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Pharma GmbH & Co. KG BI Trial No.: 1160.56 Page 3 13 NOV 06 04 APR 06-19 JUL 06 Title of study: Investigator: Study center(s): Publication (reference): - Clinical phase: Objectives: Methodology: No. of subjects: planned: entered: 66 actual: enrolled: 66 Diagnosis and main criteria for inclusion: Bioequivalence of two different drug product batches of 150 mg of dabigatran etexilate following oral administration in healthy male and female volunteers (double blind, randomised, single-dose, replicate design in a two-treatments, four periods crossover study) PAREXEL International GmbH, Berlin I To establish the bioequivalence of two drug product batches of dabigatran etexilate, one batch containing only polymorph I vs. the other batch containing 17% of dabigatran etexilate polymorph II in addition to polymorph I Double blind, randomised, single-dose, replicate design in a two-treatments, four periods crossover study Healthy male and female volunteers, age 65 and 85 years, BMI range: 18.5 and 32.0 kg/m 2 Test product: drug product batch A (Phase III batch containing 83% polymorph I and 17% polymorph II ) dose: 150 mg mode of admin.: Oral administration after an overnight fast with 240 ml water batch no.: 9050060 Duration of treatment: One day (single dose po) for each treatment Reference therapy: drug product batch B (polymorph I) dose: 150 mg mode of admin.: Oral administration after an overnight fast with 240 mlwater batch no.: 504808
Pharma GmbH & Co. KG BI Trial No.: 1160.56 Page 4 13 NOV 06 04 APR 06-19 JUL 06 Criteria for evaluation: Efficacy: Safety: Statistical methods: Pharmacokinetics: primary endpoints: AUC 0- and C max of total BIBR 953 ZW in plasma secondary endpoints: AUC 0- and C max of free BIBR 953 ZW in plasma, AUC 0-tz, t max, λ z, t 1/2, MRT po, CL/F, V z /F of both analytes Physical examination, vital signs (BP, PR), ECG, laboratory tests, adverse events and tolerability Primary: Scaled Average Bioequivalence approach: One-sided 90% CIs for the square of the intra-subject ratio (as estimated by the geometric mean of the ratio) of each of AUC 0- and C max of total BIBR 953 ZW, divided by the square of the within-subject variability of the reference formulation were calculated to determine whether the CIs are contained in the scaled acceptance range for bioequivalence (80-125% divided by square of the scaling variability of 0.25). Additionally, the corresponding point estimators (geometric means) for the median intra-subject ratios were provided. Secondary: Unscaled Average Bioequivalence approach: Two-sided 90% CIs for the intra-subject ratio (as estimated by the geometric mean of the ratio) of each of AUC 0- and C max of total BIBR 953 ZW will be calculated to determine whether the CIs are contained in the acceptance range of 80-125% for bioequivalence. Additionally, the corresponding point estimators (geometric means) for the median intra-subject ratios were provided. The statistical model was ANOVA on log transformed parameters including effects for "sequence", "subjects nested within sequences", "period" and "treatment". CIs were based on the residual error from ANOVA. Descriptive statistics for all other parameters were calculated. SUMMARY CONCLUSIONS: Efficacy results: After administration of the test and reference formulations of dabigatran etexilate, the arithmetic mean plasma concentration-time profiles of dabigatran were virtually identical. The geometric mean (gmean) maximal plasma concentration (C max ) of total dabigatran after administration of dabigatran etexilate test formulation (83% modification I and 17% modification II) was 104 ng/ml compared to 103 ng/ml observed with the reference formulation (modification I). The corresponding gmean AUC 0- were 1080 and 1070 ng h/ml, respectively.
Pharma GmbH & Co. KG BI Trial No.: 1160.56 Page 5 13 NOV 06 04 APR 06-19 JUL 06 Efficacy results (cont.): The test/reference ratios of total and free AUC 0- and C max were close to 1.0 and their 90% confidence intervals were completely located within the bioequivalence acceptance limits of 80-125%. Thus, average bioequivalence of the test formulation containing a blend of 83% modification I and 17% of the modification II and the reference formulation containing modification I was demonstrated. Results of the average bioequivalence for total dabigatran, based on the ANOVA for replicated design are shown in the table below. PK Test Reference Ratio Two-sided 90% CI Parameter Adj. gmean (gcv [%]) C max (ng/ml) AUC 0- (ng h/ml) 104.6 (55.0) 1090.2 (49.7) Adj. gmean (gcv [%]) 103.9 (63.6) 1075.6 (55.6) Adj. gmean [%] (gse) 100.65 (1.07) 101.36 (1.06) Lower Limit (%) Upper Limit (%) 89.93 112.65 91.62 112.14 With regard to the primary analysis, the test of scaled average bioequivalence, it was shown that the intraindividual within-reference standard deviation of AUC 0- and C max were larger than the pre-specified limit of 0.25. Hence, the limits for the scaled average bioequivalence criteria were widened. Based on two different approaches, a bootstrap procedure and an approximate calculation of the 90% confidence limit of the test/reference ratios of total and free AUC 0- and C max, scaled average bioequivalence was demonstrated. Peak plasma concentrations after administration of the reference and test formulation were attained at median 2 hours with ranges of 1.00-6.00 hours and 1.48-4.02 hours, respectively. The gmean terminal half-life of total dabigatran was 10.7 h for both treatments. Interindividual variability of dabigatran pharmacokinetic parameters was high. The geometric coefficients of variation (gcv%) of the reference and test formulation were 75.2% and 72.1% for AUC 0-. The gcvs for C max were 82.3 % (reference) and 78.8% (test), respectively. In general, higher plasma concentrations were observed in female subjects. For both formulations, AUC 0- and C max in females were about 1.5 fold higher than in male subjects. Gender differences in dabigatran plasma concentrations were in the same order of magnitude as observed in previous trials. The gmean fraction of conjugated dabigatran in male and female subjects for both formulations amounted to 15.9%.
Pharma GmbH & Co. KG BI Trial No.: 1160.56 Page 6 13 NOV 06 04 APR 06-19 JUL 06 Safety results: Conclusions: Eleven subjects reported at least one adverse event, starting during screening in one case and during treatment with 150 mg dabigatran etexilate in eleven cases. All events were of mild or moderate intensity. All subjects had fully recovered. Headache (n=5) was regarded drug related in two of the five cases by the investigator. Nausea, vomiting, haemarthrosis and dysaesthesia (n=1 each) were also regarded drug related by the investigator. Nasopharyngitis, rhinitis and back pain (n=1 each) were not regarded drug related by the investigator. Bioequivalence of two drug product batches of dabigatran etexilate, one batch containing only polymorph I vs. the other batch containing 17% of dabigatran etexilate polymorph II in addition to polymorph I was established. was safe and well tolerated in the given single doses of 150 mg.