A Randomized Comparison of Personalized Care Based on Heart Disease Staging Versus Usual Care for Prevention of Events

Study Overview
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Brief Summary
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TRANSFORM is a prospective, randomized, open blinded endpoint (PROBE), event-driven, pragmatic trial in patients who are at increased risk for atherosclerotic cardiovascular (CV) disease but with no known symptomatic CV disease. The trial tests the hypothesis that a personalized care strategy based on quantitative analysis and staging of coronary atherosclerosis reduces CV events compared with usual care.

Detailed Description
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Cardiovascular disease (CVD) persists as the leading cause of morbidity and mortality worldwide at high societal cost. The current primary CVD prevention strategy relies upon risk stratification using population health markers such as age, sex, diabetes, hypertension, dyslipidemia and tobacco use, with preventive therapy intensified in higher risk strata. Since these risk factors are indirect surrogate markers of the underlying disease, atherosclerosis, this strategy leads to treatment of individuals with risk factors who do not have atherosclerosis and failure to treat those with significant atherosclerosis who lack risk factors. The current strategy also cannot determine which individuals are inadequately treated despite effective risk factor management (residual risk). With the current approach, the CV death rate is trending upward in the US despite evidence that screening asymptomatic patients reduces CV events and the widespread availability of effective preventive therapies. This randomized, controlled, pragmatic trial is designed to address the unmet need for better strategies to identify asymptomatic individuals at increased risk for CV events due to atherosclerosis and to personalize their treatment based on CV risk estimates using coronary artery disease (CAD) visualization and quantification. This study enrolls patients without out known symptoms of ASCVD but who are at increased risk for ASCVD due to their age and having diabetes, prediabetes or metabolic syndrome and tests the hypothesis that a personalized care strategy based on quantitative analysis and staging of coronary atherosclerosis reduces CV events compared with usual care. The Cleerly personalized care strategy incorporates imaging-based evaluation for coronary atherosclerosis (CAD Staging System), algorithm-supported pharmacotherapy and personalized education about their CAD.

Official Title
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A Randomized Comparison of Personalized Care Based on Coronary Artery Disease Staging Versus Usual Care for Primary Prevention of Cardiovascular Events

Conditions
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Diabetes Mellitus, Type 2, PreDiabetes, Metabolic Syndrome

Intervention / Treatment
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* Device: The Cleerly CAD Staging System


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided electronic or written informed consent Men > 55, women > 65 years of age Type 2 diabetes mellitus requiring pharmacologic therapy, prediabetes (most recent HbA1c 5.7 to 6.4% and/or fasting glucose 100-125 mg/dL [5.6-6.9 mmol/L]) and/or metabolic syndrome. Metabolic syndrome is defined as > 3 of the following criteria (International Diabetes Federation 2006): Body mass index ≥ 27 kg/m2 or abnormal waist circumference defined as > 80 cm (31.5 inches) for women, >94 cm (37 inches) for men; for South and East Asian men (e.g., Asian Indian, Chinese, Japanese) ≥ 90 cm (35.4 inches) Fasting triglycerides > 150 mg/dL (1.7 mmol/L) or treated hypertriglyceridemia HDL-cholesterol (HDL-C) < 40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.29 mmol/L) in women or treatment for this lipid abnormality Systolic blood pressure (BP) > 130 and/or diastolic BP > 85 mm Hg and/or treated hypertension Fasting blood glucose > 100 mg/dL (5.6 mmol/L) or HbA1c > 5.7% Have a device (e.g., smartphone, tablet, computer) for communication with the central cardiologist-led team managing drug treatment for the personalized care group Exclusion Criteria: History of symptomatic CVD defined as prior MI, exertional or unstable angina, ischemic stroke, claudication, arterial revascularization for atherosclerosis or other CVD being actively managed by a cardiologist, e.g. atrial fibrillation, heart failure Planned arterial revascularization Inability to complete screening CCTA or any condition that would increase the risk associated with CCTA or increase likelihood of uninterpretable scan including: eGFR < 60 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) or Modification of Diet in Renal Disease (MDRD) equation (www.kidney.org/professionals/kdoqi/gfr_calculator) Allergy to iodinated contrast or history of contrast-induced nephropathy (including adverse reaction to contrast at screening CCTA) or screening laboratory values consistent with untreated hyperthyroidism. Participants with elevated thyroid-stimulating hormone (TSH) may be enrolled but should be referred to their physician for evaluation for treatment. Thyroid cancer in the previous five (5) years or planned radioactive iodine treatment Weight > 300 lbs. (136 kg) or above manufacturer-recommended limit for scanner and table at the site Inability to hold breath for > 10 seconds Active arrhythmia (atrial fibrillation, atrial flutter, frequent premature atrial, or ventricular contractions) with poorly controlled rate (i.e., > 80 beats per minute at screening or prior to CCTA) Contraindication to dosing with beta blocker or nitroglycerin on day of screening CCTA Any other factor that, in the opinion of the investigator, would increase participant risk or increase the chance of an uninterpretable CCTA Unsuitable as a trial participant in the opinion of the investigator for reasons including significant left main stenosis (e.g. ≥ 70%; site will be notified by Cleerly), other health condition with life expectancy < 3 years or being at risk of poor compliance with study procedures (e.g., active substance abuse or untreated mental illness that, in the opinion of the investigator, is likely to adversely affect adherence or retention)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, open blinded endpoint (PROBE), event-driven pragmatic trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual Care<br>The usual care group will be managed by their usual care provider. CCTA results will be centrally archived and will remain blinded to the usual care provider until the end of the study. | |
| Experimental: Personalized Care<br>The personalized care group will receive personalized care centrally managed by a remote cardiologist-led team. Cleerly CAD Staging System results will be discussed with participants and serve as the basis for algorithm-supported pharmacotherapy which will be intensified if plaque burden has progressed at 24 months. | Device: The Cleerly CAD Staging System<br>* The Cleerly CAD Staging System is software that utilizes a proprietary algorithm to identify CAD, stage the severity of CAD when present, and generate a prognostic risk score to inform treatment decisions that support CV disease prevention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to determine whether the Cleerly CAD Staging System-based personalized care strategy reduces CV events compared with usual care in participants with no known symptomatic CV disease | The primary endpoint is total (first and subsequent) events for the composite endpoint of CV death, non-fatal MI, non-fatal ischemic stroke, non-fatal acute limb ischemia, clinically driven arterial revascularization, and hospitalization or urgent visit for heart failure | Through study completion- an average of 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are time to first event from the primary composite endpoint. | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are total events with addition of renal events (kidney failure, sustained eGFR decrease >40% from baseline, death from renal cause) to the primary composite endpoint. | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are first and total coronary events (coronary death, non-fatal MI, and urgent coronary revascularization.) | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are time to first event from MI or ischemic stroke. | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are days alive and out of inpatient medical facility. | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are all-cause mortality. | Through study completion- an average of 3.5 years | 
| The secondary objectives are to determine whether the personalized care strategy reduces CV/renal events, improves biomarkers and reduces health resource utilization | The secondary endpoints are biomarker change from baseline to 90 days within the personalized care group and between group change from baseline to 90 days and 24 months. | Through study completion- an average of 3.5 years |