Clinical Trial Result Information

Title of Study:
Comparative, monocenter, randomized, single-blind, cross-over study in healthy volunteers comparing local pain after subcutaneous injection of epoetin beta (NeoRecormon®) versus darbepoetin alfa (Aranesp®).

Fast Facts:

Protocol number:	ML18355
Sponsor:	Roche SAS
Company division:	Pharmaceutical
Product name:	NeoRecormon
Generic name:	epoetin beta
Phase of development:	IV
Therapeutic area, approved indication:	Anemia
Date of report:	3/1/2007

Clinical study summary:
This was a comparative, randomized, single-blind, cross-over study comparing local pain experienced after subcutaneous injections of NeoRecormon versus darbepoetin alfa.

Study center(s) :
1 center in France.

Objectives:
Primary: To demonstrate that NeoRecormon (epoetin beta) subcutaneous (SC) injection was less painful than darbepoetin alfa SC injection.
Secondary: To demonstrate that pain due to darbepoetin alfa SC injection in subjects previously treated with NeoRecormon was worse than pain reported in subjects previously treated with placebo injections; to assess local (absence or presence and type of cutaneous reaction at the injection site) and systemic tolerability by adverse events recording.

Methodology:
The study lasted 8 weeks for each subject, including a 2-week screening period, and a 2-week treatment period with 3 consecutive injections each separated by a one-week washout period. Following injection of placebo (to act as a reference and to take into account the great variability of local pain perception among individuals), subjects were randomized to receive either (a) NeoRecormon followed by darbepoetin alfa, or (b) darbepoetin alfa followed by NeoRecormon. After the last injection, subjects were monitored for adverse events for a further 4 weeks.
Pain intensity after SC injection was measured using an ungraduated 10-cm Visual Analogue Scale (VAS, qualitative evaluation with a cursor placed between 0 [no pain] and 10 [maximum pain]) and a 6-categories Verbal Rating Scale (VRS, qualitative evaluation: no pain, minimal, mild/slight, moderate, severe and very severe pain).
Safety was assessed through recording of all adverse events, laboratory safety parameters and vital signs. Local reaction at the injection site was also recorded. If an individual's Hb or hematocrit level increased (HB≥16g/dL for males or ≥15g/dL for females; hematocrit ≥47% for males and ≥42% for females) they were excluded from receiving any further injections.

Number of patients (planned/analyzed):
41 patients were included in this study.

Diagnosis and main criteria for inclusion:
Healthy adult subjects.

Test product, dose and mode of administration or test procedure:
NeoRecormon (epoetin beta) supplied in pre-filled 1 ml syringes containing 6000 IU (0.3mL final volume) with a 27.5 gauge SC separable needle.

Duration of treatment:
3 injections, each separated by 1 week.

Reference therapy, dose and mode of administration or reference procedure:
Aranesp® (darbepoetin alfa) supplied in pre-filled 1 ml syringes containing 30μg (0.3mL final volume) with a 27 gauge SC inserted needle.

Criteria for evaluation (efficacy, safety):
Primary: The primary endpoint was local pain assessed quantitatively and qualitatively immediately after each injection (T0) for both NeoRecormon and darbepoetin alfa.
Secondary: The secondary endpoints were local pain assessed quantitatively and qualitatively one hour after injection (T1) for NeoRecormon compared with darbepoetin alfa and local pain at T0 for NeoRecormon and darbepoetin alfa versus placebo.

Statistical methods:
Determination of sample size: A sample size of 40 patients was calculated (assuming 10% major protocol deviations) as required to detect a significant difference in reported pain based on a previous VAS evaluation with a power of 90% and at an alpha two-sided significance level of 5%.
Analysis Plan: Quantitative variables from the VAS evaluation were compared by paired t-test or paired non-parametric tests according to the type of distribution (normal versus none). The non-parametric tests used were the paired sign test, the Wilcoxon signed rank test, and the Hahn and Mecker test. Category variables from the VAS evaluation were compared by the Chi-square contingency test including all 6 categories (if represented).
An analysis of variance (ANOVA) was performed to test any carry-over effect and to provide least square means (LSMEANS) estimations for the analysis of superiority. In case of non-Gaussian distribution, non-parametric analyses or logarithmic transformation were performed.
A 95% confidence interval of the mean difference was calculated from the LSMEANS values (obtained with ANOVA model). If this Confidence Interval did not contain the 0 value, superiority was concluded.
The per-protocol population (primary population) included all subjects who received at least one dose of study medication and completed the three study periods.

Summary (efficacy, safety, other results):
Pain assessments: When measured by the VAS, subjects experienced significantly less pain at T0 after NeoRecormon SC injection than after darbepoetin alfa SC injection (mean VAS score: 1.2 ± 1.7 versus 2.8 ± 2.4; p<0.0001). The mean VAS score for NeoRecormon was similar to that experienced with placebo injection (1.2 ± 1.7 versus 1.4 ± 2.0; p=non-significant). In contrast, the mean VAS score for darbepoetin alfa was significantly greater than placebo (2.8 ± 2.4 versus 1.4 ± 2.0; p<0.0001). One hour after injection, no significant difference in VAS scores was observed between NeoRecormon, darbepoetin alfa and placebo.
VAS data for NeoRecormon and darbepoetin alfa were corrected by subtraction of basal pain (ie pain experienced on placebo injection). The mean value differences compared with placebo at T0 were -0.2 and 1.4 for NeoRecormon and darbepoetin alfa, respectively, confirming that SC injection of NeoRecormon was significantly less painful than SC injection of darbepoetin alfa (p<0.001; all tests).
Pain evaluation by the VRS also demonstrated that the proportion of subjects experiencing no pain immediately after SC injection was greater with NeoRecormon and placebo SC injection (both 51%) than with darbepoetin alfa SC injection (16%). In addition, only 5% of subjects receiving NeoRecormon reported moderate or severe pain compared with 38% of subjects receiving darbepoetin alfa. A comparison of VRS scores demonstrated that subjects experienced significantly less pain at T0 with NeoRecormon (χ2=17.34; p=0.0002) and placebo (χ2=14.09; p=0.0006) compared with those injected with darbepoetin alfa. In addition, the pain experienced with NeoRecormon was similar to that with placebo (χ2=1.04; p=non-significant).

Safety: No local reaction at the injection site was observed with placebo at either T0 or T1. In general, SC injection of NeoRecormon and darbepoetin alfa was locally well tolerated with only two local adverse events in the 37 patients that completed the study. Following injection with NeoRecormon, one subject experienced a very small hematoma at the injection site at T1. Similarly, following injection of darbepoetin alfa, one subject developed a small hematoma that was noticed immediately (T0) and persisted until one hour later (T1).
Six treatment-emergent AEs were reported by 6 subjects during the study. Only 2 (deltoid hematoma in the darbepoetin alfa group, and headache in the NeoRecormon group) were considered to be related to treatment.
No clinically significant physical or laboratory abnormalities were reported during the study. In general, reported AEs were consistent with those described in the SmPCs of the drugs.

Conclusions:
In healthy volunteers, SC injection of NeoRecormon (epoetin beta) was significantly less painful than SC injection of Aranesp (darbepoetin alfa), and comparable with SC injection of placebo. Aranesp and NeoRecormon administrations were well tolerated.