Clinical Trial Result Information

Protocol number
BA16740

Title of Study
A randomized, controlled, open-label, multi-center, parallel-group study to demonstrate the efficacy and safety of Mircera when administered subcutaneously 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
The study was a randomized, controlled, open-label, parallel-group, non-inferiority study comparing two dosing intervals (once every two weeks and once every four weeks) of Mircera (methoxy polyethylene glycol-epoetin beta) to continued epoetin treatment.

Study center(s)
This study was conducted in 89 centers in Belgium, Brazil, Czech Republic,  Denmark, Finland, France, Germany, Hungary, Italy, Mexico, New Zealand, Panama, Poland, South Africa, Spain, Sweden, Taiwan, Thailand, UK and USA.

Phase of development
III

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

Methodology
A 4-week screening period was followed by a dose titration period (28 weeks), an evaluation period for the assessment of efficacy parameters (8 weeks), and a long-term safety observation period (16 weeks). At the end of the screening/baseline period, eligible patients were randomized in a 1:1:1 ratio to continue sc epoetin alfa or beta at their current weekly dose and dosing interval (one, two or three times weekly) (group C) or to change to Mircera 1x/2 weeks (group A) or 1x/4 weeks (group B) with the same route of administration. Patients randomized to groups A and B 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: 465 patients. Enrolled: 572 patients.

Diagnosis and main criteria for inclusion
Adult patients (≥18 years old) with chronic renal anemia on dialysis therapy who receive sc epoetin maintenance treatment.

Test product, dose and mode of administration or test procedure
Mircera was administered subcutaneously 1x/2 weeks or 1x/4 weeks.
The starting Mircera dose was based upon the previous epoetin dose as follows:

Weekly epoetin dose (IU/week)	Group A Mircera starting dose (µg/2weeks)	Group B Mircera starting dose (µg/4weeks)
<8000	60	120
8000-16000	100	200
>16000	180	360

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 through 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
Patients randomized to the epoetin reference group continued receiving sc epoetin alfa or beta at their current weekly dose and dosing interval (one, two or three times weekly) during weeks 1 through 52, with dose adjustments as 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, safety hematology and blood chemistry (including iron) laboratory tests, assessment of dialysis adequacy, anti-erythropoietin antibody testing, vital signs and 12-lead ECGs.

Statistical methods
Primary efficacy analysis: For the comparison of change in Hb concentration between the baseline and evaluation periods, time adjusted average Hb values were calculated for both periods. The two Mircera dosing schedules were compared separately to the epoetin reference, using analysis of covariance (ANCOVA). The tests for non-inferiority in both cases were based on the lower limit of the two-sided 97.5% confidence interval for the difference between the two groups. When the lower limit was greater than or equal to -0.75g/dL the Mircera groups were regarded as non-inferior to the epoetin reference group. The confidence level of 97.5% was chosen to adjust for multiplicity.
Secondary efficacy analysis: 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 155 patients per treatment group (465 patients in total) are required to conclude non-inferiority with 90% power, assuming that the true difference between the Mircera groups and the reference is 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 the lower limits of 97.5% confidence interval for the mean difference in Hb between baseline and week 36 was -0.098 g/dL and -0.262 g/dL for the Mircera 1x/2 weeks and Mircera 1x/4 weeks groups, respectively. Since the lower limits for both comparisons were greater than -0.75 g/dL, the Mircera groups were regarded as clinically non-inferior to the epoetin reference group. 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: In the ITT population, during the 8-week evaluation period, the number of patients maintaining a stable Hb was 75.6% in the Mircera 1x/2 weeks group, 66.1% in the Mircera 1x/4 weeks, and 72.2% in the epoetin group; the incidence of RBC transfusions up to the end of the evaluation period was 6.3% in the Mircera 1x/2 weeks group, 10.5% in the Mircera 1x/4 weeks group and 9.9% in the epoetin group.

Safety: The overall incidence of AEs was similar in the three treatment groups, Mircera 1x/2 weeks, Mircera 1x/4 weeks and epoetin (90%, 93.2% and 87.4%, respectively). The most common AEs in the Mircera 1x/2 weeks, Mircera 1x/4 weeks and epoetin groups, respectively, were hypertension (14%, 16% and 13%), procedural hypotension (9%, 15% and 10%) and nasopharyngitis (9%, 10% and 9%). The majority of AEs reported was of mild or moderate intensity and assessed as unrelated to trial medication.
The incidence of SAEs was similar in the Mircera 1x/2 weeks and Mircera 1x/4 weeks groups (37% and 38% respectively) but higher in the epoetin group (45%). The majority of SAEs were considered unrelated to trial medication.
A total of 3 patients (1 patient in the Mircera 1x/2 weeks group [hypertension] and 2 patients in the epoetin group [hemorrhagic gastritis and PRCA]) discontinued treatment prematurely due to an AE.
In the study, 43 deaths occurred and included 13 (7%) in the Mircera 1x/2 weeks group, 18 (9%) in the Mircera 1x/4 weeks group, and 12 (6%) in the epoetin group. The most common cause of death was cardiac disorders, accounting for the death of 3 patients in the Mircera 1x/2 weeks group, 11 patients in the Mircera 1x/4 weeks group, and 9 patients in the epoetin group. Comparison of risk factors in the patients who died of cardiac disorders with risk factors at baseline showed that the cardiovascular risk factors were much more common in those who died of cardiac disorders than in the overall study population.
There were no consistent trends between treatment groups in safety laboratory parameters, vital signs or ECGs. Neither was there a pattern of AEs related to safety parameter abnormalities. No anti-erythropoietin or anti-Mircera antibodies were detected in any patient except for one patient treated with epoetin beta.

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 three treatment groups. Safety findings were characteristic of the population of the study and comparable between treatment groups.

Publications (references, if available)
Clin J Am Soc Nephrol 2:637-646, 2007.

Date of report
3/1/2006

Click here for the protocol registry listing of this trial.