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Page 1 BI Trial No.: 1144.3 U09-1 of 4 Title of trial: A Phase I open-label, randomised, single dose, three-way crossover relative bioavailability study of ranitidine hydrochloride (Maximum Strength ZANTAC 150 ) compared to two different 150 mg ranitidine hydrochloride oral disintegrating tablet (ODT) formulations following oral administration in fasting, healthy male volunteers Principal Investigator: Trial sites: Publication (reference): Clinical phase: Objectives: Methodology: No. of subjects: CEDRA Clinical Research, LLC, San Antonio, TX planned: enrolled: 90 entered: 42 I The objective of this study is to establish the relative bioavailability (BA) of two different ranitidine hydrochloride 150 mg ODT formulation in comparison to the current, over the counter (OTC) ranitidine hydrochloride (Maximum Strength ZANTAC 150 ) formulation following oral single dose administration in fasting healthy male volunteers Open-label, randomised, single dose, three-way crossover with a 7-day washout between each treatment period actual: enrolled: 90 entered: 42 Treatment T1/T2/R: Treatment T1/R/T2: Treatment T2/T1/R: Treatment T2/R/T1: Treatment R/T1/T2:
Page 2 BI Trial No.: 1144.3 U09-2 of 4 Treatment R/T2/T1: Diagnosis and main criteria for inclusion: Fasting healthy male subjects, age >18 and <60 years, BMI >18.5 and <29.9 kg/m2 and body weight of >121 lbs (55 kg) Test products: ODT 150 mg Vanilla-Mint (ODT #1) ODT Reduced Mannitol (RM) 150 mg Vanilla-Mint (ODT#2) dose: mode of admin.: batch no.: Reference therapy: dose: mode of admin.: batch no.: Duration of treatment: Criteria for evaluation: Efficacy / clinical pharmacology: Safety: 150 mg Oral B093000129 (ODT #1, bulk lot no.) B093000130 (ODT #2, bulk lot no.) (Maximum Strength ZANTAC 150 ) standard film coated tablets 150 mg Oral (standard film coated tablets) A36292 One day per treatment Primary endpoints: AUC 0- and C max Pharmacokinetics: secondary endpoints: AUC 0-tz, t max, λ z, t 1/2, MRT po, CL/F, V z /F Medical history, physical examination (pulse rate, diastolic and systolic blood pressure, body temperature, body weight and height), 12-lead ECG (baseline), laboratory tests (haematology, clinical chemistry and urinalysis/drug screen ), adverse events and concomitant therapies and global assessment of tolerability (1 = good, 2 = satisfactory, 3 = not satisfactory, 4 = bad)
Page 3 BI Trial No.: 1144.3 U09-3 of 4 Statistical methods: Point estimators (geometric means) of the median intra-subject ratios of AUC 0- and C max and their two-sided 90% confidence intervals (CI) were calculated. SUMMARY CONCLUSIONS: Efficacy / clinical pharmacology results: Safety results: The statistical model was analysis of variance (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. The relative bioavailabilities of the two ODT formulations of ranitidine were assessed on the basis of AUC0- and Cmax exposures. Both formulations were similar except one formulation, ODT#2, had a reduced mannitol level. AUC0- values were generally lower for the ODT#1 and ODT#2 formulations compared to the reference Maximum Strength ZANTAC. Adjusted geometric mean test/reference AUC0- ratios were 86.0% and 85.0% for the ODT#1 and ODT#2 RM formulations, respectively. The 90% confidence intervals of the ratios were within the 80-125% range, so that, based on AUC 0- exposure, the ODT formulations could be considered bioequivalent to the Maximum Strength ZANTAC formulation. C max exposures of the two test ranitidine hydrochloride ODT formulations were generally lower than the exposures from the reference Maximum Strength ZANTAC 150 formulation. The adjusted geometric mean test/reference C max ratios were 82.4 and 82.1 for both the ODT#1 and ODT#2 formulations, respectively. The lower limits of the 90% confidence intervals of the C max test/reference ratios of both test formulations were below 80%, that means the 90% confidence intervals of both ratios were outside the 80-125% range, so that, based on C max exposure, the ODT formulations could not be considered bioequivalent to the Maximum Strength ZANTAC formulation. Tmax and t½ values did not vary among treatments to any great extent. There were no SAEs or AEs related to drug that lead to discontinuation during this trial. Of the 42 patients entered into the trial, a total of 2 subjects experienced 2 AEs of mild intensity. The investigator considered one of the AEs, a post treatment subject with hepatic enzyme increase to be drug related.
Page 4 BI Trial No.: 1144.3 U09-4 of 4 Conclusions: In general, there were no notable findings with respect to the clinical laboratory evaluations, vital signs and ECG recordings. The investigator global assessment of tolerability was assessed as good for all subjects in each treatment period. Overall the single doses of 150 mg ranitidine hydrochloride were well tolerated by all healthy subjects. AUC0- and C max exposures of the two test ranitidine hydrochloride ODT formulations were generally lower than the exposures from the reference Maximum Strength ZANTAC 150 formulation. The lower limits of the 90% confidence intervals of the AUC 0- test/reference ratios of both the original ranitidine hydrochloride ODT formulation and the ranitidine hydrochloride ODT formulation with reduced mannitol were both slightly above 80%, the upper limits were below 125%. Therefore, these formulations could be considered bioequivalent to the Zantac reference by the AUC criterion. However, the lower limits of the 90% confidence intervals of the C max test/reference ratios of both test formulations were below 80%. This indicates that both test ODT formulations were not bioequivalent to the Maximum Strength ZANTAC 150 reference formulation by the C max criterion. Overall, the single doses of 150 mg ranitidine hydrochloride were well tolerated by all healthy subjects.