PREPARE (A5361s) Ancillary Study of REPRIEVE (A5332)
- Registration Number
- NCT03070223
- Lead Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 602
- 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.
- Inability to ambulate independently (use of a cane or a walker is permitted) or rise from a chair without assistance.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pitavastatin Pitavastatin Participants who were randomized to pitavastatin in the main study REPRIEVE. Placebo Placebos Participants who were randomized to placebo for pitavastatin in the main study REPRIEVE.
- Primary Outcome Measures
Name Time Method Physical Function: Rate of Change in Chair Rise Rate Entry and months 12, 24, 36, 48, 60 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.
Mechanistic: Rate of Change in Inflammatory Index Score (IIS) Baseline and 12 months 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.
Muscle Quality: Paraspinal Muscle Density Baseline and 24 months 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).
- Secondary Outcome Measures
Name Time Method Physical Function: Rate of Change in Gait Speed Entry and months 12, 24, 36, 48 and 60. 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.
Physical Function: Rate of Change in Grip Strength Entry and months 12, 24, 36, 48 and 60 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.
Physical Function: Rate of Change in Risk of Impairment According to Balance Entry and months 12, 24, 36, 48, 60 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.
Physical Function: Rate of Change in Modified SPPB Score Entry and months 12, 24, 36, 48 and 60 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.
Physical Function: Rate of Change in Risk of Impairment According to SPPB Entry and months 12, 24, 36, 48, 60 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.
Physical Function: Impairment According to DASI Baseline, month 24 and end of REPRIEVE (average at 5.6 years) 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).
Frailty Phenotype Entry and months 12, 24, 36, 48, 60 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.
Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week Baseline and months 12, 24, 36, 48, 60 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?
Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day Baseline and months 12, 24, 36, 48, 60 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?
Muscle Quality: Pectoral Muscle Density Baseline and month 24 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.
Muscle Quality: Infraspinatus Muscle Density Baseline and month 24 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.
Muscle Area: Paraspinal Muscle Area Baseline and month 24 Paraspinal muscle (a back muscle) area was measured from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.
Muscle Area: Pectoral Muscle Area Baseline and month 24 Pectoral muscle (a chest muscle) area was measured from central reading of CT scans performed as part of A5333s, the Mechanistic Substudy of REPRIEVE.
Muscle Area: Infraspinatus Muscle Area Baseline and month 24 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.
Mechanistic: Serum Concentrations of Biomarkers Baseline and month 12 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.
Trial Locations
- Locations (31)
Alabama CRS (31788)
🇺🇸Birmingham, Alabama, United States
University of Southern California (1201)
🇺🇸Los Angeles, California, United States
University of California, Los Angeles CARE Center CRS (601)
🇺🇸Los Angeles, California, United States
2701 Northwestern University CRS
🇺🇸Chicago, Illinois, United States
Johns Hopkins University CRS (201)
🇺🇸Baltimore, Maryland, United States
New Jersey Medical School Clinical Research Center CRS (31786)
🇺🇸Newark, New Jersey, United States
Weill Cornell Chelsea CRS (7804)
🇺🇸New York, New York, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
🇺🇸Rochester, New York, United States
Greensboro CRS (3203)
🇺🇸Greensboro, North Carolina, United States
The Miriam Hospital (TMH) ACTG CRS (2951)
🇺🇸Providence, Rhode Island, United States
Trinity Health and Wellness Center CRS (31443)
🇺🇸Dallas, Texas, United States
Houston AIDS Research Team (HART) CRS (31473)
🇺🇸Houston, Texas, United States
Ucsd, Avrc Crs (701)
🇺🇸San Diego, California, United States
Ucsf Aids Crs (801)
🇺🇸San Francisco, California, United States
Harbor-UCLA Med. Ctr. CRS (603)
🇺🇸Torrance, California, United States
University of Colorado Hospital CRS (6101)
🇺🇸Aurora, Colorado, United States
Rush Univ. Med. Ctr. ACTG CRS (2702)
🇺🇸Chicago, Illinois, United States
Washington University CRS (2101)
🇺🇸Saint Louis, Missouri, United States
Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
🇺🇸New York, New York, United States
Columbia Physicians and Surgeons CRS (30329)
🇺🇸New York, New York, United States
Unc Aids Crs (3201)
🇺🇸Chapel Hill, North Carolina, United States
Univ. of Cincinnati CRS (2401)
🇺🇸Cincinnati, Ohio, United States
Case CRS (2501)
🇺🇸Cleveland, Ohio, United States
The Ohio State Univ. AIDS CRS (2301)
🇺🇸Columbus, Ohio, United States
Hosp. of the Univ. of Pennsylvania CRS (6201)
🇺🇸Philadelphia, Pennsylvania, United States
Pittsburgh CRS (1001)
🇺🇸Pittsburgh, Pennsylvania, United States
Massachusetts General Hospital (MGH) CRS (101)
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hosp. ACTG CRS (107)
🇺🇸Boston, Massachusetts, United States
Vanderbilt Therapeutics CRS (3652)
🇺🇸Nashville, Tennessee, United States
University of Washington AIDS CRS (1401)
🇺🇸Seattle, Washington, United States
Puerto Rico-AIDS CRS (5401)
🇵🇷San Juan, Puerto Rico