Clinical Trial Result Information

Protocol number
BA17284

Title of Study
A randomized, controlled, open-label, multi-center, parallel-group study to demonstrate the efficacy and safety of Mircera when administered with pre-filled syringes 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 Mircera (methoxy polyethylene glycol-epoetin beta). Once every two weeks (1x/2 weeks, pre-filled syringes) with continued epoetin treatment (vials) for the treatment of anemia in dialysis patients with chronic kidney disease (CKD).

Study center(s)
This study was conducted at 62 sites in Canada, France, Germany, Italy, Poland, Portugal, Spain, Taiwan, Thailand, UK and USA.

Phase of development
III

Objectives
Primary: To demonstrate that Mircera administered with pre-filled syringes maintains hemoglobin (Hb) concentrations in dialysis patients on prior intravenous (iv) or subcutaneous (sc) epoetin maintenance treatment of chronic renal anemia.
Secondary: To assess the safety and tolerability of Mircera administered with pre-filled syringes in this patient population.

Methodology
The 4-week screening period was followed by a dose titration period (28 weeks) and an evaluation period for assessment of efficacy parameters (8 weeks). At the end of the screening/baseline period, eligible patients were randomized to continue epoetin alfa or beta at their current weekly dose, route and dosing interval (1 – 3x/week) (group B) or to change to Mircera (pre-filled syringes) 1x/2 weeks (group A) with the same route of administration. Patients randomized to group A received a starting dose of Mircera that was based on the epoetin dose administered during the week preceding the switch to the study drug.

Number of patients (planned/analyzed)
Planned: 264 patients. Enrolled: 336 patients

Diagnosis and main criteria for inclusion
Adult patients (≥18 years) with chronic renal anemia on hemodialysis or peritoneal dialysis who received iv or sc epoetin maintenance treatment.

Test product, dose and mode of administration or test procedure
Mircera was administered either iv or sc with pre-filled syringes 1x/2 weeks.
The starting Mircera dose was based upon the previous epoetin dose as follows:

Previous weekly epoetin dose (IU/week)	Weekly Mircera dose (µg/2 weeks)
<8000	60
8000-16000	100
>16000	180

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.

Duration of treatment
36 weeks

Reference therapy, dose and mode of administration or reference procedure
Patients randomized to the epoetin reference group continued receiving epoetin alfa or beta at their current weekly dose and dosing interval (1-3x/week) during weeks 1 through 36.
The dose of epoetin 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 between the baseline and evaluation periods.
The secondary 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 red blood cell (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 electrocardiograms (ECGs).

Statistical methods
For the primary efficacy analysis, time adjusted average Hb values were calculated for baseline and evaluation periods. The Mircera group was compared to the epoetin 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 epoetin 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 (PP) 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 result using the ANCOVA model showed that treatment with Mircera was non-inferior to treatment with epoetin. The lower limit of the 95% confidence interval for the mean difference in Hb between baseline and week 36 was -0.116 g/dL for the Mircera group. 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. The effect of route of administration was not significant (p=0.52), and therefore, had no impact in the primary efficacy analysis.
Secondary Endpoints: In the ITT population, during the 8-week evaluation period, the number of patients maintaining a stable Hb was 68.5% in the Mircera group and 67.7% in the epoetin group. The incidence of RBC transfusions up to the end of the evaluation period was 9.7% in the Mircera group and 11.3% in the epoetin group.

Safety: The overall incidence of AEs was similar between the two treatment groups. The most common AEs in the Mircera and epoetin groups, respectively, were hypertension (18% and 14%), diarrhea (both 13%) and upper respiratory tract infection (16% and 6%). The majority of AEs reported were of mild or moderate intensity and assessed by the investigators as unrelated to trial medication.
The incidence of SAEs was 30.9% in the Mircera group and 41.1% in the epoetin group. The majority of SAEs were considered unrelated to trial medication.
A total of 5 patients discontinued treatment prematurely due to an AE. Two patients in the Mircera group experienced headache and hypersensitivity, respectively, and 3 patients in the epoetin group experienced intestinal ischemia, cardiac arrest, and subdural hematoma, respectively.
Among the patients who died in the study (4% in the Mircera group and 6% in the epoetin group), baseline risk factors for vascular events and hemorrhages were more common than in the overall study population. The patients in the Mircera and epoetin groups who died had similar baseline risk factor profiles.
There were no consistent trends in laboratory parameters nor a pattern of AEs related to laboratory abnormalities. Platelet values, while lower in the Mircera group than in the epoetin group, were within the standard reference range for both groups throughout the study. No anti-erythropoietin or anti-Mircera antibodies were detected.

Conclusions
Treatment with Mircera was non-inferior to treatment with epoetin in maintaining Hb levels (p<0.0001) in patients on stable maintenance treatment. Variability in Hb values over time was comparable in the treatment arms. The dose adjustment guidance in the protocol resulted in Hb values which were virtually identical between the baseline and evaluation periods. Safety findings were characteristic of the population under study and comparable between treatment groups.

Date of report
3/1/2006

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