PREPARE (A5361s) Ancillary Study of REPRIEVE (A5332) (PREPARE)

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

Aging with HIV is associated with earlier development of frailty (weakness) or disability, including loss of physical and muscle strength, and 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 ancillary study was done to determine the impact of the drug pitavastatin on physical and muscle function.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Pitavastatin; Drug: Placebos

Detailed Description

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE (A5332), subsequently referred to as REPRIEVE; NCT02344290) was a prospective, randomized, placebo-controlled, multicenter phase III trial to evaluate pitavastatin as prevention for cardiovascular disease events among people with HIV. PREPARE (A5361s, subsequently referred to as PREPARE) was an ancillary study of REPRIEVE to determine the effects of pitavastatin on physical and muscle function. The study enrolled participants:

1. enrolled in both REPRIEVE and its Mechanistic Substudy (A5333s, subsequently referred to as Mechanistic Substudy) within 24 of their REPRIEVE enrollment
2. enrolled in REPRIEVE alone concurrently with their REPRIEVE enrollment.

The target sample size was 600 participants. The study was conducted at the REPRIEVE U.S. sites participating in the Mechanistic Substudy, and enrollment from the Mechanistic Substudy was prioritized to maximize the number of participants with computed tomography (CT) scan data performed as part of the Mechanistic Substudy.

Treatment groups (pitavastatin vs placebo) were defined according to randomization in REPRIEVE. Participants were enrolled into PREPARE blinded to their REPRIEVE treatment allocation. No intervention was provided in this ancillary study.

Originally the study duration was 48 months after participants' REPRIEVE entry. An additional visit was added at Month 60 due to missed in-person evaluations during the COVID-19 related restrictions in 2020 through early 2021.

Study visits were scheduled at PREPARE entry and at months 12, 24, 36, 48 and 60 after REPRIEVE entry. Each study visit included 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 or its Mechanistic Substudy were used.

• Study Type: Interventional
• Enrollment (Actual): 602
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Puerto Rico-AIDS CRS (5401)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama CRS (31788)
  • California
    • Los Angeles, California, United States, 90033-1079
      • University of Southern California (1201)
    • Los Angeles, California, United States, 90035
      • University of California, Los Angeles CARE Center CRS (601)
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs (701)
    • San Francisco, California, United States, 94110
      • Ucsf Aids Crs (801)
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS (603)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS (6101)
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS (2702)
    • Chicago, Illinois, United States, 60611
      • 2701 Northwestern University CRS
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University CRS (201)
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hosp. ACTG CRS (107)
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital (MGH) CRS (101)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University CRS (2101)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School Clinical Research Center CRS (31786)
  • New York
    • New York, New York, United States, 10032
      • Columbia Physicians and Surgeons CRS (30329)
    • New York, New York, United States, 10011
      • Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
    • New York, New York, United States, 10010
      • Weill Cornell Chelsea CRS (7804)
    • Rochester, New York, United States, 14642
      • University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • Unc Aids Crs (3201)
    • Greensboro, North Carolina, United States, 27401
      • Greensboro CRS (3203)
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS (2401)
    • Cleveland, Ohio, United States, 44106
      • Case CRS (2501)
    • Columbus, Ohio, United States, 43210
      • The Ohio State Univ. AIDS CRS (2301)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS (6201)
    • Pittsburgh, Pennsylvania, United States, 15213
      • Pittsburgh CRS (1001)
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital (TMH) ACTG CRS (2951)
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Therapeutics CRS (3652)
  • Texas
    • Dallas, Texas, United States, 75208
      • Trinity Health and Wellness Center CRS (31443)
    • Houston, Texas, United States, 77030
      • Houston AIDS Research Team (HART) CRS (31473)
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS (1401)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Study Population

It is desired that a substantial proportion of participants are enrolled in A5333s.

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pitavastatin; Participants who were randomized to pitavastatin in the main study REPRIEVE.	Drug: Pitavastatin; One tablet (4 mg) taken once daily, orally with or without food for the entire time participant was in REPRIEVE follow-up.
Placebo Comparator: Placebo; Participants who were randomized to placebo for pitavastatin in the main study REPRIEVE.	Drug: Placebos; One tablet taken once daily, orally with or without food for the entire time participant was in REPRIEVE follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical Function: Rate of Change in Chair Rise Rate	Chair rise rate was calculated as the number of chair stands performed divided by the time to complete 10 chair stands. Participants unable to attempt the test were assigned the worst time (9 seconds/stand for every stand not done). Linear mixed effects models for repeated measures were used to estimate annualized rate of change (slope), and the difference between treatment groups (interaction between slope and treatment group). Negative annualized rate of change reflects decline over time, positive improvement over time.	Entry and months 12, 24, 36, 48, 60
Mechanistic: Rate of Change in Inflammatory Index Score (IIS)	Conditional on the positive findings on the primary physical function, 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 specimens collected as part of the main study REPRIEVE, and used to evaluate mechanistic pathways through which pitavastatin affects physical function.	Baseline and 12 months
Muscle Quality: Paraspinal Muscle Density	Paraspinal muscle (a back muscle) density was measured in Hounsfield units (HU, lower values indicate fattier muscle) from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE. HU are used to measure the radiation attenuation of muscle in CT scans. Muscle tissue was identified as voxels with attenuation of -190 HU (very low density muscle, the fattiest) to 100 HU (high density muscle, the leanest).	Baseline and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical Function: Rate of Change in Gait Speed	Gait speed was calculated as 4 meters divided by the average time to complete the 4-meter walk. Participants unable to attempt the test were assigned the worst gait speed (0 meters/second). Linear mixed effects models for repeated measures were used to estimate annualized rate of change (slope), and the difference between treatment groups (interaction between slope and treatment group). Negative annualized rate of change reflects decline over time, positive improvement over time.	Entry and months 12, 24, 36, 48 and 60.
Physical Function: Rate of Change in Grip Strength	Grip strength was calculated as the average of three measurements in the dominant hand by Jamar Hydraulic Hand Dynamometer. Participants unable to attempt the test were assigned the worst result (0 kg). Linear mixed effects models for repeated measures were used to estimate annualized rate of change (slope), and the difference between treatment groups (interaction between slope and treatment group). Negative annualized rate of change reflects decline over time, positive improvement over time.	Entry and months 12, 24, 36, 48 and 60
Physical Function: Rate of Change in Risk of Impairment According to Balance	Physical function impairment according to balance was defined as inability to hold single-leg stand for 30 seconds. Annualized risk of impairment year-over-year (ratio of risk per year, compared to risk per previous year) was estimated using log-binomial regression models for repeated data using GEE (relative risk of >1 reflects an increase in risk compared to previous year, relative risk <1 a decrease in risk compared to previous year). GEE (generalized estimating equations) is a statistical method for analyzing repeated measures, such as measurements of the outcome in participants at multiple time points.	Entry and months 12, 24, 36, 48, 60
Physical Function: Rate of Change in Modified SPPB Score	Modified SPPB score (on scale from 0-worst to 3-best) was calculated as a sum of the following components each divided by the maximal possible performance: (1) chair rise rate (stands/second) divided by maximal performance of one stand/second; (2) proportion of total standing balance time calculated as the total time each of the semi-tandem, tandem and one-leg stand positions were held (maximum 30 seconds each) divided by 90 seconds; and (3) gait speed (meters/second) based on average of the 4-meter walk results divided by maximal performance of 2 meters/second. Linear mixed effects models for repeated measures were used to estimate annualized rate of change (slope), and the difference between treatment groups (interaction between slope and treatment group). Negative annualized rate of change reflects decline over time, positive improvement over time.	Entry and months 12, 24, 36, 48 and 60
Physical Function: Rate of Change in Risk of Impairment According to SPPB	Physical function impairment according to composite Short Physical Performance Battery (SPPB, consisting of repeated chair stands, balance and gait speed tests) was defined as score <=10. In the absence of trend over time, average relative risk of impairment over follow-up time (ratio) was estimated using log-binomial regression models for repeated data using GEE (relative average risk of >1 reflects an increase in risk over follow-up time, relative average risk <1 a decrease in risk over follow-up time). GEE (generalized estimating equations) is a statistical method for analyzing repeated measures, such as measurements of the outcome in participants at multiple time points.	Entry and months 12, 24, 36, 48, 60
Physical Function: Impairment According to DASI	Impairment was classified according to self-administered Duke Activity Status Index questionnaire score (on scale from 0-worst to 58.2-best) as no impairment (the max score of 58.2), some impairment (score of 34.7-<58.2), moderate impairment (9.95-<34.7) and severe impairment (0-<9.95).	Baseline, month 24 and end of REPRIEVE (average at 5.6 years)
Frailty Phenotype	Frailty Phenotype was defined based on the following components: (1) weight loss (self-report of unintentional weight loss of 10 or more pounds in the prior year), (2) exhaustion (experiencing at least three to four times per week the feeling that "everything I do is an effort" or "sometimes I cannot get going", (3) low physical activity (being "limited a lot" in response to the Short Form 36 question "does your health limit you in vigorous activities such as running, lifting heavy objects, or participating in strenuous sports?", (4) slow gait by average of two 4-meter walk times, and (5) weak grip by average of three measurements on a handheld Jamar dynamometer. Participants were classified as non-frail if they had no components present, pre-frail with one or two components present, and frail with three or more components present.	Entry and months 12, 24, 36, 48, 60
Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week	Self-reported physical activity evaluated by the questionnaire "Rapid Eating and Activity Assessment for Patients" (REAP) question 27: In an average week, how often do you do <30 minutes of physical activity 3 or more days a week?	Baseline and months 12, 24, 36, 48, 60
Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day	Self-reported physical activity evaluated by the questionnaire "Rapid Eating and Activity Assessment for Patients" (REAP) question 28: In an average week, how often do you do watch >2 hours of TV or videos a day?	Baseline and months 12, 24, 36, 48, 60
Muscle Quality: Pectoral Muscle Density	Pectoral (a chest muscle) density was measured in Hounsfield units (HU) from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.	Baseline and month 24
Muscle Quality: Infraspinatus Muscle Density	Infraspinatus (an upper back muscle) density was measured in Hounsfield units (HU) from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.	Baseline and month 24
Muscle Area: Paraspinal Muscle Area	Paraspinal muscle (a back muscle) area was measured from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.	Baseline and month 24
Muscle Area: Pectoral Muscle Area	Pectoral muscle (a chest muscle) area was measured from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.	Baseline and month 24
Muscle Area: Infraspinatus Muscle Area	Infraspinatus muscle (an upper back muscle) area was measured from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.	Baseline and month 24
Mechanistic: Serum Concentrations of Biomarkers	Conditional on the positive findings on the primary physical function, 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 will be used to evaluate mechanistic pathways through which pitavastatin affects physical function. The specific list of biomarkers of interest will be finalized closer to the time of analysis, incorporating the developments in the field over the few years from study development to completion.	Baseline and month 12

Collaborators and Investigators

• Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA)
• Investigators: Study Chair: Todd Brown, MD, PhD, Johns Hopkins University; Study Chair: Kristine Erlandson, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Erlandson KM, Umbleja T, Lu MT, Taron J, Ribaudo HJ, Overton ET, Presti RM, Haas DW, Sax PE, Yin MT, Zhai BK, Louis R, Upadhyay N, Eslami P, Douglas PS, Zanni MV, Fitch KV, Fulda ES, Fichtenbaum CJ, Malvestutto CD, Grinspoon SK, Brown TT. Associations of Muscle Density and Area With Coronary Artery Plaque and Physical Function. J Acquir Immune Defic Syndr. 2023 Oct 1;94(2):174-184. doi: 10.1097/QAI.0000000000003244.
• Abidi MZ, Umbleja T, Overton ET, Burdo T, Flynn JM, Lu MT, Taron J, Schnittman SR, Fitch KV, Zanni MV, Fichtenbaum CJ, Malvestutto C, Aberg JA, Fulda ES, Eckard AR, Manne-Goehler J, Tuan JJ, Ribaudo HJ, Douglas PS, Grinspoon SK, Brown TT, Erlandson KM. Cytomegalovirus IgG is Associated With Physical Function But Not Muscle Density in People With HIV. J Acquir Immune Defic Syndr. 2024 Apr 15;95(5):470-478. doi: 10.1097/QAI.0000000000003377.
• Umbleja T, Brown TT, Overton ET, Ribaudo HJ, Schrack JA, Fitch KV, Douglas PS, Grinspoon SK, Henn S, Arduino RC, Rodriguez B, Benson CA, Erlandson KM. Physical Function Impairment and Frailty in Middle-Aged People Living With Human Immunodeficiency Virus in the REPRIEVE Trial Ancillary Study PREPARE. J Infect Dis. 2020 Jul 9;222(Suppl 1):S52-S62. doi: 10.1093/infdis/jiaa249.

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2017
• Primary Completion (Actual): August 21, 2023
• Study Completion (Actual): August 21, 2023

Study Registration Dates

• First Submitted: February 22, 2017
• First Submitted That Met QC Criteria: March 2, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): October 28, 2024
• Last Update Submitted That Met QC Criteria: October 24, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pitavastatin
• Other Study ID Numbers: ACTG A5361s; UM1AI068636 (U.S. NIH Grant/Contract); R01AG054366 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No