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    Summary
    EudraCT Number:2019-002558-21
    Sponsor's Protocol Code Number:AT-001-2001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-01-21
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-002558-21
    A.3Full title of the trial
    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 / Stage B Heart Failure at High Risk of Progression to Overt Heart Failure (Stage C Heart Failure)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to evaluate the safety and efficacy of AT-001 in patients who may be at risk for a heart condition known as diabetic cardiomyopathy (DbCM) as a complication of a type 2 diabetes mellitus (T2DM)
    A.3.2Name or abbreviated title of the trial where available
    ARISE-HF
    A.4.1Sponsor's protocol code numberAT-001-2001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorApplied Therapeutics Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportApplied Therapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street AddressWallace House, 17-21 Maxwell Place
    B.5.3.2Town/ cityStirling
    B.5.3.3Post codeFK8 1JU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number44(0)17460 400, ext. 24404
    B.5.5Fax number44(0)20741 6496
    B.5.6E-mailregsubmissions@medpace.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAT-001
    D.3.2Product code AT-001
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot Available
    D.3.9.1CAS number Not Assigned
    D.3.9.2Current sponsor codeAT-001
    D.3.9.3Other descriptive nameAT-001
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Diabetic Cardiomyopathy (DbCM) / Stage B Heart Failure (SBHF)
    E.1.1.1Medical condition in easily understood language
    Heart condition known as diabetic cardiomyopathy (DbCM) as a complication of a Type 2 diabetes mellitus (T2DM), that may progress to heart failure
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012647
    E.1.2Term Diabetic cardiomyopathy
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that AT-001 compared with placebo decreases the worsening of performance on a cardiopulmonary exercise test (CPET) in patients with Diabetic Cardiomyopathy (DbCM) / Stage B Heart Failure (SBHF)
    E.2.2Secondary objectives of the trial
    • the efficacy of AT-001 compared with placebo in preventing
    progression from SBHF to Stage C Heart Failure
    • the effect of AT-001 compared with placebo in patients with
    DbCM/SBHF on the levels of NT-proBNP
    • the effect of AT-001 compared with placebo in patients with
    DbCM/SBHF on the score of the mKCCQ
    • the effect of AT-001 compared with placebo in patients with
    DbCM/SBHF on the percentage of patients with any changes and
    clinically significant changes (>6%) in peak oxygen uptake
    • the effect of AT-001 compared with placebo in patients with
    DbCM/SBHF on the significant worsening of DbCM from baseline
    • the effect of AT-001 compared with placebo in patients with
    DbCM/SBHF on the changes in global longitudinal strain, left ventricular
    hypertrophy, left atrial enlargement, diastolic dysfunction, and right
    ventricular systolic pressure by echocardiography
    • the safety of chronic administration of AT-001 to patients with
    DbCM/SBHF
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The study also includes 2 substudies:
    • In the neuropathy substudy, patients will have peripheral nerve conduction testing assessments done at randomization (baseline) and at Month 27.
    • In the retinopathy substudy patients will have dilated-pupil fundus photography assessments done at randomization (baseline) and at Month 27.
    E.3Principal inclusion criteria
    1. Type 2 Diabetes Mellitus (T2DM)
    2. One of the following age-related criteria:
    • Age ≥ 60 years OR
    • Age ≥ 40 to < 60 years AND at least 1 of the following 7 risk factors:
    o Hemoglobin A1c (HbA1c) > 7.5% (there is no requirement for a minimum HbA1c level for patients who have at least one of the other 6 risk factors listed below)
    o Duration of diabetes ≥ 10 years
    o High-sensitivity troponin T (HsTnT) >15.0 pg/mL for men and >10.0 pg/mL for women
    o Body mass index (BMI) >30 kg/m2
    o eGFR < 60 mL/min/1.73 m2
    o Prior diagnosis of diabetic neuropathy
    o Prior diagnosis of diabetic retinopathy
    3. NT-proBNP > 125 pg/mL (≥ 100 pg/mL if BMI > 30 kg/m2)
    4. Echocardiographic demonstration of the following, as confirmed by the central core lab:
    • Left Ventricular Ejection Fraction (LVEF) >= 45% AND
    • At least 2 of the following 5 abnormalities:
    o Global longitudinal strain (GLS) <-16%
    o Left ventricular hypertrophy (LVH) defined as left ventricular mass index (LVMI) > 109 g/m2 in women and >132 g/m2 in men
    o Left atrial enlargement (LAE) defined as left atrial volume index (LAVi) ≥ 34 mL/m2
    o Diastolic Dysfunction defined as E/E’ ≥ 13
    o Right ventricular systolic pressure (RVSP) > 35 mmHg
    5. CPET demonstration of both, as confirmed by the CPET core lab:
    • Impaired functional capacity, i.e., Peak VO2 < 75% of predicted
    • Ability of maximal effort, i.e., achieve a RER ≥1.05
    E.4Principal exclusion criteria
    1.Prior diagnosis of overt/symptomatic heart failure / stage C heart failure, including any prior or current symptom or sign that led to a diagnosis of overt/symptomatic heart failure / stage C heart failure.
    2. Any prior echocardiographic measurement indicating ejection fraction (EF) < 40%
    3. History of acute coronary syndrome (ACS), including acute myocardial infarction
    4. History or planned coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI)
    5. Prior diagnosis of coronary artery disease (CAD) defined as ≥ 50%
    stenosis of any major coronary artery
    6. History of severe mitral, aortic, tricuspid, or pulmonary valve disease, or moderate valve disease requiring intervention
    7. History of any clinically significant arrhythmia (including permanent atrial fibrillation or history of paroxysmal atrial fibrillation requiring hospitalization)
    8. History of stroke
    9. History of congenital, infective, toxic (e.g., chemotherapy or radiation), infiltrative (e.g., amyloidosis, sarcoidosis, or hemochromatosis), post-partum, or hypertrophic cardiomyopathy
    10. Myocarditis induced by active autoimmune disease (e.g., Graves’ disease or systemic lupus erythematosus)
    11. Pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1)
    12. Blood pressure (BP) > 140 mmHg (systolic) or > 90 mmHg (diastolic) at screening
    13. History of hospitalization for hypertensive emergency
    14. BMI > 40 kg/m2
    15. Antihyperglycemic treatment has not been stable in the 12 weeks prior to screening in the opinion of the Investigator
    16. Treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS) has not been stable in the 12 weeks prior to screening in the opinion of the Investigator
    17. Use of thiazolidinediones
    18. Planned start of a SGLT2-inhibitor during the study
    19. Use of a loop diuretic
    20. Pregnant or breastfeeding women
    21. Females of childbearing potential not willing to use an acceptable form of birth control from screening until the Study Closeout Visit, or Post-Treatment Follow-up Visit, whichever occurs later
    22. Severe disease or short life expectancy (<12 months) making implementation of the protocol or interpretation of the study results difficult (This includes clinically significant hematopoietic, renal, hepatic (including hepatitis B and C), endocrine, pulmonary, neurological, psychiatric, immunological (including HIV-AIDS), dermatological, or gastrointestinal diseases or active malignant tumor [except for non-melanoma skin cancer] or conditions capable of altering the absorption, metabolism, or elimination of drugs, or conditions that would impact the performance of a CPET [e.g., chronic lung or neuro-muscular disease].)
    23. Morbid obesity or any other condition that prevents the obtainment of a good quality echocardiogram at baseline
    24. History of substance abuse (including alcohol)
    25. History of clinically significant drug allergy or drug hypersensitivity reactions
    26. Severe lower extremity complications (such as skin ulcers, osteomyelitis and gangrene) and/or history of non-traumatic amputations
    27. Prior diagnosis of proliferative diabetic retinopathy
    28. Investigators, site personnel directly affiliated with this study, and their immediate families (Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.)
    29. Any other condition that, in the opinion of the Investigator, precludes the patient from following and completing the protocol
    30. Use of any investigational drug within 5 half-lives prior to screening
    31. HbA1c > 8.5% at Screening
    32 Hemoglobin (Hb) < 10.0 g/dL at Screening
    33. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or total bilirubin (except in case of Gilbert’s syndrome) > 1.5 x upper limit of normal (ULN) at Screening
    34. An eGFR < 45 mL/min/1.73 m2 (as calculated by the MDRD formula) at Screening
    35. UACR > 300 mg/g at Screening
    E.5 End points
    E.5.1Primary end point(s)
    Changes in CPET performance (peak oxygen uptake [peak VO2]) from baseline to Month 15 (>=15 months and ≤ 18 months after randomization) and possibly to Month 27 (>= 27 months and ≤ 30 months after randomization)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to Month 15 (>=15 months and ≤ 18 months after randomization) and possibly to Month 27 (>= 27 months and ≤ 30 months after randomization)
    E.5.2Secondary end point(s)
    • Changes in NT-proBNP from baseline to Month 15
    • Progression to SCHF, defined by the occurrence of at least 1 of the following events by Month 27:
    o CV death
    o Hospitalization for HF
    o Urgent HF visit
    o New diagnosis of HF (requiring initiation of a loop diuretic)
    • Changes in NT-proBNP
    • Changes in the mKCCQ score from baseline to Month 27
    • Percentage of patients with a clinically significant decrease in peak VO2 (i.e., > 6%) from baseline to Month 27
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to Month 27
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Czech Republic
    France
    Germany
    Poland
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months54
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 270
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 405
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 675
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2024-02-09
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