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

This study is currently recruiting participants.
Verified November 2017 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02344290
First Posted: January 22, 2015
Last Update Posted: November 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Kowa Pharmaceuticals America, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
  Purpose

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).


Condition Intervention Phase
HIV Infections Cardiovascular Diseases Drug: Pitavastatin Drug: Placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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.)


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 6500
Study Start Date: March 2015
Estimated Study Completion Date: April 2020
Estimated Primary Completion Date: April 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pitavastatin
Participants will receive pitavastatin once a day for the entire time they are enrolled in the study.
Drug: Pitavastatin
One tablet (4 mg) taken once daily, orally with or without food
Placebo Comparator: Placebo
Participants will receive placebo for pitavastatin once a day for the entire time they are enrolled in the study.
Drug: Placebo
One tablet taken once daily, orally with or without food

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 72 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 ½ to 6 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).

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   40 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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 atherosclerotic cardiovascular disease (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: Subjects with successfully treated non-melanomatous skin cancer within 12 months prior to study entry are acceptable. Disseminated Kaposi Sarcoma (visceral organ involvement) within the past 12 months is exclusionary.
  • 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 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02344290


Contacts
Contact: Kathleen Fitch, ANP 617-724-8015 kfitch@mgh.harvard.edu
Contact: Barbara Bastow 301-628-3315 bbastow@s-3.com

  Show 131 Study Locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
National Heart, Lung, and Blood Institute (NHLBI)
Kowa Pharmaceuticals America, Inc.
Investigators
Study Chair: Steven Grinspoon, MD Harvard Medical School
  More Information

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02344290     History of Changes
Other Study ID Numbers: A5332
11960 ( Other Identifier: DAIDS-ES Registry Number )
1U01HL123339-01 ( U.S. NIH Grant/Contract )
1U01HL123336-01 ( U.S. NIH Grant/Contract )
First Submitted: January 16, 2015
First Posted: January 22, 2015
Last Update Posted: November 17, 2017
Last Verified: November 2017

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
HIV
Cardiovascular Disease
Myocardial Infarction
Inflammation
Statin
Computerized Tomography
Cholesterol

Additional relevant MeSH terms:
HIV Infections
Cardiovascular Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Pitavastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents