Clinical Trial Result Information
Title of Study:
Open, randomized, parallel group, multi-center study to investigate the effect of early anemia correction with epoetin beta on the reduction of cardiovascular risk in patients with chronic renal anemia who are not on renal replacement therapy (CREATE).
Fast Facts:
| Protocol number: | BA16169 |
| Sponsor: | F Hoffman-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | NeoRecormon |
| Generic name: | epoetin beta |
| Phase of development: | III |
| Therapeutic area, approved indication: | Anemia |
| Date of report: | 5/2/2005 |
Clinical study summary:
This was an open, randomized parallel group study to investigate the effect of early versus late anemia correction on cardiovascular morbidity in patients with chronic renal anemia.
Study center(s) :
A total of 129 centers in Austria, Belgium, China, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Mexico, Norway, Poland, Portugal, Russian Federation, Spain, Sweden, Taiwan, Turkey and UK.
Objectives:
The primary objective of the study was to investigate the effect of NeoRecormon (epoetin beta) treatment to a target hemoglobin (Hb) level of 13-15g/dL on cardiovascular morbidity and compare these effects with those attained with epoetin beta treatment to maintain a target Hb level of 10.5-11.5g/dL.
Secondary objectives were to demonstrate the effect of NeoRecormon treatment to reach a target Hb level of 13-15g/dL on left ventricular mass index (LVMI), progression of chronic renal failure and quality of life and compare these with NeoRecormon treatment to maintain a target Hb level of 10.5-11.5g/dL.
Methodology:
Eligible patients with a hemoglobin (Hb) level of 11-12.5g/dL were randomized into 2 equally sized groups with two different target Hb levels. Patients in Group 1 immediately started NeoRecormon treatment to reach a target Hb level of 13-15g/dL at the end of the correction phase. Patients in Group 2 only started NeoRecormon treatment once a decline in Hb level to <10.5g/dL had occurred. The target Hb level in these patients was 10.5-11.5g/dL at the end of correction phase. The starting dose of NeoRecormon in both groups was 2000 IU. During the correction phase (approximately 3 months) patients attended the center every second week. During the maintenance phase patients visited the center every 3 months. Structural and functional changes of the heart were assessed at baseline, every year and at the start of renal replacement therapy. Renal function, safety labs and iron parameters were assessed every 3 months. Nutritional status and Quality of Life were assessed every year. Adverse events were assessed on a continuous basis throughout the study.
Number of patients (planned/analyzed):
Enrolled: 605. Evaluated: 603.
Diagnosis and main criteria for inclusion:
Adult patients (≥18 years old) with chronic renal anemia who are not on renal replacement therapy, with Hb level of 11-12.5g/dL and a creatinine clearance of 15-35mL/min (Cockcroft-Gault) at screening.
Test product, dose and mode of administration or test procedure:
NeoRecormon (epoetin beta) lyophilisate in 60000 IU, 20000 IU and 10000 IU cartridges for Reco-Pen®. Starting dose 2000 IU NeoRecormon/subcutaneous injection/once weekly/to reach and maintain a hemoglobin level of 10.5-11.5g/dL.
Reference therapy, dose and mode of administration or reference procedure:
NeoRecormon (epoetin beta) lyophilisate in 60000 IU, 20000 IU and 10000 IU cartridges for Reco-Pen®. Starting dose 2000 IU NeoRecormon/subcutaneous injection/once weekly/to reach and maintain a hemoglobin level of 10.5-11.5g/dL.
Criteria for evaluation (efficacy, safety):
Efficacy: Primary variable: Combined endpoint of all protocol-specified cardiovascular events (time to first event): angina pectoris leading to hospitalization for at least 24 hrs or prolongation of hospitalization, acute heart failure, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, sudden death, transient cerebral ischemic attack (TIA), peripheral vascular disease (amputation, necrosis), cardiac arrhythmias leading to hospitalization for at least 24 hrs or prolongation of hospitalization. All cardiovascular endpoints were reviewed and adjudicated by an endpoint committee whose members were unaware of the group assignments of patients.
Secondary variables: Cardiovascular mortality, all cause mortality, chronic heart failure (NYHA classification), cardiovascular interventions: time to event and frequency of episodes; hospital admissions and duration of hospitalizations for cardiovascular reasons; left ventricular mass index, left ventricular volume, left ventricular ejection fraction, fractional myocardial shortening; Quality of Life (SF-36 questionnaire).
Safety: Blood pressure and antihypertensive medication, adverse events, laboratory test parameters.
Statistical methods:
Primary analysis: Time to first protocol-specified cardiovascular event was compared between the groups using a non parametric log-rank test stratified for underlying cardiac disease at baseline. A Cox proportional hazards model was used to evaluate the relative risk of an event in one group versus the other.
Secondary analyses: Non parametric methods (log-rank test) were used to analyze the time to cardiovascular mortality, all cause mortality, worsening NYHA class, cardiovascular interventions, first hospitalization, dialysis and target Hb level. Changes from baseline in echocardiography parameters, creatinine clearance, Hb levels, QoL and nutritional status were analyzed using an Analysis of Covariance (ANCOVA) model. Duration of hospitalization, iron medication and blood transfusions were summarized descriptively.
Multivariate sensitivity analyses on primary and secodary endpoints to evaluate bias and robustness were performed and pre-defined subgroup analyses for time to CV event, all cause mortality and dialysis performed.
Summary (efficacy, safety, other results):
Efficacy: At baseline, the mean hemoglobin level was 11.6 +/- 0.6g/dL in both groups. In group 1, 98% of patients received at least one dose of NeoRecormon, and in group 2, 32% of patients had received NeoRecormon at year 1, 52% at year 2 and 76% at the end of the study. During the study, the median weekly NeoRecormon dose was 5000 IU (range, 3000 to 8000) in group 1, and 2000 IU (range, 1000 to 3000) in group 2. The difference in the median hemoglobin level between the 2 groups was 1.9g/dL at year 1, 1.7g/dL at year 2, and 1.5g/dL at the end of the study.
As a result of the substantially lower cardiovascular event rate observed in this study (5.8%) compared with previous studies (15%), the study was underpowered for the primary endpoint and there was no statistically significant difference between the two treatment groups with respect to the time to first cardiovascular event (p=0.20). There was no significant difference in mortality between the two treatment groups either in terms of death due to cardiovascular reasons (p=0.48) or in terms of overall mortality (p=0.14). No difference between the groups in the time to worsening or onset of new chronic heart failure was found. There were also no statistically or clinically relevant differences in the distribution of all-cause or cardiovascular hospitalizations nor in the use of cardiovascular interventions between the two treatment groups. Despite a small difference in LVMI in year 1 favoring Group 1, there were no statistically or clinically relevant differences in echocardiographic variables between the two study groups. There was a highly statistically significant benefit favoring Group 1 over Group 2 in QoL at Year 1 [General Health score (p=0.003)]. A statistically significantly shorter time to dialysis (p=0.033) was seen for patients in the early correction group (Group 1) which was apparent from 12 months into the study. The two groups did not differ significantly in the mean decrease in estimated GFR over the study duration.
Safety: The most frequently recorded adverse event by patients in both treatment groups was renal failure. This event was experienced by 34% of patients in Group 1 and 32% of patients in Group 2. The majority of adverse events recorded by patients were mild or moderate in intensity. The most common adverse event related to treatment was hypertension, reported by 12% of patients in Group 1 and 2% in Group 2. Serious adverse events were reported by 53% of patients in Group 1 and 48% of patients in Group 2. The most common serious adverse events experienced by patients during the study were arrhythmia (5% of patients in each group), acute cardiac failure (4% of Group 1 patients and 6% of Group 2 patients), myocardial infarction (4% of Group 1 patients and 5% of Group 2 patients) and renal failure (6% of Group 1 patients and 4% of Group 2 patients). A total of 6% of patients in Group 1 and 4% in Group 2 were withdrawn prematurely from the study as a result of an adverse event. Only 2 of these adverse events (severe hypertension, Group 1; moderate injection site pruritus, Group 2) were considered by the investigator to be related to NeoRecormon treatment. Both events resolved without sequelae. Fifty two patients, 31 (10%) in Group 1 and 21 (7%) in Group 2, died. No clinically relevant differences between the treatment groups were seen during the study, with respect to laboratory test parameter value abnormalities or marked abnormalities.
Conclusions:
There was a substantially lower cardiovascular event rate than expected in this study, resulting in an underpowered primary endpoint. In patients with chronic kidney disease of stage 3 or 4 and mild-to-moderate anemia, the normalization of hemoglobin levels to 13.0-15.0g/dL did not reduce cardiovascular events as compared with use of a lower target range (10.5-11.5g/dL). The CREATE study adds direct evidence to confirm the current best practice guidelines, which recommend partial correction of anemia and not routine normalization of hemoglobin levels.
Publications (references, if available):
Drueke T, Locatelli F, Clyne N et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. NEJM 2006; 355 (20) 2071-2084
Click here for the protocol registry listing of this trial.
