Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults

Study Overview
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Brief Summary
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People infected with HIV are at risk for cardiovascular disease (CVD). This study will evaluate the use of pitavastatin to reduce the risk of CVD in adults infected with HIV who are on antiretroviral therapy (ART). The REPRIEVE trial consists of two parallel identical protocols: REPRIEVE (A5332) is funded by the NHLBI, with additional infrastructure support provided by the NIAID, and is conducted in U.S and select international sites (approximately 120 sites in 11 countries). REPRIEVE (EU5332) is co-sponsored by NEAT ID and MGH, and is conducted at 13 sites in Spain.

Detailed Description
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Currently, there are few strategies to prevent CVD in HIV-infected people, 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 people infected with HIV. The purpose of this study is to evaluate the use of pitavastatin to reduce the risk of CVD in adults infected with HIV who are on ART. This study will enroll adults infected with HIV who are on any ART regimen (ART is not provided by the study) for at least 6 months before study entry considered low-to-moderate risk using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline thresholds for recommended statin initiation. Total study duration will be approximately 96 months from the time the first participant is enrolled. Participants will be randomly assigned to receive 4 mg of pitavastatin or placebo once a day for the entire time they are enrolled in the study. Study visits will occur at study entry (Day 0) and Months 1 and 4. Starting at Month 4, study visits will occur every 4 months for the rest of the study. Depending on when participants enroll, they will be in the study for a total of 3 to 8 years. Study visits will include 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). Some participants will have the option of enrolling in a substudy (Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of REPRIEVE [A5333s]). The substudy will evaluate the effect of pitavastatin on the progression of non-calcified coronary atherosclerotic plaque (NCP) and inflammatory biomarkers in adults infected with HIV. Participants in the substudy will attend study visits at study entry and Months 4 and 24. The visits will include questionnaires and assessments, a blood collection, and a coronary computed tomography angiography (CCTA). NOTE: The Mechanistic Substudy of REPRIEVE (A5333s) closed to accrual on 02/06/18. Participants enrolled in REPRIEVE from select study sites, including international sites, through December, 2017, are included in the REPRIEVE Kidney Function Objectives Cohort to evaluate the effects of pitavastatin on parameters of kidney function in the setting of HIV infection. The analyses will also include an assessment of high risk groups and mechanisms driving kidney function decline in the setting of HIV infection. Women and men enrolled in REPRIEVE after February, 2016 are included in an observational cohort (REPRIEVE Women's Objectives Cohort) facilitating assessment of sex-specific mechanisms of CVD risk and risk reduction among adults with HIV. This effort also includes an evidence-based recruitment campaign to enhance women's participation in REPRIEVE. In response to the SARS-Cov-2 pandemic, a supplemental objective was added in 2020. To better understand how COVID-19 affects PWH and if pitavastatin may reduce risk, we will evaluate interrelated but independent key topics including epidemiology, host factors, and protective strategies. Starting from April 2020, COVID-19 assessment is completed at each study visit, and blood is collected for COVID-19 biomarkers.

Official Title
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Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE

Conditions
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HIV Infections, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Pitavastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected individuals 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 a: Fasting low-density lipoprotein (LDL) cholesterol as follows: If ASCVD risk score is less than 7.5%, LDL cholesterol must be less than 190 mg/dL. If ASCVD risk score is greater than or equal to 7.5% and less than or equal to 10%, LDL must be less than 160 mg/dL. If ASCVD risk score is greater than 10% and less than or equal to 15%, LDL must be less than 130 mg/dL. NOTE: If LDL is less than 70 mg/dL, participant is eligible regardless of 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 be less than or equal to 3.25 Ability and willingness of participant or legal representative to provide written informed consent Exclusion Criteria: 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 Stroke Transient ischemic attack (TIA) Peripheral arterial disease presumed to be of atherosclerotic origin Current diabetes mellitus if LDL is 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. NOTE: Exceptions: Successfully treated non-melanomatous skin cancer 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. NOTE: Use of oral prednisone less than or equal to 10 mg/day or equivalent dosage is allowed. 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

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pitavastatin<br>Participants will receive pitavastatin once a day for the entire time they are enrolled in the study. | Drug: Pitavastatin<br>* One tablet (4 mg) taken once daily, orally with or without food<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo for pitavastatin once a day for the entire time they are enrolled in the study. | Drug: Placebo<br>* One tablet taken once daily, orally with or without food<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first event of a composite of major cardiovascular events | Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary, carotid or peripheral arterial revascularization, nonfatal stroke or transient ischemic attack (TIA), peripheral arterial ischemia | Measured through participants' final study visit, at approximately Month 36 to 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first of each individual component of the primary endpoint | Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary, carotid or peripheral arterial revascularization, nonfatal stroke or transient ischemic attack (TIA), peripheral arterial ischemia | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Time to death (all-cause mortality) | Time to death (all-cause mortality) | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Time to death (all-cause mortality) and/or major adverse cardiovascular events (MACE) | Time to death (all-cause mortality) and/or major adverse cardiovascular events (MACE) | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Time to any (composite) or each (individual) of the following clinical diagnoses (including recurrent diagnoses as appropriate) | Non AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of the skin); AIDS-defining events (based on Centers for Disease Control and Prevention [CDC] 2014 classification); initiation of dialysis or renal transplantation; cirrhosis, or hepatic decompensation requiring hospitalization. | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Calculated fasting low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) cholesterol level | Change from baseline expressed as absolute change and as a percentage of baseline. For participants with triglycerides greater than 400 mg/dL and less than 500 mg/dL, direct LDL will be determined and used in the statistical analysis. | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Time to any of the following adverse events (including recurrent events as appropriate) | Serious adverse event as defined by International Conference on Harmonisation (ICH) criteria, incident diabetes mellitus (DM), grade 3 or 4 ALT, or grade 3 or 4 myopathy. | Measured through participants' final study visit, at approximately Month 36 to 96 | 
| Incidence of COVID-19 | COVID-19 is defined as COVID-19 clinical diagnosis or positive test. | Measured from 2020 to participants' final study visit, approximately for 3 years | 
| Incidence of serious COVID-19 | Serious COVID-19 is defined as COVID-19 related hospitalization or death. | Measured from 2020 to participants' final study visit, approximately for 3 years | 
| For substudy: volume of NCP at study entry and change in NCP over 2 years | Expressed as absolute change and as a percentage of baseline. | Measured through Year 2 | 
| For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP) | For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP) | Measured through Year 2 | 
| For substudy: progression of NCP | Participants with evidence of NCP at entry: any progression/increase in NCP volume; participants without evidence of NCP at entry, incident NCP. | Measured through Year 2 | 
| For substudy: number of high risk plaque features | Low Hounsfield Unit attenuation by CT assessment; positive remodeling. | Measured through Year 2 | 
| For substudy: changes in inflammatory markers | Expressed as change in CRP, Lp-PLA2, sCD163 | Measured through Year 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Cardiovascular Disease, Myocardial Infarction, Inflammation, Statin, Computerized Tomography, Cholesterol, COVID-19