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)

Conditions

Chronic Renal Anemia

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.

Francesco Locatelli, Thierry Hannedouche, Steven Fishbane, Zoe Morgan, Delphine Oguey et al. (6 authors)

Clinical Journal of the American Society of Nephrology2019-08-1623 citations

10.2215/cjn.01380219

Interventions

DRUGDarbepoetin Alfa

Darbepoetin alfa will be administered as per approved label.

DRUGEpoetin Alfa

Epoetin alfa will be administered as per approved label.

DRUGEpoetin Beta

Epoetin beta will be administered as per approved label.

DRUGmethoxy 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)

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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

Design outcomes

Primary

Measure	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

Measure	Time frame
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
Time to Non-Fatal Cardiovascular Events (Myocardial Infarction or Stroke, Whichever Occurred First)	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 All-Cause Mortality	Baseline up to approximately 8.5 years

Countries

Argentina, Australia, Belgium, Brazil, Croatia, Czechia, France, Germany, Greece, Israel, Italy, Lithuania, Malaysia, Mexico, Panama, Philippines, Poland, Russia, Serbia, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom

Participant flow

Participants by arm

Arm	Count
Erythropoiesis Stimulating Agents Participants received reference ESA according to approved label. No biosimilar ESAs were accepted in the study. The approved reference ESA compounds in the study were darbepoetin alfa, epoetin alfa and epoetin beta.	1,413
Methoxy Polyethylene Glycol-Epoetin Beta Participants not currently being treated with an ESA received 0.6 micrograms per kilogram (mcg/kg) methoxy polyethylene glycol-epoetin beta intravenously (iv) or subcutaneously (sc) once every 2 weeks for correction of renal anemia (target hemoglobin \[Hb\] 10-12 grams per deciliter \[g/dL\]). Participants currently treated with an ESA received a starting dose of 120, 200 or 360 mcg/kg methoxy polyethylene glycol-epoetin beta iv or sc once monthly based on the calculated weekly ESA dose prior to the switch for maintenance of anemia treatment. Once corrected and in participants currently being treated with an ESA, methoxy polyethylene glycol-epoetin beta was administered once monthly.	1,412
Total	2,825

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event / Intercurrent Illness	40	48
Overall Study	Death	531	545
Overall Study	Failure to Return	22	8
Overall Study	Insufficient Therapeutic Response	1	18
Overall Study	Reason Not Specified	159	126
Overall Study	Refused Treatment / Did not Cooperate	26	32
Overall Study	Renal Transplant	254	263
Overall Study	Withdrew Consent	68	69

Baseline characteristics

Characteristic	Erythropoiesis Stimulating Agents	Methoxy Polyethylene Glycol-Epoetin Beta	Total
Age, Continuous	62.6 years STANDARD_DEVIATION 14.8	62.2 years STANDARD_DEVIATION 15	62.4 years STANDARD_DEVIATION 14.9
Race/Ethnicity, Customized Asian	111 Participants	119 Participants	230 Participants
Race/Ethnicity, Customized Black or African American	40 Participants	37 Participants	77 Participants
Race/Ethnicity, Customized Other	41 Participants	38 Participants	79 Participants
Race/Ethnicity, Customized White	1221 Participants	1218 Participants	2439 Participants
Sex: Female, Male Female	581 Participants	605 Participants	1186 Participants
Sex: Female, Male Male	832 Participants	807 Participants	1639 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	557 / 1,409	558 / 1,409
other Total, other adverse events	1,171 / 1,409	1,177 / 1,409
serious Total, serious adverse events	1,123 / 1,409	1,097 / 1,409