Maintenance Treatment of Renal Anemia in Dialysis Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of molidustat in comparison to darbepoetin alfa in dialysis subjects with renal anemia who are treated with Erythropoiesis-Stimulating Agents (ESAs).

Official Title
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A Randomized, Active-controlled, Double-blinded, Double-dummy, Parallel-group, Multicenter Study to Investigate the Efficacy and Safety of Oral Molidustat in Comparison to Darbepoetin Alfa in Dialysis Subjects Treated With Erythropoiesis-Stimulating Agents (ESAs)

Conditions
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Anemia, Renal Insufficiency, Chronic

Intervention / Treatment
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* Drug: Molidustat (BAY85-3934)
* Drug: Darbepoetin alfa
* Drug: Placebo of Molidustat (BAY85-3934)
* Drug: Placebo of Darbepoetin alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject with ESKD (end-stage kidney disease) on regular dialysis (including, hemodiafiltration, hemofiltration, hemodialysis, and other modalities except for peritoneal dialysis) weekly or more than weekly for at least 12 weeks prior to randomization Body weight (after dialysis) > 40 and ≤ 160 kg at screening Male or female subject ≥ 20 years of age at screening At least one kidney Treated with weekly or bi-weekly dose of darbepoetin alfa, monthly or bi-weekly dose of epoetin beta pegol, OR weekly, biweekly, twice or three times per week dose of epoetin alfa/beta, and having had no more than one dose change within 8 weeks prior to randomization Mean screening Hb level ≥ 9.5 and < 12.0 g/dL (mean of all central laboratory Hb levels before dialysis [at least 2 measurements must be taken ≥ 2 days apart] 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 randomization Ferritin ≥ 100 ng/mL or transferrin saturation ≥ 20% at screening Serum folate level and serum vitamin B12 level above lower limit of normal (LLN) at screening Exclusion Criteria: New York Heart Association (NYHA) Class III or IV congestive heart failure History of cardio- (cerebro-) vascular events (e.g., unstable angina, myocardial infarction, stroke, pulmonary thromboembolism, and acute limb ischemia) within 6 months prior to randomization Sustained, poorly controlled arterial hypertension (defined as systolic BP (blood pressure) ≥ 180mmHg or diastolic BP ≥ 110mmHg) or hypotension (defined as systolic BP < 90mmHg) at randomization Proliferative choroidal or retinal disease, such as neovascular agerelated macular degeneration or proliferative diabetic retinopathy requiring invasive treatment (e.g., intraocular injections or laser photocoagulation) at screening

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Molidustat group<br>Subjects in the molidustat group will receive molidustat and darbepoetin alfa placebo. | Drug: Molidustat (BAY85-3934)<br>* Starting dose of molidustat will be titrated based on the subject's Hb (Hemoglobin) response. Administrated orally once daily (OD).<br>Drug: Placebo of Darbepoetin alfa<br>* Matching placebo of Darbepoetin alfa.<br>|
| Active Comparator: Darbepoetin alfa group<br>Subjects in the darbepoetin alfa group will receive molidustat placebo and darbepoetin alfa. | Drug: Darbepoetin alfa<br>* Starting dose of darbepoetin alfa will be titrated based on the subject's Hb (Hemoglobin) response. Administrated weekly or once every two weeks by intravenous injection.<br>Drug: Placebo of Molidustat (BAY85-3934)<br>* Matching placebo of Molidustat.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean Hb level during the evaluation period |  | From week 33 to 36 | 
| The change in mean Hb level during the evaluation period from baseline |  | Baseline and week 33 to 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder rate: proportion of responders among the subjects | Responder is defined as meeting all of the following criteria: (i) Mean of the Hb levels in the target range (ii) ≥ 50% of the Hb levels in the target range (iii) No rescue treatment | From week 33 to 36 | 
| Proportion of subjects who meet each component of the response | Response: (i) Mean of the Hb levels in the target range (ii) ≥ 50% of the Hb levels in the target range (iii) No rescue treatment | From week 33 to 36 | 
| Hb level |  | Up to 52 weeks | 
| Change in Hb level |  | Baseline and up to 52 weeks | 
| Proportion of subjects whose mean hemoglobin level is in the target range |  | From week 33 to 36 | 
| Proportion of subjects whose mean hemoglobin level is above the target range |  | From week 33 to 36 | 
| Proportion of subjects whose mean hemoglobin level is below the target range |  | From week 33 to 36 | 
| Proportion of subjects with hemoglobin levels in the target range |  | Up to 52 weeks | 
| Proportion of subjects with hemoglobin levels above the target range |  | Up to 52 weeks | 
| Proportion of subjects with hemoglobin levels below the target range |  | Up to 52 weeks | 
| Proportion of subjects whose maximum rise in Hb between each consecutive visits is above 0.5 g/dL/week | Defined as change in Hb level / duration between two visits (weeks) | Up to 52 weeks | 
| Number of participants with serious adverse events |  | Up to 52 weeks | 
| Maximum concentration (Cmax) |  | At baseline, week 8, week 24 and week 52 | 
| Area under the concentration-time curve (AUC) |  | At baseline, week 8, week 24 and week 52 | 
| EPO (Erythropoietin) serum concentration |  | At baseline, week 8, week 24 and week 52 |