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

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ClinicalTrials.gov Identifier: NCT02344290
Recruitment Status : Active, not recruiting
First Posted : January 22, 2015
Last Update Posted : October 22, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Kowa Pharmaceuticals America, Inc.
Gilead Sciences
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE January 16, 2015
First Posted Date  ICMJE January 22, 2015
Last Update Posted Date October 22, 2019
Study Start Date  ICMJE March 2015
Estimated Primary Completion Date March 24, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 10, 2019)
Time to the first event of a composite of major cardiovascular events [ Time Frame: Measured through participants' final study visit, at approximately Month 36 to 96 ]
Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, nonfatal stroke or transient ischemic attack (TIA), urgent peripheral arterial disease (PAD) ischemic event (acute or chronic limb ischemia, amputation, etc.)
Original Primary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
Time to the first event of a composite of major cardiovascular events [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, nonfatal stroke or transient ischemic attack (TIA), urgent peripheral arterial disease (PAD) ischemic event (acute or chronic limb ischemia, amputation, etc.)
Change History Complete list of historical versions of study NCT02344290 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 10, 2019)
  • Time to the first of each individual component of the primary endpoint [ Time Frame: Measured through participants' final study visit, at approximately Month 36 to 96 ]
    Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, nonfatal stroke or TIA, urgent PAD ischemic event (acute or chronic limb ischemia, amputation, etc.)
  • Time to death (all-cause mortality) [ Time Frame: 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 Frame: 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) [ Time Frame: Measured through participants' final study visit, at approximately Month 36 to 96 ]
    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.
  • Calculated fasting low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) cholesterol level [ Time Frame: Measured through participants' final study visit, at approximately Month 36 to 96 ]
    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.
  • Time to any of the following adverse events (including recurrent events as appropriate) [ Time Frame: Measured through participants' final study visit, at approximately Month 36 to 96 ]
    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.
  • For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP) [ Time Frame: Measured through Year 2 ]
  • For substudy: volume of NCP at study entry and change in NCP over 2 years [ Time Frame: Measured through Year 2 ]
    Expressed as absolute change and as a percentage of baseline.
  • For substudy: progression of NCP [ Time Frame: Measured through Year 2 ]
    Participants with evidence of NCP at entry: any progression/increase in NCP volume; participants without evidence of NCP at entry, incident NCP.
  • For substudy: number of high risk plaque features [ Time Frame: Measured through Year 2 ]
    Low Hounsfield Unit attenuation by CT assessment; positive remodeling.
  • For substudy: changes in inflammatory markers [ Time Frame: Measured through Year 2 ]
    Expressed as change in CRP, Lp-PLA2, sCD163
  • For substudy: changes in markers of glucose homeostasis [ Time Frame: Measured through Year 2 ]
    Expressed as change in hemoglobin A1C
Original Secondary Outcome Measures  ICMJE
 (submitted: January 16, 2015)
  • Time to the first of each individual component of the primary endpoint [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
    Includes atherosclerotic or other CVD death, nonfatal myocardial infarction, unstable angina hospitalization, coronary or peripheral arterial revascularization, nonfatal stroke or TIA, urgent PAD ischemic event (acute or chronic limb ischemia, amputation, etc.)
  • Time to death (all-cause mortality) [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
  • Time to death (all-cause mortality) and/or major adverse cardiovascular events (MACE) [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
  • Time to any (composite) or each (individual) of the following clinical diagnoses (including recurrent diagnoses as appropriate) [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
    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.
  • Calculated fasting low-density lipoprotein (LDL) and non-high-density lipoprotein (HDL) cholesterol level [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
    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.
  • Time to any of the following adverse events (including recurrent events as appropriate) [ Time Frame: Measured through participants' final study visit, at approximately Month 42 to 72 ]
    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.
  • For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP) [ Time Frame: Measured through Year 2 ]
  • For substudy: volume of NCP at study entry and change in NCP over 2 years [ Time Frame: Measured through Year 2 ]
    Expressed as absolute change and as a percentage of baseline.
  • For substudy: progression of NCP [ Time Frame: Measured through Year 2 ]
    Participants with evidence of NCP at entry: any progression/increase in NCP volume; participants without evidence of NCP at entry, incident NCP.
  • For substudy: number of high risk plaque features [ Time Frame: Measured through Year 2 ]
    Low Hounsfield Unit attenuation by CT assessment; positive remodeling.
  • For substudy: changes in inflammatory markers [ Time Frame: Measured through Year 2 ]
    Expressed as change in CRP, Lp-PLA2, sCD163
  • For substudy: changes in markers of glucose homeostasis [ Time Frame: Measured through Year 2 ]
    Expressed as change in hemoglobin A1C
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults
Official Title  ICMJE Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE (A5332)
Brief Summary

The study is funded by the National Heart, Lung, and Blood Institute, with additional infrastructure support provided by the National Institute of Allergy and Infectious Diseases.

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).

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • HIV Infections
  • Cardiovascular Diseases
Intervention  ICMJE
  • Drug: Pitavastatin
    One tablet (4 mg) taken once daily, orally with or without food
  • Drug: Placebo
    One tablet taken once daily, orally with or without food
Study Arms  ICMJE
  • Experimental: Pitavastatin
    Participants will receive pitavastatin once a day for the entire time they are enrolled in the study.
    Intervention: Drug: Pitavastatin
  • Placebo Comparator: Placebo
    Participants will receive placebo for pitavastatin once a day for the entire time they are enrolled in the study.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
7500
Original Estimated Enrollment  ICMJE
 (submitted: January 16, 2015)
6500
Estimated Study Completion Date  ICMJE March 26, 2023
Estimated Primary Completion Date March 24, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Men and women 40 to 75 years of age
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Botswana,   Brazil,   Canada,   Haiti,   India,   Peru,   Puerto Rico,   South Africa,   Thailand,   Uganda,   United States,   Zimbabwe
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02344290
Other Study ID Numbers  ICMJE A5332
11960 ( Other Identifier: DAIDS-ES Registry Number )
1U01HL123339-01 ( U.S. NIH Grant/Contract )
1U01HL123336-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Kowa Pharmaceuticals America, Inc.
  • Gilead Sciences
Investigators  ICMJE
Study Chair: Steven Grinspoon, MD Harvard Medical School
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP