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

Conditions

Diabetic Cardiomyopathies

Keywords

Type 2 Diabetes, Aldose Reductase Inhibitor, Stage B Heart Failure, Stage C Heart Failure, Cardiopulmonary Exercise Test

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.

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.

Blumer V, Januzzi JL, Liu Y, Butler J, Ezekowitz JA, Perfetti R, Rosenstock J, Del Prato S, Tang WHW, Urbinati A, Zannad F, Lewis GD, Solomon SD, Hedge S, Ibrahim NE, Lam CSP.

2025-05-082 citations

10.1016/j.jchf.2025.02.015

Health status in stage B heart failure from diabetic cardiomyopathy baseline results from ARISE-HF.

Siddiqi TJ, Liu Y, Zannad F, Tang WHW, Solomon S, Rosenstock J, Perfetti R, Marwick TH, Lewis GD, Lam CSP, Ibrahim NE, Ezekowitz J, Del Prato S, Butler J, Januzzi JL.

2025-04-25

10.1016/j.jdiacomp.2025.109059

Impaired Exercise Capacity in High-Risk Diabetic Cardiomyopathy: The ARISE-HF Cardiopulmonary Exercise Testing Subanalysis

W.H. Wilson Tang, Yuxi Liu, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz et al. (14 authors)

Circulation Heart Failure2025-01-303 citations

10.1161/circheartfailure.124.012200

Echocardiographic phenotypes of diabetic myocardial disorder: evolution over 15 months follow-up in the ARISE-HF trial.

Marwick TH, Lam C, Liu Y, Del Prato S, Rosenstock J, Butler J, Ezekowitz J, Ibrahim NE, Tang WHW, Zannad F, Perfetti R, Januzzi JL.

2025-01-133 citations

10.1186/s12933-024-02554-y

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical siabetic cardiomyopathy.

Gouda P, Liu Y, Butler J, Del Prato S, Ibrahim NE, Lam CSP, Marwick T, Rosenstock J, Tang W, Zannad F, Januzzi J, Ezekowitz J.

2024-08-023 citations

10.1186/s12933-024-02378-w

Racial Differences in Diabetic Cardiomyopathy: The ARISE-HF Trial.

Batista JL, Liu Y, Butler J, Del Prato S, Ezekowitz JA, Lam CSP, Marwick TH, Rosenstock J, Tang WHW, Perfetti R, Urbinati A, Zannad F, Januzzi JL, Ibrahim NE.

2024-07-015 citations

10.1016/j.jacc.2024.04.053

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

Januzzi JL, Butler J, Del Prato S, Ezekowitz JA, Ibrahim NE, Lam CSP, Lewis GD, Marwick TH, Perfetti R, Rosenstock J, Solomon SD, Tang WHW, Zannad F.

2024-04-0818 citations

10.1016/j.jacc.2024.03.380

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial

James L. Januzzi, Stefano Del Prato, Julio Rosenstock, Javed Butler, Justin A. Ezekowitz et al. (14 authors)

Cardiovascular Diabetology2024-02-0119 citations

10.1186/s12933-024-02135-z

450-P: N-Terminal Pro-B Type Natriuretic Peptide Concentrations in Diabetic Cardiomyopathy—Baseline Data from the ARISE-HF Trial

Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, CAROLYN S. LAM et al. (11 authors)

Diabetes2023-06-20

10.2337/db23-450-p

1238-P: The Face of Diabetic Cardiomyopathy—Baseline Characteristics from the ARISE-HF Trial

Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, CAROLYN S. LAM et al. (11 authors)

Diabetes2023-06-20

10.2337/db23-1238-p

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy.

Januzzi JL, Butler J, Del Prato S, Ezekowitz JA, Ibrahim NE, Lam CSP, Lewis GD, Marwick TH, Rosenstock J, Tang WHW, Zannad F, Lawson F, Perfetti R, Urbinati A.

2022-11-1121 citations

10.1016/j.ahj.2022.11.003

1080-P: Addressing the Safety Challenges of Aldose Reductase Inhibition: Development of AT-001 for Diabetic Cardiomyopathy, a Potent and Selective Next Generation Aldose Reductase Inhibitor

Riccardo Perfetti, Gautham Yepuri, Nosirudeen Quadri, Ameen Ghannam, Ravichandran Ramasamy et al. (6 authors)

Diabetes2020-06-015 citations

10.2337/db20-1080-p

462-P: AT-001, a Next Generation Aldose Reductase Inhibitor with Improved Selectivity and Specificity, Protects from Cellular Damage Associated with Hyperglycemia

Riccardo Perfetti, Gautham Yepuri, Nosirudeen Quadri, Ravichandran Ramasamy, Ameen Ghannam et al. (6 authors)

Diabetes2020-06-013 citations

10.2337/db20-462-p

186-OR: Safety and Tolerability of the Next Generation Aldose Reductase Inhibitor (ARI) AT-001 Supports Initiation of the Pivotal Trial in Diabetic Cardiomyopathy (DbCM)

Riccardo Perfetti, Francesca Lawson, Julio Rosenstock, James L. Januzzi, Shoshana Shendelman et al. (7 authors)

Diabetes2020-06-01

10.2337/db20-186-or

Interventions

DRUGAT-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

DRUGPlacebo

Matching placebo will be administered as 3 capsules twice daily, before breakfast and before dinner

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

No

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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

Measure	Time frame	Description
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

Countries

Australia, Canada, Czechia, France, Germany, Hong Kong, Poland, Spain, United Kingdom, United States

Outcome results

None listed