IMPROVE-DiCE, a 2-Part, Open-Label, Phase 2a Trial Evaluating the Safety and Effectiveness of Ninerafaxstat in Patients With Cardiometabolic Syndromes
Abstract
Background: We report IMPROVE-DiCE (Improve Diabetic Cardiac Energetics), a 2-part open-label, phase 2a trial evaluating the safety and effectiveness of ninerafaxstat, a novel therapeutic designed to enhance cardiac energetics. Between May and September 2021, part 1 enrolled patients with type 2 diabetes and obesity without heart failure with preserved ejection fraction (HFpEF). Between January 2023 and June 2024, part 2 enrolled patients with type 2 diabetes, obesity, and HFpEF.
Methods: Forty-two participants received 200 mg ninerafaxstat twice daily (part 1, n=21, 43% women, 72±0.5 years of age, 4-8 weeks; part 2, n=21, 29% women, 71±6 years of age, 12 weeks). Myocardial energetics (phosphocreatine-to-ATP ratio [PCr/ATP], primary outcome) and function (rest and dobutamine stress) were assessed before and after treatment using magnetic resonance imaging, 31P- and 1H magnetic resonance spectroscopy. In part 1, hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy to assess in vivo pyruvate dehydrogenase flux (n=9) and plasma metabolomics and proteomics were also performed.
Results: In part 1, in patients with diabetes and obesity but without HFpEF, the heart was characterized by impaired pyruvate dehydrogenase flux, reduced PCr/ATP, triglyceride deposition, and diastolic impairment. Treatment with ninerafaxstat was associated with improved PCr/ATP (+0.39±0.49 [95% CI, 0.16-0.62]; Cohen's d, 0.79; P=0.002) and lower myocardial triglyceride (by 34%, P=0.03). In part…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 21 participants or records.
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