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 AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer AG. 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 bayer.com apply to the contents of this file.

2 Clinical Trial Results Synopsis Study Design Description Study Sponsor: Bayer Healthcare AG Study Number: NCT EudraCT Number: Study Phase: I Official Study Title: A multi-center, randomized, double-blind, placebo-controlled, parallel group study in 60 healthy tubal-ligated women aged 18 to 45 years investigating the pharmacodynamic effects of 5 different doses (0.1 5 mg) BAY after daily oral administration over 84 days Therapeutic Area: Women s Healthcare Test Product Name of Test Product: BAY Name of Active Ingredient: Dose and Mode of Administration: BAY mg, 0.5 mg, 1.0 mg, 2.0 mg and 5.0 mg, oral, 84 consecutive days Reference Therapy/Placebo Reference Therapy: matching placebo Dose and Mode of Administration: N.A. Oral administration, four tablets to be taken daily Duration of Treatment: 84 days Studied period: Date of first subjects first visit: 28 Nov 2011 Date of last subjects last visit: 21 Jan 2013 Premature Study Suspension / Termination: No Substantial Study Protocol Amendments: There are no substantial study protocol amendments. Latest protocol version is integrated protocol Version 2.0, dated 14 Nov 2011 Page 1 of 7

3 Study Centre(s): 6 study centers in 3 countries: 1 center in Belgium, 4 centers in Germany, 1 center in United Kingdom Methodology: Pharmacodynamic: - daily documentation of bleeding intensity (diary) - endometrium biopsies (using Pipelle) - transvaginal ultrasonography (TVU): to measure size of follicle-like structures and endometrial thickness - blood samples for hormones Pharmacokinetic: - determination of plasma concentrations of BAY and its metabolite BAY (M-4) by means of validated liquid chromatography-mass spectrometry / mass spectrometry (LC-MS/MS) methods Safety: - standard screening examination including medical history, physical and gynecological examination - blood / urine laboratory parameters including hematology, clotting status, clinical chemistry, hormones, proteins, bone marker, urine analysis - vital signs (blood pressure, pulse), body weight, electrocardiogram (ECG) - adverse events, concomitant medications Indication/ Main Inclusion Criteria: Healthy female subjects, sterilized by tubal ligation, age: 18 to 45 years, non-smokers or mild smokers (up to 10 cigarettes per day), BMI 18 and 32 kg/m² Study Objectives: Primary: - to investigate effects of BAY on bleeding pattern: nonbleeding rate Evaluation Criteria: Secondary: to assess the - return of menstrual bleeding after treatment - effects of BAY on endometrium (endometrial thickness; biopsy: histology, mrna expression) - effects of BAY on ovarian function (follicle-like structures), hormones (E2, progesterone, LH, FSH) - safety and tolerability - PK / PD relationship of BAY Efficacy: not applicable, no efficacy evaluated Safety: Adverse events (AEs) Blood / urine laboratory parameters (e.g. hematology, clotting status, clinical chemistry, hormones, proteins, bone marker, urinalysis) Physical and gynecological examination Vital signs (blood pressure, pulse) Page 2 of 7

4 Body weight Electrocardiogram (ECG) Pharmacokinetics: For metabolite M-4 (BAY ): Area under the plasma concentration-time curve from time zero to 12 hours post administration (AUC(0-12)), AUC from 0 to last data point (AUC(0-tlast)) above lower limit of quantitation (LLOQ), maximum drug concentration (Cmax), last concentration value above LLOQ (Clast), time to reach maximum drug concentration (tmax), last drug concentration in plasma above LLOQ (tlast), dose normalized Cmax, AUC(0-12), AUC(0-tlast) Pharmacodynamics: Primary variable: non-bleeding rate Return to bleeding, size of follicle-like structures, endometrial thickness, course of hormones (E2, progesterone, FSH, LH), endometrial biopsy results Page 3 of 7

5 Statistical Methods: Safety: Safety variables were summarized by descriptive statistics and frequency counts. Pharmacokinetics: The following statistics were calculated for each of the sampling points: arithmetic mean, standard deviation and coefficient of variation (CV), geometric mean, geometric standard deviation (retransformed standard deviation of the logarithms) and corresponding geometric CV, minimum, median, maximum value and the number of measurements. Pharmacodynamics: The number of subjects with non-bleeding was summarized by dose group using frequency tables. The dose-response of the non-bleeding rate was modeled by a fourparametric sigmoidal Emax function. Applying Bayesian methods, posterior distribution for these model parameters was estimated and point estimates and credible intervals were given. Further, point estimates and credible intervals were calculated for the non-bleeding rate at different doses. Number of Subjects: Planned: approx. 180 subjects to be enrolled; planned to be randomized: 60 subjects; n = 10 / dose group, minimum 48 subjects (n = 8 / dose group) to be evaluable ( per protocol set ) Analyzed: Safety analysis set (SAF): N=73; Pharmacodynamic analysis set: N=69; Per protocol set (PPS): N=67; Pharmacokinetic analysis set (PKS): N=57 Study Results Results Summary Subject Disposition and Baseline Of 163 healthy subjects (sterilized by tubal ligation) screened / enrolled, 73 subjects with a mean age of 39.4 years (range: years) were randomized and treated. Sixty-one (61, 83.6%) out of 73subjects were treated with 0.1 mg, 0.5 mg, 1 mg, 2 mg or 5 mg BAY (12, 12, 13, 12, 12 subjects each group) and 12 subjects (16.4%) received placebo. The 12 subjects included in the 2 mg-group received only BAY tablets; the 49 subjects included in the other 4 verum groups (0.1 mg, 0.5 mg, 1 mg, 5 mg) received BAY and dummy placebo tablets to preserve the blind. Four subjects did not complete the study, 3 subjects (1 mg: 2 subjects, RNR 2 and RNR 59; 5 mg: 1 subject, RNR 54) discontinued the treatment phase prematurely (intake of study medication for 77, 78 or 5 days ), and 1 subject (0.1 mg, RNR 1) did not complete the followup phase as the necessary repetition of endometrial biopsy was missing. All 73 treated subjects were included in the statistical analyses of safety (SAF: N=73), and 69, 67 and 57 subjects had valid data for the analysis of PD (PDS: N=69), PP (PPS=67) and PK (PKS: N=57). Results Summary Safety Page 4 of 7

6 Fatal or other serious treatment-emergent adverse events (TEAEs) were not reported. No subject prematurely discontinued study participation due to a TEAE. In total, 70 (95.9%) out of 73 treated subjects reported at least 1 TEAE. Fifty-eight subjects reported at least 1 TEAE after start of treatment with BAY (95.1% of 61 subjects), and 12 subjects (100% of 12) reported at least 1 TEAE after start of placebo treatment. The most commonly occurring TEAEs under treatment with BAY or placebo affecting 10 or more subjects of the total study population ( 13.7% of 73 subjects) were headache (52.5 BAY vs. 66.7% placebo), nasopharyngitis (36.1 vs. 33.3%), post procedural haemorrhage (i.e. uterine bleeding after endometrial biopsy) (32.8 vs. 41.7%), abdominal pain (21.3 vs. 16.7%), ovarian cyst (i.e. follicle 30 mm, observed during ultrasonography) (16.4 vs. 8.3%), fatigue (14.8 vs. 8.3%), vomiting (11.5 vs. 25.0%), dysmenorrhea (9.8 vs. 33.3%) and back pain (11.4 vs. 8.3%). TEAEs considered study drug-related by the investigator were reported for 39 out of 61 subjects exposed to BAY (any dose) and for 6 out of 12 subjects receiving placebo (63.9% vs. 50.0%). Procedure-related TEAEs were reported for 23 out of 61 subjects exposed to BAY and for 5 out of 12 subjects receiving placebo (37.7% vs. 41.7%). The most commonly occurring drug-related TEAEs affecting 4 or more subjects of the total study population ( 5.4% of 73 subjects) were headache (19.7 % BAY vs. 25.0% placebo), ovarian cyst (i.e. follicle 30 mm, observed during ultrasonography) (11.5% BAY ), fatigue (11.5 vs. 8.3%), abdominal pain (8.2% BAY ). Maximum intensity of TEAEs was either mild (in 16 subjects, 21.9% of total 73), moderate (in 50 subjects, 68.5%) or severe (in 4 subjects, 5.5%). Of the 4 subjects reporting a severe TEAE, 3 subjects (4.9% of 61) were treated with BAY and 1 subject (8.3% of 12) received placebo. Severe TEAES were dysmenorrhea (0.1 mg); gastrointestinal infection (1 mg), vulvovaginal candidiasis and abdominal pain (1 mg) and thirst (placebo). All but 6 TEAEs reported for 3 subjects treated with BAY (uterine cyst, decreased ferritin, hot flush and musculoskeletal pain) and by 1 subject of the placebo group (back pain and intervertebral disc protrusion) had resolved by the end of the study. Increased exposure (plasma levels) of BAY was not associated with an increase in the number or severity of TEAEs. The decreases in prolactin, androstenedione, cortisol and SHBG at the end of the treatment period were assessed as possibly drug related. Bone markers, such as osteocalcin (with 5 mg) and Type I collagen C-telopeptides (with 2 mg and 5 mg) showed a slight tendency toward an increase during treatment with BAY None of the standard laboratory parameters including hematology, clinical chemistry and hemostasis showed clinically relevant changes. No clinically relevant changes in vital signs parameters were observed. QTcB interval increases > msec occurred in single subjects, most often at single time points. Neither frequency nor intensity of these changes was dose-dependent. Results Summary Pharmacokinetics At steady state, plasma concentrations of BAY increased dose-dependently with peak plasma concentrations between 1-3 hours p.a. and similar elimination rates after multiple dosing with 0.1 mg, 0.5 mg, 1 mg, 2 mg and 5 mg. During repeated dosing (12 weeks), mean plasma concentrations of BAY Page 5 of 7

7 obtained from individual samples collected between treatment day 7 and day 84 (PK monitoring) increased dose-dependently in the dose range mg. The metabolite M-4 (BAY ) showed a similar shape of the plasma concentration-time profile as the parent compound (BAY ) with a similar time to reach peak plasma concentrations after administration of multiple increasing doses of BAY (median tmax for M-4: 2 hours after mg and 3 hours after 5 mg BAY ). The mean peak plasma concentration (Cmax) of M-4 increased dose proportionally in the dose range 0.1 and 2 mg and less than dose proportionally with the 5 mg dose. Mean maximum concentrations ranged from µg/l (after 0.5 mg) to 4.22 µg/l (after 5 mg). The coefficient of variation (geom. CV) for Cmax ranged between 16.2% (0.5 mg) to 39.8% (2 mg). The calculated areas under the plasma concentration-time curve until 12 h post administration (AUC(0-12)) for M-4 increased dose-proportionally between 1 and 5 mg with maximum mean values of 29.7 µg h/l after the highest dose of 5 mg. The AUC(0-12) of the 0.1 mg and 0.5 mg dose group could not be evaluated in all subjects due to too many concentrations < LLOQ in some samples. Results Summary Pharmacodynamics BAY caused a marked and dose-dependent reduction in the number of days with bleeding during the treatment period. A non-bleeding rate larger than 60% was reached with 95% confidence at doses 1 mg (lower limit of 90% credible interval is above 60%). At 2 mg of BAY non-bleeding rate reached saturation, with point estimate of 95% and lower 90%- credible interval of 88% at 5 mg of BAY In all subjects with amenorrhea during the treatment period a return of menstrual bleeding was observed within a maximum of 52 days after last intake of BAY (mean time intervals for the 5 doses of BAY ranged between 12.2 and 25.8 days). No suppression of follicular growth was observed during the treatment period. The maximum follicle size was slightly higher after dosages 0.5 mg as compared to placebo. The number of subjects reaching a follicle size > 30 mm was highest after 1 mg (50 %) and lower after the higher dosages (10 25 %). No persistent follicles / ovarian cysts of critical size were observed. During the treatment period, the number of subjects with elevated progesterone values decreased with increasing dosage. Low progesterone values which can be assessed as an indicator for ovulation inhibition were observed in more than 80 % of the subjects receiving either 2 or 5 mg BAY A slight tendency towards decreased serum estradiol levels was observed in the 2 mg and 5 mg groups, however the minimum of the average value did not fall below 40 pg/ml. Mean values for maximum endometrial thickness during treatment with BAY did not show a dose-related response and were comparable to mean values in the placebo group. Endometrial tissue obtained during the pre-treatment cycle biopsy was mostly assessed as proliferative endometrium which is in line with the cycle day the biopsy was taken. During treatment tissue was diagnosed most commonly as secretory endometrium in all treatment groups. The number of biopsies assessed as inactive increased with increasing dosages. At follow-up, frequency and nature of histological results were similar to pre-treatment findings. In addition to the histological assessment (see above) the pathologists documented Page 6 of 7

8 the occurrence of any supplemental observations which describe changes as observed after administration of progesterone-receptor-modulators. In case of any supplemental observation the pathologists noted all that applied in the subcategories: non-physiological secretory patterns, extensive cysts, unusual vessels and other. Assessment of endometrial biopsy tissue at the end of treatment revealed an increased occurrence of supplemental observations such as non-physiological secretory patterns, extensive cysts or unusual vessels in subjects treated with BAY at doses 0.5 mg. The number of supplemental observations was still slightly increased at follow-up as compared to pre-treatment or placebo. However, in the majority of subjects changes had completely disappeared following the first posttreatment bleeding. No treatment-emergent critical endometrial findings occurred. In line with the histological findings BAY exerted strong dose-dependent effects on gene expression in the endometrium which were mainly reversible after treatment had stopped and the first bleeding had resumed. Conclusion(s) Daily oral treatment with BAY for 12 weeks at doses ranging from 0.1 mg to 5 mg per day was safe and well tolerated with no meaningful effects on vital signs, ECG or standard laboratory parameters. BAY caused a marked and dose-dependent reduction in the number of days with bleeding during the treatment period at doses 1 mg BAY Low progesterone values which can be assessed as an indicator for ovulation inhibition were observed during the treatment period in more than 80 % of the subjects receiving either 2 or 5 mg BAY However, even the highest dosage of BAY did not suppress the development of active follicles as concluded from the follicle sizes and the estradiol serum levels observed. A slight tendency towards decreased serum estradiol levels was observed in the 2 mg and 5 mg groups, however the minimum of the average value did not fall below 40 pg/ml. Assessment of endometrial biopsy tissue revealed an increased occurrence of supplemental observations such as non-physiological secretory patterns, extensive cysts or unusual vessels in subjects treated with BAY at doses 0.5 mg. These progesterone receptor modulator associated endometrial changes (PAEC) findings were similar to those previously described for drugs belonging to this substance class. The number of supplemental observations was still slightly increased at follow-up as compared to pre-treatment or placebo. However, in the majority of subjects changes had completely disappeared following the first post-treatment bleeding. No treatment-emergent critical endometrial findings occurred In line with the histological findings BAY exerted strong dose-dependent effects on gene expression in the endometrium which were mainly reversible after treatment had stopped and the first bleeding had resumed Publication(s): none Date Created or Date Last Updated: 10 Dec 2013 Date of Clinical Study Report: 04 Dec 2013 Page 7 of 7