PRE-EMPT: Prospective RandomizEd Evaluation and Management of Premature aTherosclerosis

Official title

Prospective RandomizEd Evaluation and Management of Premature aTherosclerosis

Overview

Heart disease is the leading cause of death for men, women, and people of most racial and ethnic groups in the United States. This clinical trial will test if screening and early treatment of mild heart disease works. PRE-EMPT will screen individuals at low 10-year risk of heart disease with heart disease risk factors to identify those who already have early cholesterol build up, also called "plaque", in their heart arteries. It consists of two phases: 1. A Screening Study - Participants will be assessed for plaque by one or both of these scans. * Coronary Artery Calcium (CAC) Scan: A CT scan that looks for calcium or plaque in heart arteries. * Coronary CT Angiography (CCTA) Scan: A CT scan that uses contrast dye to create detailed 3D pictures of heart arteries to look for plaque. 2. A Treatment Trial (approximately 1,500 participants) - Based on the results of the CCTA, participants may be randomized into a two-year trial to test medications aimed at reducing or stabilizing plaque. Participants will have a 1 in 4 chance of receiving only placebo, and a 3 in 4 chance of receiving at least one active medication. Participants will take two pills once a day-either both active medications, one active and one placebo, or both placebos. * Rosuvastatin 20 mg: a cholesterol-lowering medicine * Colchicine 0.5 mg: a medication that lowers inflammation Everyone in the trial will be given information and advice on heart-healthy diet and lifestyle. Participants will have up to two in-person visits for the screening study, then phone visits for the Treatment Trial at the beginning, 3 months, 12 months and 24 months when they will also have an in-person visit for a CCTA Scan. Participants will have blood drawn using an at-home collection device mailed to their home at the beginning, 3 months, and end of the study.

Detailed description

The PRE-EMPT trial will be a 2x2 factorial, double-masked, placebo-controlled randomized trial of the effects of high-intensity statin and low-dose colchicine, alone and in combination, on CCTA-defined Non-Calcified Coronary Plaque (NCCP) volume at 2 years. Participants found through the screening study with CAC 1-99, or through the known plaque pathway, will be eligible for the trial if they have NCCP without severe stenosis or any other exclusion criteria. Study drug will be delivered directly to participants' homes, lab samples will be self-collected at home, and all study visits will be virtual except the imaging visits (up to 3 over 2 years). The only in-person study activities will be the CAC scan, if applicable, and CCTA at baseline and 2 years. The investigators anticipate that this approach will be attractive to middle-aged, busy individuals who are otherwise healthy and asymptomatic. Importantly, all participants in PRE-EMPT will receive an mHealth lifestyle intervention designed to support behavioral modification, ensuring that all individuals benefit from evidence-based strategies for cardiovascular risk reduction.

Interventions

• Drug Rosuvastatin 20 Mg Oral Tablet
  Statin
• Drug Colchicine 0.5 MG Oral Tablet Once Daily
  Anti-inflammatory
• Drug Placebo
  Placebo, non-active, drug-matched

Primary outcome measures

• Non-calcified plaque volume (NCPV) on CCTA at 2 years, adjusted for baseline NCPV. [Time frame: 2 years]

Secondary outcome measures (12)

• Number of participants with Drug Discontinuation [Time frame: Up to 2 years]
• Overall drug treatment adherence [Time frame: Up to 2 years]
• Safety events of special interest [Time frame: Up to 2 years]
• Total plaque volume [Time frame: Up to 2 years]
• Low-attenuation plaque volume [Time frame: Up to 2 years]
• Calcified plaque volume [Time frame: Up to 2 years]
• Number of participants with stenosis [Time frame: Up to 2 years]
• Segment involvement score [Time frame: Up to 2 years]
• Number of participants with qualitative calcified, partially calcified and non-calcified plaque composition [Time frame: Up to 2 years]
• Number of participants with High-risk plaque features (positive remodeling, spotty calcium, napkin ring sign) [Time frame: Up to 2 years]
• Change in LDL-C (low-density lipoprotein cholesterol) [Time frame: Baseline to 2 years]
• Change in non-HDL-C (high-density lipoprotein cholesterol) [Time frame: Baseline to 2 years]

Eligibility criteria

Inclusion criteria

• Women aged 40-60 years; Men aged 30-50 years
• Willing and able to provide informed consent and comply with study procedures
• Smart phone user
• Use of highly effective contraception by females with reproductive potential.
• CAC score 1-99 in the screening study or entry through the known plaque pathway (with mild CAC or CAC<100 if known; elevated CAC on baseline CCTA is not exclusionary in the known plaque arm)
• Diagnostic baseline CCTA with NCPV ≥10 mm3 as assessed by the central core lab

Exclusion criteria

• Clinical diagnosis of ASCVD including coronary artery disease (CAD), peripheral arterial disease (PAD) or cerebrovascular disease (CeVD)
• Current symptoms thought to be from CAD
• PREVENT ASCVD 10-year risk ≥5% (if known)
• Diabetes Mellitus (DM) as defined by any of the following: DM diagnosis in the medical record or HbA1C of 6.5% or greater. (if known)
• LDL-C ≥190mg/dL (most recent, if known)
• HIV (if known)
• Severe liver disease or untreated Hepatitis C infection (if known)
• Pregnancy, lactation or intending to become pregnant during the study period of 2 years
• eGFR <45mL/min/1.73m2 (if known)
• AST or ALT >1.5x the upper limit of normal (if known)
• BMI>40kg/m2 or unable to have a CCTA scan for any reason
• Allergy to iodinated intravenous contrast or other contraindication to CCTA
• Current or previous use of lipid lowering therapy or colchicine
• Known allergic reactions or sensitivity to the study intervention(s), including known intolerance or contraindication(s) to statin or colchicine, or long-term use of medications that are contraindicated with colchicine or rosuvastatin.
• Systemic cancer undergoing active treatment
• PREVENT ASCVD 10-year risk ≥5%
• eGFR <45 ml/min/1.73m2 per baseline labs, (2021 CKD-EPI equation will be used if multiple options are available)
• Hemoglobin A1c ≥6.5% per baseline labs
• LDL-C ≥190mg/dL per baseline labs
• Severe proximal coronary artery stenosis as determined by the central core lab (≥50% left main or ≥70% proximal major coronary artery stenosis)
• Known contraindication to follow-up CCTA (e.g., new IV contrast allergy discovered during the baseline CCTA)
• Individuals who are excluded based on any of these factors will be notified as to the reason for exclusion and encouraged to follow-up locally to address this medical issue with their treating physician.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

United States · 23 centers

• University of Alabama at Birmingham — Birmingham
• Cardiology Associates — Mobile
• University of California, Los Angeles — Los Angeles
• Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center — Los Angeles
• Wellstar Kennestone Hospital — Hiram
• University of Chicago — Chicago
• Johns Hopkins University — Baltimore
• Massachusetts General Hospital Brigham — Boston
• … and 15 more centers

Identifiers

NCT: NCT07232069 · Pro00118744 · UG3HL181434

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗