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    Summary
    EudraCT Number:2019-002558-21
    Sponsor's Protocol Code Number:AT-001-2001
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-02-12
    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 ConcernedCzechia - SUKL
    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)
    Inhibice aldózo-reduktázy za účelem stabilizace zátěžové kapacity u srdečního selhání (ARISE-HF): Multicentrická, randomizovaná, placebem kontrolovaná studie hodnotící bezpečnost a účinnost AT-001 u pacientů s diabetickou kardiomyopatií/počínajícím srdečním selháním s vysokým rizikem zhoršení (srdeční selhání stádia B) do rozvinutého srdečního selhání (srdeční selhání stádia C)
    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
    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, hard
    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 INNCaficrestat
    D.3.9.1CAS number 1355612-71-3
    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 number500
    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, hard
    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)
    Diabetická kardiomyopatie / počínající srdeční selhání s vysokým rizikem zhoršení (srdeční selhání stádia B)
    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
    Srdeční onemocnění zvané diabetická kardiomyopatie jako komplikace diabetu 2.typu vedoucí k srdečnímu selhání
    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
    Evaluate
    • 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 w. 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 w. 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 systolic function assessed by global longitudinal strain, left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction assessed by E/E, 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
    Neuropathy Sub-study: to investigate the effects of the study drug on the peripheral nerves, by performing 2 tests: the Neuropathy Total Symptom Score (NTSS), and the Modified Toronto Clinical Neuropathy Scale (mTCNS) at baseline and Month 27.
    Retinopathy Sub-study: to investigate the effects of the study drug on the eyes by performing 2 tests: a color fundus photography and an Optical Coherence Tomography (OCT) at screening and Month 27.
    Echocardiography Sub-study: to evaluate the consistency between manual human reading and fully automated machine-learning based reading of an echocardiogram for detecting DbCM.
    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 2 risk factors:
    o Duration of diabetes ≥ 10 years
    o eGFR < 60 mL/min/1.73 m2
    3. Demonstration of DbCM/ Stage B Heart Failure defined by at least one of the following 3 criteria:
    • Echocardiographic demonstration of the following, as confirmed by either the central core lab or by local review at selected study centers:
    - Left Ventricular Ejection Fraction (LVEF) >= 45%
    AND
    - At least 1 of the following 5 abnormalities:
    o Absolute value of Global longitudinal strain (GLS) < 16% (i.e., GLS >-16%)
    o Left ventricular hypertrophy (LVH) defined as left ventricular mass index (LVMI) ≥ 95 g/m2 in women and ≥115 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
    OR
    • NT-proBNP ≥ 50 pg/mL
    OR
    • HsTnT ≥ 6 ng/L
    4. CPET demonstration of both, as confirmed by the CPET core lab:
    • Impaired functional capacity, i.e., Peak VO2 < 75% of predicted, based on age and gender
    • 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 (SCHF), or prior or current symptom(s) or sign(s) that in the
    opinion of the investigator may be related to undiagnosed overt/symptomatic heart failure / SCHF.
    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; e.g., stent or angioplasty)
    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, unless successfully ablated with no episodes of recurrence for at least 3 years)
    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
    12. Blood pressure > 140 mmHg (systolic) or > 90 mmHg (diastolic) at screening, treated or untreated
    13. History of multiple hospitalizations for hypertensive emergency
    14. BMI > = 45 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 has not been stable in the 12 weeks prior to screening in the opinion of the Investigator
    17. Use of thiazolidinediones at screening and/or after randomization
    18. Planned start of a SGLT2-inhibitor after randomization (If a decision to start a SGLT2-inhibitor has already been made during the screening
    period, the treatment with a SGLT2-inhibitor should be initiated before randomization. Note that initiation of a SGLT2-inhibitor during the study
    is allowed at any time before and after randomization.)
    19. Any current or prior use of a loop diuretic
    20. Pregnant or breastfeeding women
    21. Females of childbearing potential not willing to use a highly effective form of birth control from screening until the Study Closeout Visit, or Post-Treatment Follow-up Visit, whichever occurs later
    22. Severe disease making implementation of the protocol or interpretation of the study results difficult . This includes clinically significant hematopoietic, renal, hepatic, endocrine, pulmonary, neurological, psychiatric, immunological, dermatological, or gastrointestinal diseases or active malignant tumor as well as conditions that would impact the performance of a CPET.
    23. Any condition that prevents the obtainment of a good quality echocardiogram at baseline
    24. History of substance abuse including alcohol within 3 years
    25. History of clinically significant drug hypersensitivity reactions
    26. Severe lower extremity complications and/or history of non-traumatic amputations
    27. Short life expectancy (<12 months) making implementation of the protocol or interpretation of the study results difficult.
    28. Investigators, site personnel directly affiliated with this study, and their immediate families
    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 > 1.5 x upper limit of normal (ULN) at Screening
    34. An eGFR < 45 mL/min/1.73 m2 at Screening
    35. Interventions/conditions capable of altering the absorption, metabolism, or elimination of drugs or significantly impacting body weight
    36. History of hospitalization due to COVID-19 that required ventilation, or with residual pulmonary symptoms
    37. Age > 75 years
    38. Treatment with any sensitive substrates of organic anion transporter (OAT) 3 (OAT3) or inhibitors of OAT1 or OAT3 from randomization to the Study Closeout Visit. This includes, but is not limited to the following: OAT3 substrates: adefovir, cefaclor, ceftizoxime, famotidine, ganciclovir, oseltamivir carboxylate, penicillin G; and OAT inhibitors: probenecid.
    39. Treatment with any inhibitors of OATP1B1 or OATP1B3 from randomization to the Study Closeout Visit. This includes, but is not limited to the following: clarithromycin, erythromycin, gemfibrozil, rifampin, simeprevir.
    40. History of kidney stones with >1 clinical recurrence requiring a surgical intervention during one of the recurrences
    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)
    • 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
    • Percentage of patients with a clinically significant decrease in peak VO2 (i.e., > 6%)
    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 EEA33
    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
    Australia
    Canada
    Hong Kong
    United States
    Czechia
    France
    Germany
    Poland
    Spain
    United Kingdom
    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 months58
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months58
    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 state27
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 265
    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 Decision2020-02-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-12
    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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