SYNOPSIS CLINICAL STUDY REPORT Non-interventional observational study on efficacy, safety and practicability of MIRCERA in kidney transplanted patients (BEAT) Report on non-interventional study ML21386 Sponsor: Authors: Dr. R. Prinz Emil-Barell-Straße 1 Dr. A. Wiggenhauser 79639 Grenzach-Wyhlen Germany Coordinating Investigator: PD Dr. V. Kliem Report date: 22 Nov 2012 Report version: 1.0 (final) CRO: M.A.R.C.O. GmbH & Co KG Moskauer Straße 25 40227 Düsseldorf Germany EudraCT number: Investigational product: Formulation: Indication: Phase: MIRCERA Ready-to-use syringe Renal anemia of NTx patients with chronic kidney disease (CKD) Non-interventional, phase IV study Study initiated (first subject first visit): 15 Sep 2007 Study completed (last subject completed): 17 Nov 2011 Report Version 1.0 (final) dated 05 December 2012 Page 1 of 6
TITLE OF STUDY: COORDINATING INVESTIGATOR: STUDY CENTERS: PUBLICATION (REFERENCE): STUDY PERIOD (MONTH): CLINICAL PHASE: OBJECTIVES: METHODOLOGY: Non-interventional observational study on efficacy, safety and practicability of MIRCERA in kidney transplanted patients (BEAT) PD Dr. V. Kliem Nephrologisches Zentrum Niedersachsen Vogelsang 105 D-34346 Hann. Münden 38 centers in Germany Not applicable. First subject first visit: 15Sep2007 Last subject last visit: 17Nov2011 Total study duration: 4 years 2 months Non-interventional, phase IV The intention of this non-interventional study was to raise data especially in patients, who have a kidney transplant and are consequently treated with immuno-suppressive drugs to study the efficacy and safety, and the practicability of the treatment with MIRCERA in this particular population. Non-interventional study NUMBER OF PATIENTS: Planned: 400-450 Patients Included: 290 Analyzed: 279 (safety set) 193 (efficacy set) Completed: 180 (final documentation after 9th or 15th visit) MAIN CRITERIA FOR INCLUSION: DURATION OF TREATMENT: Patients with kidney transplant and a chronic kidney disease (CKD), who need ESA therapy as part of their medical care. The transplant should function regularly and without need of continuous dialysis treatment at inclusion and also during the documentation period of this study according to treating physician s prognosis. Treatment was at the discretion of the treating physician. The documentation period lasted up to 15 months. Report Version 1.0 (final) dated 05 December 2012 Page 2 of 6
CRITERIA FOR EVALUATION: Efficacy: Primary endpoints Number of patients reaching a hemoglobin (Hb) value of 11-12 g/dl during visits 7, 8 und 9 of the observational phase. Number of patients reaching a Hb value of 11-13 g/dl during visits 7, 8 und 9 of the observational phase. Number of patients within Hb target range during months 7 to 12 and during months 7 to 15 Time on current dose, i.e. time after last dose adjustment Secondary endpoints based on Course of GFR, estimated creatinin-clearance (ml/min) Type of transplant (living / cadaveric) Route of application (s.c. or i.v.) of MIRCERA Presence of inflammatory disease (CRP >30 mg/l) Underlying diseases of CKD Acute bleeding during the study Safety: Adverse event profile Laboratory examination STATISTICAL METHODS: All aspects of this study were evaluated using descriptive statistical methods defined in a statistical analysis plan (SAP) prior to evaluation. SUMMARY: 279 patients received at least one MIRCERA dose and their data were valid for safety analysis. Of these, 94 patients (33.7%) terminated the trial prematurely. Most frequent reasons for termination were necessity of dialysis (22/94=23.4%), consent withdrawn (17/94=18.1%), administration of other ESA (17/94=18.1%), and no further indication for MIRCERA (17/94=18.1%). In total, 4 deaths occurred during the course of the study, all of these were not related to MIRCERA application. In addition, 2 patients terminated due to SAE, and 2 patients due to AE. With regard to safety population, mean age was 51 years (ranging between 18 and 86 years). 97% of the patients were Caucasians. About half of the population were male patients. All patients treated with MIRCERA had chronic kidney disease (CKD) after kidney transplantation. Main reasons of the disease were specified as: glomerulonephritis (33%), polycystic kidney Report Version 1.0 (final) dated 05 December 2012 Page 3 of 6
(9.3%), chronic pyelonephritis (9.0%), hypertensive nephrosclerosis (6.8%), and diabetic vasculopathy (5.4%) based on the safety set. About 80% of the patients received a post-mortal transplant and the other patients had received a living transplant prior to enrolment into the study. The median time since transplantation was about 6 years prior to study inclusion. Median age of the kidney donor was 50 years. Previous ESA treatments started about 9 months (median) before inclusion into this study. Most frequently used products were Aranesp in 92 (33%), MIRCERA in 45 (16%), NeoRecormon in 61 (22%), and Dynepo in 13 patients (5%). The predominant reason for change from previous ESA treatment to MIRCERA was the new and innovative application scheme quoted by 173 patients (62.2%) or failure of previously used ESA in 16 patients (5.8%). 86 patients (30.9%) received no ESA therapy prior to study start. MIRCERA administration was performed by the patient, at the surgery, by clinical staff or both by clinical staff and by the patient. Most of the patients (90%) self-administered MIRCERA at least once. 180 patients (64.5%) applied MIRCERA themselves with no clinical personnel involved at any time throughout the study. The median dose of MIRCERA applied was 76.9 µg (range: 30 µg to 360 µg). Of the 279 subjects in the safety set, 276 applied MIRCERA subcutaneously and 3 subjects applied MIRCERA i.v. and s.c. Median MIRCERA dosing intervals were 31 days with a range from 13 to 91 days. Efficacy Overall, hemoglobin levels slightly increased from pre-study with a mean value of 11.10 g/dl to 11.41 g/dl at visit 2, to 11.53 g/dl at visit 7, and to 11.57 g/dl at visit 9, the mean value at visit 15 was 11.41 g/dl. During visits 7 to 9, the hemoglobin levels remained in the target range of 11-12 g/dl in 20.7% of the patients, and in the target range of 11-13 g/dl in 40.4% of the patients. In 21.2% of the patients, the hemoglobin levels stayed in the range of 11-13 g/dl from visit 7 to 12, and in 12.2% from visit 7 to 15. With regard to the range of 10-13 g/dl, the corresponding percentages were 64.8% (visits 7 to 9), 52.6% (visits 7 to 12), and 42.1% (visit 7 to 15). Fluctuation in individual hemoglobin levels appeared low over the treatment course. In 87% of the patients hemoglobin varied only by 1 g/dl around the individual mean between visits 7 to 9, in 57.7% between visits 7 to 12, and in 41.8% of the patients between visits 7 to 15. Variations greater than 2 g/dl occurred in less 10% of the patients between visits 7 and 12. Report Version 1.0 (final) dated 05 December 2012 Page 4 of 6
On average, MIRCERA doses were kept constant for about 9 months since the last dose adaptation with regard to the current dose administered at end of the study. Hemoglobin fluctuation and the percentage of patients reaching the target ranges did not appear to be influenced by kidney function i.e. GFR at baseline (considered as subgroups"<30 ml/min" or ">30 to 60 ml/min"). Also, no influence of the type of transplant (living or post-mortal), presence of inflammatory disease, time since transplantation, or etiology of CKD on efficacy outcomes was observed. There were no acute bleedings during this study (as to be documented on the AE page associated with a Hb decrease of 2 g/dl between two sequential values between visit 1 and final documentation). Safety Overall, 55 patients (19.7%) reported 178 adverse events, including serious adverse events and deaths. The majority of adverse events were not related to MIRCERA therapy, i.e. only 7 patients reported 10 adverse events judged as at least possibly drug-related. During the course of the study 4 patients died for reasons not related to MIRCERA application. Causes were coronary artery disease (leading to brain death), sudden cardiac failure, pneumonia/septic shock/multi-organ failure, and pneumonia/sepsis/ hemodialysis with anuric renal failure. 51 adverse events in 32 patients were serious (excluding deaths), one of which was classified as possibly related to MIRCERA treatment (unstable angina pectoris) and 3 were classified as probably related to MIRCERA (deep vein thrombosis, hypertension aggravated with angina pectoris, all 3 experienced by the same patient). Of the 51 SAEs reported (excluding deaths), 11 were of mild, 36 of moderate, and 4 of severe intensity. In addition, 4 significant adverse events (other than death and SAE) were observed in 3 patients, i.e. adverse events which had led to withdrawal of study medication, namely: moderate aggravated hypertension (judged as probably related to MIRCERA), mild pancytopenia with hemolytic anemia (both possibly related), and mild bone marrow depression (not drug related). Further, at least possibly drug-related adverse events were: mild aggravated hypertension (1x), mild injections site burning (1x), and mild thrombocytopenia (1x). The frequency of reported adverse events was completely within the expected frequency ranges according to the summary of product characteristics: headache 0.7% (expected: 0.10 to 1.00%), Report Version 1.0 (final) dated 05 December 2012 Page 5 of 6
hypertension 1.1% (1.00 to 10.00%). Other adverse events that may have been expected by SmPC (hypersensitivity, shunt thrombosis, hypertensive encephalopathy, rash maculo-papular, and hot flush) were not observed in this trial. CONCLUSION: MIRCERA treatment was safe and well-tolerated Hemoglobin values well-controlled within target ranges of 11 to 12 g/dl and 11 to 13 g/dl during visits 7 to 9, visits 7 to 12, and visit 7 to 15 (corresponding to months of treatment) Hemoglobin values were found stable throughout the treatment period, i.e. with low fluctuation around individual means The time after last MIRCERA dose adaption was about 9 months on average demonstrating easy and unproblematic drug administration by avoiding frequent dose adaptions in long-term treatment Successful control of hemoglobin levels associated with low fluctuation was not influenced by any cofactors, such as GFR at baseline, type of transplant (living or post-mortal), presence of inflammatory disease, time since transplantation, or etiology of CKD Report Version 1.0 (final) dated 05 December 2012 Page 6 of 6