 
grade 
 
site assigned code (regarding the relatedness to study treatment) 
NOTE: This information corresponds to the ToxSum report prepared by the DMC, with the addition of the site assigned 
code. The site assigned code is derived from the TRAC table for events, except for those who originate from the 
EVW0206; the site assigned code for these events is derived from the EVW0206_UPDATE dataset  
[TRAC table, EVW0206_UPDATE dataset]  
 
7.9.2 
Dose escalation criteria (protocol Section 9.4.1, for dose escalation review only)  
Criteria to be used to guide the SMC when determining dose resumption or dose escalation for each cohort are 
defined as: 
a) No more than three subjects have experienced a Grade 3 AE that is probably or possibly related to study 
treatment (as judged by the core team, blinded to treatment arm) prior to or on Day 14 after the treatment 
administration;  
and 
b) None of the subjects has experienced a Grade ≥ 3 AE that is definitely related to study treatment or that is 
Grade ≥ 4 and probably or possibly related to study treatment (as judged by the core team, blinded to 
treatment arm) prior to or on Day 14 after the treatment administration. 
NOTE: The occurrence of a Grade 3 infusion site pain or tenderness that is sustained for less than 48 hours will be 
excluded from the dose escalation evaluation 
 
 


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7.9.3 
Primary safety outcome (protocol Section 9.2.1.1) 
List: Details of the following: 
Occurrence of Grade ≥ 3 AE including signs/symptoms, lab toxicities, and /or clinical events that is probably, possibly 
or definitely related to study treatment (as judged by the core team, blinded to treatment arm) any time from the time of 
study treatment administration until 28 days after the administration. 
 
7.10 Cohorts 1-3 primary efficacy outcomes (protocol Section 9.2.1.2) 
These analyses will be ‘as-treated’, such that only participants who completed study treatment/placebo administration 
will be included. 
7.10.1 Change in plasma HIV-1 RNA levels from baseline (average of pre-entry and entry values) as detected 
by single copy assay (SCA) at 24 and 48 hours (average) after the administration of RMD or placebo. 
The analysis of 7.10.1 will be combined with 7.11.1. 
SCA values below the limit of detection (LOD) will be imputed as equal to half the limit of detection (i.e., if LOD=0.4 
copies/mL, results < 0.4 copies/mL will be imputed as 0.2 copies/mL).  
a. Tables: 
 
Completeness of data for all measurement time points 
 
N (%) of SCA value < LOD at all measurement time points 
 
Baseline SCA: N, median, 25th and 75th percentiles, min, max 
 
24/48 hour SCA: N, median, 25th and 75th percentiles, min, max 
 
Change (24/48 hour – baseline) SCA: N, median, 25th and 75th percentiles, min, max 
 
SCA at 6 and 12 hours, and 7, 14, and 28 days: N, median, 25th and 75th percentiles, min, max 
 
Change (at each above time point – baseline) SCA: N, median, 25th and 75th percentiles, min, max 
 
Note: Baseline and 24/48 hour averages will be calculated using log10-transformed SCA values.  
A Wilcoxon rank sum test will be used for the comparison between groups. 
b. Figure: 
 
Longitudinal, participant-specific, (spaghetti) plots for all measurement time points with open symbol for values 
below the LOD and different symbols/colors for RMD and placebo.  
 
 


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7.10.2 Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells from baseline to 24 hours after the 
administration of RMD or placebo. 
The analysis of 7.10.2 will be combined with 7.11.2. 
a. Tables: 
 
Completeness of data for all measurement time points 
 
Baseline CA-RNA in resting CD4+ T-cells: N, median, 25th and 75th percentiles, min, max 
 
24 hour CA-RNA in resting CD4+ T-cells: N, median, 25th and 75th percentiles, min, max 
 
Day 14 CA-RNA in resting CD4+ T-cells: N, median, 25th and 75th percentiles, min, max 
 
Change (24 hour – baseline) of CA-RNA in resting CD4+ T-cells: N, median, 25th and 75th percentiles, min, 
max 
 
Change (Day 14 – baseline) of CA-RNA in resting CD4+ T-cells: N, median, 25th and 75th percentiles, min, 
max 
 
A Wilcoxon rank sum test will be used for the comparison between groups. 
b. Figure: 
Longitudinal, participant-specific, (spaghetti) plots for all measurement time points using different symbols/colors for 
RMD and placebo. 
 
7.11 Cohorts 1-3 secondary outcomes  
Unless otherwise specified, these analyses will follow the approach for the primary efficacy outcomes. 
7.11.1 Changes in plasma HIV-1 RNA levels as detected by single copy assay from baseline to 6 and 12 
hours, and 7, 14, and 28 days after the administration of RMD or placebo. 
Included in the analysis of 7.10.1 
7.11.2 Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells from baseline to 14 days after the 
administration of RMD or placebo. 
Included in the analysis of 7.10.2 
7.11.3 Changes in cell-associated HIV-1 RNA levels in total CD4+ T-cells from baseline to 6, 12, 24 and 48 
hours, and 7, 14, and 28 days after completion of RMD or placebo. 
7.11.4 Changes in histone acetylation in total CD4+ T-cells by flow cytometry from baseline to 12, 24, 48 
hours and 7 and 14 days after the administration of RMD or placebo. 
NOTE: Mean and median FI records with sample acquisition counts < 10,000 will be excluded from the analysis.  
Outcomes of interests: FICD3MED; FICD3MN, FICELMED, FICELMN  


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a. Tables: 
 
Completeness of data for all measurement time points 
 
Summaries for each outcome at each measurement time point: N, median, 25th and 75th percentiles, min, 
max 
 
Summaries for each outcome’s absolute change from baseline to each measurement time point: N, median, 
25th and 75th percentiles, min, max 
 
Wilcoxon rank sum tests will be used for the comparisons of change (from pre-dose) between groups. 
b. Figure: 
Longitudinal, participant-specific, (spaghetti) plots for all measurement time points using different 
panels/symbols/colors for RMD and placebo, separately for each cohort. 
Median (change from pre-dose) plots for combined cohorts and placebo groups.  
 
7.11.5 Changes in total HIV-1 DNA and 2-LTR circles in resting or total CD4+ T-cells from baseline to 6, 12, 24, 
and 48 hours and 7, 14, and 28 days after the administration of RMD or placebo. 
7.11.6 Pharmacokinetic parameters (AUC, Cmax, Cmin) for RMD and co-administered antiretroviral drugs 
(EFV, DTG, or RAL). 
Table summarizing of the pharmacologist-estimated PK parameters. 
 
7.11.7 Number/percent of subjects with HIV-1 RNA levels > 200 copies at the Day 7 visit 
See 7.7 
7.11.8 All reported Grade 2-4 AEs. 
List showing all the events with grade 2-4 for each study participant. The list will include the following: 
 
public ID 
 
treatment dispensation date 
 
visit week 
 
onset date 
 
resolution date 
 
event description 
 
value and units (for laboratory results) 
 
grade 
 
7.12 Cohorts 1-3 exploratory outcomes  
Unless otherwise specified, these analyses will follow the same approach for the primary efficacy outcomes. 


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7.12.1 Change in CD4+ and CD8+ T cell percent from baseline to 48 hours, 7, and 28 days after the 
administration of RMD or placebo. 
7.12.2 Changes in the percentage of CD3+ CD4+ and CD3+ CD8+ lymphocytes and cellular markers of 
immune activation (CD38/HLA-DR or CD69/CD25 expression on CD4+ and CD8+ T-cells) from baseline 
to 48 hours, and 7 and 28 days after the administration of RMD or placebo. 
7.12.3 Changes in proportion of cycling CD4+ and CD8+ T-cells (Ki67 expression) from baseline to 48 hours, 
7, and 28 days after the administration of RMD or placebo. 
7.12.4 Changes in the levels of soluble markers IL-6, C-reactive protein (CRP), and D-dimer from baseline to 7 
and 28 days after the administration of RMD or placebo. 
7.12.5 Percentage of total lymphocytes expressing annexin V and 7 amino-actinomycin D (7-AAD) at baseline, 
48 hours, 7 and 28 days after the administration of RMD or placebo. 
7.12.6 Changes in ex vivo PMA/Ionomycin and RMD inducible HIV-1 RNA expression in resting CD4+ T-cells 
from baseline to 14 days after RMD dosing. 
NOTE: Undetected values will be imputed with a value of 20 copies/mL; these are represented in the database as “< .”. 
Outcomes of interests: untreated (YUNT), PMA-treated (YPMA), and RMD-treated (YRMD). These Y variables will be 
average of the log transformed replicates, as long as the number of replicates is ≥ 3. Note that data with replicate 
number < 3 will be excluded from the analyses. 
a. Tables: 
 
Completeness of data for all measurement time points (no data,  < 3 replicates and ≥ 3 replicates) 
 
Summaries for each outcome at each measurement time point: N, median, 25th and 75th percentiles, min, 
max 
 
Summaries for ratio of RMD-treated/untreated and PMA-treated/untreated at each measurement time point: N, 
median, 25th and 75th percentiles, min, max.  
o 
RatioPMA = exp(YPMA)/exp(YUNT),  RatioRMD = exp(YRMD)/exp(YUNT), repeat for baseline and day 14. 
 
Summaries for each outcome fold change from baseline to week2 (week 2/pre-dose): N, median, 25th and 
75th percentiles, min, max 
o 
FC(YUNT) = exp(YUNT at day 14)/ exp(YUNT at baseline), repeat for PMA and RMD 
o 
FC(PMA) = (RatioPMA at day 14)/(RatioPMA at baseline), repeat for RMD  
 
Wilcoxon rank sum tests will be used for the comparisons between groups. 
b. Figure: 
Longitudinal, participant-specific, (spaghetti) plots for all measurement time points using different symbols/colors for 
RMD and placebo. 


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7.12.7 Changes in P-TEFb and HIV-1 expression; changes in PTEF-b phosphorylation in total CD4+ T-cells by 
flow cytometry from baseline to 12, 24, 48 hours and 7 and 14 days after the administration of RMD or 
placebo.  
7.13 Cohort 4 primary efficacy outcomes 
7.13.1 Change in plasma HIV-1 RNA levels from baseline (average of pre-entry and entry values) as detected 
by single copy assay before and 24 hours after each administration of RMD or placebo in Cohort 4. 
The analysis of 7.13.1 will be combined with 7.14.1. The available timepoints are: pre-entry (-35 to -28 days), pre- & 
24hr post-infusion for all 4 infusions, and 72hr post-2nd-infusion 
SCA values below the limit of detection (LOD) will be imputed as equal to half the limit of detection (i.e., if LOD=0.4 
copies/mL, results < 0.4 copies/mL will be imputed as 0.2 copies/mL).  
a. Tables: 
 
Completeness of data for all measurement time points   
 
N (%) of SCA value < LOD at all measurement time points 
 
Baseline SCA: N, median, 25th and 75th percentiles, min, max 
 
Pre- and 24hr post-infusion SCA for each infusion and 72hr post-2nd-infusion: N, median, 25th and 75th 
percentiles, min, max 
 
Change (at each post-entry time point – baseline) SCA: N, median, 25th and 75th percentiles, min, max 
 
Change (post-infusion time point – pre-infusion time point for each infusion) SCA: N, median, 25th and 75th 
percentiles, min, max 
 
NOTE: Baseline averages will be calculated using log10-transformed SCA values.  
Wilcoxon rank sum test will be used for the comparison between groups. Wilcoxon signed rank test will be used to test 
within-group changes for RMD group. Two-sided 95% confidence intervals for the shift will be calculated based on 
Hodges-Lehmann estimator.  
b. Figure: 
 
Longitudinal median (Q1, Q3) plots for all measurement time points by RMD and placebo. 
 
Longitudinal, participant-specific, (spaghetti) plots for all measurement time points with open symbol for values 
below the LOD and different symbols/colors for RMD and placebo.  
 
7.13.2 Change in cell-associated HIV-1 RNA levels in PBMCs before and 24 hours after each administration of 
RMD or placebo in Cohort 4. 
The analysis of 7.13.2 will be combined with 7.14.2. The available timepoints are the same as 7.13.1 and 7.14.1. The 
same analysis approach will be used as in 7.13.1 (except N (%) below LOD).  
NOTE: Cell-associated RNA results below the detection limit are imputed with 1 copy/million PBMCs.  
 


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7.14 Cohort 4 secondary outcomes 
7.14.1 Changes in plasma HIV-1 RNA levels as detected by single copy assay from baseline to after each 
administration of RMD or placebo in Cohort 4. 
NOTE: Only 72hr post-2nd-infusion time point was tested for the primary analysis. Testing of remaining samples is 
pending on further team discussion.  
Included in the analysis of 7.13.1. 
7.14.2 Change in cell-associated HIV-1 RNA levels in PBMCs from baseline to after each administration of 
RMD or placebo in Cohort 4. 
NOTE: Only 72hr post-2nd-infusion time point was tested for the primary analysis. Testing of remaining samples is 
pending on further team discussion.  
Included in the analysis of 7.13.2. 
7.14.3 Changes in histone acetylation in CD4+ and CD8+ T-cells from baseline to after each administration of 
RMD or placebo in Cohort 4. 
The same analysis approach will be used as in 7.13.2. 
 
7.14.4 Changes in total HIV-1 DNA in PBMCs from baseline to after each administration of RMD or placebo in 
Cohort 4. 
The same analysis approach will be used as in 7.13.2. 
Analysis of RNA/DNA ratio will be using the same approach.  
7.14.5 Pharmacokinetic parameters for RMD and co-administered antiretroviral drugs (EFV, DTG, or RAL). 
Table summarizing of the pharmacologist-estimated PK parameters. 
7.14.6 Number/percent of participants in Cohort 4 with HIV-1 RNA levels ≥200 copies/mL at scheduled post-
infusion 4 visits. 
See 7.7 
 
 


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7.14.7 All reported Grade 2-4 AEs. 
List showing all the events with grade 2-4 for each study participant. The list will include the following: 
 
public ID 
 
treatment dispensation date 
 
visit week 
 
onset date 
 
resolution date 
 
event description 
 
value and units (for laboratory results) 
 
grade 
 
7.14.8 Change in CD4+ T cell percent from baseline to after each administration of RMD or placebo in Cohort 
4. 
7.14.9 Changes in the percentage of CD3+ CD4+ and CD3+ CD8+ lymphocytes and cellular markers of 
immune activation (CD38/HLA-DR or CD69/CD25 expression on CD4+ and CD8+ T-cells) from baseline 
to after each administration of RMD or placebo in Cohort 4.  
7.14.10 Change in percentage of total lymphocytes expressing annexin V and/or 7 amino-actinomycin D (7-
AAD) from baseline to after each administration of RMD or placebo in Cohort 4. 
7.14.11 Changes in P-TEFb and HIV-1 expression; changes in PTEF-b phosphorylation in CD4+ and CD8+ T-
cells from baseline to after each administration of RMD or placebo in Cohort 4. 
 
For 7.14.8-7.14.11:  
Tables: 
 
Summaries for each outcome at each measurement time point: N, median, 25th and 75th percentiles, min, 
max 
 
Summaries for each outcome’s absolute change from baseline to each measurement time point: N, median, 
25th and 75th percentiles, min, max 
Wilcoxon rank sum test will be used for the comparison between groups. Wilcoxon signed rank test will be used to test 
within-group changes for RMD group.  
Time points tested for 7.14.8-7.14.10: pre-entry (-35 to -28 days), pre-entry (-14 to -3 days), 24hr post-1st-infusion, 
pre-4th infusion, 24hr post-4th-infusion, week 16 


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7.15 Cohort 4 exploratory outcomes 
7.15.1 Change in total virus recovery (TVR) or qVOA from baseline to after administration of all doses of RMD 
or placebo in Cohort 4 
7.15.2 Changes in proportion of cycling CD4+ and CD8+ T-cells (Ki67 expression) from baseline to after each 
administration of RMD or placebo in Cohort 4. 
7.15.3 Changes in the levels of soluble markers IL-6, C-reactive protein (CRP), and D-dimer from baseline to 
after each administration of RMD or placebo in Cohort 4. 
7.15.4 Changes in HIV-specific immune responses from baseline to after the first and fourth administration of 
RMD or placebo in Cohort 4. 
7.15.5 Changes in host RNA expression profiles by RNAseq of PBMC from after the first and fourth 
administration of RMD or placebo in Cohort 4. 
 


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Appendices 
Appendix 1 
Schedule of Events (protocol Section 6) 
Cohort 4, Screening through Step 2 
Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screenin
g 
Pre-Entry 
Pre-Entry 
Step 1 
 
 
Step 2 
 
Prem. Tx and Study   D/C 
Step 2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-
infusion) 
Week 1/ Day 3 
(72 hr post-
infusion) 
Week 1 / Day 7   
(7 days post-
infusion) 
Weeks 2 to 8 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-
infusion) 
Week 3 / Day 17 
(72 hr post-
infusion) 
Week 3 / Day 21  
(7 days post-
infusion) 
Weeks 4 to 11 
(conditional) 1 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Medication 
History 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
X 
X 
X 
X 
X 
X 
X 
Once 
each 
week 
X 
X 
X 
X 
Once 
each 
week 
X 
Complete Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Exam 
 
 
X 
X 
X 
X 
X 
Once 
each 
week 
X 
X 
X 
X 
Once 
each 
week 
X 
Hematology 
 
 
X 
 
X 
X 
X 
Wk  
2, 6 
 
X 
X 
X 
Wk 
6, 10 
X 
Potassium and 
Magnesium (see section 
6.3.7 for timing at Pre-
entry) 
 
 
X 
 
 
 
X 
Wk 
2, 6 
 
 
 
X 
Wk 6, 
10 
 
LFTs/Blood Chemistries 
(see section 6.3.7) 
 
 
X 
 
 
X 
Wk 
2, 6 
 
 
 
X 
Wk 
6, 10 
X 


A5315 Statistical Analysis Plan: Version 3.0 
 
   
 
 
 
 
 
             
 
 
 
May 7, 2018 
 
 
Page 24 of 28 
Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screenin
g 
Pre-Entry 
Pre-Entry 
Step 1 
 
 
Step 2 
 
Prem. Tx and Study   D/C 
Step 2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-
infusion) 
Week 1/ Day 3 
(72 hr post-
infusion) 
Week 1 / Day 7   
(7 days post-
infusion) 
Weeks 2 to 8 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-
infusion) 
Week 3 / Day 17 
(72 hr post-
infusion) 
Week 3 / Day 21  
(7 days post-
infusion) 
Weeks 4 to 11 
(conditional) 1 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testing 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
HBV/HCV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
X  
Hr 4 
As clinically indicated 
X  
Hr 4 
As clinically indicated 
 
CD4% 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Stored Plasma and PBMC 
for immunology testing 
(see section 6.3.9) 
 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
Plasma HIV-1 RNA real 
time 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
 
 
 
X 
Once 
each 
week 
 
 
 
X 
Once 
each 
week 
 
Plasma HIV-1 RNA by SCA 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 


A5315 Statistical Analysis Plan: Version 3.0 
 
   
 
 
 
 
 
             
 
 
 
May 7, 2018 
 
 
Page 25 of 28 
Evaluation 
(Cohort 4, Screening 
through Step 2; standard) 
Screenin
g 
Pre-Entry 
Pre-Entry 
Step 1 
 
 
Step 2 
 
Prem. Tx and Study   D/C 
Step 2 
Reg. 
 
Day -60 to Day -36 
Day -35 to Day -28 
Day -14 to Day -3 
Entry/ Hour 0 
Pre-
Infusion/Infusion 
Week 1 / Day 1 
(24 hr post-
infusion) 
Week 1/ Day 3 
(72 hr post-
infusion) 
Week 1 / Day 7   
(7 days post-
infusion) 
Weeks 2 to 8 
(conditional)1 
Week 2 / Day 14 
(+/-  48hr) 
Week 3 / Day 15 
(24 hr post-
infusion) 
Week 3 / Day 17 
(72 hr post-
infusion) 
Week 3 / Day 21  
(7 days post-
infusion) 
Weeks 4 to 11 
(conditional) 1 
Resting CD4+ T cells (see 
section 6.3.10) 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Stored PBMC for virology 
testing (see section 
6.3.10) 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
Histone Acetylation 
 
 
 
Hr 0 
X 
X 
 
 
Hr 0 
X 
X 
 
 
 
Stored PBMC for TVR 
assay (see section 6.3.10) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RMD/Placebo Infusion 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
ART Adherence 
Assessment 
X 
 
X 
X 
 
 
 
 
X 
 
 
 
 
X 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  If 
infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
 
 
 


A5315 Statistical Analysis Plan: Version 3.0 
 
   
 
 
 
 
 
             
 
 
 
May 7, 2018 
 
 
Page 26 of 28 
 
Cohort 4, Steps 3 and 4 
Evaluation 
(Cohort 4, Steps 3 and 
4; standard) 
Step 3 
 
Step 4 
 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion) 
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
Clinical Assessments 
X 
X 
X 
X 
Once 
each
week 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
 
X 
X 
X 
Wk 8, 
12 
 
X 
X 
 
X 
X 
X 
X 
X 
Potassium and 
Magnesium (see section 
6.3.7 for timing at Pre-
entry) 
 
 
 
X 
Wk 8, 
12 
 
 
 
X 
 
 
 
 
 
LFTs/Blood Chemistries 
(see section 6.3.7) 
 
 
 
X 
Wk 
8, 12 
 
 
 
X 
 
 
 
X 
X 
Urine Pregnancy 
Testing 
X 
 
 
 
 
X 
 
 
 
As clinically 
indicated 
 
ECG 
X 
As clinically indicated 
X  
Hr 4 
As clinically indicated 
X 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  
If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
CD4% 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 


A5315 Statistical Analysis Plan: Version 3.0 
 
   
 
 
 
 
 
             
 
 
 
May 7, 2018 
 
 
Page 27 of 28 
Evaluation 
(Cohort 4, Steps 3 and 
4; standard) 
Step 3 
 
Step 4 
 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion) 
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
Stored Plasma and 
PBMC for immunology 
testing (see section 
6.3.9) 
 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
Plasma HIV-1 RNA real 
time 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Plasma HIV-1 RNA 
expedited 
 
 
 
X 
Once 
each 
week 
 
 
 
 
 
X 
 
 
 
Plasma HIV-1 RNA by 
SCA 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Resting CD4+ T cells 
(see section 6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stored PBMC for 
virology testing (see 
section 6.3.10) 
X 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Histone Acetylation 
Hr 0 
X 
X 
 
 
Hr 0 
X 
X 
 
 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  
If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4). 
Stored PBMC for TVR 
(see section 6.3.10) 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
RMD/Placebo Infusion 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 


A5315 Statistical Analysis Plan: Version 3.0 
 
   
 
 
 
 
 
             
 
 
 
May 7, 2018 
 
 
Page 28 of 28 
Evaluation 
(Cohort 4, Steps 3 and 
4; standard) 
Step 3 
 
Step 4 
 
Prem. Tx and/or Study   D/C 
Step 
3 
Reg. 
 
Step 4 
Reg. 
 
Post-Infusion 4 
Follow Up 
Week 4 / Day 28 
(+/- 48hr) 
Week 5 / Day 29 
(24 hr  
post-infusion) 
Week 5 / Day 31 
(72 hr  
post-infusion) 
Week 5 / Day 35  
(7 days post-
infusion) 
Weeks 6 to 13 
(conditional1 
Week 6 / Day 42 
(+/- 48hr) 
Week 7 / Day 43 
(24 hr  
post-infusion) 
Week 7 / Day 45 
(72 hr  
post-infusion) 
Week 7 / Day 49  
(7 days post-
infusion) 
Week 8 / Day 56 
Week 11 (±3 days) 
Week 16 (± 7 days) 
Week 24 (± 7 days) 
ART Adherence 
Assessment 
X 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
PK RMD 
(Collection times are 
from the start of the 
infusion) 
X 
Hr 0 
&  
Hr 4 
 
 
 
 
X 
Hr 0  
&  
Hr 4 
 
 
 
 
 
 
 
 
PK ARVs 
(Collection time is from 
the start of the infusion) 
X 
Hr 0 
X 
 
 
 
X 
Hr 0 
X 
 
 
 
 
 
 
 
1 These “conditional” evaluation weeks are only for participants whose infusions will be delayed for the next Step.  (See section 6.2.3).  
If infusion will be delayed, go to the delayed infusion SOE (section 6.1.4).