Rationale and design of ENDEAVOR: A sequential phase 2b–3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction

Abstract

AimsMitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity‐induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b–3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF.MethodsIn phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6‐min walk distance (6MWD) of 30–400 m with a < 50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire – total symptom score (KCCQ‐TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ‐TSS. The sample size provides 85% power to detect placebo‐adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ‐TSS at overall two‐sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo.ConclusionENDEAVOR is the first phase 2b–3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF. Clincaltrials.gov: NCT04986202This article is protected by copyright. All rights reserved.

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses

“…15 The expected therapeutic dose of mitiperstat is no higher than 5 mg once daily, administered as oral tablets, and this is the highest dose being tested in the ongoing phase 2b dose‐finding study (ENDEAVOR; NCT04986202). 14 The “high clinical exposure” scenario for this dose at steady state, as defined in the ICH E14/S7B guidance questions and answers document (FDA 2022) is 0.093 μmol/L. This scenario considers the impact of renal impairment on mitiperstat exposure.…”

“…13 The highest expected therapeutic dose of mitiperstat is 5 mg once daily, and this is the highest dose being tested in the ongoing phase 2b dose-finding study in patients with HFpEF/HFmrEF (ENDEAVOR, NCT04986202). 14 Major regulatory bodies worldwide have published guidelines requiring assessment of the risk of QT interval prolongation by new drugs with systemic bioavailability. Concentration-QT (C-QT) modeling is currently accepted as the primary method for analysis of this risk.…”

“… 13 The highest expected therapeutic dose of mitiperstat is 5 mg once daily, and this is the highest dose being tested in the ongoing phase 2b dose‐finding study in patients with HFpEF/HFmrEF (ENDEAVOR, NCT04986202). 14 …”

September 2023 at a glance: focus on acute heart failure and health status

“…The dual primary endpoints are change from baseline to week 16 in the 6-min walking test and Kansas City Cardiomyopathy Questionnaire total summary score. 52 The Study to Test the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial was designed to investigate the safety and efficacy of empagliflozin in post-acute myocardial infarction (AMI) patients. Overall, 6522 patients were randomized to empagliflozin or placebo on top of standard therapy.…”

“…ENDEAVOR is a combined, seamless phase 2b–3 study of the efficacy and safety of mitiperstat in patients with LVEF>40%. The dual primary endpoints are change from baseline to week 16 in the 6‐min walking test and Kansas City Cardiomyopathy Questionnaire total summary score 52 …”