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

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ClinicalTrials.gov Identifier: NCT04083339
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : June 10, 2021
Sponsor:
Information provided by (Responsible Party):
Applied Therapeutics, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Diabetic Cardiomyopathies Drug: AT-001 Drug: Placebo Phase 3

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 675 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 20, 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: AT-001 High dose
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

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


Experimental: AT-001 Low Dose
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

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


Placebo Comparator: Placebo Comparator
Placebo capsules will be used as comparator
Drug: Placebo
Matching placebo will be administered as 3 capsules twice daily, before breakfast and before dinner




Primary Outcome Measures :
  1. Peak VO2 during cardio-pulmonary exercise test (CPET); [ Time Frame: 15 months after randomization] ]
    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).


Secondary Outcome Measures :
  1. Progression to overt heart failure (Stage C Heart Failure) [ Time Frame: 27 months after randomization ]
    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

  2. Changes in NT-proBNP [ Time Frame: 27 months after randomization ]
    Changes in NT-proBNP may reflect worsening of cardiomyopathy over time

  3. Changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score [ Time Frame: 27 months after randomization ]
    Changes in the modified KCCQ may reflect deterioration of clinical status over time


Other Outcome Measures:
  1. Worsening of diabetic cardiomyopathy [ Time Frame: 15 and 27 months after randomization ]
    Defined by either ≥ 20% increase in NT-proBNP or ≥ 5 point decrease in the mKCCQ score

  2. Changes in echocardiographic parameters [ Time Frame: 27 months after randomization ]
    Changes assessed on cardiac ultra-sound from baseline



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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 Diabetes Mellitus
  • Echocardiographic demonstration of 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04083339


Contacts
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Contact: Riccardo Perfetti, MD, PhD 212-220-9227 rperfetti@appliedtherapeutics.com
Contact: Francesca Lawson, MD, FAHA 212-220-9256 flawson@appliedtherapeutics.com

Locations
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Sponsors and Collaborators
Applied Therapeutics, Inc.
Investigators
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Study Chair: James L Januzzi, MD Harvard Medical School
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Responsible Party: Applied Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT04083339    
Other Study ID Numbers: AT-001-2001
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: June 10, 2021
Last Verified: June 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Applied Therapeutics, Inc.:
Type 2 Diabetes
Aldose Reductase Inhibitor
Stage B Heart Failure
Stage C Heart Failure
Cardiopulmonary Exercise Test
Additional relevant MeSH terms:
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Cardiomyopathies
Diabetic Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases