A Study to Assess All-Cause Mortality and Cardiovascular Morbidity in Participants With Chronic Kidney Disease (CKD) on Dialysis and Those Not on Renal Replacement Therapy Receiving Methoxy Polyethylene Glycol-Epoetin Beta (Mircera) or Reference Erythropoietin Stimulating Agents (ESAs)

Study Overview
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Brief Summary
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This 2 arm safety study will compare the outcome with respect to a composite endpoint of all-cause mortality and non-fatal cardiovascular events (myocardial infarction, stroke) in CKD participants either on dialysis or not receiving renal replacement therapy under treatment with methoxy polyethylene glycol-epoetin beta or reference ESAs. Participants will be randomized to receive intravenous (iv) or subcutaneous (sc) methoxy polyethylene glycol-epoetin beta at the following doses: for participants not already receiving ESA treatment, methoxy polyethylene glycol-epoetin beta will be administered at a starting dose of 0.6 micrograms per kilograms every 2 weeks (mcg/kg/2wks) iv or sc; for participants receiving maintenance ESA treatment, iv or sc methoxy polyethylene glycol-epoetin beta will be administered at an initial monthly dose of 120, 200 or 360 micrograms (mcg) depending on the weekly dose of ESA received prior to first methoxy polyethylene glycol-epoetin beta administration. Participants randomized to reference ESA treatment will receive iv or sc ESAs in accordance with their prescribed dosing information.

Official Title
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A Randomized, Controlled, Open-Label, Multi-Centre, Parallel-Group Study To Assess All-Cause Mortality And Cardiovascular Morbidity In Patients With Chronic Kidney Disease On Dialysis And Those Not On Renal Replacement Therapy Under Treatment With MIRCERA® Or Reference ESAs.

Conditions
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Chronic Renal Anemia

Intervention / Treatment
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* Drug: Darbepoetin Alfa
* Drug: Epoetin Alfa
* Drug: Epoetin Beta
* Drug: methoxy polyethylene glycol-epoetin beta


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants with symptomatic anemia associated with CKD Participants with renal anemia who are not treated with an ESA: Anemia was defined as hemoglobin (Hb) concentration less than (<) 11.0 grams per deciliter (g/dL) (mean of 2 screening values with at least one day and a maximum of 2 weeks between measurements) with clinical indication for ESA treatment Participants with renal anemia who are on maintenance ESA therapy: If on dialysis: regular long-term hemodialysis or peritoneal dialysis therapy with the same mode of dialysis for at least 3 months before screening Hb concentration between 10 and 12 g/dL (mean of 2 screening values with at least one day and a maximum of 2 weeks between measurements) Participants with adequate iron status defined as: serum ferritin above or equal to 100 micrograms per liter or transferrin saturation above or equal to 20 percent Exclusion Criteria: Contraindications to ESA treatment: uncontrolled hypertension, hypersensitivity to the active substance or any of the excipients, any other contraindication to ESA therapy Conditions known to cause inadequate response to ESA treatment or anemia other than symptomatic anemia associated with CKD: History of hemoglobinopathy Anemia due to hemolysis Pure red cell aplasia High likelihood of early withdrawal (for example, within 1 year) or interruption of the study Pregnancy or breast-feeding Women of childbearing potential without effective contraception Administration of another investigational drug within 1 month before screening or planned during the study period

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erythropoiesis Stimulating Agents<br>Participants will receive reference ESA according to approved label. The approved reference ESA compounds in the study will be darbepoetin alfa, epoetin alfa and epoetin beta. | Drug: Darbepoetin Alfa<br>* Darbepoetin alfa will be administered as per approved label.<br>* Other names: Aranesp®, Nespo®, Aranest®;Drug: Epoetin Alfa<br>* Epoetin alfa will be administered as per approved label.<br>* Other names: Eprex®, Epogen®, Epopen®, Erypo®;Drug: Epoetin Beta<br>* Epoetin beta will be administered as per approved label.<br>* Other names: Neorecormon®, Recormon®;Drug: methoxy polyethylene glycol-epoetin beta<br>* Participants who are currently not being treated with an ESA will receive methoxy polyethylene glycol-epoetin beta administered at a starting dose of 0.6 mcg/kg body weight once every 2 weeks. Participants who are currently being treated with an ESA will receive methoxy polyethylene glycol-epoetin beta at a dose of 120, 200 or 360 mcg once monthly (based on ESA dose administered in Week -1)<br>* Other names: Mircera®;|
| Experimental: Methoxy Polyethylene Glycol-Epoetin Beta<br>Participants not currently being treated with an ESA will receive methoxy polyethylene glycol-epoetin beta iv or sc once every 2 weeks for correction of renal anemia (target Hb 10-12 g/dL). Once corrected and in participants currently being treated with an ESA, methoxy polyethylene glycol-epoetin beta will be administered once monthly. | Drug: Darbepoetin Alfa<br>* Darbepoetin alfa will be administered as per approved label.<br>* Other names: Aranesp®, Nespo®, Aranest®;Drug: Epoetin Alfa<br>* Epoetin alfa will be administered as per approved label.<br>* Other names: Eprex®, Epogen®, Epopen®, Erypo®;Drug: methoxy polyethylene glycol-epoetin beta<br>* Participants who are currently not being treated with an ESA will receive methoxy polyethylene glycol-epoetin beta administered at a starting dose of 0.6 mcg/kg body weight once every 2 weeks. Participants who are currently being treated with an ESA will receive methoxy polyethylene glycol-epoetin beta at a dose of 120, 200 or 360 mcg once monthly (based on ESA dose administered in Week -1)<br>* Other names: Mircera®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Composite of All-Cause Mortality and Non-Fatal Cardiovascular Events (Myocardial Infarction, Stroke) Defined as Time Between First Dose of Study Medication and Date of Death or Non-Fatal Cardiovascular Events, Whichever Occurred First |  | Baseline up to approximately 8.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to All-Cause Mortality |  | Baseline up to approximately 8.5 years | 
| Time to Non-Fatal and Fatal Myocardial Infarction |  | Baseline up to approximately 8.5 years | 
| Time to Non-Fatal and Fatal Stroke |  | Baseline up to approximately 8.5 years | 
| Time to Non-Fatal Cardiovascular Events (Myocardial Infarction or Stroke, Whichever Occurred First) |  | Baseline up to approximately 8.5 years | 
| Percentage of Participants With Anti-Erythropoietin Antibody-Mediated Pure Red Cell Aplasia (PRCA) |  | Baseline up to approximately 8.5 years | 
| Percentage of Participants With Gastrointestinal Bleeding |  | Baseline up to approximately 8.5 years | 
| Percentage of Participants With Thromboembolic Events |  | Baseline up to approximately 8.5 years |