A Randomized Comparison of Stage-Based Care Versus Risk Factor-Based Care for Prevention of Cardiovascular Events (TRANSFORM)

A Randomized Comparison of Cleerly Coronary Artery Disease Stage-Based Care Versus Risk Factor-Based Care for Primary Prevention of Cardiovascular Events

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 Cleerly Coronary Artery Disease (CAD) Staging System-based care strategy reduces CV events compared with risk factor-based care.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Metabolic Syndrome; PreDiabetes
• Intervention / Treatment: Device: The Cleerly CAD Staging System

Detailed Description

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 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 CAD Staging System-based care strategy reduces CV events compared with risk factor-based care. The Cleerly CAD Staging System incorporates imaging-based evaluation for coronary atherosclerosis, algorithm-supported pharmacotherapy and personalized education about their CAD.

• Study Type: Interventional
• Enrollment (Estimated): 7500
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ryann Sardinia; Phone Number: 7205931599; Email: ryann.sardinia@cleerlyhealth.com
• Study Contact Backup: Name: Ashley Dunham, PhD; Phone Number: 7205931599; Email: ashley.dunham@cleerlyhealth.com

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
      • Contact: Steve Simon
      • Principal Investigator: Steve Simon, MD
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Recruiting
      • Flourish Medical Research
      • Contact: David Funt, MD
  • Maryland
    • Bowie, Maryland, United States, 20715
      • Recruiting
      • Flourish Bowie dba Flourish Research
      • Contact: Sara Collins, MD
  • Texas
    • Abilene, Texas, United States, 79601
      • Recruiting
      • Hendrick Health
      • Contact: Ren Zhang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Provided electronic or written informed consent
2. Men > 55, women > 65 years of age

3. 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%
4. 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:

1. 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
2. Planned arterial revascularization

3. Inability to complete screening CCTA or any condition that would increase the risk associated with CCTA or increase likelihood of uninterpretable scan including:

   1. 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)
   2. 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.
   3. Thyroid cancer in the previous five (5) years or planned radioactive iodine treatment
   4. Weight > 300 lbs. (136 kg) or above manufacturer-recommended limit for scanner and table at the site
   5. Inability to hold breath for > 10 seconds
   6. 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)
   7. Contraindication to dosing with beta blocker or nitroglycerin on day of screening CCTA
   8. Any other factor that, in the opinion of the investigator, would increase participant risk or increase the chance of an uninterpretable CCTA
4. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Risk Factor-Based Care; The risk factor-based care group will be managed by their usual care providers, with an initial pre-randomization assessment of current treatment by a centralized cardiology team to optimize care relative to primary prevention guidelines. During the trial, the centralized cardiology team will monitor the provision of medications prescribed and lab values relative to guidelines, and provide feedback and education to site investigators to support optimization. CCTA results will be centrally archived and will remain blinded to the usual care provider until the end of the study.
Experimental: Cleerly Stage-Based Care; The Cleerly Stage-Based Care group will receive personalized care centrally managed by a remote cardiologist-led team. They will also receive an initial pre-randomization assessment of current treatment by a centralized cardiology team to optimize care relative to primary prevention guidelines. Cleerly CAD Staging System results will be discussed with participants and serve as the basis for standardized algorithm-supported pharmacotherapy & education, which will be intensified if plaque burden has progressed at 24 months.	Device: The Cleerly CAD Staging System; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to compare Cleerly stage-based care with risk factor-based care on the risk of CV events.	The primary endpoint is total (first and subsequent) events for the composite endpoint of CV death, myocardial infarction (MI), ischemic stroke, 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 objective is to compare Cleerly CAD stage-based care with risk factor-based care on other clinical events of CV and renal morbidity and mortality.	The secondary endpoints are time from randomization to first occurence of an event in the primary efficacy endpoint.	Through study completion- an average of 3.5 years
The secondary objective is to compare Cleerly CAD stage-based care with risk factor-based care on other clinical events of CV and renal morbidity and mortality.	The secondary endpoints are total occurences after randomization of the primary efficacy endpoing, kidney failure, sustained estimated glomerular filtration rate (eGFR) decrease >40% from baseline, and death from renal causes.	Through study completion- an average of 3.5 years
The secondary objective is to compare Cleerly CAD stage-based care with risk factor-based care on other clinical events of CV and renal morbidity and mortality.	The secondary endpoints are first and total occurrences after randomization of coronary death, MI, and urgent coronary revascularization.	Through study completion- an average of 3.5 years
The secondary objective is to compare Cleerly CAD stage-based care with risk factor-based care on other clinical events of CV and renal morbidity and mortality.	The secondary endpoints are time from randomization to first occurrence of MI or ischemic stroke.	Through study completion- an average of 3.5 years
The secondary objective is to compare Cleerly CAD stage-based care with risk factor-based care on other clinical events of CV and renal morbidity and mortality.	The secondary endpoints are time from randomization to all-cause death.	Through study completion- an average of 3.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety objective is to assess harm with the 2 prevention strategies	The safety endpoints are Adverse events (AE) leading to discontinuation of study-recommended medication (DAE), serious AE (SAE), adverse device effect (ADE).	Through study completion- an average of 3.5 years
The safety objective is to assess harm with the 2 prevention strategies	The safety endpoints are 20-item Short Form survey (SF-20).	Through study completion- an average of 3.5 years

Collaborators and Investigators

• Sponsor: Cleerly, Inc.
• Collaborators: CPC Clinical Research
• Investigators: Study Chair: Deepak Bhatt, MD, MPH, Mt. Sinai Heart

Publications and helpful links

General Publications

• Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, Elkind MSV, Evenson KR, Eze-Nliam C, Ferguson JF, Generoso G, Ho JE, Kalani R, Khan SS, Kissela BM, Knutson KL, Levine DA, Lewis TT, Liu J, Loop MS, Ma J, Mussolino ME, Navaneethan SD, Perak AM, Poudel R, Rezk-Hanna M, Roth GA, Schroeder EB, Shah SH, Thacker EL, VanWagner LB, Virani SS, Voecks JH, Wang NY, Yaffe K, Martin SS. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. 2022 Feb 22;145(8):e153-e639. doi: 10.1161/CIR.0000000000001052. Epub 2022 Jan 26. Erratum In: Circulation. 2022 Sep 6;146(10):e141.
• Clerc OF, Fuchs TA, Stehli J, Benz DC, Grani C, Messerli M, Giannopoulos AA, Buechel RR, Luscher TF, Pazhenkottil AP, Kaufmann PA, Gaemperli O. Non-invasive screening for coronary artery disease in asymptomatic diabetic patients: a systematic review and meta-analysis of randomised controlled trials. Eur Heart J Cardiovasc Imaging. 2018 Aug 1;19(8):838-846. doi: 10.1093/ehjci/jey014.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2024
• Primary Completion (Estimated): March 5, 2029
• Study Completion (Estimated): March 5, 2029

Study Registration Dates

• First Submitted: October 2, 2023
• First Submitted That Met QC Criteria: October 31, 2023
• First Posted (Actual): November 1, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Insulin Resistance; Hyperinsulinism; Diabetes Mellitus, Type 2; Metabolic Syndrome
• Other Study ID Numbers: 202302CPC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No