HIV-1 Infection
Conditions
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.
Interventions
DRUGPitavastatin
One tablet (4 mg) taken once daily, orally with or without food for the entire time participant was in REPRIEVE follow-up.
DRUGPlacebos
One tablet taken once daily, orally with or without food for the entire time participant was in REPRIEVE follow-up.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute on Aging (NIA)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants were randomized as part of REPRIEVE.
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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? |
| 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). |
| 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. |
| 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. |
| 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. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled from March 14, 2017 to February 6, 2019 at REPRIEVE U.S. sites participating in the REPRIEVE Mechanistic Substudy.
Participants by arm
| Arm | Count |
|---|---|
| Pitavastatin Participants who were randomized to pitavastatin in the main study REPRIEVE. | 316 |
| Placebo Participants who were randomized to placebo for pitavastatin in the main study REPRIEVE. | 286 |
| Total | 602 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 34 | 27 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 22 |
Baseline characteristics
| Characteristic | Total | Pitavastatin | Placebo |
|---|---|---|---|
| Age, Continuous | 51 years | 51 years | 51 years |
| Balance: Able to hold single-leg stand for 30 seconds Able to hold position | 468 Participants | 246 Participants | 222 Participants |
| Balance: Able to hold single-leg stand for 30 seconds Not able to hold position | 133 Participants | 70 Participants | 63 Participants |
| CD4 cell count | 609 cells/mm^3 | 615 cells/mm^3 | 609 cells/mm^3 |
| Chair rise rate | 25.1 rises per minute STANDARD_DEVIATION 7.5 | 25.2 rises per minute STANDARD_DEVIATION 7.6 | 25.0 rises per minute STANDARD_DEVIATION 7.3 |
| Enrollment cohort Prospective (Mechanistic Substudy) | 165 Participants | 87 Participants | 78 Participants |
| Enrollment cohort Prospective (REPRIEVE only) | 103 Participants | 60 Participants | 43 Participants |
| Enrollment cohort Retrospective (Mechanistic Substudy) | 334 Participants | 169 Participants | 165 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 108 Participants | 56 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 489 Participants | 257 Participants | 232 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Gait speed | 1.00 meters per second STANDARD_DEVIATION 0.22 | 1.00 meters per second STANDARD_DEVIATION 0.21 | 1.00 meters per second STANDARD_DEVIATION 0.23 |
| Grip strength | 34.7 kg STANDARD_DEVIATION 9.9 | 34.3 kg STANDARD_DEVIATION 9.8 | 35.1 kg STANDARD_DEVIATION 9.9 |
| HIV-1 RNA <50 copies/mL | 550 Participants | 288 Participants | 262 Participants |
| HIV-1 RNA ≥50 copies/mL | 37 Participants | 21 Participants | 16 Participants |
| Modified SPPB score | 1.86 units on a scale STANDARD_DEVIATION 0.25 | 1.86 units on a scale STANDARD_DEVIATION 0.24 | 1.86 units on a scale STANDARD_DEVIATION 0.27 |
| Physical Function Impairment by SPPB score Impairment | 215 Participants | 104 Participants | 111 Participants |
| Physical Function Impairment by SPPB score No impairment | 385 Participants | 212 Participants | 173 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 238 Participants | 126 Participants | 112 Participants |
| Race/Ethnicity, Customized Other | 46 Participants | 27 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 313 Participants | 160 Participants | 153 Participants |
| Region of Enrollment United States | 602 participants | 316 participants | 286 participants |
| Sex: Female, Male Female | 111 Participants | 65 Participants | 46 Participants |
| Sex: Female, Male Male | 491 Participants | 251 Participants | 240 Participants |
| Sex/Gender, Customized Cisgender | 582 Participants | 304 Participants | 278 Participants |
| Sex/Gender, Customized Not reported | 9 Participants | 7 Participants | 2 Participants |
| Sex/Gender, Customized Transgender spectrum | 11 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 316 | 10 / 286 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
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.
Time frame: Baseline and 12 months
Population: The specimen testing was not performed.
Primary
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).
Time frame: Baseline and 24 months
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Quality: Paraspinal Muscle Density | Baseline | 36.8 HU | Standard Deviation 18.1 |
| Pitavastatin | Muscle Quality: Paraspinal Muscle Density | Month 24 | 36.2 HU | Standard Deviation 16.7 |
| Placebo | Muscle Quality: Paraspinal Muscle Density | Baseline | 36.4 HU | Standard Deviation 16.7 |
| Placebo | Muscle Quality: Paraspinal Muscle Density | Month 24 | 35.4 HU | Standard Deviation 18.1 |
Comparison: Comparison of Month 24 valuesp-value: 0.6295% CI: [-1.72, 2.88]Regression, Linear
Primary
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.
Time frame: Entry and months 12, 24, 36, 48, 60
Population: All participants enrolled with any chair rise rate data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Chair Rise Rate | -0.035 rises/minute per year |
| Placebo | Physical Function: Rate of Change in Chair Rise Rate | 0.07 rises/minute per year |
p-value: 0.3195% CI: [-0.3, 0.1]Mixed Models Analysis
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48, 60
Population: All participants enrolled with frailty phenotype data available. (Data availability at baseline and 12 depends on timing of PREPARE enrollment relative to REPRIEVE enrollment.)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pitavastatin | Frailty Phenotype | Baseline | Non-frail | 74 Participants |
| Pitavastatin | Frailty Phenotype | Baseline | Pre-frail | 65 Participants |
| Pitavastatin | Frailty Phenotype | Baseline | Frail | 5 Participants |
| Pitavastatin | Frailty Phenotype | Month 12 | Non-frail | 89 Participants |
| Pitavastatin | Frailty Phenotype | Month 12 | Pre-frail | 82 Participants |
| Pitavastatin | Frailty Phenotype | Month 12 | Frail | 10 Participants |
| Pitavastatin | Frailty Phenotype | Month 24 | Non-frail | 113 Participants |
| Pitavastatin | Frailty Phenotype | Month 24 | Pre-frail | 124 Participants |
| Pitavastatin | Frailty Phenotype | Month 24 | Frail | 15 Participants |
| Pitavastatin | Frailty Phenotype | Month 36 | Non-frail | 102 Participants |
| Pitavastatin | Frailty Phenotype | Month 36 | Pre-frail | 114 Participants |
| Pitavastatin | Frailty Phenotype | Month 36 | Frail | 10 Participants |
| Pitavastatin | Frailty Phenotype | Month 48 | Non-frail | 108 Participants |
| Pitavastatin | Frailty Phenotype | Month 48 | Pre-frail | 112 Participants |
| Pitavastatin | Frailty Phenotype | Month 48 | Frail | 19 Participants |
| Pitavastatin | Frailty Phenotype | Month 60 | Non-frail | 95 Participants |
| Pitavastatin | Frailty Phenotype | Month 60 | Pre-frail | 114 Participants |
| Pitavastatin | Frailty Phenotype | Month 60 | Frail | 22 Participants |
| Placebo | Frailty Phenotype | Month 48 | Pre-frail | 84 Participants |
| Placebo | Frailty Phenotype | Baseline | Non-frail | 65 Participants |
| Placebo | Frailty Phenotype | Month 36 | Non-frail | 104 Participants |
| Placebo | Frailty Phenotype | Month 12 | Pre-frail | 74 Participants |
| Placebo | Frailty Phenotype | Baseline | Pre-frail | 45 Participants |
| Placebo | Frailty Phenotype | Month 60 | Frail | 10 Participants |
| Placebo | Frailty Phenotype | Baseline | Frail | 10 Participants |
| Placebo | Frailty Phenotype | Month 36 | Pre-frail | 86 Participants |
| Placebo | Frailty Phenotype | Month 12 | Non-frail | 72 Participants |
| Placebo | Frailty Phenotype | Month 48 | Frail | 11 Participants |
| Placebo | Frailty Phenotype | Month 36 | Frail | 10 Participants |
| Placebo | Frailty Phenotype | Month 12 | Frail | 10 Participants |
| Placebo | Frailty Phenotype | Month 60 | Pre-frail | 101 Participants |
| Placebo | Frailty Phenotype | Month 24 | Non-frail | 99 Participants |
| Placebo | Frailty Phenotype | Month 48 | Non-frail | 109 Participants |
| Placebo | Frailty Phenotype | Month 24 | Pre-frail | 105 Participants |
| Placebo | Frailty Phenotype | Month 60 | Non-frail | 93 Participants |
| Placebo | Frailty Phenotype | Month 24 | Frail | 14 Participants |
Secondary
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.
Time frame: Baseline and month 12
Population: The specimen testing was not done.
Secondary
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.
Time frame: Baseline and month 24
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Area: Infraspinatus Muscle Area | Baseline | 6.3 cm^2/m | Standard Deviation 4.5 |
| Pitavastatin | Muscle Area: Infraspinatus Muscle Area | Month 24 | 6.5 cm^2/m | Standard Deviation 4.6 |
| Placebo | Muscle Area: Infraspinatus Muscle Area | Baseline | 6.3 cm^2/m | Standard Deviation 4.6 |
| Placebo | Muscle Area: Infraspinatus Muscle Area | Month 24 | 6.2 cm^2/m | Standard Deviation 4.2 |
Comparison: Comparison of Month 24 valuesp-value: 0.2195% CI: [-0.2, 0.9]Regression, Linear
Secondary
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.
Time frame: Baseline and month 24
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Area: Paraspinal Muscle Area | Baseline | 12.0 cm^2/m | Standard Deviation 4.8 |
| Pitavastatin | Muscle Area: Paraspinal Muscle Area | Month 24 | 12.1 cm^2/m | Standard Deviation 4.6 |
| Placebo | Muscle Area: Paraspinal Muscle Area | Baseline | 12.5 cm^2/m | Standard Deviation 5.1 |
| Placebo | Muscle Area: Paraspinal Muscle Area | Month 24 | 12.5 cm^2/m | Standard Deviation 4.9 |
Comparison: Comparison of Month 24 valuesp-value: 0.9895% CI: [-0.5, 0.52]Regression, Linear
Secondary
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.
Time frame: Baseline and month 24
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Area: Pectoral Muscle Area | Baseline | 8.3 cm^2/m | Standard Deviation 5.4 |
| Pitavastatin | Muscle Area: Pectoral Muscle Area | Month 24 | 8.2 cm^2/m | Standard Deviation 4.9 |
| Placebo | Muscle Area: Pectoral Muscle Area | Baseline | 8.6 cm^2/m | Standard Deviation 5.1 |
| Placebo | Muscle Area: Pectoral Muscle Area | Month 24 | 8.7 cm^2/m | Standard Deviation 5.2 |
Comparison: Comparison of Month 24 valuesp-value: 0.3195% CI: [-0.8, 0.3]Regression, Linear
Secondary
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.
Time frame: Baseline and month 24
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Quality: Infraspinatus Muscle Density | Baseline | 44.3 HU | Standard Error 17.1 |
| Pitavastatin | Muscle Quality: Infraspinatus Muscle Density | Month 24 | 44.2 HU | Standard Error 13.4 |
| Placebo | Muscle Quality: Infraspinatus Muscle Density | Baseline | 42.6 HU | Standard Error 18.1 |
| Placebo | Muscle Quality: Infraspinatus Muscle Density | Month 24 | 44.0 HU | Standard Error 15.6 |
Comparison: Comparison of Month 24 valuesp-value: 0.6795% CI: [-2.8, 1.8]Regression, Linear
Secondary
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.
Time frame: Baseline and month 24
Population: Participants who remained on study treatment at Month 24 (per-protocol set) and had data for this outcome available at both baseline and month 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pitavastatin | Muscle Quality: Pectoral Muscle Density | Baseline | 41.4 HU | Standard Deviation 15.9 |
| Pitavastatin | Muscle Quality: Pectoral Muscle Density | Month 24 | 41.5 HU | Standard Deviation 16.1 |
| Placebo | Muscle Quality: Pectoral Muscle Density | Baseline | 40.9 HU | Standard Deviation 16.2 |
| Placebo | Muscle Quality: Pectoral Muscle Density | Month 24 | 41.8 HU | Standard Deviation 15.4 |
Comparison: Comparison of Month 24 valuesp-value: 0.5595% CI: [-2.7, 1.4]Regression, Linear
Secondary
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?
Time frame: Baseline and months 12, 24, 36, 48, 60
Population: All participants enrolled with REAP Question 27 data available.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Rarely/never | 140 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Sometimes | 92 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Usually/often | 83 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Rarely/never | 119 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Sometimes | 30 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Usually/often | 51 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Rarely/never | 124 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Sometimes | 76 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Usually/often | 78 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Rarely/never | 108 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Sometimes | 52 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Usually/often | 59 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Rarely/never | 111 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Sometimes | 51 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Usually/often | 70 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Rarely/never | 115 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Sometimes | 42 Participants |
| Pitavastatin | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Usually/often | 64 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Sometimes | 38 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Rarely/never | 137 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Rarely/never | 113 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Sometimes | 82 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Usually/often | 49 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Baseline | Usually/often | 66 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Sometimes | 37 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Rarely/never | 89 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Usually/often | 54 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Sometimes | 43 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 36 | Usually/often | 51 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 12 | Usually/often | 45 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Sometimes | 36 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Rarely/never | 108 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 48 | Rarely/never | 110 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Sometimes | 80 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 60 | Rarely/never | 100 Participants |
| Placebo | Physical Activity: Frequency of <30 Minutes of Physical Activity 3 or More Days a Week | Month 24 | Usually/often | 58 Participants |
Secondary
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?
Time frame: Baseline and months 12, 24, 36, 48, 60
Population: All participants enrolled with REAP Question 28 data available.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Usually/often | 135 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Rarely/never | 67 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Rarely/never | 52 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Rarely/never | 53 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Sometimes | 58 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Sometimes | 45 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Sometimes | 55 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Usually/often | 109 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Sometimes | 88 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Rarely/never | 54 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Rarely/never | 58 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Sometimes | 54 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Usually/often | 124 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Usually/often | 92 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Rarely/never | 55 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Sometimes | 84 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Usually/often | 121 Participants |
| Pitavastatin | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Usually/often | 158 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Usually/often | 112 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Sometimes | 41 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Rarely/never | 48 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Sometimes | 92 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Baseline | Usually/often | 144 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Rarely/never | 42 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Usually/often | 89 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Rarely/never | 59 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Sometimes | 87 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 24 | Usually/often | 100 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Rarely/never | 46 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Sometimes | 56 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Sometimes | 54 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 36 | Usually/often | 101 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Rarely/never | 45 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 48 | Usually/often | 101 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 60 | Rarely/never | 32 Participants |
| Placebo | Physical Activity: Frequency of Watching >2 Hours of TV or Videos a Day | Month 12 | Sometimes | 46 Participants |
Secondary
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).
Time frame: Baseline, month 24 and end of REPRIEVE (average at 5.6 years)
Population: All participants enrolled with DASI questionnaire completed at the given time point.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pitavastatin | Physical Function: Impairment According to DASI | Month 24 | Some impairment | 84 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Baseline | Moderate impairment | 23 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Month 24 | Severe impairment | 0 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Baseline | No impairment | 219 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | End of REPRIEVE | No impairment | 135 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Baseline | Severe impairment | 0 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | End of REPRIEVE | Some impairment | 77 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Month 24 | Moderate impairment | 31 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | End of REPRIEVE | Moderate impairment | 37 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Month 24 | No impairment | 165 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | End of REPRIEVE | Severe impairment | 0 Participants |
| Pitavastatin | Physical Function: Impairment According to DASI | Baseline | Some impairment | 74 Participants |
| Placebo | Physical Function: Impairment According to DASI | End of REPRIEVE | Severe impairment | 5 Participants |
| Placebo | Physical Function: Impairment According to DASI | Baseline | Some impairment | 66 Participants |
| Placebo | Physical Function: Impairment According to DASI | Baseline | No impairment | 192 Participants |
| Placebo | Physical Function: Impairment According to DASI | Baseline | Moderate impairment | 26 Participants |
| Placebo | Physical Function: Impairment According to DASI | Baseline | Severe impairment | 1 Participants |
| Placebo | Physical Function: Impairment According to DASI | Month 24 | No impairment | 159 Participants |
| Placebo | Physical Function: Impairment According to DASI | Month 24 | Moderate impairment | 22 Participants |
| Placebo | Physical Function: Impairment According to DASI | Month 24 | Severe impairment | 2 Participants |
| Placebo | Physical Function: Impairment According to DASI | End of REPRIEVE | No impairment | 129 Participants |
| Placebo | Physical Function: Impairment According to DASI | End of REPRIEVE | Some impairment | 64 Participants |
| Placebo | Physical Function: Impairment According to DASI | End of REPRIEVE | Moderate impairment | 28 Participants |
| Placebo | Physical Function: Impairment According to DASI | Month 24 | Some impairment | 71 Participants |
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48 and 60.
Population: All participants enrolled with any gait speed data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Gait Speed | -0.013 meters/second per year |
| Placebo | Physical Function: Rate of Change in Gait Speed | -0.012 meters/second per year |
p-value: 0.6195% CI: [-0.007, 0.004]Mixed Models Analysis
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48 and 60
Population: All participants enrolled with any grip strength data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Grip Strength | -0.39 kg per year |
| Placebo | Physical Function: Rate of Change in Grip Strength | -0.36 kg per year |
p-value: 0.895% CI: [-0.25, 0.19]Mixed Models Analysis
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48 and 60
Population: All participants enrolled with any mSPPB data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Modified SPPB Score | -0.019 score on a scale per year |
| Placebo | Physical Function: Rate of Change in Modified SPPB Score | -0.014 score on a scale per year |
p-value: 0.1895% CI: [-0.013, 0.002]Mixed Models Analysis
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48, 60
Population: All participants enrolled with any balance data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Risk of Impairment According to Balance | 1.08 ratio per year |
| Placebo | Physical Function: Rate of Change in Risk of Impairment According to Balance | 1.06 ratio per year |
p-value: 0.3395% CI: [0.98, 1.06]Log-binomial regression using GEE
Secondary
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.
Time frame: Entry and months 12, 24, 36, 48, 60
Population: All participants enrolled with any SPPB data available.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pitavastatin | Physical Function: Rate of Change in Risk of Impairment According to SPPB | 1.00 ratio |
| Placebo | Physical Function: Rate of Change in Risk of Impairment According to SPPB | 0.95 ratio |
p-value: 0.4795% CI: [0.91, 1.24]Log-binomial regression using GEE