PREPARE (A5361s) Substudy of REPRIEVE (A5332)

Study Overview
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Brief Summary
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Aging with HIV may be related to an earlier development of frailty (weakness) or disability, including difficulties in tests of strength or walking speed. Few treatments have been shown to prevent or slow these impairments in people with or without HIV. Some studies have suggested that the class of drugs called statins (for example, pitavastatin) might be helpful in slowing frailty or disability. This might happen by decreasing fat within the muscle or by decreasing inflammation markers (substances in the blood that determine how the body reacts to infection or irritation) in the blood. Other studies have shown that statins increase the risk of muscle aches and pains. This substudy is being done to determine the impact of the drug pitavastatin on muscle.

Detailed Description
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A5361s is a prospective study to determine the effects of pitavastatin on physical function. The study will enroll participants enrolled in both REPRIEVE (A5332) and its mechanistic sub-study A5333s or in REPRIEVE (A5332) alone and follow them for 48 months after entry to REPRIEVE (A5332). Treatment groups (pitavastatin vs placebo) will be defined according to randomization in REPRIEVE (A5332). No intervention will be provided in this sub-study. Study visits are scheduled at PREPARE (A5361s) entry and at months 12, 24, 36 and 48 after REPRIEVE (A5332) entry. Each study visit will include evaluation of physical function, frailty and self-reported physical activity and sedentary time. In addition, demographic and clinical data, laboratory specimens and CT scans collected as part of the main study REPRIEVE (A5332) or its mechanistic sub-study A5333s will be used.

Official Title
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Pitavastatin to REduce Physical Function Impairment and FRailty in HIV (PREPARE)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Pitavastatin
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory participants enrolled in both REPRIEVE (A5332) and its Mechanistic Substudy (A5333s) or ambulatory participants who are newly enrolling into REPRIEVE (A5332) at A5333s ACTG sites. Exclusion Criteria: Inability to ambulate independently (use of a cane or a walker is permitted) or rise from a chair without assistance.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pitavastatin<br>Participants who receive pitavastatin in the main study REPRIEVE (A5332). | Drug: Pitavastatin<br>* One tablet (4 mg) taken once daily, orally with or without food<br>|
| Placebo Comparator: Placebo<br>Participants who receive placebo for pitavastatin in the main study REPRIEVE (A5332). | Drug: Placebos<br>* One tablet taken once daily, orally with or without food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change in chair rise rate | Participants will be asked to perform 10 chair stands. Chair rise rate will be calculated as time to perform chair stands divided by the number of chair stands performed. . Repeated measures analysis will be used to model chair rise rate over time and estimate rate of change. | Baseline and months 12, 24, 36 and 48 | 
| Rate of change in Inflammatory Index Score (IIS) | The IIS score will be calculated as 1/3 log [interleukin-6 (IL-6)] + 2/3 log [soluble tumor necrosis factor receptor 1 (sTNFR-1)] using samples collected as part of the main study REPRIEVE (A5332). | Baseline and 12 months | 
| Rate of change in paraspinal muscle density | Paraspinal muscle density will be measured in Hounsfield units (HU) from the CT scans performed as part of A5333s, the mechanistic sub-study of REPRIEVE (A5332). | Baseline and 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical function outcome measure: Grip strength | Participant's grip strength in the dominant hand measured by Jamar Hydraulic Hand Dynamometer. | Baseline and months 12, 24, 36 and 48 | 
| Physical function outcome measure: Gait speed | Participant's gait speed evaluated by time to complete 4-meter walk. | Baseline and months 12, 24, 36 and 48 | 
| Physical function outcome measure: Balance | Balance evaluated by participant's ability to hold one leg stand for 30 seconds. | Baseline and months 12, 24, 36 and 48 | 
| Physical function outcome measure: Physical function deficit | Physical function deficit defined as composite Short Physical Performance Battery (SPPB, consisting of repeat chair stand, balance, grip strength and gait speed tests) score <=10. | Baseline and months 12, 24, 36 and 48 | 
| Physical function outcome measure: Self-reported physical activity | Self-reported physical activity evaluated by the questionnaire Rapid Eating and Activity Assessment for Patients (REAP). | Baseline and months 12, 24, 36 and 48 | 
| Mechanistic outcome measure: Serum concentrations of biomarkers | Select biomarkers including each individual biomarker of the IIS (IL-6, sTNFR-1) as well as other biomarkers implicated in the pathogenesis of physical function impairment or those that may mediate the effects of statins on systemic inflammation. The specific list of biomarkers of interest will be finalized closer to the time of analysis, incorporating the developments in the field over the next few years. | Baseline and month 12 | 
| Mechanistic outcome measure: Shoulder muscle density | Shoulder muscle density measured in Hounsfield units (HU) from the CT scans performed as part of A5333s, the mechanistic sub-study of REPRIEVE (A5332). | Baseline and month 24 | 
| Mechanistic outcome measure: Upper back muscle density | Upper back muscle density measured in Hounsfield units (HU) from the CT scans performed as part of A5333s, the mechanistic sub-study of REPRIEVE (A5332). | Baseline and month 24 | 
| Mechanistic outcome measure: Paraspinal muscle volume | Paraspinal muscle volume (area) measured from the CT scans performed as part of A5333s, the mechanistic sub-study of REPRIEVE (A5332). | Baseline and month 24 | 
| Mechanistic outcome measure: Trunk muscle volume | Trunk muscle volume (area) measured from the CT scans performed as part of A5333s, the mechanistic sub-study of REPRIEVE (A5332). | Baseline and month 24 |