Clinical Trial Result Information

Title of Study:
An open label, randomized, multi-center, multiple dose trial to investigate the efficacy and safety of subcutaneous injections of Mircera at different dosing intervals in patients with chronic renal anemia who are not on renal replacement therapy.

Fast Facts:

Protocol number:	BA16528
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Mircera
Generic name:	methoxy polyethylene glycol-epoetin beta
Phase of development:	II
Therapeutic area, approved indication:	Anemia
Date of report:	5/26/2005

Clinical study summary:
This was an open, randomized, multicenter, dose escalation study investigating the effect of 3 doses of Mircera (methoxy polyethylene glycol-epoetin beta) and 3 different dosing intervals on renal anemia in patients not on dialysis.

Study center(s) :
22 centers in Canada, Mexico, Poland, UK and USA.

Objectives:
Primary: To determine starting dose regimens for correction of anemia in patients with chronic renal disease who are not on renal replacement therapy; to determine hemoglobin (Hb) increase over time in response to dosing regimens.
Secondary: To explore the Mircera dose-relationship; to assess exposure to Mircera following dosing regimens used in this study; to assess the safety of multiple dosing of Mircera in this patient population.

Methodology:
Eligible patients entered a two-week run-in period during which three Hb concentration and iron status determinations were made. Patients were then allocated to 3 dosing groups and treated for 6 weeks at a constant dose after which dose adjustments could be made.
This was followed by a further 12 weeks of treatment. At the end of the core treatment period the patients were allowed to begin an optional extended treatment and observation period up to 54 weeks (Extension year 1). At the final visit of the first year extended treatment period, the patients were allowed to begin a second optional extended treatment period up to 54 weeks (Extension year 2).

Number of patients (planned/analyzed):
65 randomized

Diagnosis and main criteria for inclusion:
To enter the run in period: Adult patients (≥18 years old) with anemia and progressive renal insufficiency who are not in renal replacement therapy, and with an estimated creatinine clearance of 15-50 mL/min.
To enter the treatment period (before randomization): Mean Hb value during the run-in period <11 and ≥8 g/dL, with a variation of ≤1.5 g/dL.

Test product, dose and mode of administration or test procedure:
Group 1: 0.9μg/kg Mircera over 6 weeks; Group 2: 1.8μg/kg Mircera over 6 weeks; Group 3: 3.6μg/kg Mircera over 6 weeks.
Witihin each dose group the following dose schedules were used: 1x/1 week, 1x/2 weeks and 1x/3 weeks, all by sc injection.

Duration of treatment:
18 weeks (core study period)

Reference therapy, dose and mode of administration or reference procedure:
N/A.

Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Change in Hb levels over time. Secondary: Change in hematocrit (Hct) and reticulocyte count over time.

Pharmacodynamics: Area under Hb concentration-time curve over first 6 weeks, and first 18 weeks; area under reticulocyte count-time curve over first 6 weeks, and first 18 weeks.

Safety: Vital signs, ECG, adverse events (AEs) and safety laboratory variables.

Statistical methods:
Summary statistics were provided for pharmacodynamic variables. Regression slope analysis of Hb increases over 6 weeks and ANCOVA. Response rate and time to response and relationship between response and drug exposure were explored.

Summary (efficacy, safety, other results):
Efficacy: The primary efficacy endpoint of the study was the analysis of the regression slopes of the Hb values over time between baseline and End of Initial Treatment (EOIT), defined as the period of treatment until a patient had a change in the dose of Mircera or received a blood transfusion. There was a statistically significant dose-dependent increase in Hb based on the regression slope analysis until EOIT in the ITT population. In an analysis of covariance of the Hb increases over 6 weeks using baseline Hb as covariable, the overall dose effect was highly significant (p<0.0001) in the ITT population. The relationship between schedule (dose interval) and Hb concentration increase was however not statistically significant. The per-protocol analysis confirmed the findings of the ITT analysis. There was a dose-dependent increase in response rate during the first 6 weeks of treatment before any dose change. The response rate was 38.9% in Group 1, 61.1% in Group 2 and 75.9% in Group 3. The response rate during the entire 18 weeks increased with increasing dose from 66.7% in Group 1 to 72.2% in Group 2 to 89.7% in Group 3. The median times to respond to treatment decreased markedly with dose, 89 days in Group 1, 43 days in Group 2 and 31 days in Group 3. The response to treatment was dependent on exposure, with non-responders having a significantly lower exposure to Mircera than the responders. The results suggest that 1.8 µg/kg/6 weeks is a suitable starting dose for treating anemia in this population, since this dose provided an adequate change in Hb from baseline while avoiding excessive increases in Hb within the first six weeks of the study.
A target Hb concentration between 11 and 12g/dL was achieved throughout both extension periods of the study, and the dose of Mircera could be adjusted to achieve this target Hb level. The results showed that long-term treatment with Mircera (at a frequency of 1x/week, 1x/2 weeks or 1x/3 weeks) resulted in relatively stable Hb levels.

Pharmacodynamics: In the ITT population, the mean baseline-adjusted AUC until EOIT increased from 0.29 g/dL in Group 1 to 0.95 g/dL in Group 2 and to 1.08 g/dL in Group 3. The corresponding Hct AUCs increased with dose, and there was a dose-dependent increase in the reticulocyte AUC.

Safety: Long-term sc administration of Mircera was generally well tolerated. The most commonly reported AEs in the complete study were urinary tract infection, hypertension, chronic renal failure, peripheral edema, gout and nasopharyngitis. Eight patients had AEs which were considered to be related to the study medication (xerosis, application site pain, injection site bruising, injection site pain, reversible posterior leukoencephalopathy syndrome and epistaxis). The reversible posterior leukoencephalopathy syndrome, which occurred during the core study period, was a serious adverse event of severe intensity, and led to discontinuation from the study. Two patients died during the extension phase of the study, but the deaths were not considered to be related to the study medication. No trends of significance were found in the laboratory parameters; however, 4 patients had markedly low albumin values during the study. In general, the safety profiles for Extension Year 1, Extension Year 2 and the complete study period were similar, and the safety profiles between the dosing schedule groups were comparable.

Conclusions:
The Hb concentration increased in all three treatment groups in the ITT population; the overall dose effect over 6 weeks was highly significant (p<0.0001). The dose interval had no effect on the Hb response with a dose every 3 weeks being as effective long-term as the more frequent administrations. The results suggest that the intermediate dose of 1.8μg/kg/6 weeks is appropriate for initiating correction of renal anemia in this patient population while avoiding excessive increases in hemoglobin. All doses of Mircera were generally well tolerated long-term in this study.

Publications (references, if available):
Provenzano R, Besareb A, Macdougall I et al CERA (Continuous Erythropoietin Receptor Activator) administered up to once every 3 weeks corrects anemia in patients with chronic kidney disease not on dialysis. SU-PO056; J Am Soc Nephrol 15:544A.

Provenzano R, Besareb A, Macdougall I et al. The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study. Clin Nephrol 67:306-317, 2007

Click here for the protocol registry listing of this trial.