Hemodialyzed Patients Clinical Trial
Official title:
Once-Weekly Versus Once-Fortnightly Subcutaneous Epoetin Beta Administration in the Maintenance Phase of Anaemia Treatment in Haemodialyzed Patients
Currently, less frequent than once weekly subcutaneous epoetin administration regimens were
shown to be equally effective and safe as the once-weekly schedules in stable pre-dialyzed
and peritoneal dialyzed patients Bioequivalence of once-every-two-weeks and once-weekly
subcutaneous administration of the same total dose of epoetin beta for the maintenance phase
of anemia treatment in stable, iron-replete, chronic hemodialyzed patients was therefore
prospectively investigated.
two treatment schedules will be considered equivalent if the primary efficacy parameters
will be simultaneously similar for both groups and in the predefined range of variation.
Confidence intervals (CIs) will be used to compare groups. Since the target Hb in dialyzed
patients is defined as 11g/dL (110 g/L) by the European Guidelines and as >10 g/dL (100 g/L)
by the National Guidelines, with a recommended upper limit of 13 g/dL (130 g/L), the
efficacy range for Hb in this study was predefined as 10-12 g/dL (100-120 g/L). The two
treatment schedules will be considered to have similar efficacy if the mean Hb in Group 2w
will not differ by more than ±0.5 g/dL (±5 g/L) compared to Group 1w during the assessment
period. Once similar efficacy established, drug requirements will be compared calculating
the ratio of the mean weekly epoetin doses in Group 2w/Group 1w. A range of 0.8 to 1.25 for
the ratio is considered sufficient to define bioequivalence. Equivalence of drug usage in
the two arms will be accepted if the whole 95% CI for this ratio will be within the above
limits.
Lack of difference between group means does not imply similar distribution of treatment
effects within each group. The individual hemoglobin change will be used to assess if
response to treatment was similarly variable in the two arms. The change in Hb will be
calculated for each patient as the difference between the mean Hb during the assessment
period and the mean Hb during the baseline phase.
Current European Best Practice Guidelines and the KDOQI Committee in the USA recommend
preferential subcutaneous (SC) twice- to thrice-weekly epoetin administration. SC route
significantly reduces epoetin requirements and therefore costs, compared to the intravenous
(IV) route. Additionally, there is solid evidence showed once-weekly SC administration of
epoetin beta to be equally efficient and well tolerated in hemodialyzed (HD) patients.
Clinical studies suggest that the effects of epoetin alpha are sustained for more than one
week, enabling less frequent schedules in pre-dialysis chronic kidney disease (CKD)
patients. A recent European multicenter study in peritoneal dialysis (PD) patients confirmed
that once-every-two-weeks SC epoetin beta is efficient and safe in the maintenance phase of
anemia treatment for PD patients11. Thus, the optimum epoetin dosing regimen is still yet to
be determined despite over a decade of clinical use.
All these data also suggest that the pharmacodynamic effects of epoetins could last longer
than their plasma half-lives. The survival half-life of erythrocytes produced after
exogenous epoetin administration is longer than that of erythrocytes produced in the absence
of exogenous stimulation.
Apart of the academic interest, this issue has also direct implications on cost savings and
increased patients’ convenience. Furthermore, less frequent administration would reduce
epidemiological hazards associated with populations at high risk of blood-borne viral
infections such as hepatitis, particularly important in less developed countries, with a
high prevalence of viral hepatitis infections (hepatitis B/C markers prevalences: 15.7%/45%
in Romania versus 3%/13.5% in EuroDOPPS patients). While the potential benefits of less
frequent dosing are clear, the efficacy and safety of such regimens must be fully
investigated before adoption as standard treatment.
The present study investigates for the first time the equivalence of once-weekly versus
once-every-two-weeks SC epoetin beta dosing regimens, in the maintenance phase of anemia
therapy, in stable HD patients. The aim of the study is to assess whether
once-every-other-week SC administration of the same total epoetin beta dose is as effective
and as safe as SC once-weekly dosing.
In order to avoid a carry-over effect of the weekly schedule of epoetin treatment received
prior to randomization, we defined a run-in period (weeks 1-12). Statistical analyses will
be performed for the efficacy parameters determined during the assessment period only. The
average for weeks 13-24 will be obtained by adding all values and dividing the sum by the
number of time points for each patient during this period.
The two treatment schedules will be considered equivalent if the primary efficacy parameters
will be simultaneously similar for both groups and in the predefined range of variation.
Confidence intervals (CIs) will be used to compare groups. Since the target Hb in dialyzed
patients is defined as 11g/dL (110 g/L) by the European Guidelines and as >10 g/dL (100 g/L)
by the National Guidelines, with a recommended upper limit of 13 g/dL (130 g/L), the
efficacy range for Hb in this study was predefined as 10-12 g/dL (100-120 g/L). The two
treatment schedules will be considered to have similar efficacy if the mean Hb in Group 2w
will not differ by more than ±0.5 g/dL (±5 g/L) compared to Group 1w during the assessment
period. Once similar efficacy established, drug requirements will be compared calculating
the ratio of the mean weekly epoetin doses in Group 2w/Group 1w. A range of 0.8 to 1.25 for
the ratio is considered sufficient to define bioequivalence. Equivalence of drug usage in
the two arms will be accepted if the whole 95% CI for this ratio will be within the above
limits.
Lack of difference between group means does not imply similar distribution of treatment
effects within each group. The individual hemoglobin change will be used to assess if
response to treatment was similarly variable in the two arms. The change in Hb will be
calculated for each patient as the difference between the mean Hb during the assessment
period and the mean Hb during the baseline phase. The percentages of patients with target Hb
and not requiring any increase in epoetin dose during the assessment period will be compared
with chi-squared statistic.
The study is designed to detect a difference in Hb between the study groups of at least 0.5
g/dL (5 g/L), with a probability of 95% and a power of 0.9021, assuming a standard deviation
of Hb in the HD population of 1.0 g/dL (10 g/L). A sample size of 85 patients is required in
each arm of the trial. Since the study design includes epoetin doses variations in order to
maintain target hemoglobin, it would have been expected that Hb would be constant and
epoetin dose would vary. Therefore, the power calculations using epoetin doses as the
outcome measure seem to be more appropriate. Considering a standard deviation of 39 IU/kg
per week, a probability of 95% and a power of 90%, a sample size of 70 patients in each arm
is required to detect a ± 20% difference in epoetin dose between groups. Because of an
anticipated drop-out proportion of 15%, a minimum of 100 patients have to be enrolled in
each group to satisfy both Hb and epoetin doses power conditions.
;
Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT02818465 -
Role of the Interaction Between Advanced Glycation End Products and Their Receptor RAGE in the Development and the Progression of the Uremic Vasculopathy of Hemodialyzed Patients
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N/A |