Clinical Study Synopsis for Public Disclosure

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1 abcd Clinical Study for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis - which is part of the clinical study report - had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non-approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country. Additional information on this study and the drug concerned may be provided upon request based on s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of. V1.0/2014

2 Page 1 Telmisartan/Amlodipine 1 of 4 Title of trial: Bioequivalence of 40 mg telmisartan/5 mg amlodipine fixed dose combination compared with its monocomponents in healthy male and female volunteers. An open-label, randomised, single-dose, two-period crossover study Principal Investigator: Trial site: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: Not applicable planned: Entered: 84 actual: Entered: 84 Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Reference therapy: dose: mode of admin.: batch no.: I To demonstrate the bioequivalence of 40 mg telmisartan / 5 mg amlodipine fixed dose combination vs. its monocomponents Open-label, randomised, two-sequence, two-period crossover design Healthy male and female volunteers, age 18 and 55 years, body weight 50 kg, BMI range: 18.5 and 29.9 kg/m 2 Telmisartan/amlodipine, fixed dose combination tablet 40 mg telmisartan/5 mg amlodipine Oral administration after an overnight fast of at least 10 hours, with 240 ml water B Telmisartan (Micardis) tablet and amlodipine (US-Norvasc) tablet 40 mg telmisartan/5 mg amlodipine Oral administration after an overnight fast of at least 10 hours, with 240 ml water B (Micardis), B (Norvasc)

3 Page 2 2 of 4 Duration of treatment: Criteria for evaluation: Efficacy / clinical pharmacology: Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Single-dose during each treatment period with sampling for 168 hours followed by a 14 day washout period between treatments Pharmacokinetic parameters of telmisartan and amlodipine primary endpoints: AUC 0- and C max secondary endpoints : AUC 0-tz :, t max, λ z, t 1/2, MRT po, CL/F, V z /F Physical examination, vital signs (BP, PR), 12-lead ECG, laboratory tests, adverse events and overall tolerability Pharmacokinetic parameters of telmisartan and amlodipine were evaluated separately. 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 were calculated to determine whether the CIs were contained in the acceptance range of % for bioequivalence. Additionally, the corresponding point estimators (geometric means) for the median intra-subject ratios were calculated. 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. Pharmacokinetics For amlodipine, 84 data sets (42 male, 42 female) were available for noncompartmental analysis for the fixed dose combination and 83 (42m, 41f) for the individual tablets. For telmisartan, there were 83 such data sets (41m, 42f) for the FDC and 82 (41m, 41f) for the individual tablets. For both telmisartan and amlodipine, geometric mean plasma concentration-time profiles were closely similar between the FDC and individual tablet treatments. GMean telmisartan AUC 0- (intersubject gcv%) was 633 ng h/ml (83%) for the FDC and 652 ng h/ml (79%) for the individual tablets. GMean C max was 62.5 ng/ml (gcv 84%) for FDC and 58.3 ng/ml (66%) for the individual tablets. Median t max was 1.0 h for the FDC and 1.5 h for the individual tablets. Gmean AUC 0- was very similar in males and females, but gmean C max was 39% higher in the females compared to the males.

4 Page 3 3 of 4 GMean amlodipine AUC 0- (intersubject gcv%) was 137 ng h/ml (30%) for the FDC and 138 ng h/ml (30%) for the individual tablets. GMean C max was 2.48 ng/ml (gcv 28%) for FDC and 2.48 ng/ml (26%) for the individual tablets. Median t max (6.0 h) was identical for both treatments. AUC 0- was 12-16% higher and C max was 26-29% higher in the female subjects compared to the males. The geometric mean ratios (FDC to individual tablets), 90% confidence intervals and intrasubject CVs of AUC 0- and C max were: Telmisartan 40 mg ratio (%) 90% CI intrasubject gcv (%) FDC: individual tablets lower limit (%) upper limit (%) AUC C max Amlodipine 5 mg AUC Cmax Safety results: For both telmisartan and amlodipine, the 90% CIs for both AUC 0- and C max were contained in the bioequivalence acceptance range of %. Therefore bioequivalence of the fixed dose combination compared to the individual tablets can be concluded. The high intrasubject variability of telmisartan C max (gcv 40.7%) confirmed previous results. In 49 out of 84 subjects adverse events (AEs) were observed, 46 of them investigator defined drug related AEs. None of the subjects reported AEs at screening, two subjects reported AEs during wash-out and one subject reported AEs in the post-treatment period. After start of FDC or Mic+Nor, AEs were reported by 33 and 31 subjects, respectively. The most frequently reported AEs were in the organ class nervous system disorders, i.e headache. Headache is usually a frequently reported symptom and

5 Page 4 4 of 4 also frequent in phase I studies. The global tolerability was assessed as good for all but 2 subjects with satisfactory tolerability. Conclusions: It is concluded that the fixed dose combination of telmisartan 40 mg and amlodipine 5 mg is bioequivalent to the individual marketed tablets administered together. Telmisartan and amlodipine as monocomponents or as fixed dose combination were well tolerated in single doses of 40 mg and 5 mg, respectively.