Conditions: HIV Cardiovascular Diseases
Keywords: HIV Cardiovascular Disease Myocardial Infarction Inflammation Statin Computerized Tomography Cholesterol COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7769
Healthy volunteers: no

Brief summary:
People with HIV are at risk for cardiovascular disease (CVD). This study evaluated the use of pitavastatin to reduce the risk of CVD in adults with HIV on antiretroviral therapy (ART).

The REPRIEVE trial consisted of two parallel identical protocols:

* REPRIEVE (A5332) was funded by the NHLBI, with additional infrastructure support provided by the NIAID, and was conducted in U.S and select international sites (approximately 120 sites in 11 countries).
* REPRIEVE (EU5332) was co-sponsored by NEAT ID and MGH, and was conducted at 13 sites in Spain.

Detailed description:
There are few strategies to prevent CVD in people with HIV (PWH), even though they are at high risk for developing CVD. Statin medications are used to lower cholesterol and may be effective at reducing the risk of CVD in PWH. The purpose of this study was to evaluate the use of pitavastatin to reduce the risk of CVD in PWH on ART.

This study enrolled PWH who were on any ART regimen (ART was not provided by the study) for at least 6 months before study entry and were at low to moderate risk of CVD using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline thresholds for recommended statin initiation.

Participants were randomly assigned to receive 4 mg of pitavastatin or placebo once a day for their entire study duration. Pitavastatin or placebo could be discontinued and clinically indicated statin therapy initiated at the discretion of the site investigator or the participant's care provider, with the intention of following the participant according to the intention-to-treat trial design. Study visits occurred at study entry and Months 1 and 4. Starting at Month 4, study visits occurred every 4 months for the rest of the study. Depending on when participants enrolled, they were in the study for a total of 4 to 8 years. Study visits included medical and medication history reviews, physical examinations, blood collections, assessments and questionnaires, urine collections (for some participants), and an electrocardiogram (ECG) (at study entry only).

Participants at US sites had the option of enrolling in a substudy (Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of REPRIEVE \[A5333s\]). The substudy evaluated the effect of pitavastatin on the progression of non-calcified coronary atherosclerotic plaque (NCP) and inflammatory biomarkers in PWH. Participants in the substudy attended study visits at study entry and Months 4 and 24. The visits included questionnaires and assessments, a blood collection, and a coronary computed tomography angiography (CCTA). The Mechanistic Substudy closed to accrual on February 6, 2018, when its accrual target of 800 participants had been reached. Sites that enrolled participants into the Mechanistic Substudy are indicated with asterisk (\*) at the end of the institution names in the Contacts and Locations section.

Participants enrolled in REPRIEVE from select study sites, including international sites, through December, 2017, were included in the REPRIEVE Kidney Function Objectives Cohort to evaluate the effects of pitavastatin on parameters of kidney function in the setting of HIV. These objectives include evaluating high risk groups and mechanisms driving kidney function decline in the setting of HIV.

Women and men enrolled in REPRIEVE after February, 2016 were included in an observational cohort (REPRIEVE Women's Objectives Cohort) facilitating assessment of sex-specific mechanisms of CVD risk and risk reduction among PWH. This effort also included an evidence-based recruitment campaign to enhance women's participation in REPRIEVE.

In response to the SARS-CoV-2 pandemic, a supplemental objective was added in 2020. To better understand how COVID-19 affects PWH and if pitavastatin may reduce the risk of serious COVID-19 disease, we evaluated interrelated but independent key topics including epidemiology, host factors, and protective strategies. Starting from April 2020, COVID-19 assessment was completed at each study visit, and blood was collected for COVID-19 biomarkers.

The data and safety monitoring board (DSMB) recommended stopping the trial for efficacy at the second planned review on March 30, 2023, and concluded that no unexpected safety concerns had been reported. Following the DSMB action, participants were asked to return for the final study visit. All final visits were completed by August 21, 2023. We here present the results based on the final trial database, including the full follow-up out to closeout visits.

Arms:
arm 1: Participants received pitavastatin once a day for the entire time they were in study follow-up. arm 2: Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up.

Interventions: intervention 1: Pitavastatin intervention 2: Placebo
Intervention descriptions: intervention 1: One tablet (4 mg) taken once daily, orally with or without food intervention 2: One tablet taken once daily, orally with or without food

Protocol document:
SAP_004.pdf: 
This is REPRIEVE Primary SAP Version 2.1 with names of authors, trial 
principal investigators and vice chairs redacted. 
 
 
 
 
A5332 and EU5332 
Randomized Trial to Prevent Vascular Events in HIV 
A5332 Protocol Version 6.0, EU5332 Protocol Version 6.0 
ClinicalTrials.gov Identifier: NCT02344290 
 
 
PRIMARY STATISTICAL ANALYSIS PLAN 
Version 2.1 
June 6, 2022 
 
Created by: REPRIEVE Study Statisticians 
CBAR/Harvard T. H. Chan School of Public Health 
 
 
 
 
 
 


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Version History 
Version 
Changes Made 
Date Finalized 
1.0 
Original Version 
12/21/2015 
2.0 
Sections 1, 2.1, 4.2.1, 4.3: Incorporated REPRIEVE (EU5332). 
Section 2.1: Updated Study Overview based on REPRIEVE 
(A5332) protocol version 5.0. 
Sections 2.4, 4.1, 4.2.6:  
- 
Updated Formal Efficacy and Futility Review based on the 
study design change implemented in REPRIEVE (A5332) 
protocol version 4.0 (expected total number of endpoints of 
288). 
- 
Changed to two interim reviews, at 50% and 75% 
information (refer to the DSMB recommendations from the 
December 2019 review).  
- 
Clarified that the same critical values will be used for both 
the primary and secondary outcome measures at the interim 
analyses, as discussed with the DSMB at the December 
2020 meeting.  
Sections 3.1, 3.3, 5.3, 5.3.1:  
- 
Clarified primary outcome measure to include undetermined 
deaths, as specified in the CEC Charter, version 1.0. 
Consequently, “primary MACE” was used to refer to the 
primary endpoint throughout the document. 
- 
Analysis of confirmed MACE (i.e. not including 
undetermined deaths) will be conducted if indicated by the 
primary endpoint results or requested by the DSMB. 
Sections 3.2, 5.3, 5.3.1, 6:  
- 
Added a supporting analysis of time to MACE or all-cause 
death including data from vital status and endpoint follow-up 
implemented in REPRIEVE (A5332) protocol version 5.0. 
- 
Added vital status followup and currency to report contents. 
Sections 5.1.1, 5.3: “Per-protocol” is used to refer to the 
sensitivity analysis population rather than “as-treated” to reflect 
the analysis according to randomized treatment with censoring 
at the time of its discontinuation. 
Sections 5.1.4, 5.3, 5.3.1: Specified sensitivity analyses for 
evaluating the potential impact of missing data. 
02/16/2021 


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Sections 5.1.4, 5.3.4: Analysis of lipid profiles over time will use 
mixed effects models to better handle missing data. The 
Student’s t-tests were removed. 
Section 5.1.5: It was clarified that the final primary efficacy 
analysis will use significance level adjusted for interim looks to 
ensure study-wide alpha no greater than 5%. 
Section 5.2: Following the SARS-Cov-2 pandemic, COVID-19 
and serious COVID-19 diagnoses were added to the list of 
targeted events (REPRIEVE (A5332) protocol version 5.0, CM 
#1). 
Sections 5.3, 5.3.1: The Gray’s test and model for cumulative 
incidence function specified as supporting analyses were 
removed. Cumulative incidence function will still be estimated 
and displayed. Breslow estimators of the cause-specific hazard 
from the Cox model will be used for estimation, instead of 
product-limit estimator with delta method standard errors. 
Section 5.3.2: The list of factors to include in the analyses of 
prognostic factors of MACE was updated based on the enrolled 
population, and to provide further details on definitions and 
thresholds.  
- 
Ethnicity, collected according to the NIH definition applies to 
North America and Puerto Rico only. As such, ethnicity was 
removed from this analysis of the global REPRIEVE cohort. 
- 
Hypertension will be used as a composite of systolic and 
diastolic blood pressures, use of anti-hypertensive agents 
and hypertension diagnosis, instead of using each 
component separately. 
- 
ASCVD risk score was added. 
- 
Metabolic syndrome definition was clarified. 
- 
HIV-1 RNA, nadir CD4, duration of ART exposure, BMI 
thresholds were added or edited. 
Coding details, data sources, validation requirements and 
table/figure specifications were moved into a separate Analysis 
Implementation Plan. 
The document was re-formatted and re-arranged based on the 
current CBAR standard operating procedures. 
Minor edits and clarifications were made throughout the 
document. 
 
2.1 
Protocol amendment review (V6.0) 
06/06/2022 


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− 
No changes to the analytical approaches described in this 
Primary SAP. 
− 
Analytic approaches to address COVID-19-related 
objectives are described in a separate REPRIEVE COVID 
Supplement SAP. 
− 
Title page was updated to reflect changes in the study team. 
 


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Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
GLOSSARY  ..................................................................................................................................... 3 
1 
INTRODUCTION ........................................................................................................................ 4 
1.1 
Purpose ............................................................................................................................ 4 
1.2 
Summary of Major Changes .......................................................................................... 5 
2 
STUDY OVERVIEW ................................................................................................................... 6 
2.1 
Study Design ................................................................................................................... 6 
2.2 
Hypotheses ...................................................................................................................... 7 
2.2.1 
Primary Hypothesis ............................................................................................... 7 
2.2.2 
Secondary Hypotheses ......................................................................................... 7 
2.3 
Study Objectives ............................................................................................................. 7 
2.3.1 
Primary Objective .................................................................................................. 7 
2.3.2 
Secondary Objectives ........................................................................................... 7 
2.4 
Overview of Sample Size Considerations .................................................................... 8 
3 
OUTCOME MEASURES ........................................................................................................... 8 
3.1 
Primary Outcome Measure ............................................................................................ 8 
3.2 
Secondary Outcome Measures ..................................................................................... 9 
3.3 
Other Outcome Measures ............................................................................................ 10 
4 
INTERIM REVIEW CONSIDERATIONS ................................................................................. 11 
4.1 
Overview ........................................................................................................................ 11 
4.2 
Benchmarks for Study Monitoring .............................................................................. 12 
4.2.1 
Enrollment ........................................................................................................... 13 
4.2.2 
Loss to Follow-up ................................................................................................ 14 
4.2.3 
Treatment Crossover .......................................................................................... 14 
4.2.4 
Safety .................................................................................................................. 14 
4.2.5 
Event Rate Evaluation ......................................................................................... 14 
4.2.6 
Formal Efficacy and Futility Review .................................................................... 15 
4.3 
Interim Analysis Reports .............................................................................................. 17 
4.4 
REPRIEVE Mechanistic Substudy (A5333S) Interim Review .................................... 19 
5 
STATISTICAL PRINCIPLES ................................................................................................... 19 
5.1 
General Considerations ............................................................................................... 19 
5.1.1 
Analysis Populations and Treatment Crossover ................................................. 19 
5.1.2 
Stratification ......................................................................................................... 20 
5.1.3 
Time to Event Analysis (Including Censoring and Competing Risks) ................. 20 
5.1.4 
Missing Data ........................................................................................................ 20 
5.1.5 
Statistical Significance ........................................................................................ 20 
5.1.6 
General Model Considerations, including Assumption Checks .......................... 21 
5.2 
SAFETY ANALYSIS APPROACHES ............................................................................ 21 


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5.3 
EFFICACY ANALYSIS APPROACHES ........................................................................ 22 
5.3.1 
Primary Efficacy Analyses ................................................................................... 24 
5.3.2 
Secondary Efficacy Analyses: Prognostic Factors of MACE .............................. 26 
5.3.3 
Secondary Efficacy Analyses: Serious Non-CV Events and AIDS-defining 
Illnesses ........................................................................................................ 27 
5.3.4 
Secondary Efficacy Analyses: Lipid Profiles Over Time ..................................... 28 
6 
REPORT CONTENTS ............................................................................................................. 28 
 
 
 


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Glossary 
AIP 
Analysis Implementation Plan 
ART 
Antiretroviral treatment 
ASCVD 
Atherosclerotic cardiovascular disease 
CEC 
Clinical Events Committee 
CBAR 
Center for Biostatistics in AIDS Research, the REPRIEVE statistical analysis 
center at Harvard T. H. Chan School of Public Health 
CVD 
 
Cardiovascular disease 
DSMB  
Data and Safety Monitoring Board 
ESRD  
End-stage renal disease 
IPCW  
Inverse probability censoring weights 
ITT 
 
Intention-to-treat 
MACE  
Major adverse cardiovascular events 
NHLBI  
National Heart, Lung, and Blood Institute 
PP 
 
Per-protocol 
SAE 
 
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
 
 
 


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1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the content proposed for the primary 
statistical analysis of REPRIEVE.  The REPRIEVE trial is branched into two parallel, identical 
sister protocols: 
REPRIEVE (A5332) 
funded by NHLBI with infrastructure support by the NIH Division 
of AIDS (DAIDS) and conducted in US and select international 
sites (approximately 120 sites in 11 countries). 
REPRIEVE (EU5332) co-sponsored by NEAT-ID and Massachusetts General Hospital 
and conducted at approximately 15 sites in Spain. 
Due to the different regulatory landscape in US (e.g. HIPAA) vs. EU (e.g. GDPR) and different 
funding sources, the study conduct, site monitoring, data collection and storage will be separate 
for the two identical sister protocols.  In the final analyses of the overall REPRIEVE trial, the data 
from REPRIEVE (A5332) and REPRIEVE (EU5332) will be pooled.  Likewise, the data will be 
pooled for all presentations to the Data and Safety Monitoring Board DSMB. 
The focus of this SAP is on analyses that address the primary and secondary objectives.  Plans 
for interim review by the DSMB while the study is ongoing are also provided.  As such, this 
analysis plan includes the key analyses which may lead to modification or termination of the 
study, and hence also form the core of any presentation or publication used to disseminate the 
primary conclusions of the study.  Also included is a summary of analysis plans for secondary 
outcome measures analyzed either at the time of the core final analyses or later, determined by 
the priority of the REPRIEVE study team. Outlines of analyses for other objectives and outcome 
measures will be provided in separate SAPs. Analysis plans for REPRIEVE Ancillary studies, 
including the REPRIEVE COVID Supplement are not included in this document.  
This document outlines the general statistical approaches that will be used in the analysis.  It has 
been developed to facilitate discussion of the statistical analysis components among the study 
team, and to provide agreement between the study team and statisticians regarding the statistical 
analyses to be performed and presented in the primary analysis report.  Detailed outlines of 
tables and figures that will be included in the Primary Analysis Report, and analysis coding 
descriptions are included in the separate Analysis Implementation Plan (AIP).  


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This analysis plan may be modified by the study team as new information becomes available 
outside of the study, or to reflect recommendations made by the DSMB.  In addition, some 
analyses may be omitted at interim analyses if there are insufficient data to warrant analysis or at 
the request of the DSMB.  Unless otherwise noted (for example, analyses to be presented in 
open DSMB reports), the analyses outlined in this document will be performed by treatment 
group. 
All analyses will be performed by REPRIEVE Statisticians at CBAR1.  
1.2 
Summary of Major Changes 
Analysis plan was updated to version 2.0 to reflect changes in the study design (increase in 
sample size and followup duration, change to event-driven design with expected total number of 
endpoints of 288, and implementation of vital status and endpoint follow-up), to incorporate 
REPRIEVE (EU5332), and to update formal efficacy and futility review details for a total of two 
interim looks, at 50% and 75% information, per recommendation of NHLBI endorsed by the 
DSMB at the December 2019 meeting. It was clarified that the final primary efficacy analysis will 
use significance level adjusted for interim looks to ensure study-wide alpha no greater than 5%. 
Sensitivity analyses for evaluating the potential impact of missing data were also added. The 
related key edits are listed in the version history table above and are shown in bold face 
throughout the document. Note that there were no changes to existing outcome measures or 
primary analytic approaches.  
 
 
 
 
1 While the study is ongoing, the head statistician and REPRIEVE DCC co-PI [Dr. Ribaudo] will remain 
blinded to treatment assignment and will review only pooled data summaries. The other REPRIEVE 
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2 
Study Overview 
2.1 
Study Design 
Title 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE 
Indication 
To study the efficacy of statins to reduce the risk of cardiovascular disease in HIV-infected patients 
Location 
US, EU and select international sites2 
 
Brief Rationale 
HIV-infected persons face an increased risk of CVD morbidity and mortality, yet no preventive 
strategies for CVD risk reduction have been proven for this population. Among HIV-infected individuals, 
immune activation may contribute in unique ways to atherosclerosis and ensuing cardiovascular 
events. Statins affect both traditional CVD risk factors (LDL cholesterol) and have pleiotropic effects to 
reduce inflammation and immune activation. Thus, statins may target the unique mechanisms of 
cardiovascular disease in HIV. 
Experimental 
Design 
Phase III, prospective, double-blind, randomized (1:1), placebo-controlled, parallel-group, multicenter 
efficacy study 
Sample size 
Approximately 7500 participants3,4 
Duration 
96 months from enrollment of the first participant5,6 
Treatment 
Pitavastatin 4 mg PO daily or matching placebo 
Stratification 
Sex (male/female) 
Screening CD4+ T-cell count (≤500 vs. >500 cells/mm3)7 
Abbreviated 
Study Flow 
 
 
2 REPRIEVE (A5332): US and select international sites; REPRIEVE (EU5332): Spain. 
3 Originally, 6500 participants. The sample size was increased to approximately 7500 participants per the DSMB 
recommendations following the December 2017 review. 
4 REPRIEVE (A5332): 7500 participants; REPRIEVE (EU5332): 250 participants. 
5 Originally, 72 months. The follow-up was extended per DSMB recommendations following the December 2017 
review. 
6 REPRIEVE (A5332): median participant follow-up 6 years (72 months); REPRIEVE (EU5332): median follow-up 
approximately 4 years (50 months). 
7 During REPRIEVE (A5332) mechanistic substudy A5333S enrollment, randomization was also stratified by whether or 
not a participant had elected to participate in A5333S (yes/no). 


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2.2 
Hypotheses 
Study hypotheses as specified in the study protocol are as follows. 
2.2.1 
Primary Hypothesis 
Statin therapy will prevent atherosclerotic cardiovascular disease (ASCVD)-related MACE (major 
adverse cardiovascular events) in HIV-infected persons on antiretroviral therapy (ART) in whom 
traditional CVD risk is not significantly increased.  
2.2.2 
Secondary Hypotheses 
1. Statin therapy will be associated with reductions in specific CVD-related events and all-
cause mortality. 
2. Decreases in LDL and non-HDL cholesterol levels associated with statin therapy will be 
predictive of reduction in CVD events. 
3. Statin therapy will reduce serious non-cardiovascular events, including malignancies, end 
stage kidney or liver disease.  
4. Statin therapy will be safe and well tolerated in the HIV-infected population. 
2.3 
Study Objectives 
This Primary SAP addresses the below primary and secondary objectives, as listed in the study 
protocol [the corresponding objective number in the study protocol is provided in brackets].  The 
primary analysis including these objectives will be conducted upon study completion.  Other study 
objectives in the protocol will be addressed in subsequent analysis plans. 
All objectives will be analyzed under a superiority framework. 
2.3.1 
Primary Objective 
To determine the effects of pitavastatin as a primary prevention strategy for MACE in HIV. 
[Objective 1.2.1 in the protocol.] 
2.3.2 
Secondary Objectives 
1. To evaluate the effects of pitavastatin on each of the components of the primary 
composite MACE endpoint and all-cause mortality. [Objective 1.2.2.1] 
2. To determine the effects of pitavastatin on LDL and non-HDL cholesterol in the HIV 
population and assess the relationship of changes in LDL and non-HDL to the incidence 
of MACE. [Objective 1.2.2.2] 
3. To evaluate whether baseline traditional risk factors (including smoking, hypertension, 
dyslipidemia, glucose) and time updated HIV-specific (immunological and virological) risk 
factors are predictive of MACE and pitavastatin effects on MACE in the HIV population. 
[Objective 1.2.2.3] 
4. To evaluate whether baseline and time updated inflammatory and immune activation 
biomarkers are predictive of MACE and pitavastatin effects on MACE in the HIV 
population. [Objective 1.2.2.4] 


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5. To determine the effects of pitavastatin on the incidence of serious non-cardiovascular 
events and AIDS-defining events. [Objective 1.2.2.5] 
6. To determine the safety of pitavastatin in the HIV population, including the development 
of diabetes mellitus (DM), liver dysfunction, and myopathy. [Objective 1.2.2.6] 
2.4 
Overview of Sample Size Considerations 
The REPRIEVE (A5332) protocol version 4.0 implemented an event-driven study design. To 
summarize, under the assumption that MACE events (pooled across treatment groups) will 
occur at rates consistent with those predicted by the ASCVD risk score, a total of 288 
events (i.e. participants experiencing a primary MACE event) will provide 85% power to 
detect the target 30% reduction in event rates (HR = 0.70). To accumulate this target total 
number of events, the sample size was increased to approximately 7500 participants and 
followup has been extended to 8 years from first enrollment. Further details on the original 
sample size considerations and updated design considerations are provided in protocol 
sections 9.4.1 and 9.4.2, respectively.  
3 
Outcome Measures 
3.1 
Primary Outcome Measure 
The outcome measure to address the primary objective of the study [objective 1.2.1] and 
secondary objectives 1.2.2.3 – 1.2.2.5 in the study protocol is as follows. 
Time to the first event of a composite of major cardiovascular events (MACE) including:  
• 
Atherosclerotic or other CVD death 
• 
Nonfatal myocardial infarction 
• 
Unstable angina hospitalization  
• 
Coronary or peripheral arterial revascularization 
• 
Nonfatal stroke or TIA 
• 
Urgent PAD ischemic event (acute or chronic limb ischemia, amputation, etc.) 
Supportive analyses incorporating repeated events will also be performed. 
All primary events will be prospectively determined and adjudicated by an expert Clinical Events 
Committee (CEC) based on standardized criteria used in prior cardiovascular trials and 
developed by consensus groups and the FDA [Hicks 2015].  
All deaths classified as undetermined by CEC will be considered primary MACE events for 
this outcome measure, as specified in the Clinical Event Committee Charter, Version 1.0 
(dated March 19, 2015), page 15. The MACE and undetermined deaths are subsequently 
collectively referred to as the primary MACE. 
Participants discontinuing follow-up without experiencing the event will be censored at the time of 
the last evaluation for which an assessment for MACE was made; deaths from non-CV causes 
will be considered as competing risk events in the primary analysis. For the primary analysis, 
only events identified while the participant is in study follow-up will be included. See 


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below for supportive outcome measures that incorporate vital status follow-up after 
premature study discontinuation.  
3.2 
Secondary Outcome Measures 
The corresponding secondary objectives (see Section 2.3.2) are provided in the brackets at the 
end. 
1) Time to the first of each individual component of the primary outcome measure [Objective 
1.2.2.1] 
For each event, participants discontinuing follow-up without experiencing the event will be 
censored; deaths from other causes will be considered competing risk events. 
2) Time to death (all-cause mortality) [Objective 1.2.2.1] 
Based on independent review, death will be classified as cardiovascular event or non-
cardiovascular event. Non-cardiovascular events will be further characterized as HIV-
associated clinical diagnosis, non-AIDS malignancy, accidental, suicide, homicide, other 
sudden death of unknown etiology, or other.  
3) Time to death (all-cause mortality) and/or MACE [Objective 1.2.2.1] 
Participants discontinuing follow-up without experiencing the event (death from any cause or 
MACE) will be censored. Supportive analyses incorporating repeated events will also be 
performed. An additional supportive analysis including data from vital status and 
endpoint follow-up will also be conducted.  
4) Time to any (composite) or each (individual) of the following incident clinical diagnoses 
(including recurrent diagnoses as appropriate) [Objective 1.2.2.5] 
• 
Non AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of 
the skin) 
• 
AIDS-defining events (based on CDC 2014 classification) 
• 
End-stage renal disease (ESRD), defined as initiation of dialysis or renal 
transplantation. 
• 
End-stage liver disease, defined as cirrhosis, or hepatic decompensation requiring 
hospitalization  
For specific case definitions, see MOPS. 
For each event, participants discontinuing follow-up without experiencing each event will be 
censored; deaths from other causes will be considered as competing events. 
5) Calculated fasting LDL cholesterol (LDL-C) and non-HDL cholesterol at study entry and 
annually thereafter, as well as change from baseline expressed as absolute change and as a 
percentage of baseline. For participants with triglycerides >400 mg/dL and <500 mg/dL, direct 
LDL will be used; and for participants with triglycerides ≥500 mg/dL, LDL will be missing. 
Non-HDL cholesterol will be calculated as the difference between total cholesterol and HDL 
cholesterol. [Objective 1.2.2.2] 


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6) Time to any of the following adverse events (including recurrent events as appropriate) 
[Objective 1.2.2.6] 
• 
Serious adverse event as defined by ICH criteria 
• 
Incident Diabetes mellitus (DM) 
• 
Grade 3 or 4 ALT 
• 
Grade 3 or 4 myopathy  
All events will be included regardless of relationship to treatment as determined by sites. 
Grading is defined per the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, corrected Version 2.1, July 2017. 
3.3 
Other Outcome Measures 
Other outcome measures used in supporting and exploratory analyses include the below. 
1. Time to confirmed MACE defined as the Primary Outcome Measure (Section 3.1), 
without undetermined deaths considered events; both undetermined deaths and 
non-CV deaths as competing risks. [Objective 1.2.1] 
This supporting outcome measure will be analyzed conditional on primary 
endpoint results, should the treatment effect appear driven by the undetermined 
deaths or if requested by the DSMB. 
2. Time to heart failure. [Objective 1.2.1]  
3. Strategic Timing of Retroviral Treatment (START), a composite outcome measure 
defined as time to any of the below. [Objective 1.2.2.5] 
• 
AIDS or death from AIDS 
o 
Opportunistic events consistent with the 2014 CDC expanded surveillance 
definition plus additional events associated with immunosuppression in the 
patient population targeted for enrollment. Esophageal candidiasis and 
chronic Herpes simplex infection will be counted as primary endpoints only if 
they result in death. 
• 
Non-AIDS event 
o 
CVD: myocardial infarction, stroke, coronary revascularization 
o 
ESRD: initiation of dialysis, renal transplantation 
o 
Decompensated liver disease 
o 
Non-AIDS-defining cancers, excluding basal and squamous cell skin cancers. 
Basal and squamous cell skin cancer will be counted as a primary endpoint 
only if they result in death. 
• 
Death not attributable to AIDS, including death of unknown cause. 
4. Fasting Total cholesterol level (TC) at study entry and annually thereafter. [Objective 
1.2.2.2] 
5. Fasting HDL cholesterol level (HDLC) at study entry and annually thereafter. [Objective 
1.2.2.2] 
6. LDL-C/HDL-C ratio at study entry and annually thereafter. [Objective 1.2.2.2] 
7. Triglycerides (TG) at study entry and annually thereafter. [Objective 1.2.2.2] 


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4 
Interim Review Considerations 
4.1 
Overview 
REPRIEVE will undergo interim review at least every 6 - 12 months by an NHLBI-appointed Data 
Safety Monitoring Board (DSMB) for study conduct, continued feasibility, safety, and efficacy with 
the first review before start of enrollment and the second approximately 6 months after enrollment 
of the first participant. Data from REPRIEVE (A5332) and REPRIEVE (EU5332) will be pooled for 
all presentations to the DSMB. This section outlines general considerations for REPRIEVE 
Interim Reviews. 
An outline of the focus of each review, as well as their frequency (as specified in the DSMB 
Charter V1.0), is provided in Table A below. 
Benchmarks for monitoring of study accrual, retention, and treatment cross-over are also 
provided, as well as a general overview of the framework for efficacy and futility monitoring. 
Finally, an overview of the anticipated reporting documents to be prepared for each review is 
given. Analytical details will appear in the relevant sections in the body of the SAP. 
Throughout the duration of study follow-up, the REPRIEVE DCC co-PI and lead statistician 
(herein referred to as blinded statistician) will remain blinded to data by treatment group. She will 
not have access to data broken out by treatment group (even if masked). Instead, during any 
internal CBAR review, if needed, the blinded statistician will review tables broken out by a 
randomly permuted treatment assignment. 


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Table A: Overview of DSMB Monitoring Focus and Frequency of Review 
Review Type 
Primary Focus 
Frequency of Review1 
Feasibility and 
Conduct 
Site activation, enrollment, data and visit 
completeness, rates of loss to follow-up and cross-
over. 
Approximately every 6 months 
Safety 
Rates of adverse events by treatment group 
Approximately every 6 months 
Event Rate 
Evaluation 
Pooled rates of events observed to date; predicted 
confidence interval of the pooled event rate under a 
range of realistic scenarios2 
Approximately every 6 months, starting 
1 year after enrollment of first 
participant 
Formal Efficacy and 
Futility Review 
Treatment group comparison of the Primary MACE 
events utilizing group sequential methods  
At least annually starting once the 
adequacy of the sample size has been 
established. A total of 2 interim looks 
for efficacy are planned, at 50% and 
75% of information (defined as the 
expected total number of primary 
endpoints).3 
1 Unless otherwise requested by the DSMB. 
2 To be conducted if the pooled rate falls below a specified target (see Benchmarks below). This review occurred in December 2017. 
3 Interim looks were originally scheduled at 20% (tentative, if requested by the DSMB), 40%, 60% and 80% information. Per 
recommendation of NHLBI, endorsed by the DSMB at the December 2019 meeting, there will be 2 interim looks, at 50% and 
75% information. 
4.2 
Benchmarks for Study Monitoring 
A summary of the benchmarks for interim monitoring of the various aspects of REPRIEVE are 
provided in Table B below; broader details and rationale are provided in the subsequent sections. 
These benchmarks are intended to guide the DSMB as to when corrective action or modification 
of the REPRIEVE study may be warranted; they are not intended to be used as strict rules. 
Table B: Benchmarks for Study Monitoring 
Type of Benchmark 
Threshold for concern 
1. 
Enrollment 
Accrual rate lower than 75% of the target 
2. 
Loss to follow-up 
Annualized rate of loss to follow-up more than 5% 
3. 
Treatment Crossover 
Rate of crossover in any treatment group more than 15% 
4. 
MACE Endpoint Rate 
Average pooled rate of event 10/1000PY or lower under a range of realistic scenarios 
5. 
Efficacy & Futility 
Lan & DeMets implementation of the O’Brien-Fleming group sequential boundary with 
information measured on the cumulative number of primary MACE events 


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4.2.1 
Enrollment 
REPRIEVE (A5332) Enrollment 
The original REPRIEVE (A5332) enrollment 
benchmarks, as provided in the Statistical Analysis 
Plan, Version 1.0, are included below. These were 
retained with the following addition, for 
completeness: A row was added to Table C below 
to reflect the increase in the study sample size by 
1000 participants (to a total of 7500 participants), 
as implemented in REPRIEVE (A5332) Protocol 
Version 4.0 (dated March 28, 2018), and the target 
date to complete this enrollment (April 1, 2019). 
Benchmarks for site activation and enrollment are in 
line with commitments that have been mutually agreed 
upon between the REPRIEVE (A5332) PIs and NHLBI. These benchmarks will allow the study to 
be fully enrolled in 2.5 years from the date of first enrollment and no more than 3.5 years. To 
achieve these goals, REPRIEVE (A5332) will need to enroll at a rate at least 75% of the projected 
accrual rate. Accrual targets for the entire enrollment course of REPRIEVE (A5332) have been 
set by the team and are shown in Figure A. 
Table C provides a summary of the REPRIEVE quarterly benchmarks where each quarter is 
defined based on the expected 2.5 year enrollment period. 
Table C: Accrual Benchmarks by Enrollment Quarter 
 
End Date of Enrollment 
Quarter 
Percentage of Enrollment Target 
100% 
75% 
25% 
Q1 
11/15/2015 
844 
633 
211 
Q2 
6/30/2016 
2873 
2154 
718 
Q3 
2/13/2017 
4722 
3542 
1181 
Q4 
9/30/2017 
6500 
4875 
1625 
* 
4/1/2019 
7500 
5625 
1875 
* Enrollment of additional 1000 participants according to the increased sample size in protocol version 4.0. 
REPRIEVE (EU5332) Enrollment 
The target enrollment for REPRIEVE (EU5332) is 250 participants. The enrollment 
benchmarks are: 
• 
Enroll 200 participants by May 1, 2019 
• 
Enroll 250 participants by July 1, 2019 
Figure A 


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4.2.2 
Loss to Follow-up 
Power calculations for REPRIEVE have assumed a worst case scenario of 5% dropout per year. 
While the power of REPRIEVE will be maintained if the rate of dropout is as high as this level, it is 
desired that study dropout is substantially lower than this rate at the end of the study to avoid bias 
that may be introduced by participant dropout. While it is anticipated that risk of dropout may be 
higher during the first year of follow-up than at later times, if the annual rate of dropout at any time 
exceeds the 5% threshold, it is felt that corrective action to maintain retention be advised. 
4.2.3 
Treatment Crossover 
Note that the rationale for treatment crossover monitoring benchmark is based on the original 
REPRIEVE study design, as specified in the SAP, Version 1.0. 
The original REPRIEVE study design provided 90% power to detect a 30% reduction in the 
composite CVD endpoint with statins (assumed effectiveness, or hazard ratio of 0.70 and MACE 
endpoint rate of 15/1000 PY). This assumed a true efficacy of statins for CVD prevention of 0.66 
(HR) in this population and up to an overall 10% treatment cross-over rate similarly distributed 
across both treatment groups. Simulations under equivalent conditions suggested that with 
overall crossover rates of 16% (again similarly distributed across treatment groups), the statin 
effectiveness may be further attenuated to 0.74 and reduce the power of REPRIEVE to detect a 
positive statin effect to 84%; overall crossover rate as high as 21.5% would further reduce power 
below 80% (estimated 77%).  Based on these estimates, conservatively it is felt that a corrective 
action plan to reduce treatment crossover may be warranted if the rate of treatment crossover in 
any one treatment group exceeds a 15% threshold.  
4.2.4 
Safety 
Consideration of the emergence of safety-related issues is left to the discretion of the DSMB. 
Given the known safety profile of pitavastatin, broad adverse event/safety issues of concern are 
not anticipated.  
4.2.5 
Event Rate Evaluation 
The considerations for event rate evaluation in SAP, Version 1.0, were based on the original 
REPRIEVE study design and are retained below for completeness. The formal evaluation of 
pooled event rate including a predicted confidence interval analysis occurred at the DSMB review 
in December 2017. Following that DSMB review, pooled rates of all accumulated primary MACE 
endpoints will continue to be reviewed by the DSMB at each review (see Pooled Event Summary 
Report in Section 4.3), until otherwise requested by the DSMB.  
Pooled rates of all accumulated primary MACE endpoints will be reviewed by the DSMB at all 
reviews to evaluate the adequacy of the sample size assumptions. Given the expected rate of 
accumulation of events it is anticipated that sufficient events will have been accrued to the study 
by the time of reviews occurring 2-2.5 years after enrollment of the first subject to allow 
reasonable determination of whether the underlying rate of event accumulation is inconsistent 
with observing the required total number of events to achieve 90% power to detect a HR of 0.70 


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at the study conclusion. This is illustrated by the anticipated rate of event accumulation 
dependent on the interim review timing shown in Table D below. 
Table D: Anticipated data and event accumulation dependent of interim review timing 
Timing of 
review (y) 
Number of 
subjects 
enrolled* 
Accumulated 
person years of 
follow-up* 
Expected total accumulation of 
events under given event rate in 
control group 
(assuming the target HR of 0.7) 
Expected 
number of events 
at the threshold 
of 10/1000 PY 
15/1000 
12/1000 
1.0 
1399 
616 
8 
6 
6 
1.5 
3099 
2138 
27 
22 
21 
2.0 
3609 
3393 
43 
34 
34 
2.5 
6167 
7339 
93 
74 
73 
3.0 
6500 
10595 
134 
107 
105 
3.5 
6500 
13845 
174 
140 
137 
*Assumes data freeze 4 months prior to DSMB review and enrollment benchmarks agreed with NHLBI. 
In the event that the observed pooled number of events falls short of the number expected 
number assuming a rate of 10/1000PY (see Table D), a predicted confidence interval analysis 
will be performed to assess the total expected number of MACE endpoints at trial conclusion 
based on accumulated data to date and a range of scenarios for accumulation of future data. This 
formal event rate evaluation will be performed by the REPRIEVE statisticians (blinded and 
unblinded). It will include, but not be limited to, continued accumulation as observed and a control 
MACE endpoint rate of a) 12/1000PY and b) 15/1000PY (under the target effect size of 
HR=0.70). Unless otherwise requested by the DSMB, these assessments along with 
recommendations for any study design changes will be presented only in the closed study report, 
and thus available only to members of the DSMB. Release of the information to the REPRIEVE 
Executive Committee will be at the discretion of the DSMB. Potential design changes 
recommended as a result of this assessment may include (but will not be limited to) extending the 
study duration, increasing the target sample size, and/or broadening the study entry criteria to 
include individuals with low/moderate traditional CVD risk who are willing to be randomized to 
statin therapy or placebo, for example subjects who have an ASCVD risk score of ≥ 7.5%. 
Note: Unless otherwise requested by the DSMB and agreed by the REPRIEVE PIs and NHLBI 
and NIAID representatives, to ensure that all decisions that may impact future study design 
consideration for REPRIEVE are made without knowledge of any relative treatment efficacy, all 
primary event data will be presented pooled across treatment groups until such a time as the 
DSMB is satisfied that adequacy of the sample size assumptions has been shown. 
4.2.6 
Formal Efficacy and Futility Review 
Unless there are emerging feasibility or safety concerns, guidelines for stopping or modifying the 
trial will be guided by formal efficacy and futility review. As previously noted, these guidelines are 
not intended to be kept as strict rules. Given the scope of secondary outcomes of REPRIEVE and 
the REPRIEVE (A5332) substudy, in the event of interim findings indicative of futility for the 
primary objective, deliberations should also consider the other components of the study’s 
scientific goals that could still be realized. Any consideration for early termination of the study 


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other than for participant safety should carefully weigh the value and scientific importance of all 
components of the entire trial, in addition to realization of the primary outcome. 
Formal efficacy and futility reviews will occur once the adequacy of the sample size has been 
established. A total of four interim looks were planned originally: at 20% (if requested by 
DSMB), 40%, 60% and 80% information. Per recommendation of NHLBI, endorsed by the 
DSMB at the December 2019 meeting, the timing of interim looks was changed to at 50% 
and 75% information to allow for the best possible decision about extending study follow-
up duration. The information on the efficacy and futility boundaries below has been 
updated accordingly. A Lan and DeMets implementation of the O’Brien-Fleming sequential 
stopping boundary with information measured on the cumulative number of first primary 
composite MACE endpoints will be used to guide the DSMB in interpretation of accumulated data 
for both efficacy and futility; predicted interval plots assuming a range of event rates for each 
treatment group for unobserved data may also be provided. 
Expected Information: Under the original study design, with the assumed baseline event rate of 
15/1000 PY and accrual duration of 2.5 years, a sample size of 6500 participants followed for 6 
years after the enrollment of the first participant (median follow-up 4.75 years) was projected to 
yield approximately 350 total events and provide 90% power to detect the target 30% reduction in 
event rates (hazard ratio, HR=0.70). Following the formal review of the pooled event rate 
(see Section 4.2.5), changes were made to the REPRIEVE design (REPRIEVE (A5332) 
protocol version 4.0, dated March 28, 2018) to assure that the study will have 85% power to 
detect a hazard ratio of 0.7. Specifically, study sample size was increased by 1000 
participants (to 7500 participants) and study duration was extended by 1 year (to 7 years), 
potentially further extending follow-up at a later time. As a result, the expected total 
information (i.e. final number of participants with a primary MACE event) is 288. Note that 
the follow-up was further extended to 8 years in REPRIEVE (A5332) protocol version 5.0 
(dated April 1, 2019) to ensure that the expected total number of events will be observed. 
Efficacy and Futility Boundaries: Figure B presents the O’Brien-Fleming boundaries for the 
nominal Z-statistics and hazard ratio estimates that would lead to rejection of H0 or H1 at 
analyses performed at a given number of accumulated primary events. Point estimates are 
shown at 50%, 75% and 100% (final) of the study’s expected total information of N=288 primary 
MACE endpoints; the breakdown of the ratio of observed endpoints by treatment group at these 
specific time points are further broken down in Table E. 


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Figure B: Efficacy and Futility Boundaries (On Z Scale and on Hazard Ratio Scale) 
Observe that to reach the O’Brien-Fleming efficacy boundary at the interim review with 50% 
information, the placebo group would need to have at least 34 excess MACE endpoints (55 on 
statin treatment, and 89 on placebo). This corresponds to a hazard ratio of 0.61, and a Z-score of 
2.96. At the same time, the O’Brien-Fleming futility boundary would be reached when there are 
70 observed MACE endpoints in the statin group and 74 in the placebo group, corresponding to a 
hazard ratio of 0.95 (rounded), or Z-score of 0.34. After another interim review, at the final 
analysis, the O’Brien-Fleming efficacy boundary would be reached when there are 127 events 
observed in the statin group, and 161 in the placebo group, corresponding to a hazard ratio of 
0.79 and Z-score of 2.01. 
Note that while the total expected information is based on the primary endpoint of first 
primary MACE, the same critical values will be used for secondary outcome measures at 
interim looks. 
Table E: Efficacy and Futility Boundaries at 50%, 75% and 100% information 
 
 
Efficacy Boundaries 
Futility Boundaries 
% Expected 
Information 
Observed 
Expected 
Events 
Z 
HR 
Statin 
events 
Placebo 
events 
Z 
HR 
Statin 
events 
Placebo 
events 
50% 
144 
2.96 
0.61 
55 
89 
0.34 
0.95 
70 
74 
75% 
216 
2.36 
0.73 
91 
125 
1.24 
0.85 
99 
117 
100% 
288 
2.01 
0.79 
127 
161 
2.01 
0.79 
127 
161 
 
4.3 
Interim Analysis Reports 
Unless otherwise noted, the unblinded REPRIEVE statisticians at CBAR will be responsible for all 
data analysis and report preparation to the DSMB. For each review, three summary reports will 
be prepared: an Open Report with administrative and safety information and Pooled Event Rate 


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Summary Report pooled over treatment groups, and a Closed Report containing all information 
broken down by treatment group (unmasked) distributed only to participants attending the closed 
session of the DSMB review (see DSMB Charter for details). Report distribution for the DSMB will 
occur at least one and preferably two weeks or two weekends prior to the DSMB meeting via 
secure electronic transfer utilizing secure file transfer system. 
Specific contents of reports are outlined here; more detail is provided in the relevant sections 
below and data summaries are described in the AIP. 
A. Open Administrative Report:  
Distribution: DSMB members, REPRIEVE NIH team, REPRIEVE PIs, DAIDS Clinical 
Representative, REPRIEVE Executive Committee members, NEAT-ID Representative. 
Administrative Summary: 
• 
Study Design Overview 
• 
Minutes from previous meetings 
• 
Study History including major protocol changes 
Data Summaries: 
All information will be presented pooled over treatment groups and, as appropriate, by 
Country of Enrollment and/or Continent). 
1. Screening and Enrollment (during accrual period only) 
2. Baseline Characteristics (including baseline demographics and clinical 
characteristics) 
3. Study and Treatment Status (including study disposition monitoring benchmarks, 
except treatment cross-over) 
4. Protocol Deviations 
5. Safety 
 
B. Pooled Event Rate Summary Report 
Distribution: DSMB members, REPRIEVE NIH team, REPRIEVE CCC PIs 
All information will be presented pooled over treatment groups. 
1. Accumulation of Triggers and Adjudication Status 
2. Accumulation of MACE Endpoints 
3. Pooled Event Rate Estimation for Primary, key Secondary and Supportive 
Outcome Measures overall and within key subgroups (including by ASCVD risk 
score at enrollment, age, natal sex, continent) 
C. Closed Report:  
Distribution: DSMB members, NHLBI statistician 
All information will be presented by unmasked treatment group unless otherwise noted. 
1. Study and Treatment Status (including study disposition monitoring benchmarks) 
2. Safety 


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3. Mortality 
4. Primary and Supportive Outcome Measure Analysis (efficacy/futility analyses) 
Appendices: Baseline characteristics by treatment group; adverse event details. 
 
4.4 
REPRIEVE Mechanistic Substudy (A5333S) Interim Review 
Note: A separate Substudy analysis plan will be finalized at least 6 months before A5333S final 
analysis. 
At every REPRIEVE Interim Review Meeting, A5333S Substudy data will also be reviewed, until 
A5333S completion. [Note: A5333S completed follow-up in June 2020. A5333S data are no 
longer included in the REPRIEVE Interim Reviews. The following sections are retained for 
completeness.] 
For items that are the same between the Main Study and the Substudy (such as baseline data), 
the presentation and/or analysis will be the same. 
The following Substudy data will be presented REPRIEVE Interim Review: 
• 
* Enrollment statistics, accrual benchmarks, pre-enrollment site metrics (during accrual 
period only). Differences from main study: 
- 
Enrollment status table will be subset to REPRIEVE (A5332)-enrolled 
participants from a substudy site. 
• 
* Baseline characteristics (during accrual period only) 
• 
Study and Treatment Status, substudy-specific (study treatment is main study treatment)  
• 
Data Completeness (data from MITC): 
- 
CCTA's (Number, %): expected, received, not received. 
• 
Safety (data from MITC): 
- 
Listing of Adverse CT events. 
- 
Incidental Findings (Number, %): Yes/No. 
- 
CCTA Radiation Exposure: overall and by-site (mean, median, standard 
deviation, min, max). 
* Denotes sections for which presentation and/or analysis will be the same as for the Main Study. 
5 
Statistical Principles 
5.1 
General Considerations 
5.1.1 
Analysis Populations and Treatment Crossover 
Intention-To-Treat Population 
All treatment comparisons between randomized groups will be performed according to the 
principle of "intention-to-treat” (ITT), where participants will be analyzed (and events attributed) 
according to the randomized treatment assignment, regardless of subsequent changes to that 
treatment. Note that according to the ITT principle, participants retrospectively identified not to 
have met the study eligibility criteria and participants who did not initiate study treatment will be 
included. Duplicate enrollments of the same participant will be excluded from all analyses. 


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Per-Protocol Population 
For the primary outcome measure, a sensitivity analysis following the “per-protocol” (PP) 
approach will be performed, with censoring at the time of final randomized treatment 
discontinuation.  In this approach, participants who did not initiate study treatment or received the 
wrong treatment will be censored at day 1. Duplicate enrollments of the same participant will be 
excluded from all analyses. 
Safety Population 
There will be no separate “Safety Population.” All safety analyses will use ITT population as 
defined above. Select supporting analyses following the PP approach described above may also 
be conducted. 
5.1.2 
Stratification 
All treatment group comparisons will adjust for stratification factors: sex at birth and screening 
CD4 cell count (see Section 2). 
5.1.3 
Time to Event Analysis (Including Censoring and Competing Risks) 
Unless otherwise noted, time to event is defined as time from randomization to time of event (a) 
as adjudicated by CEC (for MACE, death and heart failure) or (b) as recorded on eCRF by the 
site (non-adjudicated events).  
Unless otherwise noted, in a time-to-event analysis, participants will be censored at the time of 
their last contact on study at which an assessment for events was made. Unless otherwise 
specified, the data (events and follow-up time) from vital status and endpoint follow-up will be 
excluded. In the final analysis, death from any cause (not part of outcome measure) will be 
considered a competing risk event. 
5.1.4 
Missing Data 
Given the strong plans for participant follow-up as part of the study, it is anticipated that missing 
data will be minimized. Unless examination of the data suggest otherwise, missing data will be 
assumed to be ignorable. For time-to-event analysis, participants lost to follow-up or participants 
who otherwise discontinue study prematurely without experiencing an event will be censored. 
The rate and reasons for premature study discontinuation will be evaluated by treatment 
group. For the primary outcome measure, sensitivity analyses to account for missing data 
will be performed, as needed (see Section 5.3). 
Proportion of missing data for the lipid outcome measures will be summarized. Analyses of lipid 
outcomes will use mixed effect models that assume missing data are missing at random 
(that is, given the data observed, missing data can be assumed ignorable). 
5.1.5 
Statistical Significance 
In the final analyses, with the exception of the primary efficacy analysis, statistical 
comparisons will be performed using two-sided significance tests with a 5% Type I error, and two-
sided 95% confidence intervals will be provided. The primary efficacy analysis will use 


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significance level according to the realized Lan and DeMets implementation of the O’Brien-
Fleming sequential stopping boundary with associated repeated confidence interval (see 
Section 4.2.6). 
There will be no adjustment for multiple comparisons. However, with the primary clinical and 
substudy hypotheses and the various secondary outcome measures that have been outlined, it is 
recognized that there is a multiplicity of analyses to be performed, which leads to an increased 
probability that at least one comparison could be "significant" by chance. Although the overall 
level of significance for all treatment comparisons will be 0.05, we will be conservative in the 
interpretation of our supporting analyses, taking into account the degree of significance, and 
looking for consistency across outcome measures. 
5.1.6 
General Model Considerations, including Assumption Checks 
Modeling analyses including competing events will use cause-specific Cox proportional hazards 
models. Cox Proportional Hazards model assumptions will be checked by examining the 
standardized score process. In the event of failure of the proportional hazards assumption, 
modification of the treatment effect over time (non-proportional hazards) using piecewise constant 
hazard will be evaluated with Wald test for treatment by time interaction. Cut points for the 
piecewise hazard will be determined post-hoc via visual examination of the observed residual 
score process. In addition, the model assumptions will be checked using log(-log(survival)) vs. 
log(survival) plots, as well as via a graphical examination of the standardized score process. 
Chi-squared goodness of fit test will be used to assess Poisson regression model assumptions. 
5.2 
SAFETY ANALYSIS APPROACHES 
Unless otherwise noted, the data summaries will be presented at interim and final analyses. 
Post-entry, the protocol requires reporting of Grade 3 and higher signs/symptoms and laboratory 
events, all events that led to a change in study treatment and select diagnoses. Targeted adverse 
events of specific interest in REPRIEVE include grade 3 or higher ALT elevations, treatment-
limiting or grade 3 or higher myalgia/myopathy, rhabdomyolysis, and incident diabetes. 
Following the SARS-Cov-2 pandemic, COVID-19 and serious COVID-19 diagnoses have 
been added to the list of targeted events. 
Only adverse events that have onset date after randomization date and meet protocol reporting 
requirements will be reported. Positively adjudicated adverse events (including MACE and heart 
failure), AIDS-defining illnesses and other non-adjudicated clinical endpoints (see Section 3.2) will 
be excluded. While REPRIEVE follow-up is ongoing, all adverse events that have been submitted 
as potential MACE or heart failure triggers and are undergoing event adjudication or are 
adjudicated as not meeting endpoint criteria will also be excluded. All events will be included, 
regardless of relationship to treatment. 
Incidence estimation of each targeted event, all reportable events, serious adverse events (SAE) 
and all-cause mortality (secondary objective 1.2.2.6; Section 2.3.2) will be performed based on 
time to first qualifying event for each participant. Follow-up will be censored at last participant 


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contact on study. Incidence rates will be estimated via a Poisson model. In estimation of incident 
diabetes, participants with pre-existing diabetes at baseline will be excluded. Incidence rates will 
be compared by treatment group via incidence rate ratios with 95% confidence intervals. P-values 
will also be provided, along with event counts and total person-years at risk. In the final analysis, 
secondary analyses that incorporate repeated events with robust variance estimation and Kaplan-
Meier (K-M) Plot (time to first occurrence of each event) will be shown by treatment group; follow-
up for participants without events will be censored at last participant evaluation. 
In descriptive adverse events summaries, participants will be counted once (at the highest 
reported grade) for the MedDRA Higher Level Group Term (HLGT) (or higher level term, HLT), 
System Organ Class (SOC) and overall totals. 
5.3 
EFFICACY ANALYSIS APPROACHES 
A summary of the planned efficacy analyses is provided in Table F below. Analyses that will be 
included in the interim reviews of efficacy and futility are marked with an asterisk (*). The focus of 
the analyses below is treatment comparison of pitavastatin versus placebo for pitavastatin, except 
for analyses evaluating prognostic factors of MACE. Further details on the Primary Analyses and 
Secondary/Exploratory Analyses are in the sections that follow. 
Table F: Summary of Efficacy Analysis Approaches 
Analysis 
Analytic method 
Notes (details in respective section) 
Primary analyses 
Time to first primary MACE 
(primary outcome measure)* 
Stratified Cox Regression (primary 
analysis)* 
Analysis population: ITT 
Competing risks handled via cause-
specific hazards 
 
Stratified Cox Regression (supportive 
analysis) 
Analysis population: PP 
Competing risks handled via cause-
specific hazards 
 
Adjusted Stratified Cox Regression 
(supportive analysis)*1 
Assessment of modification of 
treatment effect by sex, race and other 
select risk factors. 
 
Cumulative Incidence (supportive 
analysis) 
Cumulative incidence functions for first 
primary MACE, and for non-CV death 
as a competing event. 
 
Stratified Cox Regression with IPCW 
(sensitivity analysis) 
For accounting for missing data, if 
needed, IPCW to adjust for a 
potential informative censoring.  
 
Event Incidence (supportive analysis)* 
Estimated via a Poisson model. 
 
Event incidence (sensitivity analysis) 
For accounting for missing data, if 
needed, imputation of events for 
unobserved follow-up under various 
event rates in each treatment group 


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[such as performed by the INSIGHT 
START Study Group, NEJM, 2015].  
Time to primary MACE (including 
repeated events) 
Event Incidence (supporting analysis) 
Estimated via a Poisson model with 
robust variance to account for repeated 
events. 
Time to first confirmed MACE2 
Stratified Cox Regression (supporting 
analysis)2* 
Analysis of time to first confirmed 
MACE, not including deaths 
classified as undetermined by CEC. 
Time to each MACE component 
(secondary outcome measure) 
Stratified Cox Regression, 
Event Incidence 
Stratified Cox Regression for time to 
the first event. Event Incidence 
estimated via a Poisson model with 
robust variance to account for repeated 
events. 
Time to all-cause death  
(secondary outcome measure) 
Stratified Cox Regression 
 
Time to MACE and/or all-cause 
death 
(secondary outcome measure)* 
Stratified Cox Regression*, 
Event Incidence 
Stratified Cox Regression for time to 
the first event. Event Incidence 
estimated via a Poisson model with 
robust variance to account for repeated 
events. 
 
Stratified Cox Regression, 
Event Incidence 
Follow-up and events from vital 
status and endpoint follow-up will be 
included. 
Stratified Cox Regression for time to 
the first event. Event Incidence 
estimated via a Poisson model with 
robust variance to account for 
repeated events.  
Secondary analyses 
Prognostic factors of MACE 
Stratified Cox Regression 
Landmarked Cox Regression 
Primary MACE outcome measure will 
be used. 
Covariates: Risk Factors (baseline and 
time-updated), biomarkers. 
Landmarked approach for HIV 
suppression. 
Serious non-CV events and AIDS-
defining illnesses 
Stratified Cox Regression 
 
Lipid profiles over time 
Stratified Mixed Effect Model 
Time will be modeled as a class 
statement to allow for estimation of 
annual treatment group difference. 
Exploratory analyses 
Lipid Profiles over time (additional) 
Stratified Mixed effect model 
Time will be modeled as a class 
statement to allow for estimation of 
annual treatment group difference. 
Restricted to participants at risk for first 
primary MACE event after 12 months 


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Time to heart failure (secondary 
outcome measure) 
Stratified Cox Regression, 
Event Incidence 
Stratified Cox Regression for time to 
the first event. Event Incidence 
estimated via a Poisson model with 
robust variance to account for repeated 
events. 
* The analyses indicated with an asterisk will be provided for the formal interim reviews. 
1If trends seen during interim analysis suggest a significant treatment effect close to the interim boundary, 
assessment of modification of treatment effect by risk factors will also be presented at interim review.  
2 If requested by the DSMB or otherwise indicated by the results of the first primary MACE 
endpoint. 
Note: It is anticipated that the Primary Manuscript will report results of the primary analysis, as 
well as the analyses of safety, lipids (both secondary and exploratory) and heart failure. Analyses 
of the prognostic factors of MACE and of the targeted non-CVD events are anticipated to be 
reported as part of secondary manuscripts. 
5.3.1 
Primary Efficacy Analyses 
The primary outcome measure to evaluate the primary objective of the study is time to first 
primary MACE (time to first event of the composite MACE outcome measure, as defined in 
Section 3.1). The primary analysis of the treatment effect on the first primary MACE in the ITT 
population (see Section 5.1.1.) will use a Cox proportional hazards regression model with cause-
specific hazards, stratified by sex at birth and screening CD4 cell count (referred to as Stratified 
Cox Regression from here on). Time from randomization to the first event of interest will be 
evaluated. Death from any cause will be incorporated as a competing risk. The relative cause-
specific hazard of pitavastatin versus placebo for Primary MACE will be estimated with a 95% 
confidence interval and compared via a Wald test; modification of the statin effect over time (non-
proportional hazards) will be evaluated with treatment by time interaction; and piecewise hazards 
will be implemented in case of failure of the proportional hazards assumption. 
Cumulative incidence function, defined as the probability that an event of interest occurs before a 
fixed time in the presence of competing events, will be estimated using the Breslow estimators of 
the cause-specific hazard from the Cox model and plotted over time for both the primary outcome 
and the competing event. Cumulative incidence rate and confidence intervals will be shown for 
both the event of interest and the competing event, by treatment group, and separately by 
treatment group and each stratification factor.  
Poisson regression with robust variance estimates will also be used to incorporate multiple and 
repeated events in evaluation of event incidence rates by treatment group and rate ratios. We 
note that Cox analysis is preferred for inference for the primary analysis of the treatment group 
comparisons over a comparison of incidence rates as it is more flexible than the Poisson model, 
allowing for a changing hazard of events over time, whereas the incidence rate (from the Poisson 
model) represents a single average rate across follow-up duration. 
Stratified Cox Regression will also be used to assess modification of the treatment effect. The 
model will be adjusted for race and other risk factors including age, hypertension, LDL and non-
HDL cholesterol at entry, BMI, metabolic syndrome and smoking status. Each of these factors will 
be included individually as a covariate in the model, with time to first primary MACE as the 


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outcome. Modification of the statin effect will be assessed via covariate interaction with treatment 
for each factor.  Further details and cut points for the continuous variables are specified in 
Section 5.3.2 and AIP.  Note that these analyses include treatment comparisons summarized by 
sex and by race, and evaluation of treatment interactions with sex and race, in line with NIH 
requirements. 
Several other supporting and sensitivity analyses are planned for the primary outcome measure 
including the following. 
• 
Stratified Cox Regression in per-protocol (PP) population, with censoring at the time of 
final randomized treatment discontinuation (see Section 5.1.1).  
• 
In the Primary MACE outcome measure, undetermined deaths are considered 
events. While it is anticipated that most deaths will be classifiable as CV or non-CV 
and undetermined deaths are rare, an analysis of confirmed MACE events (i.e. not 
including undetermined deaths as events) may also be conducted if indicated by 
the primary endpoint analysis or requested by the DSMB.  
• 
Another sensitivity analysis will censor individuals for whom critically significant Coronary 
Artery Disease (CAD) was identified during the CCTA evaluation performed as part of the 
Mechanistic Substudy of REPRIEVE (A5333S), with censoring at the date of the 
apparent CCTA study findings.  
• 
While missing data are assumed ignorable in the primary analysis, sensitivity 
analyses will be considered, as needed, to evaluate robustness of treatment effect 
and potential bias due to missing data, given the observed results and the extent 
of missing data. These may include the following. 
- 
Inverse probability censored weighting (IPCW) may be used to adjust for a 
potentially informative censoring, if appropriate. 
- 
For participants with primary outcome status unknown at the time of study 
completion, event rates may be imputed for the unobserved follow-up time 
based on a range of event rates for each treatment group [such as the analysis 
performed by the INSIGHT START Study Group, NEJM, 2015]. 
The analyses of secondary time to event outcome measures will use Stratified Cox Regression 
and, if appropriate, Poisson models to account for the repeating events as described for the 
Primary MACE outcome measure above and specified in Table F. To complement the primary 
analyses, the same analytic approach will be used for evaluation of each individual component of 
the Primary MACE outcome measure (Objective 1.2.2.1; Section 2.3.2). In the absence of a 
competing risk event, treatment comparisons of time to all-cause death and time to Primary 
MACE or all-cause death will use a stratified log-rank test. Analyses of secondary outcome 
measures will be conducted in the ITT population.  
A supporting analysis of time to death (all-cause mortality) and/or MACE will be conducted 
including the data (follow-up time and events) from the vital status and endpoint follow-up, 
after premature study discontinuation. Time will be censored at the time of participant’s 
last contact on study or at the last vital status contact after premature study 
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study compared to events identified as part of vital status and endpoint follow-up will be 
summarized. 
5.3.2 
Secondary Efficacy Analyses: Prognostic Factors of MACE 
An important secondary aim of the REPRIEVE trial is to evaluate whether baseline traditional risk 
factors, time updated HIV-specific risk factors, lipid levels, and/or biomarker values are predictive 
of MACE and pitavastatin effects on MACE in the HIV population (Objectives 1.2.2.2 – 1.2.2.4; 
see Section 2.2.2.). 
Targeted risk factors of interest at (or prior to) study entry and time-updated are listed below 
(treated as continuous, unless a cut-point is specified).  
At study entry/screening: 
1. Age  
2. Sex 
3. Race  
4. Screening ASCVD risk score (<2.5, 2.5-<5, 5-<7.5, 7.5-10, >10) 
5. HIV-1 RNA level (≤75 vs. >75 copies/mL); given sufficient numbers of participants with 
detectable HIV-1 RNA at study entry [Only a small proportion of REPRIEVE participants 
had HIV-1 RNA above the assay limit of quantification at entry; analysis will not be done.] 
6. CD4 cell count (≤500 vs. >500 cells/mm3) 
7. Nadir CD4 cell count (<50, 50-199, 200-350, >350 cells/mm3) 
8. Duration of ART exposure (<5 year, 5-10 years, 10+ years) 
9. Any exposure to thymidine analogs, protease inhibitors, or abacavir (3 separate 
measures; binary) 
10. BMI <30 vs. ≥30 kg/m2 
11. Fasting lipids and glucose 
a. LDL (<130 vs. ≥130 mg/dl) 
b. HDL-C  
c. TG  
d. Glucose 
12. Smoking status (binary) 
13. Hypertension (binary) defined as any of the following: hypertension diagnosis, use of 
antihypertensive treatment for elevated blood pressure, systolic blood pressure ≥140 
mmHg, diastolic blood pressure ≥90 mmHg 
14. Presence of metabolic syndrome (binary) as described by Alberti et al (Circ, 2009) with 
country- and sex-specific waist circumference cutoffs adapted to REPRIEVE (refer to the 
AIP for details) 
15. Self-reported level of physical activity  
16. Family history of premature CVD 
Time-updated (annually): 
1. HIV-1 RNA level (<LLQ; LLQ-<400; ≥400 copies/mL). 
[These limits are updated from original analysis plan and chosen to accommodate the 
different assays used across REPRIEVE sites.] 
2. CD4 cell count (≤500; >500 cells/mm3) 


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3. Fasting lipids (TC, HDL-C and LDL-C, HDL-C:LDL-C ratio, TG) and glucose. 
Each baseline risk factor above will be included individually as a covariate in a Stratified Cox 
Regression model to estimate the cause-specific hazard of primary MACE in the ITT population. 
Modification of the statin effect will be assessed via covariate interaction with treatment, for the 
following risk factors: 
• 
Race, sex, CD4 cell count at screening, duration of HIV-1 RNA suppression, age (<50 vs. 
≥50 years), hypertension, LDL (<130 vs. ≥130 mg/dl), and non-HDL cholesterol at entry, 
BMI (<30 vs. ≥30 kg/m2), metabolic syndrome, smoking status. 
Continuous risk factors will be assessed for functional form using Martingale Residual plots. 
To accommodate time-updated covariates, analyses will use a counting process data input. A 
given annual measurement will be assumed constant for the period of 6 months prior and 6 
months after date of collection. 
This approach will investigate associations with LDL and non-HDL levels and changes from 
baseline as time-updated covariates. The same approach to analysis will be used to assess the 
effects of other longitudinal outcomes. With respect to HIV-1 RNA levels over time, it is of 
particular interest to examine whether there is evidence of the modification of the effect of statins 
according to whether participants maintain full suppression of HIV-1 RNA levels. This will be 
examined in a 12-month landmarked Cox proportional hazards models assessing an interaction 
between continued HIV-1 RNA suppression (<400 copies/mL) over the first 12 months of the 
study as well as time-updated analysis.  
An additional lipid analysis will be restricted to participants at risk for the first primary MACE event 
after 12 months and examine the association of change in LDL and non-HDL over the first year in 
a ‘landmarked’ Cox proportional hazards model. 
Note: The analyses of biomarkers are planned for a secondary publication. Baseline and time-
updated inflammatory and immune activation biomarkers of interest will be determined closer to 
the analysis, following determination of biomarker candidates per substudy findings. The analysis 
approach for assessment of effect of selected biomarkers for MACE will be determined based on 
the sampling approach to biomarker testing. 
5.3.3 
Secondary Efficacy Analyses: Serious Non-CV Events and AIDS-defining Illnesses 
To address secondary objective 1.2.2.5 (see Section 2.2.2), Stratified Cox Regression will be 
used to evaluate the effect of pitavastatin on time to any (composite) or each (individual) clinical 
diagnosis as specified in outcome measure 4 in Section 3.2 in the ITT population, as described 
for the Primary Analyses above. Time to the first qualifying event will be modeled. Participants 
discontinuing follow-up without experiencing an event will be censored at the time of last contact 
on study. Deaths from other causes will be considered as competing events. 
As a supporting analysis, the same Stratified Cox Regression analysis approach will be used for 
the START outcome measure (see Section 3.3). 


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5.3.4 
Secondary Efficacy Analyses: Lipid Profiles Over Time 
This section addresses part of secondary objective 1.2.2.3 (Section 2.2.2): to determine the 
effects of pitavastatin on LDL and non-LDL cholesterol in the HIV population.  
Summary statistics (means and quantile distributions) will be provided to describe the 
distributions of LDL and non-HDL cholesterol from study entry and 12 month intervals over time. 
At each annual post-entry time point, the mean difference in levels between treatment groups will 
be estimated with 95% confidence interval. Mixed Effects Models adjusted by sex at birth and 
screening CD4 cell count will be used for repeated measurements of LDL and non-HDL 
cholesterol over time with time as a class covariate to allow for estimation of annual treatment 
group differences. Similar summaries and analyses will be provided for supporting lipid outcome 
measures specified in Section 3.3 (#4 – #7). 
6 
Report Contents 
The key report contents are listed below. Further details and descriptions of tables and figures 
are provided in the AIP. 
• 
[Final analysis only] CONSORT Diagram 
• 
Screening, Enrollment and Eligibility (during accrual period): 
o 
Overall Status including total screenings; total enrollment; screening failures; 
status pending; days since last enrollment; days since last screening overall and 
by network. 
o 
Accrual Benchmarks: observed vs. target accrual benchmarks 
o 
[Interim Only] Screening Disposition by Site 
o 
[Interim Only] Enrollment by Week 
o 
[Interim Only] Reasons for Screening Failure 
o 
Violations of eligibility criteria 
o 
[Interim Only] Site enrollment status 
• 
Baseline Characteristics: 
o 
Stratification, Demographics and ASCVD Risk including screening CD4 count, 
sex at birth, age, 10-year ASCVD risk score, history of statin use, race. 
o 
CVD History and Risk Factors including systolic blood pressure, weight, BMI, 
waist circumference, smoking status, years smoked and family history of 
premature CVD; final analysis will also include alcohol use, physical activity and 
diet. 
o 
Fasting Lipids/Glucose including fasting status (for screening lipids only), total 
cholesterol, triglycerides, LDL-C, HDL-C and HDL-C:LDL-C ratio. 
o 
HIV-Related Medical History including years since HIV diagnosis, risk for 
acquiring HIV and nadir CD4. 
o 
CD4 cell count and HIV-1 RNA. 
o 
ARV Regimen History including total duration of ARV use, individual ARV history 
and duration of exposure for each of abacavir, protease inhibitor, thymidine 
analog, tenofovir; ARV classes (NRTI+NNRTI, NRTI+INSTI, NRTI+PI, Other 
NRTI-containing, NRTI-sparing) and choice of NRTI, NNRTI, PI, INSTI. 


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• 
Study and Treatment Status: 
o 
Overall summary: 
 
Number on-study and on-treatment, on-study and off-treatment, 
deceased, off-study. 
 
Reasons of off-study (prematurely). 
o 
Additional Study and Treatment Status Summaries: 
 
All off-treatment reasons. 
 
Time to treatment initiation. 
 
Time to off-treatment. 
 
Cumulative probability of study discontinuation (Kaplan-Meier analysis). 
 
Cumulative probability of treatment discontinuation (Kaplan-Meier 
analysis). 
o 
Disposition Benchmarks: 
 
Incidence rate of premature study discontinuation  
 
Incidence rate of premature treatment discontinuation  
 
Incidence rate of treatment crossover 
o 
Treatment Adherence: 
 
Adherence self-rating 
 
[Interim Only; Closed Report] LDL cholesterol levels 
o 
Duration of Follow-Up: 
 
Duration of follow-up on study (months) 
 
Total person-years of follow-up on study 
 
Study year of latest clinic visit on study 
 
Time to latest contact on study 
 
Years to latest contact on study 
o 
Currency of Follow-Up 
 
Visit currency 
 
Currency by visit year 
• 
Vital Status and Endpoint Follow-Up: 
o 
Duration of follow-up 
o 
Currency of follow-up 
• 
Safety 
o 
All-Cause Mortality 
 
Mortality Summary by category of: cardiovascular event, HIV-associated 
clinical diagnosis, non-AIDS cancer, accidental, suicide, homicide, other 
sudden death of unknown etiology, or other (with possible additional 
subcategories, as adjudicated by CEC) 
 
Death Details including weeks on study at time of death, baseline and 
most recent HIV-1 RNA and CD4 count, weeks since the last dose of 
randomized treatment, weeks since the last dose of other ART treatment 
(if applicable), last ART regimen, site’s reports of primary cause of death 
(text, categorization and diagnosis), and site’s determination of 
relatedness to study treatment. 
o 
Adverse events 
 
Summary of Serious Adverse Events (SAE) by term and grade 


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 
Summary of related and possibly related adverse events by term and 
grade 
 
Summary not related  adverse events by term and grade 
 
Adverse events that resulted in study treatment withdrawal by term and 
grade 
 
Incidence rates of death (all-cause), SAEs, targeted events and protocol-
reportable AEs 
o 
Myalgia Assessment 
 
Muscle Weakness by Grade 
 
Muscle Aches by Grade 
• 
Efficacy (see Section 5.3) 
o 
Primary efficacy analyses 
 
Time to first primary MACE, supporting and sensitivity analyses 
 
[Final Analysis only] Time to Each MACE Component 
 
[Final analysis only] Time to All-Cause Death 
 
Time to MACE or All-Cause Death 
o 
Secondary efficacy analyses 
 
[Final analysis only] Prognostic Factors of MACE 
 
[Final analysis only] Serious non-CV Events and AIDS-defining Illnesses 
 
[Final analysis only] Lipid Profiles Over Time 
o 
Exploratory Analyses: 
 
[Final analysis only] Time to Heart Failure 

ICF_006.pdf: 
 DEPARTMENT OF HEALTH & HUMAN SERVICES 
Public Health Service 
National Institutes of Health 
Bethesda, Maryland 20892 
www.nih.gov 
 
Date:  
 
To:  
 
 
From:  
 
 
Subject:  
 
 
5/24/2024 
 
The A5332 Protocol Team, Principal Investigators and Study Coordinators 
 
Jui Shah, Ph.D., Chief Protection of Participants, Evaluation, and Policy 
Branch (ProPEP), Division of AIDS 
 
A5332, Version 6.0 – Final – Spanish Sample Informed Consent dated 16 May 
2022
The purpose of this letter from the Protection of Participants, Evaluation, and Policy Branch 
of the Division of AIDS is to document that the Spanish Sample Informed Consent provided in 
protocol A5332, Version 6.0 is a complete and accurate translation of the English Sample 
Informed Consent.  The Spanish Sample Informed Consent contains all the required Basic and 
Additional elements of an Informed Consent required by the Code of Federal Regulations. 
 
The translation of the English Sample Informed Consent into Spanish was performed by one of 
the qualified English to Spanish Translators supported by the DAIDS Regulatory Support 
Contract (RSC).  The English to Spanish Translators have excellent qualifications and have 
passed a quality assurance translation test facilitated by the NIH Translation Unit. 
 
 
Consent Forms:  
• Appendix I: Sample Informed Consent  
• Appendix IA: Sampled Informed Consent Addendum  
 
 
 
 
 
 
 
 
 
 


                  1 
 
 REPRIEVE (A5332) 
Versión FINAL 6.0 
16 de mayo de 2022 
 
APÉNDICE I: MODELO DE CONSENTIMIENTO INFORMADO 
 
Para el Protocolo REPRIEVE (A5332), Versión FINAL 6.0, del 16 de mayo de 202 
 
 
Ensayo Clínico Aleatorizado para Prevenir Eventos Vasculares en el VIH (El Estudio 
REPRIEVE) 
 
 
INTRODUCCIÓN 
 
Se le solicita a usted que participe en este estudio de investigación debido a que usted vive con 
el virus de la inmunodeficiencia humana (VIH), el virus que causa el SIDA, y está tomando 
medicamentos contra el VIH. 
 
Este estudio es patrocinado por los Institutos Nacionales de la Salud (NIH, siglas en inglés).  
El/La médico(a) a cargo de este estudio en este sitio es: (inserte el nombre del Investigador 
Principal).   Antes de que usted decida si quiere ser parte de este estudio, nosotros queremos 
que sepa en qué consiste el estudio.  
 
 
¿PARA QUÉ SE LLEVA A CABO ESTE ESTUDIO? 
 
Desde que las personas comenzaron a tomar medicamentos contra el VIH, las enfermedades 
causadas por el SIDA han disminuido, pero otras enfermedades graves, como la enfermedad 
cardiaca, han aumentado.  El VIH causa inflamación (irritación) dentro del organismo, que no 
puede sentirse pero se puede medir.  Estas pruebas se describirán más adelante en este 
formulario de consentimiento.  La inflamación puede contribuir a desarrollar dolencias tales 
como la enfermedad cardiaca, que se ha vuelto una de las causas principales de muerte en 
personas con VIH (PWH, siglas en inglés).  Los medicamentos contra el VIH pueden reducir la 
inflamación de cierta manera, sin embargo a veces los niveles de inflamación pueden 
permanecer altos si se comparan con el de personas sin el VIH.   
 
Las estatinas son un grupo de medicamentos que se utilizan para reducir los niveles de 
colesterol y triglicéridos (grasas en la sangre) que generan las personas, y para prevenir 
eventos relacionados con las enfermedades del corazón, tales como ataques cardiacos, en el 
caso de personas que tienen un alto riesgo de sufrir ataques cardiacos.  Los estudios han 
demostrado que las estatinas pueden tener otros beneficios; por ejemplo, disminuyendo los 
niveles de inflamación, las estatinas pueden tener un efecto protector contra las enfermedades 
cardiacas y los eventos relacionados con éstas.  Asimismo, las estatinas pueden tener algunos 
efectos beneficiosos en algunas otras enfermedades como ciertos tipos de cáncer o problemas 
renales.  
 
Las pautas más recientes del Colegio Americano de Cardiología y la Asociación Americana del 
Corazón (ACC/AHA, siglas en inglés) recomiendan el uso de estatinas si alguien está en riesgo 
de sufrir una enfermedad relacionada con el corazón, en base a varios factores diferentes, 
incluyendo el uso de una calculadora de riesgos basada en factores de riesgo conocidos como 
sexo, edad, raza, niveles de colesterol, consumo de tabaco, diabetes e hipertensión, que estima 
el riesgo a 10 años de sufrir ataque cardiaco, apoplejía u otro evento (la puntuación de riesgo 


                  2 
 
 REPRIEVE (A5332) 
Versión FINAL 6.0 
16 de mayo de 2022 
 
ASCVD, siglas en inglés).  La infección por VIH no está incluida en la calculadora de riesgo.  
Las actuales calculadoras de riesgo no pueden predecir con precisión el riesgo en las PWH.  
Sin embargo, la infección por VIH, los medicamentos contra el VIH y la inflamación crónica 
pueden poner a usted en un riesgo más alto de sufrir estas enfermedades, aunque no sabemos 
si usted se beneficiaría al tomar estatinas.  Usted es elegible para este estudio porque está en 
el grupo de riesgo bajo a moderado de sufrir enfermedad cardiaca, según las pautas actuales, y 
no existe consenso respecto a que las PWH en este grupo debieran tomar estatinas.  Su 
participación en este estudio nos ayudará a determinar si el uso de las estatinas puede prevenir 
enfermedades relacionadas con el corazón entre las PWH.  Los resultados de este estudio 
pueden ayudar a crear pautas de prevención de la enfermedad cardiaca en la infección por VIH. 
 
Para las personas VIH negativas con una puntuación de riesgo ASCVD de entre 7,5% y 15%, 
las pautas actuales recomiendan una discusión entre el proveedor de salud y los pacientes 
sobre los riesgos y beneficios de la terapia con estatinas y aconsejan iniciar las estatinas sobre 
la base de los datos de los ensayos clínicos disponibles.  Sin embargo, para las PWH y un 
riesgo moderado de enfermedad cardiaca (una puntuación de riesgo entre 7,5% y 15%), no hay 
actualmente datos disponibles que nos digan con claridad si los beneficios de la terapia con 
estatinas superan a los riesgos, incluidos los efectos secundarios y las potenciales 
interacciones de medicamento a medicamento.  Algunos proveedores de salud pueden elegir la 
terapia con estatinas para el tratamiento de PWH en este rango de riesgo moderado, y esta 
opción puede estar disponible para usted, en lugar de participar en el ensayo clínico.  En última 
instancia, los resultados de este ensayo proporcionarán datos para guiar el uso de estatinas en 
las PWH. 
 
La pitavastatina es una estatina que, junto a una dieta, ha sido aprobada por la Administración 
de Alimentos y Medicamentos de los Estados Unidos para tratar el colesterol alto.  También 
disminuye los niveles de triglicéridos en la sangre.  No ha sido estudiada para ver si reduce las 
enfermedades relacionadas con el corazón o la mortalidad.  Se eligió la pitavastatina porque se 
estima que hay pocas interacciones entre la pitavastatina y los medicamentos que se usan 
habitualmente para tratar el VIH. 
 
El propósito principal de este ensayo clínico es observar si la pitavastatina puede prevenir la 
enfermedad cardiaca y las muertes por causas cardiacas en PWH que están tomando 
medicamentos contra el VIH.  También evaluaremos la seguridad de la pitavastatina. 
 
 
¿CUÁNTAS PERSONAS ESTARÁN EN ESTE ESTUDIO? 
 
Alrededor de 7500 personas participarán en este estudio.  
 
 
¿QUÉ DEBO HACER SI ESTOY EN ESTE ESTUDIO? 
 
Visitas del estudio 
Si usted ingresa al estudio, será observado(a) en la clínica alrededor de 6 veces durante el 
primer año.  Posteriormente, las visitas del estudio serán cada 4 meses durante los siguientes 6 
a 10 años, según cuándo se incorpore.  El personal del estudio le informará cuánto tiempo 


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durará cada visita.  Más detalles sobre las visitas y procedimientos del estudio se le brindan a 
continuación.  
 
Si usted no ingresa en el estudio 
Si usted decide no participar en este estudio después de firmar el formulario de consentimiento, 
o si usted no cumple con los requisitos de elegibilidad, nosotros usaremos parte de la 
información sobre usted.  Como parte de esta visita de tamizaje, se obtiene de usted cierta 
información demográfica (por ejemplo, edad, sexo, raza), clínica (por ejemplo, condición de la 
enfermedad, diagnóstico) y de laboratorio (por ejemplo, análisis de seguridad), de modo que los 
investigadores del Grupo de Ensayos Clínicos de SIDA (ACTG, siglas en inglés) puedan ayudar 
a determinar si hay patrones o razones comunes por las cuales las personas no se incorporan a 
un estudio. 
 
Medicamentos del estudio 
Si usted ingresa al estudio, será asignado(a) aleatoriamente (como al lanzar una moneda al 
aire) para recibir ya sea la pitavastatina o el placebo de pitavastatina.  El placebo es un 
comprimido que se parece a la pitavastatina pero no contiene en él ningún medicamento activo. 
Por lo tanto, existe la probabilidad de que si usted es aleatorizado(a) para tomar el placebo no 
reciba el tratamiento durante su participación en el estudio.  En los ensayos clínicos usamos 
placebos para saber si los efectos que se observan en el ensayo se deben realmente al 
medicamento del estudio o a otras razones.  Ni usted ni el personal del estudio conocerán su 
asignación.  Usted no conocerá su asignación hasta después de que todo el estudio finalice y 
los resultados del estudio se den a conocer.  En el caso de que sea necesario para su salud, se 
le dará a conocer a usted y su médico(a) su asignación.  
 
Usted tomará el medicamento del estudio (ya sea la pitavastatina o el placebo de pitavastatina) 
una vez al día, todos los días, durante el período del estudio, con o sin comida.  La dosis es de 
4 mg.  Le recomendamos que tome el medicamento del estudio cada día a la misma hora.  El 
estudio suministra estos medicamentos.  Es muy importante que usted tome los medicamentos 
como se le indicó.   En cada visita del estudio posterior al ingreso, le preguntaremos cómo ha 
estado tomando sus medicamentos del estudio.  Los medicamentos antirretrovirales 
(tratamiento del VIH) no serán suministrados por el estudio.   
 
Procedimientos del estudio 
El personal del estudio puede contestar cualquier pregunta que usted tenga acerca de las 
visitas de estudio individuales y los procedimientos.  La tabla siguiente se puede utilizar como 
una referencia rápida, junto con las explicaciones que siguen. 
 
Apéndice I, Tabla 1: Procedimientos del Estudio 
Procedimiento 
Tamizaje1 
Ingreso2 
Mes 1 
Visitas cada 4 
meses (inician 
en el mes 4) 
Visitas 
anuales 
(inician en 
el mes 12) 
Visita final 
Examen físico 
 
X 
 
X 
 
X 
X 
Evaluación de riesgo de 
enfermedad cardiaca 
X 
 
 
 
 
 
Factores de riesgo de 
X 
 
 
 
 
 


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Procedimiento 
Tamizaje1 
Ingreso2 
Mes 1 
Visitas cada 4 
meses (inician 
en el mes 4) 
Visitas 
anuales 
(inician en 
el mes 12) 
Visita final 
enfermedad cardiaca  
Preguntas sobre dieta y 
ejercicios 
 
X 
 
 
 
X 
Información para 
cambiar el estilo de vida 
 
X 
 
 
X 
X 
Preguntas sobre la 
salud y los 
medicamentos 
X3 
X 
X 
X5 
X5 
X3,5 
Extracción de sangre 
 
X 
X 
X 
 
X 
X 
Obtención de orina 
 
 
X 
 
 
X4 
 
Análisis de embarazo 
 
X 
X 
X 
X 
X 
X 
Electrocardiograma 
 
 
X 
 
 
 
 
Píldoras dispensadas 
 
X 
 
X 
X 
 
1 Visita de tamizaje: antes de que usted pueda entrar al estudio, deberá venir a la clínica para que se le 
hagan evaluaciones y así asegurarnos de que pueda participar del estudio. 
1 Visita de ingreso: si usted cumple con los requisitos para el ingreso, usted se inscribirá en el estudio. 
2 Esto incluirá también una evaluación hormonal de las mujeres. 
3 SOLO sitios del ACTG: se obtendrá orina en los meses 12, 24 y 48 solo de las personas inscriptas en 
REPRIEVE (A5332) antes del 1 de enero de 2018. 
4 Esto incluirá también una evaluación de COVID-19 en todos los participantes. 
 
Si usted deja el estudio antes de tiempo, o tiene que dejar de tomar el medicamento del estudio 
antes de que éste finalice, se le harán a usted los procedimientos de la siguiente tabla. 
Apéndice I, Tabla 2: Discontinuación de los Procedimientos del Estudio 
Procedimiento 
Interrupción prematura del estudio o 
del tratamiento del estudio 
Examen físico 
X 
Preguntas sobre salud y 
medicamentos 
X1 
Análisis de embarazo 
X 
Extracción de sangre 
X 
Análisis de sangre en ayunas 
X 
 
1Esto también incluirá una evaluación hormonal de las mujeres y una evaluación de 
COVID-19 en todos los participantes.  
 
Explicación de los procedimientos del estudio 
 
Examen físico 


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Se le realizará a usted un examen físico en el tamizaje.  En otras visitas posteriores al ingreso, 
la extensión del examen dependerá de cómo se sienta en esa visita.  Se le controlarán los 
signos vitales, incluyendo la presión sanguínea y el pulso.  Se le medirá su cintura, peso y 
estatura.  Se le preguntará sobre su salud y sus medicamentos. 
 
Evaluación del riesgo de enfermedad cardiaca 
En el tamizaje, le haremos preguntas específicas para evaluar la elegibilidad en base al riesgo 
de que sufra una enfermedad cardiovascular.  En el tamizaje, a usted también se le harán 
preguntas sobre factores de riesgo cardiovascular, incluyendo sus antecedentes familiares, si 
fuma, bebe alcohol, consume drogas, dieta y ejercicio. 
 
Estilo de vida /orientación y apoyo psicológico para reducir el riesgo 
Si usted se incorpora al estudio, se le dará información sobre una dieta sana y la importancia de 
hacer ejercicio, dejar de fumar, seguir su terapia antirretroviral y tomar el medicamento del 
estudio tal como se le indicaron.  Le daremos esta información en todas las visitas anuales. 
 
ECG 
En el ingreso, se realizará un electrocardiograma o ECG.  Un ECG es un registro de la actividad 
eléctrica de su corazón, que puede mostrar con qué esfuerzo está funcionando.  Usted se 
acostará sin moverse durante no más de 10 minutos mientras se lleva a cabo el ECG. 
 
Extracción de sangre 
Se le extraerá sangre para diferentes análisis, si no están disponibles como parte de su 
atención médica de rutina, o bien por cuestiones de seguridad.  Se incluirán análisis de rutina 
para evaluar recuentos sanguíneos, el hígado y la función renal. 
 
En el tamizaje, usaremos los resultados de sus pruebas de la función hepática efectuadas 
como parte de su atención de rutina por su proveedor de salud.  En el mes 1 y el mes 12, a 
usted le extraeremos sangre para evaluar su función hepática.  Este análisis se exige como 
parte de su participación en el estudio.  En cada una de estas visitas, se le extraerá 
aproximadamente 1 cucharadita de sangre para efectuar este análisis. 
 
En el tamizaje y en la visita final del estudio usaremos los resultados de su CBC (siglas en 
inglés de recuento de sangre) y función renal, obtenidos por su proveedor de salud como parte 
de la atención de rutina. 
 
En el tamizaje y en las visitas anuales, usaremos los resultados de su recuento de linfocitos T 
CD4 (cuántas células que combaten las infecciones hay en su sangre), obtenidos por su 
proveedor de salud como parte de la atención de rutina. 
 
En el ingreso y en las visitas anuales usaremos los resultados de la carga viral del VIH (cuánto 
VIH hay en su sangre), obtenidos por su proveedor de salud como parte de la atención de 
rutina. 
 
En el tamizaje, usaremos los resultados de los niveles de colesterol (grasas que se hallan en la 
sangre) realizados por su proveedor de salud como parte de su atención de rutina. 
 
Se le darán a conocer los resultados de estos análisis de rutina. 


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En el ingreso, en todas las visitas anuales, y en la visita final del estudio, se le extraerá algo de 
sangre y se la almacenará para análisis que se efectuarán más adelante en el estudio o 
después de que finalice el estudio.  Estos análisis medirán los niveles de grasas y azúcar en la 
sangre.  Algunos de esos análisis se usarán para hacer análisis metabólicos en la sangre (que 
miden de qué manera su organismo usa la comida que usted ingiere).  Usted no tiene la 
obligación de aceptar que se almacene esta sangre para incorporarse al estudio y puede 
cambiar de opinión sobre el almacenamiento de la sangre cuando lo desee.  Su sangre se 
puede almacenar (con los protectores usuales de la identidad) por tiempo indefinido.  No se le 
darán a conocer los resultados de la investigación que se realice con su sangre. 
 
En cada una de estas visitas, se le extraerán y almacenarán aproximadamente 2 cucharaditas 
de sangre con estos propósitos. 
 
¿Acepta usted dejarnos almacenar sus muestras para hacer pruebas que midan los niveles de 
grasas y azúcar en su sangre? 
 
________ SÍ  ________ NO  
 _______Iniciales 
 
 
En el ingreso, todas las visitas anuales (como se indicó en la tabla de Procedimientos del 
Estudio) y en la visita final del estudio, algo de sangre se extraerá y almacenará para futura 
investigación aprobada por REPRIEVE (siglas en inglés) sobre distintas afecciones, como 
enfermedades cardiovasculares, VIH, inflamación, cáncer o medicación con estatinas.  Usted 
no tiene la obligación de aceptar que se almacene esta sangre para incorporarse al estudio y 
usted puede cambiar de opinión sobre el almacenamiento de sangre cuando lo desee.  Su 
sangre se puede almacenar (con los protectores usuales de la identidad) por tiempo indefinido.  
No se le darán a conocer los resultados de la investigación que se realice con su sangre. 
 
Hasta 15 cucharaditas de sangre se obtendrán en cada una de estas visitas para estos 
propósitos. 
 
¿Acepta usted dejarnos almacenar sus muestras para futura investigación sobre afecciones 
tales como enfermedades cardiovasculares, VIH, inflamación, cáncer y medicación con 
estatinas? 
________ SÍ  ________ NO  _______Iniciales 
 
 
Todos los sitios de ACTG agregarán a su consentimiento local: Se le extraerá alrededor de 1 
cucharadita de sangre para observar los genes que pueden afectar el riesgo de sufrir 
enfermedad cardiovascular y cómo las estatinas actúan en su organismo.  Los análisis 
genéticos son pruebas de laboratorio que observan las diferencias entre los genes de las 
personas.  Su organismo, como el de todos los seres vivos, está hecho de células, y las células 
contienen ácido desoxirribonucleico, también conocido como “ADN”.  El ADN es como una 
cadena de información reunida en un orden determinado.  Las partes de la cadena constituyen 
“genes”. Los genes contienen instrucciones sobre cómo su organismo debe funcionar y 
combatir las enfermedades.  Los análisis en este estudio se enfocarán en ciertos genes que se 
sabe que tienen un efecto sobre las enfermedades cardiovasculares y de qué manera su 


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organismo usa las estatinas.  Es posible que en el futuro se identifiquen nuevos genes de 
interés y que también puedan ser examinados.  
 
Su conformación genética es solo suya, de modo que existe el riesgo en la investigación 
genética de que, a pesar de todas las medidas de seguridad que se tomen, alguien que use sus 
muestras o su información genética pueda averiguar que esa información es de usted.  Sin 
embargo, este riesgo es muy pequeño, aunque se puede incrementar con el tiempo, dado que 
la ciencia y la tecnología progresan rápidamente. 
 
 
SOLO los sitios de ACTG en los Estados Unidos agregarán a su consentimiento local: En el 
caso de que la información genética sobre usted sea vinculada con su nombre, la ley federal de 
los Estados Unidos denominada Ley de No Discriminación por Información Genética (GINA, 
siglas en inglés), le ayuda a protegerse.  Esta norma prohíbe a las compañías de seguro de 
salud, a los planes de salud de grupos y a la mayoría de los empleadores, negarse a brindar 
servicios en base a su información genética.  Sin embargo, la ley GINA no le protege a usted 
contra la discriminación que pueda sufrir por parte de compañías que venden seguros de vida, 
seguros por discapacidad o seguros de cuidados de largo plazo. 
 
Todos los sitios de ACTG agregarán esta opción para el participante en su consentimiento 
local: Nos gustaría utilizar parte de la sangre que obtenemos de usted para observar sus genes 
(ADN). ¿Usted está de acuerdo con este estudio genético? 
 
__________SI    __________NO     __________Iniciales 
 
 
Si en una fecha posterior usted cambia de parecer y quiere que se destruyan sus muestras, 
contacte al personal de la investigación.  Hay dos formas de retirar su autorización.  Usted 
podría autorizar a los investigadores a que retiren todos los identificadores personales de sus 
muestras, de modo que estas no se puedan vincular más con usted.  Estas muestras se 
volverán anónimas.  O bien, usted puede pedirles a los investigadores que destruyan sus 
muestras, de modo que no se puedan usar en futura investigación.  Sin embargo, cualquiera 
sea el caso, los investigadores no podrán destruir las muestras o la información de la 
investigación que ya se esté llevando a cabo.   
Para todos los sitios fuera de los Estados Unidos, agregar a su consentimiento local: Sus 
muestras se pueden enviar y almacenar fuera de su país y pueden ser usadas por 
investigadores fuera de su país.  
 
Obtención de orina 
Se obtendrá orina en el ingreso para controlar las proteínas en su orina.  Los resultados de este 
análisis no se conocerán inmediatamente; por lo tanto, no le podemos asegurar que se le darán 
a conocer los resultados de este análisis. 
 
Solo los Sitios de ACTG agregarán esto a su consentimiento local: Para los participantes 


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inscriptos en REPRIEVE (A5332) antes del 1 de enero de 2018, también se recogerá orina en 
los meses 12, 24 y 48, para controlar su función renal. 
 
Análisis de sangre en ayunas 
Antes del tamizaje, en el ingreso y en todas las visitas anuales, usted no debe comer ni beber 
nada, incluida cualquier clase de comida, bebidas, caramelos o goma de mascar, durante 8 
horas antes de la visita.  Se le aconseja que tome agua antes de sus visitas.  Si usted no está 
en ayunas, le pediremos que regrese en ayunas para que se le extraiga sangre dentro de los 30 
días de la visita del estudio.  
 
Medicamentos del estudio que se le darán a usted 
Los medicamentos del estudio se le darán a usted en el ingreso y cada 4 meses.  No se le 
darán a usted medicamentos del estudio en la visita final del estudio. 
 
Cuestionarios 
Se le preguntará sobre su dieta y ejercicios en el ingreso y esto se repetirá en la visita final del 
estudio. 
¿POR CUÁNTO TIEMPO ESTARÉ EN ESTE ESTUDIO? 
 
Usted estará en este estudio alrededor de 6 a 10 años (72 a 120 meses) según cuándo se 
incorpore. 
 
 
¿POR QUÉ PODRÍA EL/LA MÉDICO(A) APARTARME DE ESTE ESTUDIO ANTES DE 
TIEMPO? 
 
El/La médico(a) del estudio puede necesitar apartarlo(a) del estudio antes de tiempo sin su 
permiso si: 
• 
El/la médico(a) cree que es lo más conveniente para usted. 
• 
Se cancela el estudio. 
• 
Usted no puede concurrir a las visitas del estudio tal como lo requiere el estudio. 
 
El/La médico(a) del estudio puede necesitar retirarle el medicamento del estudio sin su permiso 
si: 
• 
Usted no puede tomar el medicamento del estudio tal como lo requiere el estudio. 
• 
Continuar con el medicamento del estudio puede ser perjudicial para usted. 
• 
Usted necesita un tratamiento que no puede recibir mientras esté en el estudio. 
• 
Usted queda encinta. 
 
Si usted debe dejar de tomar el medicamento del estudio antes de que finalice el estudio, le 
pediremos que continúe participando del estudio y que regrese para algunas visitas y 
procedimientos del estudio. 
 
Si usted tiene que dejar de tomar de forma permanente el medicamento del estudio, o una vez 
que deje el estudio, ¿cómo se le proveerá la pitavastatina? 
 
Durante el estudio: 


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Si usted debe dejar de recibir de forma permanente el medicamento pitavastatina suministrado 
por el estudio antes de que finalice su participación en el estudio, el personal del estudio 
analizará otras opciones que puedan beneficiarlo(a).  Si usted descontinúa su participación 
activa en el estudio, el personal del estudio se pondrá en contacto anualmente con usted, sus 
contactos provistos, el departamento de registros médicos o su proveedor de salud, para 
determinar si usted ha tenido alguna enfermedad cardíaca, accidente cerebrovascular o 
enfermedad vascular, o si ha fallecido (y la causa de la muerte desde el último contacto). 
 
Después del estudio: 
Después de que usted haya completado su participación en el estudio, éste no podrá seguir 
suministrándole a usted la pitavastatina que usted recibía en el estudio.  Si continuar tomando 
éste o similares medicamentos pudiera ser beneficioso para usted, el personal del estudio 
analizará cómo puede hacer usted para obtenerla.  
¿CUÁLES SON LOS RIESGOS DEL ESTUDIO? 
 
El medicamento usado en este estudio puede tener efectos secundarios, algunos de los cuales 
se enumeran a continuación.  Tenga en cuenta que estas listas no incluyen todos los efectos 
secundarios observados con este medicamento.  Estas listas incluyen los efectos secundarios 
más graves o habituales con una relación conocida o posible.  Si usted tiene preguntas 
respecto a los efectos adicionales del medicamento del estudio, pregúntele al personal médico 
de su sitio.  
 
Existe el riesgo de sufrir efectos secundarios graves o peligrosos para la vida, cuando 
medicamentos que no son del estudio se toman junto con el medicamento del estudio.  Por su 
seguridad, usted debe informarle a el/la médico(a) o enfermero(a) del estudio sobre todos los 
medicamentos que se encuentre tomando antes de comenzar el estudio y además antes de 
comenzar a tomar cualquier nuevo medicamento mientras esté en el estudio.  Asimismo, antes 
de inscribirse en cualquier otro ensayo clínico, usted debe informárselo a el/la médico(a) o 
enfermero(a) del estudio mientras se encuentre en este estudio.  
 
Riesgos de la Pitavastatina 
• 
Problemas musculares.  La pitavastatina ocasionalmente puede causar graves problemas 
musculares, que pueden ocasionar problemas renales, incluyendo insuficiencia renal y rara 
vez la muerte.  
• 
Problemas hepáticos.  La pitavastatina ocasionalmente puede causar problemas hepáticos, 
que rara vez pueden ser graves u ocasionar la muerte.  Su enfermero(a) o médico(a) del 
estudio le realizará análisis de sangre para controlar su hígado antes de comenzar a tomar 
la pitavastatina y mientras usted se encuentre tomándola.  
• 
Asegúrese de informar a su médico(a) o enfermero(a) del estudio de inmediato si usted 
tiene alguno de los siguientes problemas:  
▪ 
Problemas musculares, como debilidad, sensibilidad, o dolores que aparecen sin una razón 
aparente, especialmente si usted también tiene fiebre o siente más cansancio que el 
habitual. 
▪ 
Náuseas y vómitos. 
▪ 
Orina de tonalidad marrón o de color oscuro. 
▪ 
Sentir más cansancio que el habitual. 
▪ 
Notar que la piel y la parte blanca de los ojos se tornan amarillas. 
▪ 
Tener dolor de estómago. 


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Otros problemas que han sido ocasionados por la pitavastatina son dolores de cabeza, 
salpullido (que rara vez puede ser grave o fatal), reacción alérgica grave o hinchazón, 
estreñimiento, gases, diarrea, dolor o entumecimiento en los brazos o las piernas, ruptura de 
tendón, infección del tracto urinario, mareos, deterioro de la memoria y depresión. Todos estos 
problemas son de infrecuentes a raros. 
 
Riesgos de las extracciones de sangre 
Extraer sangre puede causar cierto malestar, vahídos, sangrado, hinchazón o moretones donde 
la aguja penetra en el cuerpo, y en casos raros, desmayos o infección. 
 
Riesgos del ayuno 
Algunas personas encuentran que ayunar puede ser muy molesto.  Puede hacer que algunos 
individuos se sientan ansiosos, irritables o hambrientos.  Los pacientes a los que se les exigen 
que tomen sus medicamentos matutinos con comida deberían esperar hasta después de 
completar la visita para tomar sus medicamentos.   
 
Riesgos del ECG 
Usted puede sufrir una irritación leve, un enrojecimiento ligero y picazón en la piel donde se 
colocan los electrodos del electrocardiógrafo.  
 
TODOS los sitios de ACTG agregarán a su consentimiento local: 
 
Análisis Genéticos 
Los resultados de sus pruebas genéticas son sólo para fines de investigación y los resultados 
individuales no serán devueltos a usted.  Los resultados de los estudios genéticos nunca 
formaran parte de su historia clínica.  Vamos a proteger su confidencialidad en la mayor 
medida.  Las muestras de sangre para estudios genéticos serán identificadas de modo tal de 
mantener su confidencialidad. 
 
Los resultados del estudio de investigación no se les darán a miembros de su familia, 
compañías de seguro, empleadores, o terceros, sin su permiso por escrito y la aprobación de la 
Junta Institucional de Revisión en _________.  
 
 
Riesgos desconocidos 
Podrían presentarse durante el estudio otros efectos secundarios desconocidos en este 
momento.  Todos los medicamentos tienen un posible riesgo de reacción alérgica, que si no se 
trata de inmediato podría poner la vida en peligro.  Durante el estudio, se le dará a conocer 
cualquier nueva información que pueda afectar su decisión de permanecer en el estudio.  Si 
usted decide permanecer en el estudio, se le pedirá que firme un formulario de consentimiento 
actualizado.  Si usted decide dejar el estudio antes de tiempo, el personal del estudio hablará 
con usted sobre sus opciones de tratamiento.  
 
 
¿HAY RIESGOS RELACIONADOS CON EL EMBARAZO? 
 
La pitavastatina es insegura para los bebés en gestación.  Los riesgos para los bebés en 


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gestación incluyen defectos de nacimiento, parto prematuro o la muerte.  Si usted mantiene 
relaciones sexuales que pudieran conducir a un embarazo, usted debe aceptar no quedar 
encinta.  
 
Si usted puede quedar encinta, usted se debe hacer un análisis de embarazo antes de que 
ingrese a este estudio y en cada visita (se obtendrá 1 cucharadita de sangre o una muestra de 
orina) y en cada oportunidad en que se sospeche un embarazo.  Este análisis debe indicar que 
usted no está encinta.  Si usted queda encinta o piensa que puede estar encinta en cualquier 
momento durante el estudio, dígaselo de inmediato al personal del estudio.  El personal del 
estudio hablará con usted sobre sus opciones. 
 
Debido al riesgo involucrado, usted y su pareja deben usar al menos un método aceptado de 
control de la natalidad que usted analice con el personal del estudio.  Usted debe comenzar a 
usar un método aceptado de control de la natalidad al menos dos semanas antes de que 
comience a tomar el medicamento del estudio y continuar usando una forma aceptada de 
control natal hasta al menos 6 semanas después de haber interrumpido el medicamento del 
estudio.  Si usted mantiene relaciones sexuales que puedan causar un embarazo, y no usa 
ninguna forma aceptada de control natal, su médico(a) del estudio le retirará el medicamento 
del estudio.  Usted puede elegir alguno de los siguientes métodos de control natal que se 
enumeran a continuación: 
• 
Condones (masculinos o femeninos), con o sin un agente espermicida 
• 
Un diafragma o capuchón cervical, con espermicida 
• 
Un DIU (dispositivo intrauterino) 
• 
Ligadura de trompas 
• 
Microinsertos en las trompas 
• 
Anticoncepción de base hormonal 
 
Si usted queda encinta durante el estudio, el personal del estudio querría obtener información 
sobre el resultado de su embarazo (incluso si éste es posterior a que deje el estudio).  Si usted 
está tomando medicamentos contra el VIH cuando queda encinta, su embarazo será informado 
a una base de datos internacional que recopila información sobre embarazos de mujeres que 
toman medicamentos contra el VIH.  Este informe no usará su nombre ni ninguna otra 
información que pudiera identificarla. 
 
Lactancia 
Se desconoce si el medicamento del estudio pasa a través de la leche materna y puede causar 
un daño al lactante.  Las mujeres que comienzan a dar de lactar deben dejar de tomar el 
medicamento que suministra el estudio.  
 
 
¿HAY BENEFICIOS AL PARTICIPAR EN ESTE ESTUDIO? 
 
Los estudios han demostrado que las estatinas brindan un beneficio en términos de prevención 
de enfermedades cardiacas en personas sin el VIH con inflamación, pero los efectos de las 
estatinas para prevenir enfermedades cardiacas en PWH es desconocida.  Si usted participa en 
este estudio, puede haber un beneficio directo para usted, pero no se le pueden brindar 
garantías.  Es posible que usted obtenga un beneficio al conocer su riesgo de sufrir un evento 
cardiovascular, pero también es posible que usted no reciba ningún beneficio por estar en este 


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estudio, ya sea porque el medicamento no puede funcionar o porque a usted se le asignó el 
placebo.  La información adquirida en este estudio puede ayudar a otras personas que tienen el 
VIH y están en riesgo de sufrir enfermedad cardiovascular. 
 
 
¿QUÉ OTRAS OPCIONES TENGO ADEMÁS DE ESTE ESTUDIO? 
 
En lugar de estar en este estudio, usted tiene la opción de: 
• 
Tratamiento con medicamentos recetados disponibles para usted 
• 
Tratamiento con medicamentos experimentales, si usted califica 
• 
Ningún tratamiento 
• 
Continuar con la atención médica de rutina que le brinda su proveedor de atención primaria 
• 
Incorporarse a otro ensayo clínico, si usted califica 
• 
No recibir atención médica 
 
Hable con el/la médico(a) del estudio sobre estas y otras opciones disponibles para usted. Su 
médico(a) del estudio le explicará los riesgos y beneficios de estas opciones. 
¿QUÉ HAY QUE SABER ACERCA DE LA CONFIDENCIALIDAD? 
 
Para TODOS los sitios de los Estados Unidos: Nosotros haremos todo lo posible para proteger 
su privacidad.  Además de los esfuerzos del personal del estudio para ayudar a mantener en 
reserva su información personal, hemos obtenido un Certificado de Confidencialidad del 
Gobierno Federal de los Estados Unidos.  Este Certificado implica que los investigadores no 
pueden ser obligados a informarles sobre su participación a personas que no estén conectadas 
con este estudio, tales como los miembros del sistema judicial.  Asimismo, ninguna publicación 
de este estudio utilizará su nombre ni lo/la identificará a usted personalmente. 
 
Las personas que pueden revisar sus expedientes incluyen al Grupo de Ensayos Clínicos de 
SIDA (ACTG), la Oficina para la Protección de los Seres Humanos en la Investigación (OHRP, 
siglas en inglés) u otras agencias gubernamentales como parte de sus obligaciones, la 
Administración de Alimentos y Medicamentos (FDA), la IRB (siglas en inglés)/EC (siglas en 
inglés) (un grupo que protege los derechos y el bienestar de las personas en la investigación) 
del (insertar nombre del sitio), los Institutos Nacionales de la Salud (NIH), otras entidades de 
regulación locales, de Estados Unidos e internacionales, el personal del estudio, los monitores 
del estudio, las compañías farmacéuticas que apoyan este estudio y sus representantes.  El 
Certificado de Confidencialidad no impide que usted revele información sobre usted y su 
participación en el estudio. 
 
Incluso con el Certificado de Confidencialidad, si el personal del estudio se entera de un posible 
abuso de menores y/o negligencia o riesgo de daño a usted o a otras personas, estamos 
obligados a decírselo a las autoridades apropiadas. 
O BIEN 
 
Para TODOS los sitios fuera de los Estados Unidos: Se hará todo lo posible para mantener en 
reserva su información personal.  No le podemos garantizar absoluta confidencialidad.  Su 
información personal puede ser revelada si así lo exige la ley. Ninguna publicación de este 
estudio usará su nombre o lo/la identificará a usted personalmente. 


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Sus expedientes pueden ser revisados por el ACTG, OHRP (siglas en inglés), FDA, IRB (siglas 
en inglés)/EC (siglas en inglés) del (inserte el nombre del sitio), los Institutos Nacionales de la 
Salud (NIH), otras entidades de regulación locales, de Estados Unidos e internacionales, las 
agencias regulatorias/de salud nacionales, personal del estudio, monitores del estudio, la 
compañía farmacéutica que apoya este estudio y sus representantes. 
 
Toda la información recopilada sobre usted como parte del estudio se enviará de forma 
segura al centro de gestión de datos y estadísticas del ACTG en los Estados Unidos para 
combinarla con la información de otros participantes en el estudio y realizar un análisis 
estadístico de los resultados del estudio.  No se enviará su nombre ni otros 
identificadores personales.  Su sitio de investigación es responsable de enviar su 
información de acuerdo con las leyes, regulaciones y políticas de su país y sitio de 
investigación.  (No hay nuevos procedimientos en la obtención de los datos) 
 
 
Una descripción de este ensayo clínico estará disponible en htttps:www.ClinicalTrials.gov , tal 
como lo requiere la ley en los Estados Unidos.  Este sitio de Internet no incluirá información que 
pueda identificarlo(a) a usted.  Como máximo, el sitio de Internet incluirá un resumen de los 
resultados.  Usted puede consultar este sitio de Internet cuando lo desee. 
 
 
¿QUÉ OCURRE SI NO PODEMOS UBICARLO(A) DURANTE EL ESTUDIO? 
 
En el caso de que usted no pueda ser ubicado(a) después de múltiples intentos por 
contactarnos con usted, el personal del estudio puede intentar contactarse con usted a través 
de números de teléfono alternativos de familiares, amigos, del coordinador o de conocidos, 
obtenidos en el tamizaje y actualizados en cada visita.  Si usted no puede ser ubicado(a) a 
través de los contactos alternativos, intentaremos obtener información sobre usted de otras 
fuentes, tales como miembros de su familia, otros contactos designados o registros clínicos.  El 
propósito de obtener esta información desde el último contacto es determinar si usted ha 
fallecido y la causa del fallecimiento, y si usted ha tenido alguna enfermedad cardíaca, 
accidente cerebrovascular o eventos o procedimientos relacionados con una enfermedad 
vascular.  
 
Contacto con Sus Proveedores de Salud 
Los sitios pueden modificarlo según los requisitos locales para obtener registros de atención 
médica: Como se mencionó antes, actualmente no tenemos datos que nos digan si las PWH 
con un riesgo moderado de sufrir enfermedades cardiovasculares según la calculadora de 
riesgo ASCVD deberían ser tratados con estatinas.  Si usted está en este grupo de riesgo 
moderado, con un puntaje de riesgo de entre 7.5% y 15%, nos gustaría informar a su(s) 
proveedor(es) de salud sobre los fundamentos del ensayo, pero necesitamos de su permiso 
para compartir esta información. 
 
Asimismo, con su autorización, para la cual usted debería firmar un permiso, el personal del 
estudio puede contactar a sus proveedores de salud en relación con cualquier diagnóstico 


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clínico que usted pueda desarrollar durante el estudio, incluyendo diagnósticos relacionados 
con el corazón y otros diagnósticos, tales como VIH, o diagnósticos de riñón, hígado o cáncer.  
 
¿Nos autoriza usted a tomar contacto con su(s) proveedor(es) de salud para compartir 
información respecto a su puntaje de riesgo cardiovascular y los fundamentos del ensayo, para 
proveerle(s) de información respecto a los diagnósticos clínicos y hacerle saber a su médico(a) 
que él/ella podría objetar que usted participe en este estudio dado que usted tiene la 
probabilidad de recibir el placebo en lugar del tratamiento con estatinas? 
 
 
________ SÍ  ________ NO  _______Iniciales 
 
 
¿CUÁLES SON MIS COSTOS? 
 
No habrá costos para usted por los medicamentos del estudio, las visitas del estudio, los 
exámenes físicos, las pruebas de laboratorio u otros análisis que requiere el estudio.  Usted, su 
compañía de seguros o su sistema de salud serán responsables por el costo de su atención 
médica habitual y por los costos de los medicamentos que no suministre el estudio. 
 
Participar en este estudio puede implicar costos adicionales para usted y su compañía de 
seguros.  En algunos casos, es posible que su compañía de seguros no pague estos costos 
porque usted está participando en un estudio de investigación.  
 
¿RECIBIRÉ ALGÚN PAGO? 
 
Se le pagará a usted ________ en la visita de ingreso, la visita del mes 1 y en las visitas 
anuales posteriores, por su participación en el estudio.  (El equipo recomienda una 
compensación a los participantes de $25 en cada visita anual y en la visita de finalización 
del estudio.  A los sitios se les reembolsará el gasto). 
 
 


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¿QUÉ SUCEDE SI SUFRO UNA LESIÓN? 
 
Si usted se lesiona como resultado de su participación en este estudio, se le dará tratamiento 
inmediato para sus lesiones.   
 
Para todos los sitios: los NIH no tienen ningún mecanismo para proveer una 
compensación directa por lesiones relacionadas con la investigación.  
 
[Sitios: modificar (si es necesario) e insertar alguna de estas dos declaraciones, según 
corresponda a su sitio.  Si a su sitio se le exige que contrate un seguro para ensayos 
clínicos (CTI, siglas en inglés), esto se debe indicar en el consentimiento informado]. 
• 
Este sitio tiene un seguro para ensayos clínicos.  Este seguro permitirá al sitio 
suministrarle a usted una compensación monetaria si sufre un perjuicio como 
resultado de su participación en este estudio de investigación. 
O BIEN 
• 
El costo de este tratamiento se le cobrará a usted o a su compañía de seguros.  No 
hay un programa de compensación ya sea a través de esta institución o de los NIH]. 
 
Usted no renunciará a ninguno de sus derechos legales al firmar este formulario de 
consentimiento. 
 
 
¿CUÁLES SON MIS DERECHOS COMO PARTICIPANTE DE LA INVESTIGACIÓN? 
 
Participar en este estudio es totalmente voluntario.  Usted puede elegir no participar en este 
estudio  o dejar este estudio en cualquier momento.  Su decisión no tendrá ningún impacto 
sobre su participación en otros estudios dirigidos por NIH y no implicará  ninguna penalidad o 
pérdida de beneficios a los cuales de otra manera tuviese derecho. 
 
Le diremos sobre cualquier nueva información de este u otros estudios que puedan afectar su  
salud, bienestar o voluntad de permanecer en este estudio.  Si usted quiere conocer los 
resultados del estudio, hágaselo saber al personal del estudio. 
 
 
¿QUÉ HAGO SI TENGO PREGUNTAS O PROBLEMAS? 
 
Para preguntas sobre este estudio o lesiones relacionadas con la investigación, contacte a: 
 
• 
Nombre del investigador u otro miembro del personal del estudio 
• 
Número de teléfono de la persona nombrada anteriormente 
 
Para preguntas relacionadas con sus derechos como participante de la investigación, contacte 
a: 
 
• 
Nombre o cargo de la persona en la Junta Institucional de Revisión (IRB/EC) u otra 
organización apropiada para el sitio. 


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• 
Número de teléfono de la persona nombrada anteriormente. 
 
 
 


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PÁGINA DE FIRMAS 
 
Si usted ha leído este formulario de consentimiento (o el mismo le ha sido explicado), todas sus 
preguntas han sido contestadas y usted acepta participar en este estudio, por favor firme a 
continuación. 
 
 
 
 
___________________________________            _________________________________  
 
Nombre del Participante (letra de imprenta)           Firma del Participante y Fecha 
 
 
 
___________________________________            _________________________________ 
Representante Legal del Participante  
           Firma del Representante Legal y Fecha 
  
(letra de imprenta) 
(Según corresponda) 
 
 
 
_________________________________                _________________________________ 
Personal del Estudio que Conduce la                       Firma del Personal del Estudio y Fecha 
Discusión del Consentimiento 
(letra de imprenta)       
 
 
________________________________               __________________________________   
 
Nombre del Testigo (letra de imprenta)                     Firma del Testigo y Fecha 
(Según corresponda) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APÉNDICE IA: ANEXO DEL MODELO DE CONSENTIMIENTO INFORMADO 
 
Ensayo Clínico Aleatorizado para Prevenir Eventos Vasculares en el VIH - (REPRIEVE) 
(A5332) Versión FINAL 6.0, 16 de mayo de 2022 
 
 
TÍTULO CORTO DEL ESTUDIO: REPRIEVE 
 
Se le solicita a usted que firme este anexo de consentimiento porque está participando 
en un estudio de investigación en _____________, titulado “Ensayo Clínico Aleatorizado 
para Prevenir Eventos Vasculares en el VIH - (REPRIEVE) (A5332).” 
 
El propósito de este anexo es incluir información sobre el intercambio de su información 
genética desidentificada.  “Desidentificada” implica que toda la información que le 
identifique, por ejemplo, su nombre, número de registro clínico y fecha de nacimiento, ha 
sido eliminada. 
 
La información genética se obtuvo de la muestra de sangre que se extrajo de usted en la 
visita de ingreso.  Usted estuvo de acuerdo en proporcionar esta muestra en el 
consentimiento original. 
 
A excepción de las actividades descriptas en este anexo, los términos de su formulario 
de consentimiento original permanecen en plena vigencia, lo que incluye que los 
resultados del estudio de investigación no les serán entregados a sus familiares, 
compañías de seguros o empleadores sin su permiso por escrito y la aprobación de la 
Junta Institucional de Revisión/Comité de Ética en ____________________.  
 
Por favor, lea atentamente este anexo de consentimiento y tómese su tiempo para tomar 
una decisión.  Cuando el/la médico(a) o el personal del estudio hable con usted de este 
anexo, pídales que le expliquen cualquier palabra o información que usted no entienda 
con claridad.  No es necesario que firme este anexo para poder permanecer en 
REPRIEVE (A5332). 
 
INTERCAMBIO DE SU INFORMACIÓN GENÉTICA 
La enfermedad y la salud se ven afectadas por los genes o la información genética que 
tenemos dentro de nosotros.  La información genética que obtenemos en este estudio 
puede ayudar a avanzar en otros tipos de investigación.  Los Institutos Nacionales de la 
Salud (NIH) han establecido un programa que permite a los investigadores compartir la 
información genética de diferentes estudios para ayudarnos a conocer más de cada 
estudio financiado por los NIH.  Su información genética se compartirá con otros 
investigadores a través de una base de datos segura y de acceso controlado respaldada 
por los NIH.   
 
Cuando compartamos su información genética con otros investigadores a través de una 
base de datos segura y de acceso controlado respaldada por los NIH, incluidos los 
estudios del genoma completo (como la determinación de su secuencia de ADN 
completa en una sola vez), eliminaremos toda la información que le identifique.  Esta 
información desidentificada podrá utilizarse en otras investigaciones.  No creemos que 


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haya más riesgos para su privacidad y confidencialidad al compartir su información 
genética con esta base de datos de acceso controlado.  Sin embargo, no podemos 
predecir cómo se utilizará la información genética en el futuro. 
 
Su nombre u otra información directamente identificable no se facilitará a la base de 
datos de acceso controlado respaldada por los NIH.  Existen muchas otras salvaguardas 
para proteger su información mientras se almacena en la base de datos de acceso 
controlado y se utiliza para la investigación.  Aun así, es posible que en el futuro alguien 
pueda volver a identificar su información.  Además, utilizando la base de datos de 
acceso controlado, los investigadores pueden publicar o presentar los resultados 
combinados de su investigación, pero no incluirán su nombre ni otra información que 
pueda identificar a usted. 
 
No se espera que la investigación que utilice su información genética le aporte ningún 
beneficio directo.  Usted puede retirar su consentimiento para compartir su información 
genética en cualquier momento.  Sin embargo, no podemos recuperar ninguna 
información que ya se haya compartido. 
 
¿Acepta compartir su información genética? 
 
________SÍ ___________NO _________Iniciales 
 
OTRA INFORMACIÓN 
El resto de la información contenida en el consentimiento de REPRIEVE (A5332) que 
usted firmó también se aplica a este anexo del consentimiento.  Se le brindará a usted 
como referencia una copia firmada de este consentimiento en el momento en que usted 
brinde su consentimiento a la información de este anexo. 
 
PREGUNTAS RESPECTO A ESTE ANEXO DEL CONSENTIMIENTO  
Si usted tiene preguntas, preocupaciones o quejas con respecto a este anexo del 
consentimiento, contacte a el/la Dr.  (nombre) al (número) durante el horario de atención 
al público, y al (localizador) después de hora y en fines de semanas o días festivos. 
 
Para preguntas respecto a sus derechos como participante en la investigación, o para 
discutir preguntas, preocupaciones o sugerencias relacionadas con la investigación de 
este anexo del consentimiento, o para obtener información u ofrecer aportes sobre la 
investigación, contacte a la Junta Institucional de Revisión/Comité de Ética de 
_____________ al (número). 
 
DECLARACIÓN DE CONSENTIMIENTO 
"Se me ha explicado la finalidad de este anexo del consentimiento.  Se me ha permitido 
hacer preguntas, y mis preguntas han sido respondidas a mi satisfacción.  Se me ha 
dicho con quién debo ponerme en contacto si tengo preguntas, para hablar de 
problemas, preocupaciones o sugerencias relacionadas con la investigación o con este 
anexo, o para obtener información u ofrecer aportes sobre la investigación.  He leído 
este anexo y acepto las opciones que he indicado anteriormente, entendiendo que puedo 
retirar mi consentimiento en cualquier momento.  Se me ha informado que se me 
entregará una copia firmada y fechada de este anexo." 


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PÁGINA DE FIRMAS 
 
Si ha leído este formulario de consentimiento (o se lo han explicado), si ha respondido a 
todas sus preguntas y acepta participar en este estudio, firme con su nombre a 
continuación. 
 
 
 
____________________________ 
_________________________________________ 
Nombre del Participante 
Firma del Participante y Fecha 
(letra de imprenta) 
 
____________________________ 
_________________________________________ 
Representante Legal del Participante 
Firma del Representante Legal y Fecha 
(letra de imprenta) (Según corresponda) 
 
 
____________________________ 
_________________________________________ 
Personal del Estudio que Dirige la 
Firma del Personal del Estudio y Fecha 
Discusión del Consentimiento  
(letra de imprenta) 
 
____________________________ 
_________________________________________ 
Nombre del Testigo (letra de imprenta) 
Firma del Testigo y Fecha 
(Según corresponda) 
 

Prot_ICF_003.pdf: 
 
 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
 
 
Principal Investigators: 
 
Steven Grinspoon, MD 
Pamela Douglas, MD 
Michael Lu, MD, MPH 
Heather Ribaudo, PhD  
 
AIDS Clinical Trials Group  
Investigators:  
 
 
Carlos Malvestutto, MD, MPH 
 
 
 
 
 
Carl Fichtenbaum, MD 
 
 
 
 
 
Judith Aberg, MD 
 
 
 
 
 
Markella Zanni, MD 
 
Data Coordinating Center:   
Harvard School of Public Health 
 
Study Funders: 
 
 
National Heart, Lung, and Blood Institute  
 
 
 
 
 
National Institute of Allergy and Infectious Diseases 
 
National Institute of Diabetes and Digestive and 
Kidney Diseases 
 
Office of AIDS Research, National Institutes of Health 
 
Industry Support: 
 
 
Kowa Pharmaceuticals America 
 
 
 
 
 
Gilead Sciences 
 
 
 
 
 
ViiV Healthcare  
 
NHLBI Program and Medical 
Officer: 
 
 
 
Patrice M. Desvigne-Nickens, MD 
 
 
DAIDS Medical Officer:  
 
 Christine Chiou, MD 
 
 
IND Sponsor:  
 
 
 Division of AIDS, NIAID, NIH  
 
 
IND Number:  
 
 
119127 
 
 
 
 
FINAL Version 6.0 
May 16, 2022


 
 
REPRIEVE (A5332) 
 
 
FINAL Version 6.0 
 
 
16May2022 
 
 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
 
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 (eg, US National Institutes of Health, Division of AIDS) and institutional 
policies. 
 
 
 
 
 
Principal Investigator: __________________________________________________ 
Print/Type 
 
 
 
 
 
Signed:  
 
___________________________________ Date: ________________ 
Name/Title 
 


 
 
REPRIEVE (A5332) 
 
 
FINAL Version 6.0 
 
 
16May2022 
 
 
TABLE OF CONTENTS 
Page 
 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 11 
EXECUTIVE SUMMARY .......................................................................................................... 12 
1.0 
HYPOTHESES AND STUDY OBJECTIVES.................................................................. 14 
1.1 
Clinical Hypotheses ........................................................................................... 14 
1.2 
Clinical Objectives .............................................................................................. 14 
2.0 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background ........................................................................................................ 15 
2.2 
Rationale ........................................................................................................... 27 
3.0 
STUDY DESIGN ........................................................................................................... 28 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 29 
4.1 
Inclusion Criteria ................................................................................................ 29 
4.2 
Exclusion Criteria ............................................................................................... 32 
4.3 
Study Enrollment Procedures............................................................................. 33 
4.4 
Mechanistic Substudy of REPRIEVE (A5333s) Enrollment Procedures ............. 34 
4.5 
Coenrollment Guidelines .................................................................................... 35 
4.6 
Retention Procedures ........................................................................................ 35 
5.0 
STUDY TREATMENT ................................................................................................... 35 
5.1 
Regimens, Administration, and Duration ............................................................ 35 
5.2 
Study Product Formulation and Preparation ....................................................... 36 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 36 
5.4 
Concomitant Medications ................................................................................... 37 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 39 
6.1 
Schedule of Evaluations..................................................................................... 39 
6.2 
Timing of Evaluations ......................................................................................... 45 
6.3 
Instructions for Evaluations and Data Collection ................................................ 46 
6.4 
Endpoint Assessments....................................................................................... 54 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 56 
7.1 
Toxicity Management ......................................................................................... 57 
7.2 
Requirement for Precautionary or Prohibited Medications (see PSWP) ............. 60 
7.3 
Pregnancy.......................................................................................................... 60 
7.4 
Unblinding Procedures ....................................................................................... 60 


 
 
REPRIEVE (A5332) 
FINAL Version 6.0 
 
CONTENTS (Cont’d) 
16May2022 
 
 
 
Page 
 
 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 61 
8.1 
Premature and Permanent Treatment Discontinuation ....................................... 61 
8.2 
Premature Study Discontinuation ....................................................................... 61 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 62 
9.1 
General Design Issues ....................................................................................... 62 
9.2 
Outcome Measures ............................................................................................ 63 
9.3 
Randomization and Stratification ........................................................................ 65 
9.4 
Sample Size and Accrual ................................................................................... 65 
9.5 
Monitoring .......................................................................................................... 70 
9.6 
Analyses ............................................................................................................ 73 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 77 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 78 
11.1 
Records to Be Kept ............................................................................................ 78 
11.2 
Role of Data Management ................................................................................. 78 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 78 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 78 
12.0 
PARTICIPANTS ............................................................................................................ 80 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 80 
12.2 
Participant Confidentiality ................................................................................... 80 
12.3 
Study Discontinuation ........................................................................................ 80 
12.4 
Women and Minorities ....................................................................................... 80 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 80 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 81 
15.0 
STUDY GOVERNANCE ................................................................................................ 81 
16.0 
REFERENCES .............................................................................................................. 82 
APPENDIX I: SAMPLE INFORMED CONSENT ....................................................................... 93 
APPENDIX IA: SAMPLE INFORMED CONSENT ADDENDUM............................................. 108 
APPENDIX II: THE MECHANISTIC SUBSTUDY OF REPRIEVE (A5333s) ........................... 111 
APPENDIX III:  SAMPLE INFORMED CONSENT .................................................................. 136 
APPENDIX IV: REPRIEVE OBJECTIVES TO DECIPHER SEX-SPECIFIC MECHANISMS OF 
CVD RISK AND RISK REDUCTION ............................................................................ 146 
APPENDIX V: REPRIEVE ANCILLARY STUDY: EFFECT OF PITAVASTATIN ON KIDNEY 
FUNCTION IN HIV-INFECTED PERSONS ................................................................. 153 
 


 
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SITES PARTICIPATING IN THE STUDY 
 
REPRIEVE (A5332) is a multicenter study open to US clinical research sites and select 
international sites that have been approved for participation by the protocol team. Refer to the 
Site tab on the protocol-specific Web page on the ACTG Member website for the list of eligible 
sites. 


 
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PROTOCOL TEAM ROSTER  
 
Chair 
Steve Grinspoon, MD 
Metabolism Unit 
Harvard Medical School 
55 Fruit Street 
Longfellow 5, Room 207 
Boston, MA  02114 
Phone: 617-724-9109 
E-mail: sgrinspoon@partners.org 
 
Co-Chair 
Pamela Douglas, MD  
Duke University Medical Center 
7022 North Pavilion 
Durham, NC  27715 
Phone: 919-681-2690 
E-mail: pamela.douglas@duke.edu 
 
Vice Chairs 
Judith Aberg, MD 
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place, Box 10190 
New York, NY  10029 
Phone: 212- 241-6741 
E-mail: Judith.aberg@mountsinai.org 
 
Carl Fichtenbaum, MD 
University of Cincinnati 
200 Eden Avenue, Room 3114  
Mail Location 405 
Cincinnati, OH  45267 
Phone: 513-584-6361  
E-mail: fichtecj@ucmail.uc.edu 
 
Carlos Malvestutto, MD, MPH 
Ohio State University Medical Center 
410 West 10th Avenue 
Columbus, OH  43205 
Phone: 614-366-5405 
E-mail: carlos.malvestutto@osumc.edu 
 
Vice Chairs (Cont’d) 
Markella V. Zanni, MD 
Metabolism Unit 
Harvard Medical School,  
55 Fruit Street, Longfellow 5, Room 209 
Boston, MA  02114  
Phone: 617-724-6926 
E-mail: mzanni@mgh.harvard.edu 
 
Vice-Chair and Co-Project Manager 
Kathleen V. Fitch, MSN 
Metabolism Unit 
Harvard Medical School 
55 Fruit Street 
Longfellow 5, Room 207 
Boston, MA 02114 
Phone: 617-724-8015 
E-mail: kfitch@mgh.harvard.edu 
 
Mechanistic Substudy  
Michael T. Lu, MD, MPH 
MGH Cardiovascular Imaging Research 
Center, Harvard Medical School 
165 Cambridge Street, Suite 400 
Boston, MA  02114 
Phone: 617-726-1255 
E-mail: mlu@mgh.harvard.edu 
 
DAIDS Medical Officer 
Christine Chiou, MD 
HIV Research Branch 
TRP, DAIDS, NIAID, NIH 
5601 Fishers Lane, Room 9F41 
Rockville, MD  20852 
Phone: 240-507-9611 
E-mail: cchiou@niaid.nih.gov  
 
NHLBI Program and Medical Officer 
Patrice M. Desvigne-Nickens, MD 
Heart Failure and Arrhythmias Branch 
DCS, NHLBI, NIH  
6705 Rockledge Drive, Room 312-B2 
Bethesda, MD  20817 
Phone: 301-435-0504 
E-mail: desvignp@nhlbi.nih.gov 


 
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Clinical Trials Specialists 
Laura E. Moran, MPH 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3373 
E-mail: laura.moran@dlhcorp.com 
 
Nada Saleh, MS 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., 
A DLH Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-0204 
E-mail: nada.saleh@dlhcorp.com 
 
Statisticians 
Amy Kantor  
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-7129 
E-mail: akantor@sdac.harvard.edu 
 
Jorge Tomas Leon-Cruz 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-7469 
E-mail: jleoncru@sdac.harvard.edu 
 
Heather Ribaudo, PhD 
Center for Biostatistics in AIDS Research 
Harvard School of Public Health 
655 Huntington Avenue  
Boston, MA  02115 
Phone: 617-432-2897 
E-mail: ribaudo@sdac.harvard.edu 
 
Statisticians (Cont’d) 
Triin Umbleja, MSc 
Statistical and Data Analysis Center 
Harvard School of Public Health 
FXB Building, Room 512A 
651 Huntington Avenue 
Boston, MA 02115 
Phone: 617-432-0118 
E-mail: tumbleja@sdac.harvard.edu 
 
Project Manager 
Kayla Paradis, BA 
Cardiovascular Imaging Research Center 
Department of Radiology, Massachusetts 
General Hospital 
165 Cambridge Street, Suite 400  
Boston, MA 02114 
Phone: 978-870-4535 
E-mail: kparadis@mgh.harvard.edu 
 
Data Managers 
Mark Byroads 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7341 
E-mail: byroads@frontierscience.org 
 
Kenneth Wood, MA 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7235 
E-mail: wood@frontierscience.org 
 
DAIDS Pharmacist 
Oladapo Alli 
5601 Fishers Lane 
Room 9E18, MSC #9829 
Rockville, MD  20852 
Phone: 240-627-3593 
E-mail: oladapo.alli@nih.gov 
 


 
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Investigator 
Gerald Bloomfield, MD 
Associate Professor of Medicine 
Duke University School of Medicine 
200 Morris Street 
Durham, NC 27701 
Phone: 919-668-8702 
E-mail: gerald.bloomfield@duke.edu 
 
Field Representative 
Erin Elizabeth Hoffman, BS 
UNC AIDS CRS 
130 Mason Farm Road 
Chapel Hill, NC  27599 
Phone: 919-843-0720 
E-mail: Erin_Hoffman@med.unc.edu 
 
Laboratory Technologist 
Francoise Giguel 
Division of Infectious Diseases 
Partners AIDS Research Center 
Massachusetts General Hospital 
65 Landsdowne Street, Room 435 
Cambridge. MA  02139 
Phone: 617-768-8374 
E-mail: fgiguel@mgh.harvard.edu 
 
Community Scientific Subcommittee (CSS) 
Representatives 
Karl Shaw, BBA 
19140 Ohio Street 
Detroit, MI 48221 
Phone: 313-861-1979 
E-mail: kedshaw@hotmail.com  
 
Kate Starr, BS 
Ohio State University CRS 
6285 Rygate Drive 
Reynoldsburg, OH 43068 
Phone: 614-353-2944 
E-mail: borloglou@gmail.com 
 
International Program Specialist 
Akbar Shahkolahi, PhD 
ACTG Network Coordinating Center 
Social & Scientific Systems, Inc., A DLH 
Holdings Company 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3318 
E-mail: akbar.shahkolahi@dlhcorp.com 
 
Industry Representatives 
Kathy Melbourne, PharmD 
Gilead Sciences 
333 Lakeside Drive 
Foster City, CA 94404 
Phone: 401-261-7360 
E-mail: kathy.melbourne@gilead.com 
 
James Rooney, MD 
Gilead Sciences, 333 Lakeside Drive 
Foster City, CA  94404 
Phone: 650-522-5708 
E-mail: jim.rooney@gilead.com 
 
Craig Sponseller, MD 
Kowa Pharmaceuticals America, Inc. 
530 Industrial Park Boulevard 
Montgomery, AL  36117 
Phone: 334-288-1288 x127 
E-mail: csponseller@kowapharma.com 
 
Laboratory Data Managers 
Frederic Bone 
Frontier Science and Technology Research 
Foundation. 4033 Maple Road 
Amherst, NY  14226 
Phone: 716-834-0900 x7306 
E-mail: bone@frontierscience.org 
 
David Vlieg 
Frontier Science and Technology 
Research Foundation 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7333 
Email: vlieg@frontierscience.org 


 
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STUDY MANAGEMENT 
 
This section provides important instructions on how to attempt to have questions about 
REPRIEVE (A5332) answered. Following these instructions will help you receive an answer as 
quickly as possible, generally within 24 hours. Sites are responsible for documenting phone 
calls made to team members. 
 
Protocol E-mail Group 
The protocol logon is the primary vehicle for distributing important information about the study to 
sites. It is the site’s responsibility to add all relevant personnel to this e-mail group as soon as 
possible. Contact actg.user.support@fstrf.org to be added to the “actg.protA5332” e-mail group 
and, for sites participating in the mechanistic substudy, to the “actg.prota5333s” substudy e-mail 
group.  
 
IND (Investigational New Drug) Number or Questions  
E-mail Regulatory@tech-res.com. 
 
To Request Study Product Package Inserts and/or Investigator Brochures 
E-mail RIC@tech-res.com. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 1+ 301-294-0741. 
 
Questions about Study Product, Dose, Supplies, Records, and Returns 
E-mail protocol pharmacist Oladapo Alli at PABREPRIEVEPEP@mail.nih.gov.  
 
Protocol Registration Questions 
E-mail Protocol@tech-res.com or call 1+ 301-897-1707.  
 
Participant Registration and Randomization Issues and Study Identification Number (SID) Lists 
E-mail rando.support@fstrf.org or call 1+ 716-834-0900 x7301.   
 
FSTRF Portal Problems and Data Management Questions 
• 
E-mail actg.support@fstrf.org or call 1+ 716-834-0900 x7302 (US sites) or 1+ 716-834-0900 
x7200 (non-US sites).  
• 
For nonclinical questions about randomization/registration, inclusion/exclusion criteria, 
OpenClinica, electronic case report forms (eCRFs), transfers, and other data management 
issues, e-mail reprieve.dmc@fstrf.org. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 1+ 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 


 
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Other Questions 
• 
For all other questions about REPRIEVE (A5332), e-mail actg.corea5332@fstrf.org.  
• 
For all questions about the Mechanistic Substudy A5333s, including coronary computed 
tomography angiography (CCTA), e-mail actg.corea5333s@fstrf.org. 
 
Protocol-Specific Web Page (PSWP) 
Additional information about protocol management can be found on these PSWPs: 
• 
A5332: https://member.mis.s-3.net/cms/study/53278/10260 
• 
A5333s: https://member.mis.s-3.net/cms/study/53279/10264 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
ACC 
American College of Cardiology 
ACTG 
AIDS Clinical Trials Group 
AHA 
American Heart Association 
AMI 
acute myocardial infarction 
ART 
antiretroviral therapy 
ASCVD 
atherosclerotic cardiovascular disease 
CAD 
coronary artery disease 
CCTA 
coronary computed tomography angiography 
CEC 
Clinical Events Committee  
CKD 
chronic kidney disease 
CVD 
cardiovascular disease 
DAIDS 
Division of AIDS 
DM 
diabetes mellitus 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
EDC 
electronic data capture system 
FDG-PET 
fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
FIB-4 
Fibrosis 4 Score 
HDL 
high-density lipoprotein 
IVUS 
intravascular ultrasound 
LDL 
low-density lipoprotein 
MACE 
major adverse cardiovascular events 
NAC 
non-AIDS complications 
NCEP 
National Cholesterol Education Panel  
NHLBI 
National Heart, Lung, and Blood Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
PAB 
Pharmaceutical Affairs Branch (DAIDS) 
PAD 
peripheral arterial disease  
PSWP 
protocol-specific web page 
PWH 
people with HIV 
RCT 
randomized controlled trial 
SAP 
Statistical Analysis Plan 
TIA 
transient ischemic attack


 
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EXECUTIVE SUMMARY 
 
Title 
Randomized Trial to Prevent Vascular Events in HIV – REPRIEVE (A5332) 
Indication 
To study the efficacy of statins to reduce the risk of cardiovascular disease 
(CVD) in people with HIV (PWH). 
Location 
Multicenter trial conducted at US trial sites and select international sites 
Brief 
Rationale 
PWH face an increased risk of CVD morbidity and mortality, yet no preventive 
strategies for CVD risk reduction have been proven for this population. Among 
PWH, immune activation may contribute in unique ways to atherosclerosis and 
ensuing cardiovascular events. Statins affect both traditional CVD risk factors 
(LDL cholesterol) and have pleiotropic effects to reduce inflammation and 
immune activation. Thus, statins may target the unique mechanisms of 
cardiovascular disease in HIV. 
Study 
Design and 
Duration 
Prospective, double-blind, randomized, placebo-controlled, multicenter efficacy 
study in 6500 participants, with individual participants to be followed for up to 72 
months. The sample size was increased to approximately 7500 participants with 
follow-up for up to 84 months per the December 2017 Data and Safety 
Monitoring Board (DSMB) recommendations. Follow-up was further increased to 
96 months, which was endorsed at the December 2018 DSMB meeting. Follow-
up is now planned to continue, up to Month 120, until the study reaches its 
target of 288 primary MACE endpoints or is otherwise recommended for 
closure by the DSMB. 
Treatment 
Pitavastatin 4 mg PO daily or placebo for pitavastatin. 
Primary 
Objective 
To determine the effects of pitavastatin as a primary prevention strategy for major 
adverse cardiovascular events (MACE) in HIV. 
Key 
Secondary 
Objectives 
1. The effects of pitavastatin on the components of MACE and all-cause 
mortality. 
2. The effects of pitavastatin on LDL and non-HDL in relationship to MACE. 
3. Whether baseline traditional risk factors and time updated HIV-specific 
immunological risk factors are predictive of MACE and pitavastatin effects on 
MACE. 
4. The effects of pitavastatin on the incidence of serious non-CVD events.  
5. The safety of pitavastatin in the HIV population. 
Ancillary 
Objectives 
1. To assess the influence of sex/reproductive aging status on immune 
activation and statin induced immunomodulation in relation to clinical CVD 
events. 
2. To determine the effects of pitavastatin on the incidence of changes in kidney 
function. 
Primary 
Endpoint 
Major adverse cardiovascular events (MACE) 
Secondary 
and Safety 
Endpoints  
Primary components of MACE, all-cause mortality, LDL cholesterol, immune 
function, non-CVD events (malignancy, end stage liver and kidney disease, 
AIDS-defining events), and safety endpoints, including diabetes mellitus 


 
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Abbreviated 
Study Flow 
 


 
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1.0 
HYPOTHESES AND STUDY OBJECTIVES 
 
1.1 
Clinical Hypotheses  
 
1.1.1 Primary Clinical Hypothesis 
 
Statin therapy will prevent atherosclerotic cardiovascular disease (ASCVD)-
related MACE (major adverse cardiovascular events) in PWH on antiretroviral 
therapy (ART) in whom traditional cardiovascular disease (CVD) risk is not 
significantly increased.  
 
1.1.2 Secondary Clinical Hypotheses 
 
1.1.2.1 Statin therapy will be associated with reductions in specific CVD-related 
events and all-cause mortality. 
 
1.1.2.2 Decreases in LDL and non-HDL cholesterol levels associated with statin 
therapy will be predictive of reduction in CVD events. 
 
1.1.2.3 Statin therapy will reduce serious non-cardiovascular events, including 
malignancies, end stage kidney or liver disease.   
 
1.1.2.4 Statin therapy will be safe and well tolerated in PWH. 
 
1.2 
Clinical Objectives 
 
1.2.1 Primary Clinical Objective 
 
To determine the effects of pitavastatin as a primary prevention strategy for 
MACE in HIV. 
 
1.2.2 Secondary Clinical Objectives  
 
1.2.2.1 To evaluate the effects of pitavastatin on each of the components of the 
primary composite MACE endpoint and all-cause mortality. 
 
1.2.2.2 To determine the effects of pitavastatin on LDL and non-HDL 
cholesterol in the HIV population and assess the relationship of changes 
in LDL and non-HDL to the incidence of MACE. 
 
1.2.2.3 To evaluate whether baseline traditional risk factors (including smoking, 
hypertension, dyslipidemia, glucose) and time updated HIV-specific 
(immunological and virological) risk factors are predictive of MACE and 
pitavastatin effects on MACE in the HIV population. 
 


 
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1.2.2.4 To evaluate whether baseline and time updated inflammatory and 
immune activation biomarkers are predictive of MACE and pitavastatin 
effects on MACE in the HIV population.  
 
1.2.2.5 To determine the effects of pitavastatin on the incidence of serious non-
cardiovascular events and AIDS-defining events.  
 
1.2.2.6 To determine the safety of pitavastatin in the HIV population, including 
the development of diabetes mellitus (DM), liver dysfunction, and 
myopathy. 
 
1.2.2.7 To collect blood to enable the evaluation of the relationship of host 
genetics to study endpoints in subsequent ancillary studies. 
 
1.2.2.8 Characterize the epidemiology and pathobiology of SARS-CoV-2 
infection, particularly with respect to CVD, among individuals 
aging with HIV globally. 
 
1.2.2.9 Identify which host factors influence risk with respect to SARS-
CoV-2 infection and COVID-19-related CVD outcomes. 
 
1.2.2.10 Determine whether statin therapy protects against SARS-CoV-2 
infection and/or mitigates the severity of COVID-19-related CVD 
complications. 
 
1.2.3 Ancillary Objectives 
 
1.2.3.1 To assess the influence of sex/reproductive aging status on immune 
activation and statin induced immunomodulation in relation to clinical 
CVD events.  
 
1.2.3.2 To determine the effects of pitavastatin on the incidence of changes in 
kidney function.  
 
2.0 
INTRODUCTION 
 
2.1 
Background  
 
Over 34 million people worldwide, including 1.7 million people in the US, are chronically 
infected with HIV-1 [WHO 2012]. Due to the remarkable success of ART, PWH are now 
living longer [Lewden 2007]. By the year 2015, greater than half of the population living 
with HIV in the US is expected to be 50 or older [WHO 2012; Greene 2013]. Yet, even 
while ART has reduced AIDS-related deaths [Palella 2006], CVD and CVD-related 
deaths have increased in PWH, who have 1.5-2 times increased risk compared with 
HIV-negative individuals [Antiretroviral Therapy Cohort Collaboration 2010; Data 
Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group 2010; Sackoff 


 
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2006]. Currently, there are no treatment strategies proven to prevent CVD in PWH, 
despite the higher risk. A State of the Science Conference on CVD in HIV sponsored by 
the American Heart Association (AHA) highlighted the critical need to test preventive 
therapies for CVD in HIV and to develop HIV-specific guidelines [Grinspoon 2008]. 
Experts agree that existing strategies for CVD prevention in the general population are 
likely inadequate with increasing evidence suggesting HIV-associated immune activation 
accelerates the process of atherosclerosis and atherothrombosis [Hsue 2012; Zanni 
2012] such that relatively young PWH with modest traditional CVD risk factor scores still 
face high CVD risk. Most of these patients would not meet current guidelines for 
preventive CVD therapies. The imperative to identify a safe and efficacious strategy for 
CVD prevention in HIV is best met by a randomized controlled trial (RCT) of an 
intervention addressing both traditional and immune CVD risk factors.  
 
2.1.1 Increased Risk of CVD in HIV  
 
CVD-related deaths—including sudden cardiac death—are increased in PWH 
compared with people without HIV [Antiretroviral Therapy Cohort 
Collaboration 2010; Tseng 2012]. With respect to acute myocardial infarction 
(AMI), the most common cause of CVD-related deaths, studies show a 1.5- to 2-
fold increased relative risk of this in PWH versus people without HIV [Currier 
2003; Durand 2011; Freiberg 2013; Klein 2002; Lang 2010; Obel 2007; Triant 
2007]. Controlling for traditional CVD risk factors does not fully mitigate the 
heightened CVD risk among PWH [Freiberg 2013; Triant 2007], suggesting a 
unique pathobiology of atherosclerosis in HIV and highlighting the need for an 
effective, tailored primary CVD prevention strategy. 
 
2.1.2 Unique Biology of CVD in HIV  
 
2.1.2.1 Inadequate Explanation of CVD Risk in HIV by Traditional CVD Risk 
Factors  
 
Early studies of CVD in HIV suggested that heightened risk stemmed, 
indirectly, from an effect of ART to exacerbate traditional CVD risk 
factors (eg, diabetes, hypertension, dyslipidemia, and abdominal fat 
accumulation). For example, in the Data Collection on Adverse Events 
of Anti-HIV Drugs (D:A:D) study, use of protease inhibitors was 
associated with increased AMI risk, and this risk was partially attenuated 
after controlling for dyslipidemia [Friis-Moller 2003]. In contrast, recent 
studies demonstrate no independent association of ART with AMI and 
indicate that higher rates of AMI persist with HIV infection despite 
controlling for traditional CVD risk factors [Freiberg 2013; Triant 2007]. 
In large epidemiologic studies, immune dysfunction (low CD4 count) and 
degree of viremia have been identified as important independent 
contributors to CVD risk in HIV [Triant 2010]. Moreover, data from the 
Strategies for Management of Antiretroviral Therapy (SMART) study 
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risk: In the SMART study, patients were randomized to continuous ART 
or to an ART conservation strategy based on a CD4-guided algorithm. 
CVD occurred 60% more often in the drug conservation group, 
highlighting a benefit from more continuous and suppressive ART 
[Strategies for Management of Antiretroviral Therapy (SMART) 
Study Group 2006]. Subsequent studies from the SMART group have 
focused on specific markers of inflammation and coagulation that are 
significantly increased with drug conservation, related to viremia, and 
independently associated with increased CVD rates [Kuller 2008]. Work 
from the SMART group thus reinforces the principle that chronic viral 
infections and the subsequent immune response contribute to CVD, 
independently of traditional risk pathways highlighting the need to 
consider a possible role for an immune modulating strategy to prevent 
CVD.  
 
2.1.2.2 Relationship between HIV-Associated Systemic Immune Activation and 
CVD Risk 
 
HIV infection induces a paradoxical state of both immune suppression 
(low CD4 count and increased risk of opportunistic diseases) and 
immune activation [Deeks 2011]. A paucity of CD4+ T regulatory cells in 
the gut mucosa enables heightened microbial translocation and ensuing 
activation of both the innate and adaptive arms of the immune system 
[Brenchley 2006]. Concomitantly, depletion of circulating CD4+ T 
regulatory cells, coupled with opportunistic co-infection (hepatitis, 
cytomegalovirus), results in further immune activation. The net result, in 
PWH, is persistent activation of circulating monocytes and T-cell 
subsets [Deeks 2011]. Such chronic immune activation translates into 
an exhausted T-cell phenotype and a pro-inflammatory milieu that is 
manifest by higher circulating levels of soluble inflammatory and 
immune activation markers in PWH versus HIV-negative controls. 
Elevated inflammatory and immune activation biomarkers in PWH 
include pro-inflammatory cytokines (eg, IL-6), acute phase proteins (eg, 
CRP), leukocyte adhesion molecules (eg, sICAM-1), and fibrin 
degradation products (eg, d-dimer) [Dolan 2005; Ross 1999; Ross 
2008]. 
 
Immune activation in HIV is highly relevant to atherosclerosis [Hsue 
2012; Zanni 2012]—an inflammatory disease [Libby 2002] resulting in 
AMI and sudden cardiac death. Atherosclerosis as a process features 
an intricate interplay between activated immune cells―particularly 
monocytes―and vascular endothelial cells [Hulten 2009; Koenen 2010; 
Libby 2002; Libby 2011; Packard 2009]: Circulating monocytes target 
the tunica intima of affected coronary arteries in response to 
chemokines and adhesion molecules produced by activated endothelial 
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internalization of oxidized LDL, to foam cells which form the lipid core of 
the developing atheroma. Plaque macrophages, along with resident T 
cells, also secrete cytokines and matrix metalloproteinases, which can 
degrade the fibrous cap overlying an atheroma, thus precipitating 
plaque rupture/AMI [Hulten 2009; Koenen 2010; Libby 2002; Libby 
2011; Packard 2009]. With HIV infection―a state of persistently 
activated circulating monocytes and T cells and increased circulating 
levels of pro-inflammatory cytokines―all stages of atherogenesis and 
atherothrombosis are likely exacerbated. 
 
2.1.2.3 Novel Atherosclerotic Phenotype in HIV  
 
Initial studies to radiographically characterize subclinical atherosclerosis 
in HIV focused on carotid intima media thickness (cIMT) [Hulten 2009], 
which has been found in this population to relate largely to traditional 
CVD risk factors and not to inflammatory indices [Stein 2013]. In contrast, 
studies employing coronary computed tomography angiography (CCTA) 
and cardiac fluorodeoxyglucose-positron emission tomography (FDG-
PET) have shown PWH to have 1) predominantly non-calcified coronary 
atherosclerotic plaque [Burdo 2011], 2) a higher prevalence of high-risk 
morphology features (including low attenuation and positive remodeling) 
[Zanni 2013], and 3) vascular inflammation reflected in clustering of 
glucose-avid macrophages in the subendothelial matrix [Subramanian 
2012; Yarasheski 2012]. The clinical relevance of these observations is 
that inflamed vulnerable plaque which has yet to calcify is more prone to 
rupture, resulting in AMI [Hou 2012; Kitagawa 2009; Rominger 2009]. Of 
note, in PWH, non-calcified, vulnerable, and inflamed coronary 
atherosclerotic plaque has been found to relate to specific markers of 
monocyte activation, including soluble CD163, and has been observed 
even in those ART-treated PWH with low traditional CVD risk factors 
[Burdo 2011; Subramanian 2012; Zanni 2013]. 
 
2.1.3 Rationale for Statin Therapy to Prevent Primary CVD in HIV 
 
An ideal intervention to prevent CVD in HIV would affect both conventional lipid 
and HIV-specific immune mediators of CVD and would have minimal risk. Statin 
therapy uniquely meets these criteria. 
 
2.1.3.1 LDL, Immunomodulatory, and Plaque Stabilizing Effects of Statins  
 
Statins, which address both conventional and inflammatory mechanisms 
for atherosclerosis, may have unique utility for primary CVD prevention 
in HIV. In the general population, statins have long been known to 
potently reduce LDL cholesterol and to prevent CVD events [Downs 
1998; Sacks 1996; Scandinavian Simvastatin Survival Study (4S) 
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anti-inflammatory and immunomodulatory characteristics, which may 
also contribute to cardio-protective effects [Greenwood 2007]. Indeed, in 
vitro, animal, and human studies have shown that statins decrease 
monocyte activation - reflected in a) decreased monocyte chemotaxis 
and endothelial adhesion [Fujino 2006; Han 2005; Montecucco 2009], b) 
reduced monocyte uptake of oxidized LDL cholesterol [Han 2004], and 
c) decreased monocyte secretion of cytokines/chemokines and matrix 
metalloproteinases [Guo 2009; Waehre 2003]. Moreover, statins 
decrease T-cell activation [Bu 2010; Kwak 2000; Singh 2009] while 
recruiting regulatory T cells [Mira 2008], suppress endothelial cell 
activation [Mulhaupt 2003; Romano 2000; Veillard 2006; Zheng 2013; 
Zineh 2006], and decrease lipid oxidation [Aviram 1992; Giroux 1993; 
Vasankari 2001]. Further, data from cardiovascular imaging studies in 
HIV-negative participants reveal that statins stabilize vulnerable 
coronary atherosclerotic plaque and even induce plaque regression. 
Specifically, statins have been shown to decrease atherosclerotic 
plaque vulnerability features on CCTA and intravascular ultrasound 
(IVUS) [Inoue 2010; Kodama 2010; Nakamura 2008; Shimojima 2012], 
to reduce atherosclerotic plaque inflammation on cardiac FDG-PET 
[Tawakol 2013], and to reduce non-calcified plaque volume [Burgstahler 
2007; Hiro 2009]. Based on these data, statins may be uniquely tailored 
to address important mechanisms of CVD in HIV. 
 
2.1.3.2 Statin Effects on Non-CVD Events in HIV 
 
Due to the efficacy and widespread use of potent combination ART, 
mortality patterns among HIV patients have changed, with a decline in 
the proportion due to AIDS and a concomitant rise in the proportion due 
to non-AIDS-related diseases [ARTCC 2010; DAD 2010; French 2009; 
Lewden 2008; Marin 2009; Neuhaus 2010; Palella 2006; Wada 2013; 
Weber 2013]. In this regard, cardiovascular, end-stage liver and renal 
disease, and non-AIDS-related malignancies represent important 
causes of mortality among HIV patients in the current era of potent ART. 
Based on animal models and in-vitro and in-vivo data that statins may 
decrease the systemic inflammation that has been associated with many 
of these events, and epidemiologic data suggesting statins alter the risk 
of these events, including these key comorbidities in a secondary 
endpoint analysis of REPRIEVE (A5332) is warranted. 
 
Beyond an excellent safety record in persons with liver disease, current 
data suggest that statins may improve various aspects of liver disease. 
In animal models of non-alcoholic fatty liver disease, several different 
statins, including pitavastatin, have improved hepatic steatosis and 
decreased fibrosis mediated by anti-inflammatory and antifibrotic effects 
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have demonstrated similar improvements in steatosis and liver fibrosis 
[Ekstedt 2007; Foster 2011; Gomez-Dominguez 2006; Simon 2015]. 
 
Statins appear to have a beneficial effect on kidney function, particularly 
among persons with pre-existing microalbuminuria, a common finding 
among PWH [Amarenco 2014; Colhoun 2009]. Meta-analyses have 
demonstrated either a modest benefit or uncertain effects of statins on 
renal function [Douglas 2006; Nikolic 2013; Palmer 2014]. The limited 
data in HIV patients indicated improvement in renal function with 
rosuvastatin that correlated with reductions in inflammatory biomarkers 
and T-cell activation [Longenecker 2014]. 
 
HIV infection remains associated with an increased risk of cancer 
[Crum-Cianflone 2009; Deeken 2012]. While there are numerous factors 
that contribute to the excess risk of cancer, persistent inflammation and 
alterations in the immune system, particularly altering normal tumor 
surveillance, are considered key contributors to the excess risk, even in 
the setting of viral suppression and partial immunologic reconstitution 
experienced with ART [Borges 2014; Tenorio 2014]. Statins have been 
demonstrated to have anticancer activity which have been related to 
consequences of blocking the mevalonate pathway, including arresting 
cell cycle progression, inducing apoptosis, reducing oxidative stress, 
and decreasing systemic inflammation [Carlberg 1996; Wong 2002; 
Yasui 2007]. While the data from observational studies and post-hoc 
analyses for cancers in the general population have failed to 
consistently demonstrate an anticancer effect for statins, data from 
studies including PWH, while limited, suggest potential anticancer 
effects of statins due to the fact that persistent inflammation is likely an 
important driver [Galli 2014; Overton 2013]. 
 
Despite a declining incidence, AIDS events continue to occur and 
remain the leading cause of death among PWH. Clearly, advanced 
immunosuppression and a maladaptive inflammatory response, both 
related to uncontrolled HIV infection, are important drivers of the 
underlying mechanisms of AIDS events. While there are limited data 
regarding the impact of statins on the risk of developing AIDS events, 
the effects of statins on markers of both cellular and soluble markers of 
inflammation indicate that there may be benefit to assess the effect of 
statins on AIDS events, in conjunction with end stage renal and liver 
disease, as well as cancers in REPRIEVE (A5332). These data are 
critical to obtain in order to understand the potential overall impact of 
statins on PWH. 
 


 
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2.1.3.3 Efficacy of Statin Therapy in HIV 
 
In PWH, statins safely and effectively lower LDL cholesterol [Calza 
2012; Ganesan 2011; Silverberg 2009]. and also exert 
immunomodulatory effects to 1) decrease monocyte activation - 
reflected in decreased circulating levels of sCD14 and the macrophage-
derived phospholipase, Lp-PLA2 [Eckard 2014; Funderburg 2014, 2015] 
and 2) decrease T-cell activation in some studies [De Wit 2011; 
Ganesan 2011]. Statins are generally well tolerated among PWH and 
introduce minimal risks balanced against their significant potential to 
prevent CVD in this population [Singh 2011]. In a large cohort study, 
Silverberg et al. demonstrated that statins can be safely administered to 
PWH. Increased relative rates of grade III myositis (1.9% vs. 0.5%) and 
liver function test (LFT) abnormalities (1.1% vs. 0.3%) were seen in 
PWH versus control participants, but absolute rates were low [Silverberg 
2009]. With respect to the potential to induce DM development with 
statin use in PWH, non-randomized cohort studies recently reported 
contrasting results, with one study showing increased DM risk 
[Lichtenstein 2015] and two others suggesting no increased risk 
[Overton 2013; Spagnuolo 2017]. Unlike other agents with immune 
suppressant effects [Paton 2012], statins have not been shown to have 
adverse effects on viral replication [Moncunill 2005; Negredo 2006]. 
Indeed, in vitro studies suggest numerous mechanisms through which 
statins may actually reduce viral replication although clinical data 
suggests little impact on measured changes in plasma HIV viral loads 
while on statin therapy [Amet 2008; del Real 2004; Giguere 2004; 
Gilbert 2005; Nabatov 2007]. 
 
2.1.3.4 Selection of Pitavastatin 
 
Several statins are currently FDA approved and commercially available, 
with a limited number available in generic form; however, the use of 
select statins in PWH is complicated by, or in some cases 
contraindicated based on, complex interactions with antiretroviral agents 
[Aberg 2017; Ahmed 2012; Eckard 2014; Funderburg 2014, 2015]. Most 
statins are primarily metabolized by the CYP3A4 system. HIV protease 
inhibitors inhibit CYP3A4 and thus markedly increase exposure to these 
statins, as reflected in the area under the plasma drug concentration-
time curve (AUC) [Chauvin 2013]. As such, simvastatin and lovastatin 
are contraindicated in PWH taking protease inhibitors. Atorvastatin is 
partially metabolized by the CYP3A4 system, and the exposure to this 
statin is moderately increased by protease inhibitor therapy. Pravastatin 
exposure may be decreased by co-administration with ritonavir, but 
increased with co-administration with ritonavir-boosted darunavir. 
Similarly, rosuvastatin exposure is increased by co-administration with 
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significant effects of darunavir or lopinavir/ritonavir on pitavastatin were 
seen [Aberg 2017; Eckard 2014; Funderburg 2014, 2015; Malvestutto 
2014]. Other effects are also seen, for example between efavirenz, a 
widely prescribed ART, on the AUC of various common statins, 
including atorvastatin (-43% AUC), pravastatin (-40% AUC), and 
simvastatin (-58% AUC) [Gerber 2005], in contrast there was only an 
11% change in pitavastatin AUC with efavirenz [Malvestutto 2014]. 
 
Pitavastatin is a relatively new statin with comparable efficacy in terms 
of LDL reduction and anti-inflammatory effects as other potent statins 
[Eriksson 2011a]. It is an excellent choice for PWH as it is not 
metabolized by the CYP3A4 system but is instead metabolized primarily 
by glucuronidation [Gotto 2010]. Consequently, there are minimal 
documented interactions between pitavastatin and antiretroviral agents, 
including minimal effects of pitavastatin on exposure to ritonavir (+8% 
AUC), darunavir (+3% AUC), atazanavir (+6% AUC), lopinavir (-9% 
AUC) [FDA package insert]. Similarly, relatively modest effects of 
individual antiretroviral drugs are seen with respect to pitavastatin AUC 
[FDA package insert]. Indeed, there is no contraindication or 
recommendation for dose adjustment when pitavastatin is used in 
concert with any specific antiretroviral agent. Importantly, pitavastatin 4 
mg/day has been shown to effectively decrease LDL cholesterol among 
ART-treated PWH: the INTREPID study randomized PWH to 
pitavastatin 4 mg/day versus pravastatin 40 mg/day [Aberg 2017]. 
Results demonstrated that pitavastatin was superior to pravastatin with 
respect to LDL cholesterol lowering (-49.4 mg/dL (-31.1%) vs. -33.6 
mg/dl (-20.9%)) over a 12-week period with results sustained over 52 
weeks [Aberg 2017]. Moreover, relative to pravastatin, pitavastatin 
showed significantly greater ability to lower total cholesterol, non-HDL 
cholesterol, TC:HDL ratio, and Apo B lipoprotein levels. Tolerability and 
toxicity profiles were similarly benign for both agents: myalgias and LFT 
abnormalities were rare in both groups; no effects on HIV RNA or CD4 
were seen. Of note, pitavastatin, like pravastatin, had a neutral effect on 
blood glucose and HgbA1c levels in PWH [Aberg 2017]. Pitavastatin 
has compared favorably to other statins in randomized trials among 
people without HIV as well [Eriksson 2011a; Eriksson 2011b; 
Gumprecht 2011; Maruyama 2011]. Additionally, pitavastatin has 
demonstrated little impact on glucose metabolism and may even 
improve insulin resistance, an additional benefit when compared with 
other statins [Aberg 2017; Eckard 2014; Funderburg 2014, 2015; 
Teramoto 2010; Yamakawa 2008; Yokote 2009]. 
 
2.1.4 Opportune Timing for Randomized Control Trial of Statin Therapy in HIV  
 
The JUPITER trial demonstrated that among individuals in the general population 
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sensitivity C-reactive protein >2 mg/L), statin therapy resulted in a 44% reduction 
in CVD events [Ridker 2008]. To date, there are no large scale randomized trials 
of statin therapy to prevent CVD among PWH. Non-randomized studies in PWH 
demonstrate that use of statins is associated with reduced overall mortality 
[Moore 2011], especially among those diagnosed with co-morbidities 
[Rasmussen 2013]. Moore et al. showed that statin use was associated with a 
with a three-fold reduction in hazard ratio for all-cause mortality among PWH, 
adjusting for age, CD4, HIV-1 RNA, cholesterol levels, and prior ART use [Moore 
2011]. Observational studies also show a trend toward reduction in non-AIDS 
complications among ART-treated PWH on high potency statins [Drechsler 
2017]. 
 
Despite the potential appeal of statins, their use is relatively low in PWH―19.6% 
in a 2013 survey commissioned from the ACTG. Another recent analysis 
reported significant clinical inertia for the utilization of statin therapy in well 
controlled people living with HIV highlighting that both patient and provider 
factors weigh into the decision whether to utilize statins [Willig 2008]. The low 
use of statins in PWH reflects in part the relatively low prevalence of increased 
LDL cholesterol in this group [Freiberg 2013], but more importantly, the uncertain 
efficacy for CVD prevention and the potential side effects and ART interactions. 
These factors suggest equipoise and opportune timing for a large randomized 
trial to assess efficacy and safety of a statin therapy strategy for primary CVD 
prevention in HIV among those not meeting recommendations for statins under 
the 2013 American College of Cardiology/American Heart Association 
(ACC/AHA) guidelines.  
 
In 2013, the ACC/AHA released Blood Cholesterol Guidelines to replace the 
guidelines from the Third Report of the Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 
Novel aspects of the guidelines included 1) delineation of four statin benefit 
groups—patients age ≥21 with clinical ASCVD and/or with LDL cholesterol ≥190 
mg/dL and patients age ≥40 and ≤75 with diabetes and/or with 10-year ASCVD 
risk estimated to be ≥7.5% by the Pooled Cohort Equations and 2) abandonment 
of LDL cholesterol and non-HDL cholesterol treatment goals. In addition, the new 
guidelines deemphasized the use of non-statin lipid lowering therapies and 
focused exclusively on the use of statins for primary CVD prevention [Stone 
2014]. In this regard, pitavastatin is included as a recommended therapy in the 
new guidelines for primary prevention. Although these guidelines are now 
recommended for general use in clinical practice, they do not incorporate into risk 
prediction novel HIV-specific factors, including degree of systemic immune 
activation. REPRIEVE (A5332) provides a critical opportunity, in line with the 
hypothesis of the grant, to test whether patients without significant traditional risk, 
eg, those with ASCVD scores <7.5%, are an appropriate group for statin primary 
prevention. The currently proposed trial achieves equipoise by testing the 
efficacy and safety of statin therapy for primary CVD prevention in HIV among 
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guidelines and speaks directly to critical knowledge gaps identified by the 
recently published ACC/AHA guidelines for cholesterol management and the 
AHA sponsored State of the Science Conference on CVD in HIV. In alignment 
with these guidelines, individuals aged 40-75 will be recruited for REPRIEVE 
(A5332). In order to be fully aligned with the 2013 ACC/AHA Guidelines, persons 
with diabetes and LDL <70mg/dL or ASCVD risk score ≥7.5% and LDL 
<70mg/dL are not recommended to initiate statins, thus these two groups will be 
included in the study. 
 
Although we do not anticipate a change in the guidelines occurring during the 
REPRIEVE (A5332) study, we will address any future changes in the guidelines 
by obtaining Data and Safety Monitoring Board (DSMB) review to determine 
whether equipoise has been disturbed and whether any changes to the study 
should be made as a result, updating the informed consent documents to inform 
participants about the change, and providing participants with a letter describing 
the new guidelines to take to their personal physicians to determine whether they 
should continue to participate in the study in light of the change. 
 
2.1.5 Rationale for the Change in 10-Year ASCVD Risk Score  
 
Following the launch of REPRIEVE (A5332), the team found that a number of 
candidates were being excluded from the trial in the moderate risk category with 
an ASCVD risk score ≤10%. These individuals were not otherwise being offered 
statins clinically, and equipoise exists for their entry into this randomized, 
placebo-controlled trial. Moreover, it was noted by the team that certain 
demographic and risk factor groups were being excluded from the trial 
disproportionately based on higher ASCVD risk scores, despite relatively low 
LDL cholesterol levels. For example, black/African American men and smokers 
were often excluded at very young ages, despite uncertainty about the efficacy of 
statins among HIV+ individuals with such risk factors. The exclusion from the 
study of certain demographic groups overrepresented in the US HIV epidemic 
reduces the generalizability of the study and precludes from study a large 
number of individuals with moderate risk for whom the question of statin use for 
primary CVD prevention was critical.  
 
During a DSMB meeting on June 8, 2015, the REPRIEVE (A5332) team leadership 
reported these findings and proposed a change in the ASCVD risk score entry 
criteria in order to improve the generalizability of the study results and the 
enrollment of participants for whom statins are not generally offered. The DSMB 
agreed with the study team’s assessment and proposal to raise the upper bound 
for the enrollment ASCVD risk score from <7.5% to ≤10%, if those individuals 
between 7.5% and 10% had an LDL <160 mg/dL. The rationale for having a lower 
threshold for the LDL cholesterol for persons with an ASCVD risk score between 
7.5% and 10% was to focus study enrollment on those persons with low or 
moderate risk who were unlikely to be prescribed statin therapy. The comments 
from the DSMB affirm their agreement with this assessment and proposal and 


 
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noted: “1) there are no trial data validating the ASCVD risk prediction equations in 
PWH; 2) there are no definitive data for PWH with ASCVD risk scores of 7.5%-10% 
regarding the use of statins; 3) the use of statins in this group is not mandated by 
clinical experience or guidelines, allowing for the necessary equipoise for inclusion 
of this group in REPRIEVE (A5332); 4) the consent should ensure the opportunity 
for an informed discussion between patients and providers with ASCVD risk scores 
between 7.5%-10% and patients/providers could elect not to pursue the trial; and 
5) raising the ASCVD risk score might permit enrollment of study populations, 
including smokers and minority patients, that would be more representative of the 
actual HIV population in the United States.” The DSMB further agreed that the 
2013 guidelines were designed to encourage a discussion of the relative risk and 
benefits of statins for persons with an ASCVD risk score between 7.5%-15% 
(considered the moderate risk category), and that prescription of statins was not 
mandatory in this group, especially in the case of PWH for whom there were no 
trial data. Furthermore, the requirement to limit trial participants in the range of 
7.5%-10% ASCVD risk category to those with an LDL cholesterol <160 mg/dL 
would help to ensure that those with relatively higher ASCVD risk and elevated 
LDL levels were not enrolled into the trial. This level of LDL cholesterol was 
selected based on the recently updated National Lipid Association 
Recommendations that suggest consideration for initiating statin therapy for 
moderate risk individuals (ie, risk score <15%) [Jacobson 2014]. 
 
During a DSMB meeting on June 24, 2016, the REPRIEVE (A5332) team 
proposed a further change in the 10-year ASCVD risk score entry criteria after 
finding that a partial increase in the risk score cutoff from 7.5% to 10% only slightly 
increased the median risk of the study population. Approximately 6 months after 
the change, the median risk remained low at 3.6%. Moreover, persons of black 
race tended to be disproportionately excluded as the scoring is weighted such that, 
for this racial group, the ASCVD risk score is higher for a given set of parameters. 
The net result of the use of the score at the current level has been: 
• 
Enrollment of a low-risk population with fewer black participants and smokers 
than would be representative of the relevant at-risk population. 
• 
Enrollment of a non-representative, low-risk population for whom prevention 
is less relevant.  
• 
An adverse impact on enrollment and perhaps a reduction in event rates to a 
level that was not envisioned.  
 
REPRIEVE (A5332) is the first prospective study to assess the accuracy of the 
ASCVD scoring system in HIV+ individuals, but will be limited in its utility if participants 
are clustered at the very low end of this risk scale. Moreover, the 2013 ACC/AHA 
Prevention Guidelines are designed to assess 10-year and lifetime risk, and it is not 
yet known how well it will predict rates over 3 to 5 years in a trial. To rectify this 
situation, the team proposed, and the DSMB approved, an increase in the threshold for 
exclusion from ≤10% to ≤15%, requiring an LDL <130 mg/dL for those with a risk score 
>10% and ≤15%. Recent data [Nayor 2016] highlight the uncertainty of the correct 


 
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threshold for statin initiation to be used with the ASCVD criteria, and this change is in 
line with the recommendation of at least one major guideline, from Canada.  
 
In alignment with the guidelines, this change in the risk score threshold will 
facilitate enrollment of the intended population of intermediate risk participants for 
whom uncertainty and equipoise exist, and will permit a more generalizable and 
relevant study population, representative of the at-risk HIV population. Enrollment 
of participants with a broader range of scores will also better permit REPRIEVE 
(A5332) to assess the relative utility of the ASCVD score in the HIV population, 
leveraging the study for a critical purpose. The graded LDL requirement will 
further ensure equipoise, and will help to prevent any significant crossover rate. 
 
2.1.6 Rationale for the Enrollment Cap for 10-Year ASCVD Risk Score <2.5% 
 
Based on recommendations of the REPRIEVE (A5332) DSMB following their 
December 2017 review, the REPRIEVE team has capped enrollment of persons 
with a very low cardiovascular risk (10-year ASCVD risk score <2.5%) at 
approximately 2000 participants to ensure that final study population reflects the 
targeted low-to-moderate-risk population that the study is intending to enroll. 
Despite the previous expansion of the upper bound of the allowable entry criteria 
to allow enrollment of persons with 10-year ASCVD risk score ≤15%, the DSMB 
noted that median ASCVD risk score for the entire cohort remained low at 3.4% 
with approximately 2000 participants with a 10-year ASCVD risk score <2.5%. 
 
The cessation of enrollment of persons with very low 10-year ASCVD score will 
ensure that the study enrolls a study cohort that is more reflective of the entire 
HIV population at risk for ASCVD and ensures that the study maintains adequate 
power to determine the efficacy of pitavastatin for primary ASCVD prevention in 
the setting of HIV infection over a broad range of scenarios for the rate of events 
of interest. 
 
2.1.7 Rationale for the Enrollment Cap for 10-Year ASCVD Risk Score <5% 
 
Based on a recommendation from the National Institutes of Health (NIH) (the 
National Heart, Lung, and Blood Institute [NHLBI] and the Division of AIDS 
[DAIDS] at the National Institute of Allergy and Infectious Diseases [NIAID]) in 
April 2018, the REPRIEVE team is capping enrollment of persons with low 
cardiovascular risk (10-year ASCVD risk score <5%) at approximately 4200 
participants to ensure that the final study population reflects the targeted low-to-
moderate-risk population. 
 
2.1.8 Rationale for the Study of SARS-CoV-2 
 
The COVID-19 pandemic gripped the globe in 2020 and continues to have 
significant impact, with SARS-CoV-2 predicted to infect a large percentage of 
the global population and cause significant morbidity and mortality [Walker 


 
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2020]. Cardiovascular (CV) involvement is common, including myocarditis, 
heart failure, ischemic events due to thromboembolism and supply/demand 
mismatch, and arrhythmias [Madjid 2020; Zheng 2020]. The impact of COVID-
19 on the large global population of persons with HIV who have excess risk for 
CV disease is unknown. REPRIEVE is uniquely positioned to serve as a 
platform to understand the epidemiology, genetics, and pathobiology of 
COVID-19-related CVD in HIV, as well as the effects of statins on COVID-19 in a 
large, global RCT.  
 
COVID-19 may increase CVD through immunological pathways that have been 
characterized as part of the cytokine release syndrome [Saghazadeh 2020]. 
Even without such advanced disease presentations, the HIV population is 
particularly important to study, given that PWH concomitantly experience 
reduced immune function and increased innate immune activation [Lederman 
2013]. Investigation in this population may provide insights into COVID-19 of 
relevance to the general population.  
 
REPRIEVE will be used to identify host factors influencing risk for SARS-CoV-2 
infection, COVID-19 disease, and CV complications of COVID-19. 
 
The randomized design of REPRIEVE is ideal to study whether statins’ 
pleotropic immune-modulatory actions and known protection against virally-
mediated myocardial injury [Guan 2010] and acute lung injury [Brett 2011] 
impact COVID-19 infection. Statins have been shown to reduce 
hyperinflammatory subphenotype of acute respiratory distress syndrome, 
increasing 28-day survival [Calfee 2018], and thus may be particularly useful to 
reduce inflammatory conditions in other systems, including CVD. Moreover, 
ongoing use of statins, rather than as acute therapy, may be protective and 
help to prevent such disease before it becomes advanced and difficult to treat. 
Pitavastatin therapy―the statin used in REPRIEVE―has the most potent 
immune modulatory effects in PWH [Toribio 2017], affects multiple potentially 
relevant immune pathways in this population [deFilippi 2020], and has 
inhibitory activity against SARS-CoV-2 proteins [Xu 2020]. In this regard, we 
will test whether the therapy in REPRIEVE will ameliorate COVID-19-related 
hospitalization and ensuing COVID-19-related cardiovascular events including 
myocardial infarction and/or heart failure.  
 
2.2 
Rationale 
 
PWH face an increased risk of CVD morbidity and mortality, yet no preventive strategies 
for CVD risk reduction have been proven for this population. Existing primary CVD 
preventive strategies for the general population cannot simply be extrapolated to PWH, 
in whom immune dysfunction/activation contributes in unique ways to atherosclerosis 
and ensuing cardiovascular events. The rationale of testing statins for primary CVD 
prevention in HIV is multifold: First, statins affect both traditional CVD risk factors (LDL 
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activation. The latter effect is critical, as immune activation and persistent inflammation 
in HIV are thought to contribute importantly to the development of non-calcified, 
vulnerable, and inflamed coronary atherosclerotic plaque even in relatively young PWH 
on ART with low traditional CVD risk indices [Subramanian 2012; Yarasheski 2012; 
Zanni 2013]. In such patients, statin therapy may stabilize high-risk coronary 
atherosclerotic plaque, precluding rupture and AMI. Moreover, statins are generally safe 
in the HIV population, exerting anti-inflammatory properties without enhancing viremia 
[Aberg 2017; Eckard 2014; Funderburg 2014, 2015; Ganesan 2011; Nabatov 2007; 
Negredo 2006; Silverberg 2009]. Based on this rationale, the REPRIEVE (A5332) study 
was designed to assess the efficacy of statins as a primary prevention strategy for CVD 
events in PWH on ART not meeting 2013 ACC/AHA guideline thresholds for 
recommended statin initiation. The study will also definitively determine the safety of 
statins in PWH, including statin effects on non-CVD events such as incident diabetes, 
malignancies, kidney or liver failure, and AIDS-defining events in PWH. In addition to 
enrolling participants in the main study, select sites will have the option of coenrolling 
participants in a Mechanistic Substudy of REPRIEVE (A5333s). As part of this substudy, 
described in detail in Appendix II, coenrolled patients will undergo detailed coronary CT 
angiography and biochemical immunophenotyping. The Mechanistic Substudy of 
REPRIEVE (A5333s) will allow for determination of statin effect on non-calcified 
coronary atherosclerotic plaque burden and morphology, as well as lipid and immune 
parameters predictive of this effect. REPRIEVE (A5332) addresses an urgent national 
healthcare priority to prevent CVD among persons living with HIV.  
REPRIEVE will address critical knowledge gaps regarding SARS-CoV-2 infection and 
COVID-related CV complications among PWH. We will focus on three interrelated but 
independent key topics: epidemiology and scope of COVID-19-related CVD in HIV, 
host factors, and protective strategies. Uniform study-wide eCRF assessment tools to 
ascertain symptoms (including long-term COVID-19 effects) and antibody testing will 
allow for an objective and unbiased determination of epidemiology of COVID-19, its 
effects on CVD in HIV, and statin effects across the globe for the first time in HIV. The 
results of this work will provide critical information on COVID-19-related CVD in HIV, 
and critical effects of statins to mitigate effects of the SARS-CoV-2 virus-related 
infection, disease severity, and MACE. These results will be broadly generalizable to 
the large population of PWH simultaneously at risk for COVID-19 and CVD and also to 
other populations at risk for CVD experiencing COVID-19 infection.   
 
3.0 
STUDY DESIGN 
 
REPRIEVE (A5332) is a prospective, double-blind, randomized, placebo-controlled, 
multicenter phase III efficacy study that will examine the effects of 4 mg daily pitavastatin 
on cardiovascular-related events among adults with HIV who are currently on ART. The 
randomization in the study will be stratified by sex at birth, CD4+ T-cell counts (≤500 vs. 
>500 cells/mm3), and by whether or not a participant has elected to participate in the 
Mechanistic Substudy of REPRIEVE (A5333s) (yes/no). 
 


 
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Men and women ≥40 and ≤75 years of age, on any ART regimen (ART not provided by 
the study) for at least 6 months prior to study entry, with any plasma HIV-1 RNA level, 
with CD4+ T-cell count >100 cells/mm3 considered low-to-moderate risk using the 2013 
ACC/AHA guideline thresholds for recommended statin initiation will be enrolled into this 
study. Per the December 2017 DSMB recommendations, the study sample size was 
increased to approximately 7500 participants, follow-up was extended to approximately 
84 months from the time the first participant enrolled, and on 01/19/18, total enrollment 
of individuals with very low cardiovascular risk (10-year ASCVD risk score <2.5%) was 
capped at approximately 2000 participants to ensure that final study population reflects 
the targeted low-to-moderate-risk population. Subsequent to a new recommendation 
from the NIH, the total enrollment of individuals with low cardiovascular risk (10-year 
ASCVD risk score <5.0%) was capped at approximately 4200 participants to ensure that 
the final study population reflects the targeted low-to-moderate-risk population. At this 
same time the NIH recommended to increase follow-up to 96 months. This increase was 
endorsed by the DSMB at the December 2018 meeting. Follow-up is now up to 120 
months in order to continue until the study reaches its target of 288 primary 
MACE endpoints or is otherwise recommended for closure by the DSMB (see 
section 9.1 for more details). 
 
At study entry, participants will be randomized to one of the following arms: 
ARM A:  At Day 0, initiate pitavastatin at a daily dose of 4 mg. 
ARM B:  At Day 0, initiate placebo for pitavastatin daily. 
 
Clinical assessments will be performed at month 1, month 4, and then every 4 months 
for the duration of the study.  
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Documentation of HIV-1 infection by means of any one of the following: 
• 
Documentation of HIV diagnosis in the medical record by a licensed health 
care provider;  
• 
OR HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating 
>1000 RNA copies/mL; 
• 
OR any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a HIV-
1 Western blot confirmation or HIV rapid Multispot antibody differentiation 
assay. 
 
NOTE: A “licensed” assay refers to a US FDA-approved assay, which is required 
for all IND studies. Non-US sites are encouraged to use FDA-approved methods; 
if not available, then each non-US site must use an assay that has been certified 
or licensed by an oversight body within that country and validated internally.  
 


 
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WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must 
use a test that is different from the one used for the initial assessment. 
 
4.1.2 Combination antiretroviral therapy (ART) for at least 180 days prior to study 
entry. 
 
NOTE: Treatment interruptions for up to 30 days total in the last 180 days are 
permitted as long as the participant has been continuously on therapy for the 30 
days prior to study entry. 
 
4.1.3 CD4+ cell count >100 cells/mm3 obtained within 180 days prior to study entry at 
any US laboratory that has a Clinical Laboratory Improvement Amendments 
(CLIA) certification or its equivalent, or at any network-approved non-US 
laboratory that operates in accordance with Good Clinical Laboratory Practices 
and participates in appropriate external quality assurance programs. 
 
4.1.4 Laboratory values drawn at screen and/or obtained from clinical care (as 
indicated in section 6.1 Schedule of Evaluations) within 90 days prior to study 
entry at any US laboratory that has a Clinical Laboratory Improvement 
Amendments (CLIA) certification or its equivalent, or at any network-approved  
non-US laboratory that operates in accordance with Good Clinical Laboratory 
Practices and participates in appropriate external quality assurance programs. 
 
• 
Fasting LDL cholesterol as follows: 
o If ASCVD risk score <7.5%, LDL cholesterol must be <190 mg/dL 
o If ASCVD risk score ≥7.5% and ≤10%, LDL must be <160 mg/dL 
o If ASCVD risk score >10% and ≤15%, LDL must be <130 mg/dL 
 
NOTE: If LDL <70 mg/dL, participant is eligible regardless of 10-year ASCVD 
risk score in line with the ACC/AHA 2013 Prevention Guidelines. 
 
• 
Fasting triglycerides <500 mg/dL 
• 
Hemoglobin 8 g/dL for female participants and 9 g/dL for male participants 
• 
Glomerular filtration rate (GFR) ≥60 mL/min/1.73m2 or creatinine clearance 
(CrCl) ≥60 mL/min 
NOTE: See the A5332 Manual of Procedures (MOPS) for links to GFR and 
CrCl calculators. 
• 
ALT ≤2.5 x ULN  
NOTE: Participants co-infected with chronic active hepatitis B or C must have 
ALT ≤2 x ULN.  
 
4.1.5 For persons with known chronic active hepatitis B or C, calculated FIB-4 score 
must be ≤3.25. 
 


 
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NOTE: Active is defined as hepatitis B surface antigen positive, hepatitis B DNA 
positive, or hepatitis C RNA positive. 
 
NOTE: Refer to the calculator for the FIB-4 equation in the MOPS. 
 
4.1.6 Female participants of reproductive potential (defined as women who have not 
been post-menopausal for at least 24 consecutive months, ie, who have had 
menses within 24 months prior to study entry, and women who have not 
undergone surgical sterilization, specifically hysterectomy or bilateral 
oophorectomy) must have a negative serum or urine pregnancy test within 48 
hours prior to entry by any US laboratory or clinic that has a CLIA certification or 
its equivalent, or is using a point-of-care (POC)/CLIA-waived test, or at any 
network-approved non-US laboratory or clinic that operates in accordance with 
Good Clinical Laboratory Practices and participates in appropriate external 
quality assurance programs. 
 
NOTE: Participant-reported history is considered acceptable documentation of 
hysterectomy, bilateral oophorectomy, and menopause. Women are considered 
menopausal if they have not had a menses for at least 12 months and have a 
FSH (follicle stimulating hormone) of greater than 40 IU/L or, if FSH testing is not 
available, they have had amenorrhea for 24 consecutive months. 
 
4.1.7 For women of reproductive potential, willingness to use contraceptives as 
described in the product information for pitavastatin. Contraceptives must be 
used at least two weeks before initiation of study drug and must be continued 6 
weeks after cessation of study drug. 
If participating in sexual activity that could lead to pregnancy, women must use a 
form of contraceptive. At least one of the following methods must be used 
appropriately: 
• 
Condoms (male or female) with or without spermicidal agent 
• 
Diaphragm or cervical cap with spermicidal agent 
• 
Intrauterine device (IUD) 
• 
Hormone-based contraceptive 
• 
Tubal ligation 
• 
Tubal micro-inserts 
 
Women who are not of reproductive potential as defined above are eligible 
without the use of contraception. 
 
4.1.8 Men and women age ≥40 and ≤75 years of age.  
 
4.1.9 Ability and willingness of participant or legal representative to provide written 
informed consent. 
 


 
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4.2 
Exclusion Criteria 
 
4.2.1 Clinical ASCVD, as defined by 2013 ACC/AHA guidelines, including a previous 
diagnosis of any of the following:  
• 
AMI  
• 
Acute coronary syndromes 
• 
Stable or unstable angina  
• 
Coronary or other arterial revascularization 
• 
Stroke  
• 
TIA  
• 
Peripheral arterial disease presumed to be of atherosclerotic origin  
4.2.2 Current diabetes mellitus if LDL ≥70 mg/dL 
 
NOTE: Current diabetes is defined by patient report of physician diagnosis. 
Participants with a history of diabetes that has resolved and no longer requires 
therapy are not considered to have current diabetes, eg, women with a history of 
gestational diabetes, steroid-induced or medication-induced. 
 
4.2.3 10-year ASCVD risk score estimated by Pooled Cohort Equations >15% 
 
NOTES: 
• 
If LDL <70 mg/dL, participant is eligible regardless of risk score in line with 
the ACC/AHA 2013 Prevention Guidelines. 
• 
See inclusion criterion 4.1.4 for LDL requirements by risk score. 
• 
See section 6.3.4, Cardiovascular Risk Assessment Tool, for detailed 
instructions concerning access and use of the 10-year ASCVD risk score 
calculator. 
 
4.2.4 Active cancer within 12 months prior to study entry. 
 
NOTE: Exceptions: 
• 
Successfully treated non-melanomatous skin cancer 
• 
Kaposi sarcoma without visceral organ involvement 
 
4.2.5 Known decompensated cirrhosis. 
 
4.2.6 History of myositis or myopathy with active disease in the 180 days prior to study 
entry. 
 
4.2.7 Known untreated symptomatic thyroid disease. 
 
4.2.8 History of allergy or severe adverse reaction to statins. 
 
4.2.9 Use of specific immunosuppressants or immunomodulatory agents, including but 
not limited to tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, 


 
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TNF-alpha blockers or antagonists, azathioprine, interferon, growth factors, or 
intravenous immunoglobulin (IVIG), in the 30 days prior to study entry. 
 
NOTE: Use of oral prednisone ≤10 mg/day or equivalent dosage is allowed.  
 
NOTE: Refer to the MOPS for clarification regarding medications in these 
categories. 
 
4.2.10 Current use of erythromycin, colchicine, or rifampin. 
 
4.2.11 Use of any statin drugs, gemfibrozil, or PCSK9 inhibitors in the 90 days prior to 
study entry. 
 
4.2.12 Current use of an investigational new drug that would be contraindicated. 
 
NOTE: Please contact the protocol core team via e-mail as described in the 
Study Management section for guidance on coenrollment of participants on 
investigational new drugs. 
 
4.2.13 Serious illness or trauma requiring systemic treatment or hospitalization in the 30 
days prior to study entry. 
 
4.2.14 Known active or recent (not fully resolved within 30 days prior to study entry) 
systemic bacterial, fungal, parasitic, or viral infections (except HIV, HBV, human 
papillomavirus [HPV], or HCV). 
 
4.2.15 Current breastfeeding. 
 
4.2.16 Alcohol or drug use that, in the opinion of the site investigator, would interfere 
with completion of study procedures. 
 
4.2.17 Other medical, psychiatric, or psychological condition that, in the opinion of the 
site investigator, would interfere with completion of study procedures and or 
adherence to study drug. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by 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 
Center (RSC). The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received. 
 


 
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Initial site-specific informed consent forms (ICFs) will be reviewed and approved 
by the DAIDS PRO, and sites will receive an Initial Registration Notification from 
the DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site’s regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site’s regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-protocol-registration-policy-
and-procedures-manual. 
 
Once a candidate for study entry has been identified, details including risks and 
benefits will be carefully discussed with the participant. The participant (or, when 
necessary, the legal representative if the participant is under guardianship) will 
be asked to read and sign the approved protocol consent form.  
 
For participants from whom a signed informed consent has been obtained, a 
REPRIEVE Screening Checklist must be entered through the Data Management 
Center (DMC) Participant Enrollment System. 
 
4.3.2 Participant Randomization 
 
Participants will be randomized according to standard data management 
procedures. For participants from whom informed consent has been obtained, 
but who are deemed ineligible or who are not randomized into REPRIEVE 
(A5332), a Screening Outcome form must be recorded in the Electronic Data 
Capture system (EDC).  
 
4.4 
Mechanistic Substudy of REPRIEVE (A5333s) Enrollment Procedures  
 
If applicable, the Mechanistic Substudy of REPRIEVE (A5333s) enrollment will occur at 
the same time as enrollment into REPRIEVE (A5332), ie, completion of enrollment into 
A5333s should occur no later than one business day after enrollment into REPRIEVE 
(A5332). Please see Appendix II for additional information regarding substudy 
enrollment procedures. 


 
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NOTE: The Mechanistic Substudy of REPRIEVE (A5333s) closed to accrual on 
02/06/18. 
 
4.5 
Coenrollment Guidelines  
 
US ACTG sites are encouraged to coenroll participants in A5128, “Plan for Obtaining 
Informed Consent to Use Stored Human Biological Materials (HBM) for Currently 
Unspecified Analyses.” Non-US ACTG sites are encouraged to coenroll participants in 
A5243, “Plan for Obtaining Human Biological Samples at Non-US Clinical Research 
Sites for Currently Unspecified Genetic Analyses.” Coenrollment in A5128, observational 
studies, or studies that do not involve a random treatment assignment does not require 
permission from the REPRIEVE (A5332) protocol team. 
 
For specific questions and approval for coenrollment in other studies (including HCV or 
HIV treatment trials and adjunctive treatment trials), sites should first check the PSWP or 
contact the protocol core team via e-mail as described in the Study Management 
section. 
 
4.6 
Retention Procedures  
 
Participants who miss visits should be contacted to make up the visit and to permit 
determination of whether a major event occurred. If a participant refuses to communicate 
with study staff in any context and avoids further participation in the study after repeated 
attempts or the site is unable to contact the participant by phone, mail, primary care 
physician, next of kin, home visits, or emergency contact numbers after repeated 
attempts, then the participant should be taken off study.  
 
Participants who self-withdraw from study medications should be followed (if they agree) 
and evaluated.  
 
See MOPS for recruitment and retention procedures, including contact and data 
collection for participants in the event of missed visits. 
 
5.0 
STUDY TREATMENT  
 
Study treatment is defined as pitavastatin and placebo for pitavastatin, both of which will 
be provided by the study. 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 Regimens 
 
At study entry (day 0), participants will be randomized to one of the following 
arms: 
 
ARM A: Pitavastatin 4 mg one tablet once daily taken orally with or without food. 


 
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ARM B: Placebo for pitavastatin one tablet once daily taken orally with or without 
food. 
 
5.1.2 Administration  
 
The appropriate dose of pitavastatin or placebo for pitavastatin can be 
administered at any time of the day, with or without food. The drug should be 
taken as close to the same time of day as possible. With the exception of 
participants enrolled in the Mechanistic Substudy (A5333s) or select other 
approved REPRIEVE (A5332) ancillary studies, participants must begin 
treatment within 72 hours after randomization. 
 
NOTE: For participants coenrolled in the Mechanistic Substudy (A5333s) or other 
specified approved REPRIEVE (A5332) ancillary studies with ancillary study 
procedures, the initiation of treatment must be held until after the entry CCTA or 
relevant ancillary study procedure (see the A5332 MOPS for more details), even 
if the CCTA or relevant ancillary study procedure occurs more than 72 hours 
after randomization but not more than 14 days after randomization. See the 
A5332 MOPS for more details regarding the specified ancillary studies. 
 
Study product will be dispensed in accordance with the Drug Dispensation 
schedule as described in the MOPS.  
 
NOTE: The drug dispensation schedule described in the MOPS is a preferred 
guidance schema. Sites should notify the DAIDS Pharmaceutical Affairs Branch 
(PAB) at PABREPRIEVEPEP@mail.nih.gov of any deviation from this schema 
and document such occurrences in dispensation/accountability logs. 
 
5.1.3 Treatment Duration 
 
Participants will remain on study treatment for approximately 120 months 
depending on the time they enrolled in the study. 
 
5.2 
Study Product Formulation and Preparation  
 
Pitavastatin and placebo for pitavastatin should be stored at room temperature between 
15–30°C (59–86°F). The product should be stored out of direct sunlight. The container 
should be kept tightly closed retaining the silica gel desiccant in the bottle. Dispense only 
in the original container. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
Pitavastatin and placebo for pitavastatin will be provided by Kowa 
Pharmaceuticals America, Inc. These study products will be available through the 


 
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NIAID Clinical Research Products Management Center (CRPMC). The clinical 
research site (CRS) pharmacist can obtain the study products for this protocol by 
following the instructions in the manual Pharmacy Guidelines and Instructions for 
Division of AIDS (DAIDS) Clinical Trials Networks. 
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products must be returned to the NIAID CRPMC (or as otherwise directed by the 
sponsor) after the study is completed or terminated. The procedures to be 
followed are provided in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities. At non-US CRSs, the site pharmacist must follow the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks for the destruction of unused study products. 
 
5.4 
Concomitant Medications  
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. Site 
staff are encouraged to contact the core protocol team via e-mail with any questions 
about required, prohibited, or precautionary medications. Refer to MOPS section 5.0 for 
additional information.  
 
Additional drug information may be found on the updated ACTG Precautionary and 
Prohibited Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search. 
This database was created to assist investigators and research staff to access the most 
current pharmacokinetic data on drug interactions with antiretrovirals. You do not need to 
register or login to use this resource. 
 
5.4.1 Required Medications 
 
Combination ART for at least 180 days prior to study entry.  
 
NOTE: Treatment interruptions for up to 30 days total in the last 180 days are 
permitted as long as participant has been continuously on therapy for the 30 
days prior to study entry. 
 
5.4.2 Recommended Medications 
 
Prophylaxis for HIV-related opportunistic infections should be administered as 
per the “Guidelines for the Prevention and Treatment of Opportunistic Infections 
in Adults and Adolescents with HIV: Recommendations from the Centers for 


 
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Disease Control and Prevention, the National Institutes of Health, and the HIV 
Medicine Association of the Infectious Diseases Society of America.” 
 
5.4.3 Prohibited Medications 
 
Refer to the PSWP for a list of prohibited medications. 
 
5.4.4 Precautionary Medications 
 
Refer to the PSWP for a list of precautionary medications.    


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations  
 
Table 6.1a: Screening – Months 96 
Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Documentation of 
HIV-1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x3 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medication history 
x 
x3 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Myalgia symptom 
assessment 
 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COVID-19 
assessment 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Calculate 10-year 
ASCVD risk score 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CVD risk factor 
assessment  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x16 
x16 
x16 
REAP & DASI 
questionnaires 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Screening physical 
exam 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Targeted physical 
exam 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Height  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Waist circumference 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
ECG4 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense lifestyle 
information 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Labs captured from clinical care 
CD4+/CD8+5 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Plasma HIV-1 RNA6 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
CBC7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Serum creatinine7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Calculated 
creatinine clearance 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid panel 7,8 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT 7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST 10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FIB-410 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs to be collected (drawn) 
ALT (local lab) 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Evaluation 
Screening2 Entry 
Day 0 
Post-Entry Evaluations (months)1 
Study Termination Visit2 
Discontinuation 
Visits2 
Visit Window 
±7 days for month 1; ±30 days for all other visits 
Prem. Treatment D/C 
Evals 
±30 days2 
Prem. Study D/C Evals2 
1 4 
8 122 16 20 242 28 32 362 40 44 482 52 56 602 64 68 722 76 80 842 
88 92 
962 
Pregnancy testing 
x 
x 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fasting lipid panel 
(stored)9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Fasting glucose9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Fasting 
plasma/serum for 
biomarkers – stored9 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Urine 
albumin/creatinine11 
 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
genetic testing12 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety labs if 
indicated13 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense study drug 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Medication 
adherence 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Vital status and 
endpoint follow-up14  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Endpoint 
assessments15 
 
 
x x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1 
For the purposes of the study, 1 month equals 30 days. 


 
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2 
 If a participant is not fasting for a visit for which fasting blood is obtained, reschedule the appointment within 30 days of the original 
appointment date. See section 6.2.3.  
3 
 Update any changes from the screening assessment (medical and medication history). 
4  ECG available to site PI, all ECGs will be sent for central read and storage until end of study, no specific ECG findings are 
exclusionary, except findings which in the judgment of PI render the participant clinically unstable as per clinical read, central readings 
will not be available to sites, see MOPS. 
5  At the screening visit, CD4+/CD8+ from clinical care within 180 days prior to entry will be used; if not available, this will be drawn as 
part of the study. For post-entry CD4+/CD8+, the most recent values obtained since the last annual visit will be used. At discontinuation 
visits, CD4+/CD8+ from clinical care within 180 days of that visit will be used.  
6  For the entry visit, an HIV-1 RNA from clinical care from the prior 180 days will be used; if not available, do not collect. For post-entry 
evaluations, the most recent viral load obtained from clinical care since the last annual visit will be used. At discontinuation visits, 
plasma HIV-1 RNA from clinical care within 180 days of that visit will be used. 
7  At the screening visit, results of CBC, creatinine, lipid panel, and ALT (and when needed per footnote #10, AST) will be obtained from 
clinical care if available within 90 days prior to entry; if not available, draw as part of the study. At discontinuation visits, CBC and 
creatinine from clinical care within 180 days of that visit will be used. 
8  At the screening visit, direct LDL must be determined if triglyceride 400-500 mg/dL.  
9  Fasting lipid panels, glucose, and plasma/serum for biomarkers from entry visit forward will be performed centrally. Participants may 
choose to opt out of these entry and post-entry labs.  
10 
 AST is only required for persons with known chronic active HCV and/or HBV in order to calculate FIB-4 at screening. Use results from 
clinical care if available within 90 days prior to entry; if not available, draw as part of the study. 
11  The urine for creatinine/albumin is required of all participants at entry. At months 12, 24, and 48, collect only for participants at ACTG 
sites who enrolled in REPRIEVE (A5332) prior to 01/01/2018. 
12  Whole blood for genetic testing will be drawn at ACTG sites only. 
13  Additional safety labs will be checked at the discretion of site investigator based on participant symptoms (see section 7.1). 
14  Please refer to section 6.3.10 for details. 
15  Please refer to section 6.4 for details. 
16 Hormonal/reproductive health assessments relevant to CVD risk will be determined at study termination/discontinuation 
visits. 
 
 
 


 
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Table 6.1b: Months 100–120 
Evaluation 
Post-Entry Evaluations (months)1 
Study 
Termination 
Visit2 
Discontinuation Visits2 
 
Visit Window 
±7 days for month 1; ±30 days for 
all other visits 
 
Prem. 
Treatment 
D/C Evals 
±30 days2 
Prem. Study D/C 
Evals2 
 
100 
104 1082 112 
116 1202 
 
 
 
Medical history 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medication history 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Myalgia symptom assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
COVID-19 assessment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CV risk factor assessment  
 
 
 
 
 
 
x10 
x10 
x10 
REAP & DASI questionnaires 
 
 
 
 
 
 
x 
x 
x 
Targeted physical exam 
 
 
x 
 
 
x 
x 
x 
x 
Weight 
 
 
x 
 
 
x 
x 
x 
x 
Waist circumference 
 
 
 
 
 
 
x 
x 
x 
Dispense lifestyle information 
 
 
x 
 
 
x 
x 
x 
x 
Labs captured from clinical care 
CD4+/CD8+3 
 
 
x 
 
 
x 
x 
x 
x 
Plasma HIV-1 RNA4 
 
 
x 
 
 
x 
x 
x 
x 
CBC5 
 
 
 
 
 
 
x 
x 
x 
Serum creatinine5 
 
 
 
 
 
 
x 
x 
x 
Labs to be collected (drawn) 
Pregnancy testing 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fasting lipid panel (stored)6 
 
 
x 
 
 
x 
x 
x 
x 
Fasting glucose6 
 
 
x 
 
 
x 
x 
x 
x 
Fasting plasma/serum for biomarkers – stored6 
 
 
x 
 
 
x 
x 
x 
x 
Safety labs if indicated7 
x 
x 
x 
x 
x 
x 
x 
x 
x 


 
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Evaluation 
Post-Entry Evaluations (months)1 
Study 
Termination 
Visit2 
Discontinuation Visits2 
 
Visit Window 
±7 days for month 1; ±30 days for 
all other visits 
 
Prem. 
Treatment 
D/C Evals 
±30 days2 
Prem. Study D/C 
Evals2 
 
 
100 
104 
108 
112 
116 
120 
 
 
 
Dispense study drug 
x 
x 
x 
x 
x 
x 
 
 
 
Medication adherence 
x 
x 
x 
x 
x 
 
 
 
 
Vital status and endpoint follow-up8  
 
 
 
 
 
 
x 
 
x 
Endpoint assessments9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1  For the purposes of the study, 1 month equals 30 days. 
2 
 If a participant is not fasting for a visit for which fasting blood is obtained, reschedule the appointment within 30 days of the 
original appointment date. See section 6.2.3.   
3  For post-entry CD4+/CD8+, the most recent values obtained since the last annual visit will be used. At discontinuation visits, 
CD4+/CD8+ from clinical care within 180 days of that visit will be used.  
4  For post-entry evaluations, the most recent viral load obtained from clinical care since the last annual visit will be used. At 
discontinuation visits, plasma HIV-1 RNA from clinical care within 180 days of that visit will be used. 
5  At discontinuation visits, CBC and creatinine from clinical care within 180 days of that visit will be used. 
 
6  Fasting lipid panels, glucose, and plasma/serum for biomarkers will be performed centrally. Participants may choose to opt 
out of these post-entry labs.  
7  Additional safety labs will be checked at the discretion of site investigator based on participant symptoms (see section 7.1). 
8  Please refer to section 6.3.10 for details. 
9  Please refer to section 6.4 for details. 
10 Hormonal/reproductive health assessments relevant to CVD risk will be determined at study termination/discontinuation 
visits. 
 
 


 
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6.2 
Timing of Evaluations  
 
NOTE: For the purposes of the study, 1 month = 30 days. 
 
6.2.1 Screening Evaluations  
 
• 
Screening evaluations must occur prior to randomization and any study 
treatment or intervention. 
• 
Screening evaluations to determine eligibility must be completed within 90 
days prior to entry unless otherwise specified. 
• 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be 
captured in a Screening Outcome form in the EDC.  
 
6.2.2 Entry Evaluations 
 
• 
Entry evaluations will normally occur at least 24 hours after screening 
evaluations unless otherwise specified. In certain circumstances, screening 
and entry visits may occur sequentially in real time as long as all screening 
criteria are confirmed prior to entry. 
• 
Entry evaluations must occur after randomization and be completed before 
initiating study treatment. 
• 
Participants must begin treatment within 72 hours after randomization. 
 
NOTE: For participants coenrolled in the Mechanistic Substudy (A5333s) and 
other specified approved REPRIEVE (A5332) ancillary studies with ancillary 
study procedures, treatment must be held until after the entry CCTA or 
relevant ancillary study procedure (see MOPS for more details) even if that 
occurs more than 72 hours but not more than 14 days after randomization. 
 
6.2.3 Post-Entry Evaluations 
 
On-Study Evaluations  
All on-study evaluations must be scheduled as per section 6.1 with a ±7-day 
window for the month 1 visit and a ±30-day window for all other visits. 
 
Participants who miss visits should be contacted to make up the visit and to 
permit determination of whether a major event occurred. See section 6.4 for 
additional considerations for endpoint assessments in the event of missed visits. 
 
Return Fasting Visit (as needed) 
This visit is only required for participants who are in a non-fasting state for visits 
that require fasted assessments. Participants should return for fasted 
assessments within 30 days for a fasting evaluation. 
 


 
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Study Termination Evaluation  
The study termination evaluation will be completed as the participant’s final on-
study visit.  Please follow the Schedule of Evaluations (SOE) regarding data 
collection for the Study Termination Visit.  
 
Since REPRIEVE is an endpoint-driven trial, the study termination will be 
when the target number of endpoints has been reached or when 
determined by the DSMB at a later date. The study team will notify all sites 
of when to begin conducting the Study Termination Visit. 
 
Event-Driven Evaluations  
Evaluations must be scheduled as per section 7.0. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered or Randomized Participants Who Do Not Start Study 
Treatment 
For participants who withdraw from the study before initiating study treatment, 
complete all eCRFs for the period up to and including the entry visit. 
 
Premature Treatment Discontinuation Evaluations 
Participants who discontinue the study treatment before the end of the study will 
have the premature treatment discontinuation evaluations completed within 30 
days after stopping the study drug. At this visit, study drug will not be dispensed 
but adherence assessment will be performed for these individuals. After 
completion of the premature treatment discontinuation evaluations and until the 
study termination visit, participants will follow the clinical assessment and 
laboratory schedules as per section 6.1. Medication adherence will be assessed.  
 
Premature Study Discontinuation Evaluations 
Participants who prematurely discontinue from the study will have the premature 
study discontinuation evaluations performed as per section 6.1 prior to being 
taken off study. 
 
NOTE: Sites will capture and document reasons for premature discontinuation 
(eg, related to AE), and whether premature discontinuation pertains to consent 
for follow-up and/or treatment.  
 
For participants who prematurely discontinue from the study for reasons other 
than withdrawal of consent, sites will attempt to obtain information regarding vital 
status and endpoints annually (see section 6.3.10).  
 
6.3 
Instructions for Evaluations and Data Collection  
 
Each study site and laboratory involved in this study will comply with the DAIDS 
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Trials Policy, which is available at 
https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf. 
 
All clinical and laboratory information required by this protocol is required to be maintained in 
the source documents (see MOPS for additional details). Sites must refer to the Source 
Document Guidelines on the DAIDS website for information about what must be included in the 
source document: https://www.niaid.nih.gov/sites/default/files/score-source-documentation-
requirements.pdf. 
 
All stated evaluations are to be recorded in the EDC unless otherwise specified. This 
includes events that meet the International Conference on Harmonization (ICH) 
definitions for a serious adverse event: 
• 
Results in death 
• 
Life-threatening 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Congenital anomaly/birth defect 
• 
Other important medical event (may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the events listed above). 
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), corrected Version 2.1, July 2017, is available on the DAIDS RSC website 
at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables. 
 
The protocol team and/or study monitoring entity may determine that additional 
source data associated with procedures or evaluations performed per protocol 
should be entered into eCRFs so that the data can be used for analysis or to 
otherwise assist with interpretation of study findings. In such cases, sites will be 
officially instructed to enter the additional data into eCRFs from available source 
documentation.  
 
6.3.1 Documentation of HIV-1 
 
Section 4.1.1 specifies requirements for HIV-1 documentation. HIV-1 
documentation is not recorded in the EDC. 
 
6.3.2 Medical History 
 
The following diagnoses should be recorded in the EDC at screening and 
updated at entry, regardless of when the diagnosis was made: 
• 
Hypertension 
• 
Diabetes mellitus 
• 
AIDS-defining events  


 
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• 
Any malignancy (exclusive of basal/squamous cell skin cancer) 
• 
Prior history of dialysis or renal transplantation 
• 
Chronic active hepatitis C 
• 
Chronic active hepatitis B 
• 
Venous thromboembolism (VTE) 
• 
Pulmonary thromboembolism (PTE) 
• 
Nadir CD4 cell count (verbal history accepted) 
• 
COVID-19 
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.3 Medication History 
 
A limited medication history must be performed at screening and updated at 
entry and post-entry visits as per Table 6.3.3-1 below. Record all modifications to 
ART, including participant-initiated modifications (more than 7 consecutive 
missed days), provider-initiated modifications, and permanent discontinuation. 
See Table 6.3.3-1 below and MOPS for more details. 
 
Table 6.3.3-1: Medication History  
Medication Category 
Complete History or Timeframe 
Record in 
EDC 
(Yes/No) 
Antiretroviral therapy 
Cumulative duration of protease inhibitor, 
thymidine analogs, abacavir, tenofovir, and 
overall ART duration 
Yes 
Current ART therapy 
Current  
Yes 
Blinded study therapy (other 
than for REPRIEVE) 
Current 
Yes 
Statin therapy  
Any prior or current exposure  
Yes 
Nonstatin lipid lowering 
therapy 
Current 
Yes 
Antidiabetic medications 
Current 
Yes 
Aspirin therapy (ongoing 
regular therapy) and 
anticoagulant medications 
Current  
Yes 
Antihypertensive 
medications* 
Current  
Yes 
Antihepatitis medications  
Current 
Yes 
Hormonal contraceptives or 
hormone replacement 
therapy* 
Current  
Yes 
Testosterone therapy* 
Current 
Yes 


 
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Medication Category 
Complete History or Timeframe 
Record in 
EDC 
(Yes/No) 
COVID-19 medications 
(including vaccines)* 
Any prior or current exposure 
Yes 
*Refer to the MOPS for more information about recording these classes of drugs. 
Study Treatment Modifications 
The study drugs are pitavastatin and placebo for pitavastatin. Record all study 
drug modifications, participant-initiated and protocol-mandated modifications, 
inadvertent and deliberate interruptions of more than 7 consecutive days. Record 
any permanent discontinuation of treatment. 
 
6.3.4 Clinical Assessments 
 
Signs and Symptoms 
At entry, all grades that occurred ONLY within the 30 days before entry are to be 
collected and maintained in the source documents but are not required to be 
recorded in the EDC at this time. If a participant develops future signs and 
symptoms, the signs and symptoms recorded in source documents at entry can 
be referred to, in order to see if they are truly incident or recurrent.  
 
After entry, only the following signs and symptoms are to be recorded in the EDC: 
• 
Signs and symptoms Grade 3. 
• 
All signs and symptoms that led to a change in treatment (pitavastatin or 
placebo) regardless of grade. 
 
NOTE: If signs and symptoms are related to a diagnosed event, record the 
primary event in the EDC and do not grade or record related signs and 
symptoms. If Grade 3 signs and symptoms occur independent of a related 
diagnosis, they should be recorded in the EDC.  
 
Further evaluation will be required for those events that meet EAE or ICH 
reporting requirements. 
 
Diagnoses 
All incident diagnoses listed in section 6.3.2 will be assessed at all visits post entry; 
refer to section 6.4 for requirements for intervening medical history review related 
to primary MACE and other secondary serious non-cardiovascular events.  
 
Assessment of Potential Myalgia Toxicity 
Potential statin effects on the liver will be assessed with ALT at month 1 and 
month 12 visits; potential effects on muscle will be assessed by a myalgia 
symptom assessment at entry and onward.  
 


 
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Cardiovascular Risk Assessment Tool 
The ACC/AHA 2013 10-year ASCVD risk score should be performed as part of 
screening. MOPS section 2.1, Atherosclerotic Cardiovascular Disease Risk 
Assessment Tool, provides detailed instructions concerning access and use of 
the 10-year ASCVD risk score calculator. It is important to use only the 10-Year 
ASCVD Risk Score, not the “risk with optimal risk factors” or the “lifetime ASCVD 
Risk calculator” results. 
 
NOTE: For the purposes of calculation of the 10-year ASCVD risk score using 
the Pooled Cohort Equations: 
• 
For participants whose values of HDL cholesterol, total cholesterol, and/or 
systolic blood pressure fall below or above the acceptable calculator bounds 
for those parameters, values at the lower or upper bounds, respectively, will 
be entered.  
• 
Participants of mixed race will be asked to identify themselves as 
predominantly African American or predominantly other, and the race of 
predominant identification will be entered; as per calculator guidelines, non-
African American race is entered as White or other race. 
• 
Participants will be asked to report sex at birth, and this sex will be entered.  
• 
Only participants currently on 1 or more antihypertensive medications will be 
counted as undergoing treatment for high blood pressure.  
• 
Only participants who report current active smoking will be counted as smokers.  
 
NOTE: When calculating the ASCVD risk score, the use of e-cigarettes is not 
considered as current active smoking. Please mark “no” for persons who 
report only the use of e-cigarettes. 
 
Cardiovascular Risk Factor Assessment 
An assessment of general cardiovascular risk factors, current smoking, alcohol 
use, substance use, and family history of premature CVD. will be assessed at 
screen. Hormonal/reproductive health assessments relevant to CVD risk 
will be assessed at screening and study termination visits. 
 
Diet and Functional Capacity Assessment 
Diet (Rapid Eating and Activity Assessment for Patients [(REAP] questionnaire), 
functional capacity (Duke Activity Status Index [DASI] questionnaire), will be 
completed at entry, and study termination visits.  
 
Screening Physical Exam 
A screening physical examination is to include auscultation of the chest, cardiac 
exam, examination of the lower extremities for edema, and vital signs. 
 
Targeted Physical Exam 
A targeted physical examination is to include vital signs, and is to be driven by 
any previously identified or new signs or symptoms, including muscle aches, 
pains, tenderness, weakness, malaise, or fever. A targeted physical exam will 


 
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also be driven by any diagnoses that the participant has experienced since the 
last visit. The targeted physical exam will occur at month 1 and each annual visit. 
 
Height 
Measurement of height will occur at screening. 
 
Weight 
Measurement of weight will occur at screening and each annual visit. 
 
Waist Circumference 
Measurement of iliac waist circumference will occur at screening and study 
termination visits. Please see MOPS for instructions on waist circumference 
measurement. 
 
ECG 
Resting 12-lead ECG results, including heart rate will be performed at entry. 
Please see MOPS for instructions. 
 
6.3.5 Lifestyle Information 
 
Participants will be provided information regarding healthy diet and activities in 
the Lipid-Lowering Diet, Activity Guide, and Smoking Cessation located on the 
REPRIEVE (A5332) PSWP. In addition, participants will be reminded to adhere 
to prescribed antiretroviral regimen and study medication. This is to be provided 
at entry and annual visits. 
 
6.3.6 Laboratory Evaluations 
 
All laboratory values collected for REPRIEVE (A5332) must be recorded in the 
EDC. This includes laboratory values performed as part of toxicity 
management (eg, all CK assessments performed as part of management of 
myalgias and myopathy). 
 
Post entry, all Grade 3 laboratory values and all laboratory values regardless of 
grade that led to a change in treatment must be recorded as adverse events. 
Further evaluation will be required for those events that meet EAE or ICH 
reporting requirements. 
 
Laboratory testing for screening or safety assessment must be performed in a 
CLIA or equivalent certified laboratory or at any network-approved non-US 
laboratory that operates in accordance with Good Clinical Laboratory Practices 
and participates in appropriate external quality assurance programs. 
 
When labs are being captured from clinical care, the most recent lab value 
should be the value recorded in the EDC. Screening labs captured from clinical 
care should be within 90 days prior to entry unless otherwise indicated. 


 
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Fasting is defined as nothing to eat or drink except water and required 
prescription medications for at least 8 hours. Drinking black decaffeinated coffee 
without sweetener or creamer is permissible, but is not advised. Participants 
must be evaluated in a fasting state for those evaluations indicated as “fasting” 
unless otherwise specified. Participants will be asked whether they have fasted, 
and if not, they should be scheduled to return in a fasting state within 30 days to 
complete the fasting evaluations. 
 
Participants should be instructed with the exact time beyond which they are to be 
fasting, such as: “Your visit is scheduled for 8:00 a.m. You should not have any 
food or drink by mouth except water and medication after 12 a.m.” 
 
In order to minimize diurnal variation, fasting samples for individual participants 
should be obtained consistently in the morning, if possible. Participants will be 
encouraged to take the study drug consistently at the same time and this 
information will be collected in the medication adherence assessment. 
 
CD4+/CD8+ 
Screen: Absolute CD4+/CD8+ count and percentages will be obtained from 
clinical care within 180 days prior to entry; if not available, draw as part of study. 
 
Post-entry evaluations: CD4+/CD8+ obtained from clinical care since the last 
annual study visit. For post-entry evaluations, all laboratories must possess 
a CLIA certification or equivalent (US sites) or IQA certification (non-US 
sites). 
 
NOTE: If CD8+ cell count is not available, CD4+ cell count alone is acceptable. 
 
Plasma HIV-1 RNA 
At all visits indicated on the Schedule of Evaluations, collect results of plasma 
HIV-1 RNA determinations that are obtained through clinical care. For the entry 
visit, a viral load from the prior 180 days should be recorded in the EDC. If not 
available, it will not be collected. For all post-entry evaluations, the most recent 
viral load obtained since the last annual study visit should be recorded in the 
EDC. For post-entry evaluations, all laboratories must possess a CLIA 
certification or equivalent (US sites) or must be VQA certified (non-US 
sites).  
 
Hematology  
At screening, hemoglobin, hematocrit, white blood cell count (WBC) and platelets 
will be captured from clinical care within 90 days prior to entry; if not available, 
draw as part of the study. At study termination visits, results must be within 
180 days prior to that visit. 
 
Serum creatinine and calculated creatinine clearance/GFR: at screening, 
creatinine result will be obtained from clinical care within 90 days prior to entry; if 


 
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not available, draw as part of the study. At study termination visits, results 
must be within 180 days prior to that visit; calculated creatinine clearance/GFR 
is not required at study termination visits.  
 
NOTE: See the A5332 MOPS for links to GFR and CrCl calculators. 
 
Fasting Lipid Panel  
Screen: Total cholesterol, HDL cholesterol, direct or calculated LDL cholesterol if 
triglycerides are ≤400 mg/dL (direct LDL must be determined if triglycerides are 
>400 mg/dL and <500 mg/dL), and triglycerides will be collected from clinical 
care within 90 days prior to entry; if not available, draw as part of the study. 
 
NOTE: If the screening lipid values to determine study eligibility are taken from 
existing clinical care assessments and are within the range specified by inclusion 
criterion 4.1.4, fasting status and documentation of fasting status are not required.  
 
The screening lipid panel will be reviewed with the potential participant and 
shared with his or her medical provider along with the study rationale to confirm 
support of participant participation. Specimens from entry onward will be stored 
to be tested centrally. Participants may opt out of these entry and post-entry labs. 
 
Liver Function Tests 
Screen: ALT (SGPT) will be obtained from clinical care within 90 days prior to 
entry; if not available; draw as part of the study. Persons with HCV or HBV 
should also have AST (SGOT) obtained from clinical care within 90 days prior to 
entry to facilitate calculation of fibrosis by the FIB-4 equation. 
 
At month 1 and month 12, ALT will be drawn as part of the study.  
 
NOTE: Refer to the MOPS for link to the FIB-4 calculator.  
 
Pregnancy Testing 
For women with reproductive potential: serum or urine -HCG (urine test must 
have a sensitivity of <25 mIU/mL) will be performed as part of the study at each 
visit and whenever pregnancy is suspected. Record pregnancy and pregnancy 
outcome. Refer to the MOPS for guidance. 
 
Fasting glucose at entry and onward will be performed as part of the study. 
Specimens will be tested centrally. Participants may opt out of these entry and 
post-entry labs.  
 
NOTE: Fasting is defined as above (see 6.3.6 for Fasting Lipid Panel). 
 
Urine Albumin/Creatinine Ratio 
Urine for urine albumin/creatinine ratio will be collected from all participants at 
entry. Specimens will be tested centrally. 


 
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ACTG sites will collect urine at subsequent visits per section 6.1 only from 
participants who enrolled in REPRIEVE (A5332) prior to 01/01/2018. These 
specimens will be tested centrally. 
 
6.3.7 Immunologic, Hormonal, and Biomarker Studies 
 
Additional serum and plasma will be batched and stored in the ACTG Specimen 
Repository for analyses by a central core laboratory. Refer to the Laboratory 
Processing Chart (LPC) for details. Participants may opt out of these entry and 
post-entry labs. 
 
6.3.8 Stored Whole Blood for Future Genetic Studies  
 
A single whole blood sample will be obtained from all study volunteers for human 
genotyping of selected polymorphisms that may predispose to CVD or alter 
pitavastatin levels or effectiveness. This sample will be drawn at ACTG sites only 
and will be collected in addition to any samples collected for participants in 
A5128 or A5243. 
 
6.3.9 Medication Adherence Assessment 
 
Site personnel will perform an assessment of adherence to study medication at 
every visit after the entry visit. 
 
6.3.10 Vital Status and Endpoint Follow-up 
 
For participants who prematurely discontinue study for reasons other than 
withdrawal of consent, site personnel will attempt to obtain information regarding 
vital status (including date last seen alive, date of death, and primary cause of 
death) and endpoints (see sections 6.4.1-6.4.2) from participant or other sources 
(such as family members, other designated contacts, or clinic records) annually 
from the time off study. Please see MOPS for additional information.  
 
6.4 
Endpoint Assessments 
 
At entry and onward, a comprehensive review of the intervening medical history of the 
participant will be performed to capture the data for adjudication of the primary and 
secondary endpoints, including diagnoses and any hospitalization. Participants will be 
specifically asked about hospitalization, emergency room visits, urgent care visits, 
physician visits, and any symptoms that are suggestive of CVD. Information regarding 
potential events will be recorded in the EDC and via source documents and prepared for 
transmission after de-identification to the Clinical Event Committee (CEC) for 
adjudication, as appropriate. Participants who miss visits will be contacted to make up 
the visit and to permit determination of whether major event occurred, the assessment 
will be completed using other sources such as designated contact, physician contact, or 
medical records (refer to the MOPS for details). Events will be reviewed and categorized 


 
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by a CEC unaware of the treatment assignment based on established definitions 
described below.  
 
Non-CVD events as described below will be assessed but will not be formally 
adjudicated by the CEC. 
 
6.4.1 Definitions of Major Adverse Cardiovascular Events (MACE) Components  
 
The primary endpoint of Major Adverse Cardiovascular Events (MACE) includes 
the composite of Cardiovascular Death, Myocardial Infarction, Hospitalization for 
Unstable Angina, Coronary, Carotid or Peripheral Arterial Revascularization, 
Transient Ischemic Attack, Stroke, and Peripheral Arterial Ischemia. 
 
Formal definitions for each of these components and additional secondary and 
exploratory endpoints are contained within the CEC charter, and are based on 
the Standardized Definitions for Cardiovascular and Stroke End Point Events in 
Clinical Trials [Hicks 2015]. 
 
General principles guiding these definitions are described below.  
 
CVD death: includes death resulting from an acute myocardial infarction (MI), 
sudden cardiac death, death due to heart failure (HF), death due to stroke, death 
due to cardiovascular (CV) procedures, death due to CV hemorrhage, and death 
due to other CV causes. 
 
Myocardial infarction: The diagnosis of MI requires the combination of: evidence 
of myocardial necrosis (either changes in cardiac biomarkers or post mortem 
pathological findings); and supporting information derived from the clinical 
presentation, electrocardiographic changes, or the results of myocardial or 
coronary artery imaging suggesting an event consistent with coronary ischemia. 
 
The totality of the clinical, electrocardiographic, and cardiac biomarker 
information will be considered to determine whether or not an MI has occurred. 
Specifically, timing and trends in cardiac biomarkers and electrocardiographic 
information will be included whenever possible, but the diagnosis can still be 
determined if these results are not available. 
 
Unstable angina hospitalization: ischemic discomfort or equivalent requiring 
hospitalization within 24 hours with objective signs of coronary ischemia in 
absence of MI. ECG, angiographic and imaging criteria will be considered.  
  
Coronary, carotid, or peripheral arterial revascularization: invasive percutaneous 
or surgical procedure intended to restore or improve blood flow in a coronary or 
peripheral artery including but not limited to angioplasty, stent, stent graft, or 
bypass graft. 
 


 
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Stroke: an acute episode of focal or global neurological dysfunction caused by 
brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction. 
 
Transient Ischemic Attack: a transient episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without stroke. 
 
Peripheral Arterial Ischemia (PAD): Peripheral arterial ischemia hospitalization: 
Urgent hospitalization for insufficiency of the peripheral arterial circulation, 
including but not limited to, acute limb ischemia, chronic limb ischemia, 
amputation, or other vascular abnormality of an ischemic and noninfectious 
nature.  
 
6.4.2 Causes of Death  
 
In addition to CVD death which is a component of the primary endpoint, all 
deaths will be adjudicated by the CEC to determine likely cause.  
 
6.4.3 Cardiac Events to be adjudicated but not included in REPRIEVE (A5332) MACE 
Definition: 
• 
Heart Failure, including all COVID-19-related events resulting in 
hospitalization (see CEC Charter) 
 
6.4.4 Non-CVD Events 
 
Clinical assessments will also include assessing the participant regarding the 
occurrence of the following diagnoses: 
• 
AIDS-defining events  
• 
Non AIDS defining cancers (except squamous/basal cell of the skin) 
• 
End stage kidney disease, requiring initiation of dialysis or renal 
transplantation 
• 
End stage liver disease (incident cirrhosis or hepatic decompensation 
requiring hospitalization) 
• 
Incident diabetes mellitus requiring use of diabetes medications 
• 
Venous thromboembolism (VTE) 
• 
Pulmonary thromboembolism (PTE) 
 
For diagnostic criteria for these non-CVD events, refer to the MOPS. All identified 
events should be reported in the EDC regardless of grade. These events do not 
undergo CEC adjudication. 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
Only toxicities related to the study drug (pitavastatin and placebo for pitavastatin) are 
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multiple toxicities or AEs, the guidelines pertaining to the most severe event should take 
precedence.  
 
The grading system is located in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, 
is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
Please refer all questions to the REPRIEVE (A5332) core protocol team via email. 
 
7.1 
Toxicity Management 
 
7.1.1 General Reactions 
 
Grade 1 or 2 
Participants who develop a Grade 1 or 2 toxicity may continue study treatment. 
 
Grade 3 
Participants who develop a Grade 3 toxicity that is judged by the site investigator 
to be study drug-related should have the study drug held and the study team 
should be consulted. The participant should be followed closely and if the toxicity 
does not return to Grade 2 within 2 weeks, the study drug must be permanently 
discontinued with participant evaluations as per section 6.2.4. 
 
If the study drug is resumed and the same Grade 3 toxicity recurs within 4 weeks 
of reintroduction, and the site investigator considers this AE related to the study 
drug, the drug must be permanently discontinued. 
 
With a Grade 3 toxicity that is judged not related to the study drug by the site 
investigator, the study drug may be continued at the discretion of the site 
investigator in consultation with the study team. 
 
Grade 4 
Participants who develop a Grade 4 toxicity will have the study drug held and the 
study team should be consulted. Participants experiencing Grade 4 toxicities 
should be followed closely with additional clinical assessments and laboratory 
testing as clinically indicated.  
 
If the investigator feels that the toxicity is clearly related to another cause and 
that the toxicity is not caused by the study drug, and after consultation with the 
study team, dosing may continue. 
 
Otherwise, if the toxicity does not return to Grade 2 within 2 weeks, the study 
drug must be permanently discontinued with participant evaluations as per 
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NOTE: Direct and indirect bilirubin elevations that reach Grade 4 elevations 
according to the DAIDS AE Grading Table and are related to atazanavir are 
excluded from reporting. 
 
7.1.2 ALT Elevations  
 
ALT levels will be routinely evaluated at visits at month 1 and month 12. All other 
evaluations of ALT will be performed at the discretion of the site investigator 
based on participant symptoms.  
Grade 3 
Participants who develop asymptomatic >5 x ULN ALT elevations (Grade 3), 
study drug should be held for 1 week and the individual should be re-evaluated 1 
week after drug discontinuation. If at that time the ALT elevation is 5 x ULN and 
participants remain asymptomatic, the participants are eligible to continue on 
study treatment at the discretion of the site investigator. If the ALT does not 
return to ≤5 x ULN within the 1-week period, the study drug must be permanently 
discontinued unless the ALT elevations are deemed not related to study drug 
upon further assessment as per the discretion of the PCP (ie, acute hepatitis A or 
other clear causation). 
 
For any symptomatic (eg, fatigue, nausea and vomiting, right upper quadrant 
pain, rash or eosinophilia) ALT >5 x ULN (Grade 3), study drug should be held. 
Participants should be asked to return to the research site for repeat testing 1 
week later. If repeat ALT is ≤3 x ULN and the participant is no longer 
symptomatic, study drug can be resumed. 
 
Grade 4 
For any ALT >10 x ULN (Grade 4), study drug should be discontinued. The 
participant should be brought back for repeat testing every 1 week until the ALT 
≤5 x ULN.  
 
NOTE:  If the Grade 3 or 4 elevation is clearly related to another cause and not 
related to study drug (eg, acute hepatitis A infection), the participant should be 
brought back for repeat testing every 2 weeks for Grade 3 or every 1 week for 
Grade 4 until the ALT ≤3 x ULN. The local site investigators should contact the 
study team for approval before resuming study drug. Participants who 
permanently discontinue study drug will be followed on study, off treatment 
through the study termination visit with participant evaluations as per section 
6.2.4. 
 
NOTE: For those participants with ALT >3 x ULN upon repeat testing, whether 
symptomatic or not, AST, alkaline phosphatase, and total bilirubin or INR, should 
also be performed as part of the study to help determine etiology of increased 
LFTs. For participants on atazanavir, performance of INR rather than bilirubin is 
preferred. Other labs including hepatitis serologies may also be indicated and 
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NOTE: If the participant has recurrent elevations of ALT >3 x ULN but the site 
investigator deems the elevation not related to study drug, the site investigator 
must contact the study team to discuss continuation of study drug.  
 
Abnormal ALT determinations occurring in the course of clinical care should be 
repeated by the treating clinician. Persistently abnormal values which would 
trigger the toxicity guidelines above should be reported to the REPRIEVE 
(A5332) team. If the ALT abnormality is not due to another cause, eg, acute 
hepatitis, the REPRIEVE (A5332) site PI will follow the toxicity algorithm above. 
7.1.3 Myalgias and Myopathy 
 
Persons who present with significant myalgias (Grade ≥3, ie, muscle pain 
causing inability to perform usual social and functional activities) should be 
evaluated with a clinical assessment that includes an evaluation of CK, serum 
creatinine, potassium, and urinalysis. Myopathy is defined as muscle aches, 
soreness, tenderness, or weakness with CK >10 x ULN not related to exercise or 
other causes, including trauma. If the symptoms are associated with Grade 3 
elevation in CK (10 x ULN) (See Table 7.1.3-1 below) that is not related to 
exercise or other cause, study medications should be permanently discontinued. 
Participants will be followed on study, off treatment through the study termination 
visit with participant evaluations as per section 6.2.4.  
 
NOTE:  Mitochondrial toxicity related to nucleoside therapy and not related to 
study medication is a possibility, and evaluations for lactic acidosis should be 
considered by the participant’s primary care provider. 
 
Table 7.1.3-1: Serum CK Toxicity Grading* 
Toxicity Grade 
Value 
Grade 1 
3 – <6 x ULN 
Grade 2 
6 – <10 x ULN 
Grade 3 
10 – <20 x ULN 
Grade 4 
≥20 x ULN 
 
 
*Not related to exercise or other cause 
 
7.1.4 Rhabdomyolysis 
 
Rhabdomyolysis is defined as the presence of myopathy as per section 7.1.3 
plus one or more of the following: 
• 
Hematuria on urine dipstick in the absence of microscopic hematuria 
(myoglobinuria) 
• 
Grade 2 hyperkalemia 
• 
Grade 2 creatinine elevation 
 
If rhabdomyolysis occurs, study medications should be permanently 
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study, off treatment through the study termination visit with participant 
evaluations as per section 6.2.4. In addition, CK will be added to the laboratory 
evaluations performed until it has declined to ≤1 x ULN. 
 
7.2 
Requirement for Precautionary or Prohibited Medications (see PSWP) 
 
Participants who need to initiate therapy with erythromycin, colchicine, systemic (oral or 
intravenous) cyclosporine, or rifampin should be asked to hold study drug. If use of one 
of these precautionary medications is anticipated to be short-term, the site investigator 
may consider restarting study drug after use of prohibited medication is discontinued. 
Participants who begin a statin medication provided through clinical care should 
discontinue study drug. Taking two statins can increase the risk of toxicity.  
 
Participants who temporarily or permanently discontinue study treatment will be followed 
on study, off treatment through the study termination visit with participant evaluations as 
per section 6.2.4. 
 
7.3 
Pregnancy  
 
If the pregnancy test is positive at entry, then the participant should not start study 
treatment. No further evaluations are necessary, provided that the participant did not 
initiate study drug. 
 
Participants who become pregnant after study entry must discontinue study treatment 
immediately. These participants should be seen for a premature treatment 
discontinuation evaluation within 7 days. Participants will be followed on study, off 
treatment through the study termination visit with participant evaluations as per section 
6.2.4. The core team must be notified of any pregnancies that occur in participants on 
study. Management of the background ART is at the discretion of the site investigator.  
 
All pregnancies should be followed until the final outcome can be determined. In the 
event that the pregnancy has not been completed by the final study visit, the site should 
contact the participant through monthly phone calls and review of medical records, if 
possible, until the pregnancy outcome can be ascertained. See the MOPS for guidance 
on documenting pregnancy outcomes. 
 
Pregnancies that occur on study should be reported prospectively to The Antiretroviral 
Pregnancy Registry. More information is available at www.apregistry.com. Phone: 800-
258-4263; Fax: 800-800-1052 (Non-US sites: Fax: 44-1628-789-666 or 910-246-0637; 
phone: 910-679-1598.) 
 
7.4 
Unblinding Procedures 
 
For unblinding requests, including emergency unblinding, refer to the ACTG Unblinding 
Participants Standard Operating Procedure (SOP) 123 at   
https://member.mis.s-3.net/cms/dl/10466 


 
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Note: Unblinding is rarely allowed as study medications can most often be withdrawn in 
a participant experiencing adverse effects without the need for unblinding. Any decision 
on unblinding should be made with reference to the ACTG SOP. 
 
In the event that emergency disclosure of treatment assignment is thought to be 
required, the site investigator must follow the ACTG Unblinding Participants SOP 123. 
 
The protocol chairs and DAIDS Medical Officer will be notified of such a request through 
the ACTG DMC unblinding program. All site e-mails to the team should be carefully 
worded to prevent unblinding the team, if possible. 
Unblinding of all study participants will take place after the last participant has completed 
the study, all data have been entered into the database and cleaned for primary and 
secondary endpoints, and MACE endpoint verification is complete. The time necessary 
to finalize the data can be up to 3 months or more after study closure. 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Premature and Permanent Treatment Discontinuation 
 
• 
Participant refusal to continue study treatment. 
• 
Drug-related toxicity per section 7.0. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
section 7.0. 
• 
Pregnancy or breast-feeding. 
• 
Use of prohibited and some precautionary medications per section 7.0. See PSWP 
for precautionary and prohibited medication list for further information. Please 
contact the study team if you have questions. 
 
NOTE: Participants who permanently discontinue study treatment will be followed on 
study, off treatment through the study termination visit with participant evaluations per 
section 6.2.4. 
 
8.2 
Premature Study Discontinuation 
 
• 
Refusal by the participant of further study follow-up. 
• 
Request by the participant to withdraw consent. 
• 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 
• 
At the discretion of the ACTG, IRB/EC, Food and Drug Administration (FDA), Office 
for Human Research Protections (OHRP), NHLBI, NIAID, other government 
agencies as part of their duties, investigator, or pharmaceutical supporter.  
 
If a participant misses clinic visits for >1 year, it is at the discretion of the site PI whether 
or not to discontinue the participant from study participation. Participants who 


 
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prematurely discontinue from the study will have the premature study discontinuation 
evaluations performed as per section 6.1 and then be taken off study. 
 
In the event that a participant prematurely discontinues from the study, unless they have 
withdrawn consent, sites will attempt to obtain information regarding vital status 
(including date last seen alive, date of death, and primary cause of death) and MACE 
events from other sources (such as family members, other designated contacts, or clinic 
records) per section 6.2.4. 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
General Design Issues 
 
REPRIEVE (A5332) is a prospective, randomized, double-blind, placebo-controlled, 
phase III study of the effect of pitavastatin on major cardiovascular events in PWH who 
do not meet current guidelines for statin therapy. The study was originally designed to 
enroll 6500 participants with HIV on stable ART and not eligible for statins as per the 
2013 ACC/AHA guidelines. Enrollment was anticipated to take 30 months with study 
follow-up continuing for approximately 72 months after the enrollment of the first 
participant. Based on recommendations of the REPRIEVE (A5332) DSMB following their 
December 2017 review, the study sample size was increased to approximately 7500 
participants with follow-up continuing for approximately 84 months after the enrollment of 
the first participant. Based on recommendations of the NIH and the REPRIEVE DSMB 
following their December 2018 review, follow-up was extended to 96 months. Follow-up 
will now continue until the study reaches the targeted 288 primary MACE events 
or is otherwise recommended for closure by the DSMB. 
 
Further, a cap of approximately 2000 participants total enrollment of individuals with very 
low cardiovascular risk (estimated 10-year ASCVD risk score <2.5%) was implemented 
to ensure that the final study population reflects the targeted low-to-moderate-risk 
population. Subsequent to a new recommendation from the NIH, the total enrollment of 
individuals with low cardiovascular risk (10-year ASCVD risk score <5.0%) was capped 
at approximately 4200 participants, to ensure that the final study population reflects the 
targeted low-to-moderate risk population. 
 
All primary analyses will be performed as intention-to-treat and include all participants as 
randomized. 
 
A complete firewall will be maintained to ensure that investigators have no access to the 
data. All data will be kept on secure systems at Frontier Science & Technology 
Research Foundation (FSTRF). A complete description of the firewall procedures, data 
organization, and security is included in the final statistical analysis plan. The plans and 
procedures will be consistent with NHLBI and NIAID policy with respect to maintenance 
of data integrity. 
 


 
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Ancillary studies are investigations that are not part of REPRIEVE (A5332), but that 
propose questions and test hypotheses that are relevant to and further the goals and 
purposes of REPRIEVE (A5332). It is recognized that well-designed ancillary studies, 
consistent with the goals of REPRIEVE (A5332), can leverage the trial’s resources to 
provide critical answers to highly relevant questions for the field. Successful ancillary 
studies should have secured adequate funding through peer review, through either the 
ACTG, NIH, or other funding sources. To protect the integrity of REPRIEVE (A5332), 
ancillary study proposals are reviewed and approved by the REPRIEVE Ancillary 
Studies Committee and the DSMB prior to implementation. In addition to meeting the 
standard for high scientific merit, the major criterion for approval of an ancillary study is 
that it does not negatively affect the conduct of the parent REPRIEVE trial. 
For more details regarding the ancillary studies approved for implementation as part of 
REPRIEVE (A5332), please see Appendices IV and V. 
 
9.2 
Outcome Measures 
 
For all time to event study endpoints, time will be measured from the date of 
randomization to the onset date of the event of interest. 
 
9.2.1 Primary Endpoint 
 
The primary endpoint will be time to the first event of a composite of major 
cardiovascular events (primary MACE) including:  
• 
Atherosclerotic or other CVD death 
• 
Nonfatal myocardial infarction 
• 
Unstable angina hospitalization  
• 
Coronary or peripheral arterial revascularization 
• 
Nonfatal stroke or TIA 
• 
Urgent PAD ischemic event (acute or chronic limb ischemia, amputation, etc.) 
 
All primary events will be prospectively determined and adjudicated by an expert 
Clinical Events Committee based on standardized criteria used in prior 
cardiovascular trials and developed by consensus groups and the FDA [Hicks 
2015] (see section 6.4.1). Deaths adjudicated as of undetermined cause will 
be included as primary MACE endpoints. 
 
Participants discontinuing follow-up without experiencing the event will be 
considered censored at the time of their contact at which an assessment for 
primary endpoints was made; deaths from known non-CVD causes will be 
treated as competing risk events in the primary analysis. See section 9.6 for 
additional supportive analyses.  
 


 
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9.2.2 Supportive and Secondary Endpoints  
 
9.2.2.1 Time to the first of each individual component of the primary endpoint. 
 
For each event, participants discontinuing follow-up without 
experiencing the event will be considered censored; deaths from other 
causes will be considered competing risk events. 
 
9.2.2.2 Time to death (all-cause mortality)  
 
Based on independent review, death will be classified as cardiovascular 
event or non-cardiovascular event. Non-cardiovascular events will be 
further characterized as HIV-associated clinical diagnosis, non-AIDS 
malignancy, accidental, suicide, homicide, other sudden death of 
unknown etiology, or other. See Statistical Analysis Plan (SAP) for 
further details. 
9.2.2.3 Time to death (all-cause mortality) and/or MACE 
 
Participants discontinuing follow-up without experiencing the event 
(death from any cause or MACE) will be considered censored. A 
supportive outcome measure including data from vital status and 
endpoint follow-up (see section 6.3.10) will also be conducted. See SAP 
for further details. 
 
9.2.2.4 Time to any (composite) or each (individual) of the following incident 
clinical diagnoses (including recurrent diagnoses as appropriate) 
 
• 
Non AIDS-defining cancers (excluding basal cell and squamous cell 
carcinomas of the skin) 
• 
AIDS-defining events (based on CDC 2014 classification) 
• 
Initiation of dialysis or renal transplantation. 
• 
Cirrhosis, or hepatic decompensation requiring hospitalization  
 
For specific case definitions, see MOPS. 
 
For each event, participants discontinuing follow-up without 
experiencing each event will be treated as censored; deaths from other 
causes will be treated as competing risk events. 
 
9.2.2.5 Calculated fasting LDL and non-HDL cholesterol level at study entry and 
annually thereafter as well as change from baseline expressed as 
absolute change and as a percentage of baseline. For participants with 
triglycerides >400 mg/dL and <500 mg/dL, direct LDL will be determined 
and use in the statistical analysis. 
 


 
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9.2.2.6 Time to any of the following adverse events (including recurrent events 
as appropriate) 
 
• 
Serious adverse event as defined by ICH criteria 
• 
Incident Diabetes mellitus (DM) 
• 
Grade 3 or 4 ALT 
• 
Grade 3 or 4 myopathy 
• 
COVID-19 diagnosis 
• 
Serious COVID-19 diagnosis (ie, a COVID-19 diagnosis that is 
Grade 4 or results in hospitalization or death)  
 
All events will be included regardless of relationship to treatment as 
determined by sites. 
 
Grading will be defined per the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, corrected Version 2.1, July 2017. 
See section 11.4 for link to the document. 
For COVID-19 outcomes, time will be measured from January 1, 2020. 
 
9.2.2.7 Antibody-positive COVID-19 infection assessed cross-sectionally 
at specific calendar time points from samples collected annually. 
 
9.2.3 Exploratory Endpoints  
 
9.2.3.1 Fasting Total and HDL cholesterol and LDL-C/HDL-C ratio at study entry 
and annually thereafter. 
 
9.2.3.2 Time to heart failure  
 
9.3 
Randomization and Stratification 
 
At study entry, participants will be assigned with equal probability to one of the two 
treatment arms. Randomization will use permuted blocks with stratification by sex 
(male/female) and screening CD4+ T-cell counts (≤500 vs. >500 cells/mm3). Additionally, 
to ensure balanced treatment allocation for the Mechanistic Substudy of REPRIEVE 
(A5333s), randomization will also be stratified by whether or not a participant has elected 
to participate in the mechanistic substudy (yes/no). Total enrollment of individuals with 
low cardiovascular risk (10-year ASCVD risk score <5.0%) was capped at approximately 
4200 participants, to ensure that the final study population reflects the targeted low-to-
moderate risk population. It is anticipated that the study will take 48 months to fully 
enroll.  
 
9.4 
Sample Size and Accrual 
 
The original target sample size of REPRIEVE (A5332) was 6500 individuals. This was 
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December 2017 DSMB. Sample size considerations for the original target are provided 
below. Additional considerations providing justification for the increased sample size and 
duration of follow-up are also provided.  
 
9.4.1 Original Sample Size Considerations 
 
The original sample size for the main study was determined to provide 90% 
power to detect a 30% reduction in the composite CVD endpoint with statins 
(statin effectiveness equating to Hazard Ratio (HR) of 0.70). This desired effect 
size equates to a 5-year number needed to treat of 47. The effect size is more 
than the 22% based on LDL reduction alone seen in the Cholesterol Treatment 
Trialists’ collaboration [Cholesterol Treatment Trialists’ (CTT) Collaboration 
2010], consistent with the hypothesis of REPRIEVE (A5332), that statins will 
have an effect beyond LDL lowering. The HR is a more conservative effect size 
than was observed in JUPITER (a primary CVD prevention trial in people 
without HIV)―an HR of 0.56 or 44% reduction in the composite endpoint 
[Ridker 2008]. This more modest clinical effect is felt justified based on the higher 
absolute risk of CVD outcomes in PWH as well as some anticipated cross-over 
between the two study groups.  
 
Assuming a fixed sample size of 6500 individuals and total follow-up of 6 years, 
Table 9.4.1-1 shows the power under a range of alternative scenarios. For 
example, under the baseline assumption of an event rate of 15/1000 PY and 
accrual duration of 2.5 years, the sample size of 6500 participants will ensure 
90% power to detect a 30% reduction in event rates (HR = 0.70; 5-year NNT = 
47). However, with slower accrual (2.75 yrs) and lower event rates (14/1000 PY) 
REPRIEVE (A5332) will still have adequate power at 89% and 88%, respectively. 
Moreover, while power will be reduced to 83% in the case of severely reduced 
event rates of 12/1000 PY and a slower accrual rate of 2.75 years, contingencies 
to extend REPRIEVE (A5332) for a total follow up of 6.5 years while remaining 
within the scope of the current budget, will ensure a reasonable 85% power. 
 
Table 9.4.1-1: Power to Detect Given Hazard Ratio (HR) with Total Sample Size of 6500 Based 
on 2.5 Years of Accrual and 6 Years Maximal Follow-up 
 
The assumptions and justification underpinning the original REPRIEVE (A5332) 
study sample size are as follows:  
 
Design Assumptions 
Power to Detect 
Given HR 
Control rate 
of MACE 
5y event rates 
5y NNT for given 
HR 
Control 
Statin (for given HR) 
0.65 
0.70 
0.75 
0.65 
0.70 
0.75 
0.65 
0.70 
0.75 
18/1000 PY 
8.7% 
5.7% 
6.1% 
6.5% 
34 
39 
48 
99% 
94% 
83% 
15/1000 PY 
7.3% 
4.8% 
5.1% 
5.5% 
41 
47 
57 
97% 
90% 
76% 
12/1000 PY 
5.8% 
3.8% 
4.1% 
4.4% 
50 
58 
70 
93% 
83% 
67% 


 
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A composite CVD event rate of 15/1000 PY in the absence of statin therapy: 
Event rates for a similar composite endpoint were queried in the Partners 
Research Patient Data Registry (RPDR) for individuals ≥ 40 years of age, and 
determined for 3,213 thousand PWH and 26,309 thousand people without HIV 
matched on age/gender/race followed over 10 years from 2000-2009 (14,942 
person-years for PWH and 106,853 person-years for non-HIV). Event rates were 
21/1000 PY in PWH and 15/1000 PY in the non-HIV group. Further refining the 
Partners database query for incident MI, stroke, angina, revascularization among 
PWH ≥40 years, without diabetes mellitus and no recent history of statin use 
demonstrated (in alignment with the LDL independent definition of potentially 
eligible participants for REPRIEVE (A5332)) a MACE rate of 13/1000 PY. Since 
CVD death could not be obtained as part of this query, this rate likely 
underestimates the rate that could be expected in REPRIEVE (A5332). In 
JUPITER, CVD death represented 20% of all MACE. A similar adjustment would 
bring the HIV CVD event rate in Partners to 16.2/1000 PY. The placebo rate for 
MACE in JUPITER, among people without HIV was 13.6/1000 PY. The assumed 
event rate of 15/1000 PY for REPRIEVE (A5332) was felt to be a reasonable 
compromise between these rates. 
Enrollment will be completed in 30 months: Given the total study duration of 6 
years after enrollment has begun, individual participant follow-up will range from 
3.5 to 6 years, with a median follow-up of 4.75 years. REPRIEVE (A5332) will be 
conducted at approximately 100-130 sites including the majority of all domestic 
ACTG sites, and selected non-US ACTG sites as well as protocol specific sites. 
The assumed enrollment period of 30 months requires an average enrollment 
rate of 2.2 participants per site per month. Given a staggered rate of site 
activation, actual site enrollment will need to be between 3 to 4 participants per 
site per month. This enrollment rate is consistent with enrollment rates observed 
in recent large ACTG trials and with the expectations of the study sites based on 
a site survey. Further, a site survey conducted in early 2014 has suggested 
broad availability of the target study population. As of May 29, 2014, of sites 
queried, a total of 153 sites have expressed an interest in participating in 
REPRIEVE (A5332) and estimated being able to enroll 10,551 out of an 
estimated pool of 46,395 eligible participants. 
 
An annual 5% loss to follow-up rate: Since 1999, the ACTG has actively followed a 
large cohort of individuals on a limited visit schedule. During that time, the annual 
rate of lost to follow up was observed to be around 5.6%. We believe that we will be 
able to achieve a rate lower than this in REPRIEVE (A5332) since participants may 
also be receiving active treatment. Indeed, while this conservatively high estimate 
maintains power of study even in the event of 25% rate of loss over the duration of 
the study, it is desired that the observed rate will be no more than 15% over 6 years. 
 
Estimated treatment cross-over rates of 10%: REPRIEVE (A5332) is powered to 
detect a statin effectiveness equating to a HR of 0.70. The influence of treatment 
switching (crossover) on the effectiveness of statin treatment for the prevention 
of MACE and impact of this crossover on the power of the REPRIEVE (A5332) 


 
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study to detect a statin benefit as currently designed was broadly assessed via a 
simulation study. Briefly, clinical trials were simulated according to the 
REPRIEVE (A5332) design and analysis considerations. Simulated MACE times 
were accelerated and decelerated for discontinuation or initiation of statin 
treatment (for active and placebo groups respectively) over a range of crossover 
rates that were varied according to underlying MACE risk—simulated cases in 
the placebo group of higher underlying CVD risk as well as those in the statin 
group with the lowest CVD risk were assumed to have the highest rate of 
crossover. Average statin effectiveness over 6 years was estimated based on 
uncensored follow-up over >3,000,000 simulated cases. Under the base case, an 
overall rate of crossover of 10% resulted in an estimated statin effectiveness at 
the target of 0.70 for an underlying statin efficacy of 0.66. For the same statin 
efficacy, a 16% overall rate of crossover was associated with an estimated statin 
effectiveness of 0.74.  
 
9.4.2 Design Considerations following December 2017 and 2018 DSMB Reviews 
 
In follow-up to their December 2017 review, the REPRIEVE (A5332) DSMB 
recommended the following actions: 1) to cease study enrollment of patients with 
10-year ASCVD risk score less than 2.5%; 2) increase study sample size by 
approximately 1,000 participants of higher risk population; and 3) increase the 
follow-up by 1 year now and consider re-evaluation of an additional follow-up 
extension in the future [implemented following the December 2018 DSMB 
Review]. These recommendations respond to the higher than anticipated 
enrollment of participants with very low risk and ensure that REPRIEVE (A5332) 
will maintain power to detect the targeted effect of interest under a broader range 
of scenarios for the rate of MACE in the absence of a pitavastatin (control rate). 
Specifically, a total of 288 primary MACE endpoints are needed to ensure 
that the study will have 85% power to detect a hazard ratio of 0.7.  
 
9.4.3 Power Considerations for non-MACE Clinical Endpoints 
 
Since the composite rate of serious non-MACE of interest (see section 9.2.2.4) in 
the absence of statin is expected to exceed the rate of MACE, REPRIEVE 
(A5332) will be well powered to detect statin effectiveness equating to a 25% 
reduction in non-MACE or higher. 
 
If the incidence of any specific class of non-MACE in the absence of statin 
therapy is 5/1000 PY or higher, REPRIEVE (A5332) will have 90% power to 
detect a statin effect equating to a 50% reduction in the non-MACE event rate or 
higher. Published data from the ALLRT cohort [Overton 2013] suggest that the 
incidence of each of these events of interest will exceed this 5/1000 PY 
threshold. 
 


 
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9.4.4 Power Considerations for COVID-19 Objectives 
 
In March 2020, when SARS-CoV-2 infections and COVID-19 diagnoses were 
emerging in REPRIEVE enrollment areas, approximately 6650 REPRIEVE 
participants remained in follow-up.  
 
It was hypothesized that 30% of REPRIEVE participants will be antibody 
positive for exposure to SARS-CoV-2. This rate is considered a 
conservative estimate based on widespread successful implementation of 
mitigation strategies. Recent studies from NYC and other large US urban 
areas indicate infection rates of up to 30%, and this is anticipated to 
increase further, especially in less-developed Global Burden of Disease 
regions that recruited into REPRIEVE. With the use of comprehensive 
sensitive and specific state of the art antibody testing, as proposed in this 
supplement, we will be well-poised to capture a significant number of 
cases, independent of any differences in more localized testing rates. 
 
Allowing for 5% additional losses to follow-up, this will yield approximately 
2000 cases and 4650 controls for analyses, including about 200 
hospitalizations (10% of infections, ie, serious disease), and will provide 
ample numbers for the proposed epidemiology, pathobiology, genetic, and 
clinical investigations (see Table 9.4.4-1). For example, with this rate of 
antibody positivity, we will be able to estimate infection risk with a 
precision of at least ±1.2%, and will have 90% power to show a 12% 
reduction in the infection risk in the pitavastatin group (RR=0.88, 30% risk 
in the placebo group compared to 26% risk in the pitavastatin group), and 
80% power to detect a 35% relative risk reduction (RR=0.65) in serious 
disease (see table cells in blue font). Detectable effect sizes for antibody 
positivity rates of 15%-30% and power of 80%-90% are shown in the table 
below. 
 
Table 9.4.4-1: Detectable Effect Sizes for Antibody Positivity Rates of 15%-30% and 
Power of 80%-90% 
 
Power Proportion of Participants COVID-19 Antibody Positive (Control) 
30% 
20% 
15% 
Precision to 
estimate 
infection risk 
- 
±0.012% 
±0.0135% 
±0.015% 
Detectable risk 
reduction with 
given power 
90% 
12% (RR=0.88) 
15% (RR=0.85)  
18% (RR=0.82) 
85% 
11% (RR=0.89) 
14% (RR=0.86) 
17% (RR=0.83) 
80% 
10% (RR=0.90) 
13% (RR=0.87) 
16% (RR=0.84) 
 
 
Proportion of COVID-19 antibody positives experiencing serious disease 
 
 
10% 
20% 
10% 
20% 
10% 
20% 


 
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Detectable risk 
reduction with 
given power 
90% 
40% (0.60) 29% (0.71) 48% (0.52) 
35% (0.65) 
55% (0.45) 
40% (0.60) 
85% 
38% (0.62) 27% (0.73) 45% (0.55) 
33% (0.67) 
51% (0.49) 
38% (0.62) 
80% 
35% (0.65) 25% (0.75) 43% (0.57) 
31% (0.69) 
48% (0.52) 
35% (0.65) 
* Assumes sample size of 6650 with evaluable COVID-19 antibody results equally distributed 
between pitavastatin and placebo groups (see text for rationale for this number). 
 
9.5 
Monitoring 
 
The following is a summary of the data and safety monitoring plan for REPRIEVE 
(A5332). Prior to enrollment of the first participant, a detailed study monitoring and 
analysis plan document will be prepared that will more fully describe these data 
monitoring aspects including timelines and responsibilities for preparation.  
 
Summaries of accrual rates, deaths, SAEs, and targeted AEs across regimens as well 
as study conduct (in terms of off-study rates, and completeness of study visits) will be 
reviewed on a regular basis by the protocol core team with all data pooled across study 
arms. Further, in line with the NHLBI Accrual Guidelines of observed against target 
accrual benchmarks will be reviewed by NHLBI program staff at a minimum of 25%, 
50%, and 75% of the anticipated accrual period. Additional accrual reporting to NHLBI 
will be provided as requested. The timing and anticipated enrollment by 25%, 50%, and 
75% of the accrual period are shown in Table 9.5-1. 
 
Table 9.5-1: Accrual Benchmarks at 25%, 50%, and 75% of the Accrual Period 
Recruitment Period 
Time after First Patient 
Enrollment 
Projected Accrual 
25% 
7.5 months 
767 
50% 
15 months 
2740 
75% 
22.5 months 
4635 
 
The study will undergo at least annual review by an NIH appointed DSMB for study 
conduct, continued feasibility, safety, and efficacy.  
 
Unless otherwise noted, the unblinded REPRIEVE (A5332) statisticians will be 
responsible for all data analysis and report preparation to the DSMB. The DSMB will be 
appointed by NHLBI in consultation with DAIDS. For each review, the statisticians will 
prepare 3 summary reports: 1) a closed report containing all information broken down by 
masked treatment group distributed only to the DSMB; 2) a report for REPRIEVE 
(A5332) PIs and the NIH (NHLBI and DAIDS) team that will include MACE endpoint 
information pooled over both treatment groups; and 3) an open administrative report with 
administrative and safety information pooled over treatment groups. Specific contents of 
reports will be discussed with the DSMB prior to the first review. An outline of the focus 
of each review is provided in Table 9.5-2 below; further details and rationale are 
provided in the text below. These details are provided in broader detail in the Statistical 
Analysis Plan. 
 


 
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Table 9.5-2: Overview of DSMB Monitoring Focus 
Focus 
Timeframe 
Feasibility and 
conduct 
Site activation, enrollment, data and visit 
completeness, rates of loss to follow-up 
and cross-over 
At all interim reviews occurring at 
least annually 
Safety 
Rates of adverse events by treatment 
group 
At all interim reviews occurring at 
least annually 
Event rate 
evaluation 
Pooled rates of events observed to date; 
predicted confidence interval of the 
pooled event rate under a range of 
realistic scenarios* 
At all interim reviews occurring at 
least annually 
Formal 
efficacy and 
futility review 
Treatment group comparison for the 
primary endpoint utilizing group 
sequential methods 
Interim looks for efficacy are 
planned at approximately 50% 
and 75% statistical information, 
or as otherwise 
recommended**.  
* To be conducted if the pooled rate falls below a specified target (see Statistical Analysis 
Plan). 
** Statistical information for the MACE endpoint is based on the total number of expected 
MACE endpoints (see Statistical Analysis Plan for more details). 
 
The first feasibility review will occur approximately one year after the accrual of the first 
participant with a focus on site activation and patient accrual and retention as well as 
rates of treatment crossover. Benchmarks for these aspects are provided in detail in the 
Statistical Analysis Plan that will be reviewed and agreed upon by the DSMB.  
In addition to these aspects, pooled rates of events observed to date will be reviewed by 
the DSMB at all reviews to evaluate the adequacy of the sample size assumptions. 
Given the expected rate of accumulation of events it is anticipated that sufficient events 
will have been accrued to the study by the time of reviews occurring 2-2.5 years after 
enrollment of the first participant to allow reasonable determination of whether the 
underlying rate of event accumulation is inconsistent with observing the required total 
number of events to achieve 90% power to detect a HR of 0.70 at the study conclusion. 
This is illustrated by the anticipated rate of event accumulation dependent on the interim 
review timing shown in Table 9.5-3. 
 
Table 9.5-3: Anticipated Data and Event Accumulation Dependent of Interim Review Timing 
Timing of 
review (y) 
Number of 
participants 
enrolled* 
Accumulated 
person years of 
follow-up* 
Expected total accumulation of events under 
given event rate in control group (all cases 
assume the target HR of 0.7) 
15/1000 
12/1000 
10/1000 
1 
508 
127 
2 
1 
1 
1.5 
1944 
972 
12 
10 
7 
2 
3609 
707 
34 
28 
21 
2.5 
5414 
5685 
72 
58 
43 
3 
6500 
8125 
103 
82 
62 
3.5 
6500 
11375 
143 
115 
86 
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The event rate evaluation will be performed by a blinded REPRIEVE (A5332) statistician. In 
the event that the observed number of events falls short of the predetermined benchmarks 
providing in the statistical analysis plan, a predicted confidence interval analysis will be 
performed for the total expected number of MACE at trial conclusion based on accumulated 
data to date and a range of scenarios for accumulation of future data. These will include but 
not be limited to continued accumulation as observed and, under the target effect size of 
HR = 0.70, control MACE rate of 12/1000 PY and 15/1000 PY. Unless otherwise requested 
by the DSMB, these assessments along with recommendations for any study design 
changes will be presented only in the closed study report, and thus available only to 
members of the DSMB. Release of the information to the REPRIEVE (A5332) Executive 
Committee will be at the discretion of the DSMB.  
 
If any of these assessments suggest that the anticipated total number of events appear 
substantially smaller than the rate assumed for sample size considerations or if accrual 
is below anticipated, consideration will be given to modifying the design of the study. 
Such considerations may include (but will not be limited to) extending the study duration, 
increasing the target sample size, and broadening the study entry criteria to include 
individuals with low/moderate traditional CVD risk who are willing to be randomized to 
statin therapy or placebo, for example, participants who have an ASCVD risk score of 
≥7.5%. 
 
Unless there are emerging feasibility or safety concerns, guidelines for stopping or 
modifying the trial will be guided by formal efficacy review to occur once sample size 
adequacy for the study has been established. A total of four interim looks were 
planned originally: at 20% (if requested by DSMB), 40%, 60%, and 80% 
information. Per recommendation of NHLBI, endorsed by the DSMB at the 
December 2019 meeting, the timing of interim looks was changed to 50% and 75% 
information to allow for the best possible decision about extending study follow-
up duration. Inference at each interim efficacy review will be guided by a Lan-
DeMets implementation of the O’Brien-Fleming sequential stopping boundary with 
information measured on the cumulative number of primary MACE endpoints at the 
time of the review. This implementation permits early stopping only for very strong 
positive or negative effects and maintains most of the nominal power for when the 
majority of information has accrued. For example, under the hypothesized effect 
size (HR=0.7), the cumulative probability that the interim result will cross a 
boundary at 50% information is 33% compared to a 78% probability at 75% 
information. The ultimate recommendation of all reviews—irrespective of whether 
boundary p-values have been achieved—will be at the discretion of the DSMB. 
 
9.5.1 Monitoring of COVID-19-Related Outcomes 
 
The incidence of COVID-19 diagnoses and hospitalizations (pooled over 
treatment groups) will be described as part of the routine (monthly) 
REPRIEVE adverse event monitoring reports and as targeted events at 
each DSMB review. 
   


 
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9.6 
Analyses 
 
9.6.1 General Analysis Considerations 
 
The following sections provide a brief overview of the analysis considerations for 
REPRIEVE (A5332). Prior to the start of enrollment, a detailed Statistical 
Analysis Plan fully delineates all planned statistical analyses. In the event of a 
DSMB recommendation to stop the trial for efficacy at interim review, full 
analysis and publication of the primary trial results will be prepared based 
on the frozen data for the DSMB meeting. Subsequent analyses (including 
a database prepared for future data-sharing requests) will be performed 
based on the final trial database including all final study termination visits. 
In the event of a DSMB recommendation to stop for futility, full analysis 
and publication of the primary trial results will be performed based on the 
final trial database including all final study termination visits. 
 
All major treatment comparisons between the randomized groups will be 
performed according to the principle of "intention-to-treat;" that is, participants will 
be analyzed (and endpoints attributed) according to the randomized treatment 
assigned regardless of subsequent changes to that treatment; as-treated 
analyses will also be performed. Descriptive summaries of the distribution of 
continuous baseline variables will be presented in terms of percentiles (eg, 
median, 25th and 75th percentiles), while discrete variables will be summarized 
in terms of frequencies and percentages. Statistical comparisons will be 
performed using two-sided significance tests with a 5% Type I error. 
 
Unless otherwise noted, comparison of time to event outcomes will use methods 
for competing risks, notably Cox proportional hazards models for estimation of 
cause-specific hazard ratios and Gray’s test for comparison of cumulative 
incidence curves. 
 
Treatment group comparisons of continuous outcomes will use t-tests with 
transformation as needed. In the event of non-Normal distributions even after 
transformation, Wilcoxon rank sum tests will be preferred. With respect to 
discrete outcomes, Wilcoxon rank sum tests with be used for ordinal outcomes; 
Chi-squared test will be used otherwise; Fisher’s exact test will be preferred in 
the event of small cell numbers. All testing will be stratified by sex and CD4 cell 
count per randomization: while the primary analyses will not be further stratified 
by enrollment in the Mechanistic Substudy of REPRIEVE (A5333s), sensitivity 
analyses will be performed including this stratification. Additional perspective 
regarding the interpretation of the data will be provided through extensive use of 
confidence intervals and graphical displays. 
 
Given the strong plans for participant follow-up as part of the study, it is 
anticipated that missing data will be minimized. Unless examination of the data 
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lost to follow-up before experiencing a prior endpoint will be considered non-
informatively censored. For all participants lost to follow-up, cardiovascular risk 
factors at the time of their final study visit will be described. In addition, a 
supportive analysis of time to death from any cause or MACE (outcome measure 
9.2.2.3), including data from vital status and endpoint follow-up following 
premature study discontinuation will be conducted. 
 
With the primary clinical and mechanistic hypotheses and the various secondary 
endpoints that have been outlined, it is recognized that there is a multiplicity of 
analyses to be performed, which leads to an increased probability that at least 
one of the comparisons could be "significant" by chance. Although the overall 
level of significance for all treatment comparisons will be 0.05, we will be 
conservative in the interpretation of our supporting analyses, taking into account 
the degree of significance, and looking for consistency across endpoints. 
Assessment will be made for any differences in major disease indices between 
participants in the Mechanistic Substudy of REPRIEVE (A5333s) and REPRIEVE 
(A5332). Such differences are unlikely, given that all participants in the 
Mechanistic Substudy will be eligible for REPRIEVE (A5332) and vice versa. 
Moreover, a subset of sites will be performing both and there will be overlap in 
the capacity to do both studies at selected sites. Nonetheless, we will analyze for 
any differences in the main and Mechanistic Substudy populations and account 
for any such differences in our interpretation of the Mechanistic Substudy and 
main study results. 
 
9.6.2 Primary MACE and Supportive Analyses 
 
The primary comparison of study arms for the primary composite endpoint will be 
time to event analyses and therefore based on the time from randomization to 
the first of any of the components of the primary composite endpoint. Deaths 
from non-CVD causes will be treated as competing risk events and participants 
completing follow-up without experiencing the event will be considered censored 
at the time of their last contact at which an assessment for primary endpoints 
was made. 
 
A Stratified cause-specific Cox proportional hazards model will be the primary 
analytic methods used for assessing outcome differences between the two 
treatment groups with stratification by sex and CD4 cell count at screening as 
previously noted. The relative cause specific hazard of pitavastatin versus 
placebo for MACE will be estimated with a repeated 95% confidence interval and 
compared via a Wald test; modification of the statin effect over time (non-
proportional hazards) will be evaluated with treatment by time interaction. In 
supportive analyses, the cumulative incidence of MACE will be estimated using 
the Breslow estimators of the cause-specific hazard from the Cox model 
and plotted over time by treatment group and compared via a stratified Gray 
test. 
 


 
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To complement the primary analyses, the same analytic approach will be used 
for evaluation of individual components of the primary MACE endpoint. In the 
absence of a competing risk event, treatment comparisons of all-cause mortality 
and a composite of MACE and all-cause mortality will use a stratified log-rank 
test.  
 
Poisson regression with robust variance estimates will also be used to 
incorporate multiple and repeated events in evaluation of event incidence rates 
by treatment group and rate ratios. Sensitivity analyses will be performed that 
censor individuals for whom critically significant CAD was identified as a result of 
the Mechanistic Substudy of REPRIEVE (A5333s) CCTA evaluation; censoring 
will occur at the date of the apparent CCTA study findings. 
 
9.6.3 Secondary MACE and Lipid Analyses 
 
Analyses of targeted serious clinical diagnoses (see section 9.2.2.4) will use the 
same methods as described for the primary MACE endpoint for the composite 
and individual outcomes. Analyses of a further composite outcome including the 
primary MACE outcomes (the START endpoint) will also be performed. 
 
Summary statistics (means and quantile distributions) will be provided to 
describe the distributions of LDL and non-HDL cholesterol from study entry and 
12 month intervals over time. At each annual post-entry time point, the mean 
difference in levels between treatment groups will be estimated with 95% 
confidence interval. Mixed effects models adjusted for sex and screening CD4 
cell count will be used for repeated measurements over time to estimate 
annual treatment group differences; the same analyses will be applied for other 
lipid fractions.  
 
Prognostic Factors of MACE: Important secondary aims of REPRIEVE (A5332) 
are to evaluate whether baseline traditional risk factors and time updated HIV-
specific risk factors are predictive of MACE and pitavastatin effects on MACE in 
the HIV population.  
 
Targeted risk factors of interest at (or prior to) study entry and time-updated (as 
indicated) are as follows: 
 
At study entry/screening: 
• 
Age, sex, race  
• 
ASCVD risk score 
• 
HIV-1 RNA level 
• 
CD4 cells count 
• 
Nadir CD4 cell count 
• 
Duration of ART exposure and any exposure to thymidine analogs, protease 
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• 
Weight, BMI, waist circumference 
• 
Fasting lipid (TC, HDL-C and LDL-C, HDL:LDL ratio, TG) and glucose 
• 
Smoking status 
• 
Systolic and diastolic BP and use of antihypertensive agents 
• 
Presence of metabolic syndrome defined according to current guidelines at 
the time of the analysis. 
• 
Self-reported level of physical activity 
• 
Family history of heart disease 
 
Time-updated (annually unless otherwise noted): 
• 
HIV-1 RNA level 
• 
CD4 cells count 
• 
Fasting lipid (TC, HDL-C and LDL-C, HDL:LDL ratio, TG) and glucose and 
their changes expressed as absolute change and as percent of baseline 
 
Analyses will use stratified Cox proportional hazards models to estimate the 
cause-specific hazard of MACE with respect to the risk factors of interest, 
including the selected biomarkers representing surrogates from plaque 
progression as described above. In the full cohort we will include the baseline 
risk factors and evaluate modification of the statin effect by key subgroups (ie, 
race/ethnicity sex, and CD4 cell count at screening as well as HIV-related and 
CV risk factors including age, hypertension, LDL and non-HDL cholesterol at 
entry, BMI, metabolic syndrome (as defined by current NCEP guidelines at the 
time of the analysis) and smoking) by interaction terms in these models. 
  
This approach will investigate associations with LDL and non-HDL levels and 
changes from baseline as a time-updated covariate. The same approach to 
analysis will be used to assess the effects of other longitudinal outcomes. With 
respect to HIV-1 RNA levels over time, it is of particular interest to examine 
whether there is evidence of the modification of the effect of statins according to 
whether participants maintain full suppression of HIV-1 RNA levels. This will be 
examined in a 12-month landmarked Cox proportional hazards models assessing 
an interaction between continued HIV-1 RNA suppression (<400 copies/mL) over 
the first 12 months of the study as well as time-updated analysis. The analysis 
approach for assessment of effect of selected biomarkers for MACE will be 
determined based on the sampling approach to biomarker testing. Depending on 
power consideration, sampling may involve testing of the entire REPRIEVE 
(A5332) study population or a restricted sampling approach such as a case-
cohort sampling. In this case, the same analytic approach as described above 
would be utilized with appropriate weighting for the sampling fractions; an 
alternative would be case-control sampling with analyses performed using 
logistic regression. 
 
The frequency with which serious adverse events (excluding study defined 
clinical endpoints) occur will be tabulated and descriptively summarized. 


 
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Additional targeted and pre-specified adverse events that will be summarized will 
include incident diabetes, elevated liver function tests, and myositis. Statistical 
comparisons of the randomized arms with respect to adverse events will use chi-
square or other appropriate two-sample methods depending on the nature of the 
event, interpreting such comparisons in the context of differences between the 
two randomized arms in the primary and major secondary clinical endpoints.  
 
9.6.4 COVID-19 Analyses  
 
All analyses will be restricted to participants who remained in REPRIEVE 
study follow-up as of January 1, 2020. Person years of follow-up will be 
measured from January 1, 2020. 
 
The incidence of COVID-19 diagnoses and COVID-19 hospitalizations will 
be estimated, including the statin effect on the incidence of COVID-19 and 
serious COVID-19 disease via estimation of the incidence rate ratio by 
randomized treatment group. Log binomial regression will be utilized to 
assess host factors associated with COVID-19 infection as defined by a) 
SARS-CoV-2 antibody positivity and b) severe disease requiring 
hospitalization. 
 
Analyses will be stratified by global burden of disease region and 
randomized treatment and control for comorbid conditions (including 
hypertension, diabetes, kidney disease, and obesity). Further extension of 
these analyses will evaluate the influence of targeted concomitant 
medications (such as lopinavir/ritonavir and of ACE inhibitors and ARBs), 
and COVID-19 vaccination on rates of SARS-CoV-2 infection. 
 
In all analyses, death (not due to COVID-19) will be considered a censoring 
event. Discontinuation of randomized treatment will be ignored in primary 
analyses; a supportive analysis will censor at randomized treatment 
discontinuation and use inverse probability of censoring weights (IPCW) to 
estimate the statin effect when statins are being taken per protocol. 
Likewise, COVID-19 vaccination will be ignored in the primary analysis; a 
supportive analysis will censor at COVID-19 vaccination and use IPCW to 
estimate the statin effect in the absence of COVID-19 vaccination.  
 
More detailed analysis plans are provided in the REPRIEVE Statistical 
Analysis Plan. 
 
10.0 
PHARMACOLOGY PLAN 
 
Not applicable. 
 


 
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11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Electronic case report forms (CRF) are available on the DMC website. Participants must 
not be identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID), screening number (SN), and study identification number 
(SID) provided by the DMC upon randomization. 
 
11.2 
Role of Data Management 
 
Instructions concerning the recording of study data on eCRFs will be provided by the 
DMC. Each CRS is responsible for recording the data in a timely fashion. 
 
It is the responsibility of the DMC to ensure the quality of computerized data for each 
study. This role extends from protocol development to generation of the final study 
databases. 
 
11.3 
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 [FDA, 2021]. 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).   
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an Internet-based 
reporting system, must be used for expedited AE reporting to DAIDS. In the 
event of system outages or technical difficulties, expedited AEs may be 
submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES (now part of the NIAID Clinical Research Management System) at 


 
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CRMSsupport@niaid.nih.gov. Site queries may also be sent from within the 
DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: https://rsc.niaid.nih.gov/clinical-research-
sites/paper-eae-reporting. For questions about EAE reporting, please contact the 
RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study with certain exceptions as noted below. 
Unless the site investigator considers the following events to be study drug-
related, DO NOT REPORT them as EAEs:  
• 
AIDS-defining events (see MOPS for a listing) 
• 
REPRIEVE MACE (see section 9.2.1 for complete listing) and related CVD 
events: CVD death, MI, stroke, TIA, unstable angina, peripheral ischemia, 
coronary or peripheral reperfusion procedures, heart failure, and all deaths 
(because they are components of the primary endpoint or additional 
adjudicated CVD endpoint). See MOPS for details about reporting CVD 
Endpoints). 
• 
COVID-19 hospitalizations. 
 
NOTE: COVID-19 is a novel disease that has emerged since protocol 
version 5.0 was distributed. Given our evolving understanding of this viral 
infection, and the likelihood of subclinical cardiac injury during COVID-19 
hospitalization, the requirement for reporting COVID-19 infection has been 
outlined in greater detail in the MOPS.  
 
The study agents for which expedited reporting are required are pitavastatin and 
placebo for pitavastatin. 
  
11.4.3 Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017, is 
available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/daids-adverse-event-grading-tables. 
 
11.4.4 Expedited AE Reporting Period 
 
The expedited AE reporting period for this study is the entire study duration for 
an individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason). 
 


 
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After the protocol-defined AE reporting period, unless otherwise noted, only 
SUSARs (suspected unexpected serious adverse reactions) as defined in 
Version 2.0 of the EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
12.0 
PARTICIPANTS 
 
12.1 
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/EC responsible for oversight of 
the study. A signed consent form will be obtained from the participant (or legal 
representative). 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 representative, and this fact will be documented in the 
participant’s record. Risks, including potential risks of pitavastatin, and protection against 
risk are described in the accompanying sample informed consent form. 
 
12.2 
Participant Confidentiality  
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the ACTG, IRB/EC, FDA, NHLBI, 
NIAID, OHRP, and other local, US, and international regulatory entities as part of their 
duties, or the industry supporters or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, FDA, NIAID, NHLBI, 
OHRP, or the industry supporter, or other government agencies as part of their duties to 
ensure that research participants are protected. 
12.4 
Women and Minorities  
 
REPRIEVE (A5332) will aim to recruit women and minority participants commensurate 
with the population demographic for HIV in the US. The prevalence of HIV among 
women in the US is approximately 22%, while over half of PWH in the US are minorities 
(CDC 2014). 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by NHLBI and NIAID policies. 
 


 
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14.0 
BIOHAZARD CONTAINMENT  
 
All dangerous goods and materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  
 
15.0 
STUDY GOVERNANCE 
 
• 
There is an Executive Committee, a DSMB, and an External Advisory Board. 
• 
There are various other operational committees to ensure that the trial progresses 
smoothly.  
• 
There is a Clinical Events Committee (CEC) charter.  
 
 


 
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Subramanian S, Tawakol A, Burdo TH, et al. Arterial inflammation in patients with HIV. 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
For the REPRIEVE (A5332) Protocol, FINAL Version 6.0, 16May2022 
 
Randomized Trial to Prevent Vascular Events in HIV (The REPRIEVE Study) 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are living with the human 
immunodeficiency virus (HIV), the virus that causes AIDS, and you are taking HIV medications.  
 
This study is sponsored by the National Institutes of Health (NIH). The doctor in charge of this 
study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a 
part of this study, we want you to know about the study.  
 
 
WHY IS THIS STUDY BEING DONE? 
 
Since people started taking HIV medications, illness from AIDS has decreased, but other 
serious diseases, like heart disease, have increased. HIV causes inflammation (irritation) inside 
the body that cannot be felt but can be measured. These tests will be described later in this 
consent form. Inflammation may contribute to diseases such as heart disease that have become 
some of the leading causes of death in people with HIV (PWH). HIV medications can lower 
inflammation somewhat, however sometimes the levels of inflammation can remain higher 
compared to people without HIV. 
 
Statins are a group of medicines used to lower the levels of cholesterol and triglycerides (fat in 
the blood) that people make and to prevent heart-related disease events such as heart attacks 
in persons with high risk for heart attacks. Studies have shown that statins may have other 
benefits. For example, by decreasing levels of inflammation, statins may have an effect to 
protect against heart disease and its related events. In addition, statins may have some 
beneficial effects on some other diseases like some cancers or kidney problems. 
 
The most recent guidelines from the American College of Cardiology and the American Heart 
Association (ACC/AHA) recommend the use of statins if someone is at risk of heart-related 
disease based on many different factors, including the use of a risk calculator based on known 
risk factors including gender, age, race, cholesterol levels, tobacco use, diabetes, and 
hypertension that estimates the 10-year risk of heart attack, stroke, or other event (the ASCVD 
risk score). HIV infection is not included in the risk calculator. The current risk calculators may 
not accurately predict the risk in PWH. However, HIV infection, HIV medications, and chronic 
inflammation may put you at higher risk for these diseases, although we do not know if you 
would benefit from taking a statin. You are eligible for this study because you are in a low-to-
moderate-risk group for heart disease under the current guidelines, and there is no consensus 
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determine if the use of statins can prevent heart-related disease among PWH. The results of 
this study may help to create guidelines for the prevention of heart disease in HIV infection. 
For HIV-negative individuals with an ASCVD risk score between 7.5% and 15%, the current 
guidelines recommend a discussion between the health care provider and patients about the 
risks and benefits of statin therapy and recommend initiating statins based on available clinical 
trial data. However, for PWH with a moderate-risk for heart disease (a risk score between 7.5% 
and 15%), no currently available data clearly tell us whether the benefits of statin therapy 
outweigh the risks, including adverse effects and potential drug-drug interactions. Some health 
care providers may elect to treat PWH in this moderate-risk range with statin therapy, and this 
option may be available to you, rather than participating in the trial. Ultimately, the results of this 
trial will provide data to guide the use of statins for PWH. 
 
Pitavastatin is a statin that, along with a diet, has been approved by the US Food and Drug 
Administration for the treatment of high cholesterol. It also lowers triglyceride levels in the blood. 
It has not been studied to see if it reduces heart-related disease or death. Pitavastatin was 
chosen because there are thought to be few interactions between pitavastatin and commonly 
used HIV medications. 
 
The main purpose of this clinical trial is to see if pitavastatin can prevent heart disease and 
heart-related deaths in PWH who are taking HIV medications. We will also study the safety of 
pitavastatin.  
 
 
HOW MANY PEOPLE WILL BE IN THIS STUDY? 
 
About 7500 people will take part in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Study visits 
If you enter the study, you will be seen in the clinic about 6 times the first year. After that, the 
study visits are every 4 months for the next 6-10 years depending on when you join. The 
study staff will tell you about how long each visit will be. More details about the visits and 
procedures are below. 
 
If you do not enter the study 
If you decide not to take part in this study after signing the consent form, or if you do not meet 
the eligibility requirements, we will still use some of your information. As part of this screening 
visit, some demographic (for example, age, gender, race), clinical (for example, disease 
condition, diagnosis), and laboratory (for example, safety tests) information is being collected 
from you so that AIDS Clinical Trials Group (ACTG) researchers may help determine whether 
there are patterns or common reasons why people do not join a study.  
 


 
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Study drugs 
If you enter the study, you will be randomly assigned (as if by the toss of a coin) to get either 
pitavastatin or a placebo for pitavastatin. The placebo is a tablet that looks just like pitavastatin 
but does not contain any active medication. Therefore, there is a chance that if you are 
randomized to the placebo you will receive no treatment during your participation in the study. 
We use placebos in clinical studies to learn if the effects seen in the trial are truly from the study 
medicine or from other reasons. Neither you nor the study staff will know your assignment. You 
will not find out your assignment until after the entire study is over and the results of the study 
are known. You and your doctor can be told of the assignment at any point if it is necessary for 
your health. 
 
You will take the study medicine (either pitavastatin or the placebo for pitavastatin) once a day, 
every day, throughout the study period, with or without food. The dose is 4 mg. We recommend 
that you take the study medicine at the same time each day. These drugs are provided by the 
study. It is very important that you take your medicines as directed. At every visit after entry, we 
will ask you about how you have been taking your study drugs. Antiretroviral drugs (treatment 
for HIV) will not be provided by the study. 
 
Study procedures 
The study staff can answer any questions you have about individual study visits and the 
procedures. The table below can be used as a quick reference, along with the explanations that 
follow. 
 
Appendix I, Table 1: Study Procedures 
Procedure 
Screening1 
Entry2 
Month 1 
Visits every 4 
months 
(starting at 
month 4) 
Annual visits 
(starting at 
month 12) 
Final visit 
Physical exam 
X 
 
X 
 
X 
X 
Heart disease risk 
assessment 
X 
 
 
 
 
 
Heart disease risk 
factors  
X 
 
 
 
 
 
Diet and exercise 
questions 
 
X 
 
 
 
X 
Dispense lifestyle 
information 
 
X 
 
 
X 
X 
Health and medicine 
questions 
X3 
X 
X 
X5 
X5 
X3, 5 
Blood collected 
X 
X 
X 
 
X  
X 
Urine collected 
 
X 
 
 
X4 
 
Pregnancy test 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
 
X 
 
 
 
 
Pills dispensed  
 
X 
 
X 
X 
 
1  Screening visit: before you can enter the study, you will need to come to the clinic to have evaluations 
done to make sure that you can take part in the study. 
2 Entry visit: if you meet the entry requirements, you will enroll in the study. 


 
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3 This will also include hormonal assessment for women.  
4 ACTG Sites ONLY: Urine will be collected at months 12, 24, and 48 only for people enrolled in 
REPRIEVE (A5332) before January 1, 2018. 
5 This will include a COVID-19 assessment for all participants. 
 
If you leave the study early, or have to stop taking the study medication before the study is over, 
you will have the procedures listed in the table below. 
Appendix I, Table 2: Discontinuation Study Procedures  
Procedure 
Stopping the study or the study 
treatment early 
Physical exam 
X 
Health and medicine questions 
X1 
Pregnancy test 
X 
Blood collected 
X 
Fasting blood tests 
X 
1 This will also include hormonal assessment for women and a COVID-19 assessment 
for all participants.   
 
Explanation of study procedures 
 
Physical exam 
You will have a physical exam at screening. At other visits after entry, the extent of the exam will 
depend on how you are feeling at that visit. You will have vital signs taken, including, blood 
pressure and pulse. You will have measurements taken of your waist and height and weight. 
You will be asked questions about your health and medicines.  
 
Heart disease risk assessment 
At screening we will ask specific questions to assess eligibility based on cardiovascular disease 
risk. At screening you will also be asked about cardiovascular risk factors including your family 
history, smoking, alcohol use, substance use, diet, and exercise. 
 
Lifestyle /risk reduction counseling 
If you join the study, you will be given information about a healthy diet and the importance of 
exercise, smoking cessation, and taking your antiretroviral therapy and study medication as 
prescribed. We will provide this information at all annual visits. 
 
ECG 
An electrocardiogram, or ECG, will be done at entry. An ECG is an electrical tracing of your 
heart that can show how hard it is working. You will have to lie very still for up to 10 minutes 
while the ECG is being done. 
 
Blood collected 
Blood will be collected from you for different tests if they are not available as part of your routine 
medical care or for safety reasons. These include routine tests to evaluate your blood counts, 
liver, and kidney function. 
 


 
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At screen we will use the results of your liver function tests done as part of routine care by your 
medical provider. At month 1 and month 12 we will collect blood from you to evaluate your liver 
function. This test is required as part of your participation in the study. Approximately 1 
teaspoon of blood at each of these visits will be collected for this test. 
 
At screen and the end of study visit we will use the results of your CBC (blood count) and kidney 
function done as part of routine care by your medical provider. 
At screen and annual visits we will use the results of your CD4 T-cell count (how many infection 
fighting cells are in your blood) done as part of routine care by your medical provider.  
 
At entry and annual visits we will use the results of your HIV viral load (how much HIV is in your 
blood) done as part of your routine care by your medical provider.  
 
At screen we will use the results of your cholesterol (fat found in your blood) levels done as part 
of routine care by your medical provider. 
 
You will be told the results of these routine tests. 
 
At entry, all annual visits, and the end of study visit, some blood will be collected and stored for 
tests that will be done later on in the study or after the study is over. These tests will measure 
the levels of fat and sugar in your blood. Some of these tests will be used for metabolic blood 
tests (measures how your body uses the food that you eat). You do not need to agree to store 
this blood to join the study and you may change your mind about storing your blood at any time. 
Your blood may be stored (with usual protectors of identity) for an indefinite length of time. You 
will not be told of the results of the research done on your blood.  
 
At each of these visits, approximately 2 teaspoons of your blood will be collected and stored for 
these purposes.  
 
Do you agree to let us store your samples for tests to measure the levels of fat and sugar in 
your blood? 
 
________ YES ________ NO 
_______Initials 
 
At entry, all annual visits (as indicated in the Study Procedures table), and the end of study visit, 
some of your blood will be collected and stored for future REPRIEVE-approved research on 
conditions including cardiovascular disease, HIV, inflammation, cancer or statin medications. 
You do not need to agree to store this blood to join the study and you may change your mind 
about storing your blood at any time. Your blood may be stored (with the usual protectors of 
identity) for an indefinite length of time. You will not be told of the results of the research done 
on your blood.  
 
Up to 15 teaspoons of blood will be collected at each of these visits for these purposes.  
 
Do you agree to let us store your samples for future research on conditions including 
cardiovascular disease, HIV, inflammation, cancer, and statin medications? 


 
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________ YES ________ NO 
_______Initials 
 
 
 
 
 
 
If at a later date you change your mind and want your samples destroyed, contact the research 
staff. There are two ways to withdraw your permission. You could allow researchers to remove 
all your personal identifiers from your samples, so that they are not linked to you anymore. 
These samples will then become anonymous. Or, you can ask researchers to destroy your 
samples, so that they cannot be used for future research. However, in either case, researchers 
will not be able to destroy samples or information from research that is already underway. 
 
 
 
All ACTG sites will add to their local consent: Approximately 1 teaspoon of blood will be collected 
to look at genes that may affect your risk for cardiovascular disease and how statins work in your 
body. Genetic testing is a laboratory test that looks at differences in people’s genes. Your body, 
like all living things, is made up of cells, and cells contain deoxyribonucleic acid, also known as 
“DNA.” DNA is like a string of information put together in a certain order. Parts of the string make 
up “genes.” Genes contain instructions on how to make your body work and fight disease. The 
testing in this study will focus on certain genes that are known to have an effect on cardiovascular 
disease and how your body uses statins. New genes of interest may be identified in the future and 
may also be looked at.  
 
Your body’s genetic makeup is unique to you, so there is a risk with genetic research that even 
with all of the security measures in place, someone using your samples or genetic information 
may still find out which information is yours. However, this risk today is very small, but it may 
increase with time since science and technology are developing rapidly.  
ONLY ACTG sites in the US will add to their local consent: In the event that your genetic 
information becomes linked to your name, the US federal law called the Genetic Information 
Nondiscrimination Act (GINA) helps protect you. This law prohibits health insurance companies, 
group health plans, and most employers from denying services based on your genetic information. 
However, GINA does not protect against discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance. 
All ACTG sites will add this participant opt-out to their local consent: We would like to use some of 
the blood we collect to look at your genes (DNA). Do you agree to this genotyping? 
 
________ YES ________ NO 
_______Initials 
For all Non-US sites to add to their local consent: Your samples may be shipped and stored 
outside of your country and may be used by researchers outside of your country. 


 
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Urine collected 
Urine will be collected at entry to check for protein in your urine. The results from this test will 
not be known immediately; therefore we cannot make sure that you will be told the results of this 
test. 
 
Fasting blood tests 
Before the screen, entry and all annual visits you should not eat or drink anything, including 
food, beverages, candy, or gum for 8 hours before your visit. You are encouraged to drink water 
before your visits. If you are not fasting we will ask you to return while fasting to have your blood 
drawn within 30 days of the study visit.  
 
Study drugs given to you 
Study drugs will be given to you at entry and every 4 months. No study drugs will be given to 
you at your final study visit. 
 
Questionnaires 
You will be asked questions about your diet and exercise at entry and this will be repeated the 
final study visit. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study about 6-10 years (72-120 months) depending on when you join.  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the doctor thinks it is in your best interest 
• 
the study is cancelled 
• 
you are not able to attend the study visits as required by the study 
  
The study doctor may also need to take you off the study drug without your permission if: 
• 
you are not able to take the study drug as required by the study 
• 
continuing the study drug may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you become pregnant 
 
If you must stop taking the study drug before the study is over, we will ask you to continue to be 
part of the study and return for some study visits and procedures. 
 
Only ACTG Sites will add to their local consent: For participants enrolled in RERIEVE 
(A5332) before January 1, 2018, urine will also be collected at months 12, 24, and 48 to 
check measures of kidney function. 


 
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If you have to permanently stop taking the study drug, or if you leave the study, how would 
pitavastatin be provided? 
 
During the study: 
If you must permanently stop taking study-provided pitavastatin before your study participation 
is over, the study staff will discuss other options that may be of benefit to you. If you discontinue 
active participation in the study, study staff will contact you, your provided contacts, the medical 
records department, or your health care provider annually to determine if you have had any 
heart disease, stroke, or vascular-related disease events or procedures, or if you have died (and 
the cause of death since last contact). 
 
After the study: 
After you have completed your study participation, the study will not be able to continue to 
provide you with the pitavastatin you received on the study. If continuing to take this or a similar 
drug would be of benefit to you, the study staff will discuss how you may be able to obtain the 
drug. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
The drug used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with this drug. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious or life-threatening side effects when non-study medications are taken 
with the study drug. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
  
Risks of Pitavastatin 
• 
Muscle problems. Pitavastatin can occasionally cause serious muscle problems that can 
lead to kidney problems, including kidney failure and rarely, death.  
• 
Liver problems. Pitavastatin can occasionally cause liver problems that may rarely be 
serious or cause death. Your study nurse or doctor will do blood tests to check your liver 
before you start taking pitavastatin and while you take it. 
• 
Be sure to let your doctor or study nurse know immediately if you have any of these 
problems:  
▪ 
Muscle problems like weakness, tenderness, or pains that happen without a good reason, 
especially if you also have a fever or feel more tired than usual. 
▪ 
Nausea and vomiting. 
▪ 
Passing brown or dark-colored urine. 
▪ 
Feeling more tired than usual. 
▪ 
Noticing the skin and whites of your eyes become yellow.  


 
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▪ 
Having stomach pain. 
Other problems that have been caused by pitavastatin include headaches, rash (which rarely 
may be severe or fatal), severe allergic reaction or swelling, constipation, gas, diarrhea, pain or 
numbness in arms or legs, tendon rupture, urinary tract infection, dizziness, memory 
impairment, and depression. All of these problems are uncommon to rare. 
 
Risks of drawing blood 
Taking blood may cause some discomfort, lightheadedness, bleeding, swelling, or bruising 
where the needle enters the body, and in rare cases, fainting, or infection. 
 
Risks of fasting 
Some people find fasting to be bothersome. It may make some individuals feel anxious, irritable, 
or hungry. Patients who are required to take their morning medications with food should wait 
until after the visit has been completed to take their medications. 
 
Risks of ECG 
You may experience mild irritation, slight redness and itching on your skin where the electrodes 
from the electrocardiogram machine are placed. 
 
 
 
Unknown risks 
Other side effects that are not known at this time could happen during the study. All drugs have 
a possible risk of an allergic reaction, which if not treated right away, could become life-
threatening. During the study, you will be told about any new information that may affect your 
decision to stay in the study. If you decide to stay in the study, you will be asked to sign an 
updated consent form. If you decide to leave the study early, the study staff will talk with you 
about your treatment options. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
Pitavastatin is unsafe for unborn babies. The risks to the unborn baby include birth defects, 
premature delivery, or death. If you are having sex that could lead to pregnancy, you must 
agree not to become pregnant. 
ALL ACTG sites will add to their local consent:  
 
Genetic Testing 
The results of your genetic tests are for research purposes only and no individual results will be 
given back to you. The results of the genetic studies will never become a part of your medical 
record. We will protect your confidentiality to the fullest extent. Blood samples for genetic studies 
will be identified in a way in order to maintain your confidentiality. 
 
Research study results will not be given to your family members, insurance companies, 
employers, or third parties without your written permission and approval of the Institutional Review 
Board at _________.  


 
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If you can become pregnant, you must have a pregnancy test before you enter this study and at 
every visit (1 teaspoon of blood or a urine specimen will be collected) and at any time that 
pregnancy is suspected. This test must show that you are not pregnant. If you become pregnant 
or think you may be pregnant at any time during the study, tell your study staff right away. The 
study staff will talk to you about your choices. 
 
Because of the risk involved, you and your partner must use at least one accepted form of birth 
control that you discuss with the study staff. You must start an accepted form of birth control at 
least two weeks before you start study drug and continue to use an accepted form of birth 
control until at least 6 weeks after you stop the study drug. If you are having sex that could lead 
to pregnancy, and do not use an accepted form of birth control, your study doctor will take you 
off of the study drug. You may choose from the birth control methods listed below: 
• 
Condoms (male or female), with or without a spermicidal agent 
• 
A diaphragm or cervical cap with spermicide 
• 
An IUD (intrauterine device) 
• 
Tubal ligation 
• 
Tubal micro-inserts 
• 
Hormone-based contraceptive 
 
If you become pregnant while on study, the study staff would like to obtain information from you 
about the outcome of the pregnancy (even if it is after your participation in the study ends). If 
you are taking anti-HIV drugs when you become pregnant, your pregnancy will be reported to 
an international database that collects information about pregnancies in women taking anti-HIV 
drugs. This report will not use your name or other information that could be used to identify you. 
 
Breastfeeding 
It is not known whether the study drug pass through the breast milk and may cause harm to 
your infant. Women who start breastfeeding must stop taking the provided study drug. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
Studies have shown statins to provide a benefit in terms of preventing heart disease in people 
without HIV with inflammation, but the effects of statins to prevent heart disease in PWH is not 
known. If you take part in this study, there may be a direct benefit to you, but no guarantee can 
be made. You may benefit from learning about your risk of a cardiovascular event, but it is also 
possible that you may receive no benefit from being in this study either because the drug may 
not work or because you are assigned to placebo. Information learned from this study may help 
others who have HIV and are at risk of cardiovascular disease. 
 
 


 
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WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study, you have the choice of: 
• 
Treatment with prescription drugs available to you 
• 
Treatment with experimental drugs, if you qualify  
• 
No treatment 
• 
Continue routine medical care from your primary care provider 
• 
Joining another trial if you qualify 
• 
Not getting medical care 
 
Please talk to your study doctor about these and other choices available to you. Your study 
doctor will explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
 
For ALL US sites: We will do everything we can to protect your privacy. In addition to the efforts of 
the study staff to help keep your personal information private, we have gotten a Certificate of 
Confidentiality from the US Federal Government. This certificate means that researchers cannot 
be forced to tell people who are not connected with this study, such as the court system, about 
your participation. Also, any publication of this study will not use your name or identify you 
personally. 
 
People who may review your records include the AIDS Clinical Trials Group (ACTG), Office for 
Human Research Protections (OHRP) or other government agencies as part of their duties, Food 
and Drug Administration (FDA) (insert name of site) IRB/EC (a group that protects the rights and 
well-being of people in research), National Institutes of Health (NIH), other local, US, and 
international regulatory entities, study staff, study monitors, the drug companies supporting this 
study, and their designees. Having a Certificate of Confidentiality does not prevent you from 
releasing information about yourself and your participation in the study.  
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities.  


 
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OR 
 
 
 
A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required 
by US law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
 
WHAT IF WE CAN NO LONGER REACH YOU DURING THE STUDY? 
 
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained at screening and updated at each visit. If you are unable to be reached 
through the alternate contacts we will attempt to obtain information about you from other 
sources such as family members, other designated contacts, or clinic records. The purpose of 
obtaining this information is to determine if you have died and the cause of death since last 
contact and if you have had any heart disease, stroke, or vascular-related disease events or 
procedures. 
 
Contacting Your Health Care Providers 
Sites to modify per local requirements for obtaining health care records: As mentioned above, 
we do not currently have data to tell us if PWH with moderate cardiovascular disease risk by the 
ASCVD risk calculator should be treated with statins. If you are in this moderate-risk group, with 
a risk score between 7.5% and 15%, we would like to inform your health care provider(s) about 
the rationale for the trial, but we need your permission to share this information. 
 
Also, with your permission, for which you would need to sign a waiver, study staff may contact 
your health care providers regarding any clinical diagnoses you may develop during the study, 
For ALL Non-US sites: Efforts will be made to keep your personal information confidential. We 
cannot guarantee absolute confidentiality. Your personal information may be disclosed if required 
by law. Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by the ACTG, OHRP, FDA, (insert name of site) IRB/EC, National 
Institutes of Health (NIH), other local, US, and international regulatory entities, national 
regulatory/health agencies, study staff, study monitors, and the drug company supporting this 
study and its designees. 
 
All information collected about you as part of the study will be sent securely to the ACTG 
statistical and data management center in the United States for combining with information 
from other study participants and statistical analysis of study results. Your name and other 
personal identifiers will not be sent. Your research site is responsible for sending your 
information in accordance with the laws, regulations, and policies of your country and 
research site. (No new procedures in data collection) 


 
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including heart related diagnoses and other diagnoses, such as HIV, kidney, liver or cancer 
diagnoses.  
 
Will you allow us to contact your health care provider(s) to share information regarding your 
cardiovascular risk score and rationale for the trial, and to provide information regarding clinical 
diagnoses and to let your doctor know that he/she could object to your taking part in this study 
since you have a chance of getting placebo instead of treatment with statins? 
 
 
________ YES ________ NO 
_______Initials 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for the study drugs, the study visits, physical examinations, 
laboratory tests or other tests required by the study. You or your insurance company, or your 
health care system will be responsible for the costs of your regular medical care as well as for 
the costs of drugs not given by the study. 
 
Taking part in this study may lead to added costs to you and your insurance company. 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 be paid ________ at the entry visit, the month 1 visit, and annual visits thereafter for 
participation in the study. (The team recommends compensation to participants of $25 at every 
annual visit and study termination visit). Sites will be reimbursed for the expense.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries.  
 
For all sites: NIH does not have a mechanism to provide direct compensation for 
research-related injury.   
 
[Sites: Please modify (if necessary) and insert one of these two statements, as 
appropriate to your site. If your site is required to carry CTI, this must be indicated in the 
informed consent.] 
• 
This site has clinical trials insurance. This insurance will allow the site to provide you 
with monetary compensation if you suffer harm as a result of participating in this 
research study.  
OR 


 
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• 
The cost for this treatment will be charged to you or your insurance company. There 
is no program for compensation either through this institution or the NIH.] 
 
 
You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
  
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
name or title of person on the Institutional Review Board (IRB/EC) or other organization 
appropriate for the site 
• 
telephone number of above 
 
 


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


 
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APPENDIX IA: SAMPLE INFORMED CONSENT ADDENDUM 
 
For the Randomized Trial to Prevent Vascular Events in HIV ‒ (REPRIEVE) (A5332) 
FINAL Version 6.0, 16May2022 
 
 
SHORT TITLE FOR THE STUDY: REPRIEVE 
 
You are being asked to sign this consent addendum because you are participating in a 
research study at _____________, entitled “Randomized Trial to Prevent Vascular Events 
in HIV ‒ REPRIEVE (A5332).” 
 
The purpose of this addendum is to include information about sharing your de-identified 
genetic information. “De-identified” means that all information that identifies you, for 
example, your name, medical record number, and date of birth, has been removed. 
 
The genetic information was obtained from the blood sample that was collected from you 
at the entry visit. You consented to provide this sample in the original consent. 
 
Except for the activities described in this addendum, the terms of your original consent 
form remain in full effect, including that research study results will not be given to your 
family members, insurance companies, or employers without your written permission 
and approval of the Institutional Review Board/Ethics Committee at 
____________________.  
 
Please read this consent addendum carefully and take your time making your decision. 
As your study doctor or study staff discusses this addendum with you, please ask them 
to explain any words or information that you do not clearly understand.   
You do not have to sign this addendum to remain in REPRIEVE (A5332). 
 
SHARING OF YOUR GENETIC INFORMATION 
Illness and health are affected by the genes or genetic information we have inside of us. 
The genetic information we collect in this study may help advance other types of 
research. The National Institutes of Health (NIH) has established a program to let 
researchers share genetic information from different studies to help us learn more from 
each study that is funded by the NIH. Your genetic information will be shared with other 
researchers through a secure, controlled-access database supported by the NIH.   
 
When we share your genetic information with other researchers through a secure, 
controlled-access database supported by the NIH, including whole genome studies (such 
as determining your complete DNA sequence at a single time), we will remove all 
information that identifies you. This de-identified information may be used in other 
research. We do not think that there will be further risks to your privacy and 
confidentiality by sharing your genetic information with this controlled-access 
database. However, we cannot predict how genetic information will be used in the future. 


 
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Your name or other directly identifiable information will not be given to the controlled-
access database supported by the NIH. There are many other safeguards in place to 
protect your information while it is stored in the controlled-access database and used for 
research. Even so, it may become possible in the future that someone can re-identify 
your information. Also, using the controlled-access database, researchers may publish 
or present combined results of their research, but they will not include your name or 
other information that can identify you. 
 
There is no expected direct benefit to you from research using your genetic information. 
You can withdraw consent for sharing your genetic information at any time. However, we 
cannot get back any information that has already been shared. 
 
Do you agree to share your genetic information? 
 
________YES ___________NO _________Initials 
 
OTHER 
All other information that is contained in the REPRIEVE (A5332) consent that you signed 
also applies to this consent addendum. A copy of this signed consent will be provided 
for you as a reference at the time you consent to the information in this addendum. 
 
QUESTIONS REGARDING THIS CONSENT ADDENDUM  
If you have any questions, concerns, or complaints concerning this consent addendum, 
please contact Dr. (name) at (number) during regular business hours, and at (pager) after 
hours and on weekends and holidays. 
 
For questions about your rights as a research participant, or to discuss questions, 
concerns, or suggestions related to the research or this consent addendum, or to obtain 
information or offer input about the research, please contact the 
_____________Institutional Review Board/Ethics Committee Office at (number). 
 
STATEMENT OF CONSENT 
“The purpose of this consent addendum has been explained to me. I have been allowed 
to ask questions, and my questions have been answered to my satisfaction. I have been 
told whom to contact if I have questions, to discuss problems, concerns, or suggestions 
related to the research or this addendum, or to obtain information or offer input about the 
research. I have read this addendum and agree to the choices I have indicated above, 
with the understanding that I may withdraw my consent at any time. I have been told that 
I will be given a signed and dated copy of this addendum.” 
 
 
 
 


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


 
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APPENDIX II: THE MECHANISTIC SUBSTUDY OF REPRIEVE (A5333s) 
 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: 
Mechanistic Substudy of REPRIEVE 
 
 
Principal Investigators: 
Steven Grinspoon, MD 
 
Pamela Douglas, MD 
 
Udo Hoffmann, MD, MPH 
 
Heather Ribaudo, PhD 
 
 
AIDS Clinical Trials Group  
Investigators: 
Turner Overton, MD 
 
Carl Fichtenbaum, MD 
 
Judith Aberg, MD 
 
Markella Zanni, MD 
 
 
Data Coordinating Center: 
Harvard School of Public Health 
 
 
Study Funders: 
National Heart, Lung, and Blood Institute 
 
National Institute of Allergy and Infectious Diseases 
 
Office of AIDS Research, National Institutes of Health 
 
 
Industry Support: 
Kowa Pharmaceuticals America 
Gilead Sciences 
ViiV Healthcare 
 
NHLBI Program and Medical 
Officer: 
Patrice M. Desvigne-Nickens, MD 
 
 
DAIDS Medical Officer: 
Karin L. Klingman, MD 
 
 
IND Sponsor: 
Division of AIDS, NIAID, NIH 
 
 
IND Number: 
119127 
 
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SITES PARTICIPATING IN THE MECHANISTIC SUBSTUDY of REPRIEVE (A5333s) 
 
The Mechanistic Substudy of REPRIEVE (A5333s) is open to selected sites that are 
participating in the REPRIEVE (A5332) study. 
 
EXECUTIVE SUMMARY 
 
Title 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers:  
Mechanistic Substudy of REPRIEVE (A5333s) 
Indication 
Assess the effects of statins on critical plaque and inflammatory characteristics to understand 
mechanism of action in HIV 
Location 
Selected sites of the REPRIEVE (A5332) study 
Brief 
Rationale 
The Mechanistic Substudy of REPRIEVE (A5333s) will determine, among HIV-infected persons, 
potential statin effects to halt progression of non-calcified atherosclerotic plaque and to stabilize 
morphologic features of plaque vulnerability. Moreover, the study will identify biological factors 
mediating these changes – be it lipid parameters, such as LDL cholesterol, or markers of 
inflammation and immune activation. 
Study Design 
and Duration 
Randomized, placebo-controlled multicenter substudy of REPRIEVE (A5332) in 800 subjects, 
with individual subjects participating in the substudy for 2 years. 
Treatment 
Pitavastatin 4 mg PO daily or placebo for pitavastatin. 
Primary 
Objective 
To determine the effects of pitavastatin on the morphology and composition of non-calcified 
coronary atherosclerotic plaque (NCP), including the progression of plaque volume and whether 
these effects are modulated by markers of inflammation and immune activation. 
Key 
Secondary 
Objectives 
1. The effects of pitavastatin on the progression of high risk plaque features including low 
attenuation plaque and positive remodeling. 
2. The effects of pitavastatin on detailed markers of immune activation, immune activation, 
inflammation, coagulation, and traditional CVD risk indices including detailed parameters of 
glucose homeostasis (insulin, glucose and related indices of insulin resistance such as 
HOMA-IR, HgbA1c). 
3. The relative contributions of baseline and pitavastatin induced changes in HIV-specific 
immune activation and traditional risk factors, including LDL, on the presence and 
progression of coronary plaque and high risk morphological features in HIV. 
Primary 
Endpoint 
Noncalcified plaque volume on coronary computed tomography angiography (CCTA) 
Secondary 
Endpoints 
High risk plaque features on CCTA 
Detailed immune phenotyping measures and inflammatory and coagulation indices as well as 
detailed measures of glucose homeostasis 
Abbreviated 
Study Flow 
Subjects will be coenrolled at specific sites participating in the Mechanistic Substudy of 
REPRIEVE (A5333s). Enrollment and treatment will be identical as in REPRIEVE (A5332), but 
endpoints will be collected over 2-year study duration for each enrolled patient. 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES  
 
1.1 
Primary Mechanistic Hypothesis  
 
Statin therapy will reduce progression of non-calcified coronary atherosclerotic plaque 
volume over two years as measured by serial coronary computed tomography 
angiography (CCTA) as compared with placebo in HIV-infected patients on ART in 
whom traditional CVD risk is not significantly increased. The mechanisms underlying the 
effect of statins will include a) reduction in non-calcified coronary atherosclerotic plaque, 
b) reduction in vulnerability features of non-calcified coronary atherosclerotic plaque, and 
c) improvement in critical indices of immune activation and inflammation. 
 
1.2 
Secondary Mechanistic Hypotheses  
 
1.2.1 Decreases in LDL cholesterol levels associated with statin therapy will be 
predictive of improvement in non-calcified coronary atherosclerotic plaque 
burden and/or vulnerability features. 
 
1.2.2 Statin therapy will reduce indices of general inflammation, coagulation, monocyte 
activation, and arterial inflammation. 
 
1.2.3 Statin therapy will reduce levels of pro-inflammatory monocyte populations. 
 
1.2.4 Statin therapy will reduce levels of T-cell activation and exhaustion. 
 
1.2.5 Changes in levels of immune activation and inflammatory markers will be 
associated with changes in morphology and composition of non-calcified 
coronary atherosclerotic plaque. 
 
1.2.6 Statin therapy will not have a clinically significant effect on glucose and insulin 
resistance. 
 
1.3 
Primary Mechanistic Objective 
 
To determine the effects of pitavastatin on the morphology and composition of non-
calcified coronary atherosclerotic plaque (NCP), including the progression of plaque 
volume and whether these effects are modulated by markers of inflammation and 
immune activation. 
 
1.4 
Secondary Mechanistic Objectives 
 
1.4.1 To determine the effects of pitavastatin on the progression of high risk plaque 
features including low attenuation plaque and positive remodeling. 
 
1.4.2 To determine the effects of pitavastatin on detailed markers of immune 
activation, including immune function (CD4, viral load), immune activation 


 
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(%CD14+CD16+ monocytes, sCD163, sCD14, MCP-1 and T-cell markers), 
inflammation (Lp-PLA2, hsCRP, IL-6), coagulation (D-Dimer and tissue factor) 
and traditional CVD risk indices including detailed parameters of glucose 
homeostasis (insulin, glucose and related indices of insulin resistance such as 
HOMA-IR, HgbA1c). 
 
1.4.3 To determine the relative contributions of baseline and pitavastatin induced 
changes in HIV-specific immune activation and traditional risk factors, including 
LDL, on the presence and progression of coronary plaque and high risk 
morphological features in HIV. 
 
1.4.4 To collect blood to enable the evaluation of the relationship of host genetics to 
study endpoints in subsequent ancillary studies. 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
HIV-infected persons face a 1.5- to 2-fold risk of myocardial infarction (MI), even after 
controlling for increased prevalence of traditional CVD risk factors [Triant 2007; Freiberg 
2013]. This increased risk is thought to be mediated, in large part, by immune activation 
and inflammation as emerging major contributors to the markedly increased prevalence 
of high risk coronary atherosclerosis in the HIV-infected population [Hsue 2012; Zanni 
2012], such that young patients without known CVD and with relatively low Framingham 
risk scores may still be high-risk. Traditional CVD prevention paradigms tested in the 
HIV-negative population fail to adequately assess and specifically target HIV-associated 
immune-mediated CVD risk. The proposed randomized trial of statin therapy in HIV-
infected individuals with minimal traditional cardiovascular risk leverages the LDL-
lowering [Silverberg 2009] and immunomodulatory properties of statins [Kwak 2000], 
targeting both traditional CVD risk factors (dyslipidemia), and HIV-specific immune 
activation. Embedded in the larger events trial is a mechanistic sub-study in which 
coenrolled participants will undergo coronary CT angiography for determination of 
atherosclerotic plaque morphology and composition, as well as detailed profiling of lipid 
and inflammatory/immune parameters. The mechanistic sub-study will provide several 
key scientific insights of crucial relevance to predicting and preventing CVD in HIV. Data 
from the mechanistic sub-study will highlight whether CCTA-based plaque morphology 
relates to CVD events in HIV, independent of lipid and inflammatory/immune 
parameters, and whether potential effects of statins to stabilize atherosclerotic plaque 
morphology – rendering plaques less likely to rupture and cause acute myocardial 
infarction – are mediated primarily through lipid-lowering or through immunomodulatory 
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2.1.1 HIV-infected patients have a novel phenotype of atherosclerotic plaque linked to 
immune activation  
 
HIV-infected individuals without known CVD have been shown to have more non-
calcified coronary atherosclerotic plaque relative to HIV-negative controls 
matched on traditional cardiovascular risk factors [Burdo 2011]. The significance 
of non-calcified plaque – namely, the higher likelihood it has to rupture, relative to 
calcified plaque – is highlighted by the MACE trial of over 5000 HIV-negative 
outpatients. This study showed that over 3 years of follow-up, 22.7% of patients 
with non-calcified plaque experienced a major adverse cardiac event compared 
with 5.5% of patients with calcified plaque [Hou 2012]. HIV-infected individuals 
without known CVD also have more vulnerable atherosclerotic plaque on 
coronary CTA relative to HIV-negative controls matched on traditional CVD risk 
factors. Features used to characterize vulnerability include low CT attenuation 
(correlating with necrotic lipid core) and positive remodeling (reflecting eccentric 
plaque extension) [Zanni 2013]. Among HIV-negative individuals with suspected 
CVD, low attenuation and positively remodeling have been demonstrated to 
prospectively predict the development of acute coronary syndrome (ACS). In a 
large study of over 1000 patients, Motoyama et al. demonstrated that in patients 
without significant CAD the occurrence of either low CT attenuation or positive 
remodeling was accompanied by a 22 fold increase in relative risk for suffering 
from an adverse cardiovascular event [Motoyama 2009]. These results were 
confirmed in another study that demonstrated that those persons with 
atherosclerotic plaques characterized by two vulnerability features were far more 
likely than individuals with atherosclerotic plaques absent of vulnerability features 
to develop ACS (22.2% vs. 0.5%, respectively) [Kitagawa 2009; Motoyama 
2009]. Importantly, non-calcified and vulnerable plaque in HIV-infected 
individuals relates to levels of soluble CD163, a monocyte/macrophage activation 
marker [Burdo 2011; Zanni 2013]. This latter finding suggests that immune 
activation in HIV may be contributing to the development of a novel 
atherosclerotic plaque phenotype which is prone to rupture and result in acute 
MI. Numerous other studies have linked immune activation markers – including 
monocyte activation markers LPS, sCD14, sMCP-1, and sCD163, as well as T-
cell activation markers – to subclinical atherosclerosis, cardiovascular events, 
and mortality [Merlini 2012; Kelesidis 2012; Sandler 2011; Kaplan 2011; Liu 
1997; Hunt 2011; Giorgi 1999; Burdo 2011; Zanni 2013; Subramanian 2012]. 
 
2.1.2 Statin Effects 
 
2.1.2.1 Statins lower LDL cholesterol and dampen immune activation  
In the general population, statins have long been known to potently 
reduce LDL cholesterol and to prevent CVD events [Sacks 1996; 
Shepherd 1995; Downs 1998]. In addition, statins have pleiotropic anti-
inflammatory and immunomodulatory characteristics, which may also 
contribute to cardio-protective effects. Indeed, in vitro, animal, and 
human studies have shown that statins decrease monocyte activation – 


 
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reflected in a) decreased monocyte chemotaxis and endothelial 
adhesion [Montecucco 2009; Fujino 2006; Han 2005] b) reduced 
monocyte uptake of oxidized LDL cholesterol [Han 2004]), and c) 
decreased monocyte secretion of cytokines/chemokines and matrix 
metalloproteinases [Guo 2009; Waehre 2003]. Moreover, statins 
decrease T-cell activation [Kwak 2000; Singh 2009; Bu 2010] while 
recruiting regulatory T cells [Mira 2008], and statins also suppress 
endothelial cell activation [Zheng 2013; Romano 2000; Mulhaupt 2003; 
Veillard 2006; Zineh 2006]. In HIV-infected persons, statins, and 
specifically pitavastatin, effectively lower LDL cholesterol [Silverberg 
2009; Eckard 2014; Funderburg 2014, 2015; Aberg 2017]. In HIV-
infected persons, statins also exert immunomodulatory effects to 1) 
decrease monocyte activation – reflected in decreased circulating levels 
of sCD14 and the macrophage-derived phospholipase, Lp-PLA2 
[Eckard 2014; Funderburg 2014, 2015], and 2) reduce T-cell activation 
[Ganesan 2011; De Wit 2011]. 
 
2.1.2.2 Statins may stabilize rupture-prone coronary atherosclerotic plaque 
 
Findings from observational CT imaging studies and large randomized 
IVUS trials demonstrate that statin therapy results in regression of NCP 
volume and potentially stabilizes coronary atherosclerotic plaque 
morphology in HIV-negative populations [Shimojima 2012; Inoue 2010; 
Kodama 2010; Nakamura 2008]. In addition, statins have been 
demonstrated to reduce atherosclerotic plaque inflammation on cardiac 
FDG-PET [Takawol 2013], and to reduce non-calcified plaque volume 
[Burgstahler 2007; Hiro 2009]. 
 
2.1.2.3  The effect of statins to stabilize rupture-prone atherosclerotic plaque 
may be mediated through LDL lowering and/or through the exertion of 
anti-inflammatory effects  
 
The JUPITER trial was a landmark study in that it showed a significant 
effect of statin therapy to prevent CVD events among non-HIV patients 
without known heart disease, with relatively low LDL cholesterol (<130 
mg/dl), and with evidence of generalized inflammation (CRP >2 mg/L) 
[Ridker 2008]. The CVD preventive benefits seen in JUPITER, 
surprisingly, were found to be proportional to reductions in CRP. This 
observation suggests that in the general population, anti-inflammatory 
pleiotropy may contribute significantly to the cardioprotective effects 
exerted by statins [Ridker 2009]. However, event reduction was also 
consistent with the known magnitude of expected effect from LDL 
lowering. Thus, although the JUPITER trial demonstrated a marked 
reduction in CVD events with statins among patients with relatively low 
LDL cholesterol but generalized inflammation, the lack of mechanistic 
assessment precluded determination of how this effect was achieved. In 


 
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a study of the MESA cohort, a population similar to the JUPITER trial 
cohort, major adverse cardiovascular events correlated better with high 
risk coronary atherosclerotic features than inflammatory markers such 
as hsCRP [Blaha 2011]. This data highlights the importance of 
performing assessments of plaque volume and morphology to 
characterize the mechanisms by which statins have their effect. Hence, 
the currently proposed study will determine, in the HIV-infected 
population, the effects of statins to prevent CVD events and, 
importantly, mechanisms through which statins may achieve this effect 
including a reduction of these high risk morphologic features.  
 
2.2 
Rationale 
 
The proposed REPRIEVE (A5332) study is a multi-center, prospective randomized 
placebo controlled trial testing the effect of statin primary preventive therapy on CVD 
events in HIV-infected patients on ART without significantly increased traditional 
cardiovascular disease risk and no prior history of CVD. The trial described in this 
appendix is a mechanistic substudy embedded in the larger REPRIEVE (A5332) clinical 
events trial. In the Mechanistic Substudy of REPRIEVE (A5333s), coenrolled participants 
will undergo coronary computed tomography angiography (CCTA) for determination of 
atherosclerotic plaque morphology, as well as detailed profiling of lipid and 
inflammatory/immune parameters.  
 
The Mechanistic Substudy of REPRIEVE (A5333s) will determine, among HIV-infected 
persons, potential statin effects to halt progression of non-calcified atherosclerotic 
plaque and to stabilize morphologic features of plaque vulnerability. Moreover, the study 
will identify biological factors mediating these changes – be it lipid parameters, such as 
LDL cholesterol, or markers of inflammation and immune activation. Finally, the study 
will demonstrate whether presence and morphology of subclinical atherosclerotic plaque 
at baseline relates to CVD events independently of traditional CVD risk factors and 
markers of HIV-specific immune activation. 
 
Findings from the study will have implications for predicting CVD risk in HIV-infected 
individuals, for whom traditional risk prediction paradigms such as those used in the 
2013 ACC/AHA guidelines may fall short (for failing to factor in the contributions of HIV-
specific immune activation) [Stone 2013]. Moreover, findings from the mechanistic 
substudy will have implications for the development of targeted CVD preventive 
strategies in the HIV-infected population: If statins stabilize coronary atherosclerotic 
plaques and prevent CVD events primarily via LDL lowering, then further LDL lowering 
strategies may be indicated. On the other hand, if statins stabilize coronary 
atherosclerotic plaques and prevent CVD events primarily through immunomodulation, 
then complementary immune-suppressant therapies in HIV-infected patients – such as 
inhibitors of monocyte activation – will need to be further explored. Overall, the 
mechanistic sub-study will provide new, critical knowledge about the biology of 
atherosclerosis in HIV.  
 


 
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3.0 
STUDY DESIGN 
 
A5333s is an optional mechanistic substudy of REPRIEVE (A5332). Approximately 800 
HIV-infected males and females who are enrolled in REPRIEVE (A5332) will coenroll in 
the Mechanistic Substudy of REPRIEVE (A5333s). To ensure treatment balance in 
treatment assignment in the Mechanistic Substudy of REPRIEVE (A5333s), 
randomization in REPRIEVE (A5332) will be stratified by anticipated substudy 
participation. Participants will be followed for 24 months in the Mechanistic Substudy of 
REPRIEVE (A5333s). 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS  
 
4.1 
Inclusion Criteria  
 
4.1.1 Enrollment in REPRIEVE (A5332). 
 
4.1.2 Willingness to complete procedures required for the study. 
 
4.1.3 Signed informed consent. 
 
4.1.4 Glomerular filtration rate (GFR) ≥60 mL/min/1.73m2 or creatinine clearance 
(CrCl) 60 mL/min, as per REPRIEVE (A5332) 
 
NOTE:  Results of creatinine must be obtained and GFR or CrCl must be 
calculated within 14 days prior to CCTA. The GFR must be ≥60 mL/min/1.73m2 
or the CrCl must be ≥60 mL/min for the subject to proceed with CCTA both at 
entry and at month 24. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Known allergy to iodinated contrast agent. 
 
4.2.2 Currently symptomatic asthma. 
 
4.2.3 Allergy to beta blockers. 
 
4.2.4 Contraindication to beta blockers (ie, taking daily asthma medications). 
 
4.2.5 Positive pregnancy test within 24 hours prior to study entry. 
 
NOTE: Female subjects of reproductive potential (defined as women who have 
not been post-menopausal for at least 24 consecutive months, ie, who have had 
menses within 24 months prior to study entry, and women who have not 
undergone surgical sterilization, specifically hysterectomy or bilateral 
oophorectomy) must have a negative serum or urine pregnancy test within 24 
hours prior to CCTA by any US laboratory or clinic that has a CLIA certification or 
its equivalent, or is using a point-of-care (POC)/CLIA-waived test, or at any 


 
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network-approved non-US laboratory or clinic that operates in accordance with 
Good Clinical Laboratory Practices and participates in appropriate external 
quality assurance programs. 
 
NOTE: Subject reported history is considered acceptable documentation of 
hysterectomy, bilateral oophorectomy, and menopause. Women are considered 
menopausal if they have not had a menses for at least 12 months and have a 
FSH (follicle stimulating hormone) of greater than 40 IU/L or, if FSH testing is not 
available, they have had amenorrhea for 24 consecutive months. 
 
4.2.6 Any condition that prohibits the individual from completing the CCTA. 
 
4.2.7 Body mass index (BMI) ≥40 kg/m2. 
 
NOTE:  Refer to the MOPS for the link to the BMI calculator. 
 
4.2.8 Cardiac arrhythmia at enrollment precluding CCTA; such as atrial fibrillation with 
heart rate >80 beats per minute or frequent ectopic beats. Please see MOPs for 
scanner-specific details. 
 
4.3 
Enrollment Procedures  
 
The Mechanistic Substudy of REPRIEVE (A5333s) will be limited to select sites 
participating in REPRIEVE (A5332). Prior to implementation of the substudy, each site 
must have the protocol and the protocol consent form approved, as appropriate, by their 
local IRB/EC and any other applicable regulatory entity (RE).  
 
Site inclusion criteria for the Mechanistic Substudy of REPRIEVE (A5333s) will include 
the following: 
• 
Site participating in REPRIEVE (A5332). 
• 
Site radiology or cardiology department/facility must conduct >1000 CT/per year.  
• 
MD oversight/supervision of CT scans. 
• 
CT scanner must be at least 2nd generation 64-slice. 
• 
The facility must utilize level III readers. 
• 
The radiology/cardiology facility must be capable of all of the following  
o prospective triggering/gating 
o using low KV 
o have capacity to premedicate subjects  
 
Once a candidate for entry has been identified, details will be carefully discussed with 
the subject. The subject (or when necessary, the legal representative) will be asked to 
read and sign the approved Mechanistic Substudy of REPRIEVE (A5333s) consent 
form. 
 
Enrollment into the Mechanistic Substudy of REPRIEVE (A5333s) will occur concurrently 
with enrollment and randomization into REPRIEVE (A5332), ie, completion of enrollment 


 
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into A5333s should occur no later than one business day after enrollment into 
REPRIEVE (A5332), in recognition that lab results needed to determine eligibility into 
A5333s may not be available on the same day. Note this does not change the 
requirement that CCTA for A5333s must be performed within 14 days after 
randomization. 
 
NOTE: The Mechanistic Substudy of REPRIEVE (A5333s) closed to accrual on 
02/06/18. 
 
4.4 
Subject Registration 
 
Subjects who meet enrollment criteria will be registered to the substudy according to 
standard DMC procedures. 
 
5.0 
STUDY TREATMENT  
 
No medications are provided by the Mechanistic Substudy of REPRIEVE (A5333s). 
Study treatment will be distributed and administered as per REPRIEVE (A5332). See 
section 5.0 of REPRIEVE (A5332) for study treatment requirements and concomitant 
medications. 
 
6.0 
EVALUATIONS 
 
6.1 
Schedule of Evaluations for the Mechanistic Substudy of REPRIEVE (A5333s)  
Evaluation1 
Entry 
Month 4 
±21 days 
Month 24 
± 28 days 
Premature 
Study Disc. 
Evaluations 
Calculate BMI3 
X 
 
X 
 
REAP and DASI Questionnaires 
 
 
X 
X 
QOL assessment 
X 
 
X 
X 
Pregnancy Testing 
X4 
 
X4 
X 
Serum Creatinine 
X5 
 
X5 
X 
CBC with differential 
X5 
 
X5 
X 
CD4+/CD8+ 
X5 
 
X5 
X 
Plasma HIV-1 RNA 
X5 
 
X5 
X 
Fasting Lipid Panel 
 
X6 
 
 
Fasting Plasma/Serum for 
Biomarkers – Planned Analysis7 
X 
X 
X 
X 
Cryopreserved PBMCs for Flow 
Cytometry – Planned Analysis 
X 
 
X 
X 
Whole blood for RNA 
X 
 
X 
X 
CCTA 
X 
 
X 
X2 


 
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1 Subjects in the mechanistic substudy will have all evaluations as per REPRIEVE (A5332) Schedule of 
Evaluations; additional testing and/or unique processing instructions specific to the mechanistic 
substudy are listed here in section 6.1 of the mechanistic substudy. 
2  Premature Study Discontinuation before month 12 should include all evaluations listed except CCTA. 
Premature Study Discontinuation at month 12 or later should include all evaluations including the 
second CCTA.  
3 For BMI calculation at entry, use height and weight obtained at screen from REPRIEVE (A5332). For 
month 24 BMI calculation, use height obtained at screen and weight obtained at month 24 from 
REPRIEVE (A5332). 
4 Pregnancy testing must be performed and reviewed prior to CCTA for mechanistic substudy 
participants at entry and month 24 to ensure subject eligibility.  
5  CD4+/CD8+, HIV viral load, CBC, and serum creatinine at entry and month 24 will be performed as 
part of substudy. Serum creatinine results must be drawn and GFR or creatinine clearance must be 
reviewed within 14 days prior to CCTA to ensure subject eligibility. If drawn more than 14 days before 
CCTA, repeat creatinine must be drawn. The CBC must be drawn on the same day as PBMC. 
6 Fasting lipid panel from month 4 will be performed centrally. 
7  HgbA1c, Lp-PLA2, sCD163, sCD14, MCP-1, IL-6, D-dimer (will not be collected at month 4), hsCRP, 
troponin, insulin, glucose. Related indices of insulin resistance such as HOMA-IR will be calculated.  
 
6.2 
Timing of the Evaluations  
 
6.2.1 Entry 
 
Registration to the Mechanistic Substudy of REPRIEVE (A5333s) will occur at 
the entry visit and is concurrent with enrollment to the main study, ie, completion 
of enrollment into A5333s should occur no later than one business day after 
enrollment into REPRIEVE (A5332), in recognition that lab results needed to 
determine eligibility into A5333s may not be available on the same day. Substudy 
entry evaluations (including CCTA evaluations) must be completed prior to the 
initiation of REPRIEVE (A5332) study medications. The baseline CCTA scan 
should be completed within 14 days after randomization. 
 
6.2.2 Post-entry 
 
Month 4 substudy evaluations must be performed ± 21 days; month 24 substudy 
evaluations must be performed  28 days. 
 
6.2.3 Discontinuation Evaluations 
 
Premature Discontinuation of REPRIEVE (A5332) Study Treatment  
Subjects who prematurely discontinue REPRIEVE (A5332) study treatment may 
continue participation in the substudy with all evaluations performed as per 
section 6.0. 
 


 
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Premature Discontinuation of REPRIEVE (A5332) Study Participation 
Subjects who prematurely discontinue participation in the REPRIEVE (A5332) 
study will be discontinued from the Mechanistic Substudy of REPRIEVE 
(A5333s). 
 
Premature Discontinuation of the Mechanistic Substudy of REPRIEVE (A5333s) 
Participation 
Subjects who discontinue participation in the Mechanistic Substudy of 
REPRIEVE (A5333s) may continue participation in REPRIEVE (A5332). 
 
Subjects who prematurely discontinue participation in the Mechanistic Substudy 
(A5333s) should complete the Premature Discontinuation of Substudy visit. 
Premature Study Discontinuation before month 12 should include all evaluations 
listed except CCTA. Premature Study Discontinuation at month 12 or later should 
include all evaluations including the second CCTA.  
 
Subjects who become pregnant while on the Mechanistic Substudy of 
REPRIEVE (A5333s) must immediately be discontinued from the substudy 
without any further evaluations performed. 
 
6.3 
Instructions for Evaluations 
 
6.3.1 Clinical Assessments 
 
Targeted Physical Exam 
A targeted physical examination as described in REPRIEVE (A5332) will be 
performed as per section 6.1 and findings will be recorded on the REPRIEVE 
(A5332) CRFs. Blood pressure and pulse should also be taken. Blood pressure 
should be recorded on the REPRIEVE (A5332) CRFs at all substudy visits. 
Record any changes that occur after entry on the REPRIEVE (A5332) CRF. 
 
Calculation for Body Mass Index will be performed prior to entry and month 24 
CCTA. See MOPS for link to calculator. 
 
Cardiovascular Risk Factor Assessment 
Diet, using the Rapid Eating and Activity Assessment for Patients (REAP) 
questionnaire and functional capacity using the Duke Activity Status Index (DASI) 
questionnaire will be performed at the month 24 visit.  
 
Quality of Life Assessment using the SF-36v2 questionnaire will be performed at 
entry and month 24. 
 


 
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6.3.2 Laboratory Evaluations 
 
Pregnancy Testing 
For women with reproductive potential: serum or urine beta-HCG (urine test must 
have a sensitivity of 15-25 mIU/mL). A negative pregnancy test result must be 
obtained before the CCTA. 
 
Serum Creatinine 
For entry and month 24, serum creatinine will be performed as part of the 
Mechanistic Substudy of REPRIEVE (A5333s). Serum creatinine must be drawn 
and GFR or CrCl must be calculated within 14 days prior to CCTA. The GFR 
must be ≥60 mL/min/1.73m2 or CrCl must be ≥60 mL/min for the subject to 
proceed with CCTA both at entry and at month 24. 
 
CBC with Differential 
For entry and month 24, a CBC with differential will be performed as part of the 
Mechanistic Substudy of REPRIEVE (A5333s). The CBC must be drawn on the 
same day as the PBMC collection. 
CD4+/CD8+ T-cell Counts  
CD4+/CD8+ T-cell count and percentage assays at entry and month 24 must be 
performed as part of the substudy at a CLIA-certified or equivalent laboratory that 
is certified for protocol testing by the DAIDS Immunology Quality Assurance 
(IQA). 
 
Plasma HIV-1 RNA 
HIV-1 RNA must be performed at entry and month 24 by a laboratory that 
possesses a CLIA certification or equivalent. 
 
Fasting Lipids 
Serum lipid and lipoproteins (total cholesterol, HDL cholesterol, LDL cholesterol, 
non–HDL, triglycerides, particle size, lipid subfractions, oxidized LDL) are 
collected only for the Mechanistic Substudy of REPRIEVE (A5333s) at month 4. 
These samples will be batched and stored in the ACTG Specimen Repository for 
analyses by a central laboratory.  
 
Fasting Insulin  
Fasting insulin samples will be batched and stored in the ACTG specimen 
repository for analyses by a central laboratory. HOMA-IR will be calculated from 
fasting insulin determined from the Mechanistic Substudy of REPRIEVE 
(A5333s) and fasting glucose determined from REPRIEVE (A5332). 
 
HgbA1C 
Samples for HgbA1C will be batched and stored in the ACTG Specimen 
Repository for analyses by a central laboratory. 
 


 
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6.3.3 Immunologic and Biomarker Studies  
 
Fasting Plasma/Serum for Biomarkers – Planned Analysis 
The following primary biomarker assays will be performed using frozen samples: 
Lp-PLA2, sCD163, sCD14, MCP-1, IL-6, D-dimer, hsCRP, troponin. These 
samples will be batched and stored in the ACTG Specimen Repository for 
analyses by a central core laboratory. Refer to the Laboratory Processing Chart 
(LPC) for details. Additional biomarker and coagulation marker assays may be 
performed.  
 
PBMCs for Monocyte and T Lymphocyte Activation – Planned Analysis 
PBMCs for pre-specified flow cytometric analysis on monocytes and T 
lymphocytes will be batched and stored in the ACTG Specimen Repository for 
analyses by a central core laboratory. Refer to the LPC for details. 
 
Whole Blood RNA 
Whole blood will be obtained and processed for RNA. Samples will be batched 
and stored to enable the evaluation of ancillary studies to assess RNA changes. 
 
6.3.4 CT Angiogram and Risks of Radiation Dose 
 
Coronary computed tomography angiography (CCTA) is performed in 
accordance with best practice standards as delineated in the imaging guidelines 
of the Society of Cardiovascular Computed Tomography [Abbara 2009] by 
competent and appropriately credentialed physicians. This includes the 
optimization of the scan protocol to limit radiation dose. Specific protocols for 
each CT scanner, manufacturer, and model will be provided and performed in the 
MOPS. In general, both retrospective and prospective ECG gated protocols are 
permitted. The Core Lab will conduct an initial quality assurance screen to 
ensure correct imaging parameters (kVp, mAs, FOV, slice thickness, slice 
interval, reconstruction kernel). When a data set is received by the CT core lab, 
quality analysis (QA) will be performed and if accepted, a case acceptance notice 
will be sent to the site. If the data set does not pass QA, the site will be sent a 
query to resolve the issue. The CRA will determine if the data set requires 
resubmission or if the correspondence with the site can resolve the query. If the 
site does not respond to the query the CRA will follow the query escalation plan. 
When the query is resolved, the site will be sent a case acceptance notification 
and the data set will be moved to the reader work list. Prior to the follow up 
CCTA, the Core Lab will send the site a reminder including the baseline scan 
parameters with a request to perform the follow up as closely as possible 
resembling the baseline protocol. Refer to the Mechanistic Substudy of 
REPRIEVE (A5333s) MOPS for detailed instructions.  
 
Risks of Radiation Exposure from CT: CT scanning results in a measurable 
radiation exposure. For most patients participation in this study will be associated 
with an estimated cumulative radiation exposure of approximately 11 mSv with a 


 
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maximum dose of about 16 mSv over two years (median radiation exposure per 
exam: 5.6 mSv, range 3-8 mSv).  
 
By comparison, radiation exposure from a single stress nuclear myocardial 
perfusion imaging, another test commonly used to detect heart disease, is about 
14 mSv. The average annual radiation exposure from natural background 
sources in the US is between 2 and 3.6 mSv.  
 
The radiation exposure from this study is only 10% of the maximally allowed 
annual radiation exposure to radiation workers such as radiology technologists, 
radiologists, or workers in nuclear plants (50 mSv per year). Overall, each CT 
scan adds a very small theoretical risk of less than 0.05% to the 7% lifetime risk 
of lung cancer for men and women and to the 12% lifetime risk of breast cancer 
for women. 
 
Pregnant subjects must not have a CCTA scan. 
 
7.0 
TOXICITY MANAGEMENT 
 
See section 7.0 in protocol REPRIEVE (A5332). Specific CCTA-related events should be 
handled as per standard treatment guidelines, eg, for acute contrast-related events. 
 
8.0 
CRITERIA FOR SUBSTUDY DISCONTINUATION 
 
• 
Subjects who discontinue participation in REPRIEVE (A5332). Discontinuation of 
REPRIEVE (A5332) at A5332 study closure does not constitute premature 
discontinuation.  
• 
The subject refuses further participation. 
• 
The site investigator determines further participation would be detrimental to the 
subject’s health or well-being. 
• 
The subject becomes pregnant. 
• 
The subject fails to complete the entry CCTA. 
• 
Subject develops impaired renal function defined as confirmed CrCl <60 mL/min or 
GFR <60 mL/min/1.73m2 at month 24 visit. 
• 
The subject develops new onset clinically significant asthma. 
• 
The subject develops new onset/previously undiagnosed allergy to IV contrast. 
• 
Body mass index (BMI) is ≥40 kg/m2 at month 24 visit. 
 
9.0 
STATISTICAL CONSIDERATION 
 
General Design Considerations 
The overarching aim of the Mechanistic Substudy of REPRIEVE (A5333s) is to better 
understand the modulation of critical features of coronary plaque morphology with statin 
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(NCP) volume in HIV and the biological factors mediating these effects during statin 
treatment in HIV.  
 
9.1 
Endpoints 
 
9.1.1 Primary Endpoints 
 
9.1.1.1 Evidence of non-calcified coronary atherosclerotic plaque (NCP) at 
study entry and 2 years. 
 
9.1.1.2 Volume of non-calcified coronary atherosclerotic plaque (NCP) at study 
entry and change in NCP over 2 years (expressed as absolute change 
and as a percentage of baseline). 
 
9.1.1.3 Progression of NCP where progression will be defined as follows: 
a) Among subjects with evidence of NCP at entry, any 
progression/increase in NCP volume 
b) Among subjects without evidence of NCP at entry, incident NCP. 
 
9.1.2 Secondary and Supportive Endpoints 
 
9.1.2.1 Number of segments with NCP 
 
9.1.2.2 Presence and number of each of the following high-risk plaque features 
• 
Low Hounsfield Unit attenuation by CT assessment 
• 
Positive remodeling 
 
9.1.2.3 Levels at study entry, 4 months, and 2 years, and changes from study 
entry to 4 months and 2 years in the following biomarkers 
• 
Markers of HIV-1 disease: CD4 cell count, HIV-1 RNA level (entry to 
2 years only) 
• 
Soluble markers of monocyte activation: sCD163, sCD14, MCP-1 
• 
Various monocyte populations including %CD14+CD16+ monocytes 
(entry to 2 years only) 
• 
Markers of T-cell activation and exhaustion (entry to 2 years only) 
• 
Markers of inflammation: Lp-PLA2, hsCRP, IL6, troponin 
• 
Markers of coagulation: D-Dimer and tissue factor (excluding D-
Dimer at month 4; D-Dimer will be available at entry and month 24 
only) 
 
9.1.2.4 Fasting lipid fractions (Total, non-HDL, and HDL cholesterol) and 
LDL:HDL ratio at study entry, month 4 and 2 years. 
 


 
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9.1.2.5 Fasting insulin, HgbA1c, and HOMA-IR at study entry, month 4, and 2 
years (excluding HgbA1c at month 4; HgbA1c will be available at entry 
and month 24 only). 
 
9.1.2.6 Time to the first major cardiovascular events as defined in section 9.2.1 
of REPRIEVE (A5332). 
 
9.2 
Sample Size 
 
The target sample size for the Mechanistic Substudy of REPRIEVE (A5333s) is 800 
participants that will be approximately equally distributed between the study arms. 
 
This sample size was determined to have high power to detect clinically relevant 
differences between the two study groups both with respect to plaque progression 
(among those with plaque at study entry) and rates of incident plaque (among those 
plaque-free at entry). Specifically, the total sample size of 800 subjects will provide 90% 
power to detect a 6% difference between the study groups in the percent change in NCP 
volume over 2 years among those with plaque at entry and 90% power to detect 13 
percentage point difference in the probability of plaque development over 2 years. These 
effect sizes translate to a combined estimated 14 percentage point difference in the 
probability of NCP progression over two years and are based on the following 
assumptions: 
• 
50% of study participants will have evidence of NCP at study entry [Lo 2010] 
• 
A SD of 20% for the percent change over 2 years among participants with evidence 
of plaque at entry 
• 
An annual rate of incident plaque development of 12% among participants without 
plaque at entry 
• 
15% of participants entering the substudy will not be evaluable for study entry or 2 
year NCP volume. 
 
Together, the effects of statins acting in these two groups (those with and without 
evidence of NCP at study entry) will provide for a 7% lower prevalence of NCP after 2-
years of statin treatment. Expectations for NCP prevalence and progression both as a 
whole and according to whether NCP was present at study entry are illustrated in the 
table below. These estimates are based on a simulation that further assumed the 
following: 
• 
Average volume NCP 250mm3 (SD=200) among participants with NCP at entry. 
• 
Average volume NCP 40mm3 (SD=20) at 2 years among participants without NCP at 
entry without statin treatment. 
• 
Average volume NCP 20mm3 (SD=20) at 2 years among participants without NCP at 
entry with statin treatment. 
• 
NCP distributions were also assumed to follow a gamma distribution with size and 
shape parameters determine to provide the desire mean and standard deviations. 
 


 
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Table 9.2-1: Cells constituting the primary targeted group comparisons are shown in bold. 
 
At study entry 
At two 2 years 
 
NCP 
(%) 
NCP volume (mm3) NCP 
(%) 
NCP volume (mm3) 
Change in NCP 
volume (mm3) 
Percent change in NCP 
volume (%)2 
Mean (SD) [P5, P95] 
Mean (SD) [P5, P95] Mean (SD) [P5, P95] Mean (SD) 
[P5, P95] 
Control Overall1 
50% 
121 (186) 
[0, 509] 59% 140 (210) [0, 573] 
19 (51) 
[-21, 103] 17% (33%) [-10%, 100%] 
No plaque at entry 
- 
- 
21% 
9 (19) 
[0, 51] 
9 (19) 
[0, 51] 
21% (41%) [0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
40 (20) 
[17, 79] 
40 (20) 
[17, 79] 100% (0%) [100%, 100%] 
Plaque at entry 
251 (198) [26, 637] 
 
281 (231) [28, 730] 
30 (68) 
[-38, 153] 12% (20%) [-14%, 49%] 
Statin 
Overall1 
50% 
120 (185) 
[0, 507] 52% 127 (198) [0, 536] 
7 (45) 
[-42, 76] 
7% (24%) 
[-17%, 60%] 
No plaque at entry 
- 
- 
8% 
2 (8) 
[0, 14] 
2 (8) 
[0, 14] 
8% (27%) 
[0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
23 (19) 
[2,60] 
23 (19) 
[2,60] 
100% (0%) [100%, 100%] 
Plaque at entry 
250 (197) [26, 633] 
 
262 (216) [26, 682] 
12 (64) 
[-66, 123] 5% (20%) 
[-21%, 43%] 
1  In estimation of overall means, participants without evidence of NCP are assigned a value of 0 for 
volume and change. 
2 In estimation of percentage change, participants without evidence of NCP at study entry with NCP at 2 
years are assigned a value of 100%. 
 
These desired statin effects on NCP volume are similar to those seen in intravascular 
ultrasound (IVUS) studies [Nissen 2006; Nicholls 2005]. Although no data exist to 
directly inform the clinical relevance of these differences, randomized comparisons of 
high vs. low dose statin therapy among non HIV-infected patients have demonstrated 
favorable effects on atherosclerotic plaque of a similar magnitude as well as on adverse 
cardiac events, among non HIV patients [Nissen 2006]. Further, data from the "Coronary 
CT Angiography Evaluation for Clinical Outcomes (CONFIRM) registry suggest that the 
presence of non-obstructive CAD is predictive major adverse cardiac events 
independent of traditional risk factors, degree of stenosis and coronary artery 
calcification (HR 2-5) [Hulton 2013]. The proposed mechanistic study will further add to 
this body of evidence investigating, for the first time in HIV-infected population, the 
association of NCP (both the presence and magnitude) as well as changes in volume 
relate to events. For this exploratory analysis, a larger sample size will be beneficial, in 
order to accrue CVD events to relate to plaque morphology. 
 
9.3 
Randomization/Registration 
 
Participants will be enrolled into the Mechanistic Substudy of REPRIEVE (A5333s) via 
the enrollment system at the same time as they are randomized into REPRIEVE 
(A5332). To ensure balanced treatment allocation in the mechanistic study, REPRIEVE 
(A5332) randomization will be stratified by planned mechanistic substudy participation.  
 
9.4 
Monitoring 
 
Ongoing monitoring of accumulating data for the Mechanistic Substudy of REPRIEVE 
(A5333s) by the study team (pooled by treatment group) will occur for study conduct and 
data completeness. Since scans will be read and biomarkers tested in batch at the end 


 
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of the study, data completeness focus will be for tracking of scan and specimen 
completeness. 
 
Such issues will be monitored by the jointly appointed NIAID/NHLBI DSMB at the time of 
DSMB review of REPRIEVE (A5332). 
 
9.5 
Analysis Plan 
 
9.5.1 General analysis considerations 
 
The presence and extent of coronary artery disease (CAD) in this population will 
be described including non-obstructive or obstructive CAD, volume of NCP and 
calcified plaque, and Agatston score, as well as the prevalence of high risk 
plaque features such as positive remodeling and low CT attenuation, and levels 
of inflammatory, and immunomodulatory biomarkers. 95% confidence intervals 
will be provided for CAD characteristic for the mechanistic study subgroup as 
whole and by randomization. 
 
All treatment group comparisons will be performed ITT using a 5% type error. 
Unless otherwise noted, analyses will be performed by subgroups defined 
according to the presence of NCP at study entry. Since CCTA will not be 
available at the time of randomization, balance by treatment arm cannot be 
guaranteed within these subgroups, but given the large sample size and 
stratification according to sex and HIV-1 disease severity relative balance 
between the group sample sizes is expected. 
 
9.5.2 Analysis plan 
 
Statin effects on coronary plaque morphology: Among participants with plaque at 
entry, descriptive statistics for the change and percentage change in NCP 
volume over 2 years will be provided by treatment group with group comparisons 
made with stratified t-test. Among those without NCP at entry, the prevalence of 
incident NCP over 2 years will be compared with stratified chi-squared test. To 
assess the mechanistic study population as a whole patients will be classified as 
progressors (any progression/increase in NCP volume OR incident NCP) or non-
progressors (no progression in NCP volume OR no incident NCP); the probability 
of progression over two years will be compared by treatment group using a 
stratified chi-squared test. 
 
The statin effect on high risk plaque features, including low HU attenuation and 
positive remodeling, will be assessed by comparing differences in the 2-year 
prevalence of high risk plaque morphology features between treatment groups 
using chi-squared (or Fisher’s exact) tests as appropriate; these analyses will be 
performed overall and by subgroups defined by the presence of NCP at study 
entry. Exploratory analysis will be performed for additional high risk plaque 
features that have been described in CCTA and IVUS studies including the 


 
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Napkin Ring Sign, Minimal luminal area, plaque burden, and segments with NCP. 
The analytic approach will be similar as described above. 
 
Statin effects on blood biomarkers: Statin effects on the distributions of blood 
biomarkers belonging to distinct pathways (ie, monocyte activation, generalized 
inflammation, and coagulation) will be assessed via treatment group 
comparisons of these respective markers via t-tests; modification of statin effect 
on these markers by HIV-1 and traditional risk factors (including sex, age, 
screening CD4, duration of suppressive ART, and presence of NCP at study 
entry). Since the hypothesized mechanism is that sustained high levels of 
immune activation and inflammation precede and contribute to progression of 
NCP volume and high risk plaque features, these analyses will relate short term 
changes in these biomarkers (over 4 months) to longer term changes in NCP 
volume and morphology after two years. 
 
LDL and blood biomarkers as mediators for plaque progression: In the event that 
both statin effects on NCP progression and biomarker changes are apparent, the 
association between changes in LDL and these biomarkers and NCP 
progression will be examined using graphical techniques and normal errors and 
logistic regression (for the subpopulations with and without NCP at entry 
respectively. A mediating effect of these biological factors will be evaluated by  
examination of changes in the estimated statin effect on NCP upon adjustment 
for these biological factors. Those biomarkers with the strongest mediating effect 
on plaque progression will be measured in the entire REPRIEVE (A5332) cohort 
to determine their association with MACE.  
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING  
 
Serious adverse events (SAEs) that occur as part of participation in the Mechanistic 
Substudy (A5333s) are reported as expedited adverse events (EAEs) through 
REPRIEVE (A5332). These SAEs are reported on a CRF for the Mechanistic Substudy 
(A5333s); they are not reported on the CRF for REPRIEVE (A5332). There are 
additional non-serious AEs (ie, non-serious contrast reactions) that may occur as part of 
the Mechanistic Substudy (A5333s) that will also be recorded on the CRF. Please see 
the Mechanistic Substudy (A5333s) MOPS for more details regarding AE reporting for 
A5333s. 
 
11.0 
HUMAN SUBJECTS 
 
IRB/EC review, subject confidentiality, and study discontinuation procedures will be the 
same as in REPRIEVE (A5332). Subjects must sign a separate informed consent form 
for the Mechanistic Substudy of REPRIEVE (A5333s). Risks, including potential risks of 
CCTA, and protection against risk are described in the accompanying sample informed 
consent form. 
 


 
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12.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of the Mechanistic Substudy of REPRIEVE (A5333s) will be 
governed by NIH policies. 
 
13.0 
BIOHAZARD CONTAINMENT 
 
Precautions and procedures will be as in REPRIEVE (A5332). 
 
 
 


 
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14.0 
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Liu Z, et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the 
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virologically effective cART with early atherosclerosis. PLoS One 2012;7(9):e46073.  
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APPENDIX III:  SAMPLE INFORMED CONSENT 
 
For The Mechanistic Substudy of REPRIEVE (A5333s), FINAL Version 6.0, 16May2022 
 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers:  
Mechanistic Substudy of REPRIEVE  
 
SHORT TITLE FOR THE STUDY: The REPRIEVE Mechanistic Substudy 
 
 
INTRODUCTION 
 
You are being asked to take part in this research substudy because you will be taking 
pitavastatin or the placebo for pitavastatin for REPRIEVE (A5332). This study 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 substudy 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? 
 
The purpose of this substudy is to learn about the effects of pitavastatin on the vessels that 
supply your heart with blood “coronary arteries” and the atherosclerotic plaque within the wall of 
these vessels (known as “hardening of the arteries”), as well as inflammatory biomarkers (blood 
tests that indicate the body’s immune system is active) among people with HIV (PWH). 
 
 
HOW MANY PEOPLE WILL BE IN THIS SUBSTUDY? 
 
About 800 people will take part in this study. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS SUBSTUDY? 
 
If you agree to be in this substudy and sign this consent form, you will be asked to come in for 3 
visits. Each visit will last about 2-3 hours and will occur at the same time as your main study 
visits whenever possible. The visits are at entry (when you join the substudy), month 4, and 
month 24.  
 
Before all visits for the substudy you should not eat or drink anything, including food, beverages, 
candy, or gum for 8 hours before your visit. You are encouraged to drink water before your 


 
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visits. If you are not fasting, we will ask you to return to have your blood drawn within 21 days of 
the study visit.  
 
The procedures described below will be done in addition to your participation in the REPRIEVE 
(A5332) study. 
 
Explanation of study procedures 
You will be asked to fill out a questionnaire about your quality of life at entry and month 24. 
 
Study staff will ask you questions about your diet and physical activity at month 24. 
 
For women capable of having children, a pregnancy test will be done immediately before the CT 
of your heart. This test is required as part of your participation in this study. You will be told the 
results of the pregnancy test. You must notify the research staff if you are pregnant, think you 
may be pregnant, or if you are trying to become pregnant. If do become pregnant while on the 
substudy, you will be taken off the substudy and will not have any more substudy tests. 
 
At entry and month 24 we will check your kidney function, complete blood count (CBC), CD4 T-
cell count (how many infection fighting cells are in your blood), and HIV viral load (how much 
HIV is in your blood). The test to check your kidney function is required as part of your 
participation in this research study. Approximately 3 teaspoons of blood will be collected at each 
the entry and month 24 visits for these tests. 
 
You will be told the results of these tests. 
 
You will have about 1-4 tablespoons of blood drawn in addition to the blood drawn for 
REPRIEVE (A5332) at the entry, month 4 and month 24 visits. This blood will be collected and 
stored for tests that will be done later on in the study or after the study is over. These tests will 
measure various substances in your blood related to cholesterol (fat in your blood), blood sugar, 
metabolic tests (how your body processes food), inflammation, and immune function (how your 
body reacts to infection). You do not need to agree to store this blood to join the study and you 
may change your mind about storing your blood at any time. You will not be told of the results of 
the research done on your blood.  
 
Do you agree to let us store your samples for these tests? 
 
________ YES ________ NO 
_______Initials 
 
Approximately 1 teaspoon of blood collected will be used to look at genes that may affect your 
risk for cardiovascular disease. Genetic testing is a laboratory test that looks at differences in 
people’s genes. Your body, like all living things, is made up of cells, and cells contain 
deoxyribonucleic acid, also known as “DNA.” DNA is like a string of information put together in a 
certain order. Parts of the string make up “genes.” For the substudy, we will do a test to look at 
your RNA. RNA is made from DNA and is short for ribonucleic acid. RNA is a genetic material 
that has a major role in making proteins. Proteins are the building blocks of your body, cells, and 
organs. Genes contain instructions on how to make your body work and fight disease. The 


 
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testing in this study will focus on certain RNA’s that are known to be related to cardiovascular 
disease and effects of statins. New RNA’s of interest may be identified in the future and may 
also be looked at. You do not need to agree to store this blood to join the study and you may 
change your mind about storing your blood at any time. You will not be told of the results of the 
research done on your blood. 
 
Your body’s genetic makeup is unique to you, so there is a risk with genetic research that even 
with all the security measures in place, someone using your samples or genetic information may 
still find out which information is yours. However, this risk today is very small, but it may 
increase with time since science and technology are developing rapidly. 
 
In the event that your genetic information becomes linked to your name, the US federal law 
called the Genetic Information Nondiscrimination Act (GINA) helps protect you. This law 
prohibits health insurance companies, group health plans, and most employers from denying 
services based on your genetic information. However, GINA does not protect against 
discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. 
 
We would like to use some of the blood we collect to look at your genes (RNA). Do you agree to 
this genotyping? 
 
________ YES ________ NO 
_______Initials 
 
If at a later date you change your mind and want your samples destroyed, contact the research 
staff. There are two ways to withdraw your permission. You could allow researchers to remove 
all your personal identifiers from your samples, so that they are not linked to you anymore. 
These samples will then become anonymous. Or, you can ask researchers to destroy your 
samples, so that they cannot be used for future research. However, in either case, researchers 
will not be able to destroy samples or information from research that is already underway. 
 
You will have a computed tomography (CT) scan (“Cat” scan) of your heart at entry and month 
24. A CT scan is a special kind of x-ray that takes pictures of the inside of the body using a 
small amount of radiation. A small amount of dye (intravenous contrast) will be injected into your 
arm during the CT scan to better see the vessels that supply your heart with blood. If your heart 
rate is more than 65 beats per minute, we may inject a drug called a beta-blocker into your arm 
via the intravenous line. A beta-blocker is used to slow down your heart rate. A low heart rate is 
needed in order to make the best pictures of your heart and coronary arteries. In addition, a 
drug called nitroglycerin will be given to you by mouth in order to obtain better images of the 
blood vessels of the heart. We will also check your heart rhythm with an electrocardiogram 
(ECG). To do this, wires with sticky pads attached will be placed on your chest before the scan. 
 
You will be asked to lie quietly while your body is moved inside a large machine and the x-ray is 
taken. The CT scan takes about 15 minutes. For women, a pregnancy test will be performed 
prior to CT scanning. Pregnant women will not be allowed to undergo CT scanning. For all 
patients, a blood test for kidney function will be performed before the CT scan and patients with 
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Because the test results are being used for research only, the results created by this study will 
not become part of your hospital record unless we discover an unexpected medical problem that 
must be communicated to the study doctors or your primary care physician. If you are found to 
have a critical blockage of the vessels supplying your heart with blood or another important non-
cardiac abnormality that may affect your health, we will provide the results of the CT to your 
study doctor. The cost of any additional testing will not be covered by the study. 
 
Other Information 
You may withdraw from this substudy at any time and still remain on the main study. If you 
decide to withdraw from the substudy early (before month 24) or if you decide to withdraw from 
the main study you will be asked to return to the clinic to have the procedures listed in the table 
below.  
 
Appendix III, Table 1: Discontinuation Procedures 
Procedure 
Stopping the study  
Fasting Blood 
X 
Blood Collected 
X 
Pregnancy Testing 
X 
Computed Tomography of your Heart (CT scan) 
X 
Quality-of-Life Assessment 
X 
 
If you leave the study before month 12, you will not have a CT scan at the discontinuation visit. 
 
 
HOW LONG WILL I BE IN THIS SUBSTUDY? 
 
You will be in this substudy for about 2 years. 
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
the doctor thinks it is in your best interest 
• 
the study is cancelled 
• 
you are not able to attend the study visits as required by the study 
• 
you are unable to complete the computed tomography of your heart at the entry visit 
• 
you become pregnant 
• 
you have to stop participating in the main study 
• 
your kidney function becomes abnormal during your study participation 
• 
you develop asthma during your study participation 
• 
you develop an allergy to the contrast dye during your study participation 
• 
your body mass index (a measure of body fat based on your height and weight) is greater or 
equal to 40. 
 


 
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WHAT ARE THE RISKS OF THE SUBSTUDY? 
 
The scanning on CT machines will not cause any physical discomfort other than from having to 
lie still on the table for the duration of the test. 
 
Risks of Radiation Dose from CT 
You will have two CTs, one at entry and one at month 24. CT results in a measurable radiation 
dose. For most people the dose from each CT will be approximately twice the amount you get 
from natural background radiation (sun and earth) each year. Your dose may be higher or lower 
based on your size, your heartbeat, and the CT scanner. To put the total dose from the two CTs 
in further context, it is similar to the radiation dose from a cardiac imaging stress test (another 
test commonly used to detect heart disease) and much less (approximately 10%) of the 
maximum allowed exposure for radiation workers such as medical technologists, radiologists, or 
nuclear plant technicians.  
 
The lifetime risk of lung cancer for men and women is 7%. The lifetime risk of breast cancer in 
women is 12%. Each CT scan adds a very small theoretical risk of 0.05%.  
 
Radiation Dose  
Cardiac CT scanning results in a measurable radiation dose. In order to minimize risk for 
participants in this study we have implemented the following measures: 
• 
Exclude subjects <40 years of age 
• 
Exclude pregnant and breast feeding women 
• 
Application of cardiac CT protocols to minimize radiation dose  
• 
Review and approval of these CT protocols by the IRB/EC 
 
Risks of Intravenous Contrast Dye 
You will receive intravenous contrast dye as part of the CT scan and there is a small risk (2 out 
of 1,000) of an allergic reaction. More than 90% of such adverse reactions are very mild and 
allergic-like (itching, rash) and can be effectively treated with available drugs (ie, antihistamine). 
Severe reactions occur in 2 out of 10,000 and one death occurred in approximately 60,000 
contrast dye injections. 
 
Contrast-Induced Nephropathy (CIN)  
CIN is a kidney injury caused by contrast and is usually reversible. CIN almost always occurs in 
people who already have abnormal kidney function. To be enrolled in this study you must have 
normal kidney function, and for this reason CIN is very unlikely (less than 5 out of 1,000). 
  
Risks of IV Needle Placement  
• 
Hemorrhage (bruise at the injection site) 
• 
Infection (catheter related infection) at the injection site (very rare) 
• 
Leaking of contrast agent outside of the vein at the place where the IV is inserted. 
• 
Minor discomfort 
• 
Bleeding 


 
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• 
Infection 
• 
Bruising 
 
Risks of Beta-blockers and Nitroglycerin 
Beta-blockers and nitroglycerin are used by millions of Americans and are generally considered 
safe. These drugs are routinely administered prior to cardiac CT to improve the quality and 
interpretability of the study. 
 
The risk of beta-blockers includes slow heart rate (bradycardia), low blood pressure 
(hypotension), and wheezing (bronchospasm). Allergic reactions to beta-blockers are rare. 
Persons with asthma treated with inhalers should not receive beta-blockers. Study staff will 
assess this and other reasons for you not to have beta-blockers with you prior to the CT. 
 
The side-effects and risks of nitroglycerin are generally mild and of short duration and include 
low blood pressure (hypotension), high heart rate and abnormal rhythm (tachyarrhythmia), 
headache, lightheadedness, and visual disturbance. Persons who take erectile dysfunction 
medications such as Viagra, Cialis, or Levitra (sildenafil, tadalafil, or vardenafil) will need to stop 
these drugs at least 5 days prior to receiving nitroglycerin on the day of the cardiac CT scan. 
Nitroglycerin should not be given to persons with a low blood pressure. Study staff will assess 
this and other reasons for you not to have nitroglycerin with you prior to the CT. 
 
Other Risks/ Additional Risks of CT Scans 
• 
Discomfort 
• 
Claustrophobia 
 
Risks of Drawing Blood 
Having your blood drawn may cause discomfort, bleeding, and bruising where the blood is 
drawn. Occasionally, there is swelling in the area where the needle enters the body and there is 
a small risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 
Risks of Fasting 
Some people find fasting to be bothersome. It may make some individuals feel anxious, irritable, 
or hungry. Patients who are required to take their morning medications with food should wait 
until after the visit has been completed to take their medications. 
 
Genetic Testing 
The results of your genetic tests are for research purposes only and no individual results will be 
given back to you. The results of the genetics studies will never become a part of your medical 
record. We will protect your confidentiality to the fullest extent. Blood samples for genetic 
studies will be identified in a way in order to maintain your confidentiality. 
Research study results will not be given to your family members, insurance companies, 
employers, or third parties without your written permission and approval of the Institutional 
Review Board at _________.  
 


 
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Additional Risks 
The CT scan of your heart is being done to answer research questions, not to examine you 
medically. This scan is not a substitute for one your doctor would order. If the radiologist thinks 
that there may be an abnormality in your scan, we will contact you and will help you get medical 
follow-up for the problem. If you have a primary care doctor, we can contact your doctor, with 
your permission, and help him or her get the right follow-up for you. It is possible that you could 
be unnecessarily worried if a problem were suspected, but not actually found. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS SUBSTUDY? 
 
If you take part in this substudy, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
• 
participating in REPRIEVE (A5332) only 
• 
not participating 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the U.S. Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally. 
 
People who may review your records include the AIDS Clinical Trials Group (ACTG), OHRP, 
(insert name of site) IRB/EC, government agencies such as the National Institutes of Health 
(NIH) and Food and Drug Administration (FDA), other local, US, and international regulatory 
entities, study staff, study monitors, the drug company supporting this study, and its designee. 
Having a Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 


 
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A description of this clinical trial will be available on www.ClinicalTrials.gov. This web site will 
not include information that can identify you. At most, the web site will include a summary of the 
results. You can search this Web site at any time. 
 
 
WHAT IF WE CAN NO LONGER REACH YOU DURING YOUR STUDY PARTICIPATION? 
 
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained at screening and updated at each visit. If you are unable to be reached 
through the alternate contacts we will attempt to obtain information about you from other 
sources such as family members, other designated contacts, or clinic records. The purpose of 
obtaining this information is to determine if you have died and the cause of death since last 
contact. 
 
 
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 be paid ________ per visit for participation in the substudy. (The team recommends 
compensation to participants of $25 at the entry and the month 24 visits. Sites will be 
reimbursed for the expense.) 
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. 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. 


 
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We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research participant, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB/EC) or other organization 
appropriate for the site 
• 
telephone number of above 
 
 
OTHER 
 
All other information that is contained in the main study REPRIEVE (A5332) consent that you 
signed also applies to this substudy consent. A copy of the signed main study consent will be 
provided for you as a reference at the time you consent to participate in the substudy.  
 
 


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


 
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APPENDIX IV: REPRIEVE OBJECTIVES TO DECIPHER SEX-SPECIFIC MECHANISMS OF 
CVD RISK AND RISK REDUCTION 
 
BACKGROUND 
 
HIV-infected individuals face a markedly increased risk of cardiovascular disease (CVD), even 
when viremia is suppressed by combined antiretroviral therapy (cART) [Freiberg 2013; Triant 
2007]. Mechanisms underlying HIV-associated CVD risk are incompletely understood [Zanni 
2014] and specific guidelines on cardioprotective care for this population are not available 
[Stone 2014]. Characterizing and reducing CVD risk among HIV-infected women represents a 
particular challenge. HIV-infected women are less likely than HIV-infected men to be offered 
preventive cardiac care in clinical practice [Willig 2008]. However, data suggest women with HIV 
are just as likely as their male counterparts to incur an MI [Triant 2007]. Indeed, a large-scale 
US epidemiologic study shows that among HIV-infected women, unadjusted rates of MI 
modestly exceed those among HIV-infected men [Triant 2007]. Moreover, the same study 
reveals a significantly higher adjusted relative risk of MI in HIV infected-women versus 
uninfected females (2.89) as compared with HIV-infected men versus uninfected males (1.4) 
[Triant 2007]. The proposed objectives aim to identify sex-specific mechanisms of CVD risk and 
risk reduction in relation to adjudicated clinical CVD events in HIV. Immune activation is 
increased in HIV-infected women (versus HIV-infected men) [Fitch 2013] and especially among 
those HIV-infected women who have undergone menopause [Looby 2015]. Moreover, among 
women with HIV, reduced ovarian reserve has been shown to relate to subclinical 
atherosclerotic plaque even after controlling for traditional CVD risk factors, including age 
[Looby 2015]. Building on these observations, our aims interrogate immune and hormonal 
pathways hypothesized to contribute to CVD risk in HIV-infected women across the reproductive 
aging spectrum. 
 
 
OBJECTIVES  
 
OBJECTIVE 1: To assess among HIV-infected individuals ages 40-75 sex-based differences in 
immune activation and statin-induced immunomodulation in relation to clinical CVD events. 
In order to achieve this objective, we will add to the REPRIEVE trial blood sample collection on 
female and male participants and sample processing for immune activation markers relevant to 
atherogenesis in HIV (beginning with monocyte activation markers including sCD14, and then 
exploring other immune activation markers). HYPOTHESES: Baseline relationships: A) Levels 
of immune activation markers will be higher in HIV-infected women versus men. B) High-level 
immune activation will relate to CVD events in HIV, and this association will be stronger in 
women versus men. Statin effects: C) Statins will decrease levels of immune activation markers 
to a greater extent in HIV-infected women versus men. D) CVD risk-reduction will be mediated 
in part through statin-induced immunomodulation, more so in HIV-infected women versus men. 
 
OBJECTIVE 2: To characterize among HIV-infected women ages 40-75 how menopause status 
and ovarian reserve relate to immune activation, statin-induced immunomodulation, and clinical 
CVD events. In order to achieve this objective, we will add to the REPRIEVE trial blood sample 
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hormone (AMH) and estradiol (E2). Coupling hormonal data with menstrual history, we will 
categorize women as pre-menopausal and post-menopausal. We will also define the subset of 
pre-menopausal women with reduced ovarian reserve. HYPOTHESES: Baseline relationships: 
A) Post-menopausal HIV-infected women will have higher levels of immune activation markers 
versus pre-menopausal HIV-infected women. B) Among both pre- and post-menopausal HIV-
infected women, reduced ovarian reserve (undetectable AMH) will relate to risk of first CVD 
event. Statin effects: C) Statins will decrease levels of immune activation markers to a greater 
extent in post-menopausal HIV-infected women versus pre-menopausal HIV-infected women. 
D) CVD risk-reduction will be mediated in part through statin-induced immunomodulation, more 
so in post-menopausal (vs. pre-menopausal) HIV-infected women. 
 
 
SIGNIFICANCE 
 
Overall, we will assess whether immune activation contributes uniquely to CVD risk among HIV- 
infected women across the reproductive aging spectrum and how statins may reduce CVD risk 
through effects on this pathway. Answers to these critical questions will influence the 
development of CVD prediction and prevention strategies tailored to the aging female HIV-
infected population worldwide. Maximizing our power to elucidate sex-specific CVD 
mechanisms in HIV, we will also design, implement, and evaluate the effectiveness of an 
evidence-based education/awareness recruitment campaign to enhance female enrollment in 
the REPRIEVE trial. Identification of innovative strategies to recruit women to an interventional 
clinical trial could have far-reaching practical implications for future trial-based, sex-specific 
research across disciplines. 
 
 
INTEGRATION OF OBJECTIVES INTO A5332  
 
In order to address the objectives above, the REPRIEVE trial protocol has been amended to 
permit for additional collection of fasting blood stored for assessment of biomarkers at entry, 1 
year, and at end of study. The end of study blood draw will facilitate future assessment of 
whether observed changes in immune markers at 1 year are sustained. Please see A5332 
protocol section 6.1, Schedule of Evaluations.  
 
 
STATISTICAL CONSIDERATIONS  
 
Overview Considerations 
 
Overall sample size assumptions: The projected sample size is 5446 persons, or approximately 
80% of the total REPRIEVE study sample.  
 
General analysis plans: As comparison groups to address the objectives listed below (eg, 
groups classified by sex for Objective 1 and by menopause/hormone status for Objective 2) will 
not have been assigned by randomization, the distributions of baseline characteristics will be 
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.adjusted models specified below. Baseline covariates anticipated to differ by sex (eg, race, 
hypertension, smoking, substance use, lipids, BMI) [Hatleberg 2014] will be carefully explored 
and considered, particularly when they are hypothesized to be prognostic for the outcome. 
Where treatment effect is included in the analysis plan below (eg, statin effect), this variable will 
use intent-to-treat formulation.  
 
General monitoring considerations: Safety of human participants participating in the objectives 
described will be monitored by the REPRIEVE DSMB as part of the REPRIEVE trial study 
monitoring plan. 
 
Outcome Definition, sample size justification, and analysis plans by objective/hypothesis 
 
Objective 1: To assess among HIV-infected individuals ages 40-75 sex-based differences in 
immune activation and statin-induced immunomodulation in relation to clinical CVD events.  
 
Hypothesis A) Levels of immune activation markers will be higher in HIV-infected women versus 
men. The outcome being tested in this sub-objective is baseline (pre-treatment) immune 
activation, as measured by the levels of each of select immune activation markers such as 
sCD14. A non-parametric alternative to t-test (eg, Mann-Whitney test) will compare the pre-
treatment distribution of each biomarker between groups assigned by sex. If 22% female 
enrollment is achieved, then the comparison group sample sizes to address this hypothesis will 
be 1198 women versus 4248 men (with no adjustments for losses as outcome assessed at 
baseline). Using these sample sizes and the standard deviations of select biomarkers [Fitch 
2013], and adjusting the significance level to 0.0167 by Bonferroni to account for the biomarkers 
being tested, there will be 90% power to detect sex differences of 214 ng/mL for sCD14. 
Covariate adjusted models performed as part of the analysis of this hypothesis will use 
multivariable regression (linear, with log transformation if indicated based on biomarker 
distribution).  
 
Hypothesis B) High-level immune activation will relate to CVD events in HIV, and this 
association will be stronger in women versus men. The primary outcome being tested in this 
sub-objective is the composite clinical outcome of MACE occurring at any time during follow-up. 
The secondary outcome being tested is the time from randomization to first MACE occurring 
any time during follow-up. High-level immune activation with respect to each tested biomarker 
will be classified by the observed highest quartile of the pre-treatment distributions. Fisher’s 
exact test will be used for testing the main effect of immune activation. Taking the sample size 
of 5446 from the overall sample size assumptions above, there is an expectation of 4084 in the 
low immune activation group and 1362 (highest quartile) in the high immune activation group. 
Assuming ~6% of the study sample will experience a MACE event (from control arm incidence 
estimate of 15/1000 person-years and statin effect hazard ratio of 0.70; see REPRIEVE protocol 
section 9.0 for more details), with sample sizes as above and a Bonferroni-adjusted significance 
level of 0.0167, there will be  90% statistical power to detect 5% MACE rate in the low immune 
activation group compared with 7.8% MACE rate in the high immune activation group (ie, 
absolute difference of 2.8% pts in MACE rate between groups). Assessing whether the 
association of baseline immune activation and MACE will be higher in women versus men 
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the outcome of MACE. To assess power for interaction effect, methods described in 
[VanderWeele 2012] will be used under the following assumptions: 4.9% of men with low 
immune activation will have a qualifying MACE outcome; the main effect odds ratios (OR) for 
sex and immune activation are each 2.1 (eg, 4.9% MACE in one group compared with 9.8% in 
the other); a multiplicative interaction OR of 1.33; association between sex and high/low 
immune activation of 1.33; and 22% female enrollment. Based on these assumptions and using 
a significance level adjusted to 0.0167, the statistical power for additive interaction effect (eg, as 
excess in relative risk attributed to interaction) is estimated as 80%. Testing for interaction 
effects and covariate adjusted models will use multivariable logistic regression (for the primary 
outcome) and Cox proportional hazards regression (for the secondary, time- to-event 
formulation outcome). 
 
Hypothesis C) Statins will decrease levels of immune activation markers to a greater extent in 
HIV-infected women versus men. The outcomes being tested in this sub-objective are the 
changes from pre-treatment to 1 year of follow-up of the immune activation markers tested. For 
this hypothesis, statistical interactions of sex and treatment effects will be tested using linear 
(log transformed as indicated) models, which can also incorporate covariate adjustment. With 
estimates of 5% per year loss to follow-up, the effective sample size for this sub-aim is 5174 
persons. For the biomarker sCD14, standard deviation of the outcome measure for this sub-aim 
is estimated assuming standard deviation of 1-year measurements same as baseline and intra-
person correlation of 0.65. Further, assuming under additivity a 125 ng/mL effect of sex on 
sCD14 differences at 1 year and the same effect of statins on sCD14 differences at 1 year, 
there will be 80% power to detect an additive interaction effect of 220 ng/mL. 
 
Hypothesis D) CVD risk-reduction will be mediated in part through statin-induced 
immunomodulation, more so in HIV-infected women versus men. For this sub-objective, 
structural equation modeling (SEM) will be employed to investigate the pathways and 
mechanisms leading to this clinical outcome while incorporating other prognostic factors. 
Specifically, the SEM model will apply an analysis of covariance structure incorporating multiple 
biomarker data into a single model for CVD clinical outcome. Furthermore, the model will test 
the covariates and directionality of effects with CVD outcome, and include temporal ordering. 
For this sub-objective, some of these pathways include the following: direct effect of sex on 
CVD, direct effect of sex on immunomodulation, direct effect of immunomodulation on CVD, sex 
effect on CVD through immunomodulation, direct effect of statin on CVD and on 
immunomodulation, and sex effect on CVD through statin effect. 
 
Objective 2: To characterize among HIV-infected women ages 40-75 how menopause status 
and ovarian reserve relate to immune activation, statin-induced immunomodulation, and clinical 
CVD events.  
 
The comparison groups will be formulated by combining hormonal data with data on menstrual 
history in order to categorize women as pre-menopausal and post-menopausal. Comparison 
groups will also define the subset of pre-menopausal women with reduced ovarian reserve.  
 
Hypothesis A) Post-menopausal HIV-infected women will have higher levels of immune 
activation markers versus pre-menopausal HIV-infected women. As in Objective 1A, the 


 
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outcome being tested in this sub-objective is baseline (pre-treatment) immune activation, as 
measured by levels of certain biomarkers such as sCD14. A non-parametric alternative to t-test 
(eg, Mann-Whitney test) will compare the pre-treatment distribution of each biomarker within 
women between groups assigned by menopause status. As per Objective 1A, 22% female 
enrollment is assumed. Further assuming a 1:1 ratio between female comparison groups, 
sample sizes for the pre-menopausal and post-menopausal groups will be 599 each. Using 
these sample sizes, standard deviations for biomarker as in Objective 1A, and Bonferroni-
adjusting the significance level to 0.0167, there will be 90% power to detect differences between 
the pre- and post-menopausal groups of 378 ng/mL for sCD14. Alternatively, if the ratio 
between female comparison groups is 1:2, sample sizes for the pre-menopausal and post-
menopausal group will be 399 and 799, respectively. Under this contingency, the minimal 
detectable differences between female comparison groups for 90% power are only slightly 
higher at 401 ng/mL.  
 
Hypothesis B) Among both pre- and post-menopausal HIV-infected women, reduced ovarian 
reserve (undetectable AMH) will relate to risk of first CVD event. As in Objective 1B: The 
primary outcome being tested in this sub-objective is the same composite clinical outcome of 
MACE occurring any time during follow-up. The secondary outcome being tested is the time 
from randomization to first MACE. Assuming 22% female enrollment in REPRIEVE and that a 
negligible proportion of the pre-menopausal women have reduced ovarian reserve such that the 
ratio of women with adequate versus reduced ovarian reserve is 1:1, then sample sizes for each 
group will be 599. As per Objective 1B, it is assumed that the overall rate of MACE among 
women will be 7%. Applying this event rate with the sample sizes above and using Fisher’s 
exact test for analysis, there will be 90% power (at 5% significance) to show a difference of 5% 
points between groups (namely, 4.5% MACE in one group and 9.4% MACE in the other.) 
Alternatively, if a significant proportion of the pre-menopausal women have reduced ovarian 
reserve such that the ratio of women with adequate versus reduced ovarian reserve is 1:4, then 
sample sizes will be 299 for the adequate ovarian reserve group and 898 for the reduced 
ovarian reserve group. In this scenario, there will be 90% power to show a difference of 5.7% 
between groups. Covariate adjusted models for this hypothesis will use multivariable logistic 
regression for the primary outcome formulation, and Cox proportional hazards modeling for the 
time-to-initial event formulation.  
 
Hypothesis C) Statins will decrease levels of immune activation markers to a greater extent in 
post-menopausal HIV-infected women versus pre-menopausal HIV-infected women. The 
outcomes being tested in this sub-objective are the changes from pre-treatment to 1 year of 
follow-up of each of the immune activation markers tested parallel to Objective 1C. Interactions 
by menopause status and treatment will be tested using linear (log transformed as indicated) 
models, which can also incorporate covariate adjustment. Assuming a 22% female enrollment 
and a 5% per year loss to follow up, the effective sample size for this analysis is 1138. 
Assuming a 1:1 ratio of female comparison groups, the sample sizes will be 569 for the pre- and 
post-menopausal groups. Using analysis assumptions from Objective 1C, and under additivity 
assuming a 375 ng/mL effect of menopause on sCD14 differences at 1 year as well as a similar 
effect of statins on sCD14 differences at 1 year, there will be 80% power to detect an additive 
interaction of menopause and statin of 390 ng/mL.  
 


 
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Hypothesis D) CVD risk-reduction will be mediated in part through statin-induced 
immunomodulation, more so in post-menopausal (vs. pre-menopausal) HIV-infected women. 
Parallel to Objective 1D, the SEM model will be used to incorporate all biomarker data into a 
single model for CVD clinical outcome, and then to test the covariate pathways, including 
directionality and temporal ordering. For this sub-objective, some of these pathways to be tested 
include the following: direct effect of menopause status on CVD, direct effect of menopause 
status on immunomodulation, direct effect of immunomodulation on CVD, menopause effect on 
CVD through immunomodulation, direct effect of statin on CVD and on immunomodulation, and 
menopause effect on CVD through statin effect. 
 
 
 


 
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REFERENCES 
 
Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and 
immune activation in HIV-infected women. J Infect Dis 2013;208(11):1737-46. 
Freiberg MS, Chang CCH, Kuller LH, et al. HIV infection and the risk of acute myocardial 
infarction. JAMA Intern Med 2013;173(8):614-22. 
Hatleberg CI, Ryom L, El-Sadr W, et al. Gender differences in HIV-positive persons in use of 
cardiovascular disease-related interventions: D:A:D study. J Int AIDS Soc 2014;17(4 Suppl 
3):19516. 
Looby SE, Fitch KV, Srinivasa S, et al. Reduced ovarian reserve relates to monocyte 
activation and subclinical coronary atherosclerotic plaque in women with HIV. AIDS 2015 
Published ahead of print. doi: 10.1097/QAD.0000000000000902. 
Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the 
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a 
report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889-2934. 
Triant VA, Hang Lee, Hadigan C, Grinspoon SK, et al. Increased acute myocardial infarction 
rates and cardiovascular risk factors among patients with human immunodeficiency virus 
disease. J Clin Endocrinol Metab 2007;92(7):2506-12. 
VanderWeele TJ. Sample size and power calculations for additive interactions. Epidemiol 
Method 2012;1(1):159-88. 
Willig JH, Jackson DA, Westfall AO, et al. Clinical inertia in the management of low-density 
lipoprotein abnormalities in an HIV clinic. Clin Infect Dis 2008;46(8):1315-18. 
Zanni MV, Schouten J, Grinspoon SK, Reiss P. Risk of coronary heart disease in patients 
with HIV infection. Nat Rev Cardiol 2014;11(12):728-41. 
 


 
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APPENDIX V: REPRIEVE ANCILLARY STUDY: EFFECT OF PITAVASTATIN ON KIDNEY 
FUNCTION IN HIV-INFECTED PERSONS 
 
BACKGROUND 
 
With advances in HIV therapy, the incidence of HIV-associated nephropathy and subsequent 
end-stage renal disease (ESRD) have declined substantially [Lucas 2014; Lucas 2008; SMART 
2006]. Still, 30-40% of HIV-infected persons are estimated to have Stage 1 or greater chronic 
kidney disease (CKD) [Gupta 2004; Overton 2012; Szczech 2004], and HIV infection remains 
an established risk factor for CKD, even after adjusting for traditional risk factors [Althoff 2015; 
Coresh 2003]. Black race, diabetes mellitus (DM) and hypertension (HTN) are common among 
HIV-infected persons and associated with an increased risk for CKD [Gathogo 2014; Jotwani 
2012]. In fact, the effect of HIV may be additive to traditional risk factors like diabetes [Medapalli 
2012].  
 
This increased risk of CKD among HIV-infected individuals is likely mediated by inflammation 
[Mallipattu 2013]. HIV infection induces a paradoxical state of both immune suppression (low 
CD4+ T-cell count with increased risk of opportunistic pathogens) and immune activation 
[Deeks 2011]. The depletion of CD4+ T cells in the gut-associated lymphoid tissue facilitates 
excess microbial translocation and ensuing activation of both the innate and adaptive arms of 
the immune system [Brenchley 2006]. Such chronic immune activation translates into a well-
characterized exhausted T-cell phenotype and a persistent pro-inflammatory milieu with 
elevated inflammatory cytokines and cellular immune activation markers, as well as markers of 
oxidative stress [Dolan 2005; Ross 2008]. Identifying adjunctive therapies that target these 
inflammatory pathways has the potential to prevent CKD in HIV-infected individuals. 
 
In certain risk groups in the general population (DM, HTN, and pre-existing CVD), post-hoc 
analyses of randomized controlled trials (RCTs) have suggested that HMG-CoA reductase 
inhibitors (ie, statins) have a beneficial effect on the kidney. For example, in an RCT of 
atorvastatin for secondary prevention of strokes, eGFR improved with atorvastatin but not 
placebo, independent of baseline kidney function [Amarenco 2014]. These findings corroborate 
an analysis from the Collaborative Atorvastatin Diabetes Study, in which persons with diabetes 
and normal LDL-cholesterol were randomized to atorvastatin or placebo. Participants assigned 
to statin therapy demonstrated statistically significant improvement in eGFR that was most 
pronounced among persons with pre-existing microalbuminuria [Colhoun 2009]. These 
beneficial effects of statins have been shown to be most robust in persons with higher 
inflammatory biomarkers at baseline [Tonelli 2005]. These data suggest that the kidney 
protective effect of statins may be mediated through anti-inflammatory pathways, highly relevant 
in the setting of HIV infection. A recent Cochrane review of statins administered in the setting of 
CKD concluded that statins have uncertain effects on progressive CKD and additional 
prospective trials are warranted, particularly among persons with diabetes and other high-risk 
populations [Palmer 2014]. These post-hoc analyses from HIV negative individuals indicate that 
equipoise exists as to whether statins protect kidney function, particularly in populations with 
increased systemic inflammation, such as seen with HIV infection. Given the established 
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interventions that prevent eGFR decline and albuminuria may also have important implications 
for CVD and all-cause mortality. 
OBJECTIVES  
 
OBJECTIVE 1: To evaluate the effects of pitavastatin on clinically relevant parameters of kidney 
function among HIV-infected individuals on ART.  
 
OBJECTIVE 1A: To determine whether pitavastatin is associated with a lower incidence of 
clinically relevant eGFR decline in HIV-infected persons.  
 
OBJECTIVE 1B: To determine whether pitavastatin is associated with a lower prevalence of 
albuminuria.  
 
HYPOTHESES: 1. We hypothesize that randomization to pitavastatin versus placebo will be 
associated with a lower incidence of clinically relevant eGFR decline, defined as ≥30% decline 
from baseline, a Food and Drug Administration/National Kidney Foundation (FDA/NKA) 
recommended surrogate endpoint for CKD [Inker 2014]. 2. We hypothesize that randomization 
to pitavastatin versus placebo will be associated with a lower prevalence of albuminuria, defined 
as urine albumin/creatinine ratio (ACR) >30 mg/g. 
 
OBJECTIVE 2: To assess whether the effect of pitavastatin 4 mg/daily on eGFR and 
albuminuria is stronger in high-risk groups defined by older age, black race, hypertension, lower 
CD4 cell counts, or the use of tenofovir disoproxil fumarate (TDF)-containing regimens.  
 
HYPOTHESIS: We hypothesize the kidney protective effect of pitavastatin will be stronger in 
high-risk groups.  
 
OBJECTIVE 3: To determine whether the effect of pitavastatin on kidney function is mediated 
through anti-inflammatory effects.  
 
HYPOTHESIS: We hypothesize that effects of pitavastatin on eGFR and albuminuria will be 
mediated by systemic and vascular inflammation and oxidative stress, as measured by 
circulating levels of key inflammatory biomarkers. 
 
 
SIGNIFICANCE 
 
By adding collection of urine and blood longitudinally in at least 2500 participants, this ancillary 
study will definitively assess whether pitavastatin therapy will prevent significant decline in 
kidney function and the development of albuminuria (ACR >30 mg/g). This sample will further 
provide the opportunity to evaluate the effect of pitavastatin in sub-groups of HIV-infected 
participants for whom the risk of CKD has been demonstrated to be higher, including persons of 
older age, black race, hypertension, lower CD4 T-cell counts, and on tenofovir-containing 
regimens. Finally, the mechanisms of action will be assessed to determine whether the 
protective effect of pitavastatin is mediated through pathways involving inflammation and 
oxidative stress. Ultimately, the findings of this study will provide longitudinal data on the 


 
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epidemiology of CKD in the setting of HIV infection, provide mechanistic insights into whether 
statins prevent CKD by modulating inflammation and oxidative stress, and potentially change 
guidelines for the prevention of CKD in this at-risk population. 
INTEGRATION OF OBJECTIVES INTO A5332  
 
This ancillary study requires only modest changes to the procedures of the parent study as it will 
leverage the existing study infrastructure, data collection, and trial visits to allow for additional 
stored blood and urine collection for a longitudinal assessment of relevant kidney function 
parameters. As CKD and albuminuria are independent risk factors for ASCVD, this ancillary 
study will provide additional insight into the primary focus of the parent trial. Furthermore, only 
modest changes to the parent protocol and informed consent are required to facilitate these 
evaluations, including collection of stored blood and urine at entry and years 1, 2, and 4 of study 
follow up. 
 
STATISTICAL CONSIDERATIONS  
 
Overview Considerations  
 
Overall sample size assumptions: This ancillary study is projected to include at least 2500 
persons, or approximately 38% of the total REPRIEVE study sample. The ancillary study will 
only recruit participants from the ACTG study sites. 
 
General analysis plans: A baseline assessment of kidney function will be performed to assess 
baseline measures of kidney function and to assess clinical parameters associated with lower 
eGFR and albuminuria at baseline. For Objective 1, an intention-to-treat approach will be used 
based on randomization to pitavastatin or placebo for pitavastatin in the parent trial. For 
Objective 2, the effect of pitavastatin will be assessed in high-risk subgroups (HTN, age, race, 
tenofovir use) as outlined below. Objective 3 will utilize a case-control design to determine 
relevant mechanistic pathways through which the effects of pitavastatin are mediated.  
 
General monitoring considerations: Safety of human participants participating in the kidney 
ancillary study will be monitored by the REPRIEVE DSMB as part of the REPRIEVE trial study 
monitoring plan. 
 
OBJECTIVE 1: To evaluate the effects of pitavastatin on clinically relevant parameters of kidney 
function among HIV-infected individuals on ART. 
 
Endpoints 
For the primary analysis, we will use accepted measures of decreased eGFR. We have 
selected 30% decline in eGFR or ESRD for our primary outcome based on recommendations 
from a joint NKF-FDA workshop, which concluded that this should be considered as an 
alternative CKD endpoint for clinical trials [Inker 2014]. Specifically, in a pooled cohort of 
850,096 individuals with eGFR ≥60 mL/min/1.73 m2, a decline in eGFR ≥30% over 3 years of 
follow-up was associated with a hazard ratio of 7.0 for developing ESRD over the following 
decade. In secondary analysis, we will consider the more stringent endpoints of 40% decline in 
eGFR and development of eGFR <60 mL/min/1.73m2. We will use the CKD Epidemiology 


 
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Collaboration (CKD-EPI) creatinine equation to estimate GFR, as it has been demonstrated to 
be more accurate than other creatinine-based formulas in both the general population and in  
HIV-infected cohorts [Matsushita 2010; Levey 2015; Inker 2012; Gagneux-Brunon 2012; Bhasin 
2013]. The CKD-EPI creatinine equation had statistically significantly higher accuracy and less 
bias than the cystatin C equation in HIV-infected persons [Inker 2012].  
 
Albuminuria will be quantified by ACR calculated as urinary albumin in mg/dL divided by urinary 
creatinine in g/dL. Albuminuria is an easily assessed marker of kidney damage, which may 
precede eGFR decline, and is strongly linked to adverse clinical outcomes [Gerstein 2001]. 
Even at levels of albuminuria >30 mg/g, persons are at increased risk for CVD events and all-
cause mortality [Gerstein 2001; Wyatt 2010; Wyatt 2011]. We will use the ACR as a measure of 
albuminuria, as it is widely available in clinical practice and recommended by the IDSA Clinical 
Practice Guideline for CKD in HIV-Infected persons [Lucas 2014]. The ACR from a random 
urine sample is simple to obtain, correlates well with data from 24-hour urine collections, but is 
more practical and less prone to error than a 24-hour collection [Eknoyan 2003].  
 
Data Analysis Plan  
Aim 1A: Determine whether pitavastatin 4mg daily is associated with a lower incidence of >30% 
eGFR decline in HIV-infected persons. We will use an intention-to-treat approach for Aim 1. 
Descriptive statistics for participant characteristics will be presented by randomization 
assignment. The percent change in eGFR from baseline at study visits at 1, 2, and 4 years post-
randomization, separately, will be calculated as follow-up eGFR minus baseline eGFR divided 
by baseline eGFR. For our primary analysis, the CKD endpoint will be a decline in eGFR ≥30% 
from the baseline visit or incident ESRD. The percentage of participants randomized to 
pitavastatin and, separately, placebo having a decline in eGFR ≥30% will be calculated at each 
follow-up visit. Additionally, the cumulative proportion of participants with ≥30% decline in eGFR 
throughout follow-up will be calculated by randomization arm and differences in these 
percentages of participants reaching the endpoint during follow-up will be compared using a chi-
square test. We will assess these differences using logistic regression adjusted for key risk 
covariates as a confirmatory analysis. Additionally, we will evaluate time-to-event using interval 
censored regression models. Interval censored regression models are proposed as we do not 
know the exact date an individual reaches the CKD endpoint - only that it occurred between two 
visits. 
 
Sample Size 
We will enroll a sample size of at least 2500 participants. This sample size will provide adequate 
statistical power to achieve our aims. We anticipate an annual event rate of 2.5% based on 
previous reported results [Lucas 2007; Lucas 2008]. Therefore, over 4 years, we anticipate 10% 
of participants will meet our primary outcome of eGFR decline. As we do not know the exact 
incidence of eGFR decline, we provide the minimal detectable difference based on this event 
rate and also for 8% and 15% incidence of eGFR decline (ie, annual event rates of 2% and 
3.75%, respectively). Based on sample size of 2500 participants (50% randomized to 
pitavastatin and 50% placebo), a two-tailed alpha error of 5% and assuming 5% of participants 
will be lost during follow-up, we will have 90% statistical power to detect clinically relevant 
differences in the cumulative incidence of eGFR decline across randomization arms. For 
example, if 10% of participants randomized to placebo develop our primary endpoint over the 4-


 
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year follow-up period, we will have 90% power to detect an absolute reduction in incidence of 
3.6% associated with pitavastatin (10% in placebo vs. 6.4% in pitavastatin arm; Table 1). Given 
that albuminuria is anticipated to be a more frequent endpoint than ≥30% eGFR decline, we will 
have 90% power to detect clinically relevant differences in the percentage of participants 
developing this outcome measure. Previous RCTs of pitavastatin in individuals with diabetes 
and persons with hyperlipidemia demonstrated a 52% and 67% reduction in measures of 
albuminuria, respectively [Nakamura 2005; Yagi 2011]. Although we expect to see at least a 
50% reduction in albuminuria in the pitavastatin group (from 15% to 7.5%) and a modest 
increase in prevalence of albuminuria in the placebo group [Szczech 2010], we will be powered 
to detect smaller differences. 
 
Table 1. Minimal detectable difference in incidence of CKD 
endpoint in REPRIEVE participants randomized to pitavastatin vs 
placebo. 
 
Proportion of control population 
developing CKD 
Aim 1A eGFR decline 
8% 
10% 
15% 
90% statistical power 
3.2% 
3.6% 
4.3% 
80% statistical power 
2.6% 
3.2% 
3.5% 
 
Proportion of control population with 
albuminuria 
Aim 1B % with 
albuminuria 
15% 
20% 
25% 
90% statistical power 
4.3% 
4.9% 
5.4% 
80% statistical power 
3.8% 
4.3% 
4.7% 
 
OBJECTIVE 2: Assess whether the effect of pitavastatin on CKD is stronger in high-risk groups 
defined by older age, black race, hypertension, lower CD4 cell counts, or the use of TDF-
containing regimens. We will divide the cohort based on the median age to evaluate differences 
between the groups above and below the median age. Similar dichotomous approaches will be 
taken for black race, hypertension (systolic blood pressure ≥140 mmHg, diastolic blood 
pressure ≥90 mmHg or antihypertensive medication use), and TDF-containing regimens. Within 
each sub-group studied, participant characteristics will be calculated by randomization 
assignment (pitavastatin or placebo). The percentage of participants developing ≥30% eGFR 
decline and separately, with ACR >30 mg/g during follow-up will be calculated for participants 
randomized to pitavastatin and, separately, their counterparts randomized to placebo. The 
statistical significance of differences within sub-groups will be calculated using interval censored 
regression models and chi-square tests as described in Aim 1 above. We will use multiplicative 
interaction terms (eg, black race * pitavastatin) to assess differences in the effect of pitavastatin 
on CKD across sub-groups. We will evaluate CD4 count as a continuous variable to determine if 
there is a threshold below which statin therapy has greater benefit for kidney function. We will 
model the interaction between pitavastatin versus placebo and CD4 count as a continuous 
variable with interval censored regression models and logistic regression for the cumulative 
incidence [Howard 2011].   
 


 
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OBJECTIVE 3: To determine whether the effect of pitavastatin on kidney function is mediated 
through anti-inflammatory effects. This analysis will follow the traditional case-cohort design. 
The case-cohort design combines the advantages of cohort studies and case-control analyses. 
In a case-cohort design, the comparison group is not defined on the basis of the “absence” of 
the outcome (≥30% eGFR decline or ACR >30 mg/g; as in a traditional “case-control” study 
design). This is advantageous for the following reasons: 1) the strategy allows for studying 
multiple endpoints using the same "control" group (ie, the sub-cohort); 2) it bypasses a certain 
degree of arbitrariness unavoidable when attempting to define the comparison group intended 
to include only “non-cases” (ie, the inclusion of “false negatives”); 3) the strategy allows a 
random sample of the cohort for valid cross-sectional comparisons (eg, the association between 
baseline ACR and biomarkers of CKD and systemic and vascular inflammation and oxidative 
stress in the cohort random sample); and 4) it allows calculation of hazard ratios using survival 
models rather than relying on logistic regression and calculation of odds ratios. 
 
The distribution of biomarkers at baseline and during follow-up will be graphed. For biomarkers 
that are not normally distributed, an appropriate transformation will be performed (eg, log 
transformation). Mean baseline and change in the levels of these biomarkers will be calculated 
for participants who experience a ≥30% decline in eGFR and the sub-cohort. Differences will be 
calculated using ANOVA with weighting to account for the probability of selection into the sub-
cohort. Next, we will calculate the association between biomarkers of CKD, systemic and 
vascular inflammation and oxidative stress with CKD progression using a pseudo-likelihood, 
weighted Cox regression model. Using the approach of Barlow and Prentice for case-cohort 
analysis, we will calculate the hazard ratio for a ≥30% decline in eGFR associated with each 
biomarker separately. Initial models will control for age, race, and sex. Subsequent models will 
include further adjustment for systolic blood pressure, total and HDL-cholesterol, cigarette 
smoking, waist circumference, and baseline eGFR and ACR. A final model will include further 
adjustment for log10 HIV RNA load and CD4+ T-cell counts.  
 
Next, we will conduct a mediation analysis to test whether pitavastatin lowers the incidence of 
≥30% eGFR decline by reductions in biomarkers assessed. To address mediation that 
pitavastatin will reduce the incidence of eGFR decline through improvements in systemic and 
vascular inflammation and oxidative stress, we will apply the regression technique described by 
Judd and Kenny and elaborated by MacKinnon [Judd 1981; MacKinnon 1994]. The technique, 
will account for each biomarker separately and for all biomarkers simultaneously (mediators) 
using two regression equations (Table 2). Y is the outcome result (eg, eGFR decline ≥30%), Xp 
is randomization to pitavastatin versus placebo and Xi represents the k biomarkers, our 
purported mediators. The total effect of pitavastatin on the outcome (measured by the 
coefficient, ) is the sum of direct effect () of treatment and the mediated, or indirect, effects. 
The assessment of the amount of change in these biomarkers mediating the effect of 
pitavastatin on eGFR decline will be addressed by considering two multivariable regression 
models (see Table 2). First, a regression model that estimates the decreased risk of a ≥30% 
eGFR decline with pitavastatin without mediating risk factors but considering other risk factors 
(eg, age, race, sex, hypertension) and a second Cox regression model that further makes 
adjustment for the mediating risk factor (ie, biomarkers of inflammation and oxidative stress). 
For these analyses, the parameter of interest (ie, log hazard ratio) is not the impact of 
pitavastatin on outcomes, but rather the difference in the estimated impact of pitavastatin 


 
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between the two models ( - ), which serves as a direct measure of the degree to which the 
effect of pitavastatin is due to improvements in these biomarkers. Whether the biomarkers 
“significantly” mediate the benefits of pitavastatin can be addressed by creating empirical 
confidence intervals around the change in its coefficient. Confidence interval of the change in 
the coefficient associated with the disparity will be calculated using bootstrap methods. 
 
 
 
 
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chronic kidney disease in HIV-infected adults: data from the Veterans Aging Cohort Study. J 
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Nakamura T, Sugaya T, Kawagoe Y, Ueda Y, Osada S, Koide H. Effect of pitavastatin on 
urinary liver-type fatty acid-binding protein levels in patients with early diabetic nephropathy. 
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Palmer SC, Navaneethan SC, Craig JC, et al. HMG CoA reductase inhibitors (statins) for 
people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 
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Ross AC, Armentrout R, O’Riordan MA, et al. Endothelial activation markers are linked to 
HIV status and are independent of antiretroviral therapy and lipoatrophy. J Acquir Immune 
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Szczech LA, Hoover DR, Feldman JG, et al. Association between renal disease and 
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Szczech LA, Menezes P, Quinlivan EB, van der Horst C, Bartlett JA, Svetkey L. 
Microalbuminuria predicts overt proteinuria among patients with HIV-infection. HIV Med 
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Wyatt CM, Hoover Dr, Shi Q, et al. Microalbuminuria is associated with all-cause and AIDS 
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Wyatt CM, Hoover Dr, Shi Q, et al. Pre-existing albuminuria predicts AIDS and non-AIDS 
mortality in women initiating antiretroviral therapy. Antivir Ther 2011;16(4):591-6.  
Yagi S, Akaike M, Aihara KI, et al. Effect of low-dose (1 mg/day) pitavastatin on left 
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SAP_005.pdf: 
Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of 
REPRIEVE (A5333S) 
October 4, 2023 (Version 1.1) 
Page 1 of 2 
Effects of Pitavastatin on Coronary Artery Disease and 
Inflammatory Biomarkers: Mechanistic Substudy of 
REPRIEVE (A5333S) 
CBAR Author: A5333S Study Statistician 
This is REPRIEVE (A5333S) Primary SAP Version 1.1 with names of authors and 
investigators removed. Other redactions for public release are as indicated 
throughout the document.
1 Background 
A5333s is an optional mechanistic substudy of REPRIEVE (A5332). Approximately 800 people with HIV 
(PWH) who are enrolled in REPRIEVE (A5332) were targeted for Mechanistic Substudy of REPRIEVE 
(A5333s) enrollment.  
The overarching aim of the Mechanistic Substudy of REPRIEVE (A5333s) is to better understand the 
modulation of critical features of coronary plaque morphology with statin therapy, including the 
progression of noncalcified coronary atherosclerotic plaque (NCP) volume in HIV and the biological 
factors mediating these effects during statin treatment in HIV. The Substudy will determine potential statin 
effects to halt progression of non-calcified atherosclerotic plaque and to stabilize morphologic features of 
plaque vulnerability. Moreover, the study will identify biological factors mediating these changes – be it 
lipid parameters, such as LDL cholesterol, or markers of inflammation and immune activation. Finally, the 
study will evaluate whether presence and morphology of subclinical atherosclerotic plaque at baseline 
relates to CVD events independently of traditional CVD risk factors and markers of HIV-specific immune 
activation. 
This is the Primary Statistical Analysis Plan for the Mechanistic Substudy of REPRIEVE. It expands on 
details of the statistical analysis plan that were defined in Appendix II of the REPRIEVE (A5332) protocol 
document. Major changes from the details defined in the protocol are outlined in the version history table 
below. An overview of the Substudy design is provided below; details of the substudy sample size 
considerations are in Appendix I, copied verbatim from the protocol. 
In preparation for public release of the document with publication of the data, preliminary substudy data 
and published work from other groups that were used as sample tables have been redacted. 
Version History 
Version 
Changes Made 
Date Finalized 
(Protocol) 
Original Version (Version 2.0) 
Dec 19, 2014 
1.0 
Clarification that primary outcomes are related to noncalcified plaque; 
additional secondary plaque outcomes added.  
HIV-1 RNA and CD4 moved from secondary outcomes to risk factors. 
HgA1C removed throughout (no longer being tested). 
Mar 20, 2023 
1.1 
For Published release of the SAP … 
Section 7: Sample tables of published work from other groups redacted. 
Appendix II: Draft consort based on early preliminary data removed. 
October 4, 2023 


Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of 
REPRIEVE (A5333S) 
October 4, 2023 (Version 1.1) 
Page 2 of 3 
1.1 A5333S Design Overview 
Enrollment into A5333s occurred concurrently with enrollment and randomization into REPRIEVE 
(A5332) at select US ACTG sites participating in REPRIEVE (A5332). To ensure balance in treatment 
assignment in the Substudy, randomization in REPRIEVE (A5332) was stratified by anticipated Substudy 
participation. 
Substudy participants were followed for 2 years with serial coronary computed tomography angiography 
(CCTA) performed at study entry and 2 years. Fasting blood samples for assessment of lipids and select 
soluble biomarkers were drawn at entry, month 4, and year 2; PBMCs for assessment of cellular markers 
of immune function were drawn at entry and year 2. The Substudy also included a 2-year assessment of 
REAP (diet and physical activity) and DASI (physical function), as well as quality of life assessment using 
the SF-36 at entry and year 2. 
Entry blood draws and CCTA were scheduled to occur within 14 days after randomization and prior to the 
start of randomized treatment. Month 4 evaluations were to be performed ± 21 days and year 2 
evaluations were to be performed ±28 days. In light of scheduling concerns and to maximize the 
collection of follow-up CT scans, the window for year 2 data collection was extended to up to 30 months 
after the entry CT. 
1.2 A5333S Hypotheses 
1.2.1 
Primary Hypothesis 
Statin therapy will reduce progression of noncalcified coronary atherosclerotic plaque (NCP) volume over 
two years as measured by CCTA, as compared with placebo in HIV-infected persons at low to moderate 
traditional ASCVD risk.  
1.2.2 
Secondary Hypotheses 
•
Decreases in LDL cholesterol levels associated with statin therapy will predict improvement in NCP
burden and/or plaque vulnerability features.
•
Statin therapy will reduce indices of general inflammation, coagulation, monocyte activation, and
arterial inflammation.
•
Statin therapy will reduce levels of pro-inflammatory monocyte populations.
•
Statin therapy will reduce levels of T-cell activation and exhaustion.
•
Changes in levels of immune activation and inflammatory markers will be associated with changes in
morphology and composition of NCP.
•
Statin therapy will not have a clinically significant effect on glucose and insulin resistance.
1.3 A5333S Timeline 
•
The Substudy opened to enrollment on April 14, 2015; first enrollment occurred on May 6, 2015.
•
Substudy enrollment closed on February 6, 2018.
•
A memo was sent to Substudy sites on March 12, 2020, requesting completion of all follow-up CT
scans by June 1, 2020. The Substudy did not formally close to follow-up at this time, pending a
possible extension and additional follow-up CT scan.


Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of 
REPRIEVE (A5333S) 
 
 
 
October 4, 2023 (Version 1.1) 
 
 
Page 3 of 4 
 
Table of Contents 
1 
BACKGROUND ................................................................................................................................................. 1 
Version History ........................................................................................................................................ 1 
1.1 
A5333S Design Overview ........................................................................................................... 2 
1.2 
A5333S Hypotheses .................................................................................................................... 2 
1.2.1 
Primary Hypothesis ................................................................................................................... 2 
1.2.2 
Secondary Hypotheses ............................................................................................................. 2 
1.3 
A5333S Timeline .......................................................................................................................... 2 
TABLE OF CONTENTS ........................................................................................................................................... 3 
2 
OBJECTIVES AND ESTIMANDS ................................................................................................................... 5 
2.1 
Primary Objective ........................................................................................................................ 5 
2.2 
Secondary Objectives ................................................................................................................. 5 
3 
OUTCOME MEASURES ................................................................................................................................... 6 
3.1 
Analysis Windows for Evaluations ........................................................................................... 6 
3.2 
Primary, Secondary, and Associated Supportive Outcome Measures ................................. 6 
3.2.1 
Change NCP volume over 2 years (Primary) ............................................................................ 6 
3.2.2 
Progression of NCP over 2 years (Primary) .............................................................................. 6 
3.2.3 
NCP on the 2 year CT (supportive) ........................................................................................... 6 
3.2.4 
NCP volume at 2 years (supportive) ......................................................................................... 7 
3.2.5 
Total plaque volume .................................................................................................................. 7 
3.2.6 
Change in relative composition of coronary plaque .................................................................. 7 
3.3 
Exploratory Plaque Outcomes ................................................................................................... 7 
3.3.1 
Number of segments with plaque .............................................................................................. 7 
3.3.2 
Number of segments with noncalcified portion ......................................................................... 7 
3.3.3 
Presence of vulnerable plaque features ................................................................................... 7 
3.3.4 
Alternative definition of noncalcified plaque volume, using a threshold of <130 HU ................ 7 
3.3.5 
Low attenuation plaque volume (<30 HU)................................................................................. 7 
3.3.6 
Stenosis ..................................................................................................................................... 8 
3.3.7 
Progression of NCP over 2 years .............................................................................................. 8 
3.3.8 
Coronary artery calcium (CAC), Leaman, and Segment Involvement (SIS) scores ................. 8 
3.4 
Markers of Immune Function ..................................................................................................... 8 
3.5 
Markers of Glucose Homeostasis ............................................................................................. 8 
3.6 
Descriptive Outcomes ................................................................................................................ 9 
3.6.1 
Time to the first major cardiovascular event ............................................................................. 9 
3.6.2 
Fasting lipid fractions ................................................................................................................ 9 
4 
ANALYSIS SETS AND HANDLING OF MISSING DATA .......................................................................... 9 
4.1 
Primary (Intent-to-treat) .............................................................................................................. 9 
4.2 
Per Protocol (Treated) ................................................................................................................ 9 
5 
ADMINISTRATIVE DETAILS ........................................................................................................................ 9 
5.1 
Participant Enrollment ................................................................................................................ 9 
5.2 
Participant Study and Treatment Disposition ........................................................................ 10 
5.3 
CT Scan Availability .................................................................................................................. 10 
5.4 
Consort ....................................................................................................................................... 11 
5.5 
Biomarker Availability .............................................................................................................. 11 


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6 
PARTICIPANT CHARACTERISTICS AND OTHER RISK FACTORS ................................................. 12 
7 
ANALYSIS PLAN ........................................................................................................................................... 13 
7.1 
General analysis Considerations ............................................................................................ 13 
7.2 
Statin effects on coronary plaque morphology ..................................................................... 13 
7.3 
Statin effects on markers of immune function and markers of glucose homeostasis ...... 14 
7.4 
Statin effects on lipids .............................................................................................................. 14 
7.5 
LDL and blood biomarkers as mediators for plaque progression ....................................... 14 
APPENDIX I 
SAMPLE SIZE CONSIDERATIONS ................................................................................. 15 
 


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2 Objectives and Estimands 
2.1 Primary Objective 
To determine the effects of pitavastatin on the morphology and composition of coronary atherosclerotic 
plaque, (including the progression of noncalcified plaque (NCP) volume), and whether these effects are 
modulated by markers of inflammation and immune activation. 
Primary Estimand 
Estimand 
description 
An estimand defines the target of estimation for a particular trial objective (i.e. “what is to be 
estimated”). This combines all the estimand elements outlined below into a single, succinct 
sentence. 
Treatment 
Treatment groups 
Pitavastatin 4mg per day 
Pitavastatin 4mg per day or placebo 
Target population 
Analysis set 
PWH on stable ART with low to moderate 
cardiovascular risk and no known current indication for 
statin treatment. 
All randomized participants with a REPRIEVE (A5332) 
entry visit. Participants who were consented but never 
returned to the clinic for their REPRIEVE (A5332) entry 
visit (regardless of whether the participant was formally 
randomized) will be considered inadvertent enrollments 
and excluded. 
Variable(s) 
Outcome measure(s) 
Change in noncalcified plaque volume (NCP) 
Change in volume of plaque and calcified plaque will be 
examined as secondary variables. 
See Section 3 for more detailed outcome descriptions 
• Absolute change in NCP volume from entry to year 2.
• NCP progression defined as any increase (>0) in
NCP volume or incident NCP for those without NCP
at entry (based on qualitative read)
For sensitivity analyses, 
• Qualitative assessment of at least one segment with
NCP on the 2 year CT.
• Quantitative NCP volume at 2 year CT
Handling of intercurrent events 
Handling of missing data 
Failure to start statin: Included per randomized 
treatment (treatment policy) 
Change in statin strategy: Included per randomized 
treatment (treatment policy) Includes discontinuation or 
change of statin 
Evidence of critical stenosis at treatment start: Included 
per randomized strategy (treatment strategy) 
Interval stent placement or bypass*: Included per 
randomized strategy (treatment policy strategy) 
Death prior to Year 2 scan: Treated as missing data 
(hypothetical policy) 
Missing data due to missed visits or unreadable scans 
will be assumed missing completely at random and 
ignored i.e., the primary analysis will be a complete 
case analysis including participants with pair baseline 
and year 2 scans. 
Sensitivity analyses will include multiple imputation for 
missing data. 
Population-level summary measure 
Analysis approach 
Mean change NCP volume over 2 years 
Linear regression (normal errors assumption). 
In the event of extreme violation of normality, outcomes 
will be log transformed (giving a percentage change 
interpretation of the treatment effect). 
Modeling will adjust for CD4 and sex (stratification 
factors), and for baseline NCP volume. 
* Stented or bypassed coronary artery segments are not considered on the entry and year 2 scan as part of the
read protocol for plaque volume.
2.2 Secondary Objectives 
•
To determine the effects of pitavastatin on the progression of high risk plaque features including low
attenuation plaque and positive remodeling.
•
To determine the effects of pitavastatin on detailed markers of immune function including, immune
activation (%CD14+CD16+ monocytes, sCD163, sCD14, MCP-1 and T-cell markers), inflammation
(Lp-PLA2, hsCRP, hs troponin, oxLDL IL-6), coagulation (D-Dimer) and traditional CVD risk indices


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including detailed parameters of glucose homeostasis (insulin, glucose and related indices of insulin 
resistance such as HOMA-IR). 
•
To determine the relative contributions of baseline and pitavastatin induced changes in HIV-specific
immune activation and traditional risk factors, including LDL, on the presence and progression of
coronary plaque and high-risk morphological features in HIV.
3 Outcome Measures 
3.1 Analysis Windows for Evaluations 
Evaluations drawn within the windows of evaluation defined below will be included in outcome measures; 
evaluations outside these windows will be excluded. It is noted that analysis windows for month 24 
evaluations were widened from those originally planned to accommodate scheduling complications due to 
COVID restrictions. 
Evaluation 
Entry* 
Month 4 
Year 2 (Month 24) 
CT scan 
Any date < (First dose+14 days) 
- 
Target date – 6 months (180 days) to 
Target date + 12 months (360 days) 
i.e. Month 18 to Month 36
Fasting lipids 
Any date < First dose 
Target date ± 60 days 
Soluble biomarkers 
Any date < First dose 
Target date ± 60 days 
Flow cytometry 
Any date < First dose 
- 
Questionnaires 
Any date < First dose 
- 
* For participants who never start treatment, evaluations < 30-days after A5332 entry.
Target date = A5332 entry date + (Month*30)
3.2 Primary, Secondary, and Associated Supportive Outcome Measures 
The primary variable of interest for the Substudy is the morphology and composition of noncalcified 
coronary atherosclerotic plaque. The following NCP outcome measures will be described and compared 
by treatment group. Corresponding outcomes at entry will be described when appropriate. For the primary 
analysis, a threshold of <350 HU will be used to define non-calcified plaque.  
3.2.1 
Change NCP volume over 2 years (Primary) 
•
Continuous outcome:
−
Absolute change: NCP volume at 2 years – NCP volume at entry
−
Percentage change: (NCP volume at 2 years – NCP volume at entry) / NCP volume at entry
(Supportive)
•
Based on quantitative read whenever available (including for participants with no evidence of
NCP based on the corresponding qualitative read).
−
Participants without a quantitative read and no evidence of NCP based on the corresponding
qualitative read will be assigned a value of zero for both absolute and percentage change.
3.2.2 
Progression of NCP over 2 years (Primary) 
•
Binary outcome (Yes, No)
•
Based on both quantitative and qualitative reads
−
Among participants without evidence of NCP at entry on the qualitative read, evidence of
NCP at 2 years.
−
Among participants with evidence of NCP at entry on qualitative read, >0% increase in NCP
volume
−
Participants with discordant outcomes based on qualitative and quantitative reads,
progression will be defined by the quantitative read.
3.2.3 
NCP on the 2 year CT (supportive) 
•
Binary outcome (Yes, No)
•
Based on qualitative read
•
Outcome is defined regardless of availability of an entry scan


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3.2.4 
NCP volume at 2 years (supportive) 
•
Continuous outcome
•
Based on quantitative read whenever available (including for participants with no evidence of
NCP on the corresponding qualitative read).
−
Participants without a quantitative read and no evidence of NCP on the corresponding
qualitative read will be assigned a value of zero.
•
Outcome is defined regardless of availability of an entry scan
3.2.5 
Total plaque volume 
•
Analogous outcomes to those in Section 3.2.1-3.2.4 but defined based on total plaque volume
(rather than NCP)
•
Outcomes will be described for the cohort at entry and year 2, with formal comparisons by
treatment group.
3.2.6 
Change in relative composition of coronary plaque 
•
Continuous outcome
•
Calculated as the ratio of NCP to overall plaque volume
3.3 Exploratory Plaque Outcomes 
The following are additional CT-related outcomes that will be described for the cohort at entry and year 2, 
as appropriate. Note: Not all of these analyses will be included in the primary manuscript; but will be 
included in the packet of primary analyses for completeness. 
3.3.1 
Number of segments with plaque 
•
Ordinal outcome: (0, 1-2, >3)
•
Based on qualitative read
3.3.2 
Number of segments with noncalcified portion 
•
Ordinal outcome: (0, 1-2, >3)
•
Based on qualitative read
3.3.3 
Presence of vulnerable plaque features 
•
Five binary (Yes, No) outcomes based on the qualitative read
•
Presence of any following vulnerable features (main outcome) and the prevalence of each feature
descriptively (four outcomes)
−
Positive remodeling
−
Low attenuation plaque
−
Positive remodeling and low attenuation plaque
−
Napkin ring sign
3.3.4 
Alternative definition of noncalcified plaque volume, using a threshold of <130 HU 
•
Continuous outcome:
−
Absolute change: NCP volume at 2 years – NCP volume at entry
−
Percentage change: (NCP volume at 2 years – NCP volume at entry) / NCP volume at entry
(Supportive)
•
Based on quantitative read whenever available (including for participants with no evidence of
NCP based on the corresponding qualitative read).
−
Participants without a quantitative read and no evidence of NCP based on the corresponding
qualitative read will be assigned a value of zero for both absolute and percentage change.
3.3.5 
Low attenuation plaque volume (<30 HU) 
•
Continuous outcome
•
Based on quantitative read whenever available.


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•
Participants without a quantitative read and no evidence of low attenuation plaque on the
corresponding qualitative read will be assigned a value of zero
3.3.6 
Stenosis 
•
Three outcomes based on qualitative read
•
Presence of CAD or stenosis >0%
−
Binary (Yes, No)
•
CAD severity
−
Ordinal (Minimal, Mild, Moderate, Severe)

No stenosis

Minimal CAD, stenosis 1-24%

Mild CA D, stenosis 25%-49%

Moderate CAD, stenosis 50%-69%

Severe CAD, stenosis ≥70% or ≥50% left main
•
Presence of stenosis ≥50%
−
Binary (Yes, No)
3.3.7 
Progression of NCP over 2 years 
•
Ordinal outcome (Progression, Stable, Regression)
•
Based on both quantitative and qualitative reads
−
Progression: Defined per 3.1.4
−
Regression:

Based on quantitative read: >0% decrease in NCP volume over two years.
−
Stable:

Based on qualitative read: No evidence of NCP at entry and 2 years.

Based on quantitative read: Percentage change in NCP volume between -2% and +2%
(including exactly -2% and +2%).
−
For participants with discordant outcomes based on qualitative and quantitative reads,
progression will be defined by on the quantitative read.
3.3.8 
Coronary artery calcium (CAC), Leaman, and Segment Involvement (SIS) scores 
•
CAC: Continuous and ordinal (0, 1-10, 11-100, 100-300, >300
•
Leaman: Ordinal (0, >0-5, >=5)
•
SIS: Ordinal (0, 1, 2, 3, 4, 5+)
3.4 Markers of Immune Function 
Levels at entry, 4 months and 2 years, and changes from study entry to 4 months and 2 years (unless 
stated otherwise).  
•
Soluble markers of monocyte activation
o
sCD163, sCD14, MCP-1
•
Monocyte populations  (entry and 2 years only)
o
%CD14+CD16+ (inflammatory/intermediate) monocytes
−
Classical and non-classical subsets presented descriptively
•
Markers of T-cell activation and T-cell exhaustion (entry and Year 2 only)
o
CD38+DR+ on CD4+ and CD8+
•
Markers of inflammation:
o
Lp-PLA2, hsCRP, IL6, hs troponin, oxLDL
•
Markers of coagulation
o
D-Dimer
Future analyses will interrogate the broader spectrum of immune phenotyping that has been performed 
collected PBMCs. 
3.5 Markers of Glucose Homeostasis 
Levels at entry, 4 months and 2 years, and changes from study entry to 4 months and 2 years. 


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•
Fasting insulin, glucose, and HOMA-IR
3.6 Descriptive Outcomes 
The following REPRIEVE outcome measures will be described by treatment group for the substudy 
population but since statin effects for these outcomes will be determined based on the full REPRIEVE 
cohort, formal treatment comparisons will not be performed. 
3.6.1 
Time to the first major cardiovascular event 
•
As defined in the REPRIEVE Primary Statistical Analysis Plan
3.6.2 
Fasting lipid fractions 
•
Total, LDL, non-HDL, and HDL cholesterol, and LDL:HDL ratio at study entry, month 4, and 2
years
o
LDL will be reported as calculated LDL if triglycerides ≤400 mg/d; direct LDL if triglycerides
>400 mg/dL and <500 mg/dL; LDL will be considered missing if triglycerides ≥500 mg/dL
4 Analysis Sets and Handling of Missing Data 
4.1 Primary (Intent-to-treat) 
The primary ITT sample will include all registered substudy participants who completed their REPRIEVE 
(A5332) entry visit. Participants registered to the substudy who failed to complete a REPRIEVE (A5332) 
entry visit will be considered inadvertent enrollments and excluded from all data summaries and analyses. 
The primary analyses will assume all missing data are missing completely at random and be ignored. The 
intercurrent event of participant death during the 2 year follow-up is expected to be rare and will be 
handled using a hypothetical strategy – that is, outcomes unavailable due to death will be treated as 
missing data. Baseline and Year 2 outcomes will be described among all participants with data available 
at the respective time-point; analyses of change will include only participants with paired scans. 
Sensitivity analyses will use multiple imputation with randomization stratification factors (sex and CD4 
count) plus ASCVD risk score and BMI used to develop the model. 
4.2 Per Protocol (Treated) 
All analyses will be repeated within a per protocol sample which will be limited to participants who 
completed 24–months study follow-up on randomized treatment.  
Unless the primary sensitivity analyses demonstrate a concern for informative missingness, per protocol 
analyses will be limited to participants with paired entry and year 2 scans available with no additional 
sensitivity analyses performed. Cardiovascular risk factors associated with dropping out of the per 
protocol analysis will be examined. 
5 Administrative Details 
Limited to participants in the ITT analysis set. 
5.1 Participant Enrollment 
Figure: Enrollment over time 
•
NHLBI enrollment figure
Table: Enrollment by site and sex 
•
Including details of all participants enrolled at substudy site


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5.2 Participant Study and Treatment Disposition 
Table: Participant status 
Treatment Group 
Total 
(N=XX) 
Pitavastatin 
(N=XX) 
Placebo 
(N=XX) 
Enrolled 
XX  (xx%) 
XX (xx%) 
XX (xx%) 
Completed 24 mo follow-up 
XX  (xx%) 
XX (xx%) 
XX (xx%) 
Timing of final visit (months from 
enrollment)) Median (P10-P90) 
Min-Max 
Did not complete substudy 
XX  (xx%) 
XX (xx%) 
XX (xx%) 
Reason for Discontinuation Reasons from A5333S RP0002 
XX  
XX  
XX 
…. 
XX  
XX  
XX 
Timing of discontinuation Before 4 month visit* 
XX  (xx%) 
XX (xx%) 
XX (xx%) 
Between 4 and 24 month visits 
XX  (xx%) 
XX (xx%) 
XX (xx%) 
Figure: Time to substudy discontinuation 
•
KM plot by treatment group
Table: Treatment disposition 
Treatment Group 
Total 
(N=XX) 
Pitavastatin 
(N=XX) 
Placebo 
(N=XX) 
Days to start of study treatment* 
N 
XX 
XX 
XX 
Median (P10-P90) 
XX (XX-XX) 
XX (XX-XX) 
XX (XX-XX) 
Min-Max 
0-X,XXX
0-X,XXX
0-X,XXX
# missing 
XX 
XX 
XX 
0-2
XX (XX%) 
XX (XX%) 
XX (XX%) 
3-14
XX (XX%) 
XX (XX%) 
XX (XX%) 
>14
XX (XX%) 
XX (XX%) 
XX (XX%) 
Will never start 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Timing of treatment discontinuation 
Before 4 month visit* 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Between 4 and 24 month visits 
XX (XX%) 
XX (XX%) 
XX (XX%) 
On or after the 24 month visit 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Reasons for discontinuation 
Reasons from A5332 RP0003 
XX (XX%) 
XX (XX%) 
XX (XX%) 
… 
XX (XX%) 
XX (XX%) 
XX (XX%) 
* Includes participants who never started treatment
Figure: Time to treatment discontinuation 
•
KM plot by treatment group
5.3 CT Scan Availability 
Table: CT scan availability 
Table denominator is the ITT analysis set; table will be repeated in the per protocol analysis set. 
Treatment Group 
Total 
(N=XX) 
Pitavastatin 
(N=XX) 
Placebo 
(N=XX) 
Evaluable Entry CT scan 
Qualitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Quantitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Paired reads 
XX (XX%) 
XX (XX%) 
XX (XX%) 
No Entry CT scan scan 
XX (XX%) 
XX (XX%) 
XX (XX%) 


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Treatment Group 
Total 
(N=XX) 
Pitavastatin 
(N=XX) 
Placebo 
(N=XX) 
Reason no entry CT scan 
Out of window 
XX 
XX 
XX 
Missed visit 
XX 
XX 
XX 
.<other reasons> 
XX 
XX 
XX 
Image quality 
XX 
XX 
XX 
Evaluable Year 2 CT scan 
Paired reads 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Qualitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Quantitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
No Year 2 CT scan 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Reason no scan 
Out of window 
XX 
XX 
XX 
Premature discontinuation 
XX 
XX 
XX 
Missed visit 
XX 
XX 
XX 
<other reasons> 
XX 
XX 
XX 
Image quality 
XX 
XX 
XX 
Evaluable paired scans 
Qualitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Quantitative read 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Paired reads 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Possible <Other reasons> based on the scan tracking form might include: Refusal, Unable to place IV or 
other technical issue, Renal insufficiency, Contrast allergy, BMI >40. 
5.4 Consort 
See Appendix II for draft Consort based on scan reads. This will be expanded on to incorporate details of 
treatment status and analysis windows. 
•
Registered
o
Did not complete A5332 entry visit
•
Within the ITT sample and by treatment group, Cross-tabulation of
o
Scan availability by treatment status
−
Baseline CTA completed (in versus outside of window)
−
Diagnostics baseline CTA
−
Completed follow-up CTA (in versus outside of window)
−
Diagnostic baseline and follow-up CTA
o
Treatment status
−
Completed treatment
−
Did not start treatment
−
Early treatment discontinuation
5.5 Biomarker Availability 
Table: Data availability Like the table below but scaled down out of window visits/samples. 
of Expected Subjects 
Total Biomarkers 
Visit 
[Visit windows] 
Subjects 
Expected 
Observed 
Visits 
Biomarkers 
available 
for day 
for day 
& Baseline 
Entry 
TD-180 
TD+1 
XX 
XX (XX%) 
XX (XX%) 
XX 
Entry + 
TD+2d 
TD+59d 
XX 
XX [XX%] 
XX [XX%] 
Month 4- 
TD-60d 
TD-30d 
XX 
XX [XX%] 
XX [XX%] 
Month 4 
TD±30d 
XX 
XX (XX%) 
XX (XX%) 
XX 
XX 
Month 4+ 
TD+30d 
TD+60d 
XX 
XX [XX%] 
XX [XX%] 
Month 12 
XX 
XX [XX%] 
XX [XX%] 
Month 24- 
TD-180d 
TD-30d 
XX 
XX [XX%] 
XX [XX%] 
Month 24 
TD±30d 
XX 
XX (XX%) 
XX (XX%) 
Month 24+ 
TD+30d TD+360d 
XX 
XX [XX%] 
XX [XX%] 


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of Expected Subjects 
Total Biomarkers 
Visit 
[Visit windows] 
Subjects 
Expected 
Observed 
Visits 
Biomarkers 
available 
for day 
for day 
& Baseline 
Month 36+ 
XX 
XX [XX%] 
XX [XX%] 
TD - Target date 
6 Participant Characteristics and Other Risk Factors 
See JAMA Open Table 1. Statistics by treatment group as described will be given in the study report; the 
summaries will likely be streamlined for the manuscript. 
The following defined at study entry only unless stated otherwise. The table denominator would be the 
ITT sample. A second table of the same information will be included for those with paired scans. 
•
Demographic and Behavioral characteristics
o
Age (years): Mean (SD) and percent by group (40-49; 50-59; 60+)
o
Sex: Percent women
o
Gender identity: Percent by group (Cisgender, Transgender spectrum, Not reported)
o
Race: Percent by group (White, Black or African American, Asian, Other)
o
Ethnicity: Percent by group (Hispanic or Latino, Not Hispanic or Latino, Unknown)
o
Other substance use (cocaine, heroin, methamphetamine)
•
ASCVD Risk Score at REPRIEVE Entry
o
ASCVD risk score (%): Median (Q1, Q3) and percent by group (<2.5, 2.5-<5, 5-<10, 10+)
o
Smoking status: Percent by group (Current, Former, Never)
o
Use of antihypertensive medication: Percent yes
o
Systolic BP of those not on antihypertensive medication: Median (Q1-Q3) (P10, P90)
o
Total cholesterol (mg/dL) : Median (Q1-Q3) (P10, P90)
o
HDL-C (mg/dL) : Median (Q1-Q3) (P10, P90)
o
LDL calculated (mg/dL) : Median (Q1-Q3) (P10, P90)
o
Triglycerides (mg/dL) : Median (Q1-Q3) (P10, P90)
o
Family history of premature CVD: Percent yes
•
Other Cardiovascular / metabolic characteristics at REPRIEVE Entry
o
BMI: (kg/m2) Mean (SD) and percent by group (<24.9, 25-29.9, 30+)
o
Prior statin use: Percent yes
−
Based on site report at entry
o
Diabetes: Percent yes
o
Use of anti-diabetic therapy: Percent yes
o
Use of ACE/ARBs: Percent yes
o
Use of anti-platelets/anticoagulants: Percent yes
o
Use of non-statin lipid lowering agents Percent yes
•
Cardiovascular / metabolic characteristics at Year 2
o
BMI: (kg/m2) Mean (SD) and percent by group (<24.9, 25-29.9, 30+)
o
Prior statin use: Percent yes
−
Based on site report at entry
o
Diabetes: Percent yes
o
Use of anti-diabetic therapy: Percent yes; percent adding medication after baseline
o
Use of ACE/ARBs: Percent yes; percent adding medication after baseline
o
Use of anti-platelets/anticoagulants: Percent yes; percent adding medication after baseline
o
Use of non-statin lipid lowering agents Percent yes; percent adding medication after baseline
•
HIV-related health history (all based on site report at entry)
o
Time since HIV diagnosis (years): Median (Q1, Q3) (P10, P90)
o
Nadir CD4 count (cells/mm3): Percent by group (<50, 50-199, 200-349, >350, Unknown)
o
Total ART use duration (years): Percent by group (<5, 5-10, >10, Unknown)
o
Thymidine exposure: Percent yes
o
Abacavir exposure: Percent yes
o
TDF exposure: Percent yes
o
Protease inhibitor exposure: Percent yes


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•
HIV-related health at REPRIEVE entry
o
CD4 count (cells/mm3): Mean (SD)
o
HIV-1 RNA (copies/ml): Percent by group (<LLQ, LLQ-400, >400)
o
ART regimen: Percent by group (NRTI+INSTI, NRTI+NNRTI, NRTI+PI, NRTI-sparing, Other
NRTI containing)
o
Entry NRTI: Percent by group (No NRTI, TDF, TAF, Abacavir, Other)
o
Entry INSTI: Percent by group (No INSTI, DTG, EVG, BIC, RAL)
•
HIV-related health at Year 2
o
Most recent CD4 count (cells/mm3): Mean (SD)
o
Most recent HIV-1 RNA (copies/ml): Percent by group (<LLQ, LLQ-400, >400)
o
Change in class of ART from baseline: Percent yes
o
Current ART regimen: Percent by group (NRTI+INSTI, NRTI+NNRTI, NRTI+PI, NRTI-sparing,
Other NRTI containing)
o
Change in NRTI from entry: Percent yes.
o
Current NRTI: Percent by group (TDF, TAF, Abacavir, No NRTI, Other)
o
Change in INSTI from entry: Percent yes.
o
Current INSTI: Percent by group (No INSTI, DTG, EVG, BIC, RAL)
7 Analysis Plan 
7.1 General analysis Considerations 
Outcome distributions will be described with median, Q1, Q3, P10, P90, minimum, and maximum and 
shown graphically. All primary treatment group comparisons will be performed ITT using a 5% type error. 
For continuous outcomes, inference will be based on differences in means adjusted for baseline and 
presented with two-sided, 95% confidence intervals.   
7.2 Statin effects on coronary plaque morphology 
Outcome measures: See Sections 3.2 and 3.3 
Table: Primary and secondary plaque outcomes 
Among participants with plaque at entry, descriptive statistics for the change and percentage change in 
NCP volume over 2 years will be provided by treatment group with group comparisons made with linear 
regression with adjustment for baseline plaque volume and stratified by sex and CD4.  
Among those without NCP at entry, the prevalence of incident NCP over 2 years will be compared with 
stratified chi-squared test.  
To assess the mechanistic study population as a whole, the probability of NCP and total plaque 
progression over two years (see Section 3.2.2) will be compared by treatment group using a stratified chi-
squared test. 
The statin effect on high risk plaque features (any), including low attenuation and positive remodeling, will 
be assessed by comparing differences in the 2-year prevalence of high risk plaque morphology features 
between treatment groups using chi-squared (or Fisher’s exact) tests as appropriate; these analyses will 
be performed overall and by subgroups defined by the presence of NCP at study entry.  
Sample table from Testosterone study, JAMA  2017  
REDACTED FOR PUBLIC RELEASE OF THE SAP 
Table: Modification of statin effect on changes in NCP and total plaque volume 
•
By baseline value, sex, age, screening CD4, and duration of suppressive ART
Depending on their baseline prevalence, modification of the statin effect by use of cardiovascular 
medications may also be explored.  


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7.3 Statin effects on markers of immune function and markers of glucose homeostasis 
Outcome measures: See Sections 3.4 and 3.5 
Statin effects on the distributions of blood biomarkers belonging to distinct pathways will be assessed via 
treatment group comparisons of these respective markers via linear regression with adjustment for 
baseline and stratified by sex and CD4. 
We will examine modification of statin effect on these markers by baseline value, sex, age, screening 
CD4, duration of suppressive ART, and presence of NCP at study entry. 
Figure: Distributions of lipid fractions by treatment group over time 
•
Violin plots
Figure: Mean and 95% CI lipid fractions by treatment group over time 
Table: Median, Q1, Q3 and Mean and 95% CI lipid fractions by treatment group over time 
Sample table from Atorvastatin trial Lancet 2015 
REDACTED FOR PUBLIC RELEASE OF THE SAP 
7.4 Statin effects on lipids 
Outcome measures: See Section 3.6.2 
Figure: Distributions of lipid fractions by treatment group over time 
•
Violin plots
Figure: Mean and 95% CI lipid fractions by treatment group over time 
Table: Mean and 95% CI lipid fractions by treatment group over time 
7.5 LDL and blood biomarkers as mediators for plaque progression 
In the event that both statin effects on NCP progression and biomarker changes are apparent, the 
association between changes in LDL and these biomarkers and NCP progression will be examined using 
graphical techniques and normal errors and logistic regression (for the subpopulations with and without 
NCP at entry respectively. A mediating effect of these biological factors will be evaluated by examination 
of changes in the estimated statin effect on NCP upon adjustment for these biological factors. 
Since the hypothesized mechanism is that sustained high levels of immune activation and inflammation 
precede and contribute to progression of NCP volume and high risk plaque features, these analyses will 
relate short term changes in these biomarkers (over 4 months) to longer term changes in NCP volume 
and morphology after two years. 


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Appendix I Sample Size Considerations 
[Copied Verbatim from the REPRIEVE A5333S Protocol, Version 5.0, Section 9.2.] 
The target sample size for the Mechanistic Substudy of REPRIEVE (A5333s) is 800 participants that will 
be approximately equally distributed between the study arms. 
This sample size was determined to have high power to detect clinically relevant differences between the 
two study groups both with respect to plaque progression (among those with plaque at study entry) and 
rates of incident plaque (among those plaque-free at entry). Specifically, the total sample size of 800 
subjects will provide 90% power to detect a 6% difference between the study groups in the percent 
change in NCP volume over 2 years among those with plaque at entry and 90% power to detect 13 
percentage point difference in the probability of plaque development over 2 years. These effect sizes 
translate to a combined estimated 14 percentage point difference in the probability of NCP progression 
over two years and are based on the following assumptions: 
50% of study participants will have evidence of NCP at study entry [Lo 2010] 
A SD of 20% for the percent change over 2 years among participants with evidence of plaque at entry 
An annual rate of incident plaque development of 12% among participants without plaque at entry 
15% of participants entering the substudy will not be evaluable for study entry or 2 year NCP volume. 
Together, the effects of statins acting in these two groups (those with and without evidence of NCP at 
study entry) will provide for a 7% lower prevalence of NCP after 2-years of statin treatment. Expectations 
for NCP prevalence and progression both as a whole and according to whether NCP was present at 
study entry are illustrated in the table below. These estimates are based on a simulation that further 
assumed the following: 
Average volume NCP 250mm3 (SD=200) among participants with NCP at entry. 
Average volume NCP 40mm3 (SD=20) at 2 years among participants without NCP at entry without statin 
treatment. 
Average volume NCP 20mm3 (SD=20) at 2 years among participants without NCP at entry with statin 
treatment. 
NCP distributions were also assumed to follow a gamma distribution with size and shape parameters 
determine to provide the desire mean and standard deviations. 
Table 9.2-1: Cells constituting the primary targeted group comparisons are shown in bold. 
 
At study entry 
At two 2 years 
 
NCP 
(%) 
NCP volume (mm3) NCP 
(%) 
NCP volume (mm3) 
Change in NCP 
volume (mm3) 
Percent change in NCP 
volume (%)2 
Mean (SD) [P5, P95] 
Mean (SD) [P5, P95] Mean (SD) [P5, P95] Mean (SD) 
[P5, P95] 
Control Overall1 
50% 
121 (186) 
[0, 509] 59% 140 (210) [0, 573] 
19 (51) 
[-21, 103] 17% (33%) [-10%, 100%] 
No plaque at entry 
- 
- 
21% 
9 (19) 
[0, 51] 
9 (19) 
[0, 51] 
21% (41%) [0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
40 (20) 
[17, 79] 
40 (20) 
[17, 79] 100% (0%) [100%, 100%] 
Plaque at entry 
251 (198) [26, 637] 
 
281 (231) [28, 730] 
30 (68) 
[-38, 153] 12% (20%) [-14%, 49%] 
Statin 
Overall1 
50% 
120 (185) 
[0, 507] 52% 127 (198) [0, 536] 
7 (45) 
[-42, 76] 
7% (24%) 
[-17%, 60%] 
No plaque at entry 
- 
- 
8% 
2 (8) 
[0, 14] 
2 (8) 
[0, 14] 
8% (27%) 
[0%, 100%] 
No plaque at 2 years 
 
 
- 
- 
- 
- 
- 
- 
Plaque at 2 years 
 
 
23 (19) 
[2,60] 
23 (19) 
[2,60] 
100% (0%) [100%, 100%] 
Plaque at entry 
250 (197) [26, 633] 
 
262 (216) [26, 682] 
12 (64) 
[-66, 123] 5% (20%) 
[-21%, 43%] 
1  In estimation of overall means, participants without evidence of NCP are assigned a value of 0 for volume and 
change. 
2 In estimation of percentage change, participants without evidence of NCP at study entry with NCP at 2 years are 
assigned a value of 100%. 


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These desired statin effects on NCP volume are similar to those seen in intravascular ultrasound (IVUS) 
studies [Nissen 2006; Nicholls 2005]. Although no data exist to directly inform the clinical relevance of 
these differences, randomized comparisons of high vs. low dose statin therapy among non-HIV-infected 
patients have demonstrated favorable effects on atherosclerotic plaque of a similar magnitude as well as 
on adverse cardiac events, among non-HIV patients [Nissen 2006]. Further, data from the "Coronary CT 
Angiography Evaluation for Clinical Outcomes (CONFIRM) registry suggest that the presence of non-
obstructive CAD is predictive major adverse cardiac events independent of traditional risk factors, degree 
of stenosis and coronary artery calcification (HR 2-5) [Hulten 2013]. The proposed mechanistic study will 
further add to this body of evidence investigating, for the first time in HIV-infected population, the 
association of NCP (both the presence and magnitude) as well as changes in volume relate to events. 
For this exploratory analysis, a larger sample size will be beneficial, in order to accrue CVD events to 
relate to plaque morphology. 
 
References 
Hulten E, et al. Usefulness of coronary computed tomography angiography to predict mortality and 
myocardial infarction among Caucasian, African and East Asian ethnicities (from the CONFIRM [Coronary 
CT Angiography Evaluation for Clinical Outcomes: An International Multicenter] Registry). Am J Cardiol 
2013;111(4):479-85. PMID: 23211358. 
Lo J, et al. Increased epicardial adipose tissue volume in HIV-infected men and relationships to body 
composition and metabolic parameters. AIDS 2010;24(13):2127-30. PMID: 20588167. 
Nicholls SJ, et al. Effect of atorvastatin (80 mg/day) versus pravastatin (40 mg/day) on arterial remodeling 
at coronary branch points (from the REVERSAL study). Am J Cardiol 2005;96(12):1636-9. PMID: 
16360349. 
Nissen SE, et al. ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of 
coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295(13):1556-65. PMID: 16533939.