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Clinical Trial Results Synopsis Study Design Description Study Sponsor: Bayer HealthCare AG Study Number: 15624 NCT01388153 Study Phase: I Official Study Title: Randomized, non-blinded, 3-fold crossover study to investigate the bioequivalence between Glucobay ODT taken without and with water and the Glucobay standard tablet following single oral dosing in healthy male subjects Therapeutic Area: Diabetes Mellitus (Type 2) Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Glucobay (BAY G5421) orally disintegrating tablet (ODT) Acarbose Dose: 50 mg acarbose ODT (taken without and with water) Mode of Administration: oral Reference Therapy/Placebo Reference Therapy: Acarbose standard tablet Dose and Mode of Administration: Dose: 50 mg acarbose (taken with water) Mode of Administration: oral Duration of Treatment: Single dose each of test and reference therapy. Studied period: Date of first subjects first visit: 22 JUN 2011 Date of last subjects last visit: 31 AUG 2011 Premature Study Suspension / Termination: No Substantial Study Protocol Amendment no. 1 (dated 01 JUN 2011) specified a change in the Amendments: primary variables. For statistical reasons primary variables were changed from Cmax, AUC(0-4) for blood glucose to RatioCmax and RatioAUC for blood glucose. Study Centre(s): The study was conducted at a single center in Germany. Methodology: The study consisted of an ambulant screening visit, 3 in-house treatment periods and an ambulant follow-up visit. The total duration of the study was approximately 7 weeks. The 3 treatments (acarbose ODT with water, acarbose ODT without water, and acarbose standard tablet) were administered in the 3 treatment periods. Each study period consisted of 2 treatment days. On Day 0, a sucrose load test was conducted by administration of 75 g sucrose dissolved in 225 ml water. Blood glucose and serum insulin were determined during the following 4 hours. On Day 1, the sucrose load test was repeated with a simultaneous administration of the respective study medication and PD blood sampling done during the following 4 hours. The study medication was administered on Day 1 exactly 10 minutes (± 1 minute) before the intake of the sucrose solution. The treatment periods were separated by washout periods of at least 5 days. Page 1 of 5
Indication/ Main Inclusion Criteria: Study Objectives: Indication: Diabetes Main Inclusion Criteria: Healthy male White subjects aged 18 to 45 years with a body mass index (BMI) between 18 and 28 kg/m 2 (inclusive). Primary: The primary objective of this study was to establish the bioequivalence between acarbose ODT 50 mg and acarbose 50 mg standard tablet. Evaluation Criteria: Secondary: The secondary objective was to compare the safety and tolerability of acarbose ODT and of acarbose standard tablet in healthy male subjects. Efficacy (Primary): Efficacy (Secondary): Pharmacodynamics: Primary parameters: Difference of postprandial maximum concentration (Cmax) of blood glucose following sucrose load without (Day 0) and with Glucobay (Day 1) [RatioCmax for blood glucose] (where RatioCmax = Cmax,day1/Cmax,day0) Difference of postprandial Area under curve from 0 to 4 hours (AUC(0-4)) of blood glucose following sucrose load without (Day 0) and with Glucobay (Day 1) [RatioAUC for blood glucose] (where RatioAUC = AUC(0-4)day1/AUC(0-4)day0) Secondary parameters: Time to reach maximum drug concentration in plasma after single dose (tmax) of blood glucose following sucrose load without (Day 0) and with Glucobay (Day 1) [tmax for blood glucose] Difference of postprandial Cmax of serum insulin following sucrose load without (Day 0) and with Glucobay (Day 1) [ Cmax for serum insulin] (where Cmax = Cmax,day1 Cmax,day0) Difference of postprandial AUC(0-4) of serum insulin following sucrose load without (Day 0) and with Glucobay (Day 1) [ AUC(0-4) for serum insulin] (where AUC(0-4) = AUC(0-4)day1 AUC(0-4)day0) Tmax of serum insulin following sucrose load without (Day 0) and with Glucobay (Day 1) [tmax for serum insulin] Safety: AEs, clinical chemistry, hematology, urinalysis, physical examination, systolic and diastolic blood pressure, pulse rate, electrocardiogram (ECG) Page 2 of 5
Statistical Methods: Efficacy (Primary): Efficacy (Secondary): Pharmacodynamics: Cmax and AUC(0-4) were determined for Day 0 (i.e., sucrose load without acarbose treatment) as well as for Day 1 (i.e., sucrose load with acarbose treatment). RatioCmax and RatioAUC of blood glucose were the primary target variables for assessing bioequivalence. All of the above parameters were analyzed using descriptive statistics by day of measurement (i.e., Day 0 and Day 1). For the primary analysis, Cmax and AUC(0-4) was assumed to follow a lognormal distribution with parameters µ and σ². In the following sections, the quantity exp(µ) is denoted as "Geometric mean". Thus, RatioCmax and RatioAUC were also assumed to be lognormally distributed. For logarithmized RatioCmax or RatioAUC as dependent variable, the following analysis of variance (ANOVA) model was used: Yijk = ξik+δi+sij+πk+ε ijk, using the following notation: Yijk is the logarithmized PK parameter of interest (RatioCmax or RatioAUC) for subject j with treatment sequence i at period k. ξik is the expectation of the logarithmized PK parameter of interest (RatioCmax or RatioAUC) for the treatment given in sequence i at period k (i.e., either test or reference treatment). δi is the fixed sequence effect of sequence i. sij is the random subject effect for subject j within treatment sequence i, which is distributed normally with expectation 0 and variance σ 2 B. πk is the fixed period effect at period k, εijk is a random error distributed independently and identically as N(0;σ 2 ). Based on this model, 90%-confidence interval (CI) was calculated for ξtest - ξ Reference, where ξ denotes the expectation of the logarithmized PK parameter of interest (RatioCmax or RatioAUC) for test, respective reference treatment. Page 3 of 5
If the resulting 90% confidence interval of RatioCmax and RatioAUC of blood glucose laid within the acceptance limits of 0.8 to 1.25, the bioequivalence for acarbose was considered as established. Additionally, 90% confidence intervals of Cmax and AUC(0-4) of blood glucose were constructed for each treatment, assuming an approximate normal distribution for Cmax and AUC(0-4). Safety: Safety data were analyzed descriptively according to the respective type of the data: Number of observations, arithmetic mean, standard deviation, minimum, median, and maximum were calculated for continuous variables. Frequency tables with number of observations and percentages were used to summarize categorical variables. Number of Subjects: Planned: 33 Analyzed: 33 Study Results Results Summary Subject Disposition and Baseline Thirty-three subjects were enrolled, randomized, and valid for safety evaluation. Of these, 32 subjects completed the study and were valid for PD evaluation. One subject dropped out during the second period because of an AE. Medical history findings were reported in 33.3% of subjects. The most common medical history findings were seasonal allergy (3 subjects), drug hypersensitivity (2 subjects), and vasoligation (2 subjects). All other medical history findings occurred only in one subject each. Four subjects (12.1%) used concomitant medications, 2 of them used ibuprofen and 2 of them used paracetamol, each to treat headache. The 33 subjects enrolled in the study were Caucasians with a mean age of 32.8 years (range 18 to 45 years) and a mean BMI of 25.1 kg/m 2 (range 19.3 to 28.1 kg/m 2 ). Results Summary Efficacy Results Summary Pharmacodynamics The geometric least squares mean (LS-Mean) of RatioCmax was 1.0234 (for acarbose ODT taken without water versus the acarbose standard tablet = treatment A versus treatment C) and 1.0638 (for acarbose ODT taken with water versus the acarbose standard tablet = treatment B versus treatment C), respectively. The geometric LS-Means for the corresponding RatioAUC were 0.9899 for acarbose ODT taken without water and 1.0050 for acarbose ODT taken with water, respectively. For both variables, the 90% confidence intervals for the ratios A/C and B/C were within the acceptance range for bioequivalence of 0.8-1.25. Thus, bioequivalence between acarbose ODT and acarbose standard tablet was established. In addition to reducing the rise in blood glucose to a similar degree, all three acarbose treatments were similarly effective in reducing Cmax and to a lower extent AUC for insulin in serum following an oral sucrose load. Page 4 of 5
Results Summary Safety Of the 33 subjects enrolled in the study, one subject was withdrawn due to the AE of tendon rupture, because his right forearm was put in cast. In total, 69.7% of subjects had at least one treatment-emergent AE. The most common treatment-emergent AEs were diarrhoea, abdominal pain, headache, flatulence, and blood creatine phosphokinase increased. In 6 subjects, AEs were considered as related to study drug. These AEs were flatulence, nausea, and abdominal pain. Treatment-emergent AEs were less common after acarbose ODT treatment (in 21.9% of subject), than after treatment with acarbose ODT taken with water (42.4% of subjects) or treatment with acarbose standard tablet taken with water (39.4% of subjects). Serious AEs did not occur during the study and all AEs resolved. The worst intensity of an AE was mild in 39.4% of subjects and moderate in 30.3% of subjects. Severe AEs did not occur. All mean values in laboratory parameters were within the normal ranges. The most pronounced increase was seen for mean triglycerides. Increases in laboratory parameters were reversible during the wash-out periods, i.e., mean baseline values for each period were in a similar range, and the follow-up value was generally similar to the screening value. Individual marked laboratory abnormalities were observed in several parameters, particularly for creatine kinase. Marked laboratory abnormalities were generally transient. Adverse events of laboratory abnormalities were rare and resolved. There were no relevant changes from baseline in mean systolic blood pressure, mean diastolic blood pressure, mean heart rate, or mean arterial pressure. The most frequent ECG abnormalities were nonspecific intraventricular conduction delay (frequency range over time 18.8% to 39.4%) and incomplete right bundle branch block (frequency range over time 12.1% to 15.2%). All of these events were judged as not clinically relevant by the investigator. There was no relevant increase in the number of subjects with abnormal ECGs at any time during the study. Three subjects had QT corrected according to Bazett or QT corrected according to Fridericia (QTcB- or QTcF)-intervals >450-480 in the study; QT interval corrected for heart rate (QTc-intervals) above 480 ms were not reported. Ten subjects had an increase in QTcB >30-60 ms. One subject had an increase in QTcF >30-60 ms and an increase in QTcB >60 ms, each at the final examination. This was the only ECG finding judged as clinically relevant by the investigator. The respective AE resolved one day after it had started and was judged as not related to study drug. Conclusion(s) In this study bioequivalence between acarbose ODT 50 mg and acarbose 50 mg standard tablet was established. This study also demonstrated that acarbose ODT taken with or without water and acarbose standard tablet taken with water were both safe and well tolerated. Date Created or Date Last Updated: Publication(s): None 03 MAY 2012 Date of Clinical Study Report: 31 JAN 2012 Page 5 of 5
Marketing Authorization Holder in Germany Appendix to Clinical Study Synopsis for study 15624 Investigational Site List Name Bayer Vital GmbH Postal Address D-51368 Leverkusen, Germany Sponsor in Germany Legal Entity Name Bayer HealthCare AG Postal Address D-51368 Leverkusen, Germany List of Investigational Sites No Investigator Name Facility Name Street ZIP Code City Country 1 Tamara Papusha CRS Clinical-Research- Services Monchengladbach GmbH Hindenburgstrasse 304-306 41061 Monchengladbach Germany Page 1 of 1
Appendix to Clinical Study Synopsis Product Identification Information Product Type US Brand/Trade Name(s) Brand/Trade Name(s) ex-us Generic Name Main Product Company Code Drug Precose GLUCOR, GLUMIDA, ASUCROSE,GLUCOBAY, PREVOGIL,GLICOBASE, PRANDASE, Acarbose BAYG5421 Other Company Code(s) Chemical Description Other Product Aliases O-4,6-dideoxy- 4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)-2-cyclohexen-1-yl]amino]- -Dglucopyranosyl-(1 4)-O- -D-glucopyranosyl-(1 4)-Dglucose Date of last Update/Change: 27 Jul 2011