Clinical Trial Result Information
Protocol number
BA16738
Title of Study
An open-label, randomized, multi-center, parallel group study to demonstrate correction of anemia using subcutaneous injections of Mircera in patients with chronic kidney disease who are not on dialysis.
Sponsor
Hoffmann-La Roche Ltd
Company division
Pharmaceutical
Product name
Mircera
Generic name
methoxy polyethylene glycol-epoetin beta
Therapeutic area
Anemia
Clinical study summary
This was an open-label, randomized, parallel-group, comparative, active-controlled, multi-center study of Mircera (methoxy polyethylene glycol-epoetin beta) with one dosing interval (1x/2 weeks) during the correction and evaluation periods and two dosing intervals (1x/2 weeks and 1x/4 weeks) during the extension period.
Study center(s)
This study was conducted in 82 centers in Australia, Belgium, Canada, France, Germany, Greece, Italy, Netherlands, Spain, Sweden, UK and USA.
Phase of development
III
Objectives
Primary: To demonstrate the efficacy of Mircera treatment administered subcutaneously (sc) once every two weeks (1x/2 weeks) for correction of anemia in chronic kidney disease (CKD) patients who are not on dialysis and are not treated with epoetin.
Secondary: To assess hemoglobin (Hb) concentration over time; to assess time to response; to assess safety and tolerability of multiple sc doses of Mircera during the correction/evaluation and the extension period in this patient population.
Methodology
Correction and Evaluation Periods: Eligible patients were randomized 1:1 into one of two groups, one group receiving Mircera administered sc at a starting dose of 0.6 µg/kg 1x/2 weeks, and another group receiving darbepoetin alfa administered sc at a starting dose of 0.45 µg/kg 1x/week according to approved treatment recommendations.
Extension Period: At week 29, after 28 weeks of treatment, the responders in the Mircera group were re-randomized either to Mircera 1x/2 weeks or Mircera 1x/4 weeks and the responders in the reference (darbepoetin alfa) group either kept on their initial dosing regimen (1x/week) or changed to 1x/2 weeks, according to the individual patient response and center practice. Patients were kept on this treatment regimen for the subsequent 24 weeks of the extension period. Non-responders at the end of the evaluation period (week 28) were not re-randomized and were withdrawn from the study and treated according to individual center practice.
Number of patients (planned/analyzed)
Planned: 264 patients. Enrolled: 324 patients.
Diagnosis and main criteria for inclusion
Adult patients with chronic renal anemia who were not on renal replacement therapy and were not treated with epoetin.
Test product, dose and mode of administration or test procedure
Mircera was administered sc 1x/2 weeks during the correction and evaluation periods and 1x/2 weeks or 1x/4 weeks during the extension period.
The starting Mircera dose was 0.6 µg/kg 1x/2 weeks. During the correction and evaluation period the dose of Mircera was adjusted in order to achieve a response. Response was defined as a single Hb concentration ≥ 11.0 g/dL and an increase in Hb from baseline ≥ 1.0 g/dL, without RBC transfusion. Once Hb response had been achieved the dose of study drug was adjusted to maintain the individual patients Hb within the target range of ± 1.0 g/dL of their response Hb level and between 11.0 and 13.0 g/dL throughout the evaluation period (up to week 29) and extension period (weeks 29-52).
Duration of treatment
52 weeks
Reference therapy, dose and mode of administration or reference procedure
Darbepoetin alfa was administered sc 1x/week during the correction and evaluation periods. During the extension period (weeks 29-52) patients received darbepoetin alfa 1x/week or 1x/2 weeks, according to approved labelling. During the correction and evaluation periods the dose of darbepoetin alfa was adjusted in order to achieve a response (see above).
Criteria for evaluation (efficacy, safety)
Efficacy: The primary endpoints for this study were based on the correction and evaluation periods only. The primary endpoints were: The Hb response rate during the first 28 weeks; the change in Hb concentration between baseline and evaluation periods.
Secondary endpoints: Hb concentration over time; time to target Hb response; incidence of red blood cell (RBC) transfusions during the first 28 weeks.
Safety: Safety parameters included adverse events (AEs), vital signs, 12-lead electrocardiogram, laboratory parameters, anti-erythropoietin antibody determination and creatinine clearance.
Statistical methods
The first efficacy endpoint was to demonstrate that the response rate was at least 60% in the Mircera group. A two-sided 95% confidence interval based on the exact method of Clopper and Pearson was calculated. If the lower limit of the confidence interval was above 60%, H0 (H0: r ≤ 60%) could be rejected with a significance level of 0.025 (one sided). This would allow the conclusion that Mircera administered 1x/2 weeks results in correction of anemia.
The second efficacy endpoint was to demonstrate non-inferiority of the Mircera treatment compared to the darbepoetin alfa reference. Time adjusted average Hb values were calculated for both the baseline and the evaluation period and the Mircera regimen was compared to the darbepoetin alfa reference arm using analysis of covariance with Hb at baseline and geographical region as the covariates. Using the correspondence between tests and confidence intervals, the test for non-inferiority was based on the lower limit of the 2-sided 95% confidence interval for the difference between the two groups. If the lower limit was greater than or equal to -0.75 g/dL, the Mircera group was to be regarded as non-inferior to the darbepoetin alfa reference arm.
The analysis of the 1st and 2nd primary efficacy endpoints were performed in a hierarchical order. First, the Hb response analysis was performed. If the outcome of this test was positive, the non-inferiority test was to be performed. The hierarchical testing guaranteed that the overall significance level of 5% was not exceeded.
Secondary efficacy analysis: The Hb values and their changes from baseline over time were summarized and the treatment groups were compared using descriptive methods. The time to Hb response was analyzed using Kaplan-Meier methods. The incidence of red blood cell transfusions was summarized and the treatment groups compared using descriptive methods.
Summary (efficacy, safety, other results)
Efficacy: Primary Endpoints: The first primary efficacy endpoint was the Hb response rate in the Mircera treatment group during the correction and evaluation periods (ITT population). The response rate in the Mircera group was 97.5% (p<0.0001; 95% CI 93.8-99.3%) with the lower limit of the CI well above 60%, confirming that Mircera resulted in correction of anemia. The response rate in the darbepoetin alfa group was 96.3% (p<0.0001; CI 92.11-98.63).
The second primary efficacy endpoint was the difference in the mean change in Hb between the baseline and evaluation periods in the two treatment groups. ANCOVA was used to compare the Mircera dosing regimen to the darbepoetin alfa reference group. The change in baseline adjusted mean Hb was 2.15 g/dL for the Mircera treatment group and 1.99 g/dL for the darbepoetin alfa treatment group resulting in a treatment difference of 0.155. The lower limit of CI was -0.045. Since the lower limit is greater the -0.75, the Mircera group was regarded as clinically non-inferior to the darbepoetin alfa reference group (p<0.0001) based on the PP population. The results were consistent in the four data sets analyzed (PP, ITT, eligible and complete observations populations) with p<0.0001 in all four populations.
Secondary Endpoints: Generally, median Hb concentrations increased in both treatment groups during the correction period of the study; however, Hb concentration increased more rapidly in the darbepoetin alfa group and higher Hb values were achieved compared with the Mircera group. As patients entered the evaluation period, the median Hb concentrations began to decrease in both treatment groups. This trend was not attributable to loss of efficacy but rather to dose adjustments made once patients had achieved a response.
The time to response and Hb over time data indicated that the correction of anemia was slower in the Mircera group compared with the darbepoetin alfa group (median time to response was approximately 6 weeks in the Mircera group compared with 4 weeks in the darbepoetin alfa group).
The incidence of RBC transfusions during the correction and evaluation periods was 2.5% in the Mircera group and 6.8% in the darbepoetin alfa group.
During the extension period, median Hb concentrations were similar in the Mircera 1x /4 weeks group (range 11.5-11.85 g/dL) compared with the Mircera 1x /2 weeks and darbepoetin alfa groups (range 11.7-12.0 g/dL and 11.9-12.2 g/dL respectively). However, no patients in the Mircera 1x /4 weeks group received RBC transfusions, whereas they were given to two patients in the Mircera 1x /2 weeks and four patients in the darbepoetin alfa groups. Also, no patients were withdrawn due to lack of efficacy during the extension period. Although the median number of dose changes during the extension period were similar, more patients in the Mircera 1x /4 weeks group had dose increases and the median weekly equivalent dose of Mircera was slightly higher in the 1x /4 weeks group (range 0.17-0.22 μg/kg/week) compared with the 1x /2 weeks group (range 0.15-0.19 μg/kg/week).
Safety: Correction and Evaluation Periods: During the correction and evaluation periods, the overall incidence of AEs was similar in both treatment groups. The single most common AE reported during the correction and evaluation periods was hypertension (reported for 14% of patients in the Mircera group and 13% of patients in the darbepoetin alfa group). The incidence of related AEs was higher in the Mircera group compared with the darbepoetin group (7.5% of patients vs. 5.6%); however, the frequency of AEs leading to premature withdrawal was lower in the Mircera group compared with the darbepoetin alfa group (1.9% of patients vs. 4.3%). The incidence of SAEs was 21.1% in the Mircera group and 24.1% in the darbepoetin alfa group, and cardiac disorders were the most frequently reported SAEs (7% in each treatment group). All patients who experienced cardiac disorders had cardiovascular risk factors at baseline. A total of eight patients died during the correction and evaluation periods, five patients in the Mircera group and three patients in the darbepoetin alfa group. Five patients (4 patients on Mircera and 1 patient on darbepoetin alfa) died of cardiac disorders; all had cardiovascular risk factors at baseline. None of the deaths was considered related to trial treatment.
Extension Period: During the extension period the incidence of AEs was similar in the three treatment groups. The most commonly reported AEs were peripheral edema (7%, 1%, 7%) and diarrhea (4%, 3%, 5%) in the Mircera 1x /2 weeks, Mircera 1x /4 weeks and darbepoetin groups, respectively. SAEs were reported for 14%, 11% and 16% of patients, respectively.
Nine patients died during the extension period: 2 patients in the Mircera 1x /2 weeks group, 1 patient in the Mircera 1x /4weeks group and 6 in the darbepoetin alfa group. None of the deaths was considered related to trial treatment.
During the correction, evaluation and extension periods there were no apparent differences or trends of significance in any of the laboratory parameters. As expected, a slight decline in kidney function (CrCl) was observed over the course of the study, with no difference between treatment groups. There were no apparent differences between the treatment groups with respect to vital signs or ECG changes. No anti-Mircera antibodies were detected in any patients, and a single case of non-neutralizing anti-erythropoietin antibodies was detected in the darbepoetin alfa group.
Conclusions
Mircera administered sc was effective in correcting anemia in CKD patients who were not on dialysis, and not treated with epoetin. Treatment with Mircera as prescribed in the study protocol was non-inferior to treatment with darbepoetin alfa in correcting anemia. Dose adjustments according to protocol guidance enabled correction of anemia to target Hb levels. The Hb increase in the Mircera group (with the starting dose 0.6 µg/kg/q2w) was lower than that in the darbepoetin alfa group (with the starting dose of 0.45 µg/kg/week); however, the response rate achieved with Mircera was high (97.5%). During the extension period, median Hb concentrations were similar in the Mircera 1x /4 weeks group compared with the Mircera 1x /2 weeks and darbepoetin alfa groups.
Long term administration of sc Mircera in patients with CKD who were not on dialysis was generally well-tolerated. Safety findings were characteristic of the study population and comparable between treatment groups.
Date of report
3/1/2006
Click here for the protocol registry listing of this trial.
|
