Clinical trial NCT04840199
Conditions: HIV Infections Cytomegalovirus CMV
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2022-04-19; Completion date: 2023-11-30
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was an open-label, controlled study, conducted at US sites to evaluate the anti-inflammatory effectiveness of the study drug letermovir in adults with HIV and asymptomatic cytomegalovirus (CMV) who were on antiretroviral therapy (ART)-mediated suppression. Participants were randomly assigned to receive either letermovir once daily or no anti-CMV treatment, for 48 weeks.

The primary hypothesis of this study was that letermovir would cause a greater reduction in plasma soluble receptor for tumor necrosis factor type II (sTNFRII) levels than no anti-CMV treatment at weeks 46/48.

Detailed description:
This was a phase 2, randomized, open-label, controlled, multicenter trial to evaluate the anti-inflammatory efficacy of letermovir, administered once daily for 48 weeks in adults with HIV and asymptomatic CMV, who are on ART-mediated suppression. Participants were randomized 1:1 to receive either letermovir or no anti-CMV treatment. The target enrollment was 180 participants.

A futility analysis was planned to be performed after the first 40 participants to initiate study treatment reached their 8-week study visit. Study enrollment was to be paused after the 40th participant started the study until the results of the futility analysis were considered.

This study was terminated due to futility.

Arms: arm 1: Participants randomized to letermovir for 48 weeks followed by 12 weeks off letermovir arm 2: Participants randomized to no study intervention for 60 weeks
Interventions: intervention 1: Letermovir Oral Tablet
Intervention descriptions: intervention 1: 480 mg administered orally once daily with or without food

Protocol documents:
Prot_ICF_000.pdf: 
 
A5383 
 
Randomized, Controlled Trial to Evaluate the Anti-inflammatory Efficacy of 
Letermovir (Prevymis) in Adults with Human Immunodeficiency Virus (HIV)-1 and 
Asymptomatic Cytomegalovirus (CMV) Who Are on Suppressive ART and Its 
Effect on Chronic Inflammation, HIV Persistence, and Other Clinical Outcomes 
(ELICIT)   
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
 
Sponsored by: 
 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by: 
Merck & Company, Inc. 
 
 
IND # 151226 
DAIDS Document ID 38597 
 
 
 
The ACTG Comorbidities Transformative Science Group  
     Netanya Utay, MD, Chair 
 
Protocol Chair: 
Peter W. Hunt, MD 
 
 
Protocol Co-Chair:  
Sara Gianella, MD 
 
Protocol Vice Chair: 
Davey Smith, MD, MAS 
 
DAIDS Clinical Representative: 
Lawrence Fox, MD, PhD 
 
Clinical Trials Specialist: 
Preeti Dhillon, MPH 
 
 
FINAL Version 3.0 
02 December 2022


 
 
A5383 
 
 
FINAL Version 3.0 
 
 
02Dec2022 
 
 
A5383 
 
Randomized, Controlled Trial to Evaluate the Anti-inflammatory Efficacy of Letermovir 
(Prevymis) in Adults with Human Immunodeficiency Virus (HIV)-1 and Asymptomatic 
Cytomegalovirus (CMV) Who Are on Suppressive ART and Its Effect on Chronic Inflammation, 
HIV Persistence, and Other Clinical Outcomes 
(ELICIT)    
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 


A5383 
 
 
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TABLE OF CONTENTS 
Page 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ........................................................................................................... 10 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 
SCHEMA .................................................................................................................................. 14 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 15 
1.1 
Primary Hypothesis ............................................................................................ 15 
1.2 
Secondary Hypotheses ...................................................................................... 15 
1.3 
Exploratory Hypotheses ..................................................................................... 15 
1.4 
Primary Objective ............................................................................................... 17 
1.5 
Secondary Objectives ........................................................................................ 17 
1.6 
Exploratory Objectives ....................................................................................... 18 
2.0 
INTRODUCTION ........................................................................................................... 19 
2.1 
Background ........................................................................................................ 19 
2.2 
Rationale ........................................................................................................... 24 
3.0 
STUDY DESIGN ........................................................................................................... 27 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 28 
4.1 
Inclusion Criteria ................................................................................................ 28 
4.2 
Exclusion Criteria ............................................................................................... 30 
4.3 
Study Enrollment Procedures............................................................................. 32 
4.4 
Co-enrollment Guidelines ................................................................................... 34 
5.0 
STUDY TREATMENT ................................................................................................... 34 
5.1 
Regimens, Administration, and Duration ............................................................ 34 
5.2 
Study Product Formulation and Storage ............................................................ 35 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 35 
5.4 
Concomitant Medications ................................................................................... 35 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 38 
6.1 
Schedule of Evaluations..................................................................................... 38 
6.2 
Timing of Evaluations ......................................................................................... 41 
6.3 
Instructions for Evaluations ................................................................................ 45 
6.4 
Immunologic Studies .......................................................................................... 49 
6.5 
Virologic Studies ................................................................................................ 50 
6.6 
Stored Plasma/Peripheral Blood Mononuclear Cells (PBMCs)/Serum ............... 50 
6.7 
Plasma Pharmacokinetic (PK) Sampling ............................................................ 50 
6.8 
Adherence Assessment ..................................................................................... 51 
6.9 
Genital and Oral Secretion Collection ................................................................ 51 
6.10 
Rectal Swab Collection ...................................................................................... 52 
6.11 
Physical Function Testing .................................................................................. 52 
6.12 
Brief Neuropsychological (NP) Testing and Limited Neurophysiological 
Evaluations ....................................................................................................... 52 
6.13 
Questionnaires ................................................................................................... 52 


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TAB LE OF CONTENTS (Cont’d) 
Page 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 53 
7.1 
Definition of Adverse Events .............................................................................. 53 
7.2 
Adverse Event Collection Requirements for this Protocol ................................... 53 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 54 
7.4 
Study Monitoring ................................................................................................ 55 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 57 
8.1 
Toxicity .............................................................................................................. 57 
8.2 
Other Conditions (Specific Management of Toxicities Related to Study-Provided 
Drugs) ................................................................................................................ 58 
8.3 
Pregnancy.......................................................................................................... 59 
8.4 
SARS-CoV-2/COVID-19 Infection ...................................................................... 59 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 59 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 59 
9.2 
Premature Study Discontinuation ....................................................................... 59 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 60 
10.1 
General Design Issues ....................................................................................... 60 
10.2 
Outcome Measures ............................................................................................ 60 
10.3 
Randomization and Stratification ........................................................................ 62 
10.4 
Sample Size and Accrual ................................................................................... 63 
10.5 
Data and Safety Monitoring ................................................................................ 66 
10.6 
Analyses ............................................................................................................ 69 
11.0 
 PHARMACOLOGY PLAN ............................................................................................. 71 
11.1 
Pharmacology Objectives .................................................................................. 72 
11.2 
Pharmacology Study Design .............................................................................. 72 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 73 
12.1 
Records to Be Kept ............................................................................................ 73 
12.2 
Role of Data Management ................................................................................. 73 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 73 
13.0 
PARTICIPANTS ............................................................................................................ 74 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 74 
13.2 
Participant Confidentiality ................................................................................... 74 
13.3 
Study Discontinuation ........................................................................................ 74 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 74 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 74 
16.0 
REFERENCES .............................................................................................................. 76 
INFORMED CONSENT FORM AND  AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION ....................................................................... 82 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
A5383 is a multicenter study open to all US ACTG clinical research sites (CRSs).  
 
 
 


 
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PROTOCOL TEAM ROSTER 
 
Chair 
Peter Hunt, MD 
University of California, San Francisco 
HIV/AIDS CRS, SFGH Building 3, 6th Floor 
1001 Potrero Avenue, Room 605B 
San Francisco, CA 94110 
Phone: 628-206-8165 
E-mail: peter.hunt@ucsf.edu 
 
Co-Chair 
Sara Gianella, MD 
University of California, San Diego AntiViral 
Research Center CRS 
Center For AIDS Research (CFAR)  
9500 Gilman Drive 
La Jolla, CA 92093-0679 
Phone: 858-552-8585 Ext. 7193 
E-mail: gianella@ucsd.edu 
 
Vice Chair 
Davey Smith, MD, MAS 
University of California, San Diego AntiViral 
Research Center CRS, MC 820 
8220 Dickinson Street, Suite A 
San Diego, CA 92103 
Phone: 619-543-8080 
E-mail: davey@ucsd.edu 
 
DAIDS Clinical Representative  
Lawrence Fox, MD, PhD 
DAIDS/NIAID/NIH/DHHS 
5601 Fishers Lane, Rm 9E41 
Rockville, MD 20852 
Phone: 240-627-3069 
E-mail: lfox@niaid.nih.gov  
 
Clinical Trials Specialist 
Preeti Dhillon, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 
Phone: 301-628-3017 
E-mail: preeti.dhillon@dlhcorp.com 
 
Statisticians 
Douglas Kitch, MS 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 501, 651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-3281 
E-mail: dkitch@sdac.harvard.edu 
 
Eunice Yeh, MS 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 506, 651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-3023 
E-mail: eyeh@sdac.harvard.edu 
 
Data Manager 
Summer Oliver, BA  
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 Ext. 7329 
E-mail: oliver@frontierscience.org 
 
DAIDS Pharmacist 
Cynthia Parker, PharmD, RPh 
OSCO, DAIDS, NIAID, NIH 
Pharmaceutical Affairs Branch 
5601 Fishers Lane, 9D37 
Rockville, MD 20852 
Phone: 301-761-7199 
E-mail: cindy.parker@nih.gov 
 
Immunologist 
Michael Freeman, PhD 
Case Western Reserve University 
Division of Infectious Diseases 
2109 Adelbert Road, BRB 1034 
Cleveland, OH 44106 
Phone: 216-368-1260  
Lab: 216-368-4853 
E-mail: mlf62@case.edu 
 


 
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Virologist  
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 
 
Neurologist 
Scott Letendre, MD 
University of California, San Diego Antiviral 
Research Center CRS 
220 Dickinson Street 
Suite 200 
San Diego, CA 92103 
Phone: 619-543-8080 
E-mail: sletendre@ucsd.edu 
 
Pharmacologists 
Francesca Aweeka, PharmD 
Clinical Pharmacy 
University of California, San Francisco 
P.O. Box 0622, C152, 521 Parnassus Ave. 
San Francisco, CA 94143-0622 
Phone: 415-476-0339 
E-mail: fran.aweeka@ucsf.edu 
 
Pharmacologists (Cont'd)  
Amelia N. Deitchman, PharmD, PhD 
Clinical Pharmacy 
University of California, San Francisco 
1001 Potrero Ave., Building 100, Room 157 
San Francisco, CA 94110 
Phone: 415-476-1148  
E-mail: amelia.deitchman@ucsf.edu 
 
Neuropsychologist 
Leah Rubin, PhD, MPH 
Department of Neurology,  
Johns Hopkins University 
600 N. Wolfe Street, Meyer 6-113a 
Baltimore, MD 21287 
Phone: 410-955-7311  
E-mail: lrubin@jhu.edu 
 
Cardiac FDG/PET Imaging  
Ahmed A. Tawakol, MD 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-6750 
E-mail: atawakol@mgh.harvard.edu 
 
Cardiologist 
Priscilla Hsue, MD 
University of California, San Francisco  
Room 5G1, Cardiology SFGH 
1001 Potrero Avenue 
San Francisco, CA 94110 
Phone: 415-206-8257 
E-mail: Priscilla.Hsue@ucsf.edu  
 
Investigators 
Michael Dube, MD 
University of Southern California 
Infectious Diseases/Medicine 
1300 North Mission Road, Room 349 
Los Angeles, CA 90033 
Phone: 323-409-8288 
E-mail: mdube@usc.edu 
 
Kristine Erlandson, MD 
University of Colorado, Denver 
Department of Medicine, Division of 
Infectious Diseases, Mail Stop B168 
12700 East 19th Avenue 
Aurora CO 80045 
Phone: 303-724-4941  
E-mail: kristine.erlandson@ucdenver.edu 
 
Martin Hoenigl, MD 
University of California at San Diego AVRC 
CRS Laboratory, 200 Dickinson Street 
San Diego, CA 92103  
Phone: 619-543-8080 
E-mail: mhoenigl@ucsd.edu 
 


 
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Investigators (Cont'd) 
John Koethe, MD 
Vanderbilt Therapeutics (VT) CRS 
Infectious Disease-Medicine 
A 2200 MCN, 1161 21st Avenue, South 
Nashville, TN 37232 
Phone: 615-322-2035 
E-mail: john.r.koethe@vumc.org 
 
Khuanchai Supparatpinyo, MD 
Research Institute for Health Sciences 
Chang Mai University 
Chang Mai, Thailand 
Phone: 66-86-7303300 
E-mail: khuanchai@rihes.org 
 
Christophe Vanpouille, PhD 
National Institute of Child Health and 
Human Development 
NIH 9000 Rockville Pike 
Building 29B, Room 1E18 
Bethesda, MD 20892 
Phone: 301-594-0826 
E-mail: vanpouic@mail.nih.gov 
 
Noel Kayange, MBBS, MMED 
Johns Hopkins Research Project 
Chiptala Avenue, P.O. Box 1131 
Blantyre 265 
Malawi 
Phone: 265-187-4129  
E-mail: noelkay@yahoo.co.uk 
 
Field Representative 
Joan Gottesman, BSN, RN, CCRP 
Vanderbilt Therapeutics (VT) CRS 
One Hundred Oaks 
719 Thompson Lane, Suite 47183 
Nashville, TN 37204 
Phone: 615-936-7143 
E-mail: joan.gottesman@vumc.org  
 
Laboratory Technologist 
Brian Clagett, BA 
Case CRS 
BRB, Room 1048B, 2109 Adelbert Road 
Cleveland, OH 44106 
Phone: 216-368-4853 
E-mail: bmc@case.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Laurency Gaston 
The Ponce de Leon Center CRS 
300 Pat Mell Road #44D 
Marietta, GA 30060 
Phone: 770-256-2147 
E-mail: gastonshouse@hotmail.com 
 
Industry Representative  
Barbara Haber, MD 
Merck and Company Inc. 
UG3D-23, 351 N. Sumneytown Pike 
P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: 267-305-3729 
E-mail: barbara.haber@merck.com 
 
Laboratory Data Managers 
David Vlieg 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14266 
Phone: 716-834-0900 Ext. 7333 
E-mail: vlieg@frontierscience.org 
 
Kyle Whitson, MA RHIA 
Lead Laboratory Data Manager 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14266 
Phone: 716-834-0900 extension 7273 
E-mail: whitson@frontierscience.org  
 
 


 
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Laboratory Specialist 
Emma Duffy 
ACTG Laboratory Center at UCLA 
675 Charles E. Young Drive  
South MRL 4-774 
Los Angeles, CA 90095 
Phone: 617-407-8713 
E-mail: eduffy@milabcentral.org 


 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5383@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5383@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5383 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 vaccines, and co-
enrollment, contact the Clinical Management Committee (CMC).  
 
Send an e-mail message to actg.CMCa5383@fstrf.org. Include the protocol number, 
participant 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.teamA5383@fstrf.org (ATTENTION: Michael Freeman, 
Immunologist; Joshua Cyktor, Virologist; Francesca Aweeka and Amelia Deitchman, 
Pharmacologists). 
 
Data Management 
 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
 
For transfers, reference the Study Participant Transfer SOP 119, and contact Summer 
Oliver directly.  
 
For other questions, send an e-mail message to actg.teamA5383@fstrf.org (ATTENTION: 
Summer Oliver).  
 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification number 
SID lists:  
 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 


 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist.  
 
Send an e-mail message to actg.teamA5383@fstrf.org (ATTENTION: Preeti Dhillon). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialist.  
 
Send an e-mail message to actg.teamA5383@fstrf.org (ATTENTION: Preeti Dhillon). 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Cynthia Parker, Protocol Pharmacist, at 301-496-8213.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5383 team members.  
 
Send an e-mail message to actg.teamA5383@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 
 
alloHSCT 
allogeneic hematopoietic stem cell transplant 
ART 
 
antiretroviral therapy 
CAT-MH 
Computerized Adaptive Testing for Mental Health  
COVID-19 
coronavirus disease 2019 
CI 
 
confidence interval 
CMC  
Clinical Management Committee 
CMV  
cytomegalovirus 
CNS 
 
central nervous system 
CrCl 
 
creatinine clearance 
CSF 
 
cerebrospinal fluid 
eGFR  
estimated glomerular filtration rate 
ECG 
 
electrocardiography 
ENT 
 
entry 
GAD-7  
Generalized Anxiety Disorder-7 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GTEx  
Genotype-Tissue Expression 
HIV 
 
human immunodeficiency virus 
HOMA-IR 
homeostatic model assessment-insulin resistance  
HR 
 
heart rate 
HSCT  
hematopoietic stem cell transplantation  
IgG 
 
immunoglobulin G 
IOT 
 
initiation of treatment 
IP 
 
inducible protein 
IRIS 
 
Immune Reconstitution Inflammatory Syndrome 
IUD 
 
intrauterine device 
KT 
 
kynurenine-to-tryptophan 
M-CSF  
macrophage colony-stimulating factor 
MCP  
monocyte chemotactic protein 
MIP 
 
macrophage inflammatory protein 
NFL 
 
neurofilament light 
NIAID  
National Institute of Allergy and Infectious Diseases 
NRTI  
nucleoside reverse transcriptase inhibitors 
PAP 
 
plasmin-alpha2-antiplasmin 
PHQ-9  
Patient Health Questionnaire-9 


 
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PK 
 
pharmacokinetics  
RANTES 
regulated on activation, normal T-cell expressed and secreted 
RDW  
red blood cell distribution width 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 
SIV 
 
simian immunodeficiency virus 
SMC  
safety monitoring committee 
suPAR  
soluble urokinase plasminogen activator receptor 
STD 
 
sexually transmitted disease 
sTNFRII 
soluble receptor for tumor necrosis factor type II 
TCR 
 
T cell receptor 
TEM 
 
T effector memory cell 
TEMRA 
terminally differentiated effector memory  
TGF 
 
transforming growth factor 
TNFα  
tumor necrosis factor alpha 
VACS  
Veterans Aging Cohort Study 


 
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SCHEMA 
 
A5383 
Randomized, Controlled Trial to Evaluate the Anti-inflammatory Efficacy of Letermovir 
(Prevymis) in Adults with Human Immunodeficiency Virus (HIV)-1 and Asymptomatic 
Cytomegalovirus (CMV) Who Are on Suppressive ART and Its Effect on Chronic Inflammation, 
HIV Persistence, and Other Clinical Outcomes 
(ELICIT)   
 
 
DESIGN 
A5383 is a phase II, randomized, open-label, controlled, multicenter trial 
being conducted at US sites to evaluate anti-inflammatory efficacy of 
letermovir 480 mg once daily for 48 weeks in adults with HIV and 
asymptomatic cytomegalovirus (CMV) maintaining antiretroviral therapy 
(ART)-mediated suppression. A futility analysis will be performed after the 
first 40 participants reach their 8-week study visit. 
 
 
DURATION 
60 weeks (48 weeks on either letermovir or no anti-CMV treatment with 
12 weeks of post-treatment period follow-up).  
 
 
SAMPLE SIZE 
180 participants (90 Arm A: letermovir, 90 Arm B: no anti-CMV 
treatment). 
 
 
POPULATION 
Adults ≥40 years of age with HIV and asymptomatic CMV, with HIV RNA 
suppression for ≥48 weeks on combination ART. 
 
 
STRATIFICATION 
Participants will be stratified by sex at birth and use of sex hormones as 
well as by screening CD4+ T cell count. Our goal is that at least one third 
(30 participants in each arm) will be individuals assigned female sex at 
birth not on testosterone or individuals assigned male sex at birth on 
feminizing sex hormones. Further, we also aim to enroll at least one half 
(45 participants) in each arm with CD4+ T cell counts <350 cells/mm3.   
 
 
REGIMEN 
Participants will be randomized 1:1 to receive either letermovir 480 mg 
once daily (Arm A) or no anti-CMV treatment (Arm B) for 48 weeks.


 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Primary Hypothesis 
 
Letermovir will cause a greater reduction in plasma soluble receptor for tumor necrosis 
factor type II (sTNFRII) levels than no anti-CMV treatment at weeks 46/48. 
 
1.2 
Secondary Hypotheses  
 
1.2.1 Letermovir (480 mg once daily) will be generally tolerable over the 48 week study 
treatment period as compared to no anti-CMV treatment. 
 
1.2.2 Letermovir will reduce the frequency of detection and levels of cytomegalovirus 
(CMV) DNA in mucosal samples (throat wash, seminal plasma, and 
cervicovaginal swabs) and in blood plasma compared to no anti-CMV treatment, 
through 48 weeks of treatment. This effect will persist for 4 weeks following 
treatment discontinuation (i.e., at week 52), and return to baseline by week 60. 
 
1.2.3 Letermovir will cause a greater reduction in plasma sCD163 levels than no anti-
CMV treatment at weeks 8, 46/48, and 52, but not at week 60. 
 
1.2.4 Letermovir will cause greater reductions in plasma sTNFRII than no anti-CMV 
treatment at weeks 8 and 52, but not at week 60. 
 
1.3 
Exploratory Hypotheses 
 
1.3.1 Letermovir will cause a greater reduction in inflammatory and coagulation 
markers (sCD14, IL-6, hsCRP, and D-Dimer) than no anti-CMV treatment at 
weeks 8 and 46/48, differences that will persist at week 52, but return to baseline 
by week 60.  
 
1.3.2 Monocyte activation (cellular markers of monocyte activation, e.g., 
CD14varCD16+): Letermovir will reduce monocyte activation at weeks 8 and 48 
compared to no anti-CMV treatment, an effect that will persist for at least 4 
weeks after discontinuing study treatment. 
 
1.3.3 CMV-specific response: Letermovir will reduce CMV immunoglobulin G (IgG) titer 
and CMV-specific T cell response (reduced clonality of T cell receptor [TCR]) at 
week 48 compared to no anti-CMV treatment.   
 
1.3.4 Microbial translocation markers (B-D-Glucan, I-FABP, LBP, Zonulin): Letermovir 
will reduce biomarkers of microbial translocation at weeks 46/48 compared to no 
anti-CMV treatment, an effect that will persist for at least 4 weeks after stopping 
study treatment. 
 


 
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1.3.5 Multiplex-bead-array assay: Letermovir will modulate the cytokines network from 
baseline to weeks 8 and 46/48, compared to no anti-CMV treatment, an effect 
that will persist for at least 4 weeks after stopping study treatment.   
 
1.3.6 Detailed markers of coagulation: Letermovir will decrease markers of the 
coagulation cascade (including soluble urokinase plasminogen activator receptor 
[suPAR], plasmin-alpha2-antiplasmin complex [PAP], prothrombin fragment 1+2) 
at weeks 46/48 compared to no anti-CMV treatment. 
 
1.3.7 Letermovir will result in a greater reduction in soluble markers of endothelial 
activation at weeks 8 and 46/48 than no anti-CMV treatment (sICAM-1, sVCAM-
1, sTF, E-selectin, P-selectin), an effect that will persist for at least 4 weeks after 
stopping study treatment. 
 
1.3.8 T cell dysfunction: Letermovir will reduce T cell dysfunction (including but not 
limited to decreased activation [CD38+/HLA-DR co-expression], and exhaustion 
[PD-1] markers) in blood at weeks 8 and 48 and both decrease senescence 
markers (CD28-CD57+ T cells) and increase CD4+/CD8+ ratio at week 48, when 
compared to those receiving no anti-CMV treatment, differences that will persist 
for at least 4 weeks after study treatment discontinuation [Freeman et al., 2016; 
Fromentin et al., 2016; Smith et al., 2016].  
 
1.3.9 Insulin resistance: Letermovir will result in greater reductions in insulin resistance 
than no anti-CMV treatment at week 46 by homeostatic model assessment-
insulin resistance (HOMA-IR) and plasma levels of free fatty acids, differences 
that will persist for at least 4 weeks after study treatment discontinuation.  
 
1.3.10 Plasma free fatty acids: Letermovir will result in greater reductions in fasting free 
fatty acids, an indirect measure of adipocyte insulin sensitivity and lipid storage, 
than no anti-CMV treatment at week 46, differences that may persist for at least 4 
weeks after study treatment discontinuation. 
 
1.3.11 Letermovir will result in greater improvements than no anti-CMV treatment in 
physical function as assessed by chair rise time and frailty score (gait speed, grip 
strength) at week 46, differences that will persist for at least 4 weeks after study 
treatment discontinuation.  
 
1.3.12 Veterans Aging Cohort Study (VACS) index: Letermovir will result in greater 
improvements in VACS index than no anti-CMV treatment at weeks 46 and 60. 
 
1.3.13 HIV Reservoir: Letermovir will reduce the size of the HIV-1 reservoir as 
measured by cell-associated HIV-1 DNA at weeks 8 and 48 when compared to 
those receiving no anti-CMV treatment.  
 
1.3.14 HIV Reservoir Sequencing: Letermovir will reduce the clonality of the HIV 
reservoir in blood at week 48 when compared to those receiving no anti-CMV 
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1.3.15 Letermovir will reduce the transcriptional activity of the HIV-1 reservoir as 
measured by single copy assays of plasma HIV-1 RNA and cell-associated HIV-1 
RNA at the week 8 and 48 time points when compared to those receiving no anti-
CMV treatment.  
 
1.3.16 Letermovir will not have clinically significant (i.e., requiring dose adjustment) 
interactions with common ART drugs (i.e., TDF/TAF and integrase inhibitors) or 
allowed statins. 
 
1.3.17 Plasma letermovir levels during treatment will correlate with the extent of 
reduction in sTNFRII and CMV DNA shedding levels.  
 
1.3.18 Letermovir will alter the plasma proteome as assessed by a modified aptamer 
assay (SOMAscan), including pathways linked to cardiovascular risk. 
 
1.3.19 Central nervous system (CNS) tolerability of letermovir: Change in 
neurocognitive performance, mood, sleep quality, concentrations will each be 
similar to or better than no anti-CMV treatment at week 46. Change in 
Neurofilament light (NFL) in blood plasma will be similar or better than no anti-
CMV treatment at weeks 46/48.  
 
1.3.20 Letermovir resistance: Among letermovir-treated participants with persistent 
detectable CMV shedding, the emergence of letermovir resistance mutations will 
be observed in mucosal sites, but not plasma, and will no longer be detected at 
week 60. 
 
1.3.21 Flu vaccine responsiveness: Letermovir will reduce the humoral response to 
seasonal influenza vaccination obtained in the course of clinical care 
compared to no anti-CMV treatment (fold change from the last pre-vaccine 
time point to the first available time point between 4-12 weeks post-vaccine).  
 
1.4 
Primary Objective 
 
To determine whether letermovir 480 mg daily at weeks 46/48 will result in decreased 
plasma sTNFRII levels compared to no anti-CMV treatment in treated individuals with 
HIV. 
 
1.5 
Secondary Objectives 
 
1.5.1 Tolerability: To determine whether letermovir 480 mg daily for 48 weeks is safe 
and tolerable in treated individuals with HIV.  
 
1.5.2 CMV DNA levels: To determine if letermovir reduces mucosal and plasma levels 
of CMV DNA in treated individuals with HIV through 48 weeks of therapy and 
following treatment discontinuation.  
 


 
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1.5.3 To evaluate if letermovir reduces plasma sCD163 levels at weeks 8, 46/48, 52, 
and 60. 
 
1.5.4 To evaluate if letermovir reduces plasma sTNFRII levels at weeks 8, 52 and 60. 
 
1.6 
Exploratory Objectives 
 
1.6.1 To evaluate if letermovir affects inflammatory and coagulation markers (sCD14, 
IL-6, hsCRP, and D-Dimer) at weeks 8, 46/48, 52, and 60.  
 
1.6.2 Monocyte activation (cellular markers of monocyte activation): To evaluate if 
letermovir reduces monocyte activation at weeks 8, 48, 52, and 60. 
 
1.6.3 CMV-specific response: To evaluate if letermovir affects CMV IgG titer and CMV-
specific T cell response (reduced clonality of TCR) at week 48. 
 
1.6.4 Microbial translocation markers (B-D-Glucan, I-FABP, LBP, Zonulin): To evaluate 
if letermovir affects biomarkers of microbial translocation at weeks 8, 46/48, 52, 
and 60. 
 
1.6.5 Multiplex-bead-array assay: To evaluate if letermovir affects the cytokines 
network at weeks 8, 46/48, 52, and 60.   
 
1.6.6 Detailed markers of coagulation: To evaluate if letermovir affects the coagulation 
cascade (including suPAR, plasmin antiplasmin complexes, prothrombin 
fragment 1+2) at weeks 8, 46/48, 52, and 60. 
 
1.6.7 To evaluate if letermovir reduces soluble markers of endothelial activation at 
weeks 8, 46/48, 52, and 60. 
 
1.6.8 To evaluate if letermovir affects T cell dysfunction in blood at study weeks 8, 48, 
52, and 60.  
 
1.6.9 To evaluate if letermovir reduces insulin resistance at weeks 46 and 60.  
 
1.6.10 To evaluate if letermovir reduces plasma fasting free fatty acids at weeks 46 and 60.  
 
1.6.11 To evaluate if letermovir improves physical function and frailty at weeks 46 and 60.  
 
1.6.12 VACS index: To evaluate if letermovir improves the VACS index at weeks 46 and 
60. 
 
1.6.13 HIV Reservoir: To evaluate if letermovir reduces the size of the HIV-1 reservoir 
as measured by cell-associated HIV-1 DNA at study weeks 8 and 48.  
 
1.6.14 HIV Reservoir Sequencing: To evaluate if letermovir reduces the clonality of the 
HIV reservoir in blood at study week 48.  


 
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1.6.15 To evaluate if letermovir affects the transcriptional activity of the HIV-1 reservoir 
as measured by single copy assays of plasma HIV-1 RNA and cell-associated 
HIV-1 RNA at the week 8 and 48 timepoints.  
 
1.6.16 To evaluate interactions between letermovir and common ART drugs and 
statins. 
 
1.6.17 To evaluate correlations between plasma letermovir levels during treatment with 
the extent of reduction in sTNFRII and CMV DNA shedding levels.  
 
1.6.18 To evaluate if letermovir affects plasma proteome, including pathways linked to 
cardiovascular risk. 
 
1.6.19 To evaluate the CNS tolerability of letermovir: The tolerability measures will 
include change in neurocognitive performance, mood, sleep quality, and NFL 
concentrations in blood plasma. 
 
1.6.20 Letermovir resistance: To evaluate emergence of letermovir resistance mutations 
in participants with persistent detectable CMV shedding during study period.   
 
1.6.21 Flu vaccine responsiveness: To evaluate if letermovir affects the humoral 
response to seasonal influenza vaccination obtained in the course of 
clinical care (fold change from the last pre-vaccine time point to the first 
available time point between 4-12 weeks post-vaccine).  
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
CMV, Inflammation and End-organ Disease in Treated Individuals with HIV  
Among all viruses, CMV has one of the most dynamic and comprehensive interactions 
with the human immune system. In this complex host-virus relationship, the virus elicits 
and maintains high frequency of CMV-specific T cells that are engaged in a life-long fight 
to restrict CMV replication and prevent life-threating disease [Sylwester et al., 2005; 
Waldrop et al., 1997]. As people age with CMV, repeated immune activation and 
response to CMV can drive T cells toward a more differentiated phenotype [Di Benedetto 
et al., 2015; Gordon et al., 2017], which may promote replicative exhaustion and 
senescence [Fletcher et al., 2005]. Senescent T cells frequently bear antigen specificity 
toward CMV [Appay et al., 2011; Deeks et al., 2012; Looney et al., 1999], and the 
abundance of senescent T cells has been associated with negative outcomes in older 
adults including frailty, cardiovascular disease, and systemic infections [Deeks et al., 
2009; Kaplan et al., 2011; Nieto et al., 1996; Spyridopoulos et al., 2016]. These 
inflammatory effector CD8+ T cells typically migrate to tissues where they—along with 
low-level CMV replication itself—may contribute to local inflammation and chronic 
disease. In the context of treated individuals with HIV, CMV seropositive adults have 
higher markers of inflammation that predict morbidity and mortality (e.g., sTNFRII, 
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CD4+/CD8+ T cell ratios compared to CMV-seronegative adults [Freeman et al., 2016; 
Limaye et al., 2017; Smith et al., 2016]. 
 
sCD163, IL-6, and hsCRP have been associated with CMV infection and predict 
morbidity and mortality in treated HIV infection. Given that CMV has been shown to 
stimulate the expression of thrombogenic activity on cells independent of vascular 
damage, and to promote cell-independent thrombin production, we will also collect 
citrated plasma samples (collected into conventional blue top tubes containing 3.2% 
sodium citrate) and measure D-Dimer (among other coagulation markers in exploratory 
markers). 
 
CMV and HIV DNA Reservoir 
Chronic inflammation and immune activation contribute to maintenance of the HIV 
reservoir during ART [Christensen-Quick et al., 2017; Hatano, 2013]. Recent studies 
have demonstrated that asymptomatic CMV seminal shedding is associated with higher 
levels of total HIV DNA in both ART naïve individuals [Gianella et al., 2012] and in 
individuals suppressed on long-term ART [Gianella et al., 2014]. In a large longitudinal 
study of individuals followed since the earliest phase of HIV infection, CD4+ T cell 
associated HIV DNA in blood was associated with the frequency of detectable CMV 
DNA in blood cells over time [Gianella et al., 2015]. Although the observational design of 
these studies does not allow causal inference, the findings do support the conclusion 
that asymptomatic CMV shedding in genital secretions and in blood drives local and 
systemic immune activation with a subsequent increase in the latent HIV reservoir. For 
this reason, targeting drivers of chronic inflammation, like CMV, could contribute to HIV 
curative strategies. We will use longitudinal blood samples collected as part of this trial 
to determine the effect of suppressing CMV replication with letermovir on HIV 
persistence, in terms of circulating reservoir size and clonality as well as to explore the 
mechanisms underlying these changes (assays will be funded through a funded NIAID 
R01 to Dr. Gianella).  
 
Evidence for a Causal Role of CMV Driving Immune Activation in Treated HIV Infection 
The link between CMV shedding and systemic inflammation during HIV infection has 
been examined in a randomized controlled study conducted by Dr. Hunt that showed a 
reduction in T cell immune activation when people with HIV were treated with the anti-
CMV drug valganciclovir [Hunt et al., 2011]. Recent analysis of samples from this trial 
further revealed nearly an entire quartile reduction in sTNFRII as well as significant 
reductions in sCD163 and sCD14 levels in the valganciclovir arm [Beck-Engeser et al., 
2019], strongly suggesting an immunologic benefit of treating asymptomatic CMV co-
infection in this setting (Refer to Figure 2.2-1). While this study was limited in that only 
70% of the participants had HIV RNA suppression with ART (though there was a 
significant effect on immune activation even in the ART-suppressed subset) and the 
sample size was small (n=30), it did show a sustained reduction in CMV shedding and 
immune activation after just 8 weeks that persisted for at least 4 weeks after 
valganciclovir discontinuation. The findings support our hypothesis about CMV shedding 
and immune activation. If correct, the anti-inflammatory benefit of reducing CMV 
replication could accumulate over time, which may support a study of intermittent use of 
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While this prior trial of valganciclovir remains one of the few anti-CMV interventional trials 
that demonstrated improvement in immune activation, the trial had several limitations that 
precluded moving forward with clinical endpoint trials of anti-CMV therapy. First, 
valganciclovir’s toxicity (cytopenias and teratogenicity) creates challenges for long-term 
use. Second, insufficient evidence was generated to definitively conclude that key 
inflammatory pathways that predict disease outcome (e.g., other inflammatory markers, 
CD4+/CD8+ ratio) or cardiovascular surrogate markers were affected. The trial’s short 8-
week duration also limited the analysis of longer-lived T cell subsets like effector and 
senescent T cells. For example, terminally differentiated effector memory (TEMRA) CD4+ 
T cells from ART-suppressed individuals, which are dominated by CMV-specific cells, 
have an average half-life of nearly 9 months. TEMRA CD8+ T cells also appear quite long-
lived in simian immunodeficiency virus (SIV) models using similar direct measures of 
cellular turnover [Hansen et al., 2013a; Hansen et al., 2013b]. Thus, many months of 
suppression of CMV replication may be required to stop and/or reverse the negative 
contribution of CMV-specific effector CD8+ T cells to end-organ disease. Enrollment in the 
above trial was also limited to individuals with incomplete CD4+ T cell recovery on ART (all 
CD4+<350). Thus, it remains unclear whether inhibiting CMV shedding would benefit 
immune activation in individuals with normal CD4+ T cell count recovery on ART. Lastly, 
there were very few female participants in the valganciclovir trial, and as the effects of 
chronic viral infections on the immune system may differ by sex [Meier et al., 2009], it is 
unclear whether treating CMV would have the same or perhaps even greater effects 
among female participants. These issues will be addressed in the current protocol. 
 
Lastly, it is possible that CMV-mediated interferon- expression might actually 
contribute to more robust humoral responses to influenza. Indeed, in a recent 
study of healthy young adults without HIV receiving seasonal influenza 
vaccination, those who were CMV-seropositive had a greater fold-increase in 
influenza-specific IgG titers following vaccination than those who were CMV-
seronegative [Furman et al., 2015]. In that same publication, CMV-induced 
interferon- expression was shown to mediate enhanced protection against 
influenza challenge in a murine model. While it is unlikely that these CMV-
associated differences in flu vaccine response are clinically significant, our trial 
provides an opportunity to test the hypothesis that asymptomatic CMV replication 
contributes to influenza vaccine response for the first time in humans.    
 
CMV and Neurocognitive Dysfunction 
The CNS is a long-recognized site of CMV end-organ disease in advanced AIDS (e.g., 
retinitis, periventriculitis). Pathological changes at postmortem in Alzheimer’s disease 
have been linked to CMV. For instance, brain tissue donated by Catholic clergy with few 
confounding conditions showed that higher lifetime anti-CMV IgG titers were associated 
with the presence of neurofibrillary tangles at death [Lurain et al., 2013]. CMV-infected 
individuals in the early stages of multiple sclerosis showed greater generalized brain 
atrophy over time than CMV-participants [Zivadinov et al., 2014].  
 
Further, Dr. Letendre recently reported that higher anti-CMV IgG titer was associated 
with greater neurocognitive impairment in the CHARTER study [Letendre et al., 2018], a 
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al., 2010]. While CMV DNA was found in few cerebrospinal fluid (CSF) samples in the 
small, cross-sectional CHARTER analysis, a role for migrating CMV-specific CD8+ T 
cells or low-level CMV replication in the brain cannot be excluded.  
 
Similarly, a role of CMV in contributing to psychiatric diseases like depression and sleep 
disturbance have been debated in the psychiatry field [Simanek et al., 2014] and our 
own team has generated some data linking the immune activation pathways thought to 
be driven by CMV to depression in HIV infection [Martinez et al., 2014]. Kiecolt-Glaser 
and Glaser demonstrated in the 1980s that periods of psychological stress can lead to 
the reactivation of CMV [Glaser et al., 1985; Kiecolt-Glaser et al., 1984; Kiecolt-Glaser et 
al., 1988] and this finding has been borne out by more recent studies that have also 
highlighted the association between psychological stressors and herpesvirus titers 
[Fagundes et al., 2013; Janicki-Deverts et al., 2014; Shirtcliff et al., 2009]. Several 
studies have reported higher IgG CMV antibody titers in depressed vs. non-depressed 
participants with cardiovascular disease [Appels et al., 2000; Miller et al., 2005; Rector et 
al., 2014] and higher IgM titers were found to be associated with suicide attempts in 
participants with mood disorders [Dickerson et al., 2017]. Recently, the Detroit  
Neighborhood Health Study showed that individuals with CMV antibody titers in the top 
quartile were four times more likely to be depressed than those individuals in the bottom 
three quartiles of the population [Simanek et al., 2014]. 
 
Determining whether inhibiting low-level CMV shedding improves neuroinflammation, 
neuronal injury, neurocognitive performance, and mood is highly relevant to the ACTG 
Neurology Collaborative Science Group scientific agenda. We have included brief 
assessments and a plasma biomarker of brain damage (NFL concentration) as part of 
this protocol and plan to develop a separate sub-study to perform lumbar punctures and 
detailed neurocognitive and mood assessment.  
 
CMV and Physical Function and Frailty  
In addition to the neurocognitive effects, chronic CMV has also been associated with 
frailty, in part through greater CMV-associated inflammation [Margolick et al., 2018; 
Schmaltz et al., 2005; Wang et al., 2010]. Frailty, a key aging-related syndrome of 
vulnerability, is characterized by a loss of physiologic reserve, resulting in decreased 
resiliency to stressors and ultimately an increased risk for hospitalization, 
institutionalization, or death [Fried et al., 2001]. Frailty is commonly defined through a 
phenotype of weakness (grip strength), slowness (by 4-m walking speed), weight loss, 
exhaustion, and fatigue.  
 
Even with long-term, effective ART, impairments in physical function and frailty are more 
common than expected among people aging with HIV [Hawkins et al., 2018], and have 
been associated with an increased risk of falls, hospitalizations, and mortality [Erlandson 
et al., 2019; Tassiopoulos et al., 2017]. Furthermore, the combination of both HIV 
infection and impaired physical function is associated with a greater risk of mortality than 
the presence of HIV infection or impaired function alone [Greene et al., 2014; Piggott et 
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While more common than uninfected populations, frailty is relatively uncommon in 
middle-aged populations of persons with HIV (6% in the ACTG HAILO cohort [Erlandson 
et al., 2017]), with limited ability to detect change in the categorical scoring due to few 
frail cases. Individual objective components of frailty score assessing physical function 
such as the ability to rise from a chair, gait speed, and grip strength have similar clinical 
outcomes while using continuous outcomes to maximize power and detect changes 
across a wider range of function. Chair rise time for example, is a well-established 
measure of lower extremity strength, is associated with morbidity and mortality in the 
general population, and is a measure that is the most likely to show deficits compared to 
other physical function components [Cesari et al., 2008; Erlandson et al., 2012; Greene, 
et al., 2014].  
 
The population of adults aging with HIV is an emerging risk group for the accelerated 
development of mobility disability, and interventions to delay and prevent physical 
function impairments and frailty, and improve quality of life, are needed. CMV 
seropositivity, as measured by qualitative or quantitative CMV IgG or CMV-associated T-
cell responses have been associated with frailty in the general geriatric population 
[Margolick et al., 2018; Schmaltz et al., 2005; Wang et al., 2010], and frailty and physical  
function impairment in adults with HIV [Erlandson et al., 2015]. Whether CMV-specific 
therapy can alter physical function or frailty, however, is not known.   
 
Clinical Data Supporting Letermovir 
Letermovir (Prevymis) is a CMV DNA terminase complex inhibitor that is FDA-approved 
for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an 
allogeneic hematopoietic stem cell transplant (alloHSCT) [Bowman et al., 2017; Maidji et 
al., 2017; Marty et al., 2017]. Letermovir also has a better safety profile than 
valganciclovir. To evaluate prophylaxis with letermovir as a preventive strategy for CMV 
disease in transplant recipients at high risk for CMV reactivation, the efficacy of 
letermovir was assessed in a multicenter, double-blind, placebo-controlled phase III trial 
in 565 adult CMV-seropositive recipients of an alloHSCT. Participants were randomized 
to receive either letermovir at a dose of 480 mg once daily (adjusted to 240 mg when co-
administered with cyclosporine), or placebo. Study treatment was initiated shortly after 
alloHSCT and continued through week 14 post-transplant. Participants were monitored 
through week 24 post-transplant for the primary efficacy endpoint, with continued follow-
up through week 48 post-transplant. The primary efficacy endpoint was the incidence of 
clinically significant CMV reactivation through 24 weeks post-transplant, defined as the 
occurrence of either CMV end-organ disease, or initiation of anti-CMV pre-emptive 
therapy based on documented CMV viremia and the clinical condition of the participant.  
 
Letermovir demonstrated significant benefit compared to placebo in regard to clinically 
significant CMV disease through week 24 post-hematopoietic stem cell transplantation 
(HSCT) (18.9% vs. 44.3% cumulative rate; stratified log-rank test, two-sided p-value 
<0.0001), though this difference narrowed after discontinuation of therapy and longer 
duration of follow up. Through the week 14 post- HSCT treatment period (during 
letermovir therapy), 8% of participants in the letermovir group and 39% of participants in 
the placebo group experienced clinically significant CMV disease. Efficacy results were 
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considered safe in terms of safety and tolerability. For the primary efficacy endpoint (risk 
of clinically significant CMV infection at week 24 post-HSCT), no exposure-response 
relationship was observed. 
 
Letermovir Safety 
While there were fewer adverse events in the letermovir than placebo arms of the 
registrational trial among HSCT recipients, supporting its overall better safety profile than 
valganciclovir, cardiac events were more frequent with letermovir than placebo (12.6% 
versus 6.3%). These events included 15 cases of tachycardia (4%), 4 cases of sinus 
tachycardia (1.1%), 13 cases of atrial fibrillation (3.5%), 4 cases of atrial flutter (1.1%), 
and 5 cases of cardiac failure (1.3%). No ischemic events were reported. All of these 
events were Grade 2 or less and preclinical data do not suggest a clear mechanism by 
which letermovir might increase tachycardia or atrial arrhythmias. Nevertheless, 
electrocardiography (ECG) monitoring would be prudent in our planned trial as well as 
specific monitoring for cardiovascular events. 
 
In a fertility and early embryonic development study in rats, no effects of letermovir on 
female fertility were observed at letermovir exposures (AUC) approximately 5 times 
higher than human exposure at the recommended human dose (RHD). In male rat 
fertility studies, decreased fertility associated with irreversible testicular toxicity was 
observed at ≥180 mg/kg/day (≥3 times the human exposure at the RHD). No fertility or 
testicular effects were observed at dose levels resulting in letermovir exposures (AUC) 
similar to human exposure at the RHD) [Merck Sharp & Dohme Corp. Prevymis- 
letermovir Prescribing Information, 2017]. 
 
Letermovir Resistance 
Of note, letermovir has a lower genetic barrier to resistance as compared to gangiclovir, 
and is currently approved for CMV prophylaxis. CMV replication in the setting of HIV-
infection is mostly intermittent and low level and we expect that the potency of letermovir 
is enough to control CMV replication without developing CMV resistance in this setting.   
 
Letermovir Pharmacology 
See Pharmacology Plan, section 11.0. We propose to obtain plasma for future 
exploratory analyses to assess for potential PK drug interactions and exposure-response 
(PK/PD) between letermovir levels and study outcomes. 
 
2.2 
Rationale 
 
Rationale for Choice of Primary Inflammatory Endpoint 
The primary immunologic endpoint for the trial is the change in sTNFRII in blood from 
baseline to week 48 (measured by ELISA). This endpoint was chosen since sTNFRII is 
much higher among CMV-seropositive than CMV-seronegative individuals with HIV 
maintaining ART-mediated viral suppression [Freeman et al., 2016]. Also sTNFRII 
strongly predicts all-cause mortality, composite non-AIDS events, and specifically 
cardiovascular events in this setting [Tenorio et al., 2014; Hoenigl et al., 2019]. After 
binding with its ligand tumor necrosis factor alpha (TNFα), sTNFRII is shed from the cell 
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Centers for Disease Control and Prevention (CDC), 2013]. We also prefer to measure 
sTNFRII as the primary endpoint since TNFα is produced not just by myeloid cells, but 
also CD8+ T cells, which may be playing an important role in the pathogenesis of 
cardiovascular disease in treated HIV infection. We elected not to choose T cell 
activation as a primary endpoint as it has been less useful than innate or inflammatory 
markers in predicting clinical events in resource-rich settings, particularly in 
cardiovascular complications [Tenorio et al., 2014]. We also considered making 
CD4+/CD8+ ratio a primary endpoint marker as this predicts non-AIDS events and is also 
profoundly affected by CMV infection but chose sTNFRII as an outcome as it may 
provide more mechanistic insights. The CD4+/CD8+ ratio will nevertheless be an 
important secondary immunologic outcome. Moreover, we also chose 48 weeks as a 
duration to assess response precisely because the CD8+ T cells that produce TNFα in 
response to CMV antigens or CMV-associated inflammation may be much longer-lived 
than previously appreciated. We will also assess earlier time points to determine 
whether TNFα signaling (i.e., sTNFRII level) or CD8+ T cell counts is affected first by 
reducing CMV shedding with letermovir. 
Figure 2.2-1: Reduction of sTNFRII and sCD163 during valganciclovir treatment. Valganciclovir caused 
greater reductions (~1 quartile) in sTNFRII at 4 and 8 weeks than placebo, and nearly a quartile reduction 
in sCD163. Both sTNFRII and sCD163 declined to a greater degree with valganciclovir than placebo at 
week 8 after adjustment for concurrent fluctuations in plasma HIV RNA levels (P=0.027 and P=0.013 
respectively).   
 
Preliminary Data for sTNFRII 
Dr. Hunt’s lab pulled plasma samples from the original valganciclovir trial and assessed 
sTNFRII levels (R&D Systems, Inc. Kit) and observed significantly greater reductions in 
the valganciclovir arm than placebo at 4 and 8 weeks (P=0.011 and P=0.061; P values 
adjusted for concurrent fluctuations in plasma HIV RNA levels both <0.03; see Figure 


 
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2.2-1). The magnitude of this reduction in sTNFRII levels corresponded with an 
approximately 22% decreased risk of subsequent myocardial infarction (MI)/stroke in 
ACTG NWCS 329 [Tenorio et al., 2014]. 
 
In these preliminary data, higher baseline sTNFRII levels were strongly associated with 
greater frequencies of (CD38+HLA-DR+) CD8+ T cells (rho: 0.62, P<0.001), and with lower 
CD4+/CD8+ ratios (rho: -0.33, P=0.08). Baseline sTNFRII was also strongly associated 
with plasma kynurenine-to-tryptophan (KT) ratio (rho: 0.82, P<0.001), which has been 
linked to mortality, atherosclerosis, and depression in treated HIV infection. These data 
increase our confidence that baseline sTNFRII is an appropriate primary immunologic 
endpoint for our trial, and also that we will be able to observe a significant impact on this 
endpoint early (within the first 4-8 weeks of treatment). Subsequent analyses revealed 
significantly greater reductions in sCD163 (approximately 2/3 of a quartile reduction) in the 
valganciclovir arm than placebo at week 8 (unadjusted P=0.063, P=0.013 after adjustment 
for concurrent fluctuations in low-level plasma HIV RNA levels), supporting this marker’s 
use as a secondary immunologic marker in the planned futility analysis. 
 
Physical Function and Frailty Measures 
Repeat chair stand is a functional test of lower extremity performance that is highly 
affected by changes in muscle strength and has been proposed as a proxy measure of 
lower-extremity strength for the clinical setting [Cesari et al., 2008; Dodds et al., 2018]. 
The test requires minimal equipment (a stopwatch and a chair without arms or wheels), 
can be completed within approximately 1 minute, and is an assessment that ACTG sites 
already have experience conducting. Additional frailty measures including gait speed, 
grip strength, and subjective components of weight loss, exhaustion, and fatigue are 
already conducted at nearly all ACTG sites through protocol A5322/HAILO and will add 
minimal additional time. 
 
Changes in muscle or frailty may occur with letermovir therapy and may have important 
physiologic consequences.  
 
Futility Analysis 
The week 8 futility analysis will consist of two immunologic outcomes, sTNFRII and sCD163, 
since both of these biomarkers were reduced by nearly a quartile in the prior valganciclovir 
trial. While there is no standard threshold for stopping a clinical trial for futility, we feel that 
consideration should be given to stopping the trial early if both the sTNFRII and sCD163 
futility analyses have conditional power <20% under a range of plausible scenarios. The 
Study Monitoring Committee (SMC) will determine if the trial should be stopped early. The 
futility analysis begins after the first 40 participants who initiate study treatment have 
reached their 8 week study visit. New enrollment will pause after the 40th participant starts 
treatment and until the results of the futility analysis have been considered.   
 
Rationale for specific design choices: 
Age restriction: Enrollment is limited to adults ≥40 years of age as letermovir is indicated 
for adults [Prevymis package insert, 2017], the risk of multimorbidity is higher with older 
age, and enrichment for those expected to benefit most from the intervention is desired.  
  


 
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Stratification by CD4 count: Enrollment will be stratified based on screening CD4+ T cell 
count (<350 cells/mm3 or ≥350 cells/mm3). The rationale for this is to have a more direct 
comparison with the earlier valganciclovir trial (there has been no head to head 
comparison of letermovir versus valganciclovir for CMV suppression) and to explore 
whether there may be a role for CMV suppression to reduce immune activation not just 
among those with incomplete CD4+ T cell recovery, but also among those with 
preserved CD4+ T cell counts.  
 
Rationale for stratification by gender/sex: Since sex differences in immune response to 
viral infections have been described (both related to genetics and to hormonal status), 
we will also stratify by sex assigned by birth and gender-affirming exogenous sex 
hormone use.  
 
Rationale for observation after treatment discontinuation: Participants will be observed 
for up to 12 weeks after treatment discontinuation as the prior trial of valganciclovir 
showed a persistent effect on CMV shedding and immunologic outcomes for at least 4 
weeks after treatment discontinuation, which has been hypothesized to be a 
consequence of the reduction in immune activation (which typically promotes CMV 
shedding) [Hunt et al., 2011]. Interestingly, a similar 4-week delay in the emergence of 
CMV end-organ disease was observed in the registrational trial of letermovir following 
treatment discontinuation.  
 
3.0 
STUDY DESIGN 
 
A5383 is a phase II, randomized, open-label, controlled, multicenter trial being 
conducted at US clinical research sites (CRSs) to evaluate the anti-inflammatory efficacy 
of letermovir 480 mg once daily for 48 weeks in adults with asymptomatic CMV and HIV-
1 with ART-mediated suppression.   
 
A total of 180 participants ≥40 years of age with plasma HIV RNA <75 copies/ml using 
an FDA-approved assay and who have been on combination ART for at least 48 
weeks and who meet eligibility criteria will be randomized 1:1 to receive letermovir (Arm 
A) or no anti-CMV treatment (Arm B) for 48 weeks, followed by 12 weeks of observation 
on ART alone. The total study duration is 60 weeks. Participants will have evaluations 
per section 6.1. 
 
Enrollment will be stratified based on sex assigned at birth and use of hormonal therapy 
and by screening CD4+ T cell count. The goal is to have one third of participants in each 
arm be individuals assigned female sex at birth who are not using testosterone or 
individuals assigned male sex at birth on feminizing sex hormones. Further, the study 
aims to enroll half of all participants in each arm with CD4+ T cell counts <350 cells/mm3. 
Special outreach to transgender and gender non-binary persons will be encouraged with 
a primary stratified analysis conducted based on assigned sex at birth and use of 
hormonal therapy. Supplemental analyses will be conducted based on self-identified 
gender identity and by sex assigned at birth.  
  


 
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At study entry (pre-treatment), all participants will have evaluations to establish a stable 
assessment of biomarkers including genital CMV shedding, IL-6, D-dimer, sCD163, and 
sTNFRII. Peripheral blood will be drawn, and genital and oral secretion collection will 
occur. Treatment will be initiated (week 0) after all required pre-treatment evaluations 
have been completed. Treatment initiation must occur between 2 and 30 days after 
study entry (pre-treatment). Participants will have blood, genital, and oral secretions 
collected throughout the study.  
 
An ECG will be performed for all participants at screening and vital signs will be 
assessed at all visits. Post-screening, if a participant’s resting heart rate (HR) is >100 
beats per minute (bpm), the participant has an irregular rhythm or complains of new 
palpitations, study clinicians will be instructed to obtain an ECG, particularly to screen 
for new atrial arrhythmias. 
 
A futility analysis will be conducted after the first 40 participants to initiate study 
treatment reach their week 8 study visit. Study enrollment will be paused after the 40th 
participant starts treatment and until the results of the futility analysis have been 
considered.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 
RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies.  
 
World Health Organization (WHO) and Centers for Disease Control and 
Prevention (CDC) guidelines mandate that confirmation of the initial test result 
must use a test that is different from the one used for the initial assessment. A 
reactive initial rapid test should be confirmed by either another type of rapid 
assay or an E/CIA that is based on a different antigen preparation and/or 
different test principle (e.g., indirect versus competitive), or a Western blot or a 
plasma HIV-1 RNA viral load. 
 
4.1.2 Currently on continuous combination ART for ≥48 weeks prior to study entry. 
This is defined as continuous ART for at least the 48-week period prior to study 
entry with no ART interruption longer than 7 consecutive days.  
 
4.1.3 Screening plasma HIV-1 RNA <75 copies/ml within 90 days prior to study entry 
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performed by any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent.  
 
4.1.4 Plasma HIV-1 RNA level <75 copies/ml (using an assay with a quantification 
limit of 75 copies/mL or lower) for at least 48 weeks prior to study entry 
performed by any US laboratory that has a CLIA certification or its equivalent.  
 
NOTE: Single determinations that are between 75 and 500 copies/mL (i.e., 
“blips”) are allowed as long as the preceding and subsequent determinations are 
<75 copies/ml. The screening value may serve as the subsequent value <75 
copies/ml following a blip. In the 48 weeks prior to study entry, no more than 
three “blips” are allowed and consecutive values >75 copies/ml during this 
period are not allowed. If no plasma HIV RNA levels were measured in the 
48 weeks prior to screening, participants can still be eligible if their last 
available plasma HIV RNA level prior to this period was <75 copies/ml and 
they have not experienced an ART interruption of longer than 7 days in the 
last 48 weeks. 
 
4.1.5 CD4+/CD8+ cell count obtained within 90 days prior to study entry at any US 
laboratory that has a CLIA certification or its equivalent. 
 
4.1.6 Positive CMV IgG serology, at any time prior to study entry using a FDA-
approved assay at any US laboratory that has a CLIA certification or its 
equivalent. 
 
NOTE: If a prior positive CMV IgG serology test is confirmed in the medical 
record, a repeat CMV IgG test is not required at screening.  
 
4.1.7 The following laboratory values obtained within 90 days prior to study entry by 
any US laboratory that has a CLIA certification or its equivalent. 
 
Hemoglobin >9.0 g/dL 
 
Platelet count >75,000/mm3 
 
Aspartate aminotransferase (AST) (SGOT), alanine aminotransferase (ALT) 
(SGPT), and alkaline phosphatase ≤3  ULN 
 
Total bilirubin ≤2.5 x ULN 
 
NOTE: If an individual is taking an atazanavir-containing regimen at the time 
of screening, a total bilirubin of ≤5 x ULN is acceptable. 
 
Estimated Glomerular Filtration Rate (eGFR) >30 mL/min/1.73m2 or 
creatinine clearance (CrCl) >30 mL/min using the Cockcroft-Gault, EPI-GFR, 
or MDRD equations located on the A5383 PSWP.  
 
4.1.8 For individuals assigned female sex at birth and of reproductive potential, 
negative serum or urine pregnancy test within 24 hours prior to study entry by 
any US clinic or laboratory that has a CLIA certification or its equivalent or a CLIA 
Certificate of Waiver for those performing a point of care (POC)/ CLIA-waived 
test. (Urine test must have a sensitivity of <25 mIU/mL.).  


 
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NOTE: Persons of female sex assigned at birth and of reproductive potential are 
defined as having reached menarche and have not been post-menopausal for at 
least 24 consecutive months (i.e., have had menses within the preceding 24 
months), and have not undergone testosterone therapy for gender alignment or 
surgical sterilization such as hysterectomy, bilateral oophorectomy, tubal ligation, 
or salpingectomy. An individual’s report is considered acceptable documentation 
of reproductive status. 
 
4.1.9 All participants must agree to use at least one of the following types of 
contraception throughout the study when participating in sexual activity that 
could lead to pregnancy:  
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Hormone-based contraceptive 
 
Condoms with or without a spermicide  
 
NOTE A: Individuals who are not of reproductive potential are not required to 
use contraception.  
 
NOTE B: Sperm-producing participants should refrain from donating sperm 
during the treatment period and for at least 90 days after the last dose 
of study treatment. Similarly, ovulating participants should refrain 
from egg donation during the treatment period and for at least 90 
days after the last dose of study treatment.     
 
4.1.10 Persons age 40 years. 
 
4.1.11 Ability and willingness of individual or legal guardian/representative to provide 
informed consent. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Change in the ART regimen within 12 weeks prior to study entry or intended 
modification of ART during the study.  
 
NOTE: Modifications in the dosage or frequency (i.e., twice a day [bid] to once a 
day [qd]) of individual antiretroviral (ARV) drugs during the 12 weeks prior to 
study entry are permitted. In addition, the change in formulation (e.g., from 
standard formulation to fixed-dose combination) is allowed within 12 weeks prior 
to study entry. A within class single drug substitution (e.g., switch from atazanavir 
to darunavir, or tenofovir disoproxil fumarate to tenofovir alafenamide) is allowed 
within 12 weeks prior to study entry. A switch to any other nucleoside reverse 
transcriptase inhibitor (NRTI) from abacavir (or vice versa) is not permissible. No 
other changes in ART within the 12 weeks prior to study entry are permitted. 
 


 
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4.2.2 Use of any of the following ARV drugs in current regimen: efavirenz, nevirapine, 
etravirine, lopinavir/ritonavir, and/or once-daily dosing of raltegravir (bid dosing of 
raltegravir is acceptable). 
 
4.2.3 Two or more HIV-1 RNA determinations >200 copies/mL within the 48 weeks 
prior to study entry. 
 
4.2.4 Any febrile illness (>101°F) within 30 days prior to study entry.  
 
4.2.5 Symptomatic SARS-CoV-2 or monkeypox infection in the past 30 days, with 
or without antiviral therapy. 
 
4.2.6 Use of drugs with anti-CMV activity within 90 days prior to study entry, with the 
exception of standard-dose valacyclovir and acyclovir. 
NOTE: Refer to section 5.4.2 for a list of drugs with anti-CMV activity that are not 
acceptable. For any anti-CMV activity drug not listed, sites must consult the 
Clinical Management Committee (CMC). 
 
4.2.7 Systemic Immunosuppressive or immunomodulatory drug use as well as 
systemic drugs with immunemodulatory effects within 90 days prior to study 
entry (topical, inhaled, and/or intranasal are allowed).  
 
NOTE A: Refer to sections 5.4.2 and 5.4.3 for details on prohibited 
immunomodulatory drugs and the use of statins. Statin use is allowed as 
long as the dose is stable dose for at least the 90 days prior to study 
entry and within the allowable dosage limits [see section 5.4.3]. 
 
NOTE B: For any immunosuppressive or immunomodulatory drugs (or drugs of 
immune modulatory potential) not listed, sites must consult with the CMC. 
 
4.2.8 Concomitant use of prohibited medications listed in section 5.4.2.  
 
4.2.9 Persons who are currently breastfeeding or pregnant, or persons planning to 
become pregnant during the study. 
 
4.2.10 Participating in a study where co-enrollment is not allowed (see section 4.4).  
 
4.2.11 Receipt of any vaccination within 14 days prior to study entry  
 
4.2.12 Presence on screening ECG or a known history of atrial tachycardia (other than 
sinus tachycardia). Ventricular tachycardia is also an exclusion criterion.   
 
4.2.13 History of cardiomyopathy or congenital heart disease or evidence of advanced 
conduction system disease including second degree heart block Mobitz type II, 
third degree heart block, AV dissociation or ECG findings that may be suggestive 
of predisposition to arrhythmia (i.e., delta wave).  
 


 
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4.2.14 Known allergy/sensitivity or any hypersensitivity to components of the study drug 
or its formulation. 
 
4.2.15 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.16 Serious illness requiring systemic treatment and/or hospitalization within 90 days 
prior to study entry. Minor illnesses like a sinus infection requiring oral 
antibiotics or STD exposure requiring antibiotics are not exclusionary. 
Non-hospitalized but symptomatic SARS-CoV-2 and monkeypox infections 
are covered separately under exclusion 4.2.5. 
 
4.2.17 Known active hepatitis B virus infection within the last 24 weeks prior to study 
entry. 
 
NOTE: Known currently active is defined as hepatitis B surface antigen 
(HBsAg) positive and hepatitis B DNA (HBV DNA) positive. Persons with HBV 
DNA below level of quantification (BLQ) for >24 weeks prior to study entry are 
eligible. If no testing is available in the 24 weeks prior to study entry, and 
there is no clinical suspicion for currently active hepatitis B virus infection, 
HBV labs are not necessary to obtain at screening.  
 
4.2.18 Known active hepatitis C within the last 24 weeks prior to study entry. 
 
NOTE: Known currently active is defined as a detectable plasma hepatitis C 
virus (HCV) RNA level. Persons with HCV RNA BLQ for >24 weeks prior to study 
entry are eligible. If no testing is available in the 24 weeks prior to study 
entry, and there is no clinical suspicion for currently active hepatitis C 
virus infection, HCV labs are not necessary to obtain at screening. 
 
4.2.19 Presence or history of conditions that could account for impaired 
neuropsychological performance, including head injury with prolonged (>1 hour) 
loss of consciousness, central nervous system infection (e.g., encephalitis), 
severe learning disability, psychosis, and/or active drug or alcohol use, or 
dependence that, in the opinion of the site investigator, would interfere with 
adherence to study requirements.    
 
4.2.20 History of multi-class HIV drug resistance or intolerance, such that in the opinion 
of the investigator, an alternative fully active antiretroviral regimen cannot be 
constructed should the participant experience loss of viral suppression on their 
current regimen during the study. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent form(s) approved, as 
appropriate, by the institutional review board (IRB)/ethics committee (EC) and any 


 
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other applicable regulatory entity (RE) responsible for oversight of the study. Upon 
receiving final approval, sites will submit all required protocol registration documents 
to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration packet 
to ensure that all of the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
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 an individual for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form.  
 
Participants from whom a signed informed consent has been obtained may be 
screened and enrolled, if they otherwise qualify. An ACTG Screening Checklist 
must be entered through the DMC Study Enrollment System. 
 
4.3.2 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
4.3.3 Randomization 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  


 
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4.4 
Co-enrollment Guidelines  
 
 
Sites are encouraged to co-enroll participants in A5128, “Plan for Obtaining Informed 
Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified 
Analyses.” Co-enrollment in A5128 does not require permission from the A5383 
protocol chairs.  
 
Co-enrollment in CMV Vaccine study A5355 and/or REPRIEVE is not permitted. 
 
NOTE: Co-enrolled REPRIEVE participants may participate in the A5383 study 
as long as they are no longer taking REPRIEVE study product (for at least six 
months) and in follow-up only. Potential A5383 participants must agree not to 
resume REPRIEVE study product while participating in the A5383 study. 
  
 
For specific questions and approval for co-enrollment in other studies, sites should 
first check the PSWP or contact the protocol team via e-mail as described in the 
Study Management section. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as letermovir, which will be provided by the study.  
 
Required background ART regimens will not be provided by the study.  
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
Eligible participants will be randomized (1:1) to either 48 weeks of treatment with 
letermovir or no study treatment as follows: 
 
Arm A: letermovir 480 mg orally once daily  
 
Arm B: no anti-CMV treatment 
 
5.1.2 Administration 
 
Letermovir 480 mg will be administered by one of the following strategies: 
 
 
Letermovir 240 mg tablets administered orally as two tablets once daily with 
or without food. 
 
Letermovir 480 mg tablets administered orally as one tablet once daily with or 
without food. 
 
Participants will be able to switch administration strategy during treatment 
duration based on availability of study supply.  
 


 
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5.2 
Study Product Formulation and Storage 
 
Letermovir, labeled as PREVYMIS, will be provided as both 240 mg and 480 mg 
tablets based on study product availability.  
 
Letermovir 240 mg tablets are yellow, oval tablets debossed with “591” on one 
side and Merck logo on the other side. Tablets are packaged into a carton 
containing 2 or 4 Child Resistant (CR) Dosepaks®, each containing a 7-count 
blister card for a total of 14 or 28 tablets. 
 
Letermovir 480 mg tablets are pink, oval, bi-convex tablets debossed with “595” 
in one side and Merck logo on the other side. Tablets are packaged into a carton 
containing 2 or 4 Child Resistant (CR) Dosepaks®, each containing a 7-count 
blister card for a total of 14 or 28 tablets. 
 
Store Letermovir tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 
15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Letermovir is manufactured and supplied by Merck and Company, Inc. and is 
available through the NIAID Clinical Research Products Management Center 
(CRPMC). The site pharmacist should obtain the study product(s) for this 
protocol by following the instructions in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products must be returned to the NIAID CRPMC (or as otherwise directed by the 
sponsor) after the study is completed or terminated. The procedures to be 
followed are provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks.  
 
5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 


 
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5.4.1 Required Medications 
 
All participants will be requested to continue their ongoing ART regimen for the 
duration of the study. ART will not be provided by the study. Refer to inclusion 
criterion 4.1.2 and exclusion criteria 4.2.1 and 4.2.2 for ART regimen 
requirements.  
 
5.4.2 Prohibited Medications 
 
Pimozide, ergotamine, dihydroergotamine, and nafcillin.  
 
Anti-convulsants: phenytoin, carbamazepine, phenobarbital.  
 
Antimycobacterials: rifabutin, rifampin.  
 
Anti-psychotics: thioridazine.  
 
Endothelin antagonists: bosentan. 
 
Herbal products: St. John’s Wort. 
 
Wakefulness-Promoting agents: modafinil. 
 
Other CMV drugs including valganciclovir, ganciclovir, foscarnet, and 
cidofovir.  
 
Other ARV drugs including efavirenz, nevirapine, etravirine, lopinavir/ritonavir 
and once-daily dosing of raltegravir (bid dosing of raltegravir is acceptable).  
 
Systemic immunomodulatory or immunosuppressive therapies. Examples 
include but are not limited to: cyclosporine, sirolimus, tacrolimus, 
Interferons, Interleukins, growth hormone agonists, systemic cytotoxic. 
chemotherapy, and systemic glucocorticoids. Topical, inhaled, and intranasal 
immunomodulatory or immunosuppressive therapies are allowed. 
 
Statins: pitavastatin (see section 4.4 for REPRIEVE trial participation) and 
simvastatin are not allowed at any dose.  See precautionary medications 
below (5.4.3.) for allowable dosing of other statins. 
 
5.4.3 Precautionary Medications 
 
When letermovir is co-administered with a CYP3A substrate, refer to the 
prescribing information for dosing of the CYP3A substrate with a moderate 
CYP3A inhibitor.  
 
When letermovir is co-administered with cyclosporine or any moderate 
CYP3A inhibitor, the combined effect on CYP3A substrates may be similar to 
a strong CYP3A inhibitor. Refer to the prescribing information for dosing of 
the CYP3A substrate with a strong CYP3A inhibitor.  
 
An expanded list of precautionary medications is included below: 
 
Anti-arrhythmic agents: amiodarone, quinidine 
 
Anti-coagulants: warfarin 
 
Antidiabetic agents: glyburide, repaglinide, rosiglitazone 
 
Antifungals: voriconazole 
 
Benzodiazepines: midazolam 
 
Opiates: alfentanil, fentanyl 


 
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 
Proton pump inhibitors: omeprazole, pantoprazole 
 
Statins: statin use is allowed, but may not exceed allowable doses. 
Atorvastatin is allowed but may not exceed doses of 20 mg/day; any 
dose of rosuvastatin, lovastatin, fluvastatin, or pravastatin is allowed, but 
participants should be monitored closely for myopathy and rhabdomyolysis 
and statin dose reductions may be required. Simvastatin and pitavastatin are 
not allowed at any dose (see section 5.4.2). 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
Table 6.1-1: Schedule of Evaluations 
Evaluation 
Screening 
Study Entry 
(Pre-
Treatment 
Evaluations) 
0 ENT 
Treatment 
Initiation 
Post-Treatment Initiation Evaluations (Weeks) 
(0 IOT) 
4 
8 
16 
24 
32 
40 
46 
48 
52 
60 
Conf. 
of VF 
Disc. 
Evals 
Visit Windows 
Within 90 
days prior 
to Entry 
2-30 days 
prior to 
Treatment 
Initiation 
2-30 days 
after Study 
Entry 
±10 days 
-10/+5 
days 
-5/+10 
days 
±10 
days  
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment (see section 
6.3.4) 
X 
X 
X 
X 
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 
ECG 
X 
If applicable (see section 6.3.5) 
Hematology 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
Liver Function Tests 
(C=conditional; see section 6.3.6 
for visits marked C) 
X 
 
X 
 
X 
 
X 
 
 
X 
C 
X 
X 
 
 
Chemistry (C=conditional; see 
sections 6.3 & 6.3.6 for visits 
marked C) 
X 
 
X 
 
 
 
X 
 
 
X 
C 
 
X 
 
 
Pregnancy Testing (see section 
6.3.6) 
X 
X 
X 
If otherwise indicated 
 
 
CMV Serology (historical positive 
result can be used) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+/CD8+ 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Plasma HIV-1 RNA 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 


 
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Evaluation 
Screening 
Study Entry 
(Pre-
Treatment 
Evaluations) 
0 ENT 
Treatment 
Initiation 
Post-Treatment Initiation Evaluations (Weeks) 
(0 IOT) 
4 
8 
16 
24 
32 
40 
46 
48 
52 
60 
Conf. 
of VF 
Disc. 
Evals 
Visit Windows 
Within 90 
days prior 
to Entry 
2-30 days 
prior to 
Treatment 
Initiation 
2-30 days 
after Study 
Entry 
±10 days 
-10/+5 
days 
-5/+10 
days 
±10 
days  
Stored Plasma/PBMC/Serum 
 
X
X 
X 
X 
 
X 
 
 
X
X 
X 
X 
X 
X 
Plasma PK Sampling 
(C=conditional; see section 6.7) 
 
 
X 
X 
X 
 
 
 
 
X 
C 
 
X 
 
 
Adherence Assessment 
 
 
X
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Genital and Oral Secretion 
Collection 
 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
Rectal Swab Collection 
(C=conditional; see section 6.10 
for visits marked C) 
 
X 
C 
 
X 
 
 
 
 
X 
C 
 
X 
 
 
Physical function testing 
(C=conditional; see section 6.11 for 
visits marked C)
 
X 
C 
 
 
 
 
 
 
X 
C  
 
X 
 
 
Brief NP testing & Limited 
Neurophysiological Evaluations 
(C=conditional; see section 6.12 for 
visits marked C) 
 
X 
C 
 
 
 
 
 
 
X 
C  
 
X 
 
 
Brief mood testing (mental 
health/substance abuse disorders; 
CAT-MH, PHQ-9 & GAD-7) 
(C=conditional; see section 6.13 for 
visits marked C) 
 
X 
C 
 
X 
 
 
 
 
X 
C  
X 
X 
 
 
Brief sleep assessment 
(C=conditional; see section 6.13 for 
visits marked C) 
 
X 
C 
 
 
 
 
 
 
X 
C  
 
X 
 
 


 
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Evaluation 
Screening 
Study Entry 
(Pre-
Treatment 
Evaluations) 
0 ENT 
Treatment 
Initiation 
Post-Treatment Initiation Evaluations (Weeks) 
(0 IOT) 
4 
8 
16 
24 
32 
40 
46 
48 
52 
60 
Conf. 
of VF 
Disc. 
Evals 
Visit Windows 
Within 90 
days prior 
to Entry 
2-30 days 
prior to 
Treatment 
Initiation 
2-30 days 
after Study 
Entry 
±10 days 
-10/+5 
days 
-5/+10 
days 
±10 
days  
Sexual & Gender Identity 
Questionnaire (C=conditional; 
see section 6.13 for visits 
marked C) 
 
X 
C 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone, text message, or e-mail 
contact 
Between visits as needed (see section 6.2.4) 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening  
 
Screening evaluations must occur prior to the Study Entry visit. 
 
Screening evaluations to determine eligibility must be completed within 90 days 
prior to the Study Entry (Pre-Treatment) visit unless otherwise specified. 
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Study Entry (Pre-Treatment) Visit (0 ENT) Evaluations 
 
All screening evaluations must be complete prior to the Study Entry (Pre-
Treatment) visit. The Study Entry visit should occur within the time window 
outlined in section 6.1. The participant will be randomized to study treatment at 
the Study Entry visit.  
 
Timing of all study visits (Study Entry and all subsequent visits) 
Participants are encouraged to receive standard vaccinations, including influenza 
vaccination (i.e., flu vaccine) and COVID-19 vaccination, in the course of their 
clinical care, but the timing of these vaccinations should occur at least 14 days 
prior to any given study visit (or be administered after the study collections are 
completed). Furthermore, participants experiencing inflammatory conditions at 
the time of a scheduled visit (e.g., a febrile illness, acute infection including 
SARS-CoV-2) should be instructed to wait 7 days after resolution of the 
inflammatory condition before returning for the scheduled visit.  
 
NOTE: In cases where study visits need to be rescheduled due to illness or 
vaccination, postponement is allowed as long as the participant’s visit 
window does not overlap with the next one.  
 
The presence and resolution of an inflammatory condition is based on participant 
symptoms (i.e., fever, chills, swelling, redness) and at the judgement of the study 
clinician.  
 
Because of the diurnal variation in biomarkers that may be measured as part of 
the study (e.g., CD4+ and CD8+ T-cell counts and other biomarkers that may be 
measured on stored samples), blood draws for individual participants should be 
performed consistently in either the morning or the afternoon throughout the 
study, if possible.  Furthermore, since fasting status can affect inflammatory 
biomarkers, metabolic, and lipid measurements, all blood draws should be 
obtained in the fasting state. Please note that height will only be recorded at the 
Study Entry visit. 


 
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6.2.3 Treatment Initiation Visit Evaluations (0 IOT/DAY 0) 
 
The Treatment Initiation visit (0 IOT) should only occur after all required Pre-
Treatment Visit evaluations have been completed at Study Entry. The Treatment 
Initiation visit must occur within 2-30 days after Study Entry visit evaluations have 
been completed. If more than 30 days have elapsed after the Study Entry visit, 
the Study Entry visit must be repeated prior to the Treatment Initiation visit. 
Participants must begin treatment within 2 days after the Treatment Initiation 
visit. The rationale for separate entry and treatment initiation visits is to 
establish a stable baseline level for biomarker levels, which tend to 
fluctuate within individuals, to enhance power to detect treatment-
associated changes. Thus, the treatment initiation visit is a required visit 
for both the letermovir and “no CMV treatment” arms.  
 
6.2.4 Post-Treatment Initiation Evaluations 
 
All post-Treatment Initiation evaluations will occur per the time windows outlined 
in section 6.1. The timing of all the subsequent post-treatment initiation 
visits are based on the date of the treatment initiation visit (i.e., Week 4 is 4 
weeks after the treatment initiation visit). 
 
On-Treatment Evaluations (Weeks 4-48)  
Evaluations must occur after the Treatment Initiation visit as shown in section 
6.1. If any of the evaluation visits are missed, they should be conducted at the 
next visit. This is particularly important for evaluations that may have been 
missed at the week 46 visit. Visits on weeks 16, 32, and 40 are primarily 
designated for assessments of adverse events, changes in concomitant 
medications, adherence, and for participants to pick up refills for study 
treatment, but if the participant does not report interim adverse events and 
has sufficient supply of study medication, these visits can be conducted 
remotely by telephone at the discretion of the site investigator. In addition 
to these visits, clinical assessments for adverse events and adherence 
should be conducted at all study visits as shown in section 6.1. 
 
Post-Treatment Evaluations (Weeks 52 and 60) 
Evaluations must occur as shown in section 6.1. If any of the evaluation visits are 
missed, they should be conducted at the next visit. If the week 60 visit is missed, 
it should be rescheduled at the next and most convenient time, but not greater 
than 14 days after the originally scheduled visit.   
 
Study Completion Evaluations 
Week 60 will be the participant’s final visit on-study. 
 
Remote Data Collection 
Study visits may be conducted remotely (e.g., telephone, telehealth) in the 
following situations: 


 
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 
A participant is unable to attend a visit because of personal illness, illness 
among others in their home, or local conditions or guidelines restricting travel 
to the clinic. 
 
The site is temporarily unable to conduct non-essential visits in the clinic; the 
site must inform the core team (actg.CMCa5383@fstrf.org) when it has to 
stop non-essential visits. 
 
At the discretion of the A5383 study team. 
 
Visits would not be conducted remotely if the participants needs to 
travel to the clinic to refill study medication or report any new side 
effects or health problems that require medical attention. This is at the 
discretion of the site investigator (see criteria listed above as noted 
under [On-Treatment Evaluations Weeks 4-48]).  
 
Regardless of the situation, sites should document which visits were conducted 
remotely, attempt to obtain as much of the visit-specific required information, 
based on section 6.1, as possible, and record it. The impacted visits and 
rationale must be reported and documented, following instructions provided by 
the team or network leadership.  
 
Study drug supplies may be mailed/delivered to participants’ homes to assure 
continuous drug supply, if needed. The site PoR can ship oral study product to 
the participant by following the instructions under “Shipping Study Product to a 
Participant” in the manual entitled Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks as well as complying with institutional 
requirements. The PoR must comply with shipping requirements including 
documentation of chain of custody as detailed in the DAIDS pharmacy manual as 
well as institutional requirements.  The PoR must reach out to the protocol 
pharmacist for any shipping deviations, challenges and/or questions.  
 
Week 8 Visit (only for the first 40 participants enrolled) 
Enrollment will be paused after the first 40 participants have enrolled so that 
week 8 immunologic activity can be assessed for futility. During this first phase of 
enrollment, a blood draw at the week 8 visit is critical to complete the interim 
analysis of immunologic activity. Thus, if the participant is unable to attend an in-
person clinic visit at the scheduled time, the week 8 visit can be postponed for up 
to 6 weeks so that they can contribute to the interim analysis. All subsequent 
visits will be completed as scheduled (i.e., a postponement of the week 8 visit will 
not extend the duration of study drug treatment or result in the postponement of 
any of the subsequent scheduled visits). If the SMC allows enrollment to resume 
after the week 8 interim analysis on the first 40 participants, all subsequent 
enrollees in this second phase (i.e., enrollees 41 through 180) will no longer be  
required to have their week 8 visits performed in person and the standard remote 
data collection guidance would apply. 
 
Week 46 and 48 Visits 
Participants who complete the treatment course will perform the evaluations listed 


 
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while on study drug. If the participant is unable to attend at least one in-person clinic 
visit at the scheduled time (week 46 or 48), the week 48 visit can be postponed for 
up to 8 weeks with an extension of study drug treatment during this time so that the 
primary outcome, which requires a blood draw, can be ascertained while still 
receiving study medication. Should a need for postponement of the week 48 visit 
appear likely, the site should inform the core team (actg.CMCa5383@fstrf.org) as 
soon as possible so that the necessary increase in drug supply can be 
accommodated without an interruption of treatment.  The week 46 and 48 visits 
should not be conducted as a Remote Data Collection visit. If the week 48 visit is 
postponed, the weeks 52 and 60 visits will also be postponed accordingly (i.e. the 
off-treatment phase of the study should always be 12 weeks).  
 
6.2.5 Confirmation of Virologic Failure 
 
Confirmed virologic failure is defined as two consecutive HIV-1 RNA levels ≥200 
copies/mL by real-time HIV-1 RNA testing. Participants with a plasma HIV-1 RNA 
≥200 copies/mL at any visit will have a confirmatory viral load obtained as soon as 
possible but within 14 days after the first sample was drawn, if possible. If this visit 
coincides with a regularly scheduled visit, the evaluations should be combined. If 
the consecutive measurement of HIV-1 RNA is also ≥200 copies/mL, the 
participant will be considered to have confirmed virologic failure and the CMC 
must be notified via e-mail actg.CMCa5383@fstrf.org within 72 hours. 
 
Participants will have premature study treatment discontinuation evaluations 
performed as noted in section 6.1. These participants will remain on study, off 
study treatment and have all evaluations performed per section 6.1.  
 
6.2.6 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Complete the Treatment 
Initiation visit (and for Arm A, those who do not start letermovir) 
Participants who are randomized, but withdraw from the study prior to completing 
the treatment initiation visit (and for Arm A, those who do not start letermovir), 
should have discontinuation evaluations performed and off-study eCRFs 
completed and keyed. No further follow-up is required for these participants. 
Participants who do not complete the treatment initiation visit (and for Arm A, 
those who do not start letermovir) should be replaced.   
 
Premature Study Treatment Discontinuation Evaluations 
Participants who prematurely permanently discontinue study treatment will have 
discontinuation evaluations performed as noted in the Schedule of Events within 7 
days of discontinuation. They will have evaluations performed as per section 6.1. 
After completion of the premature treatment discontinuation evaluations and until 
week 60 participants will follow the clinical assessment and laboratory schedules as 
per section 6.1, except that pregnancy testing is not required. Plasma/PBMCs/Serum 
for biomarkers should continue to be collected as per section 6.1 through the 


 
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week 60 visit as participants who discontinue treatment prematurely will still 
contribute to the secondary intention-to-treat analyses.  
 
Study drug will not be dispensed nor will adherence assessments to study drug 
be performed (though adherence assessments for ART will continue). More 
frequent clinical and laboratory evaluations may be clinically indicated. 
 
Participants who permanently discontinue study treatment due to toxicity should 
remain in study follow-up to study completion or until the toxicity resolves to a 
Grade 2 or less (whichever is first). See section 8.1 for specific toxicity 
management instructions and evaluations to be performed. 
 
Premature Study Discontinuation Evaluations  
Participants who prematurely discontinue from the study will have the study 
discontinuation evaluations performed as soon as possible prior to being taken 
off the study.  
 
6.3 
Instructions for Evaluations 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy 
on Requirements for Laboratories Performing Testing for DAIDS-Supported and/or 
Sponsored Clinical Trials, which is available at 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), and AE reporting of 
adverse events requirements. 
 
Fasting Instructions 
With the exception of the screening visit and visits for confirmation of virologic 
failure and discontinuation evaluations, all study visits with blood draws (i.e., 
entry; treatment initiation; and weeks 4, 8, 24, 46, 48, 52, and 60) must be conducted 
when participants are fasting. Because fasting status can affect inflammatory 
biomarkers, metabolic, and lipid measurements, all blood draws should be obtained in 
the fasting state.  
 
Fasting is defined as nothing to eat or drink except oral medications and plain water for 
at least 8 hours before the evaluations. If participants are in a non-fasting state, they 
should come back to the clinic in a fasting state within 7 days of the originally scheduled 
study visit for a fasting blood draw and evaluation, unless otherwise indicated.  
 


 
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Participants should be instructed with the exact time beyond which they are to be 
fasting, such as: “Your visit is scheduled for 8:00 a.m. You should not have any food or 
drink by mouth except water and medication after 12 a.m.” See below for timing of blood 
draws. 
 
Timing of Blood Draws 
Because of the diurnal variation in biomarkers that may be measured as part of the 
study (e.g., CD4+ and CD8+ T cell counts and other biomarkers that may be measured 
on stored samples), blood draws for individual participants should be performed 
consistently in either the morning or the afternoon throughout the study, if possible. 
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the eCRF. 
 
6.3.2 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 30 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made: 
 
AIDS-defining conditions 
 
Bone fractures (verbal history accepted) 
 
Coronary heart disease 
 
Cancer (exclusive of basal/squamous cell skin cancer) 
 
Diabetes 
 
Tuberculosis 
 
Chronic hepatitis C 
 
Chronic hepatitis B 
 
Documented CMV end-organ disease (e.g., retinitis, colitis, ventriculitis, etc.) 
 
Any diagnosis of SARS-CoV-2 infection within the past year (including any 
positive SARS-CoV-2 test regardless of symptoms) 
 
Any allergies to any vaccines and medications and their formulations must also 
be documented.  
 
6.3.3 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications and vaccines 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
Within 1 year prior to study entry
Immune-based therapy
Complete History
Blinded study treatment 
Within 1 year prior to study entry  
HIV-1-related vaccines and 
bNAbs 
Complete History 
Prescription drugs for treatment of 
opportunistic infections 
Within 30 days prior to study entry 
Prescription drugs for prophylaxis 
of opportunistic infections
Within 30 days prior to study entry 
Previous anti-CMV vaccines 
Complete History 
Drugs with anti-CMV activity
Within 90 days prior to study entry
All other previous vaccines
Within 90 days prior to study entry
Prescription drugs (other) 
Within 30 days prior to study entry 
Alternative therapies
Within 30 days prior to study entry
Dietary supplements 
Within 30 days prior to study entry
Sex-hormone drugs or sex-
hormone analogues or 
antagonists*
Last 12 months except as noted 
below 
Substance use/IV Drug use
Within 30 days prior to study entry
*Includes: hormone-releasing IUDs (e.g., Mirena inserted in the last 7 
years); oral, injectable, implanted, or patch contraceptives; vaginal ring, 
creams, or inserts; estrogen, progesterone, or testosterone therapy; 
leuprolide or other synthetic gonadotropin-releasing hormone; tamoxifen, 
raloxifene, aromatase inhibitors or any other androgen, estrogen, or 
progesterone analogue or antagonist therapy. 
 
6.3.4 Clinical Assessments 
 
Clinical Assessments are conducted at the specified time points in section 
6.1 specifically to collect information on adverse events, concomitant 
medications, and study treatment modifications. These assessments can 
be performed remotely at weeks 16, 32, and 40 (see section 6.2.4). Refer to 
section 7.2 for AE collection requirements.  
 
NOTE: Sites should ask participants about tobacco use. This includes the 
participant’s history of smoking tobacco, including the number of 
cigarettes smoked per day and the number of years the participant 
smoked. This information should be recorded on the eCRF at study entry.  
If not obtained at study entry, it can be recorded at the initiation of 
treatment visit. If participants have already completed their initiation of 
treatment visit, then perform a one-time collection of tobacco use data at 
the next scheduled visit.   
 


 
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Complete Physical Examination 
A complete physical examination is to be performed at screening and is to 
include at a minimum an examination of the skin, head, mouth, and neck; 
auscultation of the chest; cardiac examination; abdominal examination; and 
examination of the lower extremities for edema. The complete physical 
examination will also include signs and symptoms, diagnoses, and vital signs 
(weight, temperature, pulse, respiration rate, and blood pressure). 
 
Targeted Physical Examination 
Post-screening, a targeted physical examination will be completed at every study 
visit (with the exception of weeks 16, 32, and 40 as noted above under 
Clinical Assessments) and will include vital signs (weight, temperature, pulse, 
respiration rate, and blood pressure), and is to be driven by any previously 
identified or new adverse event/targeted event, that the participant has 
experienced since the last visit. Height will be recorded at the study entry visit 
only. Weight should be recorded at every study visit. A targeted physical exam 
is not required as part of a confirmation of virologic failure visit. 
 
Post-entry, record any acute febrile illnesses (see section 4.2.4 for definition of 
an acute febrile illness; see section 6.2.2 for timing of visits in case of a febrile 
illness).   
 
Concomitant Medications 
Post-entry, all new and discontinued concomitant medications and vaccines 
received must be recorded.   
 
Study Treatment Modifications 
Record all study treatment modifications, including initial doses, participant-
initiated and/or protocol-mandated modifications, and inadvertent and deliberate 
interruptions of more than 3 days since the last visit. Record any permanent 
discontinuation of treatment. 
 
6.3.5 ECG 
 
An ECG will be performed at screening. Post-screening, an ECG will be 
performed to assess for new cardiac arrhythmias if the participant has a resting 
HR of >100 bpm, irregular HR, or complains of new palpitations. ECGs will be 
interpreted in real time during the study. 
 
6.3.6 Laboratory Evaluations 
 
At screening and study entry all laboratory values must be recorded. For post-
entry assessments, record the following: 
 
 
All values for hemoglobin, creatinine, AST, ALT, and platelet counts 
regardless of grade; 
 
Abnormal laboratory findings per section 7.2.  


 
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Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume 
(MCV), white blood cell count (WBC), differential WBC, absolute neutrophil count 
(ANC), and platelet count.  
 
Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), alkaline phosphatase, indirect 
bilirubin, and -glutamyl transaminase (GGT). If sites are unable to collect the 
required test values at week 46, they may collect them at week 48. 
 
Chemistry 
Fasting serum glucose, triglycerides, cholesterol (LDL, HDL, and total), 
electrolytes (sodium, potassium, chloride, phosphate, and bicarbonate), 
creatinine, blood urea nitrogen (BUN), total protein, and albumin. 
 
These tests are only required at week 48 if they were not done at week 46. If 
sites are unable to collect the required test values at week 46, they may 
collect them at week 48. Fasting serum glucose is not needed at the 
Screening visit. 
 
NOTE A: Metabolic Studies (free fatty acids [refer to the A5383 Laboratory 
Processing Chart, LPC]). Plasma free fatty acids will be assessed on 
fasting blood samples sent in batch through Quest labs using the 
Nonesterified Fatty Acids test not by the site.  
 
NOTE B: Values for HOMA-IR will be calculated by SDAC. HOMA-IR 
(incorporates fasting glucose and insulin levels [insulin from stored 
samples]) to be calculated during data analysis, not by the site.  
 
Pregnancy Test 
A negative serum or urine pregnancy test must be obtained within 24 hours prior 
to study entry. For persons assigned female sex at birth and with reproductive 
potential: Serum or urine -HCG. (Urine test must have a sensitivity of <25 
mIU/mL). Record pregnancy and pregnancy outcome per section 8.3. Post entry, 
see section 8.3 for collection requirements for pregnancy. 
 
CMV Serology  
CMV IgG serology using a FDA-approved assay at any US laboratory that has a 
CLIA certification or its equivalent. Historical positive results can be used.  
 
6.4 
Immunologic Studies 
 
CD4+/CD8+ 
Screening absolute CD4+/CD8+ count and percentages must be performed within 90 
days prior to study entry (pre-treatment) at a laboratory that possesses a CLIA 
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For entry and post-entry evaluations, all laboratories must possess a CLIA certification 
or equivalent. 
 
See section 6.3 for timing of blood draws. 
 
6.5 
Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 90 days prior to study entry at a 
laboratory that possesses a CLIA certification or equivalent. Eligibility will be determined 
based on the screening value.  
 
6.6 
Stored Plasma/Peripheral Blood Mononuclear Cells (PBMCs)/Serum 
 
PBMCs, plasma, and serum will be stored for future analysis. See section 6.3 for timing 
of blood draws. For specimen processing, storage and shipping instructions, see the 
A5383 LPC.  
 
6.7 
Plasma Pharmacokinetic (PK) Sampling  
 
At each visit indicated in section 6.1, a single PK sample will be drawn and stored for 
future exploratory analyses. Venous PK will be performed at treatment initiation and at 
weeks 4, 8, 46, and 60 (as indicated in section 6.1) so these samples must be collected 
prior to the morning doses of letermovir and/or ART.  
 
Participants should be stable on ART for at least 10 days (i.e., no ART regimen change 
for 10 days) prior to PK draws with confirmation of full adherence for the last four ART 
doses and for Arm A (for all post-treatment initiation visits) the last four doses of study 
treatment. Similarly, for statin-treated participants, full adherence should be 
confirmed for the last four statin doses prior to a PK draw. The date and time of the 
last four ART, statin (if applicable), and study treatment doses prior to each PK 
blood draw should be recorded. For participants who normally take ART, statin, 
and/or study medication doses in the morning, on the day of PK sampling, blood 
should be drawn before the morning dose of study treatment for participants in Arm A 
and before any morning dose of ART (and statin, if applicable) in both arms. In the 
case where a morning dose of study treatment, ART, or statin dose is taken before the 
PK sample is drawn, or if any of the four preceding doses have been missed, the PK 
sampling should be rescheduled during the same week, if possible. If this is not possible, 
contact the A5383 protocol team (actg.teamA5383@fstrf.org) for guidance. These tests 
are only required at week 48 if they were not done at week 46. 
 
NOTE A: Participants should not be asked to change their usual ART, statin or 
study medication dose timing. Nevertheless, participants who take an ART, statin, 
or study medication dose in the morning should delay their dose until after the 
blood draw on days that include PK sampling. Time of the last (most recent) ART, 
statin, and study treatment dose (for Arm A) should be recorded for all 
participants.  


 
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For specimen processing, shipping, and storage instructions, refer to the A5383 LPC. 
Refer to section 11.0 for the assay details. 
 
6.8 
Adherence Assessment  
 
At the time points indicated in section 6.1, participants will complete the adherence 
assessment. The assessment will collect data on ART and study treatment adherence.  
 
The adherence assessment eCRF is to be completed in the iMedidata Patient Cloud 
app. In the event a site does not have a tablet, the participant experiences 
difficulty using a tablet, or the participant speaks Spanish, the form is posted on 
the DMC Portal in the Forms Management Utility. See the A5383 MOPS for more 
information. 
 
6.9 
Genital and Oral Secretion Collection 
 
Participants must refrain from sexual intercourse and ejaculation and avoid using 
intravaginal products for 48 hours prior to sample collection. Semen will be obtained by 
masturbation at the visits indicated in section 6.1. Semen collection can be performed at 
home as long as semen is transported to the processing lab within 2 hours of collection. 
Semen should be kept at room temperature until delivery to the processing lab. Cellular 
pellet and seminal plasma will be processed according to the procedure outlined in the 
A5383 Manual of Procedures (MOPS), and stored as described in the A5383 LPC.  
 
Two (self-collected or staff-collected) vaginal swabs will be collected per section 6.1 
and placed into a sterile tube as outlined in the MOPS and LPC. Participants with a 
vagina may elect to have vaginal swab collection via self-collection (collected at home) 
or by study personnel during the study visit. 
 
NOTE: Semen and vaginal swabs are requested because it is far easier to detect 
CMV in these samples than in the blood. Thus, collecting these samples allows us 
to measure a direct effect of letermovir on CMV replication. Nevertheless, some 
participants may be uncomfortable providing (or unable to provide) semen or 
vaginal swab specimens. If a participant is uncomfortable or unable to provide 
these specimens, this is acceptable, but the reason for the missing specimen 
needs to be noted in the eCRF. 
 
Oral secretion collection will be undertaken with a throat wash (see MOPS for 
instructions). Participants should not eat, drink, chew gum, mints or candy; brush/floss 
teeth; or smoke for 90 minutes before throat wash collections.  
 
NOTE: Participants may drink water prior to throat wash collection, however, all 
other beverages are prohibited.  
 


 
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6.10 
Rectal Swab Collection 
 
Rectal swabs will be collected per section 6.1 and stored per the A5383 MOPS.  
 
NOTE A: Rectal swabs are requested because it is far easier to detect CMV in these 
samples than in the blood. Thus, collecting these samples allows us to measure a 
direct effect of letermovir on CMV replication. Nevertheless, some participants may 
be uncomfortable providing (or unable to provide) rectal swab specimens. If a 
participant is uncomfortable or unable to provide rectal swab specimens, this is 
acceptable, but the reason for the missing specimen needs to be noted in the eCRF.  
 
NOTE B: If rectal swabs cannot be performed at the Study Entry visit (0 ENT), then 
they should be obtained at the Treatment Initiation visit (0 IOT). Similarly, if rectal 
swabs cannot be performed at the week 46 visit, then they should be obtained at 
the week 48 visit. 
 
6.11 
Physical Function Testing 
 
At the time points indicated in section 6.1, participants will be asked to rise 10 times from 
a seated position from a standard height chair that does not have wheels or arms. Time 
to complete 5 and 10 rises from the chair will be captured (see the A5383 MOPS for 
further details). Frailty will be assessed by the frailty phenotype, as previously defined by 
Fried et al. (2001). Frailty assessments will include 4-meter gait speed (two measures), 
grip strength (three measures), unintentional weight loss, exhaustion, and low activity by 
self-report, identical to the methods utilized in A5322/HAILO. See the A5383 MOPS for 
further details. These tests are only required at week 48 if they were not done at week 46. 
 
NOTE: If the Physical Function Testing cannot be performed at the Study Entry visit 
(0 ENT), then they should be carried out at the Treatment Initiation visit (0 IOT). 
 
6.12 
Brief Neuropsychological (NP) Testing and Limited Neurophysiological Evaluations 
 
At the time points indicated in section 6.1, participants will complete the Trail Making A & 
B, WAIS-III Digit Symbol, and HVLT-R NP tests (see the A5383 MOPS for further 
details). These tests are only required at week 48 if they were not done at week 46. 
 
NOTE: If the Brief NP Testing and Limited Neurophysiological Evaluations cannot  
be performed at the Study Entry visit (0 ENT), then they should be carried out at 
the Treatment Initiation visit (0 IOT) or at the next scheduled study visit.  
 
6.13 
Questionnaires 
 
The questionnaires are to be completed using the iMedidata Patient Cloud app on 
either a tablet or smartphone, except the Computerized Adaptive Testing for 
Mental Health (CAT-MH), which is detailed in the A5383 MOPS and can be 
completed on a desktop or laptop computer. If a site does not have a tablet or 
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the site may download the questionnaires from the Forms Management Utility on 
the DMC Portal. For Spanish-speaking participants, these questionnaires are only 
available in paper format. The CAT-MH cannot be completed by paper and must be 
completed electronically. See the A5383 MOPs for more information about 
accessing the iMedidata Patient Cloud app and the CAT-MH. 
 
Please note that, for the following assessments and questionnaires (Brief Mood 
Test/Depression Assessment, Brief Sleep Assessment, and Sexual and Gender 
Identity Questionnaire), each assessment or test is only required at the initiation 
of treatment visit (0 IOT) if it cannot be performed at the Entry visit (0 ENT). 
 
Brief Mood Test/Depression Assessment 
At the study visits indicated in section 6.1, participants will complete the Patient Health 
Questionnaire-9 (PHQ9). In addition, the CAT-MH and the General Anxiety Disorder-7 
(GAD-7) scale, a brief measure of anxiety, will be administered. These tests are only 
required at week 48 if they were not done at week 46. 
 
Brief Sleep Assessment 
At the study visits indicated in section 6.1, participants will complete the Pittsburgh Sleep 
Quality Index. The assessment will include data on the duration of the sleep cycle, 
quality of sleep, and use of sleep medication (if applicable). These tests are only 
required at week 48 if they were not done at week 46. 
 
Sexual and Gender Identity Questionnaire 
At the study visits indicated in section 6.1, participants will complete a sexual and gender 
identity questionnaire.  
 
Telephone, text message, or e-mail contact 
Participants will be contacted via telephone, text message, or e-mail after receiving the 
study treatment to remind them of their upcoming study visits and to ask about study 
treatment adherence. Remote contact guidance is provided in the A5383 MOPS. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or diagnosis that occurs in a study participant during the 
conduct of the study REGARDLESS of the attribution (i.e., relationship of event to 
medical treatment/study product/device or procedure/intervention). This includes any 
occurrence that is new in onset or aggravated in severity or frequency from the baseline 
condition.  
 
7.2 
Adverse Event Collection Requirements for this Protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
 
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 
All AEs that led to a change in study treatment/intervention regardless of grade 
 
All AEs meeting SAE definition or EAE reporting requirement 
 
All Grade ≥2 cardiac arrhythmias (i.e., atrial fibrillation, atrial flutter, etc.)  
 
Any Grade ≥1 SARS-CoV-2 or monkeypox infection or AE related to these 
infections (including any related signs or symptoms Grade ≥1) 
o NOTE: Any positive SARS-CoV-2 PCR or antigen test result must be 
recorded on the appropriate eCRF regardless of grade and/or presence of 
associated symptoms. If more than one test is obtained in a given infection 
episode, the first and last positive test result should be recorded on the 
eCRF. 
 
Any acute febrile illness (>101°F) 
 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. The DAIDS regulatory support center (RSC) will report events to Merck as 
appropriate.   
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found 
on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
 
Results in death 
 
Is life-threatening  
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Is a congenital anomaly/birth defect 
 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
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EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 Reporting Requirements for this Study 
 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
 
The study agent for which expedited reporting is required is letermovir. 
 
In addition to the SAE reporting category identified above, DAIDS will provide 
Merck and Company, Inc., with expedited SAE reporting of the following:  
o Cancers with no other event (regardless of association), fetal losses 
(regardless of association) and Immune Reconstitution Inflammatory 
Syndrome (IRIS) events which meet seriousness criteria (regardless of 
association). 
o Any overdoses of Study Product.  
o Abnormal pregnancy outcomes  
 
Pregnancies (without abnormal outcomes or other SAE) will be reported to 
Merck and Company by DAIDS on a quarterly basis. 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this study is as per the EAE manual.  
 
After the protocol-defined EAE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs) as defined in 
Version 2.0 of the DAIDS EAE Manual, will be reported to DAIDS if the study 
staff become aware of the events on a passive basis (from publicly available 
information). 
7.4 
Study Monitoring 
 
The protocol team will monitor the conduct and safety of the study via regular summaries 
of accrual, study discontinuation, sample and data completeness, and adverse events 
pooled over treatment arms, as appropriate.  
 


 
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The DAIDS Clinical Representative will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct as per DAIDS 
policies, guidance documents, and SOPs as applicable.  
 
The study will undergo interim review at least annually by an ACTG-appointed Study 
Monitoring Committee (SMC), although the SMC may elect to deviate from this timeline. 
In the event that enrollment for the first 40 participants takes longer than 6 months, a 
separate SMC meeting will be held 6 months after the first participant is enrolled. SMC 
reviews would then continue every 6-12 months after this point. The SMC will review 
accrual, baseline characteristics, conduct of the study (including premature study and 
premature study treatment discontinuations), AEs by study treatment arm, CD4+ T cell 
counts and HIV-1 RNA levels/suppression, and plasma CMV DNA levels (and if 
applicable, letermovir resistance results) over time by study treatment arm, and 
data/sample availability. The SMC may decide to monitor the study more frequently to 
review and assess whether or not the goal of enrolling at least one third (30 participants 
in each arm) individuals assigned female sex at birth not on testosterone or individuals 
assigned male sex at birth on feminizing sex hormones, is met. Further, the SMC may 
choose to closely monitor that at least one half (45 participants) in each arm have CD4+ 
T cell counts <350 cells/mm3. The SMC may recommend protocol revisions if there is 
significant difficulty in meeting the enrollment goals for these strata. Study enrollment will 
be halted if ≥3 study participants in the letermovir arm experience confirmed loss of HIV-
1 virologic suppression. 
 
Plasma will be sent from the central repository in batches throughout the study for 
assessment of CMV DNA levels in a designated laboratory at least every 6 months. The 
first shipment will happen in time for results to be considered by the SMC at the time of 
the futility analysis. The DMC will be notified of all detectable plasma CMV DNA levels 
(at any level) at any visit after treatment initiation. If the participant is in the letermovir 
arm, the DMC will reflexively request that an aliquot of plasma from the visit be sent from 
the central specimen bank (i.e., BRI) for letermovir resistance testing (which will be 
conducted in batch every 6 months). The first interim review for tolerability will occur at 
the time of futility analysis. We expect this to occur at approximately 9 months after the 
enrollment of the first study participant, once the 40th enrolled participant has reached 8 
weeks on study, plasma samples have been tested for an initial protocol-specified 
assessment of immunologic futility, and data have been analyzed. Enrollment will pause 
after the 40th participant has started study treatment and until (and if) the SMC deems 
the intervention not to be futile, but enrolled participants will be allowed to continue on 
study (i.e., beyond week 8) while the interim analysis is being conducted. An interim 
review should also be convened if, at any time, CMV DNA levels are detectable in 
plasma in 12 or more participants while taking study medications (Arm A only), 
letermovir resistance is detected in plasma specimens in two participants (Arm A only), 
new Grade ≥2 atrial fibrillation or atrial flutter of any grade is identified in four 
participants, a participant experiences a Grade 4 AE related to study treatment, or 3 or 
more participants in the letermovir arm experience HIV-1 virologic failure or any concern 
is identified by the DAIDS clinical representative, the study chairs, or study statisticians 
in consultation with the team. See section 10.0 for statistical and other considerations 
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Consideration for modification of the study would be solely at the discretion of the SMC. 
 
Detailed plans for study monitoring will be outlined in a Study Progress Data and Safety 
Monitoring Plan (SPDSMP) developed by the Statistical and Data Management Center 
(SDMC) prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
Only toxicities related to study treatments provided through the study will be considered 
in this section.  
 
The general guidelines presented in this section apply to toxicities that are not 
specifically addressed in section 8.2. 
 
Grade 1 or 2 
Participants who develop Grade 1 or 2 AE or toxicity felt to be related to study treatment 
may continue study treatment at the discretion of the site investigator with close follow-
up. If a participant chooses to discontinue study treatment, the site should notify the 
CMC within 72 hours. Participants will have premature study treatment discontinuation 
evaluations performed as noted in section 6.1. These participants will remain on study, 
off study treatment and have all evaluations performed per section 6.1 through 
completion of the study.  
 
Grade 1 or 2 symptoms including menopausal symptoms such as hot flashes, vaginal 
dryness, and flushing will not obligate study treatment discontinuation. Similarly, nausea, 
vomiting, and diarrhea responsive to supportive measures such as antiemetics will not 
obligate study treatment discontinuation.  
 
Grade 3  
Participants who develop a Grade 3 AE or toxicity thought by the site investigator to be 
related to study treatment should have study treatment withheld and the site should 
consult with the CMC. The participant should be reevaluated weekly until the AE returns 
to Grade ≤2, at which time study treatment may be reintroduced at the discretion of the 
site investigator in consultation with the CMC.  
 
If the same Grade 3 AE or toxicity recurs within 4 weeks after reintroduction of study 
treatment, study treatment must be permanently discontinued if the site investigator 
considers the AE or toxicity related to study treatment. The CMC should be notified 
within 72 hours. However, if the same Grade 3 AE or toxicity recurs after 4 weeks, the 
management scheme outlined above may be repeated. 
 
Participants experiencing a Grade 3 AE or toxicity requiring permanent discontinuation 
of study treatment should be followed weekly until the AE resolves. Participants will have 
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6.1 and 6.2.5. These participants will remain on study, off study treatment and have all 
evaluations performed per section 6.1 through completion of the study.  
 
Grade 4 
Participants with Grade 4 asymptomatic laboratory abnormalities may continue study 
treatment if the site investigator has compelling evidence that the toxicity is NOT related 
to study treatment.  
 
Participants who develop a Grade 4 symptomatic AE or toxicity will have study treatment 
permanently discontinued. The CMC should be notified within 72 hours.  
 
Participants experiencing a Grade 4 AE or toxicity requiring permanent discontinuation 
of study treatment should be followed weekly until the AE or toxicity resolves or returns 
to baseline. Participants will have premature study treatment discontinuation evaluations 
performed as noted in sections 6.1 and 6.2.6. These participants will remain on study, off 
study treatment and have all evaluations performed per section 6.1.  
 
8.2 
Other Conditions (Specific Management of Toxicities Related to Study-Provided Drugs) 
 
Detectable plasma CMV DNA levels   
Plasma CMV DNA levels may uncommonly be detectable in ART-suppressed HIV-
infected individuals, and in this setting are usually not suggestive of the presence of 
classically defined CMV end-organ disease (e.g., retinitis, colitis, etc.). Thus, no clinical 
management action is needed for detectable plasma CMV DNA levels unless there are 
symptoms suggestive of CMV end-organ disease, which would be extremely rare in the 
proposed study population. There is also no need for a repeat visit to confirm a 
detectable CMV DNA level in plasma.  
 
Per section 7.4, the DMC will be notified of all detectable plasma CMV DNA levels (at 
any level) at any visit after treatment initiation. If the participant is in the letermovir arm, 
the DMC will reflexively request that an aliquot of plasma from the visit be sent from the 
central repository for letermovir resistance testing. If letermovir resistance is detected, 
the site investigator, participant, and SMC will be notified and study treatment will be 
discontinued.  
 
Participants will have premature study treatment discontinuation evaluations performed 
as noted in section 6.1. These participants will remain on study, off study treatment and 
have all evaluations performed per section 6.1.  
 
New onset atrial fibrillation or flutter 
If a participant is found to develop new onset atrial fibrillation or flutter during the 
treatment phase of the study, study treatment will be discontinued and the participant will 
be referred to a local cardiologist for management. The study team cardiologists can 
also assist with ECG interpretation as well as counseling teams on appropriate 
management on a case-by-case basis.  
 


 
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8.3 
Pregnancy  
 
Pregnancy and pregnancy outcome will be recorded on the eCRFs. Pregnancies that 
occur on study should be reported prospectively to The Antiretroviral Pregnancy 
Registry. More information is available at www.apregistry.com. Telephone: 800-258-
4263; Fax: 800-800-1052.  
 
Pregnancy Outcomes and Reporting 
If a participant has completed the study or chooses to discontinue from the study before 
the end of the pregnancy, then site staff should request permission to contact them 
regarding pregnancy outcomes at the end of pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted on an eCRF at the end of the pregnancy.  
 
Pregnant participants will discontinue study treatment and any remaining study visits, 
however, study discontinuation evaluations will be completed and will continue to be 
followed as part of the study. At the end of the pregnancy, outcome and adverse events 
for the participant and infant will be recorded on the outcome eCRF. See section 7.3.2 
for additional reporting requirements for abnormal pregnancy outcomes.  
 
8.4 
SARS-CoV-2/COVID-19 Infection 
 
Participants with suspected or confirmed SARS-CoV-2 infection should be referred for 
appropriate testing and/or treatment. Sites should contact the A5383 CMC 
(actg.CMCa5383@fstrf.org) regarding completion of screening.  
 
NOTE: Self-reported, positive home tests (PCR or antigen test) dates can be used 
to document a confirmed SARS-CoV-2/COVID-19 infection.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
Failure by the participant to complete the Treatment Initiation visit (and for Arm A, 
those who do not start letermovir). 
 
Drug-related toxicity (see sections 8.1 and 8.2). 
 
Requirement for prohibited medications (see section 5.4.2). 
 
Pregnancy (given conflicting data on teratogenicity in animal models, incident 
pregnancy during study will trigger discontinuation of study drug).  
 
Request by participant to terminate treatment. 
 
Clinical reasons believed life-threatening by the physician, even if not addressed in 
section 8.1 of the protocol.  
 
Presence of letermovir resistance in plasma CMV isolates of participant in the 
letermovir arm.  
 
9.2 
Premature Study Discontinuation 
 
Failure by the participant to attend two consecutive clinic visits. 
 
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 
Request by the participant to withdraw. 
 
Request of the primary care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
 
At the discretion of the ACTG, IRB/EC, FDA, NIAID, Office for Human Research 
Protections (OHRP), other government agencies as part of their duties, investigator, 
or industry supporter.   
 
10.0 
STATISTICAL CONSIDERATIONS  
 
10.1 
General Design Issues 
 
A5383 is a phase II, randomized, open-label, controlled, multicenter trial being 
conducted at US sites to evaluate the tolerability and anti-inflammatory efficacy of 
letermovir 480 mg once daily for 48 weeks in adults with HIV-1 and CMV with ART-
mediated suppression. Participants will be randomized 1:1 to receive either letermovir 
(Arm A) or no anti-CMV treatment (Arm B). Participants will be on study for 60 weeks (48 
weeks on study treatment with 12 weeks of post study treatment follow-up). The total 
sample size will be 180 participants (90 in Arm A, 90 in Arm B).  
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan (SAP), which will define the content of the Primary 
Analysis Report. This report will form the basis for the primary study manuscript and 
results reporting to ClinicalTrials.gov. Outcomes of interest for secondary and 
exploratory objectives intended for subsequent publications are listed under “Other 
Outcome Measures.” 
 
10.2.1 
Primary Outcome Measures  
 
Change from baseline to week 46/48 in sTNFRII.  
 
10.2.2 
Secondary Outcome Measures  
 
10.2.2.1 Occurrence of Grade ≥3 AE or confirmed HIV-1 virologic failure after 
initiation of study treatment. 
 
10.2.2.2 Mucosal and plasma CMV DNA levels at weeks 8, 46, 48, 52, and 
60.  
 
10.2.2.3 Change from baseline to weeks 8, 46/48, 52, and 60 in sCD163. 
 
10.2.2.4 Change from baseline to weeks 8, 52, and 60 in sTNFRII.   
 


 
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10.2.3 
Other Outcome Measures  
 
10.2.3.1 Change from baseline to weeks 8, 46/48, 52 and 60 in inflammatory 
and coagulation markers (sCD14, IL-6, hsCRP, and D-Dimer). 
 
10.2.3.2 Change from baseline to weeks 8, 48, 52, and 60 in cellular 
monocyte activation markers. 
 
10.2.3.3 Change from baseline to week 48 in CMV IgG titer. 
 
10.2.3.4 Change from baseline to week 48 in CMV-specific T-cells. 
 
10.2.3.5 Change from baseline to weeks 8, 46/48, 52, and 60 in microbial 
translocation markers (B-D-Glucan, I-FABP, LBP, and zonulin). 
 
10.2.3.6 Change from baseline to weeks 8, 46/48, 52, and 60 in multiplex-
bead-array assay output.  
 
10.2.3.7 Change from baseline to weeks 8, 46/48, 52, and 60 in markers of 
the coagulation cascade (suPAR, plasmin-alpha2-antiplasmin 
complex [PAP] and prothrombin fragment 1+2 [F1+2]). 
 
10.2.3.8 Change from baseline to weeks 8, 46/48, 52, and 60 in soluble 
markers of endothelial activation (sICAM-1, sVCAM-1, sTF, E-
selectin and P-selectin). 
 
10.2.3.9 Change from baseline to weeks 8, 48, 52, and 60 in CD4+/CD8+ ratio. 
 
10.2.3.10 Change from baseline to weeks 8, 48, 52, and 60 in CD8+CD38+HLA-
DR+ T cells. 
 
10.2.3.11 Change from baseline to weeks 8, 48, 52, and 60 in CD8+CD28-
CD57+ T cells. 
 
10.2.3.12 Change from baseline to weeks 46 and 60 in HOMA-IR and plasma 
levels of free fatty acids. 
 
10.2.3.13 Change from baseline to weeks 46 and 60 in frailty score.  
 
10.2.3.14 Change from baseline to weeks 46 and 60 in gait speed time.  
 
10.2.3.15 Change from baseline to weeks 46 and 60 in grip strength. 
 
10.2.3.16 Change from baseline to weeks 46 and 60 in continuous chair rise 
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10.2.3.17 Change from baseline to weeks 46 and 60 in VACS index score (as 
calculated here: https://vacs.med.yale.edu/calculator/IC). 
 
10.2.3.18 Change from baseline to weeks 8 and 48 in single copy assay of 
HIV-1 RNA and cell-associated HIV-1 RNA and total HIV DNA. 
10.2.3.19 Change from baseline to week 48 in the clonality of the HIV reservoir.   
 
10.2.3.20 Change in plasma levels of commonly used ART drugs (tenofovir, 
integrase inhibitors) and statins during letermovir use. 
 
10.2.3.21 Change from baseline in plasma proteomics signature at week 48 
 
10.2.3.22 Change from baseline to weeks 46 and 60 in neurocognitive 
functioning (Trail Making A & B, Digit Symbol, and HVLT-R (HAILO 
Battery). 
 
10.2.3.23  Change from baseline to weeks 46 and 60 in PHQ9. 
 
10.2.3.24  Change from baseline to weeks 46 and 60 in Pittsburgh Sleep 
Quality Index. 
 
10.2.3.25 Change from baseline to weeks 46/48 and 60 in plasma NFL. 
 
10.2.3.26 Occurrence of letermovir resistance mutations after initiation of 
letermovir.  
 
10.2.3.27 Fold-change in seasonal influenza vaccine-specific IgG titers 
from last available pre-vaccine time point to the first available 
time point 4-12 weeks post-vaccination for flu vaccinations 
occurring after the initiation of treatment visit (0 IOT). 
 
10.3 
Randomization and Stratification 
 
After eligibility is confirmed and entry (pre-treatment) evaluations have been performed, 
participants will be randomized at a 1:1 ratio (letermovir: no treatment) using permuted 
blocks without institutional balancing with stratification by sex at birth and hormonal 
status (female sex assigned at birth without use of testosterone and male sex assigned 
at birth with use of feminizing sex hormones versus others) and screening CD4+ T-cell 
count (<350 vs. ≥350 cells/mm3). Our goal is to enroll half of all participants in each arm 
to the <350 cells/mm3 stratum and one third of all participants in each arm to the stratum 
defined by female sex assigned at birth without use of testosterone or male sex 
assigned at birth with use of feminizing sex hormones. Given feasibility concerns, we will 
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10.4 
Sample Size and Accrual  
 
It is anticipated that it will take up to 2 years to accrue 180 participants that receive study 
treatment. This timeline is estimated based on the following recruitment process: 
Approximately 3 months for the futility analysis phase; 5-6 months before futility analysis 
is complete; 12 months to recruit the remaining 140 participants. Participants not 
initiating study treatment will be replaced to reach the target of 180 and will not be 
included in the analysis. Participants who received at least one dose of study treatment 
will not be replaced. The sample size for A5383 was determined based on the primary 
endpoint of sTNFRII. 
 
Immunologic primary outcome 
The primary objective of this study is to compare sTNFRII change over 48 weeks of 
treatment in participants randomized to letermovir compared to no treatment. The 
sample size calculations are based on the primary hypothesis testing Ho: µletermovir = µno 
treatment targeting 90% power in the comparison of changes in log10-transformed sTNFRII 
between letermovir and no treatment. 
 
Our assumed standard deviation (SD) of the change in sTNFRII from treatment initiation 
to week 48 was estimated from prior ACTG projects where the SD of the change in 
sTNFRII levels ranged from 0.11 to 0.21 log10 pg/mL when just a single measure was 
used at each time point. In ACTG A5325 averaging two sTNFRII values at both baseline 
and follow-up lead to a 15%-30% reduction in the change SD compared to using one 
value at each time point. Assuming a change SD of 0.15 log10 pg/mL and allowing for 
some reduction due to averaging at baseline and follow-up, we arrived at an SD 
estimate of 0.123. Using this SD of change to week 48 and a Type I error rate of 5%, an 
expected drop-out/missing data rate of up to 15% in each arm, we will have 90% power 
to detect an effect size as small as 0.065 log10 pg/mL in the sTNFRII level change from 
baseline to week 48 between groups if we enroll 90 participants in each arm (assuming 
an average of two measures at baseline and week 48).  
  
Per NWCS 329, each log10 pg/mL increase in sTNFRII levels was associated with a 
50.4-fold increased odds of MI/stroke (using year 1 biomarker assessment), which 
corresponds to a 22.5% decreased odds of a non-AIDS event for each 0.065 log10 pg/mL 
decrease in sTNFRII, a clinically relevant effect size we would want to be powered to 
detect. 
 
The following table summarizes the calculation of the sample sizes corresponding to the 
detection of various effect sizes under various assumed standard deviations, with the 
effect size, standard deviation, and adjusted sample size selected for this study shown in 
italics. 
 


 
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Table 10.4-1: Sample Size Calculations 
Effect size in log10 
sTNFRII 
(difference between 
letermovir and no 
treatment) 
Std Dev of Δ 
Baseline to 
Week 48 
Total Sample 
size 
(90% power, 
alpha=0.05) 
Adjusted 
Sample Size
(15% 
inflation) 
0.050
0.100
86*2=172
102*2=204
0.123 
129*2=258 
152*2=310 
0.150 
191*2=382 
225*2=450 
0.065
0.100
51*2=102
60*2=120
 
0.123 
77*2=154 
90*2=180 
 
0.150 
113*2=226 
133*2=266 
0.080
0.100
34*2=68
40*2=80
 
0.123 
51*2=102 
60*2=120 
 
0.150 
75*2=150 
89*2=178 
 
While this study is not fully powered to differential treatment effects by sex and gender-
affirming hormone status, those analyses are of interest. It is also important to 
understand treatment effects among transgender and gender non-binary participants. 
Similar to the above, we will not have sufficient power to detect treatment effects for 
each group, so we will conduct exploratory analyses between groups (cis-men, trans-
men, cis-women, trans-women, gender non-binary of female sex assigned at birth and 
gender non-binary of male sex assigned at birth). 
 
If one third of enrolled participants are female sex assigned at birth without use of 
testosterone or male sex assigned at birth with use of feminizing sex hormones, we 
expect 25 evaluable participants in this stratum per arm. This provides 80% power to 
detect a 0.099 log10 pg/mL difference and 90% power to detect a 0.115 log10 pg/mL 
difference.   
 
Assuming a mean change of 0 log10 pg/mL for all participants in the no anti-CMV 
treatment arm and an overall treatment effect of 0.065 log10 pg/mL, we have 
approximately 42% power to detect a sex*treatment interaction effect of 0.075 log10 pg/ 
mL (0.04 log10 pg/mL in those assigned male sex at birth and not on feminizing sex 
hormones or female sex at birth on masculinizing hormones and 0.115 log10 pg/mL in 
those assigned female sex at birth and not on masculinizing hormones or male sex at 
birth and on feminizing hormones).  
  
Tolerability secondary outcome   
A secondary objective is to assess the tolerability of letermovir. With a study sample size 
of 180 participants, 90 participants will receive no anti-CMV treatment and 90 will receive 
letermovir.  
The 90 participants receiving letermovir will provide 90% probability of observing a 
Grade ≥3 AE that would occur in 2.6% or more of participants receiving letermovir.   
 


 
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With 90 letermovir and 90 untreated participants and assuming a Grade ≥3 AE in 2% of 
the untreated participants, there will be 80% power to detect a difference between the 
arms if 11% or more of the letermovir participants have a Grade ≥3 AE. If the proportion 
with an AE in the no anti-CMV treatment arm is 5% there will be 80% power to detect a 
difference of 13% (5% vs.18%). These calculations are based on a one-sided 5% alpha 
Fisher’s exact test.   
 
CMV shedding secondary outcome: 
One main secondary objective is to determine if letermovir influences the mucosal 
shedding of CMV DNA during treated HIV infection. We hypothesize that letermovir will 
significantly reduce the frequency of mucosal shedding compared to untreated 
participants. Based on our preliminary data in participants receiving ART with 
suppressed plasma HIV-1 RNA, we expect 50% mucosal CMV shedding at any one time 
of sampling. After letermovir administration, we expect that <10% of participants will still 
be shedding CMV in their mucosal secretions at weeks 8, 46, and 48 compared to 50% 
of participants receiving no anti-CMV treatment. Since CMV shedding fluctuates over 
time, repeated observations at study entry (pre-treatment) and week 0 as well as at 
weeks 46 and 48 will provide a more stable estimate of the degree of shedding at 
baseline before starting the intervention and at the end of treatment. 
 
The binary mucosal shedding outcome will reflect the presence or absence of any 
detectable oral, rectal, and genital CMV shedding. With 77 evaluable participants per 
arm, a two-sided 5% type I error, and three repeated measurements (weeks 8, 46, and 
48) assumed to have a compound symmetry covariance structure with a within 
participant correlation of 0.60, we will have 80% power to detect a difference of at least 
19% (50% shedding in no anti-CMV treatment vs. 31% shedding in letermovir) and 90% 
power to detect a difference of at least 22% (50% vs. 28%). These power calculations 
were conducted in PASS Version 15.0.4 with the “Tests for Two Proportions in a 
Repeated Measures Design” procedure. 
 
Accrual 
Once all sites are registered and letermovir becomes available, we expect each site to 
enroll an average of two participants per month. We expect the first 40 participants to be 
enrolled within 3 months once all sites are registered. After the first 40 participants have 
started therapy, enrollment will pause until these first 40 participants reach week 8, at 
which time a futility analysis will be performed, to ensure that there is some early 
evidence for an effect on systemic immune activation (sTNFRII and sCD163 in plasma). 
Assuming that after reviewing these data, the SMC determines that the intervention is 
not futile, the study will then reopen enrollment and recruit the remaining 140 
participants to achieve the enrollment target of 180. With a planned 16 sites 
participating, at one participant per month, we expect this second phase of enrollment to 
be completed, more or less, in 12 months. 
 


 
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10.5 
Data and Safety Monitoring  
 
10.5.1 Interim Monitoring Guidelines 
 
Scheduled interim reviews are outlined in section 7.4. 
 
Interim Week 8 Futility Analysis 
The purpose of the interim futility analysis is to use early observed data to assess 
if a fully accrued trial is unlikely to attain statistically significant results. While 
futility analyses typically use observed data for a protocol’s primary outcome (for 
this study, change from baseline to week 48 in sTNFRII), the study team wished 
to look at an earlier time point since it would take over one year to obtain week 
48 sTNFRII data on any subset of participants. Therefore it was decided that the 
futility analysis will be based on changes in sTNFRII from baseline to week 8 
rather than week 48. In addition, a second futility analysis will examine change 
from baseline to week 8 in sCD163 in order to assess a different potential 
pathway for a letermovir effect.  
 
Because the team wants the futility analysis to be completed before opening the 
substudy, which involves invasive procedures, it was decided that enrollment 
would pause after the first 40 participants start treatment. At this point the futility 
analysis will be conducted. Using the observed data on the first 40 participants, 
the estimated mean and 95% confidence interval (CI) within each arm and the 
difference between arms will be provided for each futility outcome. In addition, 
the observed data on the first 40 participants will be combined with simulated, 
unobserved data for the remaining 140 future participants. This simulation will be 
repeated thousands of times in order to assess conditional power and generate 
predicted interval plots (PIPS). The future data will be simulated under a range of 
plausible scenarios, including but not limited to: the effect midway between the 
null and the currently observed effect; the effect midway between the observed 
effect and the expected effect; and the expected effect. From these simulations, 
summary statistics of the final treatment effect and 95% CI will be provided. 
 
While there is no standard threshold for stopping a clinical trial for futility, typical 
thresholds are conditional power <20% or <30%. Because our futility outcomes 
use 8 week changes and the team expects approximately 50% of the expected 
Week 48 effect to be observed at this earlier time point, we feel that each should 
be assessed at <20% under a range of plausible scenarios. Consideration should 
be given to stopping the trial early if BOTH the sCD163 and sTNFRII outcomes 
are determined to be futile. Our hope is to minimize the chances of stopping the 
trial early for futility if the reduced effect is in fact observed at week 8. 
 
The following table summarizes conditional power under a range of observed 
and future data scenarios for sTNFRII and assumes an SD of 0.123 log10 pg/mL. 
 


 
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Table 10.5.1-1: Conditional Power for sTNFRII 
Mean difference observed 
in first 40 participants 
(log10 pg/mL) 
Mean difference simulated 
for remaining 140 
participants (log10 pg/mL) 
Conditional power1 
0
0
1.3%
 
0.008125 
3.1% 
0.01625
6.7%
 
0.024375 
12.8% 
 
0.0325 
21.9% 
0.008125
0.008125
3.9%
 
0.0203125 
11.2% 
 
0.0325 
25.1% 
0.01625
0.01625
9.8%
 
0.024375 
17.6% 
0.0325
28.4%
0.024375
0.0121875
8.5%
 
0.024375 
20.4% 
0.028413
25.8%
0.0325
32.0%
0.0325 
0.01625 
13.8% 
0.024375
23.4%
0.0325
35.8%
1 PASS Sample Size Software, Conditional Power of Two-Sample T-Tests, NCSS.com 
 
Using the observed data, a supplemental logistic regression will also be done to 
estimate the odds of achieving the reduced week 8 sTNFRII reduction of 0.0325 
log10 pg/mL. For this model, each participant will have a single outcome measure 
(week 8 sTNFRII change of ≤-0.0325 log10 pg/mL vs. >-0.0325 log10 pg/mL). The 
intent of this supplementary dichotomous outcome is to explore whether the 
average treatment effect is preferentially driven by a small subset of individuals. 
Participant-level changes will also be provided to the SMC as well as stratified 
analyses exploring whether there are baseline factors that appear to predict 
treatment effects, including CD4 count (<350 vs. ≥350) and above versus below 
the median sTNFRII level at baseline.   
 
The following table summarizes conditional power under a range of observed 
and future data scenarios for sCD163. In the valganciclovir trial, the mean 
treatment effect at week 8 for sCD163 was 0.046 log10 ng/mL. As with our 
projections for sTNFRII, given a possible smaller contribution of asymptomatic 
CMV replication to immune activation in those with higher CD4+ counts, we 
expect the week 8 effect in the letermovir trial (where half will have CD4+>350) to 
be approximately half of the effect observed in the valganciclovir trial, but that 
continued treatment through week 48 will continue to decrease levels by a similar 
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(the standard deviation of the change observed in the valganciclovir trial) and 
that 50% of the hypothesized 48 week effect at week 8 will be 0.023 log10 µg/mL.  
 
Table 10.5.1-2: Conditional Power for sCD163 
Mean difference 
observed in first 40 
participants 
(log10ug/mL)
Mean difference 
simulated for remaining 
140 participants 
(log10ug/mL)
Conditional power1 
0
0
1.3%
  
0.00575 
3.2% 
0.0115
6.9%
0.01725
13.3%
  
0.023 
23.0% 
0.00575
0.00575
4.0%
0.014375
11.7%
  
0.023 
26.3% 
0.0115
0.0115
10.2%
0.01725
18.4%
  
0.023 
29.8% 
0.01725
0.08625
8.8%
0.01725
21.3%
  
0.020125 
27.1% 
0.0325
33.6%
0.023
0.0115
14.4%
  
0.01725 
24.5% 
0.023
37.5%
1 PASS Sample Size Software, Conditional Power of Two-Sample T-Tests, NCSS.com 
 
Using the observed data, a supplemental logistic regression will be done to 
estimate the odds of achieving the reduced week 8 sCD163 reduction of 0.023 
log10 µg/mL. For this model, each participant will have a single outcome measure 
(8 week sCD163 change of ≤-0.0325 log10 µg/mL vs. >-0.0325 log10 µg/mL). The 
intent of this supplementary dichotomous outcome is to explore whether the 
average treatment effect is preferentially driven by a small subset of individuals. 
Participant-level changes will also be provided to the SMC as well as stratified 
analyses exploring whether there are baseline factors that appear to predict 
treatment effects, including CD4 count (<350 vs. ≥350) and above versus below 
the median sCD163 level at baseline.   
 
If the intervention is found to be futile in the overall population for both sTNFRII 
and sCD163 outcomes, we believe that it is still important to examine the subset 
of participants with CD4+<350 in the futility analysis. It is plausible that 
asymptomatic CMV replication will be a much greater driver of immune activation 
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much greater risk of end organ disease than those who restore CD4+ counts >500 
(~35% to 2-fold increased risk for MI/Stroke in CNICS and HOPS cohorts 
respectively, and approximately a 2-fold increased risk of T2DM events in the 
Vancouver cohort). Thus, if an intervention might work for the CD4+<350 
subgroup, we would still want to develop it for the CD4+ <350 population even if it 
did not work for those with higher CD4+ counts. Our goal is to enroll at least half of 
participants in each arm with CD4+<350 even in the futility analysis phase, so 
there should be at least 10 participants in each arm within the CD4+<350 stratum. 
If there appears to be a trend toward benefit in this subpopulation, the SMC may 
consider recommending a re-design of the trial restricted to the CD4+<350 subset.  
 
10.6 
Analyses 
 
10.6.1 Efficacy Analyses 
 
All statistical tests will be two-sided with a nominal alpha level of 0.05. Because 
this is a phase II study and all potential biologic activities of the intervention are 
of interest, analyses will be as-treated, and limited to participants who 1) have 
baseline and week 48 sTNFRII measurements, 2) remain on study product 
through week 48 with self-reported adherence >50%, 3) do not have a confirmed 
virologic failure (as defined per section 6.2.4 at or prior to week 48, and 5) did not 
receive vaccines or have concurrent acute illness within 1 week of treatment 
initiation and week 48 assessments (as defined per section 6.3.4).  
 
NOTE: Participants experiencing inflammatory conditions at the time of a visit are 
instructed to wait 7 days before measurements are obtained. Measurements 
obtained while inflammatory conditions are present will not be included in the 
analysis. The presence and resolution of an inflammatory condition is based on 
participant symptoms (i.e., fever, chills, swelling, redness) and at the judgement 
of the study clinician.  
 
A supplemental intent-to-treat primary sTNFRII analysis and secondary CMV 
shedding analysis will also be performed and will include all randomized 
participants. No adjustment for multiple testing will be performed.  
 
10.6.1.1 Primary sTNFRII Analysis 
 
To reduce intra-participant variability, two blood draws will be 
performed at study entry (pre-treatment), treatment initiation, and at 
weeks 46 and 48. The measurements will be the average of two 
sTNFRII results. If repeat measurements are not available at either of  
these time points, a single measurement will be used rather than the 
average. 
  
Changes in sTNFRII from baseline to week 48 will be compared 
between the letermovir arm and the no anti-CMV treatment arm by  


 
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simple linear regression. For this model each participant will have a 
single outcome measure of sTNFRII change from baseline to week 48. 
The covariates will be study arm with screening CD4+ cell count and 
sex plus hormonal therapy (the stratification factors). 
 
A supplemental logistic regression will be done to estimate the odds of 
achieving the targeted sTNFRII reduction of 0.065 log10 pg/mL which, 
as previously stated, has been associated with a clinically relevant 
22.5% reduction in CAD events. For this model, each participant will 
have a single outcome measure (48 week sTNFRII change of ≤ -0.065 
log10 pg/mL vs > -0.065 log10 pg/mL). The covariates will be study arm 
with screening CD4+ cell count and sex plus hormonal therapy (the 
stratification factors). 
 
Six supplemental linear regression analyses will be performed. The 
first will perform the primary analysis using a modified intent-to-treat 
population (mITT) consisting of all participants who have been 
exposed to letermovir or no anti-CMV treatment. The remaining five 
will use the PP population and will assess differential letermovir effects 
by 1) baseline sTNFRII tertile, 2) CD4 strata, and 3) sex and hormonal 
therapy strata by additionally adjusting for these main effects and the 
study arm by main effect interaction, 4) presence versus absence of 
mucosal CMV shedding at baseline, and 5) baseline use of an 
allowed statin. 
 
10.6.1.2 Secondary CMV Shedding Analysis 
 
CMV DNA shedding at weeks 8, 46, and 48 will be compared between 
treatment arms using a generalized estimating equations (GEE) model 
with a binary outcome and a compound symmetry covariance structure 
(other correlation structures will be considered if appropriate). 
 
10.6.1.3 Additional Secondary and Other Analyses 
 
The remaining continuous outcome measures will be analyzed by 
simple linear regression similar to the primary sTNFRII analysis. (Other 
outcome measures will not have the supplemental regression analyses 
performed). 
 
10.6.1.4 Tolerability Analyses 
 
All statistical tests will be one-sided with a nominal alpha level of 0.05 
and will include all participants who initiated study treatment. The 
proportion of participants with an AE in each arm will be compared with 
Fisher’s exact test and the highest AE grade per participant will be 
compared across arms with the Wilcoxon rank sum test. 
 


 
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11.0 
 PHARMACOLOGY PLAN 
 
Pharmacology Rationale 
Letermovir, an anti-CMV drug approved for CMV prophylaxis in seropositive alloHSCT 
individuals (Merck Sharp & Dohme Corp 2019), has not been previously studied in 
individuals with HIV, including assessment of potential for ART drug-letermovir 
interactions. Further, in this study, letermovir is being explored for several novel 
indications, for which it is important to establish PK/PD relationships: how differences in 
letermovir PK confer clinical or biomarker responses (PD). 
Letermovir is eliminated primarily via fecal excretion (93% overall recovery, with 70% 
unchanged) and is subject to minimal metabolism by UGT1A1, UGT1A3, and potentially 
CYP3A (34). In vitro, letermovir is a time-dependent CYP3A inhibitor, a CYP2C8 
inhibitor, and a CYP2B6, CYP2C9, CYP2C19 and time-dependent CYP3A4 inducer. It is 
an in vitro substrate for the organic anion transporter polypeptides 1B1 and 1B3 
(OATP1B1/3) and P-glycoprotein (P-gp). Letermovir is an inhibitor of BCRP, bile salt 
export pump (BSEP), multi-drug resistance protein 2 (MRP2), organic anion transporter 
3 (OAT3), P-gp, and OATP1B1/3 in vitro.  Clinical in vivo CYP interactions have been 
observed, including reduced voriconazole exposure likely due to CYP2C9 and CYP2C19 
induction by letermovir, and increased midazolam exposure via CYP3A inhibition by 
letermovir. 
 
Given its relatively recent approval (2017), few clinical interaction studies have been 
performed post-approval. While there is no direct evidence supporting a UGT-mediated 
interaction with letermovir, this is a commonly shared pathway with many ARTs, 
including frequently utilized integrase inhibitors. Thus there is a need for clinical 
confirmation of the absence of drug-drug interactions with this class of ARTs.  
 
Dolutegravir, a UGT1A1/3, CYP3A, CYP1A9, BCRP, and P-gp substrate, has been a 
common subject of drug-drug interaction studies [ViiV Healthcare Company. Dovato- 
dolutegravir sodium and lamivudine tablet, film coated Research Triangle Park, NC2019 
[updated April 8, 2019; cited 2019 June 4, 2019]. Available from: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68e45422-43ed-4cfb-9356-
fae88d14a53a]. Due to a low IC90, some were not deemed clinically significant [Cottrell 
et al., 2013; Song et al., 2011], while rifampin, a UGT1A1 and CYP3A inducer, exhibited 
a clinically significantly lower than expected dolutegravir exposure warranting dose 
adjustment [Dooley et al., 2013]. Further, a study of isoniazid-rifapentine 
coadministration with dolutegravir was stopped due to serious toxicities related to 
endogenous cytokine release [Brooks et al., 2018]. While the underlying mechanism is 
not known, hypotheses have implicated metabolic pathways. Other integrase inhibitors 
and ARTs, including elvitegravir [Gilead Sciences Inc. Stribild-elvitegravir, cobicistat, 
emtricitabine, and tenofovir disoproxil fumarate tablet, film coated, Foster City, CA, 2019 
(updated January 28, 2019, cited June 4, 2019)], tenofovir [Gilead Sciences Inc. Viread-
tenofovir disoproxil fumarate tablet, coated Foster City, CA, 2019 (updated April 29, 
2019; cited 2019 June 4, 2019)] [Barcelo et al., 2016], raltegravir [Merck Sharp & Dohme 
Corp. Isentress-raltegravir tablet, film coated Whitehouse Station, NJ, 2019 (updated  


 
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March 4, 2019; cited 2019 June 4, 2019)] [Kassahun et al., 2007], abacavir [Soars et al., 
2004], and emtricitabine [Gilead Sciences Inc. Emtriva-emtricitabine capsule Foster City, 
CA, 2019 (updated December 14, 2018; cited 2019, June 4, 2019)] are UGT substrates, 
and many are substrates or inhibitors of common transporters [Custodio et al., 2014; 
Zembruski et al., 2011]. 
 
Cobicistat, used to boost elvitegravir exposure, is a substrate and strong inhibitor of 
CYP3A, which may potentiate CYP3A-mediated interactions when given with letermovir, 
also an in vivo moderate CYP3A inhibitor [Merck Sharp & Dohme Corp. Prevymis- 
letermovir tablet, film coated (package insert); Whitehouse Station, NJ, 2019 (updated 
March 5, 2019; cited June 4, 2019)]. Protease inhibitors may also be impacted by or 
impact letermovir PK: atazanavir is a strong CYP3A inhibitor/substrate and UGT1A 
inhibitor, darunavir is a CYP3A substrate [Janssen Products LP. Prezita-darunavir tablet, 
film coated. Titusville, NJ, 2019 (updated June 6, 2019; cited June 7, 2019)], and 
ritonavir is a CYP3A inhibitor and substrate [AbbVie Inc. Norvir-ritonavir tablet, film 
coated; N. Chicago, IL, 2018 (updated November 19, 2018; cited June 7, 2019)]. 
 
Complex transporter-mediated interactions may also exist and impact letermovir 
exposure and other drugs. A study of cyclosporine, tacrolimus, and sirolimus in healthy 
participants demonstrated increased exposure for cyclosporine, tacrolimus, and 
sirolimus (AUC 1.7-, 2.4, 3.4-fold respectively), and additionally cyclosporine increased 
letermovir AUC by 2.1-fold. Cyclosporine is an in vitro inhibitor of OATP1B1/3, P-gp, and 
BCRP, all potential contributors to increased letermovir exposure [McCrea et al., 2019].  
 
By collecting blood plasma for PK levels of letermovir, commonly utilized ARV drugs, 
and statins, future exploratory analyses can be performed to assess potential for 
clinically significant metabolic and transporter-mediated interactions and the need for 
further intensive PK interaction studies. Further, these samples can be utilized in future 
exploratory analyses linking PK exposure to outcomes of interests for use in dose 
optimization and characterization of potential drivers of PK and PD variability. These 
analyses may inform letermovir dosing in future studies and foster further hypothesis 
generation. 
 
11.1 
Pharmacology Objectives 
 
To obtain samples to be used for future exploratory analyses to: 
 
11.1.1 
Assess PK interactions between letermovir and ART and allowed statins.  
 
11.1.2 
To establish the PK/Pharmacodynamic (PD) relationship between letermovir 
and statin exposure and study endpoints (e.g., change in sTNFRII levels). 
 
11.2 
Pharmacology Study Design 
 
Plasma samples will be collected at the treatment initiation visit (week 0), and at the 
post-treatment initiation visits at weeks 4, 8, 46, and 60 for ART and letermovir  


 
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quantification. All samples will be stored for future batched analysis of ART, statins, and 
letermovir following study completion. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form (eCRF) screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the participant identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization. 
 
12.2 
Role of Data Management 
 
12.2.1 
Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 
It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
12.3.1 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or in 
addition to onsite visits to ensure the safety of study participants and data 
integrity [FDA Guidance Document, 2021]. The site must make available study 
documents for site monitors to review utilizing a secure platform that is HIPAA 
and 21 CFR Part 11 compliant. The Data Management Center will configure 
Medidata Remote Source Review (RSR) and make it available to all sites.  
We encourage Sites to use the DMC provided Medidata RSR platform but 
other potential platform options include: Veeva SiteVault, site-controlled 
SharePoint or cloud-based portal, and direct access to Electronic Medical 
Record (EMR), and Medidata Rave Imaging Solution. Other secure platforms 
that are 21 CFR Part 11 compliant may be utilized, as allowed by the DAIDS 
Office of Clinical Site Oversight (OCSO). 
FDA. FDA Guidance on Conduct of Clinical Trials of Medical Products 
During the COVID-19 Public Health Emergency: Guidance for Industry, 
Investigators, and Institutional Review Boards, March 2020, Updated on 
January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download 
 
12.3.2 
The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the ACTG, IRB/EC, the site monitors, FDA, the 


 
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NIAID, the OHRP, the industry supporter or designee, other local, US, and 
international regulatory entities for confirmation of the study data.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the Informed Consent Form and any subsequent modifications will be 
reviewed and approved by the IRB or EC responsible for oversight of the study. A signed 
consent form will be obtained from the participant (or legal guardian, or person with 
power of attorney for participants who cannot consent for themselves). The consent form 
will describe the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. A copy of the consent form will be given to the participant, or 
legal guardian, and this fact will be documented in the participant’s record. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties, or the 
industry supporter or designee.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, OHRP, 
other country-specific government agencies as part of their duties to ensure that 
research participants are protected, or the industry supporter. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporter prior to submission.  
 
15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the CDC and the 
National Institutes of Health. 
 


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


 
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16.0 
REFERENCES 
 
Appay V, Fastenackels S, Katlama C, et al. Old age and anti-cytomegalovirus immunity are 
associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 2011;25:1813-22. 
Appels A, Bar FW, Bar J, Bruggeman C, de Baets M. Inflammation, depressive 
symptomtology, and coronary artery disease. Psychosom Med 2000;62:601-5. 
Ballou S, Kaptchuk TJ, Hirsch W, et al. Open-label versus double-blind placebo treatment in 
irritable bowel syndrome: study protocol for a randomized controlled trial. Trials 
2017;18(1):234. doi: 10.1186/s13063-017-1964-x. PMID: 28545508. 
Barcelo C, Gaspar F, Aouri M, et al. Population pharmacokinetic analysis of elvitegravir and 
cobicistat in HIV-1-infected individuals. J Antimicrob Chemother 2016;71:1933-42. doi: 
10.1093/jac/dkw050. PubMed PMID: 27029846. 
Beck-Engeser GB, Maldarelli F, York VA, et al. Valganciclovir reduces sTNF-R2 and 
vascular dysfunction markers in treated HIV. [Abstract #643]. In: Program and Abstracts 
from the 26th Conference on Retroviruses and Opportunistic Infections, March 4-7, 2019, 
Seattle, Washington, 2019. 
Bowman LJ, Melaragno JI, Brennan DC. Letermovir for the management of cytomegalovirus 
infection. Expert Opin Investig Drugs 2017;26:235-41. 
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INFORMED CONSENT FORM 
AND  
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
Sponsor / Study Title:  
The National Institute of Allergy and Infectious Diseases 
(NIAID) / “Randomized, Controlled Trial to Evaluate the 
Anti-inflammatory Efficacy of Letermovir (Prevymis) in 
Adults with Human Immunodeficiency Virus (HIV)-1 and 
Asymptomatic Cytomegalovirus (CMV) Who Are on 
Suppressive ART and Its Effect on Chronic Inflammation, 
HIV Persistence, and Other Clinical Outcomes (ELICIT)” 
Protocol Number: 
A5383 
Principal 
Investigator:(Study 
Doctor) 
«PiFullName» 
Telephone: 
«IcfPhoneNumber» 
Address: 
«PiLocations» 
 
SUMMARY  
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate whether letermovir (Prevymis), 
taken as two 240 mg tablets (480 mg total) or one 480 mg tablet once 
daily for 48 weeks, reduces inflammation (described below) in adults with 
human immunodeficiency virus (HIV-1) who also have cytomegalovirus 
(CMV) without any symptoms and who have been on effective anti-HIV 
medication for at least one year. Reducing inflammation might in turn help 
prevent some longer-term consequences of HIV, like heart disease and 
diabetes. This study will also look at whether you experience any side 
effects to the study drug. 
 
STUDY  
TREATMENT 
Letermovir, provided as two pills (each at a dose of 240 mg) or one pill (at 
a dose of 480 mg) given by mouth once a day, is approved by the US 
Food and Drug Administration (FDA) to prevent CMV disease in patients 
who have undergone allogeneic stem cell transplant. There are two 
groups in this study. You will have a 50/50 chance of going into each of 
the two groups. Participants in one group will get letermovir and 
participants in the other group will get no anti-CMV treatment.  
 


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NUMBER OF  
PARTICIPANTS 
There will be a total of 180 participants, divided into 2 study treatment 
groups. Ninety (90) participants will receive the active study treatment 
(letermovir) and 90 participants will receive no anti-CMV treatment. 
 
LENGTH OF  
STUDY 
The study will last for about 1 year and 2 months (about 11 months on 
either letermovir or no anti-CMV treatment and then about another 3 
months of follow-up). You will be on letermovir or no anti-CMV treatment 
for 48 weeks. After the first 40 participants have started study treatment 
(either letermovir or no anti-CMV treatment) and reached their 8-week 
study visit, we will stop enrollment for a while and do an initial analysis to 
make sure that letermovir is having some effect before enrolling the 
remaining participants. If no effect is seen at that point, we will consider 
stopping the study. 
 
REQUIRED  
ACTIVITIES 
 
Blood collections 
At some clinic visits, some blood will be collected from a vein in your arm. 
  
Special procedures 
At several of the clinic visits, throat washes, rectal swabs, and genital 
secretion (semen or vaginal swab) will be collected, because it is far 
easier to detect CMV in these samples than in blood. You do not 
have to provide genital secretions or rectal swabs if you feel 
uncomfortable in doing so or are not able to provide them. Physical 
function assessments will also be done. Neuropsychological tests will 
also be performed during clinic visits. All participants will have an 
electrocardiogram (ECG) performed at the initial screening visit.  
 
RISKS  
 
The following are possible: 
 
Common letermovir side effects  
o Nausea 
o Diarrhea 
o Vomiting 
o Swelling in the arms and legs 
o Cough 
o Headache 
o Tiredness 
o Stomach (abdominal) pain 
 
Possible letermovir side effects that are uncommon but potentially 
serious: 
o Fast heart rate or pulse 
o Atrial fibrillation, a condition of the heart that can cause a fast 
heart rate and increase the risk of stroke 


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 
Possible interactions between letermovir and antiretroviral therapy 
(ART) or other medications 
 
Developing letermovir-resistant CMV 
 
Allergic reactions such as rash or hives 
 
Risks associated with blood draws 
o Pain and bruising at the site of blood draw  
o Infection 
o Hypotension (lowering of blood pressure) 
o Feeling lightheaded or fainting 
 
Mild discomfort during vaginal swab collection 
 
Mild discomfort, coughing or a tingling feeling, or slight stinging during 
throat wash 
 
You may have mild discomfort when the rectal swab is performed, 
particularly if you are already suffering from sores or hemorrhoids. If 
you are already having pain in the rectal area, be sure to let the study 
team know. 
 
BENEFITS 
No direct health benefits should be expected from participating in this 
study. Information learned from this study may help others who have HIV 
and CMV.  
 
OTHER CHOICES  
Instead of being in this study, you have the choice of treatment for 
asymptomatic CMV infection with: 
 
Treatment with other experimental drugs for asymptomatic CMV 
infection, (if you qualify), or 
 
No treatment – which is the current standard of care for asymptomatic 
CMV infection 
 
 
INTRODUCTION  
 
You are being asked to take part in this research study because you have HIV (the virus that 
causes AIDS). This study is sponsored by the National Institutes of Health (NIH). The study 
doctor in charge of this study at this site is listed on page one of this consent form. Before you 
decide if you want to be a part of this study, we want you to know about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign and date this consent form. You will get a copy 
to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
CMV is a very common virus that infects the majority of adults and over 90% of people with HIV. 
Most healthy people (those without HIV and with an intact immune system) that have CMV have 


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no symptoms at all but carry the virus in the body for their entire life. A large part of the body’s 
immune defenses is actually devoted to keeping CMV from replicating (making copies of itself). 
When the immune system is very weak, such as during advanced AIDS (for example, a CD4 
count less than 50), CMV can escape the control of the immune system, replicate at high levels, 
and cause symptoms (such as eye problems like retinitis or gut problems like colitis). While 
such high levels of CMV replication typically don’t occur anymore once the immune system gets 
stronger on HIV medications, it is possible that the immune system may not recover to 100% 
strength during anti-HIV treatment, allowing very low-level CMV replication to occur in the body. 
These low levels of CMV replication may not be enough to cause retinitis or colitis, but they may 
be enough to cause low-level inflammation (a reaction of the body to injury or infection) in the 
blood vessels and the fat tissue, possibly increasing the chance of heart disease or diabetes, 
conditions that appear to be increased in people with HIV.  
 
The investigators of this study think that treating low-level CMV might reduce inflammation in 
people with HIV who are otherwise doing well on anti-HIV medications, and reduce their risk for 
heart disease, diabetes, and other aging-related complications. The study is designed to 
specifically address this hypothesis.  
 
Letermovir (Prevymis), is FDA approved to prevent severe CMV disease in adults who carry 
CMV without any symptoms and who are receiving special cells from another person. This is 
also known as allogenic stem cell transplantation and is usually used to treat a blood cancer. 
Letermovir is not approved for others with CMV, including those with HIV. Because letermovir 
has been shown to reduce CMV disease in these people who have a weakened immune 
system, it is proposed that it may also reduce the amount of CMV and inflammation in people 
with HIV. The use of Letermovir (Prevymis) in this study is investigational because it is the first 
time that letermovir is being used in individuals living with HIV.  
 
The purpose of this study is to see if letermovir is safe and effective when given to people who 
have both well-controlled HIV infection and asymptomatic CMV infection. This study will also 
gather data on the effectiveness of letermovir to reduce inflammation when compared to no anti-
CMV treatment. In addition, the study will collect information on whether you experience any 
side effects from the study drug. The effects of letermovir in reducing the amount of CMV virus 
and inflammation in people living with HIV are still unknown.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
If you decide to take part in this study, you will have a screening visit to determine if you qualify 
for the study.  
 
There is some information that we collect on everyone who is screened for an ACTG study. As 
part of your screening visit, some demographic (such as, age, sex/gender, race), clinical (such 
as, disease condition, diagnosis, use of sex hormones), and laboratory (such as, CD4+ cell 
count, viral load) information will be collected from you. We also collect information on whether 
you use (or have used) illicit intravenous (IV) drugs. 
 


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We will collect this information even if you are found to be not eligible to receive the study drug. 
This information is collected so that ACTG researchers can determine whether there are 
patterns and/or common reasons why people do not join a study.  
 
Screening 
At the screening visit, you will be asked for your medical and medication history, you will have a 
physical exam, have your blood drawn, have a pregnancy test (if appropriate), have short 
neuropsychological testing, and receive a test for the health of your heart known as an 
electrocardiogram (ECG). The screening visit should take between 60-90 minutes to complete. 
If, during your screening visit, study staff suspect or confirm that you have a SARS-CoV-2 
infection, you will be referred to an appropriate testing and/or treatment center. 
 
Study Entry (Pre-Study Treatment) and Study Treatment Initiation Visits 
The schedule of visits and study procedures are explained in Appendix I. While some of the 
visits may occur remotely (please see Appendix I), most will occur in person. Study visits 
take place at 4, 8, 16, 24, 32, 40, 46, 48, 52, and 60 weeks after you enter the study. Each of 
these visits will take between 30 and 60 minutes. 
 
Following the screening visit, if you qualify for the study, you will have a brief physical exam, 
blood draw, pregnancy test (if appropriate), rectal swab, and provide oral and genital fluid 
samples (saliva, semen or vaginal swab). You will also complete questionnaires that ask about 
your sleep behavior (at the Study Treatment Initiation visit, and at weeks 46, 48, and 60 only), 
mood, sex and gender identity, and overall well-being. A type of blood draw called Plasma 
Pharmacokinetic (PK) sampling will also be collected at the Study Treatment Initiation visit. 
Pharmacokinetic samples allow researchers to determine how the body handles (absorbs, 
metabolizes and eliminates) the study treatment over time.  
 
Semen, vaginal, and rectal swabs are requested because it is much easier to detect CMV 
in these samples than in the blood. Thus, providing these samples allows us to better 
measure the direct effect that letermovir has on CMV. Nevertheless, we understand that 
you may be uncomfortable providing (or unable to provide) semen, vaginal, or rectal 
swab samples. You can still participate in the study if you do not wish to provide these 
samples. 
 
If you qualify for the study, you will be randomized to receive either the study treatment 
(letermovir) or no anti-CMV treatment. Randomized means that your assignment will be 
random, like rolling dice or flipping a coin to land on heads or tails. In this study, you will have a 
50/50 chance of receiving study treatment versus no anti-CMV treatment. You will receive the 
study treatment or no anti-CMV treatment for 48 weeks and will continue to take your usual HIV 
medication. HIV medication will not be provided to you through the study. 
 
Please note that you must continue your medication(s) for HIV while enrolled in this study, and 
your HIV must remain well-controlled (undetectable – meaning under 50 viral copies/ml, 
depending on the assay used) in order for you to continue to receive the study drug in this 
study.  
 


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There are a number of medications that should not be taken while you are participating in this 
study. Please inform your study doctor about any new prescriptions, other medications, or 
herbal remedies you are considering before you start taking them, so that the study doctor can 
advise whether they are safe to take while on this study. 
 
Please also note that you are encouraged to use condoms and/or other barrier methods during 
the study to prevent HIV and other disease transmission, and for at least 90 days after your last 
dose of study drug. You must also use effective contraception during this study if you or your 
partner is able to become pregnant. Sperm donation and egg donation should also be 
avoided during this period. 
 
Follow-up Visits 
You will have follow-up visits remotely or in person (see Appendix I) at weeks 4, 8, 16, 24, 32, 
40, 46, 48, 52, and 60. Most of these visits will take between 30 and 60 minutes. You will be 
asked how you are feeling, how you are sleeping, what medications you are taking, and whether 
you are taking your study treatment and HIV medications. Between 5 and 120 mL (1 teaspoon 
to 8 tablespoons) of blood may be collected at any one visit. At some of these visits, you may 
have rectal swabs collected and/or provide oral and genital fluid samples (saliva, semen, or 
vaginal swab). Saliva will be collected by a throat wash (in other words, you will gargle water 
and spit it into a cup). A Plasma PK sample will also be collected at some of the follow-up visits. 
A Plasma PK refers to a pharmacokinetic test that is done to measure the amount of study drug 
in your blood. An ECG will only be performed during follow-up visits if you have an abnormal 
heart rate, rhythm, and/or palpitations. You will also be asked about your sleep patterns and 
behaviors during some of the visits. A few visits will be shorter, allowing you to pick up refills of 
your study treatment, undergo a physical examination, and answer some questions about how 
well you are taking your study treatment and HIV medications. You will be required to fast 
(nothing to eat or drink except for water) at least 8 hours before all blood draws – except before 
any visits to recheck HIV levels after prior tests show the amount of HIV in your blood may have 
increased to a high enough level to suggest that HIV is not well controlled in your body (virologic 
failure).  
 
Remote Follow-up Visits 
Sometimes, the study staff may need to conduct a scheduled visit remotely (for example, by 
telephone, or via telehealth). This could happen for any of the reasons listed below  
 
If you are not feeling well 
 
If someone living with you is not feeling well 
 
Local conditions or guidelines prevent you from being able to travel to the clinic 
 
The site is temporarily unable to conduct non-essential visits in the clinic (for example, 
because of a problem at the facility or because of a public health emergency) 
 
At the discretion of the A5383 study team 
 
Regardless of the reason, the site study staff will attempt to contact you and obtain as much of 
the required information from you as is possible. Study drug supplies might be delivered to your 
home, if needed. Typically, visits would not be conducted remotely if you needed to travel 
to the clinic to refill study drug or had any new side effects or health problems that 
require medical attention. 


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Follow-up Visits (weeks 8, 46 and 48) 
If you are enrolled during the first phase of the study before the planned interim analysis (first 40 
participants in the overall study), and if the week 8 visit is scheduled to take place at a time 
when it is not possible to conduct an in-person visit, the site may postpone your scheduled week 
8 visit for up to 6 weeks so that you can safely attend the visit in person. 
 
If both your week 46 and 48 visits are scheduled to take place at a time when it is not possible 
to conduct an in-person visit, the site may postpone your scheduled week 48 visit for up to 6 
weeks so that you can safely attend the visit in person. If such a postponement is necessary, 
you would be asked to continue taking study drug during that period (for up to 6 weeks) so that 
you are still taking study drug at the time of the final “on treatment” study visit (for example, up 
to 54 total weeks of study drug instead of the originally planned 48 weeks). The study staff will 
try to conduct your week 48 visit in person. If the week 48 visit is delayed, the weeks 52 and 60 
visits will also be delayed (in other words, the off-treatment phase of the study would still be 12 
weeks).  
 
Telephone, E-mail, or Text Message Contact 
After receiving the study treatment, you will be contacted by telephone, text message, or e-mail 
between visits to remind you of study visits and to track your adherence to the study treatment. 
 
 
MAY I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION ARE 
USED FOR? 
 
Some of your blood and genital fluid samples will be stored and used for testing of the body’s 
immune (protective) response, swelling (inflammation), and the presence of both CMV and HIV 
that is required for this study.  
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
The tests described in this consent are required by this study. However, if you are not able to 
or do not choose to provide genital secretions or rectal swabs, then you do not have to 
provide them.  
 
Optional use of samples in other studies  
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples”. 
The ACTG will only allow your extra samples to be used in other studies if you agree to this. 
If you have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 


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Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository in the United States. 
 
There is no limit on how long your extra samples will be stored.  
When a researcher wants to use your samples and information, their research plan must be 
approved by the ACTG. Also, the researcher’s institutional review board (IRB) will review their 
plan. IRBs protect the rights and well-being of people in research. If the research plan is 
approved, the ACTG will send your samples to the researcher’s location. This means that 
researchers who are not part of the study team may use your samples without asking you again 
for your consent. The researcher is not likely to ever know who you are. You will not be paid for 
your samples.  
 
You may withdraw your consent for research on your extra samples at any time and the 
specimens will be discarded. You may decide whether or not you will permit the use of your 
stored samples for other studies in the consent signature page below. 
 
COMMERCIAL PROFIT  
 
Your biospecimens collected during this study will never be used for commercial profit. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
A total of 180 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 14 months (1 year and 2 months).  
 
 
WHY WOULD THE STUDY DOCTOR OR SPONSOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor or sponsor may need to take you off the study early without your permission if: 
 
If you are unable to attend the Study Treatment Initiation visit 
 
If you are unable to attend two consecutive study visits 
 
The study is stopped or cancelled 
 
Per the request of your primary care provider if they think the study is no longer in your best 
interest  
 
A Safety Monitoring Committee (SMC) recommends that the study be stopped early (A SMC 
is an outside group of experts who monitor the study.) 
 
You become pregnant 
 
The study doctor may also need to take you off the study treatment without your permission if: 
 
Continuing the study treatment may be harmful to you 
 
You need a treatment that you may not take while on the study 


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 
You become pregnant 
 
You are not able to take the study treatment as required by the study 
 
If you must stop taking the study treatment before the study is over, the study doctor may ask 
you to continue to be part of the study and return for some study visits and procedures. 
 
 
IF I HAVE TO PERMANENTLY STOP TAKING STUDY-PROVIDED LETERMOVIR 
(PREVYMIS), OR ONCE I LEAVE THE STUDY, HOW WOULD LETERMOVIR BE PROVIDED?  
 
During the study: 
 
 
If you must permanently stop taking study-provided letermovir before your study 
participation is over, the study staff will discuss other options that may be of benefit to 
you. 
 
After the study: 
 
 
After you have completed your study participation, the study will not be able to continue 
to provide you with the letermovir you might have received on the study. If continuing to 
take this or similar drugs/agents would be of benefit to you, the study staff will discuss 
how you may be able to obtain them.  
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
There are risks to taking part in any research study.  
 
The study treatment used in this study may have side effects, some of which are listed below. In 
a research study, all of the risks or side effects may not be known before you start the study. 
You need to tell your study doctor or a member of the study team immediately if you experience 
any health problems.  
 
Please note that these lists do not include all the side effects seen with this study drug. These 
lists include the more serious or common side effects with a known or possible relationship to 
the study drug. If you have questions concerning the additional side effects, please ask the 
medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications and/or 
vaccines are taken or given with the study treatment. For your safety, you must tell the study 
doctor or nurse about all non-study medications and/or vaccines you are taking or given before 
you start the study and also while you are on the study. You are encouraged to receive standard 
vaccinations including influenza vaccination (in other words, flu vaccine) and COVID-19 
vaccination, while you are on the study, but these vaccinations should occur at least 14 days 
before you start any study visits or right after the study visits. Also, you must tell the study 
doctor or nurse before enrolling in any other clinical trials (studies) while on this study. 


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Everyone participating in this research study will be monitored (watched carefully, through 
frequent visits and other contact between visits) for side effects. You will be monitored during 
the administration of study treatment to keep track of your blood counts and organ function, 
particularly your kidney and liver function. Side effects that you might experience may go away 
after you stop taking the study treatment. You will be monitored closely for any of the severe, 
life-threatening side effects listed below. Some of these side effects may be permanent. 
Appropriate medical care will be provided, if necessary, including additional treatment, 
hospitalization and/or surgery.  
 
Commonly reported but mild side effects of letermovir (seen in about 5% more people when 
compared to people getting no anti-CMV treatment): 
 
Nausea 
 
Diarrhea 
 
Vomiting 
 
Swelling in the arms and legs 
 
Cough 
 
Headache 
 
Tiredness 
 
Stomach (abdominal) pain 
 
These mild side effects do not generally last more than a few days and usually do not require 
treatment, but you may be given non-prescription medication to help relieve the symptoms. 
 
Less common, but potentially severe side effects of letermovir:  
 
Tachycardia (fast heart rate or pulse) 
 
Atrial fibrillation, a condition of the heart that can cause a fast heart rate and increase the 
risk of stroke. 
 
Studies of letermovir in male rats have shown that there were reduced or abnormal sperm 
counts in rats that received high doses of letermovir. Therefore, if you are a study participant 
with testicles, your sperm count may be affected. For this reason, all study participants who 
produce sperm must do the following during the study treatment period and for at least 90 days 
after the last dose of study treatment: 
 
Use contraception  
 
Refrain from donating sperm  
 
As with all drugs, you could have an allergic reaction such as a rash or hives. Allergic reactions 
can be dangerous; if you develop an allergic reaction, you will be given medication (similar to 
Benadryl) to counter the reaction. 
 
Risks of Letermovir resistance 
There is a potential risk that the CMV in your body might become resistant to letermovir. This 
would only potentially cause harm if you eventually needed to use letermovir to prevent or treat 
a severe CMV disease in the future. Since severe CMV disease primarily only occurs when the 
immune system is very weak (as with untreated and/or advanced AIDS or after a bone marrow 
or organ transplant), it is unlikely that you would need letermovir treatment in the future. It is 


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also unclear whether developing letermovir resistance while receiving the study treatment would 
result in continued CMV resistance to letermovir in the body after the study is completed. While 
letermovir resistance tests might be performed on samples obtained in this study, you will only 
receive research results that are important to your immediate health and those that require the 
need for medical treatment.  
 
Risk of not being able to suppress HIV viral load while on study drug  
While we do not anticipate significant interactions between letermovir and the anti-HIV drugs in 
your regimen, with any new medication there is always the possibility that there could be 
interactions with other medications that you are taking that we do not expect, making them less 
effective. We will monitor your HIV viral load in the study, and if your HIV viral load increases 
(and is confirmed with a second blood draw) while taking the study drug, we will stop the study 
drug but your participation in the trial will continue. If that were to happen, we would also 
perform an HIV drug resistance test to see if HIV has become resistant to one or more drugs in 
your regimen and share those results with you and your doctor. While it is unlikely that you will 
develop new HIV drug resistance, if it were to happen, it might require a change in your HIV 
drug regimen to suppress your HIV viral load again.   
 
Risks Associated With Collection of Genital Secretion (Semen or Vaginal Swabs) 
 
There are no known physical risks associated with semen collection by masturbation. 
 
You may experience mild discomfort related to the insertion of the vaginal swab. 
 
Risks Associated With Collection of Oral Secretions using Throat Washes 
 
You may experience mild discomfort during this procedure.  
 
Occasionally there can be coughing or a tingling feeling, or slight stinging. 
 
Risks of Rectal Swab 
You may have mild discomfort when the swab is performed, particularly if you are already 
suffering from sores or hemorrhoids. If you are already having pain in the rectal area, be sure to 
let the study team know. 
 
Risks Associated with Blood Draw 
Blood draws may cause pain and bruising, and rarely, infection at the site of the blood draw. 
There is also a risk of anemia (low red blood cell count) or hypotension (low blood pressure). 
Sometimes, having blood drawn will cause people to feel lightheaded or even to faint. 
 
Risks Associated with Electrocardiogram (ECG) 
An ECG traces the electrical activity of the heart.  You may have mild irritation, slight redness, 
or itching at the sites on your skin where the recording patches are placed. 
 
Risks Associated with Questionnaires 
The questionnaires used in this study may be upsetting. You do not need to answer any 
questions that you are not comfortable with. 
 
If you are having suicidal thoughts or feel in crisis, call the study doctor at the telephone 
number listed on the first page of this form.  You can also call or text the National Suicide 


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& Crisis Lifeline at 9-8-8 or 1-800-273-TALK (8255). The Lifeline numbers are answered 24 
hours a day every day of the year by a skilled, trained counselor. You can also present to 
a healthcare provider, your local emergency room, or call 9-1-1 to be connected to local 
emergency services. 
 
Unknown Risks 
You might have side effects or discomforts that are not listed in this form.  Some side effects 
may not be known yet.  New ones could happen to you.  Tell the study doctor or study staff right 
away if you have any problems. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known whether this study treatment might hurt an unborn child. For study participants 
who are able to become pregnant, the study treatment may involve risks to you (or to the 
embryo or fetus, if you become pregnant), which are currently unforeseen. There does not seem 
to be risk to an unborn child if your partner becomes pregnant. While participating in this 
research study, including the 48 weeks of study treatment and the subsequent 12 weeks of 
follow-up off study treatment, you should not become pregnant and should not nurse a baby. 
You may be provided counseling about preventing pregnancy. Let your study doctor know 
immediately if you become pregnant. Your primary doctor should also be told if this happens. If 
you are pregnant, you may not take part in this study. If you are nursing a baby and do not want 
to stop, you cannot take part in this study. If you can become pregnant, a urine or blood 
pregnancy test will be obtained before you receive the study treatment. If you think you may be 
pregnant at any time during the study, tell your study staff right away. The study staff will talk to 
you about your choices. In addition, you should avoid donating sperm or eggs while you 
are participating in the study.  
 
If you can become pregnant and are participating in sexual activity that could lead to pregnancy, 
you must use reliable birth control that you can discuss with the study staff. At least one of the 
following methods MUST be used while you are in the study: 
 
Condoms with or without a spermicide  
 
Diaphragm or cervical cap with spermicide 
 
Intrauterine device (IUD) 
 
Hormone-based contraceptive 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in participants who were 
assigned female sex at birth and of reproductive potential taking anti-HIV drugs. This report will 
not use your name or other information that could be used to identify you. 
 
 


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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
No direct health benefits should be expected from participating 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: 
 
 
Treatment with prescription drugs available to you 
 
Treatment with experimental drugs, if you qualify  
 
No preventive treatment for CMV infection, which is the current standard of care for 
asymptomatic CMV infection 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
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 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. 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. 
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties (insert name of site) Advarra institutional review board 
(IRB) (a committee that protects the rights and safety of participants in research), National 
Institutes of Health (NIH), other local, US, and international regulatory entities, study staff, study 
monitors, the drug company supporting this study, and its designees. This means that absolute 
confidentiality cannot be guaranteed.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.  
 
 


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WHAT ARE THE COSTS TO ME? 
 
The study will pay for all research-related tests and assessments and for the study drug, 
letermovir (Prevymis). Taking part in this study may lead to added costs to you and your 
insurance company. In some cases, it is possible that your insurance company will not pay for 
these costs because you are taking part in a research study.  
 
Anti-HIV medicines and birth control will not be provided by the study, and will be your 
responsibility to obtain, as advised by your treating physician and subject to coverage through 
your health insurance. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
Compensation 
 
You may be reimbursed for your time and travel expenses as part of your participation in this 
study. You will be paid up to a total of $xx.xx if you complete this study. You will be paid for the 
visits you complete according to the following schedule: 
 
$xx.xx for Visits xxx.  
 
$xx.xx for Visits xxx.  
 
$xx.xx for Visits xxx.  
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid ___________ [“after each visit,” “annually,” “bi-weekly,” etc.] 
 
If you have any questions regarding your compensation for participation, please contact the 
study staff.   
 
[OR] 
 
You will not receive any monetary compensation for your participation in this study.  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company.  
 
[Sites: Please modify (if necessary) and insert one of these two statements, as appropriate to 
your site. If your site is required to carry CTI, this must be indicated in the informed consent.] 
 
There is no program for compensation through the US National Institutes of Health, but this 
site has clinical trials insurance. This insurance will allow the site to provide you with 
monetary compensation if you suffer harm as a result of participating in this research study.  


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OR 
 
There is no program for compensation either through this institution or the NIH. 
 
You will not be giving up any of your legal rights by signing and dating this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, welfare, 
or willingness to stay in this study. If you want the results of the study, let the study staff know. 
 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
 
Or call toll free:    877-992-4724 
 
Or by email:         adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00048976. 


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SIGNATURE PAGE 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the staff any questions that you have before you indicate your selection. 
 
Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved HIV-related research that does not include human genetic testing. Genetic 
testing is a type of medical test that identifies specific characteristics of your genes. Your body, 
like all living things, is made up of cells. Cells contain deoxyribonucleic acid, also known as 
“DNA”. DNA is like a string of information put together in a certain order. Parts of the string 
make up “genes”. Genes contain instructions on how to make your body work and fight disease. 
Differences or changes in DNA explain some of the physical differences among people. These 
differences partly explain why some people get diseases like cancer or diabetes while others do 
not. Genetic testing looks at the differences in people’s DNA. This testing also looks at how 
differences affect health and the body’s response to disease and study treatment 
 
____ (initials) I understand, and I agree to this storage and possible use of my samples.  
 
OR 
____ (initials) I understand, but I do not agree to this storage and possible use of my samples. 
 
Research with Human Genetic Testing  
The ACTG has a study (A5128) that collects samples and requires consent for genetic testing: 
A5128, Plan for Obtaining Informed Consent to use Stored Human Biological Materials (HBM) 
for Currently Unspecified Analyses. 
 
Your extra samples from A5383 will not be used for human genetic testing unless you sign a 
separate consent form for study A5128. 
 
Your study site staff might ask you if you would like to participate in the A5128 study. If you 
would like to participate, you will sign and date a separate consent form. 
 
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 and date the 
form. 
 
_____________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 


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


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


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APPENDIX I: A5383 DESCRIPTION OF STUDY VISITS AND EVALUATIONS 
 
I. 
Study Visit Schedule 
 
The study site staff can answer any questions you have about individual study visits, how long they will last, or about the tests 
that will occur. The table below can be used as a quick reference for you, along with the explanations that follow.  
 
Table 1: Expected Study Visit Schedule 
Evaluation or Procedure 
Screening1 
Study 
Entry 
Study 
Treatment 
Initiation 
(Week) 
Post-Study Treatment Initiation Evaluations 
(Weeks) 
0 
4 
8 
16 
24 
32 
40 
46 
48 
52 
60 
Extra 
Visits2 
Consent & contact information 
collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV status confirmed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questions about your health and 
medications you are taking 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
 
needed only if an abnormal heart rate/rhythm is found 
 
Blood collected 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Pharmacokinetic (PK) 
sampling 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
Pregnancy test 
 
 
 
when pregnancy is suspected 
 
Study treatment adherence 
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of genital and oral 
secretions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Evaluation or Procedure 
Screening1 
Study 
Entry 
Study 
Treatment 
Initiation 
(Week) 
Post-Study Treatment Initiation Evaluations 
(Weeks) 
0 
4 
8 
16 
24 
32 
40 
46 
48 
52 
60 
Extra 
Visits2 
Rectal swab collection 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
Physical Function/Frailty testing 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
Brief thinking/memory testing 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
Brief mood questionnaires  
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
Brief sleep assessment 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
Sexual & Gender Identity 
Questionnaire 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone, text message, or e-
mail contact 
between visits as needed 
 Additional clinical 
assessments (as needed)
 
 
 
 
 
5 
 
5 
5 
 
 
 
 
 
Remote data collection 
Possible6  
1 
Screening: After you have read and signed the consent form, you will have several tests done to make sure that you meet the requirements for joining 
the study. If it appears or is confirmed that you might have SARS-CoV-2 infection, the study site staff will refer to you for appropriate testing and/or 
treatment. 
2 
Extra Visits: You will be required to attend a short number of extra study visits if the amount of HIV in your blood has increased to a high enough level 
that shows the HIV is not well-controlled in your body (virologic failure). If this is the case, you will remain in the study but stop study treatment 
(letermovir), complete a premature study discontinuation visit, and complete all remaining study visits. These visits will also be used to document 
any reasons (other than virologic failure) that may explain why you are leaving the study early.  
3 
This evaluation will be completed at the Study Treatment Initiation (week 0) visit if it was not completed at the Study Entry visit.  
4 
This evaluation will be completed on the week 48 visit if it was not completed during the week 46 visit. 


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5 
Additional clinical assessments: You may be required to complete additional clinical assessments (which might be remote), to collect 
information on any adverse effects you are experiencing, changes in medications, or changes in study treatment. These additional visits 
will happen at weeks 16, 32, and 40.  
6 
Remote data collection: You may be required to take part in remote data collection throughout the study period.   
 


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II. 
Explanation of Evaluations/Procedures 
 
Below are descriptions of the evaluations. You will be told the results of all tests performed 
with the exception of tests to look at the levels of study drug in your body and for future 
ACTG-approved testing.  
 
Consent 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 and join the study. 
 
HIV status checked 
If there is no record available, an HIV-1 test will be done. If an HIV-1 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-1 test as soon as it is available.  
 
Questions about your health and medications you are taking 
Study staff will ask you questions about your medical and medication history. 
 
Physical examination 
You will have a physical exam. Your weight will be recorded at each visit; however, your 
height will only be recorded at the Study Entry visit. You will have a complete physical exam 
at the screening visit and a brief physical exam at the other visits.  
 
Electrocardiogram (ECG) 
All participants will have an ECG collected at the initial screening visit. An ECG will be 
performed to monitor the health of your heart. After you have entered the study, an ECG is 
only needed if you have an abnormal heart rate, rhythm, and/or palpitations.  
 
Blood collected 
Blood will be collected from a vein in your arm at some visits for research tests including 
liver function tests, your HIV viral load (a measure of the amount of HIV in your blood), your 
CD4+ T-cell count (a measure of the strength of your immune system, the system that helps 
your body fight infections), and CMV serology (a measure of how much CMV antibodies are 
in your body). Antibodies are proteins made in the body in response to a foreign substance. 
In this case, the foreign substance is CMV. Other routine lab tests such as hematology and 
chemistry will also be carried out. You will also have some blood stored at most visits. Liver 
function tests check the levels of certain enzymes and proteins in your blood. Levels that are 
higher or lower than normal can indicate liver problems. 
 
Plasma Pharmacokinetic (PK) sampling 
Blood will be collected for PK testing from a vein in your arm at some visits. These blood 
samples will allow researchers to determine how the body absorbs the study treatment or 
other medications over time.  
 


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Pregnancy test  
If you are able to become pregnant and you are engaging in sexual activity that can lead to 
pregnancy, you will be asked to give a small urine or blood sample (about 5 mL or 1 
teaspoon) for a pregnancy test.  
 
Study treatment adherence assessment 
After you have started taking the study treatment, you will be asked questions about how 
well you remember to take the study treatment and how well you are taking your anti-HIV 
treatment medications. This information will be collected at all study visits up to week 48.  
 
Collection of genital secretions 
You will be asked to refrain from sexual activity and, if applicable, to avoid using intravaginal 
products 48 hours prior to the genital sample collection.  
 
Semen-producing participants: You will be asked to provide self-collected seminal 
sample by masturbation within 2 hours prior to the study visits. Semen collection can be 
performed at home as long your sample can be transported to the study clinic within 2 
hours of collection at room temperature. These samples will be used for future testing.  
 
Participants with a vagina: You will be asked to provide vaginal swabs during the study 
visits; you may choose whether to self-collect your vaginal swab or have study personnel 
obtain the sample. These samples will be used for future testing. 
 
Collection of genital secretions is requested because it is far easier to detect CMV in 
these samples than in the blood. Thus, collecting these samples allows us to better 
measure the direct effect that letermovir has on CMV. Nevertheless, if you are 
uncomfortable with providing (or unable to provide) semen or vaginal swab samples, 
you can chose not to provide these samples and still participate in the study. 
 
Collection of oral secretions 
Your saliva will be collected with a throat wash and the sample will be used for future 
testing. You should not eat, chew gum, mints or candy; brush/floss teeth; or smoke for 90 
minutes before throat wash collections. 
 
Rectal swab collection 
The rectal swab is collected to study the different kind of bacteria in your stool (poop). A 
swab will gently be inserted approximately 2 cm into the anal canal and moved side-to-side 
before being removed. These samples will be stored and will be tested after the study is 
over.  
 
Collection of rectal secretions is requested because it is far easier to detect CMV in 
these samples than in the blood. Thus, collecting these samples allows us to better 
measure the direct effect that letermovir has on CMV. Nevertheless, if you are 
uncomfortable with providing (or unable to provide) rectal swab samples, you can 
chose not to provide these samples and still participate in the study. 
 


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Physical Function/Frailty Testing 
We will assess your physical function with tests that mimic activities that you might do during 
the day. These include measuring the time it takes you to rise from a chair, walk across the 
room, and squeeze with your hand. The tests will take approximately 10 minutes.  
 
Brief thinking/memory testing 
You will have some tests that are used to diagnose a brain disorder or disease. The testing 
will evaluate different brain processes including attention, visual search/scanning, and the 
ability to make and change plans. This type of testing will also look at your verbal learning 
and memory. 
 
Brief mood questionnaires (mood test/depression assessment) 
You will complete brief mood questionnaires that are used to screen, diagnose, monitor, and 
measure the presence and/or severity of depression and anxiety. Three different 
questionnaires will be used to collect this information. One is called the Patient 
Health Questionnaire-9 (PHQ-9) which asks questions about depression. A second 
questionnaire you will complete is called the Generalized Anxiety Disorder-7 (GAD-7) 
questionnaire which asks about anxiety. A third questionnaire you will complete is 
referred to as the Computerized Adaptive Testing for Mental Health (CAT-MH). The CAT-
MH is a cloud-based data capture system. You will enter your responses into a tablet device 
and your data will be processed via a HIPAA compliant and secure Amazon Web Services 
platform. In order to ensure that your data remains confidential and to protect your privacy, a 
random number will be assigned to identify you. Only study site staff will maintain secure 
records linking you to your random number. The company that makes the CAT-MH iPad 
Application will send us the results of your questionnaires. The company will only be able to 
identify you by the random number generated for you. To protect your privacy, the company 
will not be able to link your information back to you.  
 
Brief sleep assessment 
You will have a short sleep assessment to measure your sleep patterns. The assessment 
will include information on how long you sleep, the quality of sleep, and any use of sleep 
medication.  
 
Sexual and Gender Identity Questionnaire 
You will complete a brief questionnaire about your sexual orientation and gender identity.  
 
Telephone, e-mail, or text message contact 
After receiving the study treatment, you will be contacted by telephone, text message, or e-
mail between visits to remind you of study visits and medication adherence. 
 
Additional clinical assessments (as needed) 
During your participation in the study, you may be required to complete additional 
study visits to take part in additional clinical assessments. At the additional clinical 
assessment visits, information will be collected on any adverse effects you are 
experiencing, any changes to medications you are taking, or any changes in the 
study treatment. These assessments may take place remotely.  
 


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Remote data collection 
During your participation in the study, if you are not able to attend in-person visits (for 
example, because you are not feeling well, if someone living with you is not feeling well, if 
local conditions or guidelines prevent you from being able to travel to the clinic, if the site is 
temporarily unavailable, or at the discretion of the A5383 study team), the study staff may 
need to conduct a scheduled visit with you remotely (for example, by telephone or via 
telehealth). 
 
 

SAP_001.pdf: 
Approvals 


A5383 
Primary Statistical Analysis Plan 
Version 3.0 
 
March 15, 2024 
 
Randomized, Controlled Trial to Evaluate the Anti-inflammatory 
Efficacy of Letermovir (Prevymis) in Adults with Human 
Immunodeficiency Virus (HIV)-1 and Asymptomatic 
Cytomegalovirus (CMV) Who Are on Suppressive ART and Its 
Effect on Chronic Inflammation, HIV Persistence, and Other 
Clinical Outcomes (ELICIT)   
 
ClinicalTrials.gov Identifier: NCT04840199 
Protocol Version 3.0 
 
 
This is the ACTG A5383 SAP Version 3.0 with names of authors, names of publication 
writing team members and analysis timeline redacted. 
 
 
Created by: 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 1 of 26 
 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
VERSION HISTORY ........................................................................................................................ 2 
1 
INTRODUCTION ........................................................................................................................ 3 
1.1 
Purpose ............................................................................................................................ 3 
1.2 
Version History ............................................................................................................... 3 
2 
STUDY OVERVIEW (PROTOCOL VERSION 3.0) ................................................................... 3 
2.1 
Study Design ................................................................................................................... 3 
2.2 
Hypotheses ...................................................................................................................... 4 
2.2.1 
Primary ................................................................................................................. 4 
2.2.2 
Secondary ............................................................................................................ 4 
2.2.3 
Exploratory ........................................................................................................... 4 
2.3 
Study Objectives ............................................................................................................. 6 
2.3.1 
Primary Objectives ............................................................................................... 6 
2.3.2 
Secondary Objectives .......................................................................................... 6 
2.3.3 
Exploratory Objectives ......................................................................................... 6 
2.4 
Overview of Sample Size Considerations .................................................................... 7 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 7 
3 
OUTCOME MEASURES (MODIFIED DUE TO EARLY STUDY TERMINATION) ................... 8 
3.1 
Primary Outcome Measures .......................................................................................... 8 
3.2 
Secondary Outcome Measures ..................................................................................... 8 
3.3 
Other Outcome Measures .............................................................................................. 8 
4 
GENERAL CONSIDERATIONS ................................................................................................ 9 
5 
ESTIMAND AND ESTIMATION .............................................................................................. 11 
5.1 
Primary Estimand ......................................................................................................... 11 
5.2 
Secondary Estimands .................................................................................................. 13 
5.2.1 
First Secondary Estimand .................................................................................. 13 
5.2.2 
Second Secondary Estimand ............................................................................. 14 
5.2.3 
Third Secondary Estimand ................................................................................. 16 
5.2.4 
Fourth Secondary Estimand ............................................................................... 17 
6 
ANALYSIS OF OBJECTIVES ................................................................................................. 18 
6.1 
Primary Analysis ........................................................................................................... 18 
6.2 
Secondary and Exploratory Analyses ........................................................................ 19 
7 
REPORT CONTENTS ............................................................................................................. 21 
8 
ASSOCIATED DOCUMENTS ...................................... ERROR! BOOKMARK NOT DEFINED. 
 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 2 of 26 
 
 
Version History 
 
Version 
Changes Made 
Date Finalized 
1.0 
Original Version 
10 May 2022 
2.0 
Updated title page and header.  
Added new exploratory hypothesis/objective and updated 
language in Sections 2.2.3 and 2.3.3 to match the latest protocol. 
Updated text within Section 4 General Considerations. 
10 Aug 2023 
3.0 
Due to the study closing early after the futility analysis and 
participants in the letermovir arm being brought in for treatment 
discontinuation visits the analysis approach was changed to 
account for participants in the letermovir arm having varying 
durations of treatment. Additionally, some of the original protocol 
objectives were abandoned by the team while others were 
changed from SDAC-led to outside-SDAC analyses. 
15 Mar 2024 
 
 
 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 3 of 26 
 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary estimands that 
will address specific study objectives and interim monitoring of the A5383 study. The Primary 
SAP includes general analytic approaches for all primary estimands, secondary estimands, and 
other outcome measures in the primary manuscript(s) or submitted to ClinicalTrials.gov 
(regardless of the reporting timeline). The Primary SAP facilitates discussion of the statistical 
analysis components among the lead study investigators and statisticians, helping them agree on 
the statistical analyses to be performed and presented in the primary analysis report. 
The Analysis Implementation Plan (AIP) provides detailed outlines of tables, figures, and coding 
descriptions. 
All analyses which will be performed at SDAC have been outlined in this Primary SAP.   
1.2 
Version History 
For SAP Version 3.0, major modifications are related to the planned analysis approach after the 
study was closed for futility. Due to the participants in the letermovir arm having to discontinue 
treatment after the SMC decision to close the study, the duration of treatment and the study week 
of final on-treatment evaluations differs by participant. The original cross-sectional analysis 
approach has been modified to a repeated measures approach with a treatment phase and a 
post-treatment phase to allow for varying time on treatment. Additionally, some analyses were 
abandoned and others were identified as outside-SDAC analyses. 
For SAP Version 2.0, major modifications include updates to language throughout the SAP to 
align with A5383 protocol version 3.0, the addition of an exploratory hypothesis/objective, and 
clarification of population definitions under Section 4 General Considerations. 
2 
Study Overview (Protocol Version 3.0) 
2.1 
Study Design  
A5383 is a phase II, randomized, open-label, controlled, multicenter trial being conducted at US 
sites to evaluate anti-inflammatory efficacy of letermovir 480 mg once daily for 48 weeks in adults 
with HIV and asymptomatic cytomegalovirus (CMV) on antiretroviral therapy (ART)-mediated 
suppression. A futility analysis will be performed after the first 40 participants, who have started 
study treatment, reach their 8-week study visit. Participants will be followed for 60 weeks (48 
weeks on either letermovir or no anti-CMV treatment with 12 weeks of post-treatment period 
follow-up). We plan to enroll 180 participants (90 in each arm; our goal is that at least one third 
(30 participants in each arm) will be individuals assigned female sex at birth not on testosterone 
or individuals assigned male sex at birth on feminizing sex hormones and at least one half (45 
participants in each arm) will have screening CD4+ T cell counts <350 cells/mm3). The target 
population for this study will be adults ≥40 years of age with HIV and asymptomatic CMV, with 
HIV RNA suppression for ≥48 weeks on combination ART. Participants will be randomized 1:1 to 
receive either letermovir 480 mg once daily or no anti-CMV treatment for 48 weeks. 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 4 of 26 
 
 
2.2 
Hypotheses 
2.2.1 
Primary 
Letermovir will cause a greater reduction in plasma soluble receptor for tumor necrosis 
factor type II (sTNFRII) levels than no anti-CMV treatment at weeks 46/48. 
2.2.2 
Secondary 
• 
Letermovir (480 mg once daily) will be generally tolerable over the 48 week study 
treatment period as compared to no anti-CMV treatment. 
• 
Letermovir will reduce the frequency of detection and levels of cytomegalovirus (CMV) 
DNA in mucosal samples (throat wash, seminal plasma, and cervicovaginal swabs) and 
in blood plasma compared to no anti-CMV treatment, through 48 weeks of treatment. 
This effect will persist for 4 weeks following treatment discontinuation (i.e., at week 52), 
and return to baseline by week 60. 
• 
Letermovir will cause a greater reduction in plasma sCD163 levels than no anti-CMV 
treatment at weeks 8, 46/48, and 52, but not at week 60. 
• 
Letermovir will cause greater reductions in plasma sTNFRII than no anti-CMV treatment 
at weeks 8 and 52, but not at week 60. 
2.2.3 
Exploratory 
• 
Letermovir will cause a greater reduction in inflammatory and coagulation markers 
(sCD14, IL-6, hsCRP, and D-Dimer) than no anti-CMV treatment at weeks 8 and 46/48, 
differences that will persist at week 52, but return to baseline by week 60.  
• 
Monocyte activation (cellular markers of monocyte activation, e.g., CD14varCD16+): 
Letermovir will reduce monocyte activation at weeks 8 and 48 compared to no anti-CMV 
treatment, an effect that will persist for at least 4 weeks after discontinuing study 
treatment. 
• 
CMV-specific response: Letermovir will reduce CMV immunoglobulin G (IgG) titer and 
CMV-specific T cell response (reduced clonality of T cell receptor [TCR]) at week 48 
compared to no anti-CMV treatment.   
• 
Microbial translocation markers (B-D-Glucan, I-FABP, LBP, Zonulin): Letermovir will 
reduce biomarkers of microbial translocation at weeks 46/48 compared to no anti-CMV 
treatment, an effect that will persist for at least 4 weeks after stopping study treatment. 
• 
Multiplex-bead-array assay: Letermovir will modulate the cytokines network from baseline 
to weeks 8 and 46/48, compared to no anti-CMV treatment, an effect that will persist for 
at least 4 weeks after stopping study treatment.   
• 
Detailed markers of coagulation: Letermovir will decrease markers of the coagulation 
cascade (including soluble urokinase plasminogen activator receptor [suPAR], plasmin-
alpha2-antiplasmin complex [PAP], prothrombin fragment 1+2) at weeks 46/48 compared 
to no anti-CMV treatment. 
• 
Letermovir will result in a greater reduction in soluble markers of endothelial activation at 
weeks 8 and 46/48 than no anti-CMV treatment (sICAM-1, sVCAM-1, sTF, E-selectin, P-
selectin), an effect that will persist for at least 4 weeks after stopping study treatment. 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 5 of 26 
 
 
• 
T cell dysfunction: Letermovir will reduce T cell dysfunction (including but not limited to 
decreased activation [CD38+/HLA-DR co-expression], and exhaustion [PD-1] markers) in 
blood at weeks 8 and 48 and both decrease senescence markers (CD28-CD57+ T cells) 
and increase CD4+/CD8+ ratio at week 48, when compared to those receiving no anti-
CMV treatment, differences that will persist for at least 4 weeks after study treatment 
discontinuation.  
• 
Insulin resistance: Letermovir will result in greater reductions in insulin resistance than no 
anti-CMV treatment at week 46 by homeostatic model assessment-insulin resistance 
(HOMA-IR) and plasma levels of free fatty acids, differences that will persist for at least 4 
weeks after study treatment discontinuation.  
• 
Plasma free fatty acids: Letermovir will result in greater reductions in fasting free fatty 
acids, an indirect measure of adipocyte insulin sensitivity and lipid storage, than no anti-
CMV treatment at week 46, differences that may persist for at least 4 weeks after study 
treatment discontinuation. 
• 
Letermovir will result in greater improvements than no anti-CMV treatment in physical 
function as assessed by chair rise time and frailty score (gait speed, grip strength) at 
week 46, differences that will persist for at least 4 weeks after study treatment 
discontinuation.  
• 
Veterans Aging Cohort Study (VACS) index: Letermovir will result in greater 
improvements in VACS index than no anti-CMV treatment at weeks 46 and 60. 
• 
HIV Reservoir: Letermovir will reduce the size of the HIV-1 reservoir as measured by cell-
associated HIV-1 DNA at weeks 8 and 48 when compared to those receiving no anti-
CMV treatment.  
• 
HIV Reservoir Sequencing: Letermovir will reduce the clonality of the HIV reservoir in 
blood at week 48 when compared to those receiving no anti-CMV treatment.  
• 
Letermovir will reduce the transcriptional activity of the HIV-1 reservoir as measured by 
single copy assays of plasma HIV-1 RNA and cell-associated HIV-1 RNA at the week 8 
and 48 time points when compared to those receiving no anti-CMV treatment.  
• 
Letermovir will not have clinically significant (i.e., requiring dose adjustment) interactions 
with common ART drugs (i.e., TDF/TAF and integrase inhibitors) or allowed statins. 
• 
Plasma letermovir levels during treatment will correlate with the extent of reduction in 
sTNFRII and CMV DNA shedding levels.  
• 
Letermovir will alter the plasma proteome as assessed by a modified aptamer assay 
(SOMAscan), including pathways linked to cardiovascular risk. 
• 
Central nervous system (CNS) tolerability of letermovir: Change in neurocognitive 
performance, mood, sleep quality, concentrations will each be similar to or better than no 
anti-CMV treatment at week 46. Change in Neurofilament light (NFL) in blood plasma will 
be similar or better than no anti-CMV treatment at weeks 46/48.  
• 
Letermovir resistance: Among letermovir-treated participants with persistent detectable 
CMV shedding, the emergence of letermovir resistance mutations will be observed in 
mucosal sites, but not plasma, and will no longer be detected at week 60. 
• 
Flu vaccine responsiveness: Letermovir will reduce the humoral response to seasonal 
influenza vaccination obtained in the course of clinical care compared to no anti-CMV 
treatment (fold change from the last pre-vaccine time point to the first available time point 
between 4-12 weeks post-vaccine). 


A5383 Protocol Version 3.0 
Primary Statistical Analysis Plan Version 3.0 
 
March 15, 2024 
 
Page 6 of 26 
 
 
2.3 
Study Objectives 
This Primary SAP addresses the following primary, secondary, and exploratory objectives listed 
in the study protocol. 
Analysis of the study objectives below will be analyzed under a superiority framework. These 
analyses will be finalized once the last participant has completed the study, all queries have been 
resolved, and the study database closure/data lock has been completed.  
2.3.1 
Primary Objectives 
• 
To determine whether letermovir 480 mg daily at weeks 46/48 will result in decreased 
plasma sTNFRII levels compared to no anti-CMV treatment in treated individuals with 
HIV. 
2.3.2 
Secondary Objectives 
• 
Tolerability: To determine whether letermovir 480 mg daily for 48 weeks is safe and 
tolerable in treated individuals with HIV.  
• 
CMV DNA levels: To determine if letermovir reduces mucosal and plasma levels of CMV 
DNA in treated individuals with HIV through 48 weeks of therapy and following treatment 
discontinuation.  
• 
To evaluate if letermovir reduces plasma sCD163 levels at weeks 8, 46/48, 52, and 60. 
• 
To evaluate if letermovir reduces plasma sTNFRII levels at weeks 8, 52 and 60. 
2.3.3 
Exploratory Objectives 
• 
To evaluate if letermovir affects inflammatory and coagulation markers (sCD14, IL-6, 
hsCRP, and D-Dimer) at weeks 8, 46/48, 52, and 60. 
• 
Monocyte activation (cellular markers of monocyte activation): To evaluate if letermovir 
reduces monocyte activation at weeks 8, 48, 52, and 60. 
• 
CMV-specific response: To evaluate if letermovir affects CMV IgG titer and CMV-specific 
T cell response (reduced clonality of TCR) at week 48. [NOTE: The CMV-specific T cell 
response outcome will be analyzed outside of SDAC] 
• 
Microbial translocation markers (B-D-Glucan, I-FABP, LBP, Zonulin): To evaluate if 
letermovir affects biomarkers of microbial translocation at weeks 8, 46/48, 52, and 60. 
[NOTE: This outcome will be analyzed outside of SDAC] 
• 
Multiplex-bead-array assay: To evaluate if letermovir affects the cytokines network at 
weeks 8, 46/48, 52, and 60. [NOTE: This outcome was abandoned] 
• 
Detailed markers of coagulation: To evaluate if letermovir affects the coagulation cascade 
(including suPAR, plasmin antiplasmin complexes, prothrombin fragment 1+2) at weeks 
8, 46/48, 52, and 60. [NOTE: This outcome will be analyzed outside of SDAC] 
• 
To evaluate if letermovir reduces soluble markers of endothelial activation at weeks 8, 
46/48, 52, and 60. [NOTE: This outcome will be analyzed outside of SDAC] 
• 
To evaluate if letermovir affects T cell dysfunction in blood at study weeks 8, 48, 52, and 
60.  
• 
To evaluate if letermovir reduces insulin resistance at weeks 46 and 60.  


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• 
To evaluate if letermovir reduces plasma fasting free fatty acids at weeks 46 and 60.  
• 
To evaluate if letermovir improves physical function and frailty at weeks 46 and 60.  
• 
VACS index: To evaluate if letermovir improves the VACS index at weeks 46 and 60. 
• 
HIV Reservoir: To evaluate if letermovir reduces the size of the HIV-1 reservoir as 
measured by cell-associated HIV-1 DNA at study weeks 8 and 48.  
• 
HIV Reservoir Sequencing: To evaluate if letermovir reduces the clonality of the HIV 
reservoir in blood at study week 48. [NOTE: This outcome will be analyzed outside of 
SDAC] 
• 
To evaluate if letermovir affects the transcriptional activity of the HIV-1 reservoir as 
measured by single copy assays of plasma HIV-1 RNA and cell-associated HIV-1 RNA at 
the week 8 and 48 time points. [NOTE: This outcome will be analyzed outside of SDAC] 
• 
To evaluate interactions between letermovir and common ART drugs and statins. [NOTE: 
This outcome was abandoned] 
• 
To evaluate correlations between plasma letermovir levels during treatment with the 
extent of reduction in sTNFRII and CMV DNA shedding levels. [NOTE: This outcome was 
abandoned] 
• 
To evaluate if letermovir affects plasma proteome, including pathways linked to 
cardiovascular risk. [NOTE: This outcome will be analyzed outside of SDAC] 
• 
To evaluate the CNS tolerability of letermovir: The tolerability measures will include 
change in neurocognitive performance, mood, sleep quality, and NFL concentrations in 
blood plasma. 
• 
Letermovir resistance: To evaluate emergence of letermovir resistance mutations in 
participants with persistent detectable CMV shedding during study period. [NOTE: This 
outcome was abandoned] 
• 
Flu vaccine responsiveness: To evaluate if letermovir affects the humoral response to 
seasonal influenza vaccination obtained in the course of clinical care (fold change from 
the last pre-vaccine time point to the first available time point between 4-12 weeks post-
vaccine). [NOTE: This outcome was abandoned] 
2.4 
Overview of Sample Size Considerations 
Determined based on the primary endpoint of change in levels of plasma sTNFRII, the sample 
size for A5383 is calculated to be 180 participants with a 1:1 randomization to letermovir 480 mg : 
no anti-CMV treatment ratio, 90 participants will receive letermovir 480 mg and 90 will receive no 
anti-CMV treatment. Note that this resulting sample size of 180 has been inflated to account for 
the 15% of participants not being included in the primary analysis due to missing samples, 
laboratory error, LTFU, not meeting per protocol definition, etc. Prior to inflation, 154 participants 
(77 letermovir, 77 no anti-CMV treatment) would provide 90% power to detect a 0.065 log10 
pg/mL difference in sTNFRII between the arms, using a two-sample t-test, a change SD of 0.123 
log10 pg/mL (accounting for reduced variability due to averaging two sTNFRII results pre-
treatment and two sTNFRII results at weeks 46 and 48), and a two-sided 5% alpha. 
2.5 
Overview of Formal Interim Monitoring 
The study will undergo interim review at least annually by an ACTG-appointed Study Monitoring 
Committee (SMC), although the SMC may elect to deviate from this timeline. In the event that 


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enrollment for the first 40 participants takes longer than 6 months, a separate SMC meeting will 
be held 6 months after the first participant is enrolled. SMC reviews will then continue every 6-12 
months after this point. The SMC will review summaries of accrual, baseline characteristics, 
conduct of the study (including premature study and premature study treatment discontinuations), 
adverse events (AEs) by study treatment arm, CD4+ T cell counts and HIV-1 RNA 
levels/suppression, and plasma CMV DNA levels (and if applicable, letermovir resistance results) 
over time by study treatment arm, and data/sample availability. 
The first interim SMC review for tolerability will occur at the time of futility analysis. We expect this 
to occur at approximately 9 months after the enrollment of the first study participant, once the 40th 
enrolled participant has reached 8 weeks on study, plasma samples have been tested for an 
initial protocol-specified assessment of immunologic futility, and data have been analyzed. 
Enrollment will pause after the 40th participant has started study treatment and until (and if) the 
SMC deems the intervention not to be futile, but enrolled participants will be allowed to continue 
on study (i.e., beyond week 8) while the interim analysis is being conducted.  
An interim review should also be convened if, at any time, CMV DNA levels are detectable in 
plasma in 12 or more participants while taking study medications (letermovir arm only), letermovir 
resistance is detected in plasma specimens in two participants (letermovir arm only), new grade 
≥2 atrial fibrillation or atrial flutter of any grade is identified in four participants, a participant 
experiences a grade 4 AE related to study treatment, or 3 or more participants experience HIV-1 
virologic failure in the letermovir arm or any concern is identified by the DAIDS clinical 
representative, the study chairs, or study statisticians in consultation with the team. 
3 
Outcome Measures (Modified Due to Early Study Termination) 
3.1 
Primary Outcome Measures 
• 
Absolute change from baseline to week 46/48 (or the latest result in the treatment phase) 
in sTNFRII. 
3.2 
Secondary Outcome Measures 
• 
Occurrence of Grade ≥3 AEs or confirmed HIV-1 virologic failure after initiation of study 
treatment (letermovir arm) or the IOT visit (no anti-CMV treatment arm). 
• 
Mucosal and plasma CMV DNA levels at baseline and weeks 8, 46, 48 (and/or the latest 
result in the treatment phase), 52, and 60.  
• 
sCD163 at baseline and weeks 8, 24, 46, 48 (and/or the latest result in the treatment 
phase), 52, and 60. 
• 
sTNFRII at baseline and weeks 8, 24, 46, 48 (and/or the latest result in the treatment 
phase), 52, and 60.   
3.3 
Other Outcome Measures 
• 
Coagulation markers (sCD14, IL-6, hsCRP, and D-Dimer) at baseline and weeks 8, 46, 
48 (and/or the latest result in the treatment phase), 52 and 60. 


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• 
CD14varCD16+ cells at baseline and weeks 8, 48 (and/or the latest result in the treatment 
phase), 52, and 60. 
• 
Absolute change from baseline to week 48 (and/or the latest result in the treatment 
phase) in CMV IgG titer. 
• 
CD4+/CD8+ ratio at baseline and weeks 8, 48 (and/or the latest result in the treatment 
phase), 52, and 60. 
• 
(CD8+)CD38+HLA-DR+ T cells at baseline and weeks 8, 48 (and/or the latest result in 
the treatment phase), 52, and 60. 
• 
CD8+CD28-CD57+ T cells at baseline and weeks 8, 48 (and/or the latest result in the 
treatment phase), 52, and 60. 
• 
HOMA-IR and plasma levels of free fatty acid at baseline and weeks 46 (and/or the latest 
result in the treatment phase) and 60. 
• 
Gait speed time at baseline and weeks 46 (and/or the latest result in the treatment 
phase) and 60.  
• 
Grip strength at baseline and weeks 46 (and/or the latest result in the treatment phase) 
and 60. 
• 
Chair rise time at baseline and weeks 46 (and/or the latest result in the treatment phase) 
and 60. 
• 
VACS index score at baseline and weeks 46 (and/or the latest result in the treatment 
phase) and 60. 
• 
Single copy assay of HIV-1 RNA and cell-associated HIV-1 RNA and total HIV DNA at 
baseline and weeks 8 and 48 (or the latest result in the treatment phase). 
• 
Neurocognitive functioning (Trail Making A & B, Digit Symbol, and HVLT-R [HAILO 
Battery]) at baseline and weeks 46 (and/or the latest result in the treatment phase) and 
60. 
• 
PHQ9 at baseline and weeks 46 (and/or the latest result in the treatment phase) and 60. 
• 
GAD7 at baseline and weeks 46 (and/or the latest result in the treatment phase) and 60. 
• 
Pittsburgh Sleep Quality Index at baseline and weeks 46 (and/or the latest result in the 
treatment phase) and 60. 
• 
Plasma NFL at baseline and weeks 46 (and/or the latest result in the treatment phase) 
and 60. 
4 
General Considerations 
• 
All statistical tests will be two-sided with a nominal alpha level of 0.05 (unless otherwise 
noted) and no adjustment for multiple testing.  
• 
Outcome measures will be transformed for analyses and summarized on the log10 scale, as 
appropriate, if determined not to be approximately normally distributed. 
• 
All enrolled participants make up the randomized population. 
• 
All enrolled, eligible participants make up the intent-to-treat (ITT) population. 
• 
Safety analyses will use a modified ITT (mITT) population consisting of all participants who 
initiated study treatment and all eligible participants in the control arm. 
• 
Confirmed virologic failure is defined as two consecutive HIV-1 RNA levels ≥200 copies/mL 
by real-time HIV-1 RNA testing. Participants with a plasma HIV-1 RNA ≥200 copies/mL at any 


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visit will have a confirmatory viral load obtained as soon as possible but within 14 days after 
the first sample was drawn, if possible. If the consecutive measurement of HIV-1 RNA is also 
≥200 copies/mL, the participant will be considered to have confirmed virologic failure. 
• 
“Treatment phase” refers to the time from study entry to 1) discontinuation of study treatment 
in the letermovir arm + 10 days, and 2) the last study visit on/prior to Week 48 in the control 
arm.  
• 
Because this is a phase II study and biologic activities of the intervention are of interest, 
efficacy analyses will use a per-protocol (PP) population (same as efficacy set in estimand 
tables below) limited to participants who 1) do not prematurely discontinue study product prior 
to Week 8 and have self-reported adherence >50% (letermovir arm only), and 2) do not have 
a confirmed virologic failure during the treatment phase.  
• 
Unless otherwise noted, PP analyses will exclude outcome data collected 1) after initiating a 
prohibited medication, 2) within 7 days of receiving a vaccination (vaccine administration on 
the same day as specimen collection will be assumed to have occurred after the specimen 
collection), 3) during or within 7 days of the resolution of influenza and COVID-19 diagnoses, 
and 4) within 7 days of a reported fever (≥38° C). 
• 
Any participants determined to be ineligible for A5383 will not be included in any of the safety 
or efficacy analyses.  
• 
Absolute change refers to the value at the follow-up time point minus the value at baseline. 
• 
The screening visit window will be [randomization date - 90 days, randomization date - 1 
day]. 
• 
The entry visit window will be [randomization date, initiation of treatment visit date - 2 days]. If 
the initiation of treatment visit date is missing the window will be [randomization date, 
randomization date + 30 days]. 
• 
The initiation of treatment visit window will be [initiation of treatment visit date, earliest of 1) 
initiation of treatment visit + 2 days or 2) treatment initiation date]. 
• 
Baseline refers to the most recent study evaluation at or prior to the treatment initiation visit. 
• 
Post-baseline, visit weeks will be calculated as weeks since treatment initiation and visit week 
windows will be ± 2 weeks for Week 4, -2 to +4 weeks for Week 8 and ± 4 weeks for Weeks 
16, 24, 32 and 40.  Weeks 46 and 48 will share a window which will span week 44 to week 
50. Week 52 will have a -2 to +4 week window and Week 60 will have a ± 4 week window.  
• 
For post-baseline visit weeks other than 46 and 48, in the event of multiple results within a 
study window the result closest to the scheduled evaluation week will be used, with priority 
given to on-treatment results. 
• 
Results within the weeks [44, 50] visit window will use the following logic to determine Week 
46 and Week 48 results: 
- 
If two results are collected the earlier will be Week 46 and the latter Week 48. 
- 
If one result is collected on treatment and one result is collected off treatment the on 
treatment will be Week 46 and the off treatment will be Week 48. 
- 
If only one result is collected it will be Week 48. 
- 
If three or more results are available priority will be given to those collected on treatment 
and assigned Weeks based on the above rules.   
• 
For markers run in duplicate (for the purpose of averaging) at study entry and treatment 
initiation and also at Weeks 46 and 48, “baseline” will refer to the average of study entry and 
treatment initiation and “Week 46/48” will refer to the average of Week 46 and Week 48.  If 


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only one result is available at either of these time points the single result will be used.  For the 
per-protocol analyses the “Week 46/48” calculation will only use results collected while on 
treatment (letermovir arm only). 
• 
The VACS index score outcome will use the VACS 2.0 Index equation. The eGFR 
component will use the CKD-EPI 2021 equation. 
• 
Gait speed will be calculated as the average two gait speeds if both 4-meter walks were 
completed. 
• 
Grip strength will be calculated as the mean of the available trial results (up to 3). 
• 
PHQ9 will be scored as outlined at https://www.mdcalc.com/calc/1725/phq9-patient-health-
questionnaire9. 
• 
GAD7 will be scored as outline at https://www.mdcalc.com/calc/1727/gad7-general-anxiety-
disorder7  
• 
Pittsburgh sleep quality index will be scored as outlined in PMID: 2748771 DOI: 
10.1016/0165-1781(89)90047-4. 
• 
VACS 2.0 Index will be calculated using SAS code provided by Janet Tate. 
5 
Estimand and Estimation 
5.1 
Primary Estimand 
Primary Objective 1: To determine whether letermovir 480 mg daily will result in 
decreased plasma sTNFRII levels compared to no anti-CMV treatment in treated 
individuals with HIV. 
Estimand description 
Change in sTNFRII during the treatment 
phase after initiating letermovir, among HIV-
infected adults with asymptomatic CMV who 
remain on study treatment (with ≥50% 
adherence) without virologic failure or use of 
prohibited medications. 
Treatment 
Letermovir 480 mg once daily 
Target population   
Analysis set 
Adults ≥40 years of age with HIV and 
asymptomatic CMV, with HIV RNA suppression 
for at least the prior 48 weeks on combination 
ART. 
Efficacy set (Participants who remained on 
study treatment during the treatment phase for 
at least 8 weeks with self-reported adherence 
>50% (letermovir arm only) and did not have 
confirmed virologic failure) 
Variable(s) 
Outcome measure(s) 


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Change in sTNFRII during the treatment 
phase. 
Absolute change from baseline to Week 46/48 
(or the latest result in the treatment phase) in 
sTNFRII. 
“Baseline” refers to the average of two pre-
treatment phase results. “Week 46/48” refers 
to the average of two results within one day of 
treatment discontinuation and within the week 
[44, 50] window. If two results are not 
available for averaging within a time point, a 
single result will be used. 
Handling of intercurrent events 
Handling of missing data 
The following intercurrent events are relevant 
to the estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: 
ignored (treatment policy) 
3. Use of prohibited medications: 
excluded (principal stratum) 
4. Treatment discontinuation prior to 
week 8 (letermovir arm only): excluded 
(principal stratum) 
5. Self-reported treatment adherence 
<50% (letermovir arm only): excluded 
(principal stratum) 
6. Confirmed HIV virologic failures: 
excluded (principal stratum) 
7. Vaccination or concurrent acute illness 
within 1 week of sTNFRII 
assessments: excluded (principal 
stratum) 
8. Pregnancy: excluded (principal 
stratum) 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 
Population-level summary measure 
Analysis approach 
The average change in sTNFRII during the 
treatment phase after initiating letermovir 
compared to the average change had no 
treatment been given. 
Linear regression of sTNFRII change (log10-
transformed prior to calculating change) on 
treatment arm adjusted for stratification 
factors. 
 


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5.2 
Secondary Estimands 
5.2.1 
First Secondary Estimand 
Secondary Objective 1: To determine whether letermovir 480 mg daily is safe and 
tolerable in treated individuals with HIV. 
Estimand description 
The change in the probability of Grade ≥3 
adverse events or HIV-1 virologic failure after 
initiating letermovir among HIV-infected adults 
with asymptomatic CMV. 
Treatment 
Letermovir 480 mg once daily 
Target population   
Analysis set 
Adults ≥40 years of age with HIV and 
asymptomatic CMV, with HIV RNA suppression 
for at least the prior 48 weeks on combination 
ART. 
Safety set (Participants who initiate study 
treatment (letermovir arm only) and all 
participants in the no anti-CMV treatment arm) 
Variable(s) 
Outcome measure(s) 
Occurrence of a Grade ≥3 AE or HIV-1 
virologic failure. 
Outcome measure as defined by the Variable. 
Only events occurring after the initiation of 
study treatment are included in the letermovir 
arm. All post-IOT visit events are included in 
the no anti-CMV treatment arm. 
Handling of intercurrent events 
Handling of missing data 
The following intercurrent events are relevant 
to the estimand:  
1. Change in background ART regimen: 
ignored (treatment policy) 
2. Use of prohibited medications: ignored 
(treatment policy) 
3. Treatment discontinuation prior to 
week 48 (letermovir arm only): ignored 
(treatment policy) 
4. Self-reported treatment adherence 
<50% (letermovir arm only): ignored 
(treatment policy) 
5. Pregnancy: ignored (treatment policy) 
Participants who discontinue follow-up before 
week 60 will have their outcome determined 
based on data available until the time of 
discontinuation (i.e., a participant who 
discontinued follow-up without a prior AE is 
assumed not to have an AE had they been 
observed for the intended duration [60 
weeks]). 
 
A sensitivity analysis will use the Kaplan-
Meier estimator of time to first event with 
participants censored at the time of study 
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Population-level summary measure 
Analysis approach 
For any Grade ≥3 adverse event or HIV-1 
virologic failure (yes/no), the change in the 
probability of an event after initiating letermovir 
compared to the probability of an event had 
letermovir not been given. 
Absolute difference (letermovir arm relative to 
no anti-CMV treatment arm) in the proportion 
of participants with any Grade ≥3 adverse 
event or virologic failure (yes/no) while on 
study. 
An exact 95% confidence interval around the 
observed difference in proportions (and the 
associated p-value) will be constructed based 
on the standardized statistic and inverting two 
1-sided tests (Chan-Zhang method). 
Supplementary Analyses 
A supplementary analysis will examine all reported AEs, regardless of grade.  The highest AE 
grade per participant will be summarized by treatment arm. A two-sided Wilcoxon rank sum test 
will be used to assess differences in the highest grade distribution between arms.  
5.2.2 
Second Secondary Estimand 
Secondary Objective 2: To determine if letermovir reduces mucosal and plasma levels of 
CMV DNA in treated individuals with HIV during therapy and following treatment 
discontinuation. 
Estimand description 
The change in the probability of CMV DNA 
shedding over 60 weeks after initiating 
letermovir among HIV-infected adults with 
asymptomatic CMV. 
Treatment 
Letermovir 480 mg once daily 
Target population   
Analysis set 
Adults ≥40 years of age with HIV and 
asymptomatic CMV, with HIV RNA 
suppression for at least the prior 48 weeks on 
combination ART. 
Efficacy set 
Variable(s) 
Outcome measure(s) 
Mucosal and plasma CMV DNA levels 
baseline and weeks 8, 46, 48, 52, and 60. 
1) Plasma CMV DNA shedding (detectable 
CMV DNA levels) at baseline, weeks 8, 46, 48 


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(and/or the latest result in the treatment 
phase), 52, 60. 
2) Oral CMV DNA shedding (detectable CMV 
DNA levels) at baseline, weeks 8, 46, 48 
(and/or the latest result in the treatment 
phase), 52, 60. 
3) Genital (seminal/cervicovaginal) CMV DNA 
shedding (detectable CMV DNA levels) at 
baseline, weeks 8, 46, 48 (and/or the latest 
result in the treatment phase), 52, 60. 
Handling of intercurrent events 
Handling of missing data 
The following intercurrent events are relevant 
to the estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: 
ignored (treatment policy) 
3. Use of prohibited medications: 
excluded (principal stratum) 
4. Treatment discontinuation prior to 
week 8 (letermovir arm only): excluded 
(principal stratum) 
5. Self-reported treatment adherence 
<50% (letermovir arm only): excluded 
(principal stratum) 
6. Confirmed HIV virologic failures: 
excluded (principal stratum) 
7. Vaccination or concurrent acute illness 
within 1 week of CMV DNA 
assessments: excluded (principal 
stratum) 
8. Pregnancy: excluded (principal 
stratum) 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will be 
assumed to be missing completely at random 
and thus ignored. 
Population-level summary measure 
Analysis approach 
The change in the probability of CMV DNA 
shedding during the treatment phase and post-
treatment phase compared to the probability 
had letermovir not been given. 
For each of plasma and mucosal shedding, a 
generalized estimating equations (GEE) model 
with binary outcomes and an appropriate 
covariance structure. The covariates will be 
study arm and the stratification factors, as well 
as a three-level period effect (early treatment 
phase [through Week 8], late treatment phase, 
post-treatment phase) and its interaction with 
the study arm. 
 


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5.2.3 
Third Secondary Estimand 
Secondary Objective 3: To evaluate if letermovir reduces plasma sCD163 levels at weeks 
8, 24, 46, 48, 52, and 60. 
Estimand description 
Change in sCD163 over 60 weeks after 
initiating letermovir, among HIV-infected 
adults with asymptomatic CMV. 
Treatment 
Letermovir 480 mg once daily 
Target population   
Analysis set 
Adults ≥40 years of age with HIV and 
asymptomatic CMV, with HIV RNA suppression 
for at least the prior 48 weeks on combination 
ART. 
Efficacy set 
Variable(s) 
Outcome measure(s) 
sCD163 at baseline and weeks 8, 24, 46, 48, 
52 and 60. 
sCD163 at baseline and weeks 8, 24, 46, 48 
(and/or the latest result in the treatment 
phase), 52 and 60.  
“Baseline” refers to the average of two pre-
treatment results. If two results are not 
available for averaging within a time point, a 
single result will be used. 
Handling of intercurrent events 
Handling of missing data 
The following intercurrent events are relevant 
to the estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: 
ignored (treatment policy) 
3. Use of prohibited medications: 
excluded (principal stratum) 
4. Treatment discontinuation prior to 
week 8 (letermovir arm only): excluded 
(principal stratum) 
5. Self-reported treatment adherence 
<50% (letermovir arm only): excluded 
(principal stratum) 
6. Confirmed HIV virologic failures: 
excluded (principal stratum) 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 


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7. Vaccination or concurrent acute illness 
within 1 week of sCD163 assessments: 
excluded (principal stratum) 
8. Pregnancy: excluded (principal 
stratum) 
Population-level summary measure 
Analysis approach 
The average change in sCD163 during the 
treatment phase and post-treatment phase 
compared to the average change had 
letermovir not been given. 
A generalized estimating equations (GEE) 
model with continuous outcomes and an 
appropriate covariance structure. The 
covariates will be study arm and the 
stratification factors, as well as a three-level 
period effect (early treatment phase [through 
Week 8], late treatment phase, post-treatment 
phase) and its interaction with the study arm. 
 
5.2.4 
Fourth Secondary Estimand 
Secondary Objective 4: To evaluate if letermovir reduces plasma sTNFRII levels at weeks 
8, 24, 46, 48, 52 and 60. 
Estimand description 
Change in sTNFRII over 60 weeks after 
initiation letermovir, among HIV-infected 
adults with asymptomatic CMV. 
Treatment 
Letermovir 480 mg once daily 
Target population   
Analysis set 
Adults ≥40 years of age with HIV and 
asymptomatic CMV, with HIV RNA suppression 
for at least the prior 48 weeks on combination 
ART. 
Efficacy set 
Variable(s) 
Outcome measure(s) 
sTNFRII at baseline and weeks 8, 24, 46, 48, 
52 and 60. 
sTNFRII at baseline and weeks 8, 24, 46, 48 
(and/or the latest result in the treatment 
phase), 52 and 60.  
“Baseline” refers to the average of two pre-
treatment results. If two results are not 


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available for averaging within a time point, a 
single result will be used. 
Handling of intercurrent events 
Handling of missing data 
The following intercurrent events are relevant 
to the estimand:  
1. Death: Excluded (principal stratum) 
2. Change in background ART regimen: 
ignored (treatment policy) 
3. Use of prohibited medications: 
excluded (principal stratum) 
4. Treatment discontinuation prior to 
week 8 (letermovir arm only): excluded 
(principal stratum) 
5. Self-reported treatment adherence 
<50% (letermovir arm only): excluded 
(principal stratum) 
6. Confirmed HIV virologic failures: 
excluded (principal stratum) 
7. Vaccination or concurrent acute illness 
within 1 week of sTNFRII 
assessments: excluded (principal 
stratum) 
8. Pregnancy: excluded (principal 
stratum) 
The analysis will be performed on the efficacy 
set and subset to intercurrent events (principal 
stratum). Missing data in this population will 
be assumed to be missing completely at 
random and thus ignored. 
Population-level summary measure 
Analysis approach 
The average change in sTNFRII during the 
treatment phase and post-treatment phase 
compared to the average change had 
letermovir not been given. 
A generalized estimating equations (GEE) 
model with continuous outcomes and an 
appropriate covariance structure. The 
covariates will be study arm and the 
stratification factors, as well as a three-level 
period effect (early treatment phase [through 
Week 8], late treatment phase, post-treatment 
phase) and its interaction with the study arm. 
6 
Analysis of Objectives 
6.1 
Primary Analysis 
1. sTNFRII analysis: 
a. Using the PP population, absolute changes in sTNFRII from baseline to the latest 
result in the treatment phase will be compared between the letermovir arm and 
the no anti-CMV treatment arm by linear regression. For this model each 
participant will have a single outcome measure of sTNFRII change from baseline 


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to the end of the treatment phase. The covariates will be study arm with 
screening CD4+ cell count and sex plus hormonal therapy (the stratification 
factors). 
b. A supplemental logistic regression will be done to estimate the odds of achieving 
the targeted sTNFRII reduction of 0.065 log10 pg/mL which, as previously stated, 
has been associated with a clinically relevant 22.5% reduction in CAD events. 
For this model, each participant will have a single outcome measure (last 
treatment phase sTNFRII change of ≤ -0.065 log10 pg/mL vs > -0.065 log10 
pg/mL). The covariates will be study arm with screening CD4+ cell count and sex 
plus hormonal therapy (the stratification factors). 
c. Five supplemental linear regression analyses will be performed. The first will 
perform the primary analysis using a modified intent-to-treat population (mITT) 
consisting of all participants who have been exposed to letermovir and all no anti-
CMV treatment arm participants. The remaining four will use the PP population 
and will assess differential letermovir effects by 1) baseline sTNFRII tertile, 2) 
CD4 strata, 3) sex and hormonal therapy strata, and 4) presence versus absence 
of mucosal CMV shedding at baseline by additionally adjusting for these main 
effects and the study arm by main effect interaction. 
6.2 
Secondary and Exploratory Analyses 
1. Safety secondary analysis: 
a. Using the mITT population, Grade 3+ AEs or HIV-1 virologic failures through 
Week 48 will be summarized by treatment arm. The proportion of participants in 
each arm with a Grade 3+ AE or HIV-1 virologic failure will be provided along 
with the difference in proportions and associated exact 95% CI and p-value. 
b. Using the mITT population, Kaplan-Meier curves of time from the IOT visit to first 
Grade 3+ AE or HIV-1 virologic failure (participants will be censored at time of 
study discontinuation) will be provided along with the corresponding log-rank test 
p-value. 
c. Using the mITT population, the highest grade AE for each participant through 
Week 48 will be summarized by treatment arm. The associated Wilcoxon rank-
sum test p-value will be provided. 
2. CMV DNA shedding secondary analysis: 
a. Using the PP population, binary CMV DNA shedding (yes/no) from baseline, 
weeks 8, 46, 48 (and/or the latest result in the treatment phase), 52 and 60 will 
be analyzed by GEE regression. For this model each participant will have up to 
seven outcomes of shedding at the above weeks. The covariates will be study 
arm with screening CD4+ cell count and sex plus hormonal therapy (the 
stratification factors) as well as a three-level period effect (early treatment phase 
[through Week 8], late treatment phase, post-treatment phase) and its interaction 
with the study arm. 
NOTE: this analysis will be done three times, once for each of the following: 
blood plasma CMV DNA, throat CMV DNA, and genital (seminal/cervicovaginal) 
CMV DNA. 
3. sCD163 secondary analysis: 


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a. Using the PP population, sCD163 from baseline, weeks 8, 46, 48 (and/or the 
latest result in the treatment phase), 52 and 60 will be analyzed by GEE 
regression. For this model each participant will have up to six outcomes of 
sCD163 at the above weeks. The covariates will be study arm with screening 
CD4+ cell count and sex plus hormonal therapy (the stratification factors) as well 
as a three-level period effect (early treatment phase [through Week 8], late 
treatment phase, post-treatment phase) and its interaction with the study arm. 
4. sTNFRII secondary analysis: 
a. Using the PP population, sTNFRII from baseline, weeks 8, 46, 48 (and/or the 
latest result in the treatment phase), 52 and 60 will be analyzed as the secondary 
sCD163 analysis above. 
5. Inflammatory and coagulation marker exploratory analysis: 
a. Using the PP population, sCD14, IL-6 hsCRP and D-Dimer change from 
baseline, weeks 8, 46, 48 (and/or the latest result in the treatment phase), 52 and 
60 will each be analyzed as the secondary sCD163 analysis above. 
6. Monocyte activation exploratory analysis: 
a. Using the PP population, CD14varCD16+ cells from baseline, weeks 8, 48 (and/or 
the latest result in the treatment phase), 52 and 60 will each be analyzed as the 
secondary sCD163 analysis above. 
7. CMV-specific response exploratory analysis: 
a. Using the PP population, absolute changes in CMV IgG titer from baseline to 
Week 48 (or the latest result in the treatment phase) will be compared between 
the letermovir arm and the no anti-CMV treatment arm by linear regression. For 
this model each participant will have a single outcome measure of clonality 
change from baseline to Week 48 (or the latest result in the treatment phase). 
The covariates will be study arm with screening CD4+ cell count and sex plus 
hormonal therapy (the stratification factors). 
8. T-cell exploratory analysis: 
a. Using the PP population, continuous (CD8+)CD38+HLA-DR+, PD-1, 
CD38+CD28-CD57+ and CD4+/CD8+ ratio from baseline, weeks 8, 48 (and/or 
the latest result in the treatment phase), 52 and 60 will each be analyzed as the 
secondary sCD163 analysis above. 
9. Insulin resistance exploratory analysis: 
a. Using the PP population, continuous HOMA-IR and plasma free fatty acid from 
baseline, to weeks 46 (and/or the latest result in the treatment phase) and 60 will 
each be analyzed by GEE regression. For this model each participant will have 
up to four outcomes at the above weeks. The covariates will be study arm with 
screening CD4+ cell count and sex plus hormonal therapy (the stratification 
factors) as well as a two-level period effect (treatment phase, post-treatment 
phase) and its interaction with the study arm. 
10. Physical function exploratory analysis: 
a. Using the PP population, continuous chair rise time, gait speed and grip strength 
from baseline, weeks 46 (and/or the latest result in the treatment phase) and 60 
will each be analyzed as the insulin resistance analysis above. 
11. VACS 2.0 Index exploratory analysis: 


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a. Using the PP population, continuous VACS index score from baseline, weeks 46 
(and/or the latest result in the treatment phase) and 60 will be analyzed as the 
insulin resistance analysis above. 
12. HIV reservoir exploratory analysis: 
a. Using the PP population, continuous single copy assay of HIV-1 RNA, cell-
associated HIV-1 RNA and cell-associated HIV-1 DNA from baseline, weeks 8 
and 48 (or the latest result in the treatment phase) will each be analyzed by GEE 
regression. For this model each participant will have three outcome measures of 
change at the above weeks. The covariates will be study arm with screening 
CD4+ cell count and sex plus hormonal therapy (the stratification factors) as well 
as a two-level period effect (early treatment phase [through Week 8], late 
treatment phase). 
i. For each of the three outcome measures, if over one third of the data are 
below the lower limit of quantification (LLoQ) at either baseline, week 8 
or week 48 (end of the treatment phase), the data will also be analyzed 
as binary (<LLoQ vs. ≥LLoQ) outcomes by GEE regression. 
13. CNS tolerability exploratory analysis: 
a. Using the PP population, continuous trail making A & B, digit symbol, HVLT-R, 
PHQ9, GAD7, Pittsburgh sleep quality index and plasma NFL from baseline, to 
weeks 46 (and/or the latest result in the treatment phase) and 60 will each be 
analyzed as the insulin resistance analysis above. 
7 
Report Contents 
Note that specific statistics used to describe “summary” will be more explicitly defined in the 
corresponding AIP. All sections below pertain to both the interim and final report analyses, unless 
noted otherwise. For the SMC Open Interim Report, summaries will be pooled over treatment 
arms. For the SMC Closed Interim Report as well as for final analysis, summaries will be 
presented both pooled (overall) and by treatment arms. All eligible ITT participants with available 
data will be used for the following summaries and analyses, unless specified otherwise. 
1. Study history 
a. A summary of changes to and clarifications of the protocol. 
b. A brief summary of the prior SMC reviews. 
2. Study entry (randomized population) 
a. Accrual: Tables of accrual by month and by site. 
3. Study status (reported in ClinicalTrials.gov) 
a. Number of participants off study with off study reasons. 
b. Study visit of last clinic visit. 
c. Weeks from study entry to last clinic visit. 
4. Treatment status (not included in SMC Open Interim Report) 
a. Number of participants who did not start study treatment and reason why 
treatment was not started. 
b. Number of participants off treatment with off treatment reasons. 
c. Number of days from study entry to first dose of study treatment. 


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d. Number of weeks from treatment initiation to permanent discontinuation of study 
treatment. 
5. Baseline characteristics (for mITT and PP populations, reported in ClinicalTrials.gov) 
a. Demographics: age, sex, gender, sex and use of gender-affirming hormones, 
race, ethnicity 
b. Weight and BMI 
c. HIV status: ARV regimen, CD4 count, HIV-1 RNA 
d. Laboratory results: Hemoglobin, platelet count, AST/SGOT, ALT/SGPT, alkaline 
phosphatase, bilirubin, and eGFR/CrCl. 
6. Pregnancies 
a. Listing and description of all available information related to pregnancy and 
outcome. 
7. Virologic failures 
a. Number of confirmed virologic failures. 
b. Listing of all available HIV-1 RNA data for participants who had virologic failures. 
8. Adverse events (mITT population) and deaths (randomized population) (reported in 
ClinicalTrials.gov) 
a. Summary of all reportable AEs through Week 48 by MedDRA PT grouped by 
SOC and grade. 
b. Summary of SAEs through Week 48 by MedDRA PT grouped by SOC and 
grade. 
c. Summary of SAEs that are EAEs through Week 48 by MedDRA PT grouped by 
SOC and grade. 
d. Summary of all reportable AEs through Week 60 by MedDRA PT grouped by 
SOC and grade. 
e. Summary of SAEs through Week 60 by MedDRA PT grouped by SOC and 
grade. 
f. 
Summary of SAEs that are EAEs through Week 60 by MedDRA PT grouped by 
SOC and grade. 
g. Listing of participants who died, including the primary cause of death, study week 
of death and death narrative. 
9. CD4 cell counts 
a. Summary of cross-sectional CD4 cell counts and changes from entry. 
10. Futility analysis (first closed SMC report after 40 participants have been enrolled, PP 
population) 
a. Summary of 8 week change in sTNFRII and sCD163 by treatment arm and 
difference between arms. 
b. Using observed and simulated future data for various simulation assumptions the 
following will be provided: predicted interval plots (PIPs), summary statistics of 
the final treatment effect, conditional power. 
NOTE: If the above summaries determine letermovir is futile for both sTNFRII 
and sCD163 they will be repeated in the subset of participants with screening 
CD4 <350 cells/mm3. 
c. Participant listing of baseline and 8 week changes in sTNFRII and sCD163. 


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d. Summary of 8 week odds of achieving hypothesized treatment effects (-0.0325 
log10 pg/mL for sTNFRII and -0.023 log10 µg/mL for sCD163) by treatment arm 
and odds ratio between arms. 
e. Summary of 8 week change in sTNFRII and sCD163 by treatment arm and 
difference between arms within CD4 (≤ vs > 350 cells/mm3) and baseline level (≤ 
vs > observed median sTNFRII or sCD163) subgroups. 
11. Concomitant medications (final report only) 
a. Summary of concomitant medications continued at study entry and started on 
study. 
12. Analysis of primary sTNFRII outcome (final report only, PP population unless otherwise 
noted, reported in ClinicalTrials.gov) 
a. Summary of sTNFRII at each time point as well as changes from baseline by 
treatment arm.  
b. Summary of the linear regression model of 48 week (or the latest result in the 
treatment phase) absolute change in sTNFRII with treatment arm and 
stratification factor covariates. The estimated effects, 95% CIs, and associated p-
values will be provided. 
c. Summary of the logistic regression model of 48 week (or the latest result in the 
treatment phase) absolute change in sTNFRII (≤ -0.065 vs >-0.065 log10 pg/mL) 
with treatment arm and stratification factor covariates. The estimated effects, 
95% CIs, and associated p-values will be provided. 
d. Summary of the supplemental linear regression model of 48 week (or the latest 
result in the treatment phase) absolute change in sTNFRII with treatment arm 
and stratification factor covariates using the mITT population. The estimated 
effects, 95% CIs, and associated p-values will be provided. 
e. Similar linear regression summary for the supplemental subgroup linear 
regression models assessing differential letermovir effects by 1) baseline 
sTNFRII tertile, 2) CD4 strata, 3) sex and hormonal therapy strata and 4) 
presence of mucosal CMV shedding at baseline.  
13. Analysis of secondary safety outcome (final report only, mITT population, reported in 
ClinicalTrials.gov) 
a. Summary of the number of participants with a Grade 3+ AE or HIV-1 virologic 
failure through Week 48 by treatment arm and associated difference in 
proportions and associated exact 95% CI and p-value. 
b. Kaplan-Meier curves of time from the IOT visit to first Grade 3+ AE or HIV-1 
virologic failure (participants will be censored at time of study discontinuation) will 
be provided along with the corresponding log-rank test p-value. 
c. Summary of the number of participants with an AE through Week 48 by their 
highest grade and treatment arm and associated two-sided Wilcoxon rank sum p-
value. 
14. Analysis of secondary CMV DNA shedding outcomes (final report only, PP population, 
reported in ClinicalTrials.gov) 
a. Summary of CMV DNA shedding (yes/no) in blood plasma, throat and genital 
secretion compartments. 


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b. For each compartment, summary of the GEE model of CMV DNA shedding at 
baseline, Weeks 8, 46, 48 (and/or the latest result in the treatment phase), 52 
and 60. The estimated risk ratio, 95% CIs, and associated p-values will be 
provided for each follow-up period. 
15. Analysis of secondary sCD163 outcome (final report only, PP population, reported in 
ClinicalTrials.gov) 
a. Summary of sCD163 at each time point as well as changes from baseline by 
treatment arm.  
b. Summary of GEE model of sCD163 (baseline, weeks 8, 24, 46, 48 (and/or the 
latest result in the treatment phase), 52 and 60) with treatment arm and 
stratification factor covariates. The estimated effects, 95% CIs, and associated p-
values will be provided for each follow-up period. 
16. Analysis of secondary sTNFRII outcome (final report only, PP population, reported in 
ClinicalTrials.gov) 
a. Summary of GEE model of sTNFRII (baseline, weeks 8, 24, 46, 48 (and/or the 
latest result in the treatment phase), 52 and 60) with treatment arm and 
stratification factor covariates. The estimated effects, 95% CIs, and associated p-
values will be provided for each follow-up period. 
17. Analysis of exploratory inflammatory and coagulation marker outcomes (final report only, 
PP population) 
a. Summary of sCD14, IL-6, hsCRP and D-Dimer at each time point as well as 
changes from baseline by treatment arm.  
b. Summary of GEE model of sCD14, IL-6, hsCRP and D-Dimer (baseline, weeks 
8, 46/48 (and/or the latest result in the treatment phase), 52 and 60) with 
treatment arm and stratification factor covariates. The estimated effects, 95% 
CIs, and associated p-values will be provided for each follow-up period. 
18. Analysis of exploratory monocyte activation outcomes (final report only, PP population) 
a. Summary of CD14varCD16+ cells at each time point as well as changes from 
baseline by treatment arm.  
b. Summary of GEE model of CD14varCD16+ cells (baseline, weeks 8, 48 (and/or 
the latest result in the treatment phase), 52 and 60) with treatment arm and 
stratification factor covariates. The estimated effects, 95% CIs, and associated p-
values will be provided for each follow-up period. 
19. Analysis of exploratory CMV-specific response outcomes (final report only, PP 
population) 
a. Summary of CMV IgG titer at each time point as well as changes from baseline 
by treatment arm.  
b. Summary of the linear regression models of 48 week (or the latest result in the 
treatment phase) absolute change in CMV IgG titer with treatment arm and 
stratification factor covariates. The estimated effects, 95% CIs, and associated p-
values will be provided. 
20. Analysis of exploratory T-cell outcomes (final report only, PP population) 
a. Summary of (CD8+)CD38+HLA-DR+, PD-1, CD38+CD28-CD57+ and 
CD4+/CD8+ ratio at each time point as well as changes from baseline by 
treatment arm.  


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b. Summary of GEE model of (CD8+)CD38+HLA-DR+, PD-1, CD38+CD28-CD57+ 
and CD4+/CD8+ ratio (baseline, weeks 8, 48 (and/or the latest result in the 
treatment phase), 52 and 60) with treatment arm and stratification factor 
covariates. The estimated effects, 95% CIs, and associated p-values will be 
provided for each follow-up period. 
21. Analysis of exploratory insulin resistance outcomes (final report only, PP population) 
a. Summary of HOMA-IR and plasma free fatty acid at each time point as well as 
changes from baseline by treatment arm.  
b. Summary of GEE model of HOMA-IR and plasma free fatty acid (baseline, weeks 
46 (and/or the latest result in the treatment phase) and 60) with treatment arm 
and stratification factor covariates. The estimated effects, 95% CIs, and 
associated p-values will be provided for each follow-up period. 
22. Analysis of exploratory physical function outcomes (final report only, PP population) 
a. Summary of chair rise time, gait speed and grip strength at each time point as 
well as changes from baseline by treatment arm.  
b. Summary of GEE model of chair rise time, gait speed and grip strength (baseline, 
weeks 46 (and/or the latest result in the treatment phase) and 60) with treatment 
arm and stratification factor covariates. The estimated effects, 95% CIs, and 
associated p-values will be provided for each follow-up period. 
23. Analysis of exploratory VACS index outcome (final report only, PP population) 
a. Summary of VACS index score at each time point as well as changes from 
baseline by treatment arm.  
b. Summary of GEE model of VACS index score (baseline, weeks 46 (and/or the 
latest result in the treatment phase) and 60) with treatment arm and stratification 
factor covariates. The estimated effects, 95% CIs, and associated p-values will 
be provided for each follow-up period. 
24. Analysis of exploratory HIV reservoir outcomes (final report only, PP population) 
a. Summary of single copy assay of HIV-1 RNA, cell-associated HIV-1 RNA and 
cell-associated HIV-1 DNA at each time point as well as changes from baseline 
by treatment arm.  
b. Summary of GEE model of single copy assay of HIV-1 RNA, cell-associated HIV-
1 RNA and cell-associated HIV-1 DNA (baseline, weeks 8 and 48 (or the latest 
result in the treatment phase)) with treatment arm and stratification factor 
covariates. The estimated effects, 95% CIs, and associated p-values will be 
provided. 
i. If required, summary of GEE model of unquantifiable (<LLoQ) HIV-1 
RNA, cell-associated HIV-1 RNA or cell-associated HIV-1 DNA 
(baseline, weeks 8 and 48 (end of the treatment phase)) with treatment 
arm and stratification factor covariates. The estimated risk ratio, 95% 
CIs, and associated p-values will be provided. 
25. Analysis of exploratory CNS tolerability outcomes (final report only, PP population) 
a. Summary of trail making A & B, digit symbol, HVLT-R, PHQ9, GAD7, Pittsburgh 
sleep quality index and plasma NFL at each time point as well as changes from 
baseline by treatment arm.  


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8 
Summary of GEE model of trail making A & B, digit symbol, HVLT-R, PHQ9, GAD7, 
Pittsburgh sleep quality index and plasma NFL (baseline, weeks 46 (and/or the latest result 
in the treatment phase) and 60) with treatment arm and stratification factor covariates. The 
estimated effects, 95% CIs, and associated p-values will be provided for each follow-up 
period.