Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy

Study Overview
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Brief Summary
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This is a multicenter, randomized, placebo-controlled, 2-part study to evaluate the safety and efficacy of AT-001 in adult patients (N=675) with Diabetic Cardiomyopathy at high risk of progression to overt heart failure.

Detailed Description
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The study consists of two consecutive parts: Part A and Part B. Part A will evaluate the safety and efficacy of two doses of AT-001 vs placebo. The primary objective of Part A is to demonstrate that AT-001 improves or prevents the decline of functional capacity in patients with Diabetic Cardiomyopathy. Part B is an extension of at least 12 months that will evaluate the safety and efficacy of chronic administration of AT-001 vs placebo in the same patients who had previously been evaluated in Part A. Assessments in Part B will include safety endpoints and exploratory clinical efficacy endpoints, i.e. death and hospitalization due to a cardiac event.

Official Title
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Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF): A Multicenter, Randomized, Placebo-Controlled Study to Evaluate the Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy

Conditions
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Diabetic Cardiomyopathies

Intervention / Treatment
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* Drug: AT-001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes Mellitus Diabetic cardiomyopathy Peak VO2 < 75% of predicted normal value based on age and gender Exclusion Criteria: Prior diagnosis or signs/symptoms of overt/symptomatic heart failure / stage C heart failure Prior echocardiogrphic measurement of ejection fraction (EF) < 40% Prior acute coronary syndrome (ACS), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), coronary artery disease (CAD) or stroke Severe or moderate cardiac valve disease requiring intervention Clinically significant arrhythmia Prior diagnosis of congenital, infective, toxic, infiltrative, post-partum, or hypertrophic cardiomyopathy Blood pressure > 140 mmHg (systolic) or > 90 mmHg (diastolic) at screening HbA1c >8.5% at screening Severe disease that would impact the performance of a cardio-pulmonary exercise test

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AT-001 High dose<br>The total daily doses will be of 3g. The dose selection and the frequency of dosing was based on the results of the phase 1/2 study demonstrating that 3g/day of AT-001 is capable of producing the maximum inhibition of the production of sorbitol (a pharmacodynamic biomarker of biological activity). | Drug: AT-001<br>* AT-001 will be administered as 3 capsules twice daily, before breakfast and before dinner. At present AT001 is the sole name for the active substance. No INN/genetic name is available to date<br>|
| Experimental: AT-001 Low Dose<br>The total daily doses will be of 2g. The dose selection and the frequency of dosing was based on the results of the phase 1/2 study demonstrating that 2g/day of AT-001 is capable of producing a sufficient inhibition of the production of sorbitol (a pharmacodynamic biomarker of biological activity). | Drug: AT-001<br>* AT-001 will be administered as 3 capsules twice daily, before breakfast and before dinner. At present AT001 is the sole name for the active substance. No INN/genetic name is available to date<br>|
| Placebo Comparator: Placebo Comparator<br>Placebo capsules will be used as comparator | Drug: Placebo<br>* Matching placebo will be administered as 3 capsules twice daily, before breakfast and before dinner<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak VO2 during cardio-pulmonary exercise test (CPET); | Changes in Peak VO2 during cardio-pulmonary exercise test (CPET) from baseline to approximately Month 15 (15-18 months). A CPET may be repeated at approximately Month 27 (27-30 months). | 15 months after randomization] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression to overt heart failure (Stage C Heart Failure) | Defined by the occurrence of one of the following events: cardiovascular death, hospitalization for heart failure, urgent heart failure visit, new diagnosis of heart failure | 27 months after randomization | 
| Changes in NT-proBNP | Changes in NT-proBNP may reflect worsening of cardiomyopathy over time | 27 months after randomization | 
| Changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score | Changes in the modified KCCQ may reflect deterioration of clinical status over time | 27 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Aldose Reductase Inhibitor, Stage B Heart Failure, Stage C Heart Failure, Cardiopulmonary Exercise Test