Clinical Trial Result Information

Protocol number
BA16285

Title of Study
An open-label, multi-center, randomized study to determine dose conversion factors at different frequencies of administration after switching from maintenance treatment with intravenous epoetin alfa to maintenance treatment with intravenous Mircera in hemodialysis patients with chronic renal anemia.

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 was an open-label, multi-center, randomized trial comparing 3 dose conversion factors and 2 frequencies of administration of intravenous Mircera (methoxy polyethylene glycol-epoetin beta) as maintenance treatment for chronic renal anemia in hemodialysis patients.

Study center(s)
14 centers in the USA.

Phase of development
II

Objectives
The primary objective was to determine the optimal dose conversion factor(s) from epoetin alfa to Mircera and frequencies of Mircera administration, which are most likely to provide a stable hemoglobin (Hb) course after switching from an intravenous (IV) maintenance dose of epoetin alfa to an IV maintenance dose of Mircera in patients with chronic kidney disease on hemodialysis. Secondary objectives were to assess and to document the long-term safety and tolerability of IV administration of Mircera in the defined patient population.

Methodology
Following a 2-week run-in period (to assess Hb level and iron status) patients were randomized sequentially to receive Mircera 1x/week or 1x/2 weeks. The first patients were randomized to receive a dose of Mircera calculated using a conversion factor of 0.40/150 (=100% of the assumed equi-effective dose of epoetin alfa). When the first 16 patients (eight patients within each cohort) had completed the first 6 weeks of treatment, a Data and Safety Monitoring Board reviewed the patients’ safety and efficacy data and confirmed the conversion factors of 0.25/150 and 0.60/150 for the other four treatment cohorts. Patients were treated for 19 weeks during which time Hb and Hct were assessed weekly. In addition, blood samples were collected for determination of iron parameters and safety laboratory assessments and anti-Mircera antibodies. AEs and vital signs were also monitored.
Patients who completed the core treatment period were eligible to enter an optional extended treatment period of up to 54 weeks. During this period, patients continued to receive Mircera at the same frequency of administration as during the core period, i.e., 1x/week or 1x/2 weeks. Dose adjustments were performed to maintain target Hb levels within 11-12g/dL.
Patients who completed the 54-week extension period were eligible to enter a second optional extended treatment period of up to 54 weeks. During this period, patients continued to receive Mircera at the same frequency of administration as during the first-year extension period. Dose adjustments were performed to maintain target Hb levels within 11-12g/dL.

Number of patients (planned/analyzed)
91 patients enrolled

Diagnosis and main criteria for inclusion
Adult patients (>=18 years old) with chronic kidney disease on hemodialysis who had been receiving maintenance treatment with iv epoetin alfa. The dialysis adequacy requirements were Kt/V ≥1.2 or urea reduction ration (URR) ≥65%.

Test product, dose and mode of administration or test procedure
During the core period, the weekly dose of Mircera was determined by multiplying the patient’s previous weekly epoetin alfa dose received during the run-in period by one of three conversion factors: low = 0.25/150, medium = 0.40/150, or high = 0.60/150. Mircera was administered iv once weekly (1x/week) or once every two weeks (1x/2 weeks).
During the extension years 1 and 2, Mircera was administered by IV injection either 1x/week or 1x/2 weeks, after completion of the first dialysis session of the week. The initial dose was the final dose from the previous period, which could be adjusted to maintain target Hb levels.

Duration of treatment
19 weeks (core study period)

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

Criteria for evaluation (efficacy, safety)
Efficacy: Primary parameter: Change in Hb from baseline over time.
Secondary parameter: Change in hematocrit (Hct) from baseline over time.
Safety: Adverse events (AEs), vital signs, ECG, laboratory safety tests, including hematology, blood chemistry, iron parameters, and anti-Mircera antibodies.

Statistical methods
Efficacy: The primary endpoint was analyzed by calculating a separate linear regression over time for each patient with all Hb levels until end of initial treatment (EOIT) as the dependent variable. EOIT was defined as the last observed value before a dose change or blood transfusion. The individual slopes were multiplied by 42 to give an estimate of the change in Hb over 6 weeks for each patient and corresponding initial conversion factor (low, medium, high). For each dosing schedule, a regression of these estimates on the three conversion factors was calculated. The value where the regression line crosses zero gives the estimation of the equi-effective conversion factor. The robustness of these results was checked using a time-adjusted mean approach. Similar analyses were performed for the secondary efficacy parameter of change in Hct levels.
Safety: AEs, vital signs and laboratory data were summarized descriptively.

Summary (efficacy, safety, other results)
Efficacy: In the intent-to-treat (ITT) population, the smallest median changes from baseline in Hb levels were seen in the 0.4/150 1x/week group ( 0.04 g/dL) and in the 0.6/150 1x/2 weeks group ( 0.07 g/dL). The 0.25/150 dose group showed the largest median changes from baseline in Hb levels ( 0.29 g/dL in the 1x/week schedule and 0.92 g/dL in the 1x/2 weeks schedule). These results suggest that in the present study dosing schedule had an effect on the magnitude of the change from baseline in Hb level. In the 1x/week schedule, the 0.4/150 dose gave the smallest change from baseline in Hb level, while in the 1x/2 weeks schedule this occurred with the 0.6/150 dose. The outcome of the ITT analysis was heavily influenced by one extreme outlier. For this reason, a more meaningful interpretation of the results was made with the per-protocol (PP) population. As with the ITT population, the smallest median changes from baseline in Hb levels were seen in the 0.4/150 1x/week group (-0.04 g/dL) and in the 0.6/150 1x/2 weeks group (-0.05 g/dL). These results were confirmed using a time-adjusted mean analysis.
The target Hb concentration during the extension period was between 11 and 12 g/dL. During the first extension period, the median Hb concentration ranged from 11.40-12.10 g/dL in the 1x/week dosing group and from 10.85-12.18 g/dL in the 1x/2 weeks dosing group. During the second extension period, the median Hb concentration ranged from 11.40-12.10 g/dL in the 1x/week dosing group and 10.90-12.43 g/dL in the 1x/2 weeks dosing group.
Similar to the results for Hb, there was an effect of dosing schedule on change from baseline in Hct. In the PP population, for the 1x/week dosing schedule, the smallest median changes from baseline in Hct occurred in the 0.4/150 group ( 0.32 g/dL), while for the 1x/2 weeks schedule this occurred in the 0.6/150 group (median 0.05 g/dL).

Safety: Long term iv administration of Mircera was generally well tolerated. The majority (87%) of patients experienced AEs during the overall study period (core treatment period plus extension periods) and the most commonly reported AEs were injury, poisoning and procedural complications. Seven patients had events that were considered to be related to the study medication (anemia, fatigue, influenza-like illness, accelerated hypertension and hypertension). Of these drug-related AEs, one event was an SAE (accelerated hypertension). Five patients died during the study, (none during the core study period) but no death was considered to be related to the study medication. No trends of significance were found in the laboratory parameters measured in this study.
In general, the safety profiles for extension year 1, extension year 2 and the complete study period were similar. In addition, the safety profiles between the dosing schedule groups were comparable.

Conclusions
Overall, maintenance treatment with Mircera iv resulted in stable Hb levels after switching from maintenance treatment with epoetin alfa iv in patients with chronic kidney disease on hemodialysis. The dosing schedules tested in this study had an effect on the magnitude of Hb stability; for patients receiving Mircera once weekly the 0.4/150 conversion factor led to the most stable Hb levels, while for patients receiving Mircera once every two weeks the 0.6/150 conversion factor was the most appropriate for maintaining stable Hb levels. Long-term administration of IV Mircera resulted in relatively stable Hb levels at both frequencies of administration. Mircera was generally well tolerated long term, with no marked differences between dose groups in terms of safety.

Publications (references, if available)
Besareb A et al. Efficacy and tolerability of intravenous continuous erythropoietin receptor activator : a 19 week, phase II, randomized, open-label, dose-finding study with a 12 month extension phase in patients with chronic renal disease. Clinical Therapeutics 29:629-639, 2007

Date of report
3/1/2006

Click here for the protocol registry listing of this trial.