Clinical Trial Result Information

Protocol number
BA17283

Title of Study
A randomized, controlled, open-label, multi-center, parallel-group study to demonstrate the efficacy and safety of Mircera when administered intravenously for the maintenance treatment of anemia in patients with chronic kidney disease who are 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 study was a randomized, controlled, open-label multi-center, parallel-group (2-arm), non-inferiority study comparing intravenous (iv) Mircera (methoxy polyethylene glycol-epoetin beta) 1x/2 weeks to continued darbepoetin alfa for the treatment of anemia in dialysis patients with chronic kidney disease (CKD).

Study center(s)
This study was conducted at 48 sites in Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Italy, Spain, Sweden and Switzerland.

Phase of development
III

Objectives
Primary: To demonstrate that Mircera administered iv maintains hemoglobin ( Hb) concentrations in dialysis patients on prior iv darbepoetin alfa maintenance treatment for chronic renal anemia.
Secondary: To assess the safety and tolerability of iv administration of Mircera in this patient population.

Methodology
The 4-week screening period was followed by a dose titration period (28 weeks), an evaluation period for assessment of efficacy parameters (8 weeks), and a long term observation period (16 weeks). At the end of the screening/baseline period, patients were randomized to treatment with Mircera (iv, 1x/2 weeks) or to continue with darbepoetin alfa (iv, 1x/week or 1x/2 weeks). The starting dose of Mircera was based on the dose of darbepoetin alfa at the time of randomization.

Number of patients (planned/analyzed)
Planned: 264 patients. Enrolled: 313 patients

Diagnosis and main criteria for inclusion
Adult patients (≥18 years old) on dialysis therapy who received iv darbepoetin alfa treatment for chronic renal anemia.

Test product, dose and mode of administration or test procedure
Mircera was administered iv, 1x/2 weeks. The starting Mircera dose was based upon the previous darbepoetin alfa dose as follows:

Previous weekly darbepoetin alfa dose (µg/week)*	Mircera dose (µg/week)*
<40	30
40-80	50
>80	90

*Darbepoetin alfa dosing was 1x/week or 1x/2 weeks. Mircera dosing was 1x/2 weeks.

The dose of Mircera was adjusted to maintain the individual patient’s Hb within a target range of ± 1.0 g/dL of their baseline Hb and between 10 and 13.5 g/dL throughout the dose titration/evaluation period (weeks 1 to 36).
During the long-term safety observation period (weeks 37 to 52), the dose of Mircera was adjusted to maintain the patient’s Hb levels within a range of 11 to 13 g/dL.

Duration of treatment
52 weeks

Reference therapy, dose and mode of administration or reference procedure
Darbepoetin alfa was administered iv, 1x/week or 1x/2 weeks.
The dose of darbepoetin alfa was adjusted to maintain the individual patient’s Hb within the target range (see above).

Criteria for evaluation (efficacy, safety)
Efficacy: The primary efficacy variable was the change in Hb concentration (g/dL) between the baseline and evaluation periods.
The secondary efficacy variables were: The number of patients maintaining average Hb concentration during the evaluation period within ± 1 g/dL of their average baseline Hb concentration; the incidence of RBC transfusions during the dose titration and evaluation periods.
Safety: Safety parameters included adverse events (AES), safety hematology and blood chemistry laboratory tests, assessment of dialysis adequacy, anti-erythropoietin antibody testing, vital signs and 12-lead ECGs.

Statistical methods
For the primary efficacy analysis, time-adjusted average hemoglobin values were calculated for baseline and evaluation periods. The Mircera group was compared to the darbepoetin alfa reference, using analysis of covariance (ANCOVA). The test for non-inferiority was based on the lower limit of the two-sided 95% confidence interval for the difference between the two groups. When the lower limit was greater than or equal to -0.75 g/dL, the Mircera group was regarded as non-inferior to the darbepoetin alfa reference group.
For the secondary efficacy analyses the treatment groups were compared using descriptive methods.
Sample size: Assuming 20% of the patients would not be eligible for inclusion in the per-protocol population approximately 132 patients per treatment group (264 patients in total) were required to conclude non-inferiority with 90% power, assuming that the true difference between the Mircera group and the reference was not larger than 0.3 g/dL.

Summary (efficacy, safety, other results)
Efficacy: Primary Endpoint: At the end of the 8-week evaluation period, the primary efficacy analysis using the ANCOVA model showed that treatment with Mircera was non-inferior to treatment with darbepoetin alfa in the PP population. The lower limit of the 95% confidence interval for the mean difference between baseline and week 36 was -0.049. The results were consistent in the four data sets analyzed (PP, ITT, eligible and observation complete populations) with p<0.0001 in all four populations.
Secondary Endpoint: In the ITT population during the evaluation period, a total of 91 patients (65.5%) in the Mircera group and 102 patients (71.8%) in the darbepoetin alfa group maintained a Hb concentration within ± 1 g/dL of their average baseline. The percentage of patients with mean change in Hb below 1 g/dL was 14.4% in the Mircera group and 20.4% in the darbepoetin alfa group. A total of 20.1% of patients in the Mircera group had mean change in Hb values above 1g/dL, compared with 7.7% of the patients in the darbepoetin alfa group. In the safety population up to the end of the evaluation period, the incidence of RBC transfusions was 12.4% in the Mircera group and 10.3% in the darbepoetin alfa group.

Safety: The frequencies of AEs were similar in the two treatment groups. The single most commonly reported AE during the study was diarrhea reported by 16% of Mircera patients and 10% of darbepoetin alfa patients, respectively. The next most common AE for the treatment groups, respectively was nasopharyngitis (12% and 10%), followed by influenza (12% and 8%). The majority of AEs were of mild or moderate intensity and considered by investigators to be unrelated to trial treatment.
The frequencies of SAEs were similar in the two treatment groups; 46% in the Mircera groups and 48% in the darbepoetin alfa group reported SAEs. The majority of SAEs were considered unrelated to trial medication.
One patient in the Mircera group [hypertensive encephalopathy] and one in the darbepoetin alfa group [peripheral ischemia] had AEs leading to withdrawal from study.
Among the patients who died in the study (13 in the Mircera group and 12 in the darbepoetin alfa group), baseline risk factors were more common than in the overall study population. No death in either treatment group was reported as related to study drug. The patients in the Mircera and darbepoetin alfa groups who died had similar baseline risk factor profiles for cardiovascular events and hemorrhages.
There were no consistent trends in vital signs or ECGs between the two treatment groups. Neither was there a pattern of AEs related to safety parameter abnormalities. Platelet values, while lower in the Mircera group than in the darbepoetin alfa group, were within the standard reference range in both treatment groups throughout the study. Markedly low platelet values were reported by 4% of the patients in the Mircera group and 3% in the darbepoetin alfa group, but there were no associated bleeding events in either treatment group. No anti-erythropoietin or anti-Mircera antibodies were detected in any patient.

Conclusions
Treatment with Mircera was non-inferior to treatment with darbepoetin alfa in maintaining Hb levels (p<0.0001) in patients on stable maintenance treatment. The dose adjustment guidance in the protocol resulted in Hb values which were virtually identical between the baseline and evaluation periods and a number of dose adjustments that was similar in the two treatment groups.
Safety findings were characteristic of the population in the study and comparable between the two treatment groups.

Date of report
3/1/2006

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