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)

• ClinicalTrials.gov Identifier: NCT00773513
• Recruitment Status: Completed
• First Posted: October 16, 2008
• Results First Posted: August 15, 2018
• Last Update Posted: August 20, 2019
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: October 15, 2008
• First Posted Date: October 16, 2008
• Results First Submitted Date: July 18, 2018
• Results First Posted Date: August 15, 2018
• Last Update Posted Date: August 20, 2019
• Actual Study Start Date: December 12, 2008
• Actual Primary Completion Date: July 27, 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 18, 2018): 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 [ Time Frame: Baseline up to approximately 8.5 years ]
• Original Primary Outcome Measures (submitted: October 15, 2008): Time to composite of all cause mortality and non-fatal cardiovascular events (myocardial infarctions, stroke). [ Time Frame: Event driven ]

Current Secondary Outcome Measures (submitted: July 18, 2018)

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

Original Secondary Outcome Measures (submitted: October 15, 2008)

• Time to the individual components of the composite endpoint: time to death, time to non-fatal cardiovascular events (MI or stroke), time to MI and time to stroke. [ Time Frame: Event driven ]
• Incidence of adverse events, and serious adverse events; vital signs, laboratory parameters, ECG. [ Time Frame: Throughout study ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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.
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Renal Anemia

Intervention

• Drug: Darbepoetin Alfa
  Darbepoetin alfa will be administered as per approved label.
  Other Name: Aranesp®, Nespo®, Aranest®
• Drug: Epoetin Alfa
  Epoetin alfa will be administered as per approved label.
  Other Name: Eprex®, Epogen®, Epopen®, Erypo®
• Drug: Epoetin Beta
  Epoetin beta will be administered as per approved label.
  Other Name: Neorecormon®, Recormon®
• Drug: methoxy polyethylene glycol-epoetin beta
  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)
  Other Name: Mircera®

Study Arms

• Active Comparator: Erythropoiesis Stimulating Agents
  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.
  Interventions:

  • Drug: Darbepoetin Alfa
  • Drug: Epoetin Alfa
  • Drug: Epoetin Beta
  • Drug: methoxy polyethylene glycol-epoetin beta
• Experimental: Methoxy Polyethylene Glycol-Epoetin Beta
  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.
  Interventions:

  • Drug: Darbepoetin Alfa
  • Drug: Epoetin Alfa
  • Drug: methoxy polyethylene glycol-epoetin beta

• Publications *: Locatelli F, Hannedouche T, Fishbane S, Morgan Z, Oguey D, White WB. Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial. Clin J Am Soc Nephrol. 2019 Dec 6;14(12):1701-1710. doi: 10.2215/CJN.01380219. Epub 2019 Aug 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 20, 2018): 2825
• Original Estimated Enrollment (submitted: October 15, 2008): 2800
• Actual Study Completion Date: July 27, 2017
• Actual Primary Completion Date: July 27, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Croatia, Czechia, France, Germany, Greece, Israel, Italy, Korea, Republic of, Lithuania, Malaysia, Mexico, Panama, Philippines, Poland, Russian Federation, Serbia, Singapore, Spain, Sweden, Taiwan, Thailand, Turkey, United Kingdom
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT00773513
• Other Study ID Numbers: BH21260; 2007-005129-31
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Clinical Trials, Study Director, Hoffmann-La Roche
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: August 2019