Clinical Trial Result Information
Protocol number
BA16736
Title of Study
An open-label, randomized, multi-center, parallel group study to demonstrate correction of anemia using intravenous injections of Mircera 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
This was an open-label, randomized, multi-center study of Mircera (methoxy polyethylene glycol-epoetin beta) in patients with chronic kidney disease (CKD) who are on dialysis, with one dosing interval (1x/2 weeks) during the correction period and two dosing intervals (1x/2 weeks, 1x/4 weeks) during the extension period, and with a non-comparative reference group.
Study center(s)
This study was conducted at 42 sites in Brazil, Canada, Czech Republic, Greece, Poland, Russia, South Africa, Spain, Thailand and USA.
Phase of development
III
Objectives
Primary: To demonstrate the efficacy of intravenous (IV) Mircera treatment for correction of anemia in patients with stage 5 CKD who are on dialysis.
Secondary: To assess time to hemoglobin (Hb) response; to assess the safety and tolerability of multiple doses of Mircera during the correction and extension periods in this patient population; to assess long-term safety with Mircera in this patient population.
Methodology
Eligible patients were randomized in a 3:1 ratio to receive either Mircera 0.4µg/kg IV every 2 weeks or epoetin 3x/week IV. The study consisted of a correction period (dose titration) of 24 weeks, followed by an extension period of up to 28 weeks for documentation of safety. At week 25, after 24 weeks of treatment, the responders in the Mircera group were re-randomized either to Mircera 1x/2 weeks or Mircera 1x/4 weeks. Patients were kept on this treatment regimen for the subsequent 28 weeks.
Number of patients (planned/analyzed)
Planned: 168 patients. Enrolled: 181 patients (135 Mircera, 46 epoetin)
Diagnosis and main criteria for inclusion
Adult patients with chronic renal anemia who are on dialysis and not currently receiving treatment with an erythropoiesis-stimulating agent.
Test product, dose and mode of administration or test procedure
Correction period: IV injections of 0.4 μg/kg of Mircera once every two weeks (1x/2 weeks).
The target Hb concentration during the correction period (weeks 1-24) was ≥11.0g/dL and an increase in Hb from baseline of ≥1.0 g/dL. In case of inadequate response to Mircera, dose adjustments could be performed every 4 weeks.
Extension period: Patients who achieved the target Hb concentration in the correction period were re-randomized to either Mircera 1x/2 weeks or Mircera 1x/4 weeks. The dose of Mircera was adjusted to maintain the individual patient’s Hb within a target range of 11.0 to 13.0 g/dL.
Duration of treatment
52 weeks
Reference therapy, dose and mode of administration or reference procedure
Correction Period: Three iv injections per week of epoetin alfa or beta, administered according to approved labelling. During the correction and extension periods, the dose of epoetin alfa or beta was adjusted in order to achieve and maintain a response (see above).
Criteria for evaluation (efficacy, safety)
Efficacy: The primary endpoint was the Hb response rate. The assessment of response was based on the weekly measurements and defined as an increase in Hb ≥ 1.0 g/dL from baseline and a single Hb concentration ≥ 11 g/dL, without red blood cell (RBC) transfusion before response, during the 24 weeks after first dose (until day 173).
The secondary efficacy endpoints were: The Hb values and their changes from baseline over time; the time to response assessed via Kaplan-Meier methods; the incidence of RBC transfusions during the first 24 weeks.
Safety: Safety parameters included adverse events (AEs), hematology and blood chemistry laboratory tests, assessment of dialysis adequacy, anti-erythropoietin antibody testing, vital signs and 12-lead ECGs.
Statistical methods
The study was to demonstrate that the response rate was at least 60% in the Mircera group. A two-sided 95% confidence interval based on the exact method of Clopper and Pearson was calculated. If the lower limit of this confidence interval was above 60%, H0 (H0: r ≤ 60%) could be rejected with a significance level of 0.025 (one sided). This would allow the conclusion that Mircera administered 1x/2 weeks results in correction of anemia.
Hemoglobin values and change from baseline over time and the incidence of RBC transfusions were summarized using descriptive methods. Hb values over time were also summarized descriptively during the extension period.
Safety data were summarized descriptively.
Summary (efficacy, safety, other results)
Efficacy: Primary endpoint: For the intention-to-treat population, 126 patients (93%) Mircera were responders, and the lower limit of the 95% CI for the response rate was higher than 60% (95% CI 87.7-96.9, p<0.0001). The high overall response rate allows the conclusion that Mircera administered IV 1x/2 weeks results in correction of anemia. Results were consistent for the per-protocol population and eligible populations.
Secondary endpoints: Median Hb concentrations increased in both the Mircera group and the epoetin group, although the increase was more rapid in the epoetin group compared with the Mircera group. The median time to response was 57 days in the Mircera group and 31 days in the epoetin group. Seven patients in the Mircera group and two patients in the epoetin group received RBC transfusions during the correction period.
Extension period: Median Hb concentrations were generally lower in the Mircera 1x/4 weeks group (range 11.0-12.1g/dL) compared with the Mircera 1x/2 weeks and epoetin groups (range 11.9-12.5g/dL and 11.6-12.3g/dL, respectively). Despite the lower Hb concentrations in the Mircera 1x/4 weeks group, the incidence of RBC transfusions was not higher compared with the Mircera 1x/2 weeks and epoetin groups. Moreover, no patients were withdrawn due to lack of efficacy during the extension period. Although the median numbers of dose changes during the extension period were similar, more patients in the Mircera 1x/4 weeks group had dose increases and the median weekly equivalent dose of Mircera was higher in the 1x/4 weeks group (mostly around 0.30μg/kg/week) compared with the 1x/2 weeks group (0.20-0.24 μg/kg/week).
Safety: Correction Period: The overall incidence of AEs was similar between the two treatment groups. Hypertension was the most common AE (19% and 24% in the Mircera and epoetin groups, respectively), followed by procedural hypotension (7% of patients in both groups) and arteriovenous fistula thrombosis (5% and 9% of patients in the Mircera and epoetin groups, respectively). The majority of AEs reported were of mild or moderate intensity and assessed as unrelated to study medication.
Serious AEs were reported for a higher proportion of patients in the Mircera group than in the epoetin group (22% vs. 15%), and the incidence of severe/life-threatening AEs was higher in the Mircera group compared with the epoetin group (17.8% vs. 8.7%). Although there were more SAEs and severe/life-threatening AEs reported in the Mircera group compared with the epeotin group, this imbalance was not due to any specific event, but multiple events reported in single patients. One patient in each treatment group had SAEs (vascular graft occlusion and arteriovenous fistula thrombosis) that were considered to be related to the study medication,
One patient withdrew from the study due to an AE (chronic renal failure - withdrawal of dialysis); this event was not considered to be related to the study medication.
Two patients in the Mircera group died during the correction period. Causes of death were aspiration pneumonia and chronic renal failure (withdrawal of dialysis treatment). Neither of these events was considered by the investigator to be related to the study medication.
Extension Period: The most commonly reported AEs in the extension period were muscle spasms (7%, 11%, 5%) and hypertension (5%, 10%, 8%) in the Mircera 1x/2 weeks, Mircera 1x/4 weeks and epoetin groups, respectively. Related AEs were reported only by 3%, 2% and 8% of patients, respectively. SAEs were reported by 26%, 16% and 28% of patients, respectively; two patients in the Mircera 1x/2 weeks group had SAEs which were considered to be related to the study medication (arteriovenous graft thrombosis and transient ischemic attack).
Nine patients died during the extension period: 2 patients in the Mircera 1x/2 weeks group, 3 in the 1x/4 weeks group and 4 in the epoetin group. None of the deaths was considered to be related to the study medication.
Throughout the study period, there were no apparent differences or trends of significance in any of the laboratory parameters except in the platelets, which were slightly lower in the Mircera arm compared with the epoetin arm. There were no apparent differences between the treatment groups with respect to vital signs or ECG changes. No anti-erythropoietin or anti-Mircera antibodies were detected in any patients.
Conclusions
Intravenous Mircera was effective in correcting anemia in patients with chronic kidney disease who were on dialysis. Dose adjustments of Mircera, according to protocol guidance, enabled correction of anemia to target Hb levels. During the extension period, median Hb levels were slightly lower in the Mircera 1x/4 weeks group compared with the Mircera 1x/2 weeks and epoetin groups.
Long term administration of IV Mircera in patients with chronic kidney disease on dialysis was generally well-tolerated. The safety profile of Mircera was similar when given once every 2 weeks or once every 4 weeks. Safety findings were characteristic of the study population and were generally comparable between treatment groups.
Publications (references, if available)
Klinger M et al. Efficacy of Intravenous Mircera Administered Twice Monthly Compared With Epoetin Administered Three Times Weekly in Patients Treated by Hemodialysis or Peritoneal Dialysis: a Randomized Trial. Am J Kidney Dis (in final revision)
Date of report
3/1/2006
Click here for the protocol registry listing of this trial.
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