Elsevier

American Heart Journal

Volume 256, February 2023, Pages 25-36
American Heart Journal

Trial Designs
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

https://doi.org/10.1016/j.ahj.2022.11.003Get rights and content

Background

Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF).

Methods

Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers.

Results

The ARISE-HF Trial is fully enrolled.

Conclusions

This report describes the rationale and study design of ARISE-HF.

Section snippets

Overview of study design

ARISE-HF is a Phase 3, randomized, placebo-controlled study to assess the efficacy of AT-001 compared with placebo for preservation or improvement of exercise capacity as measured by peak oxygen uptake (peak VO2) during a cardiopulmonary exercise testing (CPET) as well as assess the safety and tolerability of AT-001 over the long-term in adult study participants with T2DM and DbCM. The study has been registered at ClinicalTrials.gov under identifier NCT04083339.

The study consists of 2

Study organization

This study is conducted at 62 global sites across Australia, Canada, Czech Republic, France, Germany, Hong Kong, Poland, Spain, United Kingdom, and United States (US).

Study conduct involves the following independent committees:

  • Data Monitoring Committee (DMC)

  • Steering Committee (SC)

  • Cardiovascular Endpoint Committee (CEC)

  • Echocardiography Reading Committee (ERC)

  • Cardiopulmonary Exercise Test Committee (CPET-C)

All committees, except for the DMC, are blinded to the patients’ treatment allocations. The

Treatment and procedures

Approximately 675 patients will be randomized 1:1:1 to receive high-dose AT-001 (1,500 mg twice daily [BID], given as oral capsules), low-dose AT-001 (1,000 mg BID), or placebo (Figure 2). Each patient, on AT-001 or placebo, receives 3 capsules twice daily. The doses of AT-001 to be used in ARISE-HF are based on a previous 3-part, randomized, placebo-controlled Phase 1/2 study to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AT-001 in adults with T2DM.28

Study end points

The complete list of study end points is provided in Supplementary Appendix 3.

Exercise limitation with dyspnea and fatigue at low levels of effort or at rest are cardinal symptoms of HF.29 Accordingly, the primary end point of ARISE-HF is the change in CPET performance (peak VO2) from baseline to Month 15. A CPET may be repeated at Month 27 if the assessment at Month 15 data does not demonstrate a statistically significant difference between placebo and at least 1 of the 2 doses of AT-001.

Sample size calculation

A sample size of 675 patients was determined to be appropriate for ARISE-HF. The sample size is based on calculations for the Month 15 analysis, with an additional assessment of data at Month 27 if a statistically significant difference in the primary outcome between at least 1 of the 2 doses of AT-001and placebo is not observed at Month 15. A 2-sided α = 2.5% is proposed for each of the analysis timepoints. A sample size of 181 patients per treatment group was calculated to provide >90% power

Statistics

All efficacy analyses will be conducted using the intent-to-treat (ITT) principle with treatment groups allocated according to the randomization schedule, irrespective of the treatment actually received. The primary efficacy population will be the full analysis set (FAS), which will include all randomized patients regardless of compliance with the study procedures or investigational study treatment.

A multiple testing strategy will be used to assess the primary end point at Month 15 and again at

Ethics and regulatory considerations

This research is carried out in accordance with the protocol, the International Council for Harmonisation (ICH), Guideline for Good Clinical Practice (GCP) Consolidated Guidance (E6), and applicable regulatory requirements including clinical research guidelines established by the Basic Principles defined in the US 21 Code of Federal Regulations (CFR) Parts 50, 56, and 312; other applicable regional/local regulations, and the principles of the Declaration of Helsinki.

For all study centers, the

Discussion

Diabetes is a major risk factor for several adverse CV outcomes including HF.38 Epidemiological and observational studies have shown that T2DM increases the risk for new onset HF independently of other traditional risk factors.38 Together with the alarming increase in global prevalence of T2DM these data imply a substantial likelihood for parallel rise in HF owing to DbCM and its progression.

Despite the increased risk of progression to overt HF in individuals with DbCM, there are still no

Funding

The ARISE-HF Trial is sponsored by Applied Therapeutics, Inc. Dr Januzzi is funded in part by the Hutter Family Professorship. No extramural funding was used to support this work.

Methods

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Authors’ contributions

James L. Januzzi Jr: Writing - Review & Editing, Visualization, Supervision. Javed Butler: Supervision. Stefano Del Prato: Supervision. Justin Ezekowitz: Supervision. Nasrien E. Ibrahim: Supervision. Carolyn SP Lam: Supervision. Gregory D. Lewis: Supervision. Thomas Marwick: Supervision. Julio Rosenstock: Supervision. Wilson Tang: Supervision. Faiez Zannad: Supervision. Francesca Lawson: Supervision. Riccardo Perfetti: supervision. Alessia Urbinati: Writing - Original Draft, Visualization.

Conflict of interest

Dr Januzzi is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received research support from Abbott, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Bristol Myers, Boehringer-Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics and Siemens; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx,

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