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 09-Jan-2017 Study no Page: 1 of Synopsis Date of report: 28 Nov 2016 Study title: Sponsor s study number: NCT number: A randomized, cross-over study evaluating the PK/ PD relationship after oral doses of 20 mg rivaroxaban once daily and 5 mg apixaban twice daily over 7 days in healthy male subjects Not applicable EudraCT number: Sponsor: Clinical phase: Study objectives: Bayer Phase I Primary objectives: To assess the plasma pharmacokinetics (PK) of rivaroxaban and apixaban after multiple dosing and after discontinuation of both. Secondary objectives: To evaluate the relationship between rivaroxaban and apixaban PK and the pharmacodynamic (PD) parameter of anti-factor Xa (anti-fxa) under steady state conditions To evaluate the relationship between rivaroxaban and apixaban PK and the PD parameters of prothrombin (PT), activated partial thromboplastin time (aptt) and thrombin generation under steady state conditions Test drug: Xarelto (Rivaroxaban, BAY ) Name of active ingredient: Dose: Route of administration: Duration of treatment: Rivaroxaban 20 mg Oral, once daily, together with breakfast 7 days

3 09-Jan-2017 Study no Page: 2 of 11 Reference drug: Name of active ingredient: Dose: Route of administration: Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Study design: Methodology: Study center: Eliquis Apixaban 5 mg Oral, twice daily, together with breakfast / dinner 7 days Not applicable (Clinical Pharmacology Study) Healthy male white subjects age 18 to 55 years (inclusive) with a body mass index above or equal 18.0 kg/m² and below or equal 29.9 kg/m² Randomized, open-label, 2-period, 2-treatment, cross-over study The study was conducted as a randomized, open-label, 2-period, 2-treatment, cross-over study in 24 healthy male subjects with a screening period of 14 days, 2 treatment periods of 11 days each, including 7 days of treatment and 4 days of observation, and a follow-up period with an end-of-trial visit/ follow-up within 7 days after the last treatment with study drug. The following methods were used for determination of PD variables: The individual anti-factor Xa activity was determined ex-vivo using a photometric method according to the recommendations of the manufacturer Diagnostica Stago The PT and a PTT assays used in this study were performed on the STA Compact coagulation analyzer with the use of the STA NEOPLASTINE CI PLUS 10 and the STA C.K. Prest 5 reagents, respectively. TGA was conducted using a validated method following the method of Hemker et al. (calibrated automated thrombogram; all reagents from Thrombinoscope, Maastricht, Netherlands) For assessment of PK parameters, plasma and urine concentrations of rivaroxaban and apixaban were measured using validated methods. For the assessment of safety, adverse events, vital signs, safety laboratory and ECG data were used. One center in Germany

4 09-Jan-2017 Study no Page: 3 of 11 Publication(s) based on the study (references): None at the time of report creation Study period: First subject, first visit: 03 Sep 2015 Last subject, last visit: 13 Nov 2015 End of study: 01 Feb 2016 Early termination Number of subjects: No Planned: Analyzed: 24 subjects 24 subjects Criteria for evaluation Clinical pharmacology Pharmacokinetics: Main 1 PK parameters for rivaroxaban and apixaban after multiple dosing and after discontinuation: 7 th study day (Day 6): Cmax,md*, Cmin,md*, AUCτ*, AUC(0-24) Additional PK parameters: 7 th study day (Day 6): Cav,md*, Ctrough,md*, tmax*, t1/2, CL/F*, Vss/F, Cmax,md/Cmin,md*, PTF* * was 24h in case of rivaroxaban and 12h in case of apixaban. For apixaban, these parameters were derived for both time intervals on Day 6, i.e. the morning dose and the evening dose 1 Pharmacodynamics: Anti-factor Xa (FXa): peak activity, 24h post last dosing of rivaroxaban and 12h post last dosing of apixaban Prothrombin time (PT) and activated partial thromboplastin time (aptt): Emax,md on Day 6 and measurements after last dosing Thrombin generation assay (TGA): Emax,md of AUCE, lag time and peak thrombin generation on Day 6 and measurements after last dosing Safety: Statistical methods 2 : Physical examination, adverse events, blood pressure/ heart rate (supine), electrocardiogram and laboratory examinations To compare PK between treatments, the logarithms of the main 1 Main pharmacokinetic parameters corrected according to Amendment 1

5 09-Jan-2017 Study no Page: 4 of 11 pharmacokinetic characteristics Cmax,md (rivaroxaban, evening dose for apixaban), Cmin,md (rivaroxaban, evening dose for apixaban) and AUC(0-24)md (rivaroxaban, sum of AUC morning dose and evening dose for apixaban), and for the peak-trough ratio (i.e. Cmax,md/Cmin,md for rivaroxaban and evening dose for apixaban) were analyzed using analysis of variance (ANOVA) including sequence, subject (sequence), period, and treatment effects. Based on these analyses, point estimates and 90% confidence intervals for the treatment ratios were calculated by retransformation of the logarithmic results given by the ANOVA. To compare apixaban PK between the dosing intervals, i.e. the morning dose and the evening dose, the differences of the pharmacokinetic characteristics Cmax,md, Cmin,md, AUC,md, tmax,md, and Cmax,md/Cmin,md in terms of morning dose minus evening dose were analyzed using a paired t-test. Based on these analyses, point estimates and 90% confidence intervals for the dosing interval differences were calculated. For pharmacodynamics, characteristics of both drugs, i.e. absolutely baseline adjusted peak activity (maximum), 24h post last dosing of rivaroxaban (i.e. morning dose) and 12h post last dosing of apixaban (i.e. evening dose) in terms of peak activity minus baseline PT, aptt: relatively baseline adjusted Emax,md on day 6 (i.e. the maximum observed value in the time interval 6D00H00M to 7D00H00M for both treatments) and relatively baseline adjusted measurements after last dosing (i.e. at 7D00H00M, 7D12H00M, 8D00H00M, and 8D12H00M) in terms of measurement divided by baseline Thrombin generation: relatively baseline adjusted Emax,md of AUCE, lag time, and peak thrombin generation on day 6 (i.e. the maximum observed value in the time interval 6D00H00M to 7D00H00M for both treatments) and relatively baseline adjusted measurements after last dosing (i.e. at 7D00H00M, 7D12H00M, 8D00H00M, and 8D12H00M) in terms of measurement divided by baseline were analyzed in an explorative manner assuming log-normally distributed data. To compare the pharmacodynamics between the treatments, the logarithms of these pharmacodynamic characteristics were analyzed using ANOVA including sequence, subject(sequence), 2 Plan for statistical analysis of pharmacokinetic data specified according to Amendment 1

6 09-Jan-2017 Study no Page: 5 of 11 period, and treatment effects. Based on these analyses point estimates and 90% confidence intervals for the treatment ratios were calculated by re-transformation of the logarithmic results given by the ANOVA. Substantial protocol changes: Amendment No. 1 was issued forming the integrated protocol Version 2.0, dated 07 SEP 2015 Changes included: revision of primary/main pharmacokinetic parameters with revision of statistical analysis plan, shortening of urine sampling for PK, inclusion of a supine phase on profile day, correction of typos and errors in the list of laboratory parameters. Subject disposition and baseline: 64 healthy male subjects were screened for this study and 24 subjects (age range: years, body mass index range: kg/m²) were randomized to treatment sequences rivaroxaban-apixaban or apixaban-rivaroxaban. All subjects completed the study according to protocol and were included in the analysis sets for safety, PK and PD. Clinical pharmacology evaluation: Pharmacodynamics: For both study drugs a positive correlation was observed between plasma concentrations and calibrated anti-fxa activity with a coefficient of correlation of 0.98 respectively. High correlations were expected, as the anti-fxa assay is intended to reflect the PK and provides a read-out as plasma concentration. The increase of baseline adjusted maximum anti-fxa activity at the profile Day 6 was more pronounced after 20 mg rivaroxaban OD (210 g/l) than after apixaban 5 mg BID (84.9 g/l). Apixaban reached 40.4% of the rivaroxaban effect. 24 hours after the last dose of rivaroxaban and apixaban anti-fxa activity was lower after apixaban (24.4 g/l) compared to rivaroxaban (30.8 g/l). Peak/trough oscillation of the anti-fxa activity time curve over 24 hours was higher after rivaroxaban 20 mg OD than after apixaban 5 mg BID. High correlations were also observed between plasma concentrations of rivaroxaban and the corresponding results for baseline adjusted PT with a coefficient of correlation of The correlation between apixaban plasma concentrations and PT was less pronounced with a coefficient of correlation of Maximum PT prolongation at Day 6 was 66% higher than baseline after rivaroxaban and 14% higher than baseline after apixaban (geometric means) resulting in an apixaban effect which was 68.4% of the corresponding rivaroxaban effect. Measurements 24 h after the last dose of rivaroxaban and apixaban were not relevantly different between the treatments. Those observations underline previously published work, showing a good sensitivity of the PT assay for rivaroxaban, while most available PT reagents (including the one employed in this study, NEOPLASTIN CI PLUS) are not suited to detect apixaban effects with sufficient sensitivity.

7 09-Jan-2017 Study no Page: 6 of 11 Correlations were also high between the plasma concentrations of rivaroxaban and the corresponding results for baseline adjusted aptt with a coefficient of correlation of The corresponding correlation coefficient for apixaban was Maximum aptt prolongation after the morning dose was more pronounced after rivaroxaban 20 mg (43%) than after apixaban 5 mg (16%). The effect after apixaban reached 81.0% of the rivaroxaban effect. On average, aptt prolongation after the apixaban evening dose was not higher than the remaining aptt prolongation generated by the rivaroxaban morning dose. No relevant difference was seen between rivaroxaban and apixaban regarding aptt beyond 12 hours after the first dose on Day 6D00h. However, limitations of the aptt assay for determining effects of apixaban are similar to those described for the PT assay. Major differences between apixaban and rivaroxaban were observed in the thrombin generation assay. The maximum reduction of thrombin generation AUCE was 59.7% from baseline after rivaroxaban and of 38.5% from baseline after apixaban on Day 6 (geometric means). Reduction of AUCE for thrombin generation was less pronounced after apixaban compared to rivaroxaban at 24 hours after last drug administration. Thereafter, i.e. at 36 and 48 hours after last dosing, 24 / 18 subjects treated with rivaroxaban and 18 / 13 subjects treated with apixaban still revealed a reduction. The maximum effect of apixaban on baseline adjusted thrombin generation peak on Day 6 was 87.7% of the rivaroxaban effect and was less sustained than the rivaroxaban effect over 24, 36 and 48 hours after dosing with all subjects treated with rivaroxaban and 21 / 21 / 12 subjects treated with apixaban still revealing a reduction. Baseline adjusted thrombin generation lag time was less affected by apixaban than by rivaroxaban at Day 6 with a maximum effect of apixaban of 60.1% of the rivaroxaban effect. After the last dose of study drugs the effects converged with apixaban showing 70.5%, 89.1% and 93.5% of the rivaroxaban effects at 24, 36 and 48 hours after dosing. Effects similar to those for thrombin generation lag time were observed for time to peak thrombin generation. The effect of apixaban on maximum time to peak thrombin generation on Day 6 was 64.5% of the rivaroxaban effect. At 24, 36 and 48 hours after dosing the effects of apixaban approached rivaroxaban at 63.0%, 81.4% and 90.1% of the rivaroxaban effects. Results of the statistical analysis are provided in Table 2-1Table 2-1.

8 09-Jan-2017 Study no Page: 7 of 11 Table 2-1: Least squares mean ratios of PD-parameters (apixaban / rivaroxaban, 90% confidence intervals), PD analysis set, n=24 Parameter Time LS mean ratio (90% CI) anti-fxamax a (µg/l) Day ( ) Relative PTmax Day ( ) Relative PT 24 h post ( ) 36 h post ( ) 48 h post ( ) Relative apttmax Day ( ) Relative aptt 24 post ( ) 36 h post ( ) 48 h post ( ) TG, maximum reduction in AUCE Day ( ) Relative TG lag timemax Day ( ) Relative TG lag time 24 h post ( ) 36 h post ( ) 48 h post ( ) TG, maximum reduction of peak Day ( ) Relative TG, time to peakmax Day ( ) Relative TG, time to peak 24 h post ( ) 36 h post ( ) 48 h post ( ) 24 h post = 24 h after last dose 36 h post = 36 h after last dose 48 h post = 48 h after last dose TG = thrombin generation a different assays were used for rivaroxaban and apixaban Pharmacokinetics: Geometric mean AUC(0-24)md on the 7 th dosing day (Day 6), as a measure for total daily exposure, was comparable for 5 mg apixaban BID (1860 g*h/l) and 20 mg rivaroxaban OD (1830 g*h/l). Similar average concentrations were obtained on Day 6 for both drugs. As expected, differences between the apixaban 5 mg BID and rivaroxaban 20 mg OD regimens were evident with regard to geometric mean Cmax,md on Day 6 (evening dose for apixaban), which was lower for apixaban at 139/118 g/l for morning and evening dose compared to rivaroxaban OD with 227 g/l (ratio of LS-means apixaban [evening dose] / rivaroxaban: 0.52). Cmin,md on Day 6 was higher after apixaban BID with 35.2/35.0 g/l after morning and evening dose compared to rivaroxaban OD with 14.4 g/l (ratio of LS-means apixaban [evening dose] / rivaroxaban: 2.43). Thus, the Cmax,md/Cmin,md ratio on Day 6 was lower for apixaban morning and evening doses with 3.95/3.38 compared to rivaroxaban OD with 15.8 (ratio of LS-means apixaban [evening dose] / rivaroxaban: 0.21). Morning and evening dose of apixaban differed with respect to Cmax, which was higher following the morning than after the evening dose (mean difference: 20.7 g/l). Cmax/Cmin was also higher for the morning than the evening dose and individual tmax was reached at an earlier time point in the morning compared to the evening.

9 09-Jan-2017 Study no Page: 8 of 11 Table 2-2Table 2-2 and Table 2-3Table 2-3 summarize pharmacokinetic parameters of apixaban and rivaroxaban as geometric means and coefficient of variation as well as range. Results of the statistical analysis are provided in Table 2-4Table 2-4 (apixaban / rivaroxaban) and in Table 2-5Table 2-5 (morning - evening dose of apixaban). Table 2-2: Pharmacokinetic parameters of rivaroxaban (geometric mean / %CV(range)), all subjects valid for PK, n=24 Parameter Unit N 20 mg rivaroxaban OD %PTF % / 11.9 ( ) AUC / AUC(0-24)md µg*h/l / 19.5 ( ) Cav,md µg/l / 19.5 ( ) CL/Fmd L/h / 19.5 ( ) Cmax,md µg/l / 18.2 ( ) Cmax,md/Cmin,md / 41.1 ( ) Cmin,md µg/l / 44.3 ( ) Ctrough,md µg/l / 44.3 ( ) t½,md h / 37.6 ( ) tmax,md a h ( ) Vss/Fmd L / 20.8 ( ) a median (range) b arithmetic mean / SD (range)

10 09-Jan-2017 Study no Page: 9 of 11 Table 2-3: Pharmacokinetic parameters of apixaban (geometric mean / %CV(range)), all subjects valid for PK, n=24 Parameter Unit n 5 mg apixaban BID %PTF morning dose % / 17.1 ( ) %PTF evening dose % / 28.3 ( ) AUC (0-12)md µg*h/l / 22.6 ( ) AUC (12-24)md µg*h/l / 22.3 ( ) AUC(0-24)md µg*h/l / 21.6 ( ) Cav,md morning dose µg/l / 22.6 ( ) Cav,md evening dose µg/l / 22.3 ( ) CL/Fmd morning dose L/h / 22.6 ( ) CL/Fmd evening dose L/h / 22.3 ( ) Cmax,md morning dose µg/l / 19.1 ( ) Cmax,md evening dose µg/l / 21.5 ( ) Cmax,md/Cmin,md morning dose./ / 21.7 ( ) Cmax,md/Cmin,md evening dose./ / 31.0 ( ) Cmin,md morning dose µg/l / 34.0 ( ) Cmin,md evening dose µg/l / 38.8 ( ) Ctrough,md morning dose µg/l / 30.7 ( ) Ctrough,md evening dose µg/l / 32.1 ( ) t½,md h / 45.1 ( ) tmax,md morning dose a h ( ) tmax,md evening dose a h ( ) Vss/Fmd L / 24.0 ( ) a median (range) b arithmetic mean / SD (range) Table 2-4: Least squares mean ratios of PK-parameters (apixaban / rivaroxaban, (90% confidence interval)), all subjects valid for PK, n=24 Parameter LSMean Ratio (90% CI) AUC (0-24)md (0.9601, ) Cmax,md (0.4894, ) Cmin,md (2.0297, ) Cmax,md / Cmin,md (0.1785, )

11 09-Jan-2017 Study no Page: 10 of 11 Table 2-5: Differences between PK-parameters after morning and evening doses of apixaban (morning dose minus evening dose), all subjects valid for PK, n=24 Parameter Unit n Mean SD 90% CI lower limit upper limit AUC,md µg*h/l Cmax,md µg/l Cmin,md µg/l Cmax,md / Cmin,md./ tmax,md h Safety evaluation: Overall exposure over the 2 periods of this study was 70 mg apixaban and 140 mg rivaroxaban. Multiple doses of apixaban and rivaroxaban were well tolerated in the study population of healthy male subjects. Overall, 6 of the 24 subjects (25.0%) experienced at least one treatment emergent AE in this study. No AE was serious or caused premature termination. In 5 subjects events were of mild intensity, in 1 subject of moderate intensity. All events were resolved by the end of the study. No relevant difference with regard to the safety profile was apparent between apixaban and rivaroxaban. No AE was drug- or procedure-related. Non-drug related AEs were reported for 5 subjects after apixaban (20.8%, increased lipase, increased blood pressure with sinus tachycardia, dyspepsia, non-cardiac chest pain and increased CK) and for 2 subjects after rivaroxaban (8.3%, dyspepsia and increased lipase). Vital signs and ECG parameters were not affected by apixaban or rivaroxaban administration. Laboratory investigations showed no clinically significant abnormalities attributable to apixaban or rivaroxaban. Overall conclusions: Safety Rivaroxaban 20 mg OD and apixaban 5 mg BID administered over 7 days were well tolerated in the study population of healthy men. Pharmacokinetics Daily exposure (geometric mean AUC(0-24)md on Day 6) was comparable for 5 mg apixaban BID (1860 g*h/l) and 20 mg rivaroxaban OD (1830 g*h/l), with similar average concentrations for both drugs. Geometric mean Cmax,md on Day 6 was lower for apixaban at 139/118 g/l for morning and evening dose compared to rivaroxaban OD with 227 g/l (ratio of LSmeans apixaban (evening dose)/rivaroxaban: 0.52).

12 09-Jan-2017 Study no Page: 11 of 11 Geometric mean Cmin,md on Day 6 was higher after apixaban BID with 35.2/35.0 g/l after morning and evening dose compared to rivaroxaban OD with 14.4 g/l (ratio of LS-means apixaban (evening dose)/rivaroxaban: 2.43). Thus, Cmax,md/Cmin,md ratio on Day 6 was lower for apixaban morning and evening doses with 3.95/3.38 compared to rivaroxaban OD with 15.8 (ratio of LS-means apixaban (evening dose)/rivaroxaban: 0.21). Morning and evening dose of apixaban differed with respect to Cmax,Cmax/Cmin and tmax. Pharmacodynamics Anti-FXa activity showed a positive correlation to plasma concentrations of apixaban and rivaroxaban with a coefficient of correlation of 0.98, respectively. PT and aptt can be used to detect rivaroxaban at least for the first 12 hours after drug administration, when a sensitive assay is used. In contrast, apixaban does not influence PT and aptt if routine tests are used. As a consequence, baseline adjusted PT / aptt were positively correlated to rivaroxaban and apixaban plasma concentrations with correlation coefficients of 0.97/0.93 and 0.76/0.53. The thrombin generation assay revealed more pronounced reduction of thrombin generation peak and AUCE and more pronounced prolongation of lag time and time to peak thrombin generation after rivaroxaban compared to apixaban. For lag time, higher effects of rivaroxaban in comparison to apixaban were observed up to 36 hours after last dosing and for time to peak thrombin generation up to 48 hours and after last dosing.

13 Marketing Authorization Holder in Germany Name Postal Address Bayer AG D Berlin Deutschland Sponsor in Germany (if applicable) Legal Entity Name Bayer AG Appendix to Clinical Study Synopsis Investigational Site List Postal Address D Leverkusen, Germany List of Investigational Sites No 1 Investigator Name Facility Name Street M J Leidig CRS-Mönchengladbach Hindenburgstraße 306 ZIP Code City Country Mönchengladbach Germany Page 1 of 1

14 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 Xarelto Xarelto rivaroxaban BAY Other Company Code(s) Chemical Description Other Product Aliases IUPAC Name: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2- thiophenecarboxamide Date of last Update/Change: 04 Mar 2013