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

Sponsor

Applied Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04083339

Collaborator

(none)

675

Enrollment

Locations

Arms

74.4

Anticipated Duration (Months)

8.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Sep 20, 2019

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Peak VO2 during cardio-pulmonary exercise test (CPET); [15 months after randomization]]
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

Progression to overt heart failure (Stage C Heart Failure) [27 months after randomization]
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
Changes in NT-proBNP [27 months after randomization]
Changes in NT-proBNP may reflect worsening of cardiomyopathy over time
Changes in the modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score [27 months after randomization]
Changes in the modified KCCQ may reflect deterioration of clinical status over time

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Westside Medical Associates of Los Angeles	Beverly Hills	California	United States	90211
2	University of California, San Diego (UCSD)	La Jolla	California	United States	92093
3	Clinical Trials Research	Lincoln	California	United States	95648
4	University of California - Irvine Medical Center	Orange	California	United States	92868
5	Metabolic Institute of America	Tarzana	California	United States	91356
6	Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center	Torrance	California	United States	90509
7	ALL Medical Research, LLC	Cooper City	Florida	United States	33024
8	New Generation of Medical Research	Hialeah	Florida	United States	33016
9	Broward Research Center	Pembroke Pines	Florida	United States	33024
10	Progressive Medical Research	Port Orange	Florida	United States	32127
11	UnityPoint Health - Methodist Hospital	Peoria	Illinois	United States	61602
12	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
13	Universty of Mississippi Medical Center	Jackson	Mississippi	United States	39216
14	St. Louis Heart and Vascular Cardiology	Saint Louis	Missouri	United States	63136
15	Chear Center LLC	Bronx	New York	United States	10455
16	Montefiore Medical Center	Bronx	New York	United States	10467
17	Cleveland Clinic	Cleveland	Ohio	United States	44195
18	Remington Davis, Inc.	Columbus	Ohio	United States	43215
19	South Oklahoma Heart Research	Oklahoma City	Oklahoma	United States	73135
20	Mountain View Clinical Research - Greer	Greer	South Carolina	United States	29651
21	Mountain View Clinical Research	Greer	South Carolina	United States	29651
22	Holston Medical Group	Kingsport	Tennessee	United States	37660
23	Dallas Diabetes Research Center	Dallas	Texas	United States	75230
24	Southwest Family Medicine Associates	Dallas	Texas	United States	75235
25	University of Texas Southwestern	Dallas	Texas	United States	75390
26	Juno Research, LLC - Northwest Site	Houston	Texas	United States	77040
27	Juno Research, LLC - Southwest Houston Site	Houston	Texas	United States	77074
28	FMC Science	Lampasas	Texas	United States	76550
29	Prince Charles Hospital	Chermside	Queensland	Australia	4032
30	CORE Research Group Pty. Ltd.	Milton	Queensland	Australia	4064
31	AusTrials	Taringa	Queensland	Australia	4068
32	University of Tasmania at Hobart	Hobart	Tasmania	Australia	7001
33	Barwon Health-University Hospital Geelong	Geelong	Victoria	Australia	3220
34	Austin Health	Heidelberg	Victoria	Australia	3084
35	Baker Heart and Diabetes Institute	Melbourne	Victoria	Australia	3004
36	Baker Heart and Diabetes Institute	Melbourne	Victoria	Australia	3004
37	C-Endo - Endocrinology Centre	Calgary	Alberta	Canada	T2V 4J2
38	BC Diabetes	Vancouver	British Columbia	Canada	V5Y 3W2
39	LMC Diabetes & Endocrinology Ltd. - Brampton	Brampton	Ontario	Canada	L6S 0C6
40	LMC Diabetes & Endocrinology Ltd. - Thornhill	Concord	Ontario	Canada	L4K 4M2
41	LMC Diabetes & Endocrinology Ltd. - Etobicoke	Etobicoke	Ontario	Canada	M9R 4E1
42	Centre for Studies in Family Medicine, Western Centre for Public Health and Family Medicine, Western University	London	Ontario	Canada	N6G 2M1
43	LMC Diabetes & Endocrinology Ltd. - Toronto	Toronto	Ontario	Canada	M4G 3E8
44	Ecogene-21	Chicoutimi	Quebec	Canada	G7H 7K9
45	Institut Universitaire de Cardiologie et de Pneumologie De Quebec	Québec	Quebec	Canada	G1V 4G5
46	Edumed s.r.o.	Jaroměř		Czechia	55101
47	Nemocnice Pardubickeho kraje, a.s., Nemocnice Pardubice	Pardubice		Czechia	532 03
48	Vseobecna fakultni nemocnice v Praze	Praha		Czechia	128 08
49	Hôpital Jean-Verdier - AP-HP; Service Endocrinologie Diabétologie Nutrition	Bondy		France	93140
50	CHU Henri Mondor	Créteil		France	94000
51	CHU de Nantes, Clinique d'Endocrinologie	Nantes		France	44093
52	Centre Hospitalier de Valenciennes	Valenciennes		France	59322
53	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)	Brandenburg	Germany	15236
54	Herz-und Diabeteszentrum NRW Universitaetsklinik der Ruhr-Universitaet Bochum	Bad Oeynhausen	North Rhine Westphalia	Germany	32545
55	Cardiologicum Pirna und Dresden	Dresden	Saxony	Germany	01277
56	Klinische Forschung Berlin GbR	Berlin		Germany	10787
57	ZKS - Zentrum Klinische Studien Sudbrandenburg GmbH	Elsterwerda		Germany	04910
58	Erik Yee Mun George Fung	Sha Tin		Hong Kong
59	Prince of Wales Hospital; Chinese University of Hong Kong; Dept of Medicine and Therapeutics	Sha Tin		Hong Kong
60	Centrum Chorob Serca w USK	Wrocław	Borowska	Poland	50-556
61	NZOZ Specjalistyczny Osrodek Internistyczno - Diabetologiczny	Białystok		Poland	15-435
62	Topolowa MEDICENTER Mrózek & wspólnicy sp.j.	Kraków		Poland	31-506
63	Centrum Twojego Zdrowia	Kraków		Poland	31-526
64	Praktyka Lekarska Ewa Krzyzagorska	Poznań		Poland	61-655
65	Prywatny Gabinet Lekarski Centrum Medyczne Diabetika	Radom		Poland	26-600
66	Centrum Medyczne Medyk Stanislaw Mazur Sp. z o.o. SK	Rzeszów		Poland	35-005
67	4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu	Wrocław		Poland	50-981
68	ETG Lodz	Łódź		Poland	90-302
69	Hospital Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
70	Hospital Clinico Universitario Virgen de la Arrixaca	El Palmar	Murcia	Spain	30120
71	Hospital Abente y Lago (Complejo Universitario de la Coruña)	A Coruña		Spain	15001
72	Hospital de la Santa Creu i Sant Pau Barcelona	Barcelona		Spain	08041
73	Hospital Universitario Reina Sofia	Córdoba		Spain	14004
74	Hospital Universitario Virgen Macarena	Sevilla		Spain	41009
75	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
76	Ninewells Hospital & Medical School	Dundee		United Kingdom	DD1 9SY
77	CPS Research	Glasgow		United Kingdom	G20 0XA
78	Glenfield hospital	Leicester		United Kingdom	LE3 9QP
79	Barts and The London School of Medicine & Dentistry	London		United Kingdom	EC1M 6BQ
80	Wythenshawe Hospital	Manchester		United Kingdom	M23 9Lt