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Clinical Trial Results Synopsis Study Sponsor: Study Number: 91798 Study Phase: I Bayer HealthCare AG Study Design Description Official Study Title: Pharmacokinetics of gadobutrol after a single bolus intravenous 0.1 mmol/kg body weight dose of Gadovist injection in healthy elderly and non-elderly men and women. Therapeutic Area: Diagnostic Imaging Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Gadobutrol (Gadovist, BAY86-4875) Gadobutrol Gadobutrol 0.1 mmol/kg body weight, administered IV bolus at a rate of 2 ml/s with a power injector. Reference Therapy/Placebo Reference Therapy: Dose and Mode of Administration: Duration of Treatment: Single intravenous bolus injection[ Studied period: Date of first subjects first visit: 08 AUG 2008 Date of last subjects last visit: 14 JAN 2009 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No None Study Centre(s): This study was conducted at a single center in Germany. Methodology: This was a single-center, open-label, single-dose, single-treatment, parallel-group, non-randomized study in which 32 subjects were enrolled into one of four groups (8 non-elderly male, 8 non-elderly female, 8 elderly male, and 8 elderly female). Blood and urine samples were collected for pharmacokinetic (PK) determinations at specified time-points from 0 to 48 h post dosing. Safety assessments were done 0 h to 72 h post dosing and during the follow-up vist (Day 7 [± 1 day] end of study). Indication/ Main Inclusion Criteria: Indication: Contrast enhancement in magnetic resonance imaging of the central nervous system. Main Inclusion Criteria: Healthy subjects (male/female) aged either 18 45 years or >65 years. Page 1 of 7
Study Objectives: Evaluation Criteria: The exclusion criteria were designed so as to exclude volunteers whose health might be put at risk by participation, or whose participation could jeopardize the result of the study. Overall: To determine safety and pharmacokinetics of gadobutrol after a single bolus intravenous 0.1 mmol/kg body weight dose of Gadovist in a group of healthy young (18 45 years) male and female subjects as well as in elderly ( 65 years) male and female subjects. Efficacy (Primary): Efficacy (Secondary): Safety: AEs, laboratory values, and vital signs including blood pressure, heart rate, body temperature, and respiration rate. Pharmacokinetics: Primary variables in the study were the area under the curve (AUC) for plasma gadobutrol concentration, clearance (CL), CL/kg and half-life of excretion (t1/2). Secondary variables were maximum concentration of gadobutrol (Cmax), AUC up to the last measurement (AUC(0-tlast)), mean residence time (MRT), apparent volumes of distribution during steady state and the terminal phase (Vss and Vz), amounts excreted into urine during the complete sampling period and between given time points (AE,ur and AE,ur(t1 t2)), renal and non-renal clearance values (CLR and CLNR) based on non-compartmental analysis. Additional secondary pharmacokinetic variables were AUC, t1/2 alpha, t1/2 beta, CL, central-compartment distribution volume (Vc), Vss; and MRT based on a two-compartment model. Statistical Methods: Efficacy (Primary): Efficacy (Secondary): Safety: All adverse events were presented in frequency tables for both subject count (number of subjects reporting adverse event) and event count (number of reported adverse events). The frequency tables were based on classified data, and the classification was done according to the Medical Dictionary for Regulatory Activities (MedDRA) coding system. Other safety variables were described according to their type, i.e., frequency counts by category were performed for qualitative variables and descriptive statistics for quantitative variables. Page 2 of 7
Pharmacokinetics: Descriptive statistics were used for the analysis of PK parameters. For the PK parameters AUC and CL, log-normal distributed data was assumed. The logarithms of these parameters were analyzed by analysis of variance (ANOVA) including age, gender, and ageby-gender effects. On the basis of these analyses point estimates (least-squares means) and exploratory 90% confidence intervals for the ratios: elderly males/young males elderly females/young females young females/young males elderly females/elderly males were calculated by re-transformation of the logarithmic data using the intra-individual standard deviation of the ANOVA. Number of Subjects: Similarly, exploratory 90% confidence intervals were calculated for the ratios: elderly (overall)/young (overall) females (overall)/males (overall) The ANOVA was used to assess main effects for gender and age group as well as the age gender interaction. These analyses were performed for the populations PPS (per-protocol set) and FAS (full analysis set). Planned: 8 non-elderly male, 8 non-elderly female, 8 elderly male, 8 elderly female. Analyzed: 8 non-elderly male, 8 non-elderly female, 8 elderly male, 7 elderly female. Study Results Results Summary Subject Disposition and Baseline Ninety-four subjects were screened, of whom 32 were randomized; one of these was withdrawn before treatment due to the presence of an exclusion criterion, and the other 31 received treatment without major deviations from protocol. All these subjects were included in all analysis sets. Table 1 summarizes the age, weight, height, and BMI of subjects at study entry. Table 1: Demographic variables at study entry Page 3 of 7
Results Summary Efficacy Results Summary Safety All subjects were exposed to the standard dose (0.1 mmol/kg body weight) of gadobutrol. There were no serious and no severe adverse events. The most frequent adverse event overall was headache, followed by puncture-site disorders (hematoma, pain). Most adverse events occurred only in isolated cases. Adverse events considered related to the study drug were increased blood pressure (1 subject), headache (5 subjects), and proteinuria (1 subject). To complete safety data with regard to the complex stability of gadobutrol, the determination of urine zinc, copper, and iron in 24-h urine was performed. No increase in urine copper, zinc, and iron after Gadovist relative to baseline was observed in any age or gender group. Neither the pattern of adverse events, nor the clinical laboratory values, nor the measured vital signs raised any concern about the safety of the study treatment. Results Summary Pharmacokinetics Except for AE,UR which is expressed as arithmetic mean with the arithmetic standard deviation and the arithmetic coefficient of variation, all other parameters are expressed as geometric means and the geometric coefficients of variation. In addition, the ranges are given (Tables 2 to 4). Table 2: Primary pharmacokinetic parameters of gadobutrol in plasma (compartment model independent method) Page 4 of 7
Table 3: Secondary pharmacokinetic parameters of gadobutrol in plasma/urine (compartment model independent method) Page 5 of 7
Table 4: Pharmacokinetic parameters of gadobutrol in plasma (compartment model dependent method: 2-compartment model) After intravenous bolus injection of 0.1 mmol/kg Gadovist to non-elderly and elderly subjects, plasma concentrations of gadobutrol decreased rapidly due to instantaneous distribution into the extracellular space and subsequent renal elimination. Urinary excretion was largely complete within 12 hours in all subjects. There were no conspicuous differences between the groups. In all analysis, the ranges of the values obtained for each parameter were consistent with the inclusion criteria (healthy subjects of given age and sex), and the arithmetic means, geometric means, and medians did not differ conspicuously. As primary analysis, an analysis of variance (ANOVA) was performed, investigating the effects of subject's age group and gender as well as of the age-gender interaction on pharmacokinetic parameters AUC and CL. All ANOVA results have to be regarded as purely explorative, since no control of the overall significance level was performed. For AUC and CL, a significant effect (on significance level α=0.05) was observed for subject's age (p<0.0001 for both parameters). Regarding sex, a significant effect of gender (on significance level α=0.05) could only be observed for CL (p=0.0003), but not for AUC (p=0.6806). No significant interaction effect between sex and age group was observed (p=0.2304 for AUC/p=0.1014 for CL). Page 6 of 7
In order to explore the effect of sex on CL more deeply, an ANOVA was performed on body weight normalized clearance (CL/kg) by gender, age group, and their interaction. A significant effect (on significance level α=0.05) was observed only for age, but not for gender or the interaction between age and gender. These results indicate that the effect of gender on (unadjusted) clearance can be accounted for by the difference in body weight between genders and thus by the administered total dose. A dependency between the renal clearance of gadobutrol and creatinine clearance was observed. Conclusion(s) In this study, intravenous bolus injection of a 0.1 mmol/kg body weight Gadovist dose was safe and well tolerated in healthy, young and elderly, males and females. There was no indication of transmetallation in humans. The plasma pharmacokinetics of gadobutrol in healthy, non-elderly and elderly, male and female were characterized by a rapid distribution into the extracellular space and subsequent fast renal excretion. Gender had no significant effect on the pharmacokinetics of gadobutrol in the non-elderly subjects and elderly subjects. There was however a gender effect seen in elderly subjects, showing a slightly higher AUC and lower CL or CL/kg in elderly female. Age had a moderate effect on the pharmacokinetics of gadobutrol in plasma. In healthy elderly male and female plasma clearance was reduced by approximately 25% and 35%, respectively, as compared with non-elderly subjects paralleled by an increase in systemic exposure by 33% (male) and 54% (female) and in the terminal half-life by approximately 33% and 58%, respectively. A complete recovery of the administered dose in urine could be shown in all subjects. Publication(s): Date Created or Date Last Updated: None 22 MAY 2012 Date of Clinical Study Report: 15 JAN 2010 Page 7 of 7
Appendix to Clinical Study Synopsis for study 91798 Investigational Site List Marketing Authorization Holder in Germany 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 Facility Name Street ZIP Code City Country 1 Bayer Schering Pharma AG Bayer Schering Pharma AG Clinical Pharmacology Sellerstrasse 31 13353 Berlin 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 Gadavist Gadovist Gadobutrol BAY86-4875 Other Company Code(s) ZK 135079 Chemical Description Other Product Aliases 10 [(1SR,2RS) 2,3 dihydroxy 1 hydroxymethylpropyl] 1,4,7,10 tetraazacyclododecane 1,4,7 triacetic acid, gadolinium complex Date of last Update/Change: 3 Apr 2012