| Study characteristics |
| Methods |
|
| Participants |
General information
Setting: multicentre (56 sites) Country: multinational (Bulgaria, France, Germany, Hungary, Italy, Israel, Poland, Romania, Spain, Turkey, UK, South Korea, Australia, and Japan) Inclusion criteria: women without childbearing potential; male or female subjects ≥ 18 years with anaemia of CKD at screening; eGFR of < 60 mL/min/1.73 m² (MDRD or the formula according to Matsuo, et al); not on dialysis and not expected to begin dialysis during the treatment period of the study (at least 16 weeks from randomisation); not treated with any ESA within 8 weeks before randomisation; mean screening Hb concentration ≤ 10.5 g/dL; weight of 45 kg to 125 kg at screening Exclusion criteria: subjects with significant acute or chronic bleeding, such as overt GI bleeding; chronic inflammatory disease that could impact erythropoiesis (e.g. SLE, rheumatoid arthritis, coeliac disease) even if it is currently in remission; previous or concurrent cancer except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumours (Ta, Tis, and T1) or any cancer curatively treated > 3 years prior to randomisation; subjects treated with any ESA within the 8 weeks before randomisation; RBC containing transfusion within the 8 weeks before randomisation; history of cardio‐ (cerebro‐) vascular events (e.g. unstable angina, MI, stroke, TIA, DVT, pulmonary embolism) within the last 6 months from initial screening visit; severe rhythm or conduction disorders (e.g. heart rate < 50 or > 110 bpm, atrial flutter, prolonged QT > 500 msec, third degree atrioventricular block); NYHA class III or IV congestive heart failure; severe hepatic insufficiency (ALT or AST > 3 times ULN, total bilirubin > 2 mg/dL, or Child‐Pugh B and C) or active hepatitis, in the investigator's opinion Target Hb: not reported
Baseline characteristics
CKD stage: CKD who were not receiving dialysis treatment Number (randomised/analysed): treatment group 1 (19/19); treatment group 2 (21/21); treatment group 3 (22/22); treatment group 4 (19/19); treatment group 5 (20/20); control group (20/20) ‐ ITT and FAS Mean age ± SD (years): treatment group 1 (69 ± 12); treatment group 2 (68 ± 13); treatment group 3 (71 ± 10; treatment group 4 (70 ± 12); treatment group 5 (65 ± 13); control group (67.1 ± 15.9) Sex (M, %): treatment group 1 (14, 74%); treatment group 2 (9, 43%); treatment group 3 (13, 59%); treatment group 4 (10, 53%); treatment group 5 (10, 50%); control group (9, 45%) Time on dialysis: not applicable MeaneGFR ± SD (mL/min/1.73 m²): treatment group 1 (25 ± 14); treatment group 2 (23 ± 11); treatment group 3 (24 ± 10); treatment group 4 (25 ± 12); treatment group 5 (21 ± 14); control group (23.0 ± 11.6)
Comorbidities
CVdisease: not reported Heart disease: not reported Hypertension: not reported Diabetes (number, %): not reported Prior agents used (number, %): not reported
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| Interventions |
Treatment group 1 (low dose)*
Treatment group 2 (medium dose)
Treatment group 3 (high dose)
Treatment group 4 (medium dose)
Treatment group 5 (high dose)
Control group
Co‐interventions
*Note: this study was considered as a reference for HIF dosage |
| Outcomes |
Primary outcomes
Secondary outcomes
Change in local laboratory Hb baseline up to 12 weeks Speed of change in Hb/unit time (up to 16 weeks Duration of treatment exposure (up to 16 weeks) Number with serious adverse events as a measure of safety and tolerability (up to 16 weeks) Pharmacodynamics characterised by EPO concentration (several time points up to 16 weeks) Pharmacodynamics characterised by reticulocyte count (several time points up to 16 weeks) ECG and vital signs were measured during the study period
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| Notes |
Funding: Bayer AG Conflicts of interest: "T.A.: has received consulting fees from Astellas, Bayer Yakuhin Ltd., GlaxoSmithKline, J.T. Pharmaceuticals, Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin, Nipro Corporation, Fuso Pharmaceutical Industries Ltd., and Ono Pharmaceutical Co. Ltd., and lecture fees from Bayer Yakuhin Ltd., Chugai Pharmaceutical Co. Ltd., Kyowa Hakko Kirin, and Torii Pharmaceutical Co. Ltd. I.C.M. has received research funding for the DIALOGUE studies, honoraria for steering committee activities, and speaker fees from Bayer Pharma AG; and has received research support and speakers’ honoraria from Akebia, Astellas, FibroGen, and GlaxoSmith‐ Kline. J.S.B. has served on the executive committees for the DIALOGUE studies and for an Amgen‐sponsored darbepoetin clinical trial. M.T. and K.I. are employees of Bayer Yakuhin Ltd. T.B. is an employee of Bayer AG" |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Macdougall 2019 quote: "At the randomizations visit, the investigator had to check the patient’s eligibility and stratification factor levels; an interactive response system subsequently randomly assigned the treatment group according to computer generated randomisation lists."
No imbalance between intervention groups was apparent |
| Allocation concealment (selection bias) |
Low risk |
Macdougall 2019 quote: "At the randomizations visit, the investigator had to check the patient’s eligibility and stratification factor levels; an interactive response system subsequently randomly assigned the treatment group according to computer generated randomisation lists." No imbalance between intervention groups was apparent |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Quote: "Double‐blind."
Macdougall 2019 quote: "Both, patients and physicians were blinded to treatment allocation." |
| Blinding of outcome assessment (detection bias)
All outcomes |
Unclear risk |
Macdougall 2019 quote: "An independent adjudication committee assessed all deaths and any serious AEs of severe arrhythmias, thromboembolic events, syncope or symptomatic hypotension, or heart failure."
It was not reported if the independent adjudication committee was blinded |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Akizawa 2019 (Nephron) quote: "Of 121 patients randomized in D1, all (101 molidustat, 20 placebo) were included in the FAS and ITT population, and 60 patients (59.5%) receiving molidustat and 2 patients (10.0%) receiving placebo discontinued the study. Of those who discontinued molidustat, the majority discontinued by the last 4 weeks and had a blood Hb concentration above the upper limit of 13 g/dL or an increase in blood Hb concentration of > 1.0 g/dL in 2 weeks."
All participants were included in FAS and ITT analyses |
| Selective reporting (reporting bias) |
Low risk |
All of the planned outcomes on ClincialTrials.gov were measured and reported on in the final report
Clinically‐relevant outcomes that would be expected for this type of intervention (death and CV events) were reported |
| Other bias |
High risk |
There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups
Funder was likely to influence data analysis and study reporting or interpretation
Authors declared conflicts of interest |
