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

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.

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.