Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 7,769
- 试验地点
- 137
- 主要终点
- Incidence Rate of Major Adverse Cardiovascular Event (MACE)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Individual with HIV-1
- •Combination antiretroviral therapy (ART) for at least 180 days prior to study entry
- •CD4+ cell count greater than 100 cells/mm^3
- •Acceptable screening laboratories including:
- •Fasting low-density lipoprotein (LDL) cholesterol as follows:
- •If ASCVD risk score was less than 7.5%, LDL cholesterol must have been less than 190 mg/dL.
- •If ASCVD risk score was greater than or equal to 7.5% and less than or equal to 10%, LDL must have been less than 160 mg/dL.
- •If ASCVD risk score was greater than 10% and less than or equal to 15%, LDL must have been less than 130 mg/dL.
- •Participants with LDL less than 70 mg/dL were eligible regardless of the 10-year ASCVD risk score, in line with the ACC/AHA 2013 Prevention Guidelines.
- •Fasting triglycerides less than 500 mg/dL
- •Hemoglobin greater than or equal to 8 g/dL for female participants and greater than or equal to 9 g/dL for male participants
- •Glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m^2 or creatinine clearance (CrCl) greater than or equal to 60 mL/min
- •Alanine aminotransferase (ALT) less than or equal to 2.5 x the upper limit of normal (ULN)
- •For persons with known chronic active hepatitis B or C, calculated fibrosis 4 score (FIB-4) must have been less than or equal to 3.25
- •Ability and willingness of participant or legal representative to provide written informed consent
排除标准
- •Clinical ASCVD, as defined by 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, including a previous diagnosis of any of the following:
- •Acute myocardial infarction (AMI)
- •Acute coronary syndromes
- •Stable or unstable angina
- •Coronary or other arterial revascularization
- •Transient ischemic attack (TIA)
- •Peripheral arterial disease presumed to be of atherosclerotic origin
- •Current diabetes mellitus with LDL greater than or equal to 70 mg/dL
- •10-year ASCVD risk score estimated by Pooled Cohort Equations greater than 15%
- •Active cancer within 12 months prior to study entry, except successfully treated non-melanomatous skin cancer and Kaposi sarcoma without visceral organ involvement
- •Known decompensated cirrhosis
- •History of myositis or myopathy with active disease in the 180 days prior to study entry
- •Known untreated symptomatic thyroid disease
- •History of allergy or severe adverse reaction to statins
- •Use of specific immunosuppressants or immunomodulatory agents including but not limited to tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, tumor necrosis factor (TNF)-alpha blockers or antagonists, azathioprine, interferon, growth factors, or intravenous immunoglobulin (IVIG) in the 30 days prior to study entry.
- •Current use of erythromycin, colchicine, or rifampin
- •Use of any statin drugs, gemfibrozil, or PCSK9 inhibitors in the 90 days prior to study entry
- •Current use of an investigational new drug that would be contraindicated
- •Serious illness or trauma requiring systemic treatment or hospitalization in the 30 days prior to study entry
- •Current pregnancy or breastfeeding
- •Alcohol or drug use that, in the opinion of the site investigator, would interfere with completion of study procedures
- •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
研究组 & 干预措施
Pitavastatin
Participants received pitavastatin once a day for the entire time they were in study follow-up.
干预措施: Pitavastatin (Drug)
Placebo
Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up.
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence Rate of Major Adverse Cardiovascular Event (MACE)
时间窗: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).
MACE is a composite of cardiovascular (CV) death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack (TIA), peripheral arterial ischemia, coronary, carotid or peripheral arterial revascularization, or death from an undetermined cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).
次要结局
- Incidence Rate of Cardiac Ischemia or Myocardial Infarction(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Cerebrovascular Event (Stroke or TIA)(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Peripheral Arterial Ischemia(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2(Entry and year 2.)
- Incidence Rate of Death From CV Causes(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Death From CV or Undetermined Causes(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Cardiac Catheterization or Revascularization(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Carotid or Cerebrovascular Revascularization(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Peripheral Arterial Revascularization(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of MACE or Death(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Death (All-cause)(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Non-CV Clinical Diagnoses(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Non-AIDS-defining Cancer(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of AIDS-defining Event(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of End-Stage Renal Disease(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of End-Stage Liver Disease(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Non-fatal Serious Adverse Event(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Diabetes(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Myalgia, Muscle Weakness or Myopathy(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2(Entry and year 2.)
- Incidence Rate of Rhabdomyolysis(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Grade 3 or Higher ALT(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Incidence Rate of Adverse Event (AE)(From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).)
- Fasting Low-density Lipoprotein Cholesterol (LDL-C)(At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.)
- Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C)(At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.)
- Incidence Rate of Serious COVID-19(From January 1, 2020 through end of study; the median follow-up time was 3.3 years.)
- Incidence Rate of COVID-19(From January 1, 2020 through end of study; the median follow-up time was 3.3 years.)
- For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2(Entry and Year 2.)
- For Mechanistic Substudy: LpPLA2 Level(Entry and month 24.)
- For Mechanistic Substudy: Change in LpPLA2 From Baseline(Entry and month 24.)
- For Mechanistic Substudy: HsCRP Level(Entry and month 24.)
- For Mechanistic Substudy: Change in HsCRP From Baseline(Entry and month 24.)
- For Mechanistic Substudy: Soluble CD163 Level(Entry and month 24.)
- For Mechanistic Substudy: Change in Soluble CD163 From Baseline(Entry and month 24.)