Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayer.com apply to the contents of this file.

2 20-NOV-2017 Study no Page: 1 of 13 Date of study report: 19 JUL 2017 Study title: Sponsor s study number: NCT number: A controlled, parallel group, open-label, multicenter extension study to investigate efficacy and safety of oral BAY and darbepoetin alfa comparator in the long-term treatment of anemia in pre-dialysis subjects with chronic kidney disease in Europe and Asia Pacific NCT EudraCT number: Sponsor: Clinical phase: Study objectives: Bayer II Study objectives were assessed in pre-dialysis subjects with anemia of chronic kidney disease (CKD) for a period of up to 36 months in the Main Phase of this study. Primary objectives The primary objectives of this study were the following: To evaluate efficacy of treatment with BAY compared with darbepoetin as measured by the change from baseline to postbaseline time points in hemoglobin (Hb) levels To evaluate safety and tolerability of treatment with BAY compared with darbepoetin by events of special interest, adjudicated serious adverse events (SAEs), and SAEs. Secondary objectives The secondary objectives of this study were the following: To evaluate other efficacy variables of treatment with BAY compared with darbepoetin To evaluate other safety variables of treatment with BAY compared with darbepoetin.

3 20-NOV-2017 Study no Page: 2 of 13 Test drug: Name of active ingredient(s): Dose: Route of administration: Duration of treatment: Reference drug: Dose: Route of administration: Duration of treatment: Indication: Molidustat (BAY ) BAY Dose during Hb Stabilization (HbS) Phase Fixed initial doses of BAY (OD dose) were administered and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dl. Dose during Main Phase Based on the subject s Hb response and tolerability of previous dose, IXRS assigned the adapted dose for each subject for BAY Available dose regimens included 0, 15, 25, 50, 75, 100, and 150 mg. Oral Up to a maximum of 36 months Darbepoetin alfa (hereafter called darbepoetin) Darbepoetin was administered according to the local label and titrated at the scheduled DC visits. Intravenous (IV) or subcutaneous (SC) Up to a maximum of 36 months Anemia of CKD or renal anemia

4 20-NOV-2017 Study no Page: 3 of 13 Diagnosis and main criteria for inclusion: Subjects eligible for inclusion into the study had to meet all of the following inclusion criteria listed below: Men; women without childbearing potential, defines as (a) postmenopausal women (women with 12 months of spontaneous amenorrhea or with 6 months of spontaneous amenorrhea and serum follicle stimulating hormone concentration > 30 millimeters international unit / milliliter [miu/ml]) (b) women with bilateral tubal ligation, (c) women with bilateral ovarectomy, or (d) women with hysterectomy Not on dialysis at study entry Ability to understand and follow study-related instructions as a documented decision of the investigator. Inclusion criteria for inclusion into the HbS Phase Subjects who: Received BAY or placebo in Study and reached a stopping event, or Completed 16 weeks of treatment with BAY in Study or but had a mean Hb from the evaluation period outside the target range of 10.0 to 12.0 g/dl or Completed 16 weeks of treatment with placebo in Study and were re-assessed within 4 weeks after end of treatment (EoT) visit as eligible for the HbS Phase of Study (this extension study). Inclusion criteria for inclusion into the Main Phase Mean Hb concentration at 10.0 to 12.0 g/dl during the evaluation period of parent study for subjects who: o Completed 16 weeks of treatment (BAY arm) in Study 15141, or o Completed 16 weeks of treatment (BAY or darbepoetin arm) in Study without dose suspension lasting > 6 consecutive weeks, or HbS Phase subject (BAY or darbepoetin arm) in Study (this extension study): o Had mean Hb concentration of 10.0 to 12.0 g/dl for at least 2 consecutive visits after HbS Phase Visit 2, and o Did not have a dose suspension lasting > 6 consecutive weeks in the HbS Phase.

5 20-NOV-2017 Study no Page: 4 of 13 Study design: This is a controlled, parallel group, open-label, multicenter study Methodology: Two concurrent phases were included for this study: HbS Phase (up to 16 weeks) and Main Phase (up to 36 months). Subjects treated with placebo in Study received darbepoetin in this study. Hb Stabilization Phase overview The initial study drug dose in the HbS Phase was based on the Hb level at the time of the subject s stopping event or the average Hb levels during the last 4-week evaluation period if mean Hb was not within 10.0 to 12.0 g/dl, as well as the total daily dose level in Study or Study After the first dose control (DC) visit in this extension study, Hb was checked every 2 weeks in the HbS Phase. Main Phase overview Dose assessments were made every 4 (± 1) weeks. At the scheduled visits, interactive voice / web response system (IXRS) assigned an adapted dose regimen for BAY and darbepoetin [according to the local label] for the subject to take for the next 4 weeks of treatment to achieve and maintain Hb levels at 10.0 to 12.0 g/dl. In exceptional cases, the investigator could intervene in the dose decision based on his / her clinical judgment. Measurements from portable Hb devices were prohibited in the study. Safety laboratory parameters, heart rate (HR), blood pressure (BP), adverse events (AEs), and concomitant medications were monitored regularly throughout the study. Subjects who required administration of rescue treatment (e.g., red blood cell [RBC] containing transfusion, phlebotomy, or administration of a marked erythropoiesis-stimulating agent [ESA] treatment) were permanently discontinued from the study drug. Subjects who required hemodialysis during the study were not excluded. Three oversight committees were employed for this study, a steering committee, a data monitoring committee (DMC), and a central adjudication committee (CAC). Study center(s): 50 active centers overall that enrolled subjects in 12 countries. The participating countries were (number of centers in brackets): Bulgaria (6), France (3), Germany (2), Hungary (5), Israel (2), Italy (6), Japan (10), Poland (3), Republic of Korea (4), Romania (4), Spain (3), and United Kingdom (2).

6 20-NOV-2017 Study no Page: 5 of 13 Publication(s) based on the study (references): None at the time of report creation Study period: Study Start Date: 24 JUN 2014 Study Completion Date: 12 DEC 2016 Early termination: Yes. The study was terminated early as the study size did not meet the Regulatory Agency requirements to assess long-term treatment (safety) in this product class. Number of subjects: Planned: 190 subjects in BAY group 50 subjects in darbepoetin group Analyzed: 164 subjects Criteria of evaluation: Efficacy: Primary efficacy variable Change in local laboratory Hb level from baseline of the Main Phase to each post-baseline visit. Secondary efficacy variables Responders in Hb levels: The response defined as meeting all 3 of the following criteria (Hb levels from local laboratory): o Mean of Hb levels in the target range of 10.0 to 12.0 g/dl inclusive during the Main Phase o 50% of the Hb levels in the target range of 10.0 to 12.0 g/dl inclusive during the Main Phase o No RBC-containing transfusion during the active treatment. Time within Hb target range (10.0 to 12.0 g/dl inclusive) during study treatment measured as number of days and percentage of time in range (defined as number of days in target range / number of days on treatment) Number of subjects meeting specific Hb criteria Subjects with Hb values >13 g/dl or having excessive Hb increase Duration of exposure, defined as duration in days between first dose date and last dose date Number and percentage of subjects requiring down-titration

7 20-NOV-2017 Study no Page: 6 of 13 Number and percentage of subjects requiring up-titration Change from baseline in o Reticulocyte counts o Red blood cell (RBC) count and hematocrit (HcT) o Central laboratory Hb Safety: Statistical methods: The following primary safety variables were evaluated: o Adjudicated serious adverse events (SAEs): death and SAEs of the following events: severe arrhythmias, thromboembolic events (excluding hemodialysis vascular access events: arteriovenous shunt / fistula and arteriovenous graft events), syncope, symptomatic hypotension, and heart failure o Events of special interest: liver function-related AEs, including abnormal liver function tests and any hospitalization o SAEs. The following secondary safety variables were evaluated: o Non-serious adverse events (AEs) o HR and BP (at all time points and as change from baseline in this study) o Laboratory examinations: hematology, international normalized ratio, Quick / prothrombin time (PT), partial thromboplastin time (PTT), C-reactive protein (CRP), and chemistry, especially alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, electrolytes, amylase, and lipase. Tables displayed the results for each treatment group, as well as overall for the specified analysis population. As a general concept, data were displayed as measured at each scheduled visit and the individual changes as compared to baseline. A change was always calculated as post-baseline value minus baseline value. Population characteristics were summarized for modified intent-to-treat (mitt) and safety (SAF) datasets for the Main Phase of the study and the HbS safety set (HbSS) for the Hb Stabilization Phase. As this is an extension study, both efficacy and safety analyses were based on actual treatment received (BAY or darbepoetin). Additionally, data from all BAY treatment groups were pooled for analysis of efficacy and safety.

8 20-NOV-2017 Study no Page: 7 of 13 Efficacy: The primary efficacy variable was the change in local laboratory Hb level from baseline in the Main Phase to each post-baseline visit in the Main Phase. The primary efficacy endpoint was descriptively summarized by treatment at each post baseline visit, along with 95% confidence intervals (CIs) for mean and percent changes. In addition, mean difference (95% CI) between BAY combined dose group and comparator group was presented. Absolute Hb values at each visit including baseline visit was also descriptively summarized. Mean (with variation indicator) plots summarizing change from baseline over time was provided. In support of the above descriptive summaries, inferential analyses such as constrained longitudinal data analysis (clda) were conducted. Secondary efficacy analyses were descriptively summarized and defined in the statistical analysis plan (SAP). Analyses on changes of the following measures from baseline in parent study were not performed in this report: Reticulocyte count, RBC count and Hct, central laboratory Hb, HR, BP and 12-lead ECG data. Safety: Analyses on primary safety and tolerability were performed on the safety analysis set defined as All subjects who received at least 1 dose of study medication during the Main Phase. Descriptive summaries were provided by treatment. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 19.1 Substantial protocol changes: Global Amendment 1, dated 30 OCT 2014 To improve study feasibility and safety monitoring, Day 8HbS visit was removed and the subjects from Study who had an Hb stopping event after Day 15 in that study were added to the safety monitoring at Day 15HbS visit Heart failure was added to the list of adjudicated AEs, ECG assessments were reduced from triplicate to single measurements Statement of prescribed continuous dosing of acetaminophen / paracetamol is not allowed was included in the protocol Atrial fibrillation as an exclusion criterion was removed Clarification on time separation of intake of BAY and breast cancer resistant protein substrates.

9 20-NOV-2017 Study no Page: 8 of 13 Local Amendment 2, dated 19 NOV 2014 Protocol Amendment 2 which was a local amendment for UK and South Korea only was dated on 19 NOV 2014 (version 2.0). The purpose of this amendment was revised upon the request of regulatory authorities. As the results of Segment I toxicological studies on male fertility have become available, the male contraceptive requirements were removed as per the integrated global protocol Amendment 1. Per local request from competent authorities, the male contraceptive requirements were reinstated. Global Amendment 3, dated 24 NOV 2015 A discrepancy was identified between the BAY dose titrations (dose increase, dose decrease, and dose suspension) described in the protocol and those utilized in the IXRS system. The IXRS system has been programmed to allow dose suspension in case of high Hb (Hb > 11.7 g/dl), which was not consistently applied everywhere in the protocol text. For some sections, language was added to the protocol to add clarity to dose suspension recommended by IXRS. Subject disposition and baseline A total of 166 subjects who were previously screened and signed informed consent in the parent studies (15141 and 15261) were included in this extension trial. However, the data of 2 subjects who were randomized were excluded from all analyses as a result of an audit in Poland concluding a serious breach of compliancy issues. Thus, 164 subjects were analyzed in Of the 164 subjects, 67 (40.9%) subjects entered the HbS Phase, 97 (59.1%) subjects were included directly in the Main Phase, and 47 of 67 subjects (70.1%) rolled over from HbS Phase to Main Phase. HbS Phase Sixty-seven subjects entered the HbS Phase, 4 (6.0%) did not receive any treatment, while 63 (94.0%) subjects were treated; 46 assigned to BAY and 17 assigned to darbepoetin (these previous placebo subjects were treated with ESA for the first time). Four non-treated subjects discontinued the HbS Phase due to protocol driven decision point and a protocol violation. There was an imbalance of discontinuations between groups; 18 (36.7%) subjects on BAY and 2 (11.1%) subjects on darbepoetin. Primary reasons for discontinuation were AE (6 subjects, 30.0%) and protocol driven decision point (5 subjects, 25.0%). Two subjects withdrew treatment due to a lack of efficacy. Main Phase A total of 144 subjects were treated; 103 assigned to BAY and 41 assigned to darbepoetin. All subjects discontinued treatment, primary reason being termination of the study per sponsor s

10 20-NOV-2017 Study no Page: 9 of 13 decision (87 subjects, 60.4%). Other main reasons included AE (21 subjects, 14.6%) and protocol driven decision point (19 subjects, 13.2%). Follow-up The proportion of subjects completing follow-up was similar between BAY (82.2%) and darbepoetin (73.8%) treatment groups. Analysis sets There were 3 datasets used in this study. mitt: All subjects who received at least 1 dose of study medication during the Main Phase and had at least 1 post-baseline Hb value in the Main Phase (n=144). This population was the primary dataset for efficacy evaluation of subjects in the Main Phase. SAF: All subjects who received at least 1 dose of study medication during the Main Phase (n=144). This population was the primary dataset for safety evaluation of subjects in the Main Phase. HbSS: All subjects who received at least 1 dose of study medication during HbS Phase (n=63). This population was used to analyze and describe the effect observed in the stabilization phase only. Subjects who entered the Main Phase directly were excluded from this population. When analyzing data for the overall period, the mitt and HbSS combined population was used (n=160). The HbSS and SAF combined population was used for analyzing safety data for the overall period (n=160). Demographics Overall, the treatment groups were well-balanced with respect to demographics presented. The mean age was similar with BAY and darbepoetin (69.6 years and 68.5 years, respectively), as was the gender with male (48.3% and 52.4% respectively) and female participants (51.7% and 47.6% respectively). More than half of subjects in each treatment arm were White while a single subject in the darbepoetin group was Black. Under the BAY arm, the proportion of subjects who were Asian and Japanese (38.1% and 27.1% respectively) was higher compared to subjects in the darbepoetin group (21.4% and 11.9% respectively). Of the 160 subjects, only 4 were Hispanic or Latino and the ethnicity for 3 subjects was unknown. Diabetes mellitus (59 subjects, 36.9%) and hypertension (63 subjects, 39.4%) were the most frequently reported CKD etiology, which was also highlighted for each parent study. Other CKD etiologies were reported for < 10% of total subjects. Both groups were comparable in their mean egfr values; BAY : ml/min/1.73m 2 and darbepoetin: ml/min/1.73m 2. Efficacy evaluation Change in local laboratory Hb level from baseline of the Main Phase to each post-baseline visit in the Main Phase In this open-label extension study where subjects were randomized in the parent trials and 15261, results of the primary efficacy variable of change in local laboratory Hb level from baseline defined as:

11 20-NOV-2017 Study no Page: 10 of 13 i) as the average of scheduled Hb values from parent study visit 9-12 (evaluation period) for subjects entering the Main Phase directly ii) or defined as the average of values in HbS Phase used for inclusion into Main Phase (i.e., the last 2 clinical visits reported in the IXRS system) for subjects entering Main Phase from HbS Phase to each post-baseline visit using the mitt population demonstrated that BAY maintained Hb levels in pre-dialysis subjects who had renal anemia due to CKD. The effect of BAY on the maintenance of Hb levels in CKD subjects was similar to that of darbepoetin. The mean change from baseline at most visits was < 0.5 g/dl in both treatment groups. Mean local Hb levels were maintained within the target range of 10.0 to 12.0 g/dl during the treatment period at all visits except Week 108 for both BAY and darbepoetin groups due to study termination by the sponsor. At Week 108, only 3 subjects in total were evaluable for local Hb assessment and therefore the maintenance of Hb beyond 1 year could not be assessed. Mean (SD) local Hb values during treatment were (0.508) g/dl in the BAY group and (0.571) g/dl in the darbepoetin group. Consistent results for the change in Hb levels from baseline were observed in the observed case and last observation carried forward analyses. Furthermore, the sensitivity analysis conducted using central Hb levels confirmed the results with local Hb levels demonstrating high correlation. Responders in Hb levels For the secondary variables, responder rate defined by 3 criteria was higher in the BAY group than in the darbepoetin group; 95.1% versus 87.8% of subjects respectively had mean Hb levels within target range of 10.0 to 12.0 g/dl, 92.2% and 87.8% of subjects respectively had 50% of mean Hb within the target range, and 93.2% and 87.8% of subjects respectively had no RBCcontaining transfusion during treatment. Time within Hb target range The mean length of time spent within the Hb target range was similar between BAY and darbepoetin ( days versus days respectively). The percentage of time spent in the target range was also similar between the groups (80.68% versus 78.11% respectively). At EoT, less than 22% of total subjects in each treatment group were either below or above target range. The proportion of subjects meeting any of the 4 out of range specific local Hb criteria (i.e. >50% of Hb levels < 10.0 g/dl, or > 12.0 g/dl, or mean Hb levels < 10.0 g/dl, or > 12.0 g/dl) was lower in the BAY group compared to the darbepoetin group. The percentage of subjects with Hb > 13.0 g/dl at any time was numerically higher for darbepoetin subjects compared to BAY subjects (12.2% versus 9.7% respectively). On the contrary, those subjects that had an excessive increase > 2 g/dl over 4-week period all occurred in the BAY arm only (5 [4.9%] subjects versus none).

12 20-NOV-2017 Study no Page: 11 of 13 Number of subjects meeting specific Hb criteria Four criteria were defined for this endpoint (all occurring during the Main phase): 1. >50% of Hb levels below the lower limit of 10.0 g/dl 2. Mean of Hb levels below the lower limit of 10 g/dl 3. >50% of Hb levels above the upper limit of 12.0 g/dl 4. Mean of Hb levels above the upper limit of 12.0 g/dl The proportion of subjects meeting any of the critical or failing criteria was lower in the BAY group compared to the darbepoetin group. The number of subjects meeting each criterion was generally low for either group, i.e. 6 subjects or less. The biggest difference between the two groups was noted for criterion #2 (mean of Hb levels below the lower limit of 10.9 g/dl); 2.9% with BAY and 7.3% with darbepoetin. Subjects with Hb values >13 g/dl or having excessive Hb increase Excessive Hb increased was defined as an increase of >2.0 g/dl over a 4-week period at any time during the treatment period or a rise of >1.0 g/dl in 2 weeks. The rate of overshoot was comparable between the two treatment groups, with 12.6% of subjects in BAY group and 12.2% of subjects in the darbepoetin group meeting any of the 2 criteria (Hb > 13 g/dl and Hb increased > 2 g/dl in 4-week period). Hb >13 g/dl was experienced by 9.7% of subjects in BAY group and 12.2% of subjects in the darbepoetin group. Excessive increase with >2 g/dl over 4 weeks occurred only in the BAY group (4.9% of subjects). Duration of exposure Treatment duration for the Main Phase was defined as date of last study drug (EoT date) - date of first study drug + 1. If 0 mg occurred during the treatment period, but not as the last dose, then the suspension period was included. Mean treatment duration was similar for BAY and darbepoetin groups (399.8 ± and ± days, respectively).the minimum duration of exposure to BAY was 26 days and maximum was 760 days. Number and percentage of subjects requiring dose titration The proportion of subjects requiring up or down-titrations during the Main phase was also similar between the groups. Up-titrations were reported for 61.2% and 58.5% of subjects in the BAY and darbepoetin groups, respectively, and down-titrations were reported for 59.2% and 48.8% of subjects in the BAY and darbepoetin groups, respectively. On the other hand, a larger proportion of subjects in BAY group had dose suspensions compared to subjects in the darbepoetin group (37.9% vs. 7.3%, respectively). Change from baseline in reticulocyte, Hct and RBC counts and central Hb Consistent with the maintenance of Hb during the study, reticulocyte count, RBC count and Hct values showed little change over the study in either treatment group.

13 20-NOV-2017 Study no Page: 12 of 13 None of the pre-defined subgroups in each treatment arm were found to have a clinically significant worsening of Hb at EoT. Safety evaluation The majority of subjects (n=137, 85.6%) reported at least 1 TEAE for the overall period, the proportion of subjects was comparable between treatments (BAY : 85.6%, darbepoetin: 85.7%). The system organ classes (SOCs) investigations and vascular disorders presented the largest percent difference between the 2 groups with 12.7% and 11.7% respectively compared to other SOCs which were similar between BAY and darbepoetin. The percentage of subjects reporting the preferred term hypertension was higher in the darbepoetin group than in the BAY group (33.3% versus 20.3% respectively). Worsening of CKD reported as a TEAE was similar between the treatment groups (BAY : 17.8%, darbepoetin: 19.0%). Most other preferred terms were noted in < 10% of total subjects. Incidences of study drug-related TEAEs was low in the study (6.3% overall) reported for 8 (6.8%) subjects in the BAY group and 2 (4.8%) subjects in the darbepoetin group. Incidences of study procedure-related TEAEs was also low occurring for 3 subjects in total; 2 subjects with BAY and 1 subject with darbepoetin. Five subjects in the BAY group and 1 subject in the darbepoetin group died on study. Causes of death for BAY subjects were heart failure (2 cases, 1 case being worsening of heart failure), acute respiratory failure, pneumonia, and gangrene. Metastatic gastric cancer was the cause of death for the darbepoetin subject. No death was judged by the investigator as study drugrelated. Similar rates of serious TEAEs were reported for BAY and darbepoetin treatments (47.5% versus 52.4% respectively). In this population, worsening of CKD, pneumonia, and ESRD were the most commonly preferred terms in > 5 total subjects. Three subjects reported serious treatmentrelated events which included hypertension reported in the darbepoetin group and melena and intestinal adenocarcinoma reported in the BAY group. The CAC adjudicated all deaths, major adverse cardiovascular event (MACE), and serious TEAEs of severe arrhythmias, thromboembolic events (excluding hemodialysis vascular access events: arteriovenous shunt / fistula and arteriovenous graft events), syncope or symptomatic hypotension, and heart failure. The proportion of subjects with MACE were numerically higher in in the BAY group (6.8%) versus darbepoetin group (4.8%). The proportion of subjects reporting positively adjudicated serious TEAEs was the same in each treatment group (11.9% in each group). In addition to MACE, heart failure (total 4.4%), and death and thromboembolic events (total 3.8% each) were the most frequently reported adjudicated TEAEs across the 2 groups. For the Main Phase, treatment withdrawals / discontinuations due to TEAEs were reported in 17.5% of subjects in the BAY group and 7.3% of subjects in the darbepoetin group. This imbalance was also observed for the overall period; 21.2% of subjects in the BAY group and 9.5% of subjects in the darbepoetin group. Among all reported SOCs in the Main Phase, renal and urinary disorders were the most commonly reported SOC for treatment discontinuation across the treatment groups (BAY : 7.8% versus darbepoetin: 4.9%). Other SOCs reported occurred for < 3% of subjects in any arm. It should be noted that investigators may have chosen to discontinue subjects from oral BAY , as this was an open-label study and BAY subjects could switch to

14 20-NOV-2017 Study no Page: 13 of 13 standard of care parenteral darbepoetin once every 2 weeks (fallback option), while subjects on darbepoetin were already receiving standard of care. This reason may have contributed to the imbalance in discontinuations. Dose interruptions due to TEAEs were reported by < 10% of Main Phase subjects, driven by the SOC cardiac disorders reported for 4 out of 10 subjects. All dose interruptions were observed in the BAY group only. Other SOCs leading to dose interruption were reported in a total of 2 subjects or less. No TEAE leading to dose interruption was considered treatment-related by the investigator. The preferred terms myocardial infarction, pneumonia, traumatic subdural hemorrhage, and cardiac failure chronic were assessed as serious TEAEs that led to dose interruption. Overall, there were no clinically meaningful changes from baseline laboratory parameters or vital signs in either treatment group. The overall rate of TEAEs, SAEs, and non-fatal MACE were similar between the two treatment groups and no other safety issue was identified with BAY The incidence of deaths under BAY was 4.2% relative to 2.4% under darbepoetin. The overall results of this study show a comparable safety profile of BAY relative to darbepoetin which is standard of care. However, the number of subjects included in this study was too low (n=118) to draw meaningful conclusions on the long-term safety of BAY Overall conclusions In this open-label extension study, BAY maintained mean local Hb in the target range of g/dl throughout the study. Hemoglobin measurements performed by the central laboratory had results similar to local laboratory results. The magnitude of the effect of BAY on mean Hb levels was similar to that of darbepoetin. The results of this study show a comparable safety profile of BAY in comparison to darbepoetin which is standard of care. However, the number of subjects included in this study was too low (n=118) to draw meaningful conclusions on the long-term safety of BAY