Molidustat for the treatment of renal anaemia in patients with dialysis-dependent chronic kidney disease: design and rationale of three phase III studies

INTRODUCTION: New medications for anaemia associated with chronic kidney disease (CKD) are desirable, owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care. Molidustat is a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates erythropoietin production, predominately in the kidney. We report methodological details of three phase III trials, named MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI), designed primarily to investigate the efficacy of molidustat therapy in adults with renal anaemia and dialysis-dependent CKD. METHODS AND ANALYSIS: MIYABI Haemodialysis-Correction (HD-C) is a single-arm trial (24-week treatment duration) in approximately 25 patients on haemodialysis, currently untreated with ESAs. MIYABI Peritoneal Dialysis (PD) is a single-arm trial (36 week treatment duration) in approximately 50 patients on peritoneal dialysis, treated or untreated with ESAs. MIYABI Haemodialysis-Maintenance (HD-M) is a randomised, active-controlled, double-blinded, double-dummy trial (52-week treatment duration) comparing molidustat with darbepoetin alfa in approximately 225 patients on haemodialysis, treated with ESAs. Molidustat (starting dose 75 mg/day) will be titrated 4-weekly to maintain haemoglobin in predetermined target ranges. The primary objective is to evaluate the efficacy of molidustat, using the following measures: the rate of rise in haemoglobin (g/L/week) at the first dose change up to week 8 (MIYABI HD-C); responder rate (MIYABI HD-C and MIYABI PD); mean haemoglobin level during weeks 33–36 and non-inferiority to darbepoetin alfa shown by change in mean haemoglobin level from baseline (MIYABI HD-M). The secondary objectives are to assess safety, pharmacokinetics and pharmacodynamics. These trials will provide the first evaluations of molidustat therapy in patients receiving either peritoneal dialysis or currently untreated with ESAs on haemodialysis, and provide further evidence in patients treated with ESAs on haemodialysis. ETHICS AND DISSEMINATION: The protocols were approved by ethics committees at all participating sites. The trials will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results arising from these studies will be published in peer-reviewed journal(s). TRIAL REGISTRATION NUMBERS: NCT03351166; Pre-results, NCT03418168; Pre-results, NCT03543657; Pre-results