Clinical Trial Result Information

Title of Study:
An open-label, multi-center, multiple dose trial to investigate the efficacy and safety of subcutaneous injections of Mircera at different dosing intervals in dialysis patients with chronic renal anemia.

Fast Facts:

Protocol number:	BA16260
Sponsor:	Hoffmann-La Roche
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:	2/1/2006

Clinical study summary:
This was an open label, randomized, multi-center, dose escalation study investigating the effect of three doses of Mircera (methoxy polyethylene glycol-epoetin beta) and three different dosing intervals on renal anemia in patients on dialysis.

Study center(s) :
Total of 17 centers in France, Germany, Greece, Poland, Spain and Taiwan.

Objectives:
Primary: To determine the starting dosing regimens required for correction of chronic renal anemia in this patient population; to determine the hemoglobin (Hb) increase over time in response to dosing regimens administered in this study.
Secondary: To explore the Mircera dose-response relationship; to assess the exposure to Mircera following dosing regimens used in this study; to assess the safety of multiple dosing of Mircera in this patient population.

Methodology:
Following a 4 week run-in period to assess Hb concentration and iron status, patients were allocated to 3 dosing groups of 3 cohorts each. They were treated at a constant dose of Mircera for 6 weeks, after which dose adjustments could be made. This was followed by a further 6 weeks of treatment.

Number of patients (planned/analyzed):
61 randomized

Diagnosis and main criteria for inclusion:
To enter run in phase: Adult patients (≥18 years old) with chronic renal anemia; hemodialysis treatment for a minimum of one month or peritoneal dialysis treatment for a minimum of two months.
To enter treatment phase (before randomization): Kt/V ≥1.2 on hemodialysis and weekly Kt/V ≥1.8 on peritoneal dialysis; hemoglobin (Hb) level (mean Hb of weeks -2 and -1) <11.0g/dL and ≥8 g/dL at the end of the run-in phase; stable Hb during the run-in phase; adequate iron status at randomization.

Test product, dose and mode of administration or test procedure:
Dose Group 1: 0.9 μg/kg Mircera for 6 weeks; Dose Group 2: 1.8 μg/kg Mircera for 6 weeks; Dose Group 3: 2.7 μg/kg Mircera for 6 weeks.
Within each dose group the following dose schedules were used:
1*/week, 1*/2 weeks and 1*/3 weeks, all by subcutaneous (SC) injection.

Duration of treatment:
12 weeks

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

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

Pharmacodynamics: Area under Hb concentration-time curve to end of initial treatment (EOIT) and end of study (EOS); Area under Hct time curve to EOIT and EOS; Area under reticulocyte count-time curve to EOIT and EOS.

Safety: Vital signs, adverse events (AEs), electrocardiogram, safety laboratory parameters.

Statistical methods:
Efficacy: The primary and secondary endpoints were presented as descriptive summary statistics.
Safety: Adverse events analysis was performed by time, dose group and dosing interval.

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 EOIT. The individual regression slope estimates of Hb increase during six weeks were pooled within each stratum defined by dose group and treatment schedule. The group differences in Hb increase over six weeks of treatment with Mircera from baseline using the regression slope analysis in the ITT population were not statistically significant; however, the median Hb values for the intermediate and high dose groups (Groups 2 and 3) showed similar increases from baseline (1.16 and 1.01 g/dL, respectively) and were numerically higher than that for the low-dose group (Group 1, 0.79 g/dL).
The outcome of the ITT analysis was heavily influenced by a few early withdrawals unrelated to treatment such as kidney transplantation, especially in the high-dose group. Therefore the efficacy conclusions were based on results from the per-protocol analysis. The test for an overall dose effect in the per-protocol population using the regression slope analysis showed a p-value of 0.102. However, the test of the primary parameter data from the pooled Groups 2 and 3 (the medium and high dose groups) compared to Group 1 (the low dose group) showed a p-value of 0.035, indicating a statistically significant difference in dose response between the lowest dose group and the two pooled higher dose groups. For the results of average time-adjusted Hb increase until EOIT or end of study, the test for an overall dose effect was significant in the per-protocol population.
This study demonstrated a clinically and statistically significant dose-response. A starting dose of 0.3 µg/kg/week SC, which represents the intermediate dose level (Group 2), provided an adequate clinical response without any identifiable safety liability. The mean increase in Hb levels after 6 weeks treatment with 0.3 µg/kg/week Mircera was 1.33 g/dL in the per-protocol population. The overall response rate (defined as increase in Hb of at least 1 g/dL during the 12-week study period) with this starting dose was 93.3% (including the effects of dose increases in 26% of patients). No difference between the dosing schedules could be demonstrated in this study. This was consistent, regardless of the endpoint (regression slopes, AUC or response rate) or the selected population.

Pharmacodynamics: The medians of the baseline-corrected AUC values Hb, Hct and reticulocyte counts for Groups 2 and 3 over the whole study period were higher than those for Group 1. The values measured until EOIT for these parameters in the three dose groups were however similar.

Safety: Mircera was generally well tolerated in this study and no major safety concerns were observed. The overall safety experience in the study was characteristic of the target population, with no pattern of AEs or laboratory abnormalities suggesting a relationship to dose or schedule of Mircera administration. The numbers of patients reporting AEs was similar between the three dose groups and the most commonly reported events were gastrointestinal disorders. Only one AE (pruritic rash) was considered to be related to Mircera treatment and it resolved without sequelae. No drug-related SAEs or deaths were reported. No trends of significance were found in the laboratory parameters measured in this study.

Conclusions:
The efficacy conclusions are based on the per-protocol analysis. Mircera produced a hematopoietic response which was dose-dependent. Doses of 1.8 - 2.7 µg/kg/6 weeks administered SC over a 12-week period led to anemia correction in dialysis patients with chronic renal anemia in up to 93% of the patients, with no dosing-schedule effect demonstrated. Mircera was generally well tolerated across all dose groups and there were no major safety concerns.

Publications (references, if available):
De Francisco AL, Sulowicz W, Dougherty F et al. Subcutaneous C.E.R.A. (Continuous Erythropoiesis Receptor Activator) has potent erythropoietic activity in dialysis patients with chronic renal anemia: an exploratory multiple-dose study. J Am Soc Nephrol 14: 27A, 2003

De Francisco AL, Sulowicz W, Klinger M et al Continuous Erythropoietin Receptor Activator (C.E.R.A) administered at extended administration intervals corrects anemia in patients with chronic kidney disease on dialysis: a randomized, multicenter, multiple-dose, phase II study. Int J Clin Pract 60:1687-1696, 2006