2. Academic Validation
  3. 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

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

  • Eur J Heart Fail. 2023 Sep;25(9):1696-1707. doi: 10.1002/ejhf.2977.
Lars H Lund 1,  Carolyn S P Lam 2,  Patricia E Pizzato 3,  Anders Gabrielsen 3,  Erik Michaëlsson 3,  Karin Nelander 4,  Hans Ericsson 5,  Julie Holden 6,  Folke Folkvaljon 7,  Andrea Mattsson 8,  Anna Collén 9,  Malin Aurell 3,  Carl Whatling 10,  Stephan Baldus 11,  Grzegorz Drelich 12,  Assen Goudev 13,  Béla Merkely 14,  Niklas Bergh 15,  Sanjiv J Shah 16
Affiliations

Affiliations

  • 1 Department of Medicine, Karolinska Institute, and Heart, Vascular and Neuro Theme, Karolinska University Hospital, Stockholm, Sweden.
  • 2 National Heart Centre Singapore and Duke National University of Singapore, Singapore, Singapore.
  • 3 Early Clinical Development, Research and Early Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 4 Early Biometrics and Statistical Innovation, Data Science and AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 5 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 6 Patient Safety, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • 7 Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 8 Late-Stage Development, Cardiovascular, Renal and Metabolism - Biometrics, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 9 Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 10 Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 11 Department of Internal Medicine and Cardiology, University Hospital Cologne, Cologne, Germany.
  • 12 CenterMed Lublin, Lublin, Poland.
  • 13 Clinic of Cardiology, Tsaritsa Joanna University Hospital - ISUL, Sofia, Bulgaria.
  • 14 Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
  • 15 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • 16 Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
PMID: 37470101 DOI: 10.1002/ejhf.2977
Abstract

Aims: Mitiperstat (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.

Methods: In 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.

Conclusion: ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.

Keywords

Heart failure; Inflammation; Mildly reduced ejection fraction; Myeloperoxidase; Preserved ejection fraction; Randomized controlled trial.

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