Purpose: To evaluate efficacy and safety of intravitreal injections of aflibercept (IVT-AFL) treat-and-extend (T&E) dosing regimens in treatment-naïve patients with exudative agerelated macular degeneration (AMD).Methods: Adults aged at least 50 years old with exudative AMD and best-corrected visual acuity (BCVA) of 73-25 Early Treatment Diabetic Retinopathy Study (ETDRS) letters were included. Patients received three monthly doses of IVT-AFL 2 mg. At week 16, patients were randomized 1:1 to IVT-AFL T&E with either 2-or 4-week adjustments. The primary endpoint was mean change in BCVA from baseline to week 52. Outcomes were assessed at weeks 52 and 96. Results: Baseline characteristics were comparable between the groups (n = 123 each). Over 52 weeks, mean number of injections was 7.2 and 6.9 and mean last injection interval was 10.7 and 11.8 weeks, for the 2-and 4-week groups, respectively. From baseline, mean change in BCVA was ? 9.0 and ? 8.4 letters (week 52) and ? 7.6 and ? 6.1 letters (week 96); mean change in central retinal thickness was -134.4 lm and -126.1 lm (week 52) and -130.5 lm and -125.3 lm (week 96). Last injection interval before week 52 was at least 12 weeks in 42.3% and 49.6% of patients and 56.9% and 60.2% before week 96. Over 96 weeks, mean number of injections was 10.4 (both groups). The safety profile of IVT-AFL was consistent with previous reports. Conclusions: IVT-AFL administered using two different T&E regimens for treatment-naïve exudative AMD improved functional and anatomic outcomes at week 52 and outcomes were Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11603511.maintained to week 96. Outcomes were similar between the 2-and 4-week groups. Trial Registration: ClinicalTrials.gov identifier, NCT02305238. Key Summary PointsWhy carry out this study?The goal of proactive flexible treat-andextend (T&E) regimens is to reduce the treatment burden associated with antivascular endothelial growth factor (VEGF) therapy, while maintaining a patient's visual acuity gains.The aim of this study was to evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) T&E dosing regimens in treatment-naïve patients with exudative age-related macular degeneration (AMD).What was learned from the study?IVT-AFL administered using either 2-or 4-week adjustment T&E regimens in treatment-naïve patients with exudative AMD improved functional (best-corrected visual acuity ? 9.0 and ? 8.4 letters) and anatomic outcomes (central retinal thickness -134.4 and -126.1 lm) at 52 weeks; functional and anatomic outcomes were maintained over 96 weeks.A large proportion of patients (35.1% and 40.5%) had an intended injection interval of 16 weeks at week 52.The incidence of treatment-emergent adverse events was consistent with the known safety profile of IVT-AFL.IVT-AFL T&E regimens were efficacious and safe over 96 weeks of treatment using either 2-or 4-week adjustments.

IntroductionNew 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 analysisMIYABI 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 disseminationThe 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 numbersNCT03351166; Pre-results,NCT03418168; Pre-results,NCT03543657; Pre-results

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IntroductionAnaemia is a common complication of chronic kidney disease (CKD). Owing to the limitations of erythropoiesis-stimulating agents (ESAs), the current standard of care, there is a need to develop new therapies. Hypoxia-inducible factor prolyl-hydroxylase (HIF-PH) inhibitors might be a promising new treatment option. Molidustat is an oral HIF-PH inhibitor that stimulates the endogenous, predominantly renal, production of erythropoietin and was generally well tolerated in phase IIb clinical trials. Here, we report the design and rationale of two studies from the molidustat phase III programme: MolIdustat once dailY improves renal Anaemia By Inducing erythropoietin (MIYABI).Methods and analysisMIYABI Non-Dialysis-Correction (ND-C) and MIYABI Non-Dialysis-Maintenance (ND-M) are randomised, open-label, parallel-group, multicentre studies that aim to demonstrate the efficacy of molidustat treatment compared with darbepoetin alfa in patients with anaemia and non-dialysis-dependent CKD. The secondary objectives are to assess the safety, pharmacokinetics and pharmacodynamics of molidustat treatment. MIYABI ND-C will recruit patients currently untreated with ESAs, whereas patients treated with an ESA will enter MIYABI ND-M. Each study will recruit 150 patients who will be randomised in a 1:1 ratio to receive either molidustat or darbepoetin alfa for 52 weeks, with efficacy evaluated during weeks 30–36. Study drug doses will be titrated regularly using an interactive voice/web response system with the aim of maintaining the patients’ haemoglobin (Hb) levels between ≥110 and <130 g/L. The primary objective will be achieved if, in molidustat-treated patients, the mean Hb level remains within the target range during the evaluation period, and if the change in the mean Hb level at evaluation time points from baseline is non-inferior to darbepoetin alfa.Ethics and disseminationThe protocols were approved by ethics committees at all participating sites. These studies will be conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. Results arising from these studies will be published in peer-reviewed journal(s).Trial registration numbersNCT03350321; Pre-results,NCT03350347; Pre-results.

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