Clinical Study Synopsis

Transcription

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 16 JUN 2015 BAY / Page: 1 of 8 Date of study report: Clinical study title: Sponsor s study number: NCT number: EudraCT number: Sponsor: Clinical study phase Study sites: Publications: Clinical study period: Study Objectives: 16 Jun 2015 Prospective multicenter non-interventional study on compliance and patient / doctor behavior of VTE prevention in major orthopedic surgery (XA RU) NCT Not Applicable Bayer HealthCare Observational 53 investigational sites enrolled patients in Russia. There were no publications at the moment of this report preparation. Study start date: 1 Oct 2011 End of study date: 2 Jul 2014 Primary objective To describe how in "real life" thromboprophylaxis is carried out after the discharge from a hospital in the patients who undergo elective knee and hip replacement and who receive Xarelto during hospitalization (type of VTE prevention treatment, prescribed dose, and duration of treatment, in case of switching reason for switching). Secondary objectives To describe existence and duration of real-life gap in VTE preventive treatment after discharge from hospital. To describe patients demographics. To describe prescription behaviors of orthopedists (VTE prevention recommended at discharge) To describe AE characteristics (frequency, severity, relation to VTE prevention treatment, AE treatment, AE outcome) Study Design: This was a local, prospective, multicenter, non-interventional, observational study. The orthopedist-traumatologist evaluated the criteria of inclusion and exclusion into observational program, offered participation, explained to the patients the essence of the non-interventional study. Then, after the patient signed the informed consent form, the physician included the patient into the observational program. Patients were followed until the end of venous thromboembolism prevention therapy, in accordance to local routine practice. Physicians consulted Russian labeling information for Xarelto before enrolling patients. Within the framework of observational program 3 visits were planned - one inclusion visit and two follow-up visits. The first follow-up visit was performed before or at the moment of discharge of the patient from the hospital. The second follow-up visit was performed after the completion of thromboprophylaxis; depending on the routine practice it might be either a visit to the clinic or gathering information through a

3 16 JUN 2015 BAY / Page: 2 of 8 telephone contact with the patient. Methodology: This clinical study was a local, prospective, multicenter, noninterventional, observational study (observational program, OP). This observational program included 2293 subjects, and most data were collected for 2281 subjects, including 799 (35%) males and 1482 (65%) females not younger than 18 years undergoing elective hip or knee replacement and treated with Xarelto for venous thromboembolism prevention after the operation in the hospital conditions. At the clinical study baseline a medical examination was performed for all subjects in accordance with local institutional routine practice. Patients were followed up until the end of venous thromboembolism prevention therapy, in accordance to local routine practice. Physicians consulted Russian labeling information for Xarelto before enrolling patients. Within the framework of the observational program 3 visits were planned, including one inclusion visit and two follow-up visits. Inclusion visit contained the following procedures and was performed before the elective knee or hip replacement and after the patient signed the informed consent form: - Demographics data collection. - Clarification of the hip or knee prosthesis resource (Federal program or payment by subjects). - Medical history (clinically significant concomitant or past diseases, surgeries; main disease information, including the elective knee or hip replacement reason; drug intolerabilities; history of blood or its components transfusions). - Physical examination. - Concomitant medications assessment. - History of pre-operational anticoagulants use, including venous thromboembolism prevention and other indications (coronary artery disease etc.). - Clinically significant changes in laboratory parameters (hematology, blood biochemistry, coagulogram). - Clinically significant changes during bilateral ultrasound examination of the veins of lower extremities. The first follow-up visit was conducted before or during discharge from the hospital. For all first follow-up visit procedures a window of no more than +/-1 day from scheduled date was permitted. The following procedures were performed: - Venous thromboembolism prevention post-surgery. - Specification of the types of operation and prosthesis. - Specification of the type of anesthesia. - Determination of the volume of intraoperative bleeding. - Specification of the time of Xarelto administration after the surgery. - Registration of post-surgery complications. - Prescription of venous thromboembolism preventive treatment for the outpatient stage. - Clinically significant changes in laboratory parameters (hematology,

4 16 JUN 2015 BAY / Page: 3 of 8 blood biochemistry, coagulogram). - Clinically significant changes during bilateral ultrasound examination of the veins of lower extremities. - Concomitant medications assessment. - Recommendations concerning non-pharmaceutical venous thromboembolism prevention methods. - Adverse events (AEs) registration. - Assessment of the physician s satisfaction of venous thromboembolism prevention in hospital. - Assessment of the subject s satisfaction of venous thromboembolism prevention in hospital. The second follow-up visit was conducted after the end of venous thromboembolism prophylaxis. According to the local routine practice it might be a clinical visit or a phone contact. The second follow-up visit was planned on the day 14 after the elective knee replacement or on the day 35 after the elective hip replacement (with a permitted window of +/-5 days). The following procedures were performed at the visit: - Registration of the venous thromboembolism prevention medications actually used after discharge from the hospital (name, doses, treatment duration). - In case of thromboprophylaxis discontinuation, reason of the discontinuation. - In case of thromboprophylaxis medication change, reason of the change. - If during the outpatient period the subject was managed by the physician not participating in the observational program: registration of the physician s specialty and his work place (polyclinic, specialized center etc.). - Registration of the date of the first administration of the medication for venous thromboembolism prevention after the discharge from the hospital. - Calculation of the actual duration of venous thromboembolism prophylaxis. - Clinically significant changes in laboratory parameters (hematology, blood biochemistry, coagulogram). - Clinically significant changes during bilateral ultrasound examination of the veins of lower extremities. - Concomitant medications assessment. - Recommendations concerning non-pharmaceutical venous thromboembolism prevention methods. - Adverse events (AEs) registration. - Registration of recommended thromboprophylaxis (if planned). - Assessment of the physician s satisfaction of venous thromboembolism prevention in hospital. - Assessment of the subject s satisfaction of venous thromboembolism prevention in hospital. This observational program did not contain any follow-up after the second follow-up visit.

5 16 JUN 2015 BAY / Page: 4 of 8 In this observational program the follow-up was considered finished after conclusion of all visits, according to the observational program design; this meant conclusion of the thromboprophylaxis according to recommendations of the American College of Chest Physicians (ACCP) and National recommendations on thromboprophylaxis (14 days after elective knee replacement, 35 days after elective hip replacement). If the treating physician decided that longer venous thromboembolism prophylaxis was needed, he/she prescribed it and registered in the frame of observational program. If the treating physician decided that shorter venous thromboembolism prophylaxis was needed, he/she prescribed it and registered in the CRF. Indication Diagnosis, inclusion / exclusion criteria Venous thromboembolism prophylaxis Inclusion criteria - Males and females older than 18 years old. - Elective knee or hip replacement. - Planned prescription of Xarelto for venous thromboembolism prophylaxis. Exclusion criteria - Contraindications for Xarelto, according to the current drug information. - Any medical or non-medical reasons which, in the opinion of the physician, can hamper the subject s participation in the observational program, including potentially low compliance, or impossibility of making the final visit due to distant place of residence of the patient. Test drug Test drug: Rivaroxaban (Xarelto, BAY ) INN: rivaroxaban. Name of active ingredient(s): micronized rivaroxaban. Dose: 10 mg. Route of administration: oral.

6 16 JUN 2015 BAY / Page: 5 of 8 Reference drug Efficacy assessment criteria Duration of treatment: After elective knee replacement: 14 days. After elective hip replacement: 35 days. -Not Applicable All documented laboratory and instrumental investigations strictly met routine clinical practice. As this was a non-interventional study, and only routine analyses or investigations could be registered, the observational program data were entered in CRF only if they were obtained according to routine practice. Assessment included the following: Hospitalization stage: Time of Xarelto administration after the surgery. Total duration of therapy. Time of removal of epidural catheter (if applicable). Type and duration of mechanical thromboprophylaxis, if any. Outpatient stage: Any pauses in thromboprophylaxis, with reason clarifies. Actual duration of thromboprophylaxis. Safety assessment criteria Statistical methods All safety data were analyzed in the safety population. Following safety parameters were analyzed: Number, severity and duration of treatment emergent adverse events (AEs)/serious adverse events (SAEs) in the study groups (based on events entered into the CRF adverse event (AE) page). Detection of adverse events (AEs) and serious adverse events (SAEs) included total number of events, total number of subject with events, number of events related (at least possibly) to investigational product, number of events leading to chemotherapy interruption. Frequency and severity of all adverse events (AEs) and events related to investigational product (at least possibly) were summarized for system organ classes and tabulated along with data of therapy interruption due to adverse events (AEs). General considerations Results were presented for all study population and for selected subgroups. Levels of significance (p) and confidence intervals (CI) were estimated as two-sided, and significance of final conclusions was assessed as two-sided for the level of significance not more than If assumptions for planned analysis were not met as needed, methods were adapted for most adequate analysis. For interval variables, statistics included means, standard deviations, 95% confidence intervals, median, 25 th and 75 th percentiles, minimum and maximum. Normal distribution of general data was checked (published data with references, and Shapiro-Wilk test). For the comparison of continuous variables in related samples first step included assessment of distribution. If normal distribution hypothesis

7 16 JUN 2015 BAY / Page: 6 of 8 was not rejected, the variables were compared using Student test for dependent samples. Test for homogeneity of dispersion in groups was performed in advance using Levene test with the objective of choosing appropriate Student test option. If normal distribution hypothesis was rejected, the variables were compared using Wilcoxon test for dependent samples. For the comparison of continuous variables in non-related samples first step also included assessment of distribution. After that, depending on the results of distribution assessment, Student test or Mann-Whitney test was used. The procedure of test choosing was performed and bases similar as for related samples. For variables of frequency, statistics included absolute frequencies, percentages in a group, 95% confidence intervals for percentage. Interim analysis was not performed. Missing and/or non-valid data Missing efficacy data (presence or absence of symptoms or correspondent scale assessments) were imputed by means of last observation carried forward (LOCF) procedure to exclude a possibility of false-positive bias. Demographic and baseline characteristics were imputed using median or most frequent data in a subgroup stratified by the type of elective surgery. Number of imputed missing data was mentioned in the final report. Early termination Number of patients Number of analyzed patients Substantial protocol changes: Multiplicity of comparisons Methods of statistical analysis involved adjustment for multiplicity. If other statistic methods were needed, an additional Bonferroni adjustment was introduced and explained. AE coding system: MedDRA version 17.0 Not applicable Enrolled: 2293 Efficacy analysis: 2281 of planned 2522 Protocol (version 1.0 from the 24 th of August 2014)/(amendment ХА- 03/version 1.0) from the 4 th of March 2013 introduced the following changes: a. Start date 01 October First patient last visit 31 March 2013 Last patient last visit 20 May 2013 Patient s enrollment duration 18 month Study end date 31 December b. Start date 01 October First patient last visit 30 June 2013

8 16 JUN 2015 BAY / Page: 7 of 8 Subject Disposition and Baseline Last patient last visit 20 August 2013 Patient s enrollment duration 21 month Study end date 31 December Total number of 2293 patients were enrolled, including 804 (35%) males and 1489 (65%) females 19 to 93 years old (mean age 60.08±11.54). Statistical analysis was performed in the following populations: - Safety population: all subjects who received at least one dose of Xarelto after inclusion into this observational program (Visit 1); - Intent-to-treat population, ITT: patients who received Xarelto for venous thromboembolism prevention after elective knee or hip replacement. - Per protocol population, PP: patients who completed the observational program according to the protocol. Efficacy results The mean time of Xarelto administration after the surgery was hours in all cases, hours in hip replacement surgeries, and hours in knee replacement surgeries. Time of removal of epidural catheter was 1.5 days in all cases, 1.36 days in hip replacement surgeries, and 1.65 days in knee replacement surgeries. As for type and duration of mechanical thromboprophylaxis, in most cases it was elastic bandages/socks in 846 cases or 99,5%, elastic bandages + other and others showed low result - in twos everyone or 0.2%. There were several cases of pauses in thromboprophylaxis 0.7 % and Timeframe of administration ended, according to the institutional standards was mentioned as the most abundant reason 0,3 %. The mean time of actual duration of thromboprophylaxis was days in all cases, days in hip replacement surgeries, and days in knee replacement surgeries. Safety results During the study, 52 adverse events (AEs) were registered in 45 patients. There were 19 serious adverse events (SAEs), including death (1), life-threatening event (3), hospitalization (8), disability (1), medically significant event (3). There were 11 adverse events (AEs) related to Xarelto and 22 adverse events (AEs) related to surgery. Interruption or discontinuation of therapy with Xarelto due to adverse events (AEs) took place in 8 patients. Results of clinical examination Clinically significant changes in laboratory parameters Clinically significant changes in ultrasound parameters of lower extremities veins Gender Female Male Frequency % in column Frequency % in column No ,3% ,9% Yes 2 0,1% 2 0,3% Not done 23 1,6% 7 0,9% Total ,0% ,0% No ,8% ,4% Yes 13 0,9% 4 0,5% Not done ,3% ,1% Total ,0% ,0% Conclusion Efficacy of Xarelto was assessed as good or very good at the

9 16 JUN 2015 BAY / Page: 8 of 8 Follow-up Visit 1 in 98.2% subjects. Tolerability of Xarelto was assessed as good or very good in 99% subjects. Easiness of use of Xarelto was assessed as good or very good in 98.6% subjects. The investigational product was recommended for continued therapy in 95.1% subjects. The same parameters were evaluated at the Follow-up Visit 2: efficacy in 97.9% subjects, tolerability 98.8% subjects, easiness 98.4% subjects. After the end of the follow-up period the investigational product was recommended for continued therapy in 12% subjects. General duration of treatment was in average 1 month. Treatment was interrupted in 5% subjects. Early discontinuation of Xarelto with a shift to another antiplatelet medication took place in 6% subjects. Reasons for discontinuation included lack of efficacy (1 case) and an adverse event (AE) related to Xarelto (2 cases).

10 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