Clinical Trial Result Information

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.

Fast Facts:

Protocol number:	BA16739
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Mircera
Generic name:	methoxy polyethylene glycol-epoetin beta
Phase of development:	III
Therapeutic area, approved indication:	Anemia
Date of report:	3/1/2006

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 at 91 sites in Canada, France, Germany, Italy, Norway, Spain, Switzerland, and USA.

Objectives:
Primary: To demonstrate the Mircera administered intravenously maintains hemoglobin (Hb) concentrations in dialysis patients on prior intravenous (iv) epoetin maintenance treatment of chronic renal anemia.
Secondary: To assess safety and tolerability of iv 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 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 iv 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: 673 patients.

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

Test product, dose and mode of administration or test procedure:
Mircera was administered intravenously 1x/2 weeks or 1x/4 weeks.
The starting Mircera dose was based upon the previous 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 ± 1.0g/dL of their baseline Hb and between 10 and 13.5g/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 13g/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 iv 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 to maintain Hb levels within targets 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 ± 1g/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 ECGs.

Statistical methods:
Primary efficacy analysis: For the comparison of change in Hb concentration between 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 were not eligible for inclusion in the per-protocol population, approximately 155 patients per treatment group (465 patients in total) were required to conclude non-inferiority with 90% power, assuming that the true difference between the Mircera groups and the reference was not larger than 0.3g/dL.

Summary (efficacy, safety, other results):
αEfficacy: Primary Endpoint: For the PP population, the lower limits of the 97.5% confidence interval for the mean difference in Hb between baseline and evaluation periods between the treatment groups were -0.215 and -0.173 for the Mircera 1x/2 weeks and Mircera 1x/4 weeks, respectively. Since the lower limit was greater than -0.75g/dL, the Mircera groups were regarded as clinically non-inferior to the epoetin reference group.
At the end of the 8-week evaluation period, the primary efficacy result using the ANCOVA model showed that the mean change from baseline Hb for patients who had switched to treatment with Mircera 1x/2 weeks (-0.071 g/dL) and Mircera 1x/4 weeks (-0.025 g/dL) was non-inferior to that for patients continuing treatment with epoetin (-0.075 g/dL) (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: In the ITT population, during the 8-week evaluation period, the number of patients maintaining a stable Hb was 67.9% in the Mircera 1x/2 weeks group, 67.6% in the Mircera 1x/4 weeks, and 67.3% in the epoetin group. The incidence of RBC transfusions up to the end of the evaluation period was 9.5% in the Mircera 1x/2 weeks group, 7.3% in the Mircera 1x/4 weeks group and 7.6% in the epoetin group. 

Safety: The overall incidence of AEs was generally similar between the three treatment groups, Mircera 1x/2 weeks, Mircera 1x/4 weeks and epoetin. The most common AEs were diarrhea (17%, 12%, 13%), nasopharyngitis (13%, 18%, 11%), hypertension (10%, 13%, 16%) and arteriovenous graft thrombosis (11%, 12%, 14%) respectively. The majority of AEs in each treatment group were mild or moderate in intensity and considered by investigators to be unrelated to trial treatment.
The frequencies of SAEs were generally similar in the three treatment groups. The majority of SAEs were considered unrelated to trial medication.
A total of 16 patients (9 in the Mircera 1x/2 weeks group, 6 in the Mircera 1x/4 weeks group, and 1 in the epoetin group) withdrew prematurely due to an AE.
In the study, 51 deaths occurred, including 19 (9%) in the Mircera 1x/2 weeks group, 15 (7% in the Mircera 1x/4 weeks group, and 17 (8%) in the epoetin group. The most common causes of death were cardiac arrest and chronic renal failure. Among the patients who died in the study baseline risk factors were more common than in the overall study population.
There were no consistent trends in any laboratory parameters, nor a pattern of AEs related to laboratory abnormalities, and no consistent trends for vital signs or ECGs. No anti-erythropoietin and no anti-Mircera antibodies were detected, with the exception of one patient with low levels of anti-erythropoietin antibody present before treatment with study medication.

Conclusions:
Treatment with Mircera was non-inferior to treatment with epoetin in maintaining Hb levels (p<0.0001) in all four populations tested (PP, ITT, eligible and complete observations). Safety findings were characteristic of the population of the study and comparable between all treatment groups.

Click here for the protocol registry listing of this trial.