Anemia
Conditions
Brief summary
This 2 arm study will compare the efficacy and safety of Mircera and darbepoetin alfa in the treatment of anemia in patients with chronic kidney disease who are not on dialysis and who are receiving subcutaneous darbepoetin alfa maintenance therapy. Patients will be randomized either to remain on darbepoetin alfa therapy as per local label, or to switch to monthly subcutaneous Mircera, at a starting dose of 120, 200 or 360 micrograms, depending on the weekly dose of darbepoetin alfa administered prior to the first dose of Mircera. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.
Interventions
DRUGMircera
Starting dose of 120, 200 and 360 micrograms administered by subcutaneous injection once a month.
DRUGDarbepoetin alfa
As prescribed, subcutaneous injection once every week, once every 2 weeks or once every month as per local labeling specifications.
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 kidney disease, not requiring dialysis; * 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 malignant disease; * previous treatment with Mircera.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Baseline (measurements at Week -4, Week -2 and Day 1) and Evaluation Period (Months 8 and 9; measurements twice a month and at the final visit). | A time adjusted average baseline hemoglobin (Hb) concentration was calculated using the trapezoid rule from all available Hb measurements taken during the baseline period. The average evaluation period Hb concentration for each individual was calculated using the same method, from all their available measurements taken during the two month evaluation period. The change in Hb concentration between the baseline and evaluation periods was calculated by subtracting the baseline Hb from the evaluation period Hb. All blood samples for Hb measurements were taken prior to study drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin Concentration From Baseline Over Time | From Baseline to 9 months; blood samples for hemoglobin measurements were taken twice a month, at each study visit. | — |
| Number of Participants With Red Blood Cell (RBC) Transfusions | From randomization to Month 9 | Red blood cell (RBC) transfusions could be given during the treatment period in case of medical need, i.e., in severely anemic patients with recognized symptoms or signs of anemia (e.g., in patients with acute blood loss, with severe angina, or whose Hemoglobin decreased to critical levels). The number of participants who had at least one red blood cell transfusion during the entire study, during the Titration Period and during the Evaluation Period is presented. Participants who received more than one transfusion within a defined period are only counted once. |
| Participants With Adverse Events | Randomization to Month 10 (final visit) | Adverse events were collected during the treatment period (from the first treatment dose) up to 30 days after last dose or at least until the date of last contact if the date of last contact occurred after the specified 30 day period. |
Countries
Australia, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mircera Participants received Mircera by subcutaneous injection once every month during the dose titration (7 months) and evaluation period (2 months). The starting dose was based on the weekly dose of darbepoetin alfa administered prior to the switch to Mircera, and was either 120, 200 or 360 µg Mircera per month. The dose was then adjusted to maintain Hemoglobin levels within the defined target range and also according to the need for red blood cell transfusions (due to worsening anemia), or for toxicity related to Mircera. | 114 |
| Darbepoetin Alfa Participants continued to receive the same dose of darbepoetin alfa by subcutaneous injection once every week, once every 2 weeks or once every month as per local labeling during the dose titration (7 months) and the evaluation period (2 months). | 114 |
| Total | 228 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Evaluation Period | Adverse Event | 1 | 0 |
| Evaluation Period | Death | 1 | 1 |
| Evaluation Period | Failure to return | 1 | 0 |
| Evaluation Period | Insufficient Therapeutic Response | 1 | 0 |
| Evaluation Period | Refused treatment | 1 | 1 |
| Evaluation Period | Renal transplant | 0 | 1 |
| Evaluation Period | Site closure | 0 | 1 |
| Titration Period | Adverse Event | 2 | 0 |
| Titration Period | Death | 3 | 2 |
| Titration Period | Failure to return | 1 | 0 |
| Titration Period | Hospitalized in another hospital | 1 | 0 |
| Titration Period | Insufficient Therapeutic Response | 1 | 0 |
| Titration Period | Refused Treatment | 4 | 1 |
Baseline characteristics
| Characteristic | Total | Mircera | Darbepoetin Alfa |
|---|---|---|---|
| Age Continuous | 70.4 years STANDARD_DEVIATION 12.62 | 71.3 years STANDARD_DEVIATION 11.03 | 69.6 years STANDARD_DEVIATION 14.02 |
| Sex: Female, Male Female | 132 Participants | 66 Participants | 66 Participants |
| Sex: Female, Male Male | 96 Participants | 48 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 115 | 49 / 113 |
| serious Total, serious adverse events | 41 / 115 | 23 / 113 |
Outcome results
Primary
Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period
A time adjusted average baseline hemoglobin (Hb) concentration was calculated using the trapezoid rule from all available Hb measurements taken during the baseline period. The average evaluation period Hb concentration for each individual was calculated using the same method, from all their available measurements taken during the two month evaluation period. The change in Hb concentration between the baseline and evaluation periods was calculated by subtracting the baseline Hb from the evaluation period Hb. All blood samples for Hb measurements were taken prior to study drug administration.
Time frame: Baseline (measurements at Week -4, Week -2 and Day 1) and Evaluation Period (Months 8 and 9; measurements twice a month and at the final visit).
Population: Per Protocol population consisted of all randomized patients who had received at least one dose of trial medication and who have no major protocol violation. Data missing at the end of the evaluation period were handled using the last observation carried forward method (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Baseline Hb | 11.29 g/dL | Standard Deviation 0.382 |
| Mircera | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Change from baseline | 0.15 g/dL | Standard Deviation 0.899 |
| Darbepoetin Alfa | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Baseline Hb | 11.33 g/dL | Standard Deviation 0.397 |
| Darbepoetin Alfa | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Change from baseline | -0.03 g/dL | Standard Deviation 0.693 |
Secondary
Change in Hemoglobin Concentration From Baseline Over Time
Time frame: From Baseline to 9 months; blood samples for hemoglobin measurements were taken twice a month, at each study visit.
Population: Intent-to-treat population, including all randomized patients. n refers to the number of patients for whom data was available at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 4 Months [n=109, 110] | 0.05 g/dL | Standard Deviation 0.893 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 0.5 Months [n=113, 114] | 0.29 g/dL | Standard Deviation 0.737 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 4.5 Months [n=104, 108] | 0.18 g/dL | Standard Deviation 0.94 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 2 Months [n=112, 112] | 0.27 g/dL | Standard Deviation 0.897 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 5 Months [n=108, 111] | -0.03 g/dL | Standard Deviation 0.897 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Baseline [n=114, 114] | 11.27 g/dL | Standard Deviation 0.39 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 5.5 Months [n=105, 110] | 0.15 g/dL | Standard Deviation 0.922 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 2.5 Months [n=110, 112] | 0.45 g/dL | Standard Deviation 0.924 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 6 Months [n=103, 111] | -0.05 g/dL | Standard Deviation 0.988 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 1 Month [n=114, 113] | 0.34 g/dL | Standard Deviation 0.813 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 6.5 Months [n=100, 110] | 0.06 g/dL | Standard Deviation 1.087 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 3 Months [n=111, 112] | 0.23 g/dL | Standard Deviation 1.01 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 7 Months [n=102, 111] | 0.03 g/dL | Standard Deviation 1.008 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 8 Months [n=100, 108] | -0.04 g/dL | Standard Deviation 1.198 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 7.5 Months [n=99, 110] | 0.12 g/dL | Standard Deviation 1.166 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 8.5 Months [n=97, 107] | 0.14 g/dL | Standard Deviation 1.256 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 3.5 Months [n=108, 108] | 0.18 g/dL | Standard Deviation 1.095 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 9 Months [n=94, 101] | 0.07 g/dL | Standard Deviation 1.045 |
| Mircera | Change in Hemoglobin Concentration From Baseline Over Time | Change at 1.5 Months [n=111, 113] | 0.45 g/dL | Standard Deviation 0.866 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 9 Months [n=94, 101] | -0.06 g/dL | Standard Deviation 0.956 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 8 Months [n=100, 108] | -0.12 g/dL | Standard Deviation 0.905 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Baseline [n=114, 114] | 11.31 g/dL | Standard Deviation 0.393 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 0.5 Months [n=113, 114] | 0.03 g/dL | Standard Deviation 0.49 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 1 Month [n=114, 113] | 0.06 g/dL | Standard Deviation 0.575 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 1.5 Months [n=111, 113] | 0.11 g/dL | Standard Deviation 0.599 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 2 Months [n=112, 112] | 0.02 g/dL | Standard Deviation 0.716 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 2.5 Months [n=110, 112] | 0.16 g/dL | Standard Deviation 0.673 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 3 Months [n=111, 112] | 0.10 g/dL | Standard Deviation 0.602 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 3.5 Months [n=108, 108] | 0.05 g/dL | Standard Deviation 0.675 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 4 Months [n=109, 110] | 0.00 g/dL | Standard Deviation 0.681 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 4.5 Months [n=104, 108] | 0.13 g/dL | Standard Deviation 0.699 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 5 Months [n=108, 111] | -0.07 g/dL | Standard Deviation 0.757 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 5.5 Months [n=105, 110] | -0.03 g/dL | Standard Deviation 0.729 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 6 Months [n=103, 111] | -0.06 g/dL | Standard Deviation 0.82 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 6.5 Months [n=100, 110] | 0.04 g/dL | Standard Deviation 0.817 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 7 Months [n=102, 111] | -0.00 g/dL | Standard Deviation 0.842 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 8.5 Months [n=97, 107] | 0.02 g/dL | Standard Deviation 0.766 |
| Darbepoetin Alfa | Change in Hemoglobin Concentration From Baseline Over Time | Change at 7.5 Months [n=99, 110] | -0.00 g/dL | Standard Deviation 0.873 |
Secondary
Number of Participants With Red Blood Cell (RBC) Transfusions
Red blood cell (RBC) transfusions could be given during the treatment period in case of medical need, i.e., in severely anemic patients with recognized symptoms or signs of anemia (e.g., in patients with acute blood loss, with severe angina, or whose Hemoglobin decreased to critical levels). The number of participants who had at least one red blood cell transfusion during the entire study, during the Titration Period and during the Evaluation Period is presented. Participants who received more than one transfusion within a defined period are only counted once.
Time frame: From randomization to Month 9
Population: Safety population included all randomized patients who received at least one dose of trial medication and a safety follow-up, according to the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mircera | Number of Participants With Red Blood Cell (RBC) Transfusions | Entire Study | 9 participants |
| Mircera | Number of Participants With Red Blood Cell (RBC) Transfusions | Titration Period | 5 participants |
| Mircera | Number of Participants With Red Blood Cell (RBC) Transfusions | Evaluation Period | 5 participants |
| Darbepoetin Alfa | Number of Participants With Red Blood Cell (RBC) Transfusions | Entire Study | 3 participants |
| Darbepoetin Alfa | Number of Participants With Red Blood Cell (RBC) Transfusions | Titration Period | 1 participants |
| Darbepoetin Alfa | Number of Participants With Red Blood Cell (RBC) Transfusions | Evaluation Period | 2 participants |
Secondary
Participants With Adverse Events
Adverse events were collected during the treatment period (from the first treatment dose) up to 30 days after last dose or at least until the date of last contact if the date of last contact occurred after the specified 30 day period.
Time frame: Randomization to Month 10 (final visit)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mircera | Participants With Adverse Events | Any adverse event | 102 participants |
| Mircera | Participants With Adverse Events | Fatal Adverse event | 4 participants |
| Mircera | Participants With Adverse Events | Serious adverse event | 41 participants |
| Mircera | Participants With Adverse Events | Adverse event leading to withdrawal | 3 participants |
| Darbepoetin Alfa | Participants With Adverse Events | Adverse event leading to withdrawal | 0 participants |
| Darbepoetin Alfa | Participants With Adverse Events | Any adverse event | 88 participants |
| Darbepoetin Alfa | Participants With Adverse Events | Serious adverse event | 23 participants |
| Darbepoetin Alfa | Participants With Adverse Events | Fatal Adverse event | 3 participants |