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

Recruitment Status
ACTIVE, NOT RECRUITING
(See Contacts and Locations)Verified November 2022 by Applied Therapeutics, Inc.
Sponsor
Applied Therapeutics, Inc.
Information Provided by (Responsible Party)
Applied Therapeutics, Inc.
Clinicaltrials.gov Identifier
NCT04083339
Other Study ID Numbers:
AT-001-2001
First Submitted
August 22, 2019
First Posted
September 9, 2019
Last Update Posted
December 7, 2022
Last Verified
November 2022

ClinicalTrials.gov processed this data on December 2022. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study 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.

Condition or DiseaseIntervention/Treatment
Diabetic Cardiomyopathies
Drug: AT-001Drug: AT-001Drug: Placebo

Study Design

Study TypeInterventional
Actual Enrollment675 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingQuadruple
Primary PurposeTreatment
Official TitleAldose 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
Study Start DateSeptember 19, 2019
Actual Primary Completion DateNovember 30, 2023
Actual Study Completion DateNovember 30, 2025

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures
  1. 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).
Secondary Outcome Measures
  1. 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
  2. Changes in NT-proBNP
    Changes in NT-proBNP may reflect worsening of cardiomyopathy over time
  3. Changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score
    Changes in the modified KCCQ may reflect deterioration of clinical status over time

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
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

Contacts and Locations

Sponsors and CollaboratorsApplied Therapeutics, Inc.
Locations
Westside Medical Associates of Los Angeles | Beverly Hills California, United States, 90211University of California, San Diego (UCSD) | La Jolla California, United States, 92093Clinical Trials Research | Lincoln California, United States, 95648University of California - Irvine Medical Center | Orange California, United States, 92868Metabolic Institute of America | Tarzana California, United States, 91356Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center | Torrance California, United States, 90509ALL Medical Research, LLC | Cooper City Florida, United States, 33024New Generation of Medical Research | Hialeah Florida, United States, 33016Broward Research Center | Pembroke Pines Florida, United States, 33024Progressive Medical Research | Port Orange Florida, United States, 32127UnityPoint Health - Methodist Hospital | Peoria Illinois, United States, 61602Brigham and Women's Hospital | Boston Massachusetts, United States, 02115Universty of Mississippi Medical Center | Jackson Mississippi, United States, 39216St. Louis Heart and Vascular Cardiology | St Louis Missouri, United States, 63136Chear Center LLC | The Bronx New York, United States, 10455Montefiore Medical Center | The Bronx New York, United States, 10467Cleveland Clinic | Cleveland Ohio, United States, 44195Remington Davis, Inc. | Columbus Ohio, United States, 43215South Oklahoma Heart Research | Oklahoma City Oklahoma, United States, 73135Mountain View Clinical Research - Greer | Greer South Carolina, United States, 29651Mountain View Clinical Research | Greer South Carolina, United States, 29651Holston Medical Group | Kingsport Tennessee, United States, 37660Dallas Diabetes Research Center | Dallas Texas, United States, 75230Southwest Family Medicine Associates | Dallas Texas, United States, 75235University of Texas Southwestern | Dallas Texas, United States, 75390Juno Research, LLC - Northwest Site | Houston Texas, United States, 77040Juno Research, LLC - Southwest Houston Site | Houston Texas, United States, 77074FMC Science | Lampasas Texas, United States, 76550Prince Charles Hospital | Chermside Queensland, Australia, 4032CORE Research Group Pty. Ltd. | Milton Queensland, Australia, 4064AusTrials | Taringa Queensland, Australia, 4068University of Tasmania at Hobart | Hobart Tasmania, Australia, 7001Barwon Health-University Hospital Geelong | Geelong Victoria, Australia, 3220Austin Health | Heidelberg Victoria, Australia, 3084Baker Heart and Diabetes Institute | Melbourne Victoria, Australia, 3004C-Endo - Endocrinology Centre | Calgary Alberta, Canada, T2V 4J2BC Diabetes | Vancouver British Columbia, Canada, V5Y 3W2LMC Diabetes & Endocrinology Ltd. - Brampton | Brampton Ontario, Canada, L6S 0C6LMC Diabetes & Endocrinology Ltd. - Thornhill | Concord Ontario, Canada, L4K 4M2LMC Diabetes & Endocrinology Ltd. - Etobicoke | Etobicoke Ontario, Canada, M9R 4E1Centre for Studies in Family Medicine, Western Centre for Public Health and Family Medicine, Western University | London Ontario, Canada, N6G 2M1LMC Diabetes & Endocrinology Ltd. - Toronto | Toronto Ontario, Canada, M4G 3E8Ecogene-21 | Chicoutimi Quebec, Canada, G7H 7K9Institut Universitaire de Cardiologie et de Pneumologie De Quebec | Québec Quebec, Canada, G1V 4G5Edumed s.r.o. | Jaroměř , Czechia, 55101Nemocnice Pardubickeho kraje, a.s., Nemocnice Pardubice | Pardubice , Czechia, 532 03Vseobecna fakultni nemocnice v Praze | Prague , Czechia, 128 08Hôpital Jean-Verdier - AP-HP; Service Endocrinologie Diabétologie Nutrition | Bondy , France, 93140CHU Henri Mondor | Créteil , France, 94000CHU de Nantes, Clinique d'Endocrinologie | Nantes , France, 44093Centre Hospitalier de Valenciennes | Valenciennes , France, 59322Klinikum Frankfurt (Oder) GmbH | Frankfurt (Oder) Brandenburg, Germany, 15236Herz-und Diabeteszentrum NRW Universitaetsklinik der Ruhr-Universitaet Bochum | Bad Oeynhausen North Rhine-Westphalia, Germany, 32545Cardiologicum Pirna und Dresden | Dresden Saxony, Germany, 01277Klinische Forschung Berlin GbR | Berlin , Germany, 10787ZKS - Zentrum Klinische Studien Sudbrandenburg GmbH | Elsterwerda , Germany, 04910Erik Yee Mun George Fung | Shatin , Hong Kong, Prince of Wales Hospital; Chinese University of Hong Kong; Dept of Medicine and Therapeutics | Shatin , Hong Kong, Centrum Chorob Serca w USK | Wroclaw Borowska, Poland, 50-556NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny | Bialystok , Poland, 15-435Topolowa MEDICENTER Mrózek & wspólnicy sp.j. | Krakow , Poland, 31-506Centrum Twojego Zdrowia | Krakow , Poland, 31-526ETG Lodz | Lodz , Poland, 90-302Praktyka Lekarska Ewa Krzyzagorska | Poznan , Poland, 61-655Prywatny Gabinet Lekarski Centrum Medyczne Diabetika | Radom , Poland, 26-600Centrum Medyczne Medyk Stanislaw Mazur Sp. z o.o. SK | Rzeszów , Poland, 35-0054 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu | Wroclaw , Poland, 50-981Hospital Germans Trias i Pujol | Badalona Barcelona, Spain, 08916Hospital Clinico Universitario Virgen de la Arrixaca | El Palmar Murcia, Spain, 30120Hospital Abente y Lago (Complejo Universitario de la Coruña) | A Coruña , Spain, 15001Hospital de la Santa Creu i Sant Pau Barcelona | Barcelona , Spain, 08041Hospital Universitario Reina Sofia | Córdoba , Spain, 14004Hospital Universitario Virgen Macarena | Seville , Spain, 41009Hospital Clinico Universitario de Valencia | Valencia , Spain, 46010Ninewells Hospital & Medical School | Dundee , United Kingdom, DD1 9SYCPS Research | Glasgow , United Kingdom, G20 0XAGlenfield hospital | Leicester , United Kingdom, LE3 9QPBarts and The London School of Medicine & Dentistry | London , United Kingdom, EC1M 6BQWythenshawe Hospital | Manchester , United Kingdom, M23 9Lt
Investigators
Study Chair: James L Januzzi, MD, Harvard Medical School (HMS and HSDM)