Clinical Trial Result Information
Title of Study:
An open, randomized, multi-center trial to investigate the effect of anemia correction on cardiac structure and function in patients with early diabetic nephropathy (ACORD).
Fast Facts:
| Protocol number: | MA16620 |
| 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: | 3/1/2006 |
Clinical study summary:
This was an open-label, randomized, multi-center, parallel group study in patients with early diabetic nephropathy, to assess the effect of anemia correction with NeoRecormon on cardiac structure and function.
Study center(s) :
A total of 50 centers in Austria, Brazil, Czech Republic, Denmark, Finland, United Kingdom, Greece, Hungary, Italy, Mexico, Poland, Russia, Singapore, Spain, Sweden and Thailand participated in the study.
Objectives:
Primary: To investigate the effect of anemia correction in patients with early diabetic nephropathy on left ventricular mass index from baseline to 15 months.
Secondary: To investigate change in left ventricular volume and fractional shortening after 15 months; to determine the percentage of patients with stable hemoglobin levels between 13 - 15g/dL.
Methodology:
Eligible patients were randomized to a) receive a starting dose of 2000 IU of NeoRecormon administered subcutaneously once weekly to reach and maintain a target hemoglobin (Hb) between 13 and 15g/dL, with a minimum target increase of 1.0g/dL, or b) receive their standard treatment and only start treatment with NeoRecormon for anemia correction if the Hb was <10.5g/dL on two consecutive visits at an interval of two weeks or if the Hb level dropped below 10g/dL in a single determination. NeoRecormon treatment was initiated at a dose of 2000 IU, to reach and maintain a target Hb level of 10.5 - 11.5g/dL.
All patients were to visit the center at screening, and at intervals throughout the study, for assessment of adverse events, vital signs and laboratory parameters. In addition, patients in Group 1 visited the center every 2 weeks during the correction phase (approximately 3 months) for assessment of Hb and dose adjustment. Patients in Group 2 had additional visits every two weeks when they started NeoRecormon treatment for anemia correction.
Number of patients (planned/analyzed):
Total patients randomized: 172
Diagnosis and main criteria for inclusion:
Adult patients with diabetes mellitus, moderate anemia and early-stage renal insufficiency.
Test product, dose and mode of administration or test procedure:
NeoRecormon (epoetin beta) was administered subcutaneously with the Reco-Pen® once a week. The weekly starting dose of NeoRecormon was 2000 IU.
Duration of treatment:
15 months
Reference therapy, dose and mode of administration or reference procedure:
N/A.
Criteria for evaluation (efficacy, safety):
Efficacy: Primary variable: Left ventricular mass index (LVMI).
Secondary variables: Left ventricular end systolic volume index (LVESVI); left ventricular end diastolic volume index (LVEDVI); left ventricular ejection fraction; fractional shortening; percentage of patients with stable hemoglobin levels between 13 - 15g/dL. Other variables: Total score and sub-scales of the quality of life questionnaire (SF-36).
Safety: Adverse events, laboratory parameters, vital signs.
Statistical methods:
An analysis of covariance model with baseline LVMI as cofactor was used to assess the change from baseline in the primary endpoint, LVMI. For the secondary parameters, left ventricular end systolic and diastolic volume indices, ejection fraction and fractional shortening after 15 months therapy, an analysis of covariance model similar to that for LVMI was performed. The percentage of patients with stable hemoglobin levels between 13 - 15g/dL was tested using a χ²-test with Schouten correction.
Safety was analyzed using change from baseline tables over time for laboratory and vital signs parameters, and frequency tables for adverse events.
Summary (efficacy, safety, other results):
NeoRecormon treatment was administered to all patients in group 1 after randomization and was received at least once by all patients in this group during the study. Thirteen of 82 patients (16%) in group 2 received NeoRecormon treatment during the study to maintain their Hb level within the target range. The efficacy of NeoRecormon treatment with regard to increasing hemoglobin levels was shown by the different response rates in the two treatment groups. Patients in group 1 achieved mean target Hb levels after approximately 3 months of treatment with NeoRecormon; mean Hb at study end in Group 1 was 13.4 g/dL. In Group 2, where patients received NeoRecormon treatment only when their hemoglobin level fell below 10.5 g/dL in order to maintain a target hemoglobin level of 10.5-11.5 g/dL, the mean Hb level at study end was 11.9 g/dL.
There was no statistically significant difference between Groups 1 and 2 in mean LVMI at baseline (113.5+/-30.6g/m2 vs 116.0+/-34.6g/m2). Echocardiographic variables were well balanced at baseline in the 2 groups; however, the frequency of patients with LVH was greater in group 1 (47%) than group 2 (39%).
Analysis of the primary endpoint, baseline adjusted LVMI at month 15, revealed no statistically significant difference between the groups (p=0.8811). Mean LVMI was, however, shown to be stable throughout the study. As with the primary echocardiographic endpoint, there were no statistically or clinically significant relevant differences in all secondary and other exploratory echocardiographic parameters between the two study groups; LVESI, LVEDVI, LVEF, FS, left ventricular geometry, LVPWT, LVEDD, LVH, RWT, LV dilation and LV systolic dysfunction from baseline to month 15. Blood pressure was well maintained until study end with a mean blood pressure of 136/75 mmHg in Group 1 and 134/77 mmHg in Group 2 fulfilling the established criteria for the presence of LVH (LVMI >110 g/m² for females and >130g/dL for males). Consequently, the criteria for concentric LVH were only fulfilled by 25% of patients in Group 1 and 22% of patients in Group 2 respectively, and the criteria for eccentric LVH by 21.6% in Group 1 and 17.1% in Group 2.
The primary analysis for LVMI was confirmed by multivariate analysis. For LVMI, a difference of 6g/m2 favouring group 1 was detected. This constituted a trend in the multivariate model supporting strongly that there was at least no negative trend for LVMI in the high Hb correction group (Group 1).
Safety: The most frequently reported adverse events in Group 1 and Group 2 were hypertension (17% vs 11%), peripheral edema (9% vs 11%) and renal impairment (6% vs 6%). The most common adverse event considered related to NeoRecormon treatment was hypertension, reported in 8 patients in Group 1 and 1 patient in Group 2. The majority of adverse events were mild or moderate in intensity. Serious adverse events were reported by 24% of patients in each treatment group, the most common SAE being renal impairment, reported in 3 patients in Group 2 and 1 patient in Group 1. Three patients in Group 1 experienced serious adverse events (hypertension, myocardial infarction, deep vein thrombosis) which were considered related to study treatment. Two patients withdrew prematurely from the study as a result of adverse events; neither adverse event (asthenia, Group 1; atherosclerosis, Group 2) was considered related to trial treatment. Three patients in Group 2 died; the deaths were a result of pneumonia, coronary artery atherosclerosis and hypoglycemic encephalopathy, respectively, and none was considered related to trial treatment.
There was no clinically relevant difference between the treatment groups with respect to the change from baseline in clinical laboratory parameters and no difference between the treatment groups with respect to marked laboratory abnormalities or vital signs data.
Conclusions:
This study was designed to investigate the effect of early and complete anemia correction versus late and partial anemia correction with NeoRecormon on cardiac structure and function. Once weekly treatment with NeoRecormon resulted in a highly significant increase in Hb but there was no statistically significant difference in the primary efficacy parameter of the study, change from baseline adjusted LVMI from baseline to month 15, between the study groups. No statistically or clinically relevant differences between the two treatment groups were shown for the secondary echocardiographic parameters. Treatment with once weekly NeoRecormon was safe in terms of adverse and serious adverse event profile and there were no new or unexpected safety findings which are not already reflected in the known safety profile of NeoRecormon.
Publications (references, if available):
Ritz E, Laville M, Bilous F, et al. Target level for hemoglobin correction in patients with diabetes and CKD: Primary results of the anemia correction in diabetes (ACORD) study. Am J Kidney Dis 2007; 49:149-207.
Click here for the protocol registry listing of this trial.
