Trial DesignsRationale 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
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:
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Data Monitoring Committee (DMC)
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Steering Committee (SC)
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Cardiovascular Endpoint Committee (CEC)
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Echocardiography Reading Committee (ERC)
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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,
References (66)
- et al.
The pathophysiological basis of diabetic cardiomyopathy development
Curr Probl Cardiol
(2022) - et al.
2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
J Am Coll Cardiol
(2022) - et al.
Prevalence and prognostic implications of diabetes with cardiomyopathy in community-dwelling adults
J Am Coll Cardiol
(2021) - et al.
PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial
J Am Coll Cardiol
(2013) - et al.
The prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County, Minnesota
J Card Fail
(2014) - et al.
Diagnostic and prognostic considerations for use of natriuretic peptides in obese patients with heart failure
Prog Cardiovasc Dis
(2020) - et al.
Exercise limitation associated with asymptomatic left ventricular impairment: analogy with stage B heart failure
J Am Coll Cardiol
(2015) - et al.
2017 Cardiovascular and stroke endpoint definitions for clinical trials
J Am Coll Cardiol
(2018) - et al.
Clinical analysis of aldose reductase for differential diagnosis of the pathogenesis of diabetic complication
Anal Chim Acta
(1998) - et al.
Association of C(-106)T polymorphism in aldose reductase gene with diabetic retinopathy in Chinese patients with type 2 diabetes mellitus
Chin Med Sci J
(2014)