Anemia
Conditions
Brief summary
This 2 arm study will compare the efficacy and safety of Mircera and darbepoetin alfa, administered at extended dosing intervals, in the maintenance treatment of anemia in patients with chronic kidney disease (CKD) who are on hemodialysis. Eligible patients receiving once-weekly intravenous (IV) darbepoetin alfa maintenance treatment will be randomized to receive either intravenous Mircera once a month (at a starting dose of 120, 200 or 360 micrograms/month, depending on the weekly dose of darbepoetin alfa prior to start of study) or intravenous darbepoetin alfa every 2 weeks before switching to once monthly administration. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.
Interventions
DRUGDarbepoetin alfa
As prescribed, iv.
DRUGmethoxy polyethylene glycol-epoetin beta [Mircera]
120, 200 or 360 micrograms iv / month, starting dose
Sponsors
Hoffmann-La Roche
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
* adult patients, \>=18 years of age; * chronic renal anemia; * hemodialysis 3 times weekly for \>=12 weeks before screening, and during screening/baseline period; * receiving darbepoetin alfa maintenance therapy for \>=8 weeks before screening, and during screening/baseline period.
Exclusion criteria
* overt gastrointestinal bleeding within 8 weeks before screening or during screening/baseline period; * transfusion of red blood cells within 8 weeks before screening or during screening/baseline period; * active malignancy;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Lesser Than or Equal to One Gram Per Deciliter Decrease in Average Hemoglobin From Baseline and Maintaining Average Hemoglobin Level Greater Than or Equal to 10.5 g/dL Over Evaluation Period | Baseline (Week -4 to Week -1) and Evaluation period (Weeks 50 to 53) | Randomized participants with an average hemoglobin (Hb) decrease from Baseline (Week -4 to Week -1) not exceeding 1.0 gram per deciliter (g/dL) and an absolute average Hb \>= 10.5 g/dL during the evaluation period (Weeks 50-53) were defined as responders. Non-responders included participants without any Hb data during the second treatment period and those who did not meet the response criteria and thus were not included in the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percentage Change in MIRCERA and Darbepoetin Alpha Dose Over Time | Week 27 to Month 12 | All participants received once monthly treatment schedule of both MIRCERA and darbepoetin alpha for the respective treatment arms after Week 27 and these analyses are based on the absolute doses. The average dose in Months 11 and 12 was defined as the mean of all administered doses between study Days 302 and 363. The change in dose was calculated as the percentage change between the respective dose at Week 27 and the average corresponding dose during Months 11 and 12 in each treatment group. |
| Number of Participants With Marked Laboratory Abnormality Over Time | Up to Week 53 | Values of laboratory parameters higher (H) or lower (L) than the Roche defined reference range were considered as abnormality. The laboratory parameters with abnormality were platelets, white blood cells (WBC), albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and potassium. Blood samples were drawn before drug administration and before the dialysis session. |
| Median Blood Pressure Over Time | Baseline (Week -4 to Week -1), Week 28, and Week 52 | Systolic and diastolic blood pressures (BP) were measured before and after the dialysis session at every week from Baseline (Week -4 to Week -1) to Week 53. Median pre-dialysis diastolic blood pressure (PrD DBP) , median post-dialysis diastolic blood pressure (PoD DBP), median pre-dialysis systolic blood pressure (PrD SBP), and post-dialysis systolic blood pressure (PoD SBP) were reported at Baseline (Week -4 to Week -1) , Week 28 and Week 52. |
| Mean Pulse Rate Over Time | Baseline (Week -4 to Week -1), Week 28, and Week 52 | Pulse rate is defined as the number of heartbeats in a minute and was assessed in sitting position of the participants at every week from Baseline (Week -4 to Week -1) to Week 53. Summary data of mean values of pulse rate are presented at Baseline (Week -4 to Week -1), Week 28 and Week 52. |
| Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | From screening to Week 56 | An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. A serious adverse event (SAE) is any adverse event that can result in death or is life-threatening or required in participants hospitalization or prolongation of existing hospitalization or results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect; or is medically significant or requires intervention to prevent one or other of the outcomes listed above. SAEs were reported up to Week 56, while nonserious AEs up to Week 52. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Netherlands, Portugal, Spain, Switzerland, United Kingdom
Participant flow
Recruitment details
The study was conducted from 20 December 2006 to 27 November 2008 in Europe along with Canada and Australia. A total of 490 eligible participants were enrolled.
Pre-assignment details
Out of 490 participants, one did not receive the study drug and was excluded from the safety population.
Participants by arm
| Arm | Count |
|---|---|
| MIRCERA Participants with anemia in CKD who were on hemodialysis received MIRCERA IV once every month up to 52 weeks. The starting dose of MIRCERA administered during the treatment period was dependent on the dose of darbepoetin alfa administered during screening period and was 120, 200 and 360 mcg/month for weekly darbepoetin alfa doses of \<40, 40-80, and \>80 mcg, respectively. | 245 |
| Darbepoetin Alfa Participants with anemia in CKD who were on hemodialysis received darbepoetin alfa IV once every two weeks up to 26 weeks and received darbepoetin alfa IV twice the dose than earlier, once every month from Week 27 up to Week 52. | 244 |
| Total | 489 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Treatment Period | Adverse Event | 1 | 2 |
| First Treatment Period | Death | 6 | 7 |
| First Treatment Period | Lack of Efficacy | 1 | 1 |
| First Treatment Period | Lost to Follow-up | 0 | 1 |
| First Treatment Period | Not defined | 4 | 1 |
| First Treatment Period | Renal transplant | 11 | 7 |
| First Treatment Period | Withdrawal by Subject | 6 | 3 |
| Second Treatment Period | Adverse Event | 2 | 5 |
| Second Treatment Period | Death | 8 | 4 |
| Second Treatment Period | Lack of Efficacy | 9 | 47 |
| Second Treatment Period | Lost to Follow-up | 0 | 1 |
| Second Treatment Period | Not defined | 3 | 8 |
| Second Treatment Period | Renal transplant | 4 | 6 |
| Second Treatment Period | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | MIRCERA | Darbepoetin Alfa | Total |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 13.64 | 65.4 years STANDARD_DEVIATION 13.91 | 65.8 years STANDARD_DEVIATION 13.77 |
| Gender Female | 97 Participants | 89 Participants | 186 Participants |
| Gender Male | 148 Participants | 155 Participants | 303 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 140 / 245 | 126 / 244 |
| serious Total, serious adverse events | 99 / 245 | 94 / 244 |
Outcome results
Primary
Percentage of Participants With Lesser Than or Equal to One Gram Per Deciliter Decrease in Average Hemoglobin From Baseline and Maintaining Average Hemoglobin Level Greater Than or Equal to 10.5 g/dL Over Evaluation Period
Randomized participants with an average hemoglobin (Hb) decrease from Baseline (Week -4 to Week -1) not exceeding 1.0 gram per deciliter (g/dL) and an absolute average Hb \>= 10.5 g/dL during the evaluation period (Weeks 50-53) were defined as responders. Non-responders included participants without any Hb data during the second treatment period and those who did not meet the response criteria and thus were not included in the analysis.
Time frame: Baseline (Week -4 to Week -1) and Evaluation period (Weeks 50 to 53)
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIRCERA | Percentage of Participants With Lesser Than or Equal to One Gram Per Deciliter Decrease in Average Hemoglobin From Baseline and Maintaining Average Hemoglobin Level Greater Than or Equal to 10.5 g/dL Over Evaluation Period | 64.1 Percentage of participants |
| Darbepoetin Alfa | Percentage of Participants With Lesser Than or Equal to One Gram Per Deciliter Decrease in Average Hemoglobin From Baseline and Maintaining Average Hemoglobin Level Greater Than or Equal to 10.5 g/dL Over Evaluation Period | 40.4 Percentage of participants |
Comparison: The proportion of responders treated with methoxy polyethylene glycol-epoetin beta versus the proportion of responders treated with darbepoetin alpha during the evaluation period.p-value: <0.000195% CI: [1.83, 3.79]Chi-squared, Corrected
Secondary
Mean Percentage Change in MIRCERA and Darbepoetin Alpha Dose Over Time
All participants received once monthly treatment schedule of both MIRCERA and darbepoetin alpha for the respective treatment arms after Week 27 and these analyses are based on the absolute doses. The average dose in Months 11 and 12 was defined as the mean of all administered doses between study Days 302 and 363. The change in dose was calculated as the percentage change between the respective dose at Week 27 and the average corresponding dose during Months 11 and 12 in each treatment group.
Time frame: Week 27 to Month 12
Population: ITT population included all randomized participants. Data is presented for the participants available at the time of assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIRCERA | Mean Percentage Change in MIRCERA and Darbepoetin Alpha Dose Over Time | 6.8 percent change | Standard Deviation 51 |
| Darbepoetin Alfa | Mean Percentage Change in MIRCERA and Darbepoetin Alpha Dose Over Time | 58.8 percent change | Standard Deviation 76.5 |
Secondary
Mean Pulse Rate Over Time
Pulse rate is defined as the number of heartbeats in a minute and was assessed in sitting position of the participants at every week from Baseline (Week -4 to Week -1) to Week 53. Summary data of mean values of pulse rate are presented at Baseline (Week -4 to Week -1), Week 28 and Week 52.
Time frame: Baseline (Week -4 to Week -1), Week 28, and Week 52
Population: The Safety population was defined as all participants who received at least one dose of MIRCERA or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not. The 'n' represents the number of participants at a specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MIRCERA | Mean Pulse Rate Over Time | Week 28, n = 211, 215 | 74 beats per minute | Standard Deviation 13 |
| MIRCERA | Mean Pulse Rate Over Time | Baseline, n = 245, 244 | 73 beats per minute | Standard Deviation 11.1 |
| MIRCERA | Mean Pulse Rate Over Time | Week 52, n = 184, 147 | 73 beats per minute | Standard Deviation 12.5 |
| Darbepoetin Alfa | Mean Pulse Rate Over Time | Baseline, n = 245, 244 | 73 beats per minute | Standard Deviation 12.3 |
| Darbepoetin Alfa | Mean Pulse Rate Over Time | Week 28, n = 211, 215 | 72 beats per minute | Standard Deviation 12.6 |
| Darbepoetin Alfa | Mean Pulse Rate Over Time | Week 52, n = 184, 147 | 71 beats per minute | Standard Deviation 11.3 |
Secondary
Median Blood Pressure Over Time
Systolic and diastolic blood pressures (BP) were measured before and after the dialysis session at every week from Baseline (Week -4 to Week -1) to Week 53. Median pre-dialysis diastolic blood pressure (PrD DBP) , median post-dialysis diastolic blood pressure (PoD DBP), median pre-dialysis systolic blood pressure (PrD SBP), and post-dialysis systolic blood pressure (PoD SBP) were reported at Baseline (Week -4 to Week -1) , Week 28 and Week 52.
Time frame: Baseline (Week -4 to Week -1), Week 28, and Week 52
Population: Safety Population included all participants who received at least one dose of MIRCERA or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not. The 'n' represents the number of participants at a specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MIRCERA | Median Blood Pressure Over Time | PrD DBP, Baseline, n = 245, 244 | 75 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PrD DBP, Week 28, n = 211, 219 | 73 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PrD DBP, Week 52, n = 187, 147 | 70 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD DBP, Baseline, n = 245, 244 | 70 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD DBP, Week 28, n = 213, 218 | 70 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD DBP, Week 52, n = 186, 148 | 70 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PrD SBP, Baseline, n = 245, 244 | 140 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PrD SBP, Week 28, n = 211, 219 | 140 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PrD SBP, Week 52, n = 187, 147 | 140 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD SBP, Baseline, n = 245, 244 | 133 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD SBP, Week 28, n = 213, 220 | 134 millimeter of mercury |
| MIRCERA | Median Blood Pressure Over Time | PoD SBP, Week 52, n = 186, 148 | 139 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD SBP, Week 28, n = 213, 220 | 137 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD DBP, Baseline, n = 245, 244 | 70 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD SBP, Baseline, n = 245, 244 | 140 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD DBP, Week 28, n = 211, 219 | 71 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD SBP, Baseline, n = 245, 244 | 130 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD DBP, Week 52, n = 187, 147 | 70 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD SBP, Week 28, n = 211, 219 | 140 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD DBP, Baseline, n = 245, 244 | 70 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD SBP, Week 52, n = 186, 148 | 127 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD DBP, Week 28, n = 213, 218 | 70 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PrD SBP, Week 52, n = 187, 147 | 132 millimeter of mercury |
| Darbepoetin Alfa | Median Blood Pressure Over Time | PoD DBP, Week 52, n = 186, 148 | 65 millimeter of mercury |
Secondary
Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. A serious adverse event (SAE) is any adverse event that can result in death or is life-threatening or required in participants hospitalization or prolongation of existing hospitalization or results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect; or is medically significant or requires intervention to prevent one or other of the outcomes listed above. SAEs were reported up to Week 56, while nonserious AEs up to Week 52.
Time frame: From screening to Week 56
Population: The Safety Population was defined as all participants who received at least one dose of MIRCERA or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not. Among the 14 deaths in Darbepoetin alfa group, 3 participants died after withdrawal from the study and within 30 days after last dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIRCERA | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Participants with any AE | 222 Participants |
| MIRCERA | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Participants with any SAE | 99 Participants |
| MIRCERA | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Deaths | 14 Participants |
| Darbepoetin Alfa | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Participants with any AE | 217 Participants |
| Darbepoetin Alfa | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Participants with any SAE | 94 Participants |
| Darbepoetin Alfa | Number of Participants With Any Adverse Events, Serious Adverse Events, and Deaths | Deaths | 14 Participants |
Secondary
Number of Participants With Marked Laboratory Abnormality Over Time
Values of laboratory parameters higher (H) or lower (L) than the Roche defined reference range were considered as abnormality. The laboratory parameters with abnormality were platelets, white blood cells (WBC), albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and potassium. Blood samples were drawn before drug administration and before the dialysis session.
Time frame: Up to Week 53
Population: The Safety Population was defined as all participants who received at least one dose of methoxy polyethylene glycol-epoetin beta or darbepoetin alfa and had a safety follow-up, whether withdrawn prematurely or not. The 'n' represents the number of participants at a specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Platelets-H, n = 241, 243 | 1 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Platelets-L, n = 241, 243 | 18 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | WBC-H, n = 242, 243 | 4 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | WBC-L, n = 242, 243 | 10 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | ALT-H, n = 241, 242 | 7 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | ALP-H, n = 240, 242 | 12 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | AST-H, n = 239, 240 | 4 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Albumin-L, n = 240, 242 | 22 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Phosphate-H, n = 240, 242 | 87 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Phosphate-L, n = 240, 242 | 36 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Potassium-H, n = 240, 242 | 54 participants |
| MIRCERA | Number of Participants With Marked Laboratory Abnormality Over Time | Potassium-L, n = 240, 242 | 2 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Potassium-H, n = 240, 242 | 41 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Platelets-H, n = 241, 243 | 5 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | AST-H, n = 239, 240 | 6 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Platelets-L, n = 241, 243 | 5 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Phosphate-L, n = 240, 242 | 25 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | WBC-H, n = 242, 243 | 7 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Albumin-L, n = 240, 242 | 27 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | WBC-L, n = 242, 243 | 4 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Potassium-L, n = 240, 242 | 5 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | ALT-H, n = 241, 242 | 5 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | Phosphate-H, n = 240, 242 | 92 participants |
| Darbepoetin Alfa | Number of Participants With Marked Laboratory Abnormality Over Time | ALP-H, n = 240, 242 | 14 participants |