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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 : October 16, 2019
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 : September 2021
Estimated Study Completion Date : September 2023

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 AT001 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 AT001 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 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 performance from baseline to approximately Month 15 (+/-3). A CPET may be repeated at Month 27 (+/-3) if the assessment at Month 15 does not demonstrate a significant difference between placebo and at least one of the 2 doses of AT-001.


Secondary Outcome Measures :
  1. Changes in NT-proBNP [ Time Frame: Changes in NT-proBNP from baseline will be assessed at Month 6 (+/-3), Month 15 (+/-3), and Month 27 (+/-3). ]
    Levels of BNP and NT-proBNP are elevated in subjects with diabetes without overt HF and these biomarkers have been effectively utilized as a screening instrument to select high-risk asymptomatic diabetic patients who could benefit from therapeutic intervention aimed at preventing cardiac disease.

  2. Changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score [ Time Frame: Changes in KCCQ score from baseline will be assessed at Month 15 (+/-3), and Month 27 (+/-3). ]
    KCCQ is a valid, reliable and responsive health status measure for patients with congestive heart failure (CHF) that has also been utilized in patients at risk of HF who do not have a diagnosis of HF at baseline. For each KCCQ question, responses are assigned an ordinal number with lower numbers indicative of lower levels of function. Within each domain, missing values are assigned the average of the answered items within the domain. Scores are converted to a scale of 0 to 100 with 0 indicative of the lowest level of function. There are two summary scores. The functional status score is the combination of the scores for the physical limitation and symptom (excluding symptom stability) domains. The clinical summary score is the functional status score plus scores for the QoL and social limitation domains.

  3. Percentages of patients with clinically significant changes in Peak VO2 [ Time Frame: 27 months after randomization ]

Other Outcome Measures:
  1. Changes in echocardiographic parameters [ Time Frame: 27 months after randomization ]

    Echocardiogram parameters of interest are the following:

    • Global Longitudinal Strain (GLS)
    • Left ventricular hypertrophy (LVH)
    • Left atrial enlargement (LAE) defined as left atrial volume index (LAVi ) Diastolic dysfunction (DD) defined as E/E'
    • Right ventricular systolic pressure (RVSP)

  2. Changes in estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 27 months after randomization ]
  3. Changes in urinary albumin creatinine ratio (UACR) [ Time Frame: 27 months after randomization ]
  4. Changes in biomarkers [ Time Frame: 6, 15 and 27 months after randomization ]

    Changes in biomarkers levels from baseline will be assessed at Month 6 (+/-3), Month 15 (+/-3), and Month 27 (+/-3).

    Several biomarkers will be assessed, including the following ones:

    • Sorbitol
    • High-sensitivity troponin T (HsTNT)
    • C-reactive protein (CRP)

    Sorbitol has been selected as a biomarker of aldose reductase inhibition; high-sensitivity troponin (HsTNT) as a marker of cardiac injury and C-reactive protein (CRP) has a marker of inflammation.


  5. Percentages of patients with death or hospitalization due to a cardiac event [ Time Frame: 27 months from randomization ]


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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
  • NT-proBNP > 125 pg/ml
  • Echocardiographic demonstration of cardiomyopathy
  • Peak VO2 < 75% of predicted normal value

Exclusion Criteria:

  • Prior diagnosis of overt/symptomatic heart failure / stage C heart failure
  • EF < 40%
  • Prior acute coronary syndrome (ACS), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), coronary artery disease (CAD)
  • Severe or moderate valve disease requiring intervention
  • Clinically significant arrhythmia
  • Congenital, infective, toxic, infiltrative, post-partum, or hypertrophic cardiomyopathy

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: Ricarrdo 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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United States, South Carolina
Mountain View Clinical Research Recruiting
Greer, South Carolina, United States, 29651
Contact: Ronald Mayfield    864-334-0141    rmayfield@mvcresearch.com   
United States, Texas
Juno Research, LLC - Northwest Site Recruiting
Houston, Texas, United States, 77040
Contact: Damaris Vega    281-880-4548    Damaris_vega@junoresearch.us   
Juno Research, LLC - Southwest Houston Site Recruiting
Houston, Texas, United States, 77074
Contact: Audrey Lacour    713-779-5494    audrey_lacour@junoresearch.us   
Juno Research, LLC - Katy Recruiting
Katy, Texas, United States, 77450
Contact: Hugo Toro    713-779-5494    Hugo_Toro@junoresearch.us   
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     History of Changes
Other Study ID Numbers: AT-001-2001
First Posted: September 10, 2019    Key Record Dates
Last Update Posted: October 16, 2019
Last Verified: October 2019

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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