Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.

2 Clinical Trial Results Synopsis Study Sponsor: Bayer Healthcare AG Study Design Description Study Number: EudraCT: Study Phase: Official Study Title: I Single dose escalation study to investigate the pharmacokinetics as well as safety and tolerability of a concomitant administration of nifedipne GITS and candesartan tablets under fasting conditions in healthy male subjects in an open label, non-randomized, sequential design. Therapeutic Area: CV Risk Management Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Test drug 1:Nifedipine gastrointestinal therapeutic system (GITS) (Adalat LA, BAY a1040) Test drug 2: Candesartan (Atacand) Test drug 1:Nifedipine Test drug 2: Candesartan cilexetil Nifedipine:30 mg (Period 1), 60 mg (Period 2 and Period 3), 3 single doses, oral Candesartan cilexetil: 8 mg (Period 1), 16 mg (Period 2), 32 mg (Period 3), 3 single doses, oral Candesartan and nifedipine were administered together as loose combination with 240 ml non-sparkling water in the morning after a fasting period of at least 10 hours. Reference Therapy/Placebo Reference Therapy: Dose and Mode of Administration: Duration of Treatment: 3 single doses of each treatment, coadministration of single doses of nifedipine and candesartan tablets in each of the three study periods Studied period: Date of first subjects first visit: 19 APR 2010 Date of last subjects last visit: 07 JUN 2010 Premature Study Suspension / Termination: Substantial Study Protocol Amendments: No The study was performed according to the final protocol version 2 from 31 MAR Study Centre(s): This study was conducted at a single center in Germany. Methodology: The study was a single oral dose, single-center, sequential dose escalation, non-randomized, open-label study under fasting conditions. The study consisted of 3 treatment periods (1, 2, and 3). The sequence of the treatment periods was fixed, not randomized, and Page 1 of 6

3 Indication/ Main Inclusion Criteria: characterized by increase of dosage in each period. - Treatment period 1: Single oral dose of 30 mg nifedipine GITS and 8 mg candesartan as loose combination (Treatment A) - Treatment period 2: Single oral dose of 60 mg nifedipine GITS and 16 mg candesartan as loose combination (Treatment B) - Treatment period 3: single oral dose of 60 mg nifedipine GITS and 32 mg candesartan as loose combination (Treatment C) Before any study drug administration in each treatment period, subjects were fasted from food for at least 10 hours. Subjects continued fasting until at least 4 hours after study drug administration. The wash-out phase between treatments was 5 days. The blood collection period for pharmacokinetics after administration was 48 h. Afterwards, subjects were discharged from the ward. A safety follow-up visit was performed approximately 7 days after the last administration. Frequent blood pressure (also in sitting and standing position) and heart rate measurements were made following administration of nifedipine / candesartan for the assessment of safety of the compounds. Healthy male volunteers, age years, BMI kg/m², Systolic blood pressure (SBP) 120 and 145 mmhg Study Objectives: Overall:The objective of the study was to investigate the pharmacokinetics as well as safety and tolerability of a concomitant administration of nifedipine GITS and candesartan tablets under fasting conditions in healthy male subjects Primary: Secondary: Evaluation Criteria: Efficacy (Primary): Efficacy (Secondary): Safety: Occurrence of treatment emergent adverse events (AEs), physical examination, vital parameters, orthostatic reaction, ECG findings, laboratory findings Pharmacokinetics: The following pharmacokinetic parameters were calculated for nifedipine and candesartan. Primary target parameters: Cmax/D, AUC/D, Cmax, AUC Secondary parameters: Cmax,norm, AUCnorm, AUC(0-tn), tmax, t1/2, MRT, CL/f Page 2 of 6

4 Statistical Methods: Efficacy (Primary): Efficacy (Secondary): Number of Subjects: Planned: 12 Analysed: 11 Safety: Treatment-emergent AEs were summarized by treatment using MedDRA terms. Quantitative data (hematology, blood chemistry, vital signs, ECG) were described by the following summary statistics: arithmetic mean, standard deviation, median, minimum and maximum. These summary statistics were presented by treatment for the original data as well as for the difference to baseline. Frequency tables were provided for qualitative data. Pharmacokinetics: Pharmacokinetic characteristics (tmax excluded) were summarized by the statistics mentioned above. tmax was described utilizing minimum, maximum and median as well as frequency counts. The pharmacokinetic characteristics AUC/D, Cmax/D, AUCnorm and Cmax,norm were analyzed assuming log-normally distributed data. To investigate dose-proportionality of nifedipine GITS an explorative analysis of variance (ANOVA) including fixed factors treatment and period(treatment) and a random factor subject was performed on the log-transformed values of AUC/D, Cmax/D, AUCnorm and Cmax,norm. Based on these analyses point estimates (LS-Means) and exploratory 90 % confidence intervals for the ratio 60mg / 30mg were calculated by re-transformation of the logarithmic data using the intra-individual standard deviation of the ANOVA. To investigate dose-proportionality of candesartan explorative ANOVAs including a fixed factor treatment and a random factor subject was performed on the log-transformed values of AUC/D, Cmax/D, AUCnorm and Cmax,norm. Based on these analyses point estimates (LSMeans) and exploratory 90 % confidence intervals for the ratios 32mg / 16mg, 16mg /8mg and 32mg / 8mg were calculated by re-transformation of the logarithmic data using the intraindividual standard deviation of the ANOVA. Study Results Results Summary Subject Disposition and Baseline Twelve subjects were screened for inclusion. All 12 subjects were assigned to treatment. One subject dropped out due to withdrawal of his informed consent immediately before the first study drug application and was not replaced. Thus, 11 subjects (mean age 44.5 years, range years) were treated with study drugs as scheduled. All 11 subjects completed the study without major protocol deviations and were included in the analysis of pharmacokinetics and safety. Page 3 of 6

5 Results Summary Efficacy Results Summary Safety 11 subjects of the safety analysis set received study treatments as scheduled, ie, single doses of the combinations 30 mg nifedipine GITS / 8 mg candesartan, 60 mg nifedipine GITS/ 16 mg candesartan and 60 mg nifedipine GITS / 32 mg candesartan. Doses were administered sequentially with a wash-out phase of at least 5 days between treatments. Treatment emergent adverse events occurred in 27% of the subjects after 30 mg nifedipine/8 mg candesartan (1st study period) and in 18% of the subjects after 60 mg nifedipine / 16 mg and 32 mg candesartan (2 nd and 3 rd study period), respectively. Drug related adverse events were photopsia, upper abdominal pain, dry mouth, dizziness and headache. Drug related adverse events were mild and lasted for less than 6 hours. Photopsia was described as 'mild flickering in front of his eyes' and lasted for 6 min. Non-drug related was catheter site pain, which was related to study procedures. Table 1 summarizes the incidences of subjects with treatment-emergent drug-related adverse events. Table 1: Incidence of subjects with treatment-emergent drug-related adverse events (all subjects valid for safety, N=11) Safety laboratory assessments revealed no relevant changes of concern, ie, no elevations of laboratory parameters 1.5 times their upper limit of normal after dosing. All combinations of nifedipine and candesartan lowered blood pressure with an average maximum decrease 8 h after dosing on Day 0d. Systolic blood pressure showed an additional comparable decrease 24 hours after dosing with 60 mg nifedipine / 16 mg candesartan and with 60 mg nifedipine / 32 mg candesartan in the morning on Day 1. Mean changes of blood pressure were similar across treatment groups and clinically not relevant (30 mg nifedipine / 8 mg candesartan: systolic: -12 mmhg / diastolic: -13 mmhg; 60 mg nifedipine / 16 mg candesartan regimen: systolic: -6 mmhg / diastolic: -9 mmhg and 60 mg nifedipine / 32 mg candesartan: systolic: -3 mmhg / diastolic: -8 mmhg). Relatively minor increases of mean heart rate between 6 and 7 BPM around 8 hours after dosing were observed after 60 mg nifedipine / 16 mg candesartan and 60 mg nifedipine / 32 mg candesartan. Orthostatic intolerance was defined as a drop in blood pressure exceeding 30 mmhg. In addition, sitting and standing blood pressure procedure was performed in order to estimate the orthostatic effects of the drug on the cardiovascular system. A relevant decrease of Page 4 of 6

6 systolic blood pressure was observed once 8 hours after dosing with 30 mg nifedipine / 8 mg candesartan (from 144 mmhg to 111 mmhg, = 33 mmhg). The subject reported no clinical signs and symptoms at that time point. The sitting and standing blood pressure procedure was performed without relevant finding for all subjects. ECG assessments were normal at all times during the study. No relevant QTc prolongations beyond 60 msec over baseline or beyond 450 msec overall duration were observed. Results Summary Pharmacokinetics Pharmacokinetic characteristics of nifedipine and candesartan were analyzed using an intraindividual dose escalation design for the dose regimens '30 mg nifedipine / 8 mg candesartan', '60 mg nifedipine / 16 mg candesartan' and '60 mg nifedipine / 32 mg candesartan'. The PK analysis set contained 11 healthy male subjects, who received each combination as a single dose in 3 subsequent study periods. Nifedipine AUC of nifedipine after both 30 and 60 mg was associated with high variability, thus resulting in a wide 90% confidence interval of the AUC/D ratio '60 mg / 30 mg' of (90%, 153%) with an average 17% higher AUC/D after 60 mg than after 30 mg nifedipine. Dose adjusted Cmax/D of nifedipine was 12% higher for the 60 mg than for the 30 mg dose regimens. Median tmax showed considerable variation and was 12 hours after the 30 mg dose and 24 hours after both 60 mg dose regimens. Mean terminal half-life varied between treatments and was around 6 hours after 30 mg nifedipine / 8 mg candesartan and after 60 mg nifedipine / 32 mg candesartan, and 8.5 hours after 60 mg nifedipine / 16 mg candesartan. Table 2 summarizes the pharmacokinetic parameters of nifedipine as geometric means and coefficient of variation as well as range. Table 2: Pharmacokinetic parameters of nifedipine in plasma following a single oral dose of 30 mg nifedipine / 8 mg candesartan, 60 mg nifedipine / 16 mg candesartan and 60 mg nifedipine / 32 mg candesartan, respectively (geometric mean/%cv(range) (all subjects valid for PK, N=11) Candesartan The variability of the pharmacokinetic parameters for candesartan tended to be lower than for nifedipine. Mean AUC/D appeared to indicate dose proportionality for candesartan, which, however, should be considered with caution due to the exploratory character of this study. Page 5 of 6

7 Comparison of mean Cmax/D appeared to indicate dose proportionality for Cmax between the three doses of candesartan. Median tmax did not differ between candesartan doses and ranged between 3 and 5 hours. Terminal half-life (t1/2) was also comparable after each dose and ranged on average between 11.8 to 12.3 hours. Overall, the comparison of dose normalized AUC/D and Cmax/D indicated that dose proportionality may be observed for the free combination of nifedipine GITS and candesartan considering the exploratory nature of this study. Table 3 summarizes the pharmacokinetic parameters of candesartan as geometric means and coefficient of variation as well as range. Table 3: Pharmacokinetic parameters of candesartan in plasma following a single oral dose of 30 mg nifedipine / 8 mg candesartan, 60 mg nifedipine / 16 mg candesartan and 60 mg nifedipine / 32 mg candesartan, respectively (geometric mean/%cv(range) (all subjects valid for PK, N=11) Conclusion(s) Loose combinations of nifedipine GITS and candesartan as a 30 mg nifedipine / 8 mg candesartan, 60 mg nifedipine / 16 mg candesartan and 60 mg nifedipine / 32 mg candesartan regimen were safe and well tolerated. The effect on blood pressure in this young and healthy population was similar across treatment groups and regarded as not clinical relevant. Orthostatic intolerance was not observed during the sitting and standing blood pressure procedure. A decrease of systolic blood pressure of more than 30 mmhg from baseline was seen once 8 hours after the 30 mg nifedipine / 8 mg candesartan combination. The results of this exploratory study indicate that dose proportionality may be shown for both nifedipine and candesartan in a confirmatory study. Publication(s): Date Created or Date Last Updated: None 12 DEC 2012 Date of Clinical Study Report: 17 MAY 2011 Page 6 of 6

8 Appendix to Clinical Study Synopsis of Study Investigational Site List Marketing Authorization Holder in Germany Name Bayer Vital GmbH D Postal Address Leverkusen, Germany Sponsor in Germany (if applicable) Legal Entity Name Postal Address Bayer HealthCare AG D Leverkusen, Germany List of Investigational Sites No Investigator Name Facility Name Street ZIP Code City Country 1 Erich R. Arens, MD Bayer HealthCare AG Aprather Weg Wuppertal Germany Page 1 of 1