Pitavastatin to REduce Physical Function Impairment and FRailty in HIV (PREPARE)
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

 
 
A5361s 
 
Pitavastatin to Reduce Physical Function Impairment and 
Frailty in HIV (PREPARE) 
 
A Multicenter Observational Study of the AIDS Clinical 
Trials Group (ACTG) 
 
 
NIAID CRMS # 30140 
 
 
This file contains the current ACTG A5361s protocol, which 
includes the following document:  
 
 Clarification Memorandum #1, dated 20 August 2021 
 Protocol Version 2.0, dated 6 July 2021  
 

 
Clarification Memo #1 
          Page 1 of 2 
20 August 2021 
ACTG A5361s Protocol Version 2.0 
 
Clarification Memo #1 for: 
 
A5361s 
 
Pitavastatin to Reduce Physical Function Impairment and Frailty in HIV 
(PREPARE) 
 
A Multicenter Observational Study of the AIDS Clinical Trials Group (ACTG) 
 
NIAID CRMS # 30140 
 
Letter of Amendment Date: 20 August 2021 
 
 
ACTG NETWORK COORDINATING CENTER 
Social & Scientific Systems, Inc., a DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3000 
Fax: 301-628-3302 
 
 
 
CLARIFICATION MEMO 
 
DATE:  
20 August 2021 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM:  
A5361s Protocol Team  
 
SUBJECT: 
Clarification Memo #1 for Protocol A5361s 
 
 
This clarification memo (CM) does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your institutional review 
board (IRB); however, you must follow your IRB’s policies and procedures. If IRB review of 
clarification memos is required at your site, please submit this document for review. 
 
Each site should file a copy of this CM with the protocol for reference. 
 
The protocol clarification(s) contained in this memo should be implemented immediately.  
 
The main reason for this CM is to address the missing Principal Investigator signature and signature date 
fields on the SIGNATURE PAGE of Protocol A5361s, Version 2.0, dated 06Jul2021. 
 

 
Clarification Memo 
          Page 2 of 2 
20 August 2021 
ACTG A5361s Protocol Version 2.0 
The following is a clarification (noted in bold) to Protocol A5361s, Version 2.0, 06Jul2021, titled 
“Pitavastatin to REduce Physical Function Impairment and FRailty in HIV (PREPARE).” This will be 
included in the next version of the A5361s protocol if it is amended at a future date. 
 
 
The Principal Investigator (PI) signature and signature date fields are missing on the SIGNATURE PAGE 
on page 2 of the A5361s Version 2.0 protocol document. This oversight is corrected by the addition of the 
following to this page: 
 
Signed:  
 
 
 
 
 
 
 
Date:   
 
 
Name/Title 
 
Sites should include these fields on the SIGNATURE PAGE and then obtain PI signature.  
 

 
 
 
 
 
A5361s 
 
 
Pitavastatin to REduce Physical Function Impairment and FRailty in HIV 
(PREPARE) 
 
A Multicenter Observational Study of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
National Institute on Aging 
 
 
 
Non-IND Protocol 
 
 
 
ACTG End-organ Disease/Inflammation  
Transformative Science Group: 
E. Turner Overton, MD, Chair 
 
Protocol Co-Chairs: 
Todd Brown, MD, PhD 
 
Kristine Erlandson, MD 
 
Protocol Vice Chair: 
E. Turner Overton, MD 
 
DAIDS Clinical Representative: 
Christine Chiou, MD 
 
 
Clinical Trials Specialist: 
Jhoanna C. Roa, MD 
 
 
 
 
Final Version 2.0 
06 Jul 2021 
 
 

A5361s 
 
 
Final Version 2.0 
 
 
06 Jul 2021 
 
 
Pitavastatin to REduce Physical Function Impairment and FRailty in HIV 
(PREPARE) 
 
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 
 
 

A5361s 
 
 
Final Version 2.0 
 
 
06 Jul 2021 
 
 
TABLE OF CONTENTS 
 
 
Page 
 
SIGNATURE PAGE ...................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY ..................................................................................... 5 
PROTOCOL TEAM ROSTER ....................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................... 8 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ...................................................................... 10 
SCHEMA ..................................................................................................................................... 11 
1.0 
HYPOTHESES AND STUDY OBJECTIVES................................................................... 12 
1.1 
Hypotheses ......................................................................................................... 12 
1.2 
Primary Objectives .............................................................................................. 12 
1.3 
Secondary Objectives ......................................................................................... 12 
1.4 
Exploratory Objectives ........................................................................................ 13 
2.0 
INTRODUCTION ............................................................................................................. 13 
2.1 
Background ......................................................................................................... 13 
2.2 
Rationale ............................................................................................................. 18 
3.0 
SUBSTUDY DESIGN ...................................................................................................... 22 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 22 
4.1 
Inclusion Criteria .................................................................................................. 22 
4.2 
Exclusion Criteria ................................................................................................ 22 
4.3 
Study Enrollment Procedures .............................................................................. 22 
4.4 
Co-enrollment Guidelines .................................................................................... 24 
5.0 
STUDY TREATMENT ..................................................................................................... 24 
5.1 
Regimens, Administration, and Duration ............................................................. 24 
5.2 
Prohibited Medications ........................................................................................ 24 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ............................................................ 25 
6.1 
Schedule of Evaluations .................................................................................... 25 
6.2 
Timing of Evaluations .......................................................................................... 26 
6.3 
Instructions for Evaluations ................................................................................. 27 
7.0 
ADVERSE EVENTS AND STUDY MONITORING.......................................................... 29 
7.1 
Definition of Adverse Events ............................................................................... 29 
7.2 
Adverse Event Reporting Requirements in the Clinical Database ...................... 29 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ......................................... 30 
7.4 
Study Monitoring ................................................................................................. 30 
8.0 
CLINICAL MANAGEMENT ISSUES ............................................................................... 30 
9.0 
CRITERIA FOR DISCONTINUATION............................................................................. 30 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 30 
10.1 
General Design Issues ........................................................................................ 30 
10.2 
Outcome Measures ............................................................................................. 32 
10.3 
Randomization/Registration ................................................................................ 33 

A5361s 
 
 
Final Version 2.0 
 
 
06 Jul 2021 
 
CONTENTS (Cont’d) 
Page 
 
10.4 
Sample Size and Accrual .................................................................................... 33 
10.5 
Data and Safety Monitoring ................................................................................. 35 
10.6 
Analyses .............................................................................................................. 35 
11.0 
PHARMACOLOGY PLAN ............................................................................................... 37 
12.0 
DATA COLLECTION AND MONITORING ...................................................................... 37 
12.1 
Records to Be Kept ............................................................................................. 37 
12.2 
Role of Data Management .................................................................................. 38 
12.3 
Clinical Site Monitoring and Record Availability .................................................. 38 
13.0 
PARTICIPANTS .............................................................................................................. 38 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 38 
13.2 
Participant Confidentiality .................................................................................... 38 
13.3 
Study Discontinuation .......................................................................................... 39 
14.0 
PUBLICATION OF RESEARCH FINDINGS ................................................................... 39 
15.0 
BIOHAZARD CONTAINMENT ........................................................................................ 39 
16.0 
REFERENCES ................................................................................................................ 40 
APPENDIX I: SAMPLE INFORMED CONSENT ........................................................................ 50 
 
 

 
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SITES PARTICIPATING IN THE STUDY 
 
A5361s is open to interested US clinical research sites (CRSs) that are participating in ACTG-
approved parent protocols, REPRIEVE (A5332) and the Mechanistic Substudy of REPRIEVE 
(A5333s). 

 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Todd T. Brown, MD, PhD 
Division of Endocrinology, Diabetes, and 
Metabolism 
Johns Hopkins University 
1830 East Monument Street, Suite 333 
Baltimore, MD  21287 
Phone: 410-502-6888 
Fax: 410-367-2042 
E-mail: tbrown27@jhmi.edu 
 
Kristine M. Erlandson, MD 
Division of Infectious Diseases & Geriatric 
Medicine 
University of Colorado 
12700 E. 19th Avenue 
Aurora, CO  80045 
Phone: 303-724-4941 
Fax: 303-724-4926  
E-mail: kristine.erlandson@ucdenver.edu 
 
Vice Chair 
Edgar Turner Overton, MD 
Division of Infectious Diseases 
University of Alabama 
CCB 325 
1530 3rd Avenue S. 
Birmingham, AL  35294 
Phone:  205-996-2373 
Fax: 205-975-6027 
E-mail: toverton@uab.edu 
 
DAIDS Clinical Representative 
Christine Chiou, MD 
Division of AIDS 
Complications and Co-Infections Research 
Branch 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9F49  
Rockville, MD  20852 
Phone: 240-292-4181 
Fax: 240-507-9611 
E-mail: cchiou@niaid.nih.gov
Clinical Trials Specialist 
Jhoanna C. Roa, MD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., a DLH 
Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3196 
Fax: 301-628-3302 
E-mail: jhoanna.roa@dlhcorp.com 
 
Statisticians 
Heather Ribaudo, PhD 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 509 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-2897 
Fax: 617-432-3163 
E-mail: ribaudo@sdac.harvard.edu 
 
Triin Umbleja, MSc 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 501 
651 Huntington Avenue 
Boston, MA  02115 
Phone: 617-432-0118 
Fax: 617-432-3163 
E-mail: tumbleja@sdac.harvard.edu 
 
Data Manager 
Mark Byroads, BA 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY  14226-1056 
Phone: 716-834-0900 x7341 
Fax: 716-834-8675 
E-mail: byroads@fstrf.org

 
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PROTOCOL TEAM ROSTER (Cont’d) 
 06 Jul 2021 
 
Investigator 
Jennifer Schrack, PhD 
Department of Epidemiology 
Johns Hopkins University 
615 N. Wolfe Street, E7144 
Baltimore, MD  21205 
Phone: 410-502-9328 
E-mail: jschrac1@jhu.edu 
 
Field Representative 
Suzanne Fiorillo, MSPH 
University of Colorado Hospital CRS 
Academic Office 1, MS 8205 
P.O. Box 6511 
12631 East 17th Avenue 
Aurora, CO  80045 
Phone: 303-724-5931 
Fax: 303-724-5931 
E-mail: suzanne.fiorillo@ucdenver.edu 
 
Community Scientific Subcommittee (CSS) 
Representatives 
Kate Starr, BS 
Ohio State University CRS 
6285 Rygate Drive 
Reynoldsburg, OH  43068 
Phone: 614-353-2944 
E-mail: borloglou@gmail.com 
 
Karl Edmund Shaw, BBA 
19140 Ohio Street 
Detroit, MI  48221 
Phone: 313-861-1979 
E-mail: kedshaw@hotmail.com 
 
Consultant to the Protocol Team  
Michael Lu, MD 
MGH Cardiac MR PET CT Program 
Harvard Medical School 
165 Cambridge Street, Suite 400 
Boston, MA  02114 
Phone: 617-643-0239 
E-mail: mlu@mgh.harvard.edu 
 
Laboratory Data Managers 
Frederic Bone 
Frontier Science Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7306 
E-mail: bone@frontierscience.org 
 
DaMante' Curry, BS 
Frontier Science Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext. 7416 
Email: dcurry@frontierscience.org 
 
 
 

 
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STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.coreA5361s@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.coreA5361s@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5361s e-mail 
group. Include the protocol number in the e-mail subject line. 
 
Send an e-mail message to actg.user.support@fstrf.org. 
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Core protocol team. 
 
Send an e-mail message to actg.coreA5361s@fstrf.org. Include the protocol number, patient 
identification number (PID), and a brief relevant history. 
 
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. 
 
Electronic CRFs (eCRFs) completion guidelines and participant completed eCRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
 
For transfers, reference the Study Participant Transfer SOP 119 and contact Mark Byroads 
directly. 
 
For other questions, send an e-mail message to reprieve.dmc@fstrf.org. 
 
Include the protocol number, PID, and a detailed question. 
 
Participant Registration 
For participant registration questions or problems: 
 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301. 
 
Computer and Screen Problems 
Contact the DMC programmers. 
 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialist. 
 
Send an e-mail message to actg.coreA5361s@fstrf.org (ATTENTION: Jhoanna Roa). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send a message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website (https://www.actgnetwork.org). 
 

 
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STUDY MANAGEMENT (Cont'd) 
06 Jul 2021 
 
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, contact the Clinical Trials Specialist, Jhoanna Roa, 
at jhoanna.roa@dlhcorp.com or ACTG Site Coordination group at 
actgsitecoordination@dlhcorp.com. 
 
Phone Calls 
Sites are responsible for documenting any phone calls made to A5361s team members. 
 
Send an e-mail to actg.coreA5361s@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 
 
ART 
 
antiretroviral therapy 
BMI 
 
body mass index 
CMV IgG 
cytomegalovirus immunoglobulin G 
DASI  
Duke Activity Status Index 
HOMA-IR 
homeostasis model assessment-estimated insulin resistance 
HU 
 
Hounsfield units 
IGF-1  
insulin-like growth factor 1 
IIS 
 
inflammatory index score 
IL-6 
 
interleukin-6 
IP-10   
IFN-gamma-inducible protein 10 
LBM 
 
lean body mass 
mSPPB 
modified Short Physical Performance Battery 
NAFLD 
non-alcoholic fatty liver disease  
NHLBI  
National Heart, Lung, and Blood Institute 
NIA 
 
National Institute on Aging 
REAP  
Rapid Eating and Activity Assessment for Patients  
REPRIEVE 
Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE (A5332) 
sCD14  
soluble CD14 
sCD163 
soluble CD163 
SPPB  
Short Physical Performance Battery 
sTNFR-1  
soluble tumor necrosis factor receptor 1 
sTNFR-2  
soluble tumor necrosis factor receptor 2 
TGF-β1  
transforming growth factor beta 1 
TNF-α 
 
tumor necrosis factor α 
 
 

 
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SCHEMA 
 
 
A5361s 
Pitavastatin to REduce Physical Function Impairment and FRailty in HIV (PREPARE) 
 
 
DESIGN 
A5361s is a prospective, observational study of muscle strength 
and function among HIV-1 infected adults who are receiving 
pitavastatin or placebo as part of REPRIEVE (A5332) and are also 
enrolled in A5333s or enrolled in REPRIEVE (A5332) only. All 
participants will undergo physical function testing on an annual 
basis for up to 60 months. In addition, data from evaluations done 
on REPRIEVE (A5332) and A5333s will be used. Computed 
tomography (CT) scans will be re-analyzed for the degree of fatty 
muscle infiltration, and serum/plasma samples will be analyzed for 
changes in biomarkers. The primary study objective is to 
determine whether pitavastatin can slow or prevent the decline in 
physical function of adults aging with HIV infection. 
 
DURATION 
Up to 60 months 
 
 
SAMPLE SIZE 
600 participants 
 
 
POPULATION 
Ambulatory participants enrolled in both REPRIEVE (A5332) and 
the Mechanistic Substudy (A5333s) OR ambulatory participants 
that are newly enrolling to REPRIEVE (A5332) at A5333s 
ACTG sites. It is desired that a substantial proportion of study 
participants will be enrolled in the Mechanistic Substudy of 
REPRIEVE (A5333s). 
 

 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Hypotheses 
 
1.1.1 Measures of physical function will remain stable or show a slowed decline among 
participants assigned to pitavastatin compared to participants assigned to 
placebo. 
 
1.1.2 Participants assigned to pitavastatin will have a greater decline in systemic 
markers of inflammation and immune activation compared to participants 
assigned to placebo. 
 
1.1.3 Participants assigned to pitavastatin will have a greater reduction in fatty 
infiltration of the skeletal trunk muscles compared to placebo. 
 
1.1.4 A decrease in inflammation/immune activation and a reduction in skeletal trunk 
muscle fat infiltration will be associated with a higher level of physical function 
among HIV-infected adults. 
 
1.2 
Primary Objectives 
 
1.2.1 To determine whether pitavastatin can slow or prevent the decline in physical 
function of adults aging with HIV infection. 
 
1.2.2   To evaluate mechanistic pathways through which pitavastatin affects physical 
function. 
 
1.3 
Secondary Objectives 
 
1.3.1 To characterize muscle function and muscle attenuation and their association 
with clinical characteristics and risk factors (such as age, comorbidities, level of 
physical activity, inflammation/immune activation, lipids) in virologically 
suppressed HIV-infected older population at low cardiovascular risk. 
 
1.3.2 To determine the effects of pitavastatin on muscle fat attenuation over 24 
months. 
 
1.3.3 To determine the relationship between changes in inflammation/immune 
activation and skeletal trunk muscle fat infiltration with change in physical 
function over 60 months. 
 
1.3.4 To determine the impact of pitavastatin versus placebo on self-reported physical 
activity or sedentary time. 
 
1.3.5 To assess the impact of muscle symptoms on the effect of pitavastatin versus 
placebo on physical function. 
 

 
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1.3.6 To determine whether changes in muscle fat attenuation are independent of lipid 
changes and changes in homeostasis model assessment-estimated insulin 
resistance (HOMA-IR). 
 
1.4 
Exploratory Objectives 
 
1.4.1 To determine whether the impact of pitavastatin on physical function or fat 
infiltration is affected by baseline vitamin D levels. 
 
1.4.2 To determine whether the impact of pitavastatin on physical function or fat 
infiltration is affected by sex hormones (total and free testosterone) or 
menopausal status. 
 
1.4.3 To determine the effects of pitavastatin on physical function by subgroup (race, 
sex, CD4 count, physical activity, baseline physical function, duration of 
antiretroviral therapy [ART], and inflammation). 
 
1.4.4 To evaluate the effects of the COVID-19 pandemic on physical function. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Evidence of Impaired Physical Function and Frailty Is Present in Middle-Aged Adults 
Aging with HIV. With combination ART, longer life expectancy is changing the 
demographics of the HIV epidemic, and nearly half of those living with HIV in the United 
States are now 50 years or older [1]. However, even with long-term, effective ART, 
impairment in physical function and frailty are more common than expected in HIV-
infected populations and have been associated with an increased risk of falls, 
hospitalizations, and mortality [2,3]. 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 [4,5]. The aging HIV-infected 
population, therefore, is an emerging risk group for the accelerated development of 
mobility disability, and careful investigation to improve physical function and quality of life 
in this population is required. 
 
Inflammation Contributes to Physical Function Impairments and Frailty. In the geriatric 
literature, the well-described frailty phenotype is regarded as a terminal state of loss of 
functional homeostasis that leaves a person unable to effectively recover from various 
stressors and is associated with poor health outcomes, including excess mortality [6]. 
Frailty and physical function impairments in elderly persons have been associated with 
excess inflammation and markers of immune senescence. Interleukin-6 (IL-6), a pro-
inflammatory cytokine released systemically by T cells and macrophages, has been 
associated with low physical function [7] and low appendicular muscle mass [8]. In 
animal models, IL-6 infusion-induced peripheral muscle wasting in healthy rats [9]; 
ablation of IL-6 through a genetic knock-out [10] or IL-6 receptor antibody [11] completely 
abolished muscle wasting, indicating a direct role in muscle catabolism. In healthy young 

 
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men, IL-6 infusion suppressed skeletal muscle protein synthesis [12]. Clearly, 
inflammatory pathways are involved in the maintenance of muscle health, and excess 
inflammation detrimentally affects muscle quality and function. 
 
These very derangements in inflammatory biomarkers have been well characterized in 
HIV infection: persistent, low-grade inflammation and immune activation [13] are strongly 
associated with a heightened risk for cardiovascular disease [14-16], osteoporosis [17], 
anemia [18], physical function impairments, and frailty [7], among other non-AIDS events 
and mortality [19,20]. This pro-inflammatory state is thought to be multifactorial, driven in 
part by low-level HIV replication and/or co-infection with other pathogens such as 
cytomegalovirus (CMV) [21]. Prior and ongoing work by our team has shown a strong 
relationship between systemic inflammation and physical function impairment in HIV-
infected individuals, as detailed in the Preliminary Data section. Given the long-term 
consequences of chronic inflammation, there is an urgent need to understand the 
causes and to develop interventions that attenuate the effects of inflammation and 
immune activation in people living with HIV. 
 
The Need to Determine Statin Effects on Functional Impairment. Statins are the most 
widely prescribed class of drugs worldwide [22]. The anti-inflammatory effect of statins 
has generated interest in the use of statin therapy to attenuate the low-grade 
inflammation and immune activation in treated HIV-infection [23-25]. Most recently, in 
the SATURN-HIV trial, HIV-infected adults randomized to rosuvastatin had significant 
reduction in markers of inflammation and immune activation compared with placebo [26]. 
Among persons with chronic inflammation, the reduction in inflammatory markers with 
statin therapy is an attractive target for prevention of physical function impairment, 
ultimately to decrease progression to disability and frailty. In cancer cachexia models in 
which loss in muscle mass and function are driven by chronic inflammation, simvastatin 
attenuated loss of lean body mass (LBM) [27]. In a murine model, atorvastatin delayed 
motor dysfunction and muscle weakness, attenuated the loss of motor neurons, and 
increased biceps muscle weight by nearly 30% compared with vehicle (placebo), 
suggesting benefit at the level of both the muscle and the motor neuron [28]. 
 
 

 
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Table 2.1-1.  Systematic Review of Statins on Physical Function 
Design 
N 
Dur. 
Effect 
Ref 
Positive Effect 
RCT 
64 
6 mos 
Statins improved lower extremity blood flow in healthy adults 
[29] 
RCT 
86 
6 mos 
Statins increased walking distance in PAD 
[30] 
RCT 
354 
12 mos 
Statin-users with improved pain-free walking time, self-reported 
walking ability; no change in max walking time 
[31] 
RCT 
68 
6 mos 
Significantly improved 6-min walking time in statin arm only in CHF 
[32] 
RCT 
144 
24 mos 
Significantly greater LBM gain in statin arm, no difference in self-
reported physical activity 
[33] 
RCT 
83 
12 mos 
EX +/- lovastatin; significantly greater METS and exercise time in 
statin arm only 
[34] 
RCT 
15 
20 wks 
Cerivastatin versus placebo in heart failure patients; significantly 
improved 6-min walking distance 
[35] 
RCT 
125 
6 mos 
Pravastatin versus placebo in COPD; improved exercise time and 
dyspnea with pravastatin 
[36,3
7] 
RCT 
64 
12 wks 
Atorvastatin versus placebo in cardiomyopathy; improved 6-min 
walking distance in atorvastatin group 
[38] 
OBS 
756 
n/a 
Statin users had better timed chair stands than non-statin users 
[39] 
OBS 
641 
n/a 
Better physical function, faster gait speed and velocity among statin 
users with or without PAD 
[40] 
OBS 
5,777 
n/a 
Less decline in chair rise among oldest women on statins 
[41] 
OBS 
544 
n/a 
Less decline in lower extremity performance among PAD patients on 
statin 
[42] 
OBS 
49 
12 wks  
REx +/- statin use (pravastatin/lovastatin but not 
atorvastatin/simvastatin) greater gains in LBM 
[43] 
OBS 
3422 
n/a 
Statin use associated with improved disability scores on discharge 
from rehab 
[44] 
Null Effect 
RCT 
420 
6 mos 
No change in strength/endurance but increase in CK in statin arm  
[45] 
RCT 
41 
12 mos 
Cross-over RCT of pravastatin +/- tocopherol; no significant quality of 
life differences 
[46] 
RCT 
26 
8 wks 
No sign change with atorvastatin in resting energy expenditure, V02, 
or RER 
[47] 
RCT 
16304 
Up to 5 
yrs 
From JUPITER, no difference in self-reported fatigue or muscle 
weakness in rosuvastatin versus placebo 
[48] 
CT 
26 
12 wks 
Statin users and non-users completed 12 wks EX; similar gain in V02 
max, workload, muscle strength; similar changes in mitochondrial 
density and function 
[49] 
CT 
22 
8 wks 
Statin users/non-users completed 8 wks EX; similar gains in V02 max 
and exercise time  
[50] 
OBS 
25378 
n/a 
Longer duration low-potency statin associated with reduced frailty; no 
effect with other potency 
[51] 
OBS 
2005 
n/a 
No detrimental effect of statins on gait speed; 22% lower risk of 
decline among low-dose statins only 
[52] 
OBS 
1665 
7 yrs 
No association between statin use and institutionalization or death 
[53] 

 
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To understand the clinical impact of statins, we performed a systematic review (Table 
2.1-1). A PubMed search using (“Hydroxymethylglutaryl-CoA Reductase Inhibitors” 
[Medical Subject Heading {MeSH}] or “statins”) AND (“frailty” or “sarcopenia” or 
“muscle strength” or “physical function” or “physical performance”) with human and 
English filters yielded 59 articles. A separate search for (“Hydroxymethylglutaryl-CoA 
Reductase Inhibitors” [MeSH] AND “exercise” [MeSH]) yielded 186 articles. We 
augmented the search using the reference lists from relevant studies and prior 
systematic reviews. Each abstract was reviewed and full articles were reviewed if the 
abstract was potentially relevant. Both observational and clinical trials reporting any 
measures of physical function were reviewed. As detailed in Table 2.1-1, prior clinical 
studies among HIV-uninfected populations have found that randomized or observed 
statin therapy was associated with increased total walking distance or time [30,32,34-
38], self-reported walking ability [31], and improved chair rise time [39]. Statin use 
among adults initiating resistance exercise was associated with a greater gain in LBM 
compared with those not using statins [43]. Furthermore, as detailed in Preliminary Data, 
our SATURN-HIV study showed that HIV-infected participants assigned to low-dose 
rosuvastatin had significantly greater LBM at 96 weeks compared with placebo [33]. 
 
In contrast to the positive benefits of statins on physical function and muscle mass 
described above, myalgias are one of the most commonly reported and well-recognized 
OBS 
749 
N/a 
No difference in swim distance, sessions, or time among master 
swimmers with or without statin use 
[54] 
OBS 
317 
6 mo 
Statin-users and non-users had increase in physical function but not 
different   
[55] 
OBS 
28 
n/a 
No difference in muscle function measures between statin-users or 
non-users 
[56] 
Negative Effect 
RCT 
37 
12 wks 
EX +/- simvastatin. Greater LBM; attenuated V02 response in statin 
arm. Strength was not reported.  
[57] 
RCT 
1016 
6 mo 
Randomized simvastatin, pravastatin or placebo; lower self-reported 
energy/greater fatigue in statin arm 
[58] 
OBS 
18 
n/a 
No difference in mass, power, or strength; increased expression of 
mRNA linked to mitochondrial apoptotic signaling in statin myalgia arm 
compared with non-statin users  
[59] 
OBS 
774 
n/a 
Statin use predicted increased fall risk score and decreased leg 
strength. 
[60] 
OBS 
6966 
n/a 
Statin users tended to have lower self-reported physical function & 
self-rated health 
[61] 
OBS 
3280 
n/a 
Loss of LBM between age >60 and <75 yrs was greater in the statin 
(10.9%) than non-statin (8.5%) group.  
[62] 
OBS 
4137 
n/a 
Statin users self-reported less moderate or vigorous physical activity 
[63] 
OBS 
2207 
n/a 
Longer-duration statin associated with worsened self-reported 
physical function 
[64] 
PAD, peripheral artery disease; EX, exercise; CHF, congestive heart failure; LBM, lean body mass; COPD, 
chronic obstructive pulmonary disease; RER, respiratory exchange ratio; RCT, randomized controlled trial; CT, 
controlled trial; OBS, observational study 

 
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side effects of statin therapy. Although estimates vary, the prevalence of subjective 
myalgias or weakness with statin treatment is reportedly as high as 20% in clinical 
practice, and myalgias are a major cause of statin non-compliance and discontinuation 
[65]. While data suggest that myalgias are not associated with a decrease in physical 
function [45,59,66,67], observational cohort studies have reported lower strength [60], 
physical activity [63], and lean mass [60,62] among participants using statins. To our 
knowledge, the only randomized, placebo-controlled study to demonstrate a negative 
effect of statins was a small study of an aerobic exercise intervention with (N=18) or 
without (N=19) simvastatin; the simvastatin arm demonstrated an attenuated aerobic 
response to exercise training, but a significant increase in LBM (no increase in placebo 
arm); no measures of strength were reported [57]. A separate randomized, placebo-
controlled trial reported negative impact on energy and fatigue, but no objective 
measures were reported [58]. A large trial specifically designed to assess the impact of 
statins on skeletal muscle function randomized 468 healthy participants to atorvastatin 
versus placebo and found no significant differences in strength or endurance between 
arms; however, effects were assessed after only 6 months of therapy [45]. The authors 
concluded that the findings “should prompt studies examining the effects of more 
prolonged, high-dose statin treatment on muscular performance.” 
 
Muscle Fat, a Measure of Muscle Quality and Statins. With increasing age comes 
deterioration of muscle mass and quality. One key component of muscle quality is the 
amount of fatty infiltration, which increases with age and, as we have shown, is more 
pronounced in HIV-infected persons. Fatty infiltration of the muscle has been 
independently associated with impairments in muscle strength, chair rise time, and gait 
speed [68-70] and thus, is an important potential target for interventions aimed at 
improving physical function. Skeletal muscle lipid accumulates as the result of increased 
circulating fatty acids, enhanced fatty acid uptake, and decreased mitochondrial 
oxidation, among other mechanisms. Excess free fatty acids accumulate within the 
muscle as lipid droplets are converted to molecules involved in signaling pathways that 
may contribute to insulin resistance, inflammation, or production of reactive oxygen 
species [71-73]. A strong correlation between intramyocellular and intrahepatic lipid 
content has previously been reported and linked to excess visceral fat, as well as insulin 
resistance [74,75]. Although the effects of statins on muscle fat have not been reported, 
in animal and human models of non-alcoholic fatty liver disease (NAFLD), several statins 
have demonstrated decreases in both hepatic steatosis and decreased fibrosis [76-79]. 
In a rat model of NAFLD, pitavastatin treatment led to smaller hepatocyte lipid droplet 
size, reduced hepatic triglycerides, reduced hepatic expression of TNF-α and 
transforming growth factor (TGF)-β1 mRNA, and reduced expression of fibrogenesis 
markers [77]. Similarly, among NAFLD patients on atorvastatin, significant improvements 
were seen in NAFLD index scores, liver-to-spleen density ratio, and transaminases, with 
improvements attributed in part to a reduction in TNF-α [76]. We therefore hypothesize 
that statin therapy will similarly improve fatty infiltration of the muscle and that the 
reduction in muscle fat will be associated with improvement in measures of physical 
function and reduced inflammation. 
 
Measurement of Fatty Infiltration of the Muscle. While muscle biopsy remains the gold 
standard to measure muscle fatty infiltration, this invasive technique is associated with 

 
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increased risk of site infection, morbidity, and cost. Computed tomography (CT) can 
distinguish different tissue types by tissue density or attenuation; with a greater 
infiltration of adipose tissue indicated by lower attenuation (lower Hounsfield units [HU]). 
Skeletal muscle fat attenuation by CT scan is strongly correlated with muscle fiber lipid 
content obtained by biopsy [80] or estimated by MRI (r=0.97) [81] and has been 
associated with decreased physical function in the general population [69,70,82,83] . 
 
2.2 
Rationale 
 
With several studies suggesting benefits of statins on physical function and others 
showing potential harm or null effect, the evidence regarding the effects of statin therapy 
on physical function is mixed. As shown in Table 2.1-1, the effect of statin therapy may 
vary by statin potency. Effects of statin therapy may also vary by disease characteristics 
of the population (i.e., chronic inflammation) and the duration of follow-up. Pitavastatin 
has a potent effect on reduction in markers of systemic inflammation in HIV-uninfected 
populations [64,84] and a lower incidence of muscle complaints in comparison to other 
statins from multiple clinical trials [85-87]. We hypothesize that the effect of statins may 
also depend on the point in the physical function trajectory when therapy is introduced; 
frailty is the end result of multiple insults, and targeting inflammation in an already frail or 
nearly frail individual is unlikely to alter the frail state. Thus, a true state of equipoise 
exists, providing strong rationale for a careful examination of this endpoint in a relatively 
high-functioning, HIV-infected population within the setting of a randomized clinical trial. 
 
As CT images are already obtained in the Mechanistic Substudy of REPRIEVE 
(A5333s), we have the unique opportunity to determine whether statin therapy can 
decrease fatty infiltration of the muscle in participants without additional testing or 
radiation. 
 
The REPRIEVE (A5332) trial provides an unprecedented opportunity to investigate the 
impact of statins on physical function, in the setting of a large, randomized, double-blind 
intervention of HIV-infected adults, with available imaging, biomarkers, and established 
infrastructure. The proposed PREPARE study will fill a major gap in the understanding of 
statin’s effects on physical function among HIV-infected adults who, despite successful 
ART, continue to have heightened inflammation. No other randomized controlled trial 
including physical function outcomes has examined statin effects past 1 year, although 
statin therapy is typically prescribed for a decade or more. If statins reduce the risk of 
cardiovascular disease among otherwise healthy HIV-infected adults, as the REPRIEVE 
(A5332) study is designed to evaluate, then the risk-benefit of statin therapy becomes of 
particular importance and relevance to a large population. The potential benefits or 
harms of statin therapy on physical function over time should be thoroughly evaluated to 
best inform the decision to treat, particularly with the burden of an additional medication 
in an aging population. Results of this study will provide key insights into the longitudinal 
relationships between inflammation and physical function, and test a potential 
intervention to prevent physical function impairments and improve quality of life, results 
expected to extend beyond those aging with HIV to all older adults with inflammatory 
conditions. 
 

 
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Physical Function Impairments Are Frequent Among HIV-Infected Adults. Members of 
our team have identified impairments in physical function and frailty across several 
cohorts [88]. Among middle-aged HIV-infected men and women on effective ART in 
Colorado, a team led by Dr. Erlandson found that 50% had difficulty rising from a chair 
five times [89], and 20% met criteria for low muscle mass [90]. In the ALIVE Cohort, we 
found that more than one-third of participants had impairments on the Short Physical 
Performance Battery (SPPB), as defined by a score of ≤10 [4]. In both of these cohorts, 
the repeated (five times) chair rise was consistently the SPPB measure with the greatest 
impairment. Additionally, frailty, a clinical indicator of marked vulnerability to stressors, 
was present in between 8–15% of HIV-infected adults in a Washington University HIV 
Clinic [91], the Study to Understand the Natural History of HIV (SUN) [92], the ALIVE 
Cohort [5,93], and the Colorado cohort [88,89]. In an ongoing, multicenter longitudinal 
ACTG study of 1016 HIV-infected adults aged 40 and older, we have found that 6% of 
participants were frail and 38% were pre-frail [94]. Although impairments in physical 
function and frailty have been well described in cross-sectional observations, few studies 
have described changes over time. 
 
Declines in Physical Function Are More Common Among HIV-Infected Persons. Within 
the Multicenter AIDS Cohort Study (MACS), we found that decline in gait speed was on 
average 0.027 m/s per year greater in HIV-infected compared with HIV-uninfected men 
(p<0.001), and this difference intensified with advancing age (p=0.007); Figure 1, with a 
separation of the trajectories by HIV-serostatus occurring between ages 45 and 50. 
There was a 57% greater risk of developing clinically 
slow gait (<1.0 m/s) in HIV-infected compared with 
HIV-uninfected men (adjusted hazard ratio=1.57, 
95% confidence interval 1.28–1.92) [95]. Similar 
differences by HIV-serostatus were seen with 
longitudinal changes in grip strength in the MACS 
[96]. 
 
Physical Function Impairments and Frailty Are 
Associated with Poor Outcomes. In our previous 
studies, slow gait speed and chair rise time were 
associated with lower quality of life [94], impaired balance was associated with a 13-fold 
greater odds of recurrent falls [3], and poor self-reported physical function was 
associated with incident diabetes and insulin resistance [97]. HIV infection and impaired 
SPPB had a synergistic effect in the ALIVE Cohort, in which predicted mortality was 
significantly greater with the combination of both HIV and impaired physical function 
(HR= 6.03) compared to HIV infection (HR=2.78) or impaired SPPB score alone 
(HR=2.52) [4,5,93]. Frailty in HIV-infected adults was associated with a greater number 
of hospitalizations [89,91,96]. Similarly, the impact of both HIV infection and frailty had a 
synergistic effect on mortality (mortality OR= 2.6 with HIV infection; OR=3.3 with frailty; 
and OR=7.1 with both HIV and frailty) [5,93]. Through our research in multiple cohorts, 
we have consistently demonstrated that aging with HIV is associated with greater risk of 
physical function impairments and frailty and that these impairments are associated with 
morbidity and mortality. Our findings emphasize an urgent need to understand the 
pathophysiology and develop effective interventions. 
Figure 1. Usual Gait Speed and Age by HIV Status 

 
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Inflammation Is a Major Contributor to Functional Impairment in Persons Aging with or 
without HIV Infection. Higher IL-6 is closely linked to frailty, disability, and mortality 
among HIV-uninfected elderly [98-100]; similar relationships are seen with TNF-α 
[101,102] and neopterin [103], a measure of monocyte activation. In a case-control 
study, elevated inflammatory markers, particularly a combined inflammatory index of 
sTNFR-1 and IL-6, were associated with greater odds of low physical function and low 
appendicular muscle mass [7,104] . In the MACS Cohort, higher inflammation (sTNFR-2) 
among HIV-infected men was an independent predictor of lower subsequent grip 
strength [105], and HIV-positivity and the presence of a frailty-related phenotype was 
associated with increasing inflammation [106]. Similarly, in the ALIVE Cohort, the 
inflammatory index was predictive of both frailty and mortality [5]. Thus, our preliminary 
data provides evidence that the inflammatory milieu seen among HIV-infected persons 
plays a central role in impaired physical function during aging with HIV infection. 
 
HIV Infection Is an Independent Risk Factor for Skeletal Muscle Fat Infiltration. In 
addition to the association with impaired physical 
function, low attenuation of skeletal muscle (indicating 
increased fat infiltration) is associated with metabolic 
dysfunction, independent of visceral adiposity and body 
mass index (BMI) [107-110]. Furthermore, low 
attenuation of thigh musculature is a strong predictor of 
hip fracture, independent of BMI, percentage body fat, 
age, race, gender, and bone mineral density [108]. 
Among younger, HIV-infected persons with 
lipodystrophy syndrome, low attenuation of the psoas 
muscle was associated with insulin resistance, while 
BMI, subcutaneous fat, LBM, and ART were not [111]. 
In the MACS, we have found decreased attenuation of 
the mid-thigh muscle bundle in middle-aged HIV-infected men compared to uninfected 
men, even after multivariable adjustment including visceral and subcutaneous adipose 
tissue. The decrease in attenuation correlated with a decrease in grip strength. 
Furthermore, this measurement of muscle quality decreased with increasing age among 
the HIV-infected men, but did not decline significantly with age in the uninfected men 
(Figure 2). Particularly relevant to this study, HIV-infected men with the highest tertile of 
sTNFR-1 concentrations had the greatest fat infiltration (lowest CT attenuation), 
independent of CD4 cell count and HIV RNA [112]. The magnitude of this effect was 
equivalent to over 6 years of aging. Significant changes in both total body and leg lean 
mass were seen among SATURN-HIV participants with interferon-γ inducible protein 
(IP)-10 greater than the median level at baseline, but not among those with IP-10 levels 
below the median, suggesting that greater IP-10 changes with statin initiation may 
mediate improvements in LBM, particularly among participants with high inflammation 
[33]. These data suggest a strong association between skeletal muscle fat and 
heightened systemic inflammation, which may both contribute to the decline in physical 
function among persons aging with HIV. Moreover, fat attenuation is amenable to 
therapeutic intervention; intramuscular fat decreases with exercise, hormone 
replacement, or weight loss [113-118]. 
Figure 2.  Thigh Muscle Attenuation by 
Age in HIV+ and HIV- 

 
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Statins Decrease Markers of Inflammation and Immune Activation in HIV-Infected 
Populations. In a randomized, double-blinded trial of rosuvastatin versus placebo among 
147 HIV-infected adults with heightened inflammation or immune activation (SATURN-
HIV), rosuvastatin was associated with significant reductions in sCD14, IP-10, and T-cell 
activation markers [26]. Initiation of rosuvastatin, atorvastatin, or pravastatin therapy 
among HIV-infected patients on protease-inhibitor therapy resulted in significant 
reductions in high sensitivity C-reactive protein (hsCRP) and TNF-α [119]. Significantly 
greater reduction in hsCRP and TNF-α was seen among HIV-infected persons initiating 
ART compared to without rosuvastatin [120]. 
 
The Role of Statin Therapy in Physical Function and Frailty of HIV-Uninfected Older 
Adults Is Controversial. Data among HIV-infected adults are even further limited, with 
most evidence from early in the AIDS era, among those with HIV-associated wasting or 
lipoatrophy. Early evidence of a potential beneficial effect of statins on body composition 
was demonstrated in a placebo-controlled study of pravastatin among HIV-infected men 
with hypercholesterolemia, the majority of whom also had lipoatrophy (also associated 
with heightened inflammation); a significant increase in total, limb, and subcutaneous fat 
was seen in subjects randomized to pravastatin versus placebo, suggesting a beneficial 
effect on lipoatrophy [121]. A subsequent large, HIV cohort study led by Dr. Brown found 
a greater increase in hip circumference among statin users compared with non-statin 
users and a greater increase in thigh circumference in statin users also taking thymidine 
analogues [122]. Although imaging was not available for this analysis, the 
anthropomorphic measures are suggestive of beneficial gains in muscle. In SATURN-
HIV, participants randomized to rosuvastatin experienced gains in total LBM and leg 
lean mass compared with the placebo arm (absolute gain of 1.4 kg LBM in rosuvastatin 
arm versus 0.3 kg loss in placebo arm), without differences in total body fat or limb fat 
[8]. These findings suggest that the prior changes in anthropomorphic measures are due 
to increased LBM without gain in fat mass. 
 
Summary of Preliminary Data. Our data from multiple cohort studies have shown the high 
prevalence of physical function impairments among HIV-infected persons, a more 
pronounced age-related decline in functional performance measurements among HIV-
infected persons compared with HIV-uninfected controls beginning in middle-age, and a 
clear relationship between decreased physical function and clinical outcomes. We have 
also demonstrated strong and consistent associations between systemic inflammation 
and physical function measures in multiple studies, as well as more pronounced fatty 
infiltration of muscle among HIV-infected men versus HIV-uninfected men, suggesting that 
these would be potential pathways for interventions. Our data showing increased LBM 
gains among HIV-infected persons randomized to statin therapy also provide compelling 
rationale for the PREPARE study. 
 
Study Extension. The final, month 48, follow-up visit of A5361s occurred during 
the COVID-19 pandemic for many participants. Because a large number of final 
evaluations could not be conducted, study follow-up has been extended to month 
60. Data from these final evaluations are crucial to understanding the longer-term 
effects of statin therapy on physical function in REPRIEVE (A5332) participants. 

 
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We will also collect data on distinct changes in physical function that may have 
occurred between the month 36 and month 60 visits as a result of the COVID-19 
pandemic, either directly through infection with the virus, or indirectly due to 
changes in physical activity, weight gain, social isolation, or stress. 
 
3.0 
SUBSTUDY DESIGN 
 
A5361s is an optional substudy of REPRIEVE (A5332) and the Mechanistic Substudy of 
REPRIEVE (A5333s). Approximately 600 HIV-infected males and females who are 
enrolled in REPRIEVE (A5332) with or without coenrollment into A5333s will co-
enroll in A5361s. 
 
Participants will be followed for up to 60 months from the date of enrollment into 
REPRIEVE (A5332) for the assessment of objective and self-reported measures of 
physical function. Based on their date of enrollment into REPRIEVE (A5332), participant 
follow-up on A5361s will be between 36 and 60 months. 
 
Additional outcome measures and covariates to address the study objectives will be 
obtained from assessments performed as part of REPRIEVE (A5332) and A5333s (see 
section 10.0 for more detail). 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Ambulatory participants co-enrolled in both REPRIEVE (A5332) and the 
Mechanistic Substudy (A5333s). 
 
OR 
 
Ambulatory participants that are newly enrolling into REPRIEVE (A5332) at 
A5333s ACTG sites. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Inability to ambulate independently (use of a cane or a walker is permitted) or 
rise from a chair without assistance. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, sites must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 

 
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Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all required documents have been received. 
Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved 
by the DAIDS PRO, and sites will receive an Initial Registration Notification when 
the DAIDS PRO receives a complete registration packet. Receipt of an Initial 
Registration Notification indicates successful completion of the protocol 
registration process. Sites will not receive any additional notifications from the 
DAIDS PRO for the initial protocol registration. A copy of the Initial Registration 
Notification should be retained in their regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICFs 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. Sites should retain a copy of the Amendment 
Registration Notification in their regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form. 
 
For participants from whom a signed informed consent has been obtained, an 
ACTG Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System. 
 
4.3.2 Protocol Activation 
 
Prior to screening, sites must complete the Protocol Activation Checklist found on 
the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment. 
 
4.3.3 Participant Registration 
 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures. For participants from whom 
informed consent has been obtained, but who are deemed ineligible or who do 
not enroll into the protocol, an ACTG Screening Failure Results form must be 
completed and keyed into the database. 
 

 
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4.4 
Co-enrollment Guidelines  
 
Co-enrollment is allowed per REPRIEVE (A5332) guidelines. 
 
5.0 
STUDY TREATMENT 
 
5.1 
Regimens, Administration, and Duration 
 
No drugs will be provided by this study. Pitavastatin/placebo will be provided per 
REPRIEVE (A5332) section 5.0. 
 
Participants may enroll and continue participation in A5361s regardless of their status on 
REPRIEVE (A5332) study treatment. 
 
5.2 
Prohibited Medications 
 
Per REPRIEVE (A5332). 
 
 

 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations 
 
All study visits for A5361s assessments should be timed to coincide with regularly scheduled REPRIEVE (A5332) or A5333s 
visits. The A5361s post-entry visits are scheduled in months after REPRIEVE (A5332) entry. 
 
Evaluation 
Entry 
(± 14 
days)1 
Post-Entry Evaluations (months) 
(Preferably completed at the REPRIEVE (A5332) or A5333s visit, 
however ± 14 days of visit is acceptable)2 
0 
Month 12 Month 24 Month 36 Month 48 
Month 60 
(see 6.2.1) 
Discontinuation 
Modified Short Physical 
Performance Battery and 
Frailty Assessments  
X 
X 
X 
X 
X 
X 
X 
Rapid Eating and Activity 
Assessment for Patients 
Survey – Questions #26 
and #27 only 
 
X3 
X4 
X 
X 
X 
X 
Duke Activity Status 
Index5 
 
 
X4 
 
 
 
 
1 Entry for participants newly enrolling into A5332 and A5333s or A5332 only, OR any subsequent follow-up visits for 
co-enrolled (A5332/A5333s) participants, up to month 24. 
2 Participants co-enrolled in A5332 and A5333s can enroll at any visit, up to month 24. The second visit will then be 
completed at the next A5332 or A5333s annual visit. Depending on the time of enrollment, participants will be 
followed from between 36 to approximately 60 months. 
3 In the event that the A5361s entry visit coincides with the month 12 visit for A5332 or A5333s, REAP questions #26 
and #27 will be completed as part of a combined A5361s entry and month 12 visit. 
4 For newly enrolling A5332 participants at A5333s ACTG sites, REAP questions #26 and #27 at Months 12 and 24 and 
DASI at Month 24 will be captured as part of A5361s for participants not co-enrolled in A5333s. 
5 At month 60, the DASI evaluation from the REPRIEVE (A5332) month 96 or study termination visit will be used. 
 

 
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6.2 
Timing of Evaluations 
 
6.2.1 Entry and Post-Entry Evaluations 
 
For participants newly enrolling into REPRIEVE (A5332) and A5333s: 
Enrollment into A5361s should preferably occur on the same day as 
enrollment into A5332 or A5333s (within 14 days of the visit is acceptable), and 
prior to initiation of randomized treatment in REPRIEVE (A5332). 
 
For participants newly enrolling into REPRIEVE (A5332) only: Enrollment 
into A5361s should occur on the same day as enrollment into A5332 when 
possible (but must occur within 14 days of enrollment into A5332) and 
must occur prior to initiation of randomized treatment in REPRIEVE 
(A5332). 
 
For participants already enrolled into both REPRIEVE (A5332) and A5333s: The 
A5361s entry visit can occur at any REPRIEVE (A5332) or A5333s visit (or ± 14 
days of the visit), up to the month 24 visit. Subsequent visits will follow the 
remaining schedule in section 6.1. 
 
For all participants: All post-entry visits should be scheduled to coincide with the 
q12 month regularly scheduled REPRIEVE (A5332) visits but within 14 days of 
visit is acceptable. Post-entry visits should be scheduled from the REPRIEVE 
(A5332) entry visit. 
 
Enrollment completed in 2018 under PREPARE (A5361s) Version 1.0. In 
Version 2.0, an additional visit is added to occur at month 60. If the 
participant is past their Month 60 visit in the REPRIEVE (A5332) study, the 
PREPARE (A5361s) Month 60 evaluations can be performed at the next 
REPRIEVE (A5332) in-person visit. Refer to the A5361s Manual of 
Procedures (MOPS) for special instructions for participants who are 
already off-study. 
 
ALTERNATE COMPLETION OF POST-ENTRY EVALUATIONS 
 
 
If a participant can safely be seen for an in-person REPRIEVE 
(A5332) study visit, the A5361s visit that is due at the same time 
should also be completed. 
 
If local guidelines or restrictions prevent the site from completing 
any of the assessments (or components of the mSPPB or frailty 
assessments) required at a visit, the reason for the missing 
assessment should be documented in the source documents and on 
the corresponding CRF. Complete evaluations as possible, even if 
full mSPPB and frailty assessments cannot be performed. 
 

 
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 
If a participant has an in-person REPRIEVE (A5332) study visit but 
A5361s assessments could not be completed due to local guidelines 
or restrictions, the assessments should be completed at the next 
REPRIEVE (A5332) in-person visit if the restrictions have been 
canceled by then. 
 
 
If an in-person REPRIEVE (A5332) study visit that coincides with an 
A5361s visit is delayed or missed, the A5361s visit should be 
completed whenever the participant is next seen for an in-person 
REPRIEVE (A5332) visit. 
 
6.2.2 Discontinuation Evaluations 
 
Premature Discontinuation from REPRIEVE Study Treatment 
No additional A5361s assessments are required at the time of premature 
discontinuation from REPRIEVE (A5332) study treatment. 
 
Participants who prematurely discontinue from REPRIEVE (A5332) study 
treatment will continue to be followed as indicated in section 6.1. 
 
Premature Discontinuation from REPRIEVE (A5332) Study 
Participants who prematurely discontinue from REPRIEVE (A5332) will be 
discontinued from A5361s and have an A5361s discontinuation visit performed 
as indicated in section 6.1. 
 
Premature Discontinuation from Study A5361s 
Participants who discontinue from A5361s will have an A5361s discontinuation 
visit performed as indicated in section 6.1. 
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/score-source-documentation-
requirements.pdf. 
 
If a participant is able to ambulate independently at entry but later is unable to complete 
the assessments, the participant should remain on study, and the reason for the lack of 
assessment should be recorded. 
 
The protocol team and/or study monitoring entity (e.g., SMC) may determine that 
additional source data associated with procedures or evaluations performed per 
protocol should be entered into eCRFs so that the data can be used for analysis 
or to otherwise assist with interpretation of study findings. In such cases, sites 
will be officially instructed to enter the additional data into eCRFs from available 
source documentation.  

 
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6.3.1 modified Short Performance Battery (mSPPB) 
 
6.3.1.1 Repeat Chair Stand 
 
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. Participants rise from a standard height chair that does not have 
wheels or arms 10 times. Split times are captured after completion of 
both five rises and 10 rises (see MOPS for further details). 
 
6.3.1.2 Grip Strength 
 
Grip strength is an easily performed, inexpensive, reproducible 
assessment that is strongly associated with bone mineral density 
(BMD), fall risk, and fracture, and it is well correlated with more direct 
measures of lower-extremity strength. Three measurements with the 
dominant hand will be taken using a Jamar Dynamometer. (See MOPS 
for further details.) 
 
6.3.1.3 Standing Balance Test 
 
Participants are asked to stand in three different positions with 
progressive narrowing of the base of support, namely the side-by-side 
stand, the semi-tandem stand (i.e., heel of one foot touching the great 
toe of the other foot), the full tandem stand (i.e., heel-toe position), and 
the single-leg stand (i.e., opposite foot in hip-flexed, knee flexed 
position with toes 2 inches or more from the floor). The duration for 
which the participant can hold the stance without taking a step or 
grabbing for support is recorded. (See MOPS for further details.) 
 
6.3.1.4 Gait Speed 
 
Walking is a complex task requiring balance, mobility, strength, and 
coordination. In many functional performance batteries, including the 
mSPPB, timed walking is an integral component. It is an excellent 
predictor of lower extremity function and is well correlated with falls and 
fractures resulting from falls; it also is a strong predictor of disability and 
mortality. Two measurements of usual gait speed on a 4-meter course 
will be obtained. (See MOPS for further details.) 
 
6.3.2 Frailty Self-Reported Components 
 
These three questions inquire about an unintentional change in weight, whether 
the participant’s health leads to limitations in vigorous activities, and whether the 
participant feels that “everything that I do is an effort.” 

 
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6.3.3   REAP Questions #26 and #27 
 
These questions will be administered at 12, 36, 48, and 60 months, and at 
discontinuation as a measure of self-reported physical activity; these 
assessments are obtained at entry in REPRIEVE (A5332) and at month 24 in 
A5333s. In the event that the A5361s entry visit coincides with the month 12 
visit for A5332 or A5333s, REAP questions #26 and #27 will be completed as 
part of a combined A5361s entry and A5332/A5333s month 12 visit. 
 
For REPRIEVE (A5332) participants not enrolled in A5333s, REAP 
questions #26 and #27 at month 24 will also be completed as part of 
A5361s. 
 
The questions are as follows: In an average week, how often do you: 
(usually/often, sometimes, rarely/never, does not apply): 
 
#26 Do less than 30 total minutes of physical activity 3 days a week or more? 
(Examples: walking briskly, gardening, golf, jogging, swimming, biking, 
dancing, etc.) 
 
#27 Watch more than 2 hours of television or videos a day? 
 
6.3.4  DASI 
 
In the event that enrollment is expanded to eligible A5332 participants at US 
ACTG sites, functional capacity (Duke Activity Status Index [DASI]) questionnaire 
will be completed at month 24 for participants not enrolled in A5333s. 
 
For the month 60 evaluation, the DASI evaluation from the REPRIEVE 
(A5332) month 96 or study termination visit will be used. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
 
7.1 
Definition of Adverse Events 
 
An adverse event 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 Reporting Requirements in the Clinical Database 
 
A5361s has no adverse event reporting requirements. 
 

 
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7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
A5361s reporting of EAEs to DAIDS is not required because A5361s is an 
observational/non-interventional study (i.e., there are minimal interventional risks from 
the study for participants). 
 
7.4 
Study Monitoring 
 
The Protocol Core Team will monitor the conduct and continued feasibility of the study 
via quarterly summaries of enrollment, study retention, co-enrollment, and endpoint 
evaluability. On an annual basis the Study team will prepare a Protocol Team Review 
Summary Letter for distribution to site investigators in accordance with the ACTG SOP 
for Study Data and Safety Monitoring. 
 
The study status of PREPARE is monitored by the REPRIEVE DSMB as part of the 
REPRIEVE trial study monitoring plan. 
 
Detailed plans for data monitoring will be outlined in a Study Monitoring Plan developed 
by the Statistical and Data Management Center (SDMC) prior to enrollment of the first 
participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
Management of HIV antiretroviral therapies and complications of disease should be 
performed according to the REPRIEVE (A5332) protocol or routine clinical care, where 
applicable. 
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
 
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. 
 
Premature discontinuation from REPRIEVE (A5332). 
 
At the discretion of the study monitor, site investigator, IRB, Office of Human 
Research Protections (OHRP), National Institute on Aging (NIA), NIAID, NHLBI, or 
other government agencies as part of their duties to ensure that research 
participants are protected. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
A5361s will determine the effects of pitavastatin on physical function and evaluate 
mechanistic pathways through which pitavastatin affects physical function. 
 

 
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The study will enroll participants from REPRIEVE (A5332) and its mechanistic substudy 
(A5333s) and follow them for up to 60 months after entry to REPRIEVE (A5332). 
Treatment groups (placebo versus pitavastatin) will be defined according to 
randomization in REPRIEVE (A5332). The primary analyses for all treatment group 
comparisons will be intent to treat, while supportive secondary analyses as well as 
analyses examining mechanistic pathways will be as-treated. 
 
While measures of physical function (including both objective and long-term measures of 
self-assessment) will be assessed as part of A5361s, many of the outcome measures of 
interest will be available through data collected in REPRIEVE (A5332) and A5333s, as 
outlined in the Table 10.1-1. If the target recruitment numbers cannot be achieved 
through A5333s enrollment, the study will open to all participants in REPRIEVE (A5332) 
enrolled at US ACTG sites. For these participants, only the outcomes measured as part 
of A5361s or REPRIEVE (A5332) will be available for analysis. 
 
Table 10.1-1: Data Sources for A5361s Outcome Measures 
Outcome Measure 
REPRIEVE 
(A5332) Entry 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Physical function 
battery 
A5361s1 
A5361s2 
A5361s 
A5361s 
A5361s 
A5361s 
Frailty components 
A5361s1 
A5361s2 
A5361s 
A5361s 
A5361s 
A5361s 
Duke Activity Status 
Index (DASI) 
A53323 
 
A5333s4 
 
 
A53326 
Self-reported physical 
activity and sedentary 
time (REAP)5 
A53323 
A5361s2 
A5333s4 
A5361s 
A5361s 
A5361s 
Myalgia symptom 
assessment 
A53323 
A53323 
A5332 
A5332 
A5332 
A5332 
Samples for 
inflammatory markers  
A53323 
A53323 
 
 
 
 
Fasting lipids and 
insulin sensitivity 
A5332/ 
A5333s3 
 
A5332/ 
A5333s 
 
 
A5332 
CT scan for fatty 
infiltration of the 
skeletal trunk muscles 
A5333s3 
 
A5333s 
 
 
 
1 Will be available only to participants who enroll concurrently into REPRIEVE (A5332) and 
A5361s.  
2 Will be available only to participants who enroll into A5361s concurrently or within 12 months 
of REPRIEVE (A5332) entry. 
3 For participants who enroll into A5361s after REPRIEVE (A5332) entry, the data and samples 
collected in REPRIEVE and A5333s prior to A5361s entry will be used. 
4 In the event that enrollment is expanded to all A5332 participants, will be captured as part of 
A5361s for participants not enrolled in A5333s. 
5 Questions 26 and 27 only. 
6 The DASI evaluation from the REPRIEVE (A5332) month 96 or study termination visit 
will be used. 

 
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10.2 
Outcome Measures 
 
10.2.1 Primary Outcome Measures 
 
10.2.1.1 
Chair rise rate measured annually over 60 months 
 
This primary outcome for the primary physical function objective is a 
simple transformation of the measured outcome of time to perform 10 
chair stands. It is chosen to provide a continuous outcome for 
participants regardless of their ability to perform 10 chair stands. 
 
It is a well-established measure of lower extremity strength and our 
previous studies in HIV-infected populations have shown that, among 
components of the SPPB, this measure is the most likely to show 
deficits [8,100]. In addition, in middle-age adults from the general 
population, chair rise rate is a strong independent predictor of 
mortality [123]. 
 
10.2.1.2 
Inflammatory Index Score (IIS) quantified at 12 months 
 
The IL-6 and TNF-α pathways are both hypothesized to lead to 
sarcopenia, muscle weakness, and decreased physical function. The 
IIS was found to be a better predictor than IL-6 or measures of TNF-α 
activity alone in a geriatric population [100] and is predictive of 
mortality in an HIV cohort [5]. This validated instrument will be used to 
address the effect of pitavastatin on systemic inflammation composed 
of serum IL-6 and sTNFR-1. The score is calculated with the following 
formula: 
 
1/3 log [IL-6] + 2/3 log [sTNFR-1] 
 
10.2.1.3 
Paraspinal muscle density measured in Hounsfield units (HU) at 
REPRIEVE (A5332) entry and month 24. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 
Secondary physical function outcome measures assessed annually 
for 60 months. 
 
Raw scores for each of the additional components of the SPPB (grip 
strength, gait speed, ability to hold the one leg stand for 30 seconds) 
as well as the composite SPPB score (composite scoring of chair 
stand, balance, and gait) measured annually to month 60. 
 
Physical function deficits defined as a composite SPPB score ≤10 
assessed annually to month 60 [124,125]. 
 

 
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Frailty (classified as non-frail, pre-frail, and frail) as well as the 
frequency of its components (exhaustion, weight loss, low activity, 
slow walk, grip strength) and the number of frailty components 
present [126]. 
 
Self-reported physical activity via two questions measured on a three-
point ordinal scale on the REAP assessment. 
 
10.2.2.2 
Secondary outcome measures for the mechanistic objective quantified 
at REPRIEVE (A5332) entry and 12 months 
 
Serum concentrations of each individual biomarker of the IIS (IL-6, 
sTNFR-1) as well as other biomarkers implicated in the pathogenesis 
of physical function impairment (these may include markers such as 
sTNFR-2, IP-10, IGF-1, TGF- β1) or those that may mediate the 
effects of statin treatment on systemic inflammation (CMV IgG). 
 
The specific list of biomarkers of interest may be modified closer to 
the time of analysis based on the identification of additional 
biomarkers or pathways involved in this process. 
 
10.2.2.3 
Secondary outcome measures for the mechanistic objectives related 
to fatty infiltration of the skeletal trunk muscles assessed at 
REPRIEVE (A5332) entry and 24 months: 
 
Shoulder and upper back muscle density measured in HU. 
 
Paraspinal and trunk muscle volume (area). 
 
10.3 
Randomization/Registration 
 
Participants will be enrolled into A5361s via the ACTG enrollment system. See section 
4.0 for specific information on the timing of A5361s and REPRIEVE (A5332) enrollment. 
 
10.4 
Sample Size and Accrual 
 
600 participants will be enrolled over a period of 2 years. Participants will be followed 
until the time of their 5-year assessment on REPRIEVE (A5332) (up to 60 months 
depending on the time of enrollment). 
 
10.4.1 Sample Size Justification for Outcome Measures of Physical Function 
 
Assuming a modest exchangeable correlation between repeated measurements 
over time (rho=0.6), this sample size will provide 85% power to detect a 0.29 
rise/minute/year difference between the pitavastatin and placebo treatment 
groups and 80% power to detect a more modest difference of 0.27 
rise/minute/year difference. These power calculations are based on sample-size 

 
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formulae for testing a between group difference in slopes in a repeated measures 
design as provided by Diggle, Liang, and Zeger [123]. 
 
Preliminary data from HIV-uninfected adults in the Baltimore Longitudinal Study 
of Aging (BLSA) suggest an annual age-associated decline of 0.01 m/s in gait 
speed after age 60 [127]. Among HIV-infected men in the Multicenter AIDS 
Cohort Study (MACS) cohort, gait speed decline among HIV-uninfected men 
aged 40 and older was also 0.01 m/s per year [95]. In contrast, gait speed among 
the HIV-infected men from the MACS was 0.025 m/s per year (2.5 times faster 
decline in HIV-infected compared to HIV-uninfected). A similar annual age-
associated decline of 0.29 rises/minute in chair rise time begins at about age 40 
[Schrack, et al., unpublished data, 2015]. Based on these differences with gait 
speed trajectory and similar trajectories in grip strength, we anticipate a two-fold 
higher rate of decline in chair rise among HIV-infected participants in PREPARE 
compared to the BLSA, and thus estimate that the annual age-associated decline 
in chair rise rate in this HIV-infected population will be about 0.58 rises/minute. 
The target effect size of 0.29 rise/minute/year difference between the pitavastatin 
and placebo treatment groups thus reflects a normalization of this age-
associated decline. 
 
If the primary results of REPRIEVE (A5332) show a benefit of pitavastatin and 
statins are prescribed among middle-aged HIV-positive adults for primary 
prevention of cardiovascular disease, long-term statin therapy of 20–30 years 
would be expected to prevent a decline of 6–9 chair rises/minute into older age. 
This preservation of function is of major clinical relevance. In the Colorado 
Cohort, a difference of 5.7 rises/minute was found between non-fallers and single 
fallers, and 1.8 rises/minute between single fallers and repeat fallers [Erlandson, 
unpublished data, 2014]. Further, in a large longitudinal cohort of adults followed 
between ages 53 and 66 in England, a difference between each quintile of the 
repeat chair stand pace was between 3–5 rises/minute. A worsening from the 
second slowest to the slowest quintile in this cohort was associated with a nearly 
two-fold increase in mortality (from HR of 1.44 to 2.13) over 13 years of follow-up 
[128]. 
 
10.4.2 Sample Size Justification for Mechanistic Outcome Measures 
 
With a sample size of 300 participants in each treatment group and 
conservatively assuming 10% of participants will be inevaluable for either 
REPRIEVE (A5332) entry or follow-up outcomes; we have 90% power to detect a 
0.28 SD difference between the pitavastatin and placebo treatment groups for 
the systemic markers of inflammation and immune activation. For IIS, the 
magnitude of this change has been shown to be associated with a 10% increase 
in 10-year mortality risk [129]. 
 
For fat attenuation, with an estimated 20% drop-out or non-evaluable scans and 
standard deviation of 6 [130], we will have 95% power to detect a difference in 
paraspinal muscle density of 1.8 HU between the two groups. A difference of 1–3 

 
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HU is considered clinically significant and is the effect observed in exercise 
interventions [114,116-118] . 
 
10.5 
Data and Safety Monitoring 
 
A5361s is a prospective, observational study of participants enrolled into REPRIEVE 
(A5332) with or without co-enrollment into A5333s in which no treatment or 
intervention is provided. The statisticians will prepare quarterly administrative reports. 
These reports will include participant REPRIEVE (A5332) and A5361s entry information 
and will also note protocol execution issues such as participant accrual, participant 
retention, co-enrollment, and endpoint evaluability. 
 
Details of the aforementioned reports will be described in a Study Progress, Data, and 
Safety Monitoring Plan prepared by SDAC prior to enrollment of the first participant. 
 
10.5.1 Interim Monitoring Guidelines 
 
In accordance with the ACTG SOP for Study Data and Safety Monitoring, the 
Protocol Team will review study enrollment, conduct and feasibility. Benchmarks 
for data are as follows: 
 
Enrollment of 600 study participants will be completed over a period of 2 
years from enrollment of the first study participant. 
 
90% of expected data are available across time points. 
 
10.6 
Analyses 
 
The following sections provide a brief overview of the general analytic approaches 
for the A5361s primary analysis. A detailed plan that fully delineates all planned 
statistical analyses, and includes secondary and exploratory objectives, will be in 
a separate Statistical Analysis Plan (SAP). 
 
10.6.1 Effects of Pitavastatin on Physical Function 
 
Descriptive statistics (median, Q1, Q3, P10, P90, min, max) and graphical 
presentations of each component of the SPPB, its composite score as well as the 
prevalence of physical function deficits (SPPB ≤10) will be examined at 
REPRIEVE (A5332) entry and over time. A5361s entry evaluations performed 
after the start of REPRIEVE (A5332) study treatment will be excluded from these 
summaries. 
 
Analyses of chair rise rate will use linear mixed effects models with time modeled 
on a continuous scale, where REPRIEVE (A5332) entry is time 0. 
 
The primary parameter of interest will be the difference in the rate of change 
(slope) between placebo and pitavastatin over time (i.e., the interaction between 
treatment and time). The primary analysis will include available measured 
outcomes (including those obtained at REPRIEVE [A5332] entry) in the outcome 

 
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vector and will omit the treatment group main effect (intercept) from the model. 
This approach allows for variable evaluation time and inclusion of data for all 
participants regardless of their time of entry into A5361s. It takes advantage of 
the fact that randomized group allocation in REPRIEVE (A5332) means that 
there is no underlying difference in physical function between treatment groups at 
REPRIEVE (A5332) entry and will be the most powerful [131]. Further, the 
analysis will be robust in the event of uneven participant drop-out related to the 
rate of decline in physical impairment. In the event of non-linear change in 
outcome over time, we will first assess alternative transformations of the 
outcomes or time axis. If such transformations are not feasible, modeling will be 
performed using an arbitrary time effect (i.e., time modeled as a factor on four 
levels). In this case, the treatment effect of interest for the primary treatment 
group comparison will be the average difference across post-baseline time 
points; an interaction of treatment and time will also be assessed and secondary 
comparisons by year will also presented. It is noted that the power of the study to 
detect a comparable effect size is reduced under this alternative modelling 
framework. 
 
These primary analyses will be extended to evaluate subgroup effects of 
treatment, namely different treatment effects by race (white vs non-white), sex, 
baseline CD4 cell count (<350 cell/mm vs. ≥350 cells/mm), ART duration 
(categorized as <10 or ≥10 years), physical function deficits at REPRIEVE 
(A5332) entry (SPPB ≤10 vs. >10), and systemic inflammation (by tertile of IIS) at 
REPRIEVE (A5332) entry. Sensitivity analyses excluding participants who 
enrolled into A5361s after REPRIEVE (A5332) entry will also be performed. 
 
Given the expected discretized distribution of the remaining SPPB outcomes 
(including the overall composite score), longitudinal analyses for these measures 
as well as the self-reported physical function outcomes from the REAP 
assessment will use the methods of Wei and Johnson to provide an overall 
assessment of treatment group differences between the groups over time. 
 
The prevalence of the frailty phenotypes and their components over time and by 
treatment group will be described. Treatment group differences in the prevalence 
of the frailty phenotype (non-frail, pre-frail, frail) will be assessed via marginal 
modeling with a cumulative logit using generalized estimating equations. 
 
10.6.2 Evaluation of the mechanistic pathways through which pitavastatin affects 
physical function 
 
Distributions of the secondary biomarker outcomes as well as outcomes of fatty 
muscle infiltration will be described and plotted over time. Pointwise treatment 
group comparisons will use linear regression adjusted for baseline to provide 
estimation of the difference in the baseline-adjusted level of the outcomes at 
each time point. Outcome transformations will be applied as appropriate. 
Treatment group comparisons of markers of inflammation and immune activation 
will be limited to those not described in A5333s. Analyses of fatty infiltration of 

 
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muscle will also assess the association of these changes with changes in lipid 
components and HOMA-IR. 
 
The relationship between markers of inflammation/immune activation, fatty 
infiltration, and physical function will be assessed via longitudinal modeling of the 
chair rise rate and expanding each of the appropriate models used to assess 
treatment group difference including pre- and post-treatment biomarker and fatty 
infiltration outcomes. The analyses will also examine associations with the 
following measured covariates/risk factors: 
 
 
Demographic and behavioral variables (age, race, sex, menopausal 
status, BMI, smoking, alcohol use, physical activity by REAP) 
 
Co-morbid conditions (HBV/HCV, hypertension, diabetes mellitus, chronic 
kidney disease) 
 
Use of angiotensin-converting-enzyme inhibitor/angiotensin II receptor 
blocker (ACE-I/ARB) therapy 
 
HIV-related variables (CD4 cell count [nadir and current]), HIV RNA, 
antiretroviral exposure (cumulative and current exposure to ART) 
 
Muscle symptoms (via the myalgia symptom assessment collected 
through REPRIEVE [A5332]) 
 
Concomitant medications, specifically, ACE-I/ARB therapy and use of 
hormonal therapy 
 
Given the assumed temporal associations under study, analyses, including on-
treatment measures of biomarkers and fatty muscle infiltration, will only include 
dependent outcomes assessed from month 24 onward. These analyses will be 
conducted with and without adjustment for treatment assignment to allow 
assessment of the degree to which the effects of treatment might be mediated 
through treatment-associated changes. While further, more formal causal 
mediation analyses are planned, given the expected statistical developments in 
the relevant statistical methodology over the next 5 years, these analysis plans 
will be developed closer to the time of analysis. 
 
11.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 
12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Records to Be Kept 
 
Electronic case report form screens (eCRFs) will be made available to sites for data 
entry. Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon registration. 
 

 
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12.2 
Role of Data Management 
 
12.2.1 Instructions for entering study data on eCRFs will be provided by the ACTG 
DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.3 
Clinical Site Monitoring and Record Availability 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may 
include remote source document verification using methods specified for this 
purpose by NIAID. Remote monitoring visits may be performed in place of, or in 
addition to, onsite visits to ensure the safety of study participants and data 
integrity [132]. The site will make available study documents for site monitors to 
review utilizing a secure platform that is HIPAA and 21 CFR Part 11 compliant. 
Potential platform options include: Veeva SiteVault, site-controlled SharePoint or 
cloud-based portal, direct access to Electronic Medical Record (EMR), and 
Medidata Rave Imaging Solutions. Other secure platforms that are 21 CFR Part 11 
compliant may be utilized, as allowed by the DAIDS Office of Clinical Site 
Oversight (OCSO). 
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study. A signed consent form will be obtained from the participant (or 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, NIA, NIAID, 
NHLBI, OHRP, and other US, local, and international regulatory entities as part of 
their duties. 
 

 
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13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, NIA, NIAID, NHLBI, 
OHRP, or other government agencies as part of their duties to ensure that research 
participants are protected. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this study will be governed by ACTG and REPRIEVE 
policies. 
 
15.0 
BIOHAZARD CONTAINMENT 
 
Not Applicable 

 
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16.0 
REFERENCES 
 
1. 
High KP, Brennan-Ing M, Clifford DB, et al. HIV and aging: state of knowledge and 
areas of critical need for research. A report to the NIH Office of AIDS Research by the 
HIV and Aging Working Group. J Acquir Immune Def Syndr 2012;60 Suppl 1:S1-18. 
2. 
Desquilbet L, Jacobson LP, Fried LP, et al. A frailty-related phenotype before HAART 
initiation as an independent risk factor for AIDS or death after HAART among HIV-
infected men. J Gerontol A Biol Sci Med Sci 2011;66:1030-8. 
3. 
Erlandson KM, Allshouse AA, Jankowski CM, et al. Risk factors for falls in HIV-
infected persons. Journal of acquired immune deficiency syndromes 2012;61:484-9. 
4. 
Greene M, Covinsky K, Astemborski J, et al. The relationship of physical performance 
with HIV disease and mortality. AIDS 2014;28:2711-9. 
5. 
Piggott DA, Varadhan R, Mehta SH, et al. Frailty, Inflammation, and Mortality Among 
Persons Aging With HIV Infection and Injection Drug Use. J Gerontol A Biol Sci Med 
Sci 2015;70:1542-7. 
6. 
Newman AB, Gottdiener JS, McBurnie MA, et al. Associations of subclinical 
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130. Anderson DE, D'Agostino JM, Bruno AG, Demissie S, Kiel DP, Bouxsein ML. 
Variations of CT-based trunk muscle attenuation by age, sex, and specific muscle. J 
Gerontol A Biol Sci Med Sci 2013;68:317-23. 
131. Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. 2nd ed. Hoboken, 
New Jersey: John Wiley & Sons, Inc, 2011. 
132. 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 January 27, 2021. Accessed 
at: https://www.fda.gov/media/136238/download

 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
For Protocol A5361s: Pitavastatin to REduce Physical Function Impairment and FRailty in HIV 
(PREPARE) 
 
SHORT TITLE FOR THE STUDY: PREPARE Substudy of REPRIEVE (A5332) 
Final Version 2.0, Dated 06 July 2021 
 
SUMMARY 
 
PURPOSE: 
The purpose of this study is to investigate the effect of pitavastatin in slowing frailty 
(weakness) or disability in people who are aging with HIV. Pitavastatin belongs to a 
group of drugs called statins. Studies have shown that statins may have other benefits, 
one of which may be helping slow the development of frailty or disability that occur with 
aging. 
 
NUMBER OF PARTICIPANTS: 
About 600 people who also participate in the REPRIEVE Study (A5332) and REPRIEVE 
Mechanistic Substudy (A5333s) or the REPRIEVE Study (A5332) only. 
 
STUDY TREATMENT: 
There is no treatment provided in this study. 
 
LENGTH OF STUDY: 
Initially, you were going to be in this study for up to 48 months, depending on when you 
joined. Due to the COVID-19 pandemic, this study has been extended to up to 60 months, 
which will result in an additional visit about one year after your last on this study.   
 
REQUIRED ACTIVITIES: 
You will have physical function tests to measure your muscle strength and function: 
 
Repeated chair rises 
 
Hand grip strength test 
 
Standing balance test 
 
4-Meter (12 foot) walk 
 
RISKS: 
It is possible that you may trip, slip, or fall while doing the physical function tests. 
 
BENEFITS: 
No direct benefits should be expected from participating in this study. 
 
OTHER CHOICES: 
You have the option of not participating in this substudy and still participating in the 
REPRIEVE Study (A5332) and REPRIEVE Mechanistic Substudy (A5333s). 
 

 
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INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with human 
immunodeficiency virus (HIV), the virus that causes AIDS, and are currently enrolled in the 
REPRIEVE (A5332) with or without co-enrollment into A5333s studies at an ACTG site. The 
PREPARE A5361s substudy is sponsored by the National Institutes of Health (NIH). The doctor 
in charge of this substudy at this site is (insert name of Principal Investigator). Before you 
decide if you want to be a part of this substudy, we want you to know about the substudy. 
 
This is a consent form. It gives you information about this substudy. The study staff will talk with 
you about this information. You are free to ask questions about this substudy at any time. If you 
agree to take part in this substudy, you will be asked to sign this consent form. You will get a 
copy to keep. 
 
 
WHY IS THIS SUBSTUDY BEING DONE? 
 
Aging with HIV may be related to an earlier development of frailty (weakness) or disability, 
including difficulties in tests of strength or walking speed. Few treatments have been shown to 
prevent or slow these impairments in people with or without HIV. Some studies have suggested 
that the class of drugs called statins (for example, pitavastatin) might be helpful in slowing frailty 
or disability. This might happen by decreasing fat within the muscle or by decreasing 
inflammation markers (substances in the blood that determine how your body reacts to infection 
or irritation) in the blood. Other studies have shown that statins increase the risk of muscle 
aches and pains. This substudy is being done to determine the impact of the drug pitavastatin 
on muscle. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS SUBSTUDY? 
 
If you would like to take part in this substudy, you will be asked to sign this consent form. 
 
At the study entry visit and at yearly visits coinciding with your REPRIEVE (A5332) study visits, 
we will measure your muscle strength and muscle function through several tests. These tests 
include repeated chair rises, hand grip strength test, standing balance test, and a 4-meter (12 
foot) walk and should take no more than 20 minutes to complete. You will also be asked some 
questions about your physical activity at the month 12, 24, 36, 48, and 60 visits. You will be 
asked in an average week, how often do you: (usually/often, sometimes, rarely/never, does not 
apply): 
Do less than 30 total minutes of physical activity 3 days a week or more? 
Watch more than 2 hours of television or videos a day? 
 
Your answers to questions about your ability to perform everyday tasks that you will be 
asked at your last REPRIEVE (A5332) study visit will be used as part of your month 60 
evaluation in this substudy. 
 

 
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If you are also enrolled in A5333s, we will measure the muscle size and amount of muscle fat 
from the CT scan that was done as a part of your involvement in REPRIEVE (A5332) and 
A5333s. We will also measure changes in various substances in your blood related to 
inflammation and immune function (how your body reacts to infection) using blood that was 
collected as part of your involvement in REPRIEVE (A5332) and/or the Mechanistic Substudy of 
REPRIEVE (A5333s). Please note that no additional CT scans will be completed and no extra 
blood samples will be collected as part of this substudy. 
 
You can receive the results of your physical function assessments at the time of your visit if you 
are interested. The results of the laboratory analyses and CT scans will not be reported to you. 
 
COVID-19 Pandemic Considerations 
During the COVID-19 pandemic, the following adjustments may be made to your study 
visits: 
 
If you have an in-person REPRIEVE (A5332) study visit, you will also have the visit for 
this substudy that is due at the same time. 
 
If you have an in-person REPRIEVE (A5332) study visit but there are some tests for 
this sub-study that could not be completed because of local restrictions, the tests will 
be completed at your next in-person REPRIEVE (A5332) study visit if the restrictions 
have been lifted by then. 
 
If your in-person REPRIEVE (A5332) study visit is delayed or missed, and you had a 
visit for this substudy due at the same time, you will have the visit for this substudy 
when you are next seen in the study clinic for an in-person REPRIEVE (A5332) visit. 
 
Premature Discontinuation Evaluation 
If you stop participating in the REPRIEVE (A5332) study early you will also have to stop 
participating in this study. You will be asked to return to the clinic to have premature study 
discontinuation evaluations completed. These evaluations will take about 30 minutes and 
include the same assessment of your physical function as you would have at other study visits. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS SUBSTUDY? 
 
About 600 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS SUBSTUDY? 
 
You will be in this substudy for up to 60 months, depending on when you join. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS SUBSTUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
The substudy is stopped or cancelled. 
 
You are not able to attend the study visits as required by the REPRIEVE (A5332) study. 

 
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 
You withdraw from the REPRIEVE (A5332) study. 
 
Your primary care provider requests to take you off the study because the study is no longer 
in your best interest. 
 
 
WHAT ARE THE RISKS OF THE SUBSTUDY? 
 
The physical function tests are designed to be like your usual activities. These tests are 
associated with a small risk of tripping, slipping, or falling. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
This is an observational substudy in which no study treatment is provided, so there are no risks 
related to pregnancy in this study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS SUBSTUDY? 
 
If you take part in this substudy, there may not be a direct benefit to you. The results of your 
physical function assessments will be shared with you at the time of these assessments. 
Information learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS SUBSTUDY? 
 
You can choose not to be in this substudy and still participate in the REPRIEVE (A5332) study. 
 
Please talk to your doctor about this and other choices available to you. Your doctor will explain 
the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have 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. 
 
People who may review your records include the ACTG, Office for Human Research 
Protections, or other US, local, and international regulatory entities as part of their duties, 
(insert name of site) institutional review board (IRB) (a committee that protects the rights and 
safety of participants in research), NIH, study staff, and study monitors. Having a Certificate of 
Confidentiality does not prevent you from releasing information about you and your participation 
in the study. Even with the Certificate of Confidentiality, if the study staff learns of possible child 

 
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abuse and/or neglect or a risk of harm to your or others, we will be required to tell the proper 
authorities. 
 
 
WHAT ARE THE COSTS TO ME? 
 
Taking part in this substudy 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. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will receive $25 for each substudy visit that you complete (up to a total of $150). 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this substudy, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the NIH. You will not be 
giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this substudy is completely voluntary. You may choose not to take part in this 
substudy 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 substudy, let the study 
staff know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this substudy or a research-related injury, contact: 
 
Name of the investigator or other study staff 
 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
Name or title of person on the IRB or other organization appropriate for the site 
 
Telephone number of above

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