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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetic Cardiomyopathies
• Intervention / Treatment: Drug: AT-001; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 675
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Riccardo Perfetti, MD, PhD; Phone Number: 212-220-9227; Email: rperfetti@appliedtherapeutics.com
• Study Contact Backup: Name: Francesca Lawson, MD, FAHA; Phone Number: 212-220-9256; Email: flawson@appliedtherapeutics.com

Study Locations

• Australia
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • Prince Charles Hospital
    • Milton, Queensland, Australia, 4064
      • CORE Research Group Pty. Ltd.
    • Taringa, Queensland, Australia, 4068
      • AusTrials
  • Tasmania
    • Hobart, Tasmania, Australia, 7001
      • University of Tasmania at Hobart
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Barwon Health-University Hospital Geelong
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3004
      • Baker Heart and Diabetes Institute
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2V 4J2
      • C-Endo - Endocrinology Centre
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Y 3W2
      • BC Diabetes
  • Ontario
    • Brampton, Ontario, Canada, L6S 0C6
      • LMC Diabetes & Endocrinology Ltd. - Brampton
    • Concord, Ontario, Canada, L4K 4M2
      • LMC Diabetes & Endocrinology Ltd. - Thornhill
    • Etobicoke, Ontario, Canada, M9R 4E1
      • LMC Diabetes & Endocrinology Ltd. - Etobicoke
    • London, Ontario, Canada, N6G 2M1
      • Centre for Studies in Family Medicine, Western Centre for Public Health and Family Medicine, Western University
    • Toronto, Ontario, Canada, M4G 3E8
      • LMC Diabetes & Endocrinology Ltd. - Toronto
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Québec, Quebec, Canada, G1V 4G5
      • Institut Universitaire de Cardiologie et de Pneumologie de Quebec
• Czechia
  • Jaroměř, Czechia, 55101
    • EDUMED s.r.o.
  • Pardubice, Czechia, 532 03
    • Nemocnice Pardubickeho kraje, a.s., Nemocnice Pardubice
  • Praha, Czechia, 128 08
    • Vseobecna fakultni nemocnice v Praze
• France
  • Bondy, France, 93140
    • Hôpital Jean-Verdier - AP-HP; Service Endocrinologie Diabétologie Nutrition
  • Créteil, France, 94000
    • CHU Henri Mondor
  • Nantes, France, 44093
    • CHU de Nantes, Clinique d'Endocrinologie
  • Valenciennes, France, 59322
    • Centre Hospitalier de Valenciennes
• Germany
  • Berlin, Germany, 10787
    • Klinische Forschung Berlin GbR
  • Elsterwerda, Germany, 04910
    • ZKS - Zentrum Klinische Studien Sudbrandenburg GmbH
  • Brandenburg
    • Frankfurt (Oder), Brandenburg, Germany, 15236
      • Klinikum Frankfurt (Oder) GmbH
  • North Rhine Westphalia
    • Bad Oeynhausen, North Rhine Westphalia, Germany, 32545
      • Herz-und Diabeteszentrum NRW Universitaetsklinik der Ruhr-Universitaet Bochum
  • Saxony
    • Dresden, Saxony, Germany, 01277
      • Cardiologicum Pirna und Dresden
• Hong Kong
  • Sha Tin, Hong Kong
    • Erik Yee Mun George Fung
  • Sha Tin, Hong Kong
    • Prince of Wales Hospital; Chinese University of Hong Kong; Dept of Medicine and Therapeutics
• Poland
  • Białystok, Poland, 15-435
    • NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny
  • Kraków, Poland, 31-506
    • Topolowa MEDICENTER Mrózek & wspólnicy sp.j.
  • Kraków, Poland, 31-526
    • Centrum Twojego Zdrowia
  • Poznań, Poland, 61-655
    • Praktyka Lekarska Ewa Krzyzagorska
  • Radom, Poland, 26-600
    • Prywatny Gabinet Lekarski Centrum Medyczne Diabetika
  • Rzeszów, Poland, 35-005
    • Centrum Medyczne Medyk Stanislaw Mazur Sp. z o.o. SK
  • Wrocław, Poland, 50-981
    • 4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu
  • Łódź, Poland, 90-302
    • ETG Lodz
  • Borowska
    • Wrocław, Borowska, Poland, 50-556
      • Centrum Chorob Serca w USK
• Spain
  • A Coruña, Spain, 15001
    • Hospital Abente y Lago (Complejo Universitario de la Coruña)
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau Barcelona
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Sevilla, Spain, 41009
    • Hospital Universitario Virgen Macarena
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Clínico Universitario Virgen de la Arrixaca
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Ninewells Hospital & Medical School
  • Glasgow, United Kingdom, G20 0XA
    • CPS Research
  • Leicester, United Kingdom, LE3 9QP
    • Glenfield Hospital
  • London, United Kingdom, EC1M 6BQ
    • Barts and The London School of Medicine & Dentistry
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Westside Medical Associates of Los Angeles
    • La Jolla, California, United States, 92093
      • University of California, San Diego (UCSD)
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Orange, California, United States, 92868
      • University of California - Irvine Medical Center
    • Tarzana, California, United States, 91356
      • Metabolic Institute of America
    • Torrance, California, United States, 90509
      • Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center
  • Florida
    • Cooper City, Florida, United States, 33024
      • ALL Medical Research, LLC
    • Hialeah, Florida, United States, 33016
      • New Generation of Medical Research
    • Pembroke Pines, Florida, United States, 33024
      • Broward Research Center
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
  • Illinois
    • Peoria, Illinois, United States, 61602
      • UnityPoint Health - Methodist Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Universty of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • St. Louis Heart and Vascular Cardiology
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Bronx, New York, United States, 10455
      • Chear Center LLC
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43215
      • Remington Davis, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73135
      • South Oklahoma Heart Research
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Mountain View Clinical Research
    • Greer, South Carolina, United States, 29651
      • Mountain View Clinical Research - Greer
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Research Center
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Associates
    • Houston, Texas, United States, 77040
      • Juno Research, LLC - Northwest Site
    • Houston, Texas, United States, 77074
      • Juno Research, LLC - Southwest Houston Site
    • Lampasas, Texas, United States, 76550
      • FMC Science

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Worsening of diabetic cardiomyopathy	Defined by either ≥ 20% increase in NT-proBNP or ≥ 5 point decrease in the mKCCQ score	15 and 27 months after randomization
Changes in echocardiographic parameters	Changes assessed on cardiac ultra-sound from baseline	27 months after randomization

Collaborators and Investigators

• Sponsor: Applied Therapeutics, Inc.
• Investigators: Study Chair: James L Januzzi, MD, Harvard Medical School (HMS and HSDM)

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2019
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: August 23, 2019
• First Submitted That Met QC Criteria: September 5, 2019
• First Posted (Actual): September 10, 2019

Study Record Updates

• Last Update Posted (Estimate): December 8, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Type 2 Diabetes; Aldose Reductase Inhibitor; Stage B Heart Failure; Stage C Heart Failure; Cardiopulmonary Exercise Test
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Cardiomyopathies; Diabetic Cardiomyopathies
• Other Study ID Numbers: AT-001-2001

Drug and device information, study documents

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