| Study characteristics |
| Methods |
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| Participants |
General information
Setting: multicentre (61 sites) Country: Japan Inclusion criteria: males and females ≥ 18 years with kidney failure on regular dialysis (including, HDF, HF, HD, and other modalities except for PD) weekly or more than weekly for at least 12 weeks prior to randomisation; weight (after dialysis) > 40 and ≤ 160 kg at screening; at least one kidney; treated with weekly or bi‐weekly dose of darbepoetin alfa, monthly or bi‐weekly dose of EBP, OR weekly, twice or 3 times/week dose of epoetin alfa/beta, and having had no more than one dose change within 8 weeks prior to randomisation; mean screening Hb level ≥ 9.5 and < 12.0 g/dL during the screening period, AND all Hb level must be measured by the central laboratory, AND the difference between the lowest level and highest level is < 1.2 g/dL, with the last screening Hb level measurement within 14 days prior to randomisation; ferritin ≥ 100 ng/mL or TSAT ≥ 20% at screening; serum folate and serum vitamin B12 > LLN at screening Exclusion criteria: NYHA Class III or IV congestive HF; history of cardio‐ (cerebro‐) vascular events (e.g. unstable angina, MI, stroke, pulmonary thromboembolism, and acute limb ischaemia) within 6 months prior to randomisation; sustained, poorly controlled arterial hypertension (defined as SBP ≥ 180 mm Hg or DBP ≥ 110 mm Hg) or hypotension (SBP < 90 mm Hg) at randomisation; proliferative choroidal or retinal disease, such as neovascular age‐related macular degeneration or proliferative diabetic retinopathy requiring invasive treatment (e.g. intraocular injections or laser photocoagulation) at screening Target Hb: 10 to 12 g/dL
Baseline characteristics
CKD stage: 5D (HD) Number (randomised/analysed): treatment group (153/115); control group (76/65) ‐ ITT Mean age ± SD (years): treatment group (66.2 ± 10.3); control group (64.8 ± 10.6) Sex (M, %): treatment group (91, 59.5%); control group (49, 64.5%) Time on dialysis: not reported eGFR: not reported
Comorbidities
CV disease: not reported Heart disease: not reported Hypertension: not reported Diabetes (number, %): not reported -
Prior agents used (number, %)
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| Interventions |
Treatment group (high dose)*
Molidustat: (starting dose 75 mg/day): planned doses for titration are 5, 12.5, 25, 50, 70, 100, 150 and 200 mg once/day; Hb target range ≥ 100 to < 120 g/L Darbepoetin alfa placebo The maintenance dose of molidustat/molidustat placebo (at least 200 mg) or darbepoetin/darbepoetin placebo (at least 180 mg)
Control group
Co‐interventions
*Note: dose assessed as high according to DIALOGUE 1 2019
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| Outcomes |
Primary outcomes
Secondary outcomes
Responder rate: proportion of responders among the subjects (week 33 to 36) Proportion of subjects who meet each component of the response (week 33 to 36) Hb level (to 52 weeks) Change in Hb level (up to 52 weeks) Proportion whose mean Hb is in the target range (week 33 to 36) Proportion whose mean Hb is above the target range (week 33 to 36) Proportion whose mean Hb is below the target range (week 33 to 36) Proportion with Hb in the target range (up to 52 weeks) Proportion with Hb above the target range (up to 52 weeks) Proportion with Hb below the target range (up to 52 weeks) Proportion whose maximum rise in Hb between each consecutive visits is above 0.5 g/dL/week (up to 52 weeks) Number with serious adverse events (up to 52 weeks) Cmax at baseline, week 8, 24 and 52 AUC at baseline, week 8, 24 and 52 EPO concentration week 8, 24 and 52 HRQoL using the EQ‐5D‐5L
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| Notes |
Funding: Bayer Yakuhin Ltd. The sponsor will have access to the full trial data set Conflicts of interest: some authors reported conflicts of interest including consulting, manuscript and lecture fees Authors were contacted to request extra information but they did not reply |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Quote: "Treatment allocation was conducted via an interactive voice/web response system (IxRS), and the computer‐prepared randomisation list was provided to the IxRS supplier by the sponsor." |
| Allocation concealment (selection bias) |
Low risk |
Quote: "Treatment allocation was conducted via an interactive voice/web response system (IxRS), and the computer‐prepared randomisation list was provided to the IxRS supplier by the sponsor." |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Quote: "Double blind"
Quote: "Investigators and patients were blinded to treatment allocation." |
| Blinding of outcome assessment (detection bias)
All outcomes |
High risk |
Objective and subjective outcomes were reported |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Quote: "Of 229 patients randomized to molidustat (n=153) or darbepoetin alfa (n=76), 180 completed 52 weeks of treatment (n=115 and 65)."
151/153 participants in the intervention group and 74/76 participants in the control group completed the follow‐up period, as reported in Figure 1
Some analyses were performed on the ITT population |
| 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 |
Similar baseline characteristics, or different non‐randomised co‐interventions were reported between groups
Funder was likely to influence data analysis and study reporting or interpretation
Conflicts of interest were reported |
