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

HIV Infections Clinical Trial

— REPRIEVE  

Official title:

Randomized Trial to Prevent Vascular Events in HIV - REPRIEVE

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02344290
• Other study ID #: A5332
• Secondary ID: 119601U01HL12333
• Status: Completed
• Phase: Phase 3
• Start date: March 26, 2015
• Est. completion date: August 21, 2023

Study information

• Verified date: March 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7769
• Est. completion date: August 21, 2023
• Est. primary completion date: August 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases
• HIV Infections

Intervention

Drug:
• Pitavastatin
One tablet (4 mg) taken once daily, orally with or without food
• Placebo
One tablet taken once daily, orally with or without food

Locations

Country	Name	City	State
Botswana	Gaborone CRS	Gaborone	South-East District
Brazil	School of Medicine, Federal University of Minas Gerais CRS	Belo Horizonte	Minas Gerais
Brazil	Tropical Medicine Foundation Dr. Heitor Vieira Dourado CRS	Manaus	Amazonas
Brazil	HGNI HIV Family Care Clinic - HHFCC CRS	Nova Iguacu	Rio De Janeiro
Brazil	Hospital Nossa Senhora da Conceicao CRS	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital Federal dos Servidores do Estado CRS	Rio de Janeiro
Brazil	Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio de Janeiro
Brazil	Projeto Praça Onze Pesquisa em Saúde CRS	Rio de Janeiro
Brazil	Centro de Pesquisas Clínicas IC-HCFMUSP CRS	Sao Paulo
Brazil	Centro de Referencia e Treinamento DST/AIDS CRS	Sao Paulo	São Paulo
Brazil	Instituto de Infectologia Emilio Ribas CRS	Sao Paulo
Canada	Hamilton Health Sciences - Special Immunology Services Clinic CRS	Hamilton	Ontario
Canada	Chronic Viral Illness Service CRS	Montreal	Quebec
Canada	Centre hospitalier de l'Université Laval CRS	Quebec City	Quebec
Canada	Maple Leaf Research CRS	Toronto	Ontario
Canada	Toronto General Hospital CRS	Toronto	Ontario
Canada	Vancouver ID Research & Care Centre Society CRS	Vancouver	British Columbia
Haiti	GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS	Port-au-Prince
Haiti	Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS	Port-au-Prince
India	Chennai Antiviral Research and Treatment (CART) CRS	Chennai	Tamil Nadu
India	Byramjee Jeejeebhoy Medical College (BJMC) CRS	Pune	Maharashtra
Peru	Barranco CRS	Lima
Peru	San Miguel CRS	Lima
Puerto Rico	Puerto Rico AIDS Clinical Trials Unit CRS	San Juan
South Africa	University of Cape Town Lung Institute (UCTLI) CRS	Cape Town	Western Cape Province
South Africa	Durban International Clinical Research Site CRS	Durban	Kwa Zulu Natal
South Africa	Soweto ACTG CRS	Johannesburg	Gauteng
South Africa	Wits Helen Joseph Hospital CRS (Wits HJH CRS)	Johannesburg	Gauteng
South Africa	Famcru Crs	Tygerberg	Western Cape Province
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario de Bellvitge	Barcelona
Spain	Hospital Universitario Valle d'Hebron	Barcelona
Spain	Hospital Universitario de Basurto de Basurto	Bilbao
Spain	Hospital General Universitario De Elche	Elche
Spain	Hospital Gregorio Universitario Maranon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Thailand	Thai Red Cross AIDS Research Centre (TRC-ARC) CRS	Bangkok
Thailand	Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS	Chiang Mai
Uganda	Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site	Kampala
United States	The Ponce de Leon Center CRS	Atlanta	Georgia
United States	Augusta University Research Institute, Inc. CRS	Augusta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Johns Hopkins University CRS	Baltimore	Maryland
United States	Alabama CRS	Birmingham	Alabama
United States	Boston Medical Center CRS	Boston	Massachusetts
United States	Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS	Boston	Massachusetts
United States	Massachusetts General Hospital CRS (MGH CRS)	Boston	Massachusetts
United States	Tufts Medical Center CRS	Boston	Massachusetts
United States	James J Peters VA Medical Center CRS	Bronx	New York
United States	Cooper Univ. Hosp. CRS	Camden	New Jersey
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Medical University of South Carolina: Division of Infectious Diseases CRS	Charleston	South Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush University CRS	Chicago	Illinois
United States	UIC Project WISH CRS	Chicago	Illinois
United States	Cincinnati Clinical Research Site	Cincinnati	Ohio
United States	Case Clinical Research Site	Cleveland	Ohio
United States	Palmetto Health Clinical Trial Department CRS	Columbia	South Carolina
United States	Prisma Health CRS	Columbia	South Carolina
United States	Ohio State University CRS	Columbus	Ohio
United States	Dallas VA Medical Center CRS	Dallas	Texas
United States	Trinity Health and Wellness Center CRS	Dallas	Texas
United States	UT Southwestern HIV/ID Clinical Trials Unit CRS	Dallas	Texas
United States	Denver Public Health CRS	Denver	Colorado
United States	Henry Ford Hosp. CRS	Detroit	Michigan
United States	Duke University Medical Center CRS	Durham	North Carolina
United States	Inova Heart and Vascular Institute CRS	Falls Church	Virginia
United States	Malcom Randall VA Medical Center CRS	Gainesville	Florida
United States	Greensboro CRS	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS	Houston	Texas
United States	Michael E. DeBakey VAMC REPRIEVE CRS	Houston	Texas
United States	Indiana University Infectious Diseases Research CRS	Indianapolis	Indiana
United States	Department of Internal Medicine, University of Iowa Hospitals & Clinics CRS	Iowa City	Iowa
United States	University of Mississippi Medical Center CRS	Jackson	Mississippi
United States	Bluegrass Care Clinic/University of Kentucky Research Foundation CRS	Lexington	Kentucky
United States	Los Angeles LGBT Center CRS	Los Angeles	California
United States	Mills Clinical Research CRS	Los Angeles	California
United States	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California CRS	Los Angeles	California
United States	VA West Los Angeles Medical Center CRS	Los Angeles	California
United States	550 Clinic -University of Louisville CRS	Louisville	Kentucky
United States	AHF - South Beach CRS	Miami	Florida
United States	AHF-The Kinder Medical Group CRS	Miami	Florida
United States	The University of Miami AIDS Clinical Research Unit (ACRU) CRS	Miami	Florida
United States	University of Miami Infectious Disease Research Unit at Jackson Memorial Hospital CRS	Miami	Florida
United States	Medical College of Wisconsin, Inc. CRS	Milwaukee	Wisconsin
United States	Abbott Northwestern Hospital CRS	Minneapolis	Minnesota
United States	Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee
United States	Yale University CRS	New Haven	Connecticut
United States	Tulane - Louisiana Community AIDS Research Program (T-LaCARP) CRS	New Orleans	Louisiana
United States	Columbia P&S CRS	New York	New York
United States	Infectious Disease Clinical and Translational Research Center (CTRC) CRS	New York	New York
United States	Mount Sinai Beth Israel CRS	New York	New York
United States	Mount Sinai Downtown CRS	New York	New York
United States	Mount Sinai St. Luke's Morningside CRS	New York	New York
United States	Mount Sinai West Samuels CRS	New York	New York
United States	VA New York Harbor Healthcare System (NYHHS), NY Campus CRS	New York	New York
United States	Weill Cornell Chelsea CRS	New York	New York
United States	Weill Cornell Uptown CRS	New York	New York
United States	New Jersey Medical School Clinical Research Center CRS	Newark	New Jersey
United States	Specialty Care Center CRS	Omaha	Nebraska
United States	Orlando Immunology Center CRS	Orlando	Florida
United States	Eisenhower Health Center at Rimrock CRS	Palm Springs	California
United States	Stanford AIDS Clinical Trials Unit CRS	Palo Alto	California
United States	Center of Translational AIDS Research, Lewis Katz School of Medicine at Temple University CRS	Philadelphia	Pennsylvania
United States	Division of Infectious Diseases Clinical Research Center- Drexel University CRS	Philadelphia	Pennsylvania
United States	Penn Therapeutics, CRS	Philadelphia	Pennsylvania
United States	Positive Health Clinic CRS	Pittsburgh	Pennsylvania
United States	University of Pittsburgh CRS	Pittsburgh	Pennsylvania
United States	The Miriam Hospital Clinical Research Site (TMH CRS) CRS	Providence	Rhode Island
United States	Virginia Commonwealth University CRS	Richmond	Virginia
United States	University of Rochester Adult HIV Therapeutic Strategies Network CRS	Rochester	New York
United States	Washington University Therapeutics (WT) CRS	Saint Louis	Missouri
United States	UCSD Antiviral Research Center CRS	San Diego	California
United States	Ucsf Hiv/Aids Crs	San Francisco	California
United States	Community AIDS Network/Comprehensive Care Clinic CRS	Sarasota	Florida
United States	University of Washington AIDS CRS	Seattle	Washington
United States	St. John Newland Medical Associates CRS	Southfield	Michigan
United States	Baystate Infectious Diseases Clinical Research CRS	Springfield	Massachusetts
United States	Florida Department of Health - Hillsborough County	Tampa	Florida
United States	University of Toledo Medical Center CRS	Toledo	Ohio
United States	Harbor-UCLA CRS	Torrance	California
United States	University of Arizona CRS	Tucson	Arizona
United States	Oklahoma State University Center for Health Sciences CRS	Tulsa	Oklahoma
United States	AIDS Research and Treatment Center of the Treasure Coast CRS	Vero Beach	Florida
United States	Capital Medical Associates, PC CRS	Washington	District of Columbia
United States	Georgetown University CRS (GU CRS)	Washington	District of Columbia
United States	Infectious Diseases Clinic, Washington DC Veterans Affairs Medical Center CRS	Washington	District of Columbia
United States	Whitman-Walker Health CRS	Washington	District of Columbia
United States	VA Connecticut Healthcare System CRS	West Haven	Connecticut
United States	Wake Forest Baptist Medical Center CRS	Winston-Salem	North Carolina
Zimbabwe	Milton Park CRS	Harare

Sponsors (6)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Gilead Sciences, Kowa Pharmaceuticals America, Inc., Massachusetts General Hospital, National Heart, Lung, and Blood Institute (NHLBI), NEAT ID Foundation

Countries where clinical trial is conducted

United States,  Zimbabwe,  Botswana,  Brazil,  Canada,  Haiti,  India,  Peru,  Puerto Rico,  South Africa,  Spain,  Thailand,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Time to death (all-cause mortality)	Time to death (all-cause mortality)	Measured through participants' final study visit, at approximately Month 36 to 96
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP)	For substudy: evidence of non-calcified coronary atherosclerotic plaque (NCP)	Measured through Year 2
Secondary	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
Secondary	For substudy: number of high risk plaque features	Low Hounsfield Unit attenuation by CT assessment; positive remodeling.	Measured through Year 2
Secondary	For substudy: changes in inflammatory markers	Expressed as change in CRP, Lp-PLA2, sCD163	Measured through Year 2

External Links

•   REPRIEVE Trial Website