GSK Medicine: Study Number: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment:

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK Study Number: APP Title: An open label, balanced, randomized, three-treatment, three-period, six-sequence, crossover, single dose, comparative bioavailability pilot study of two test formulations of fixed dose combination capsules of acetylsalicylic acid (ASA) and pantoprazole (Each capsule contains ASA 100 mg and pantoprazole 20 mg) manufactured by Piramal Healthcare Limited, India for GSK comparing with Aspirin Protect 100 mg tablets (Each tablet contains ASA 100 mg) manufactured by Bayer vital GmbH, Leverkusen, Germany and Protium 20 mg gastro-resistant tablets (Each gastro-resistant tablet contains 20 mg of pantoprazole (as sodium sesquihydrate)) marketing authorisation holder Nycomed GmbH, Byk-Gulden-Straβe 2, D-78467, Konstanz, Germany in healthy, adult, human subjects, under fed conditions. Rationale: The oral doses proposed for the two drugs within the fixed-dose combinations (FDCs), namely, 100 mg acetylsalicylic acid and 20 mg pantoprazole, are each approved dosages for the drugs and are strengths at which patients are already taking these two medicines individually. The rationale for this pilot study was to determine the relative bioavailability of two FDC formulations of acetylsalicylic acid-pantoprazole compared to the two reference products taken simultaneously as separate tablets under fed conditions. Phase: 1 Study Period: 16 May July 2013 Study Design: This was a single centre, open label, balanced, randomized, three-treatment, three-period, sixsequence, cross-over, single dose, comparative bioavailability pilot study under fed conditions. Each subject was to participate in all three treatment periods. The study consisted of a screening period, 3 treatment periods, separated by a washout period of 7 days between each drug administration to ensure that acetylsalicylic acid and pantoprazole were effectively eliminated, followed by an individualized follow-up period 24 hours post-dose after treatment period 3. For each analyte, PK samples were collected at the following time points: : pre-dose, 0.17, 0.33, 0.50, 0.67, 0.83, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 10 hours post dose; pantoprazole: pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 24 hours post dose. Centres: Piramal Clinical Research (PCR), Piramal Healthcare Limited, 4th Floor, Mirrakamshetty Mall, Ramanthapur, R.R. District, Hyderabad, Andhra Pradesh , India. Indication: Ulcers, Duodenal and Gastric Treatment: Subjects were to receive the following 3 investigational products, administered orally in accordance with the randomisation schedule: Reference (R): Aspirin Protect 100 mg tablets (each enteric coated tablet contained acetylsalicylic acid 100 mg) manufactured by Bayer vital GmbH, Leverkusen, Germany. And, Protium 20 mg gastro-resistant tablets (each gastro-resistant tablet contained 20 mg of pantoprazole (as sodium sesquihydrate)); marketing authorisation holder Nycomed GmbH, Byk-Gulden-Straβe 2, D-78467, Konstanz, Germany. Test (T1): Fixed dose combination capsule of acetylsalicylic acid and pantoprazole (Each capsule contained acetylsalicylic acid 100 mg and pantoprazole 20 mg) manufactured by Piramal Healthcare Limited, India for GSK. T1 was a fixed dose combination of an enteric coated acetylsalicylic acid tablet / enteric coated pantoprazole pellets in a capsule. Test (T2): Fixed dose combination capsule of acetylsalicylic acid and pantoprazole (Each capsule contained acetylsalicylic acid 100 mg and pantoprazole 20 mg) manufactured by Piramal Healthcare Limited, India for GSK. T2 was a fixed dose combination of an enteric-coated acetylsalicylic acid tablet / enteric coated pantoprazole tablet in a capsule. Note: T1 and T2 were two different and separate dosage formulations, but the enteric coated acetylsalicylic acid tablet formulation was common to T1 and T2. 1

2 Objectives: A pilot comparative bioavailability study to assess intra- and inter-subject variability, optimize sample collection intervals and to determine the power requirements for a pivotal bioequivalence study. To compare the single oral dose bioavailability of two test products of fixed dose combination capsule of acetylsalicylic acid (ASA) and pantoprazole (each capsule contained ASA 100 mg and pantoprazole 20 mg) manufactured by Piramal Healthcare Limited, India for GSK, with that of reference product, Aspirin Protect 100 mg tablets (each tablet contained ASA 100 mg) manufactured by Bayer vital GmbH, Leverkusen, Germany and Protium 20 mg gastro-resistant tablets (each gastro-resistant tablet contained 20 mg of pantoprazole (as sodium sesquihydrate)) marketing authorisation holder Nycomed GmbH, Byk-Gulden-Straβe 2, D-78467, Konstanz, Germany in healthy, adult, human subjects, under fed conditions. To monitor the tolerability of combined administration of acetylsalicylic acid 100 mg and pantoprazole 20 mg in the subjects participating in this study. Statistical Methods: This study was designed to estimate the bioavailability of two test formulations of fixed dose combination capsules of acetylsalicylic acid and pantoprazole (Each capsule contains acetylsalicylic acid 100 mg and pantoprazole 20 mg) relative to Aspirin Protect 100 mg tablets (Each tablet contains acetylsalicylic acid100 mg) and Protium 20 mg gastro-resistant tablets (Each gastro-resistant tablet contains 20 mg of pantoprazole (as sodium sesquihydrate)). No formal hypothesis was tested. For each primary pharmacokinetic endpoint (i.e.,,, AUC(0- )), point estimates and corresponding 90% confidence intervals were constructed for the ratio of the geometric means of the test treatments to the geometric mean of the reference treatment, (µt1/µr and µt2/µr). Concentrations of acetylsalicylic acid and pantoprazole in plasma were summarised by treatment group and nominal time. Standard summary statistics were calculated (i.e. mean, standard deviation, median, minimum and maximum). Pharmacokinetic parameters were calculated by standard non-compartmental analysis according to PCR s working practices and using Phoenix WinNonlin 6.3. All calculations of non-compartmental parameters were based on actual sampling times. Separate linear mixed effect models were used to model the loge transformed,, and AUC(0- ) for acetylsalicylic acid and pantoprazole respectively as functions of sequence, treatment and period, as fixed effects, and subject nested within sequence as a random effect. Distributional assumptions underlying the statistical analyses were assessed by visual inspection of residual plots. Normality was examined by normal probability plots, while homogeneity of variance was assessed by plotting the residuals against the predicted values for the model. Point estimates and 90% confidence intervals for ratios (T1/R) and (T2/R) were calculated for, AUC (0-t) and AUC (0- ) from the linear mixed effects models. The inter- and intra-subject variability for each of the pharmacokinetic parameters were reported in terms of the coefficient of variation (C.V.). The following formulae were used: Intra-subject CV (%): 100*(e Residual -1) ½ Inter-subject CV (%): 100*(e Subject(sequence) -1) ½ Where, Residual and Subject(sequence) are the intra- and inter-subject variability estimates respectively from the mixed effects model. The estimates of the variability and T/R ratios will be used to calculate the sample size for a pivotal bioequivalence study for power in the range of 80% to 95%. Safety data were summarized using descriptive statistics. All Subjects Population Any subject enrolled into the study who received at least one dose of study medication was included in the All Subjects Population. This population was used for the study population and safety displays. Pharmacokinetic (PK) and Statistical Analysis Population The subjects in the All Subjects population who completed at least two of the three periods and received at least one of the test product (T1 or T2) and reference product (R) were included in the pharmacokinetic and statistical analysis population. 2

3 All analyses were based on actual treatment each subject received. Study Population: Healthy male or female subjects aged between years inclusive; absence of significant disease or clinically significant abnormal laboratory values on laboratory evaluations; normal 12-lead ECG and chest x- ray, non smoker, body mass index (BMI), capable of giving written informed consent, which included compliance with the requirements and restrictions listed in the consent form. A female subject was eligible to participate if she was of non-childbearing potential or if of child-bearing potential agreed to use one of the contraception methods specified in the protocol. Total Number of Subjects: 24 Planned, N 24 Randomised, N 24 Completed, n (%) 22 (92) Total Number Subjects Withdrawn, N (%) 2 (8) Withdrawn due to Adverse Events n (%) 0 Withdrawn due to Lack of Efficacy n (%) 0 Withdrawn for other reasons n (%) 2 (8) Demographics N (ITT) 24 Females: Males 0:24 Mean Age, years (SD) 28.7 (4.67) Race, n (%) Not captured Primary Efficacy Results: Derived Primary Plasma Pharmacokinetic Parameters for and Parameter (units) Statistic A: Reference B: T1 C: T2 Gmean (CVb%) (77.92) (91.90) (74.88) tmax (h) t½ (h) tmax (h) t½ (h) Gmean (CVb%) (89.62) (82.17) (83.98) n Gmean (CVb%) (n/a) n/a (7.44) n median (range) 6.00 ( ) 6.00 ( ) 7.00 ( ) n Gmean (CVb%) 0.49 (n/a) n/a 0.55 (9.02) Gmean (CVb%) (33.22) (43.40) (43.78) Gmean (CVb%) (72.93) (73.00) (76.40) n Gmean (CVb%) (81.67) (84.21) (83.41) median (range) 6.00 ( ) 5.50 ( ) 6.00 ( ) n Gmean (CVb%) 2.48 (92.44) 2.89 (78.11) 2.43 (90.30) Gmean = geometric mean. CVb% =100*sqrt[exp(SD**2)-1]. N = Number of subjects n = Number of results available for analysis A = B = FDC Treatment 1 (T1) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as pellets. C = FDC Treatment 2 (T2) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as a tablet. 3

4 Summary of Statistical Analysis of Loge Transformed Primary Plasma Pharmacokinetic Parameters for T1 vs. R N Test (T1), Geometric LSmean 1 Ratio Parameter Reference Test (T1) Reference (R) (T1/R) 90% CI %CVw (0.67, 1.58) (0.72, 1.83) n/a n/a n/a n/a (0.38, 0.51) (0.62, 0.77) (0.63, 0.79) FDC Treatment 1 (T1) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as pellets. 1 LSmean, least squares mean N = Number of results available for analysis n/a = not applicable Summary of Statistical Analysis of Loge Transformed Primary Plasma Pharmacokinetic Parameters for T2 vs. R N Test (T2), Geometric LSmean 1 Ratio Parameter Reference Test (T2) Reference (R) (T2/R) 90% CI %CVw (0.81, 1.83) (0.78, 1,90) n/a n/a n/a n/a (0.67, 0.90) (0.76, 0.94) (0.78, 0.97) FDC Treatment 2 (T2) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as a tablet. 1 LSmean, least squares mean N = Number of results available for analysis n/a = not applicable Safety Results: Adverse events (AEs) were to be collected from the start of study treatment until the follow-up contact. Serious adverse events (SAEs) were to be collected over the same time period as stated for AEs. However, any SAEs assessed as related to study participation or related to a GlaxoSmithKline product were to be recorded from the time a subject consented to participate in the study up to and including any follow-up contact. All AEs reported during the study are summarized below: Number (%) of subjects Reference N = 23 T1 N = 22 T2 N = 23 All Adverse Events Subjects with any AE(s), n (%) 0 5 (23) 3 (13) Gamma-glutamyltransferase increased (4) Alanine aminotransferase increased 0 1 (5) 0 4

5 Blood cholesterol increased (4) Eosinophil count increased 0 3 (14) 1 (4) Lymphocyte count decreased 0 1 (5) 0 Serious Adverse Events (includes both fatal and non-fatal events) Subjects with any SAE FDC Treatment 1 (T1) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as pellets FDC Treatment 2 (T2) = Single Oral Dose of Fixed dose combination capsule of acetylsalicylic acid and pantoprazole; pantoprazole as a tablet. Conclusion: The of acetylsalicylic acid was increased, on average, by 3% in the T1 formulation and 22% in the T2 formulation, compared to the reference formulation. The observed intra-subject variability (CVw) was 86%. The AUC (0-t) of acetylsalicylic acid was increased, on average, by 15% in the T1 formulation and 22% in the T2 formulation, compared to the reference formulation. The observed intra-subject variability (CVw) was 99%. The of pantoprazole was decreased by 56% in the T1 formulation and 22% in the T2 formulation compared to the reference formulation. The observed intra-subject variability (CVw) was 30%. The of pantoprazole was decreased by 31% in the T1 formulation and 15% in the T2 formulation compared to the reference formulation. The observed intra-subject variability (CVw) was 21%. No AEs were reported by the subjects. No SAEs were reported and no subject was withdrawn from the study due to an AE. Eight laboratory abnormalities were reported as clinically significant by the Investigator and reported as possibly treatment related AEs. All subjects were followed up until laboratory abnormalities had resolved. No clinically significant vital signs or ECG abnormalities were reported. 5