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01-Jun-2017 Study no. 16371 Page: 1 of 7 Date of study report: 30 AUG 2016 Study title: XANAP - Xarelto on prevention of stroke and non-central nervous system systemic (CNS) embolism in patients with non-valvular atrial fibrillation (AF) in Asia: A non-interventional study Sponsor s study 16371 (XA1205) number: NCT number: NCT01750788 EudraCT number: Not applicable Sponsor: Bayer Collaborator: Janssen Research & Development, LLC Clinical phase: Phase IV, Non-interventional study Study objectives: To validate the safety profile of rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) in routine clinical practice use in Asia Pacific. To estimate incidences of treatment-emergent safety events like major bleeding, adverse events (AEs), serious AEs (SAEs) and all-cause mortality. Test drug: Rivaroxaban (Xarelto, BAY 59-7939) Name of active Rivaroxaban, BAY 59-7939 ingredient(s): Anatomical Therapeutic Chemical Code: B01AF01 Dose: Xarelto 15 mg film-coated tablets; Xarelto 20 mg film-coated tablets Due to the non-interventional study design, the dose was at the discretion of the attending investigator Route of oral administration: Duration of treatment: Reference drug: Not applicable Indication: Due to the non-interventional study design, the duration of treatment was at the discretion of the attending investigator Prevention of stroke and non-central nervous system systemic embolism in non-valvular atrial fibrillation (NVAF)
01-Jun-2017 Study no. 16371 Page: 2 of 7 Diagnosis and main Consenting female and male patients 18 years of age with a diagnosis of criteria for inclusion: NVAF who start treatment with rivaroxaban for the prevention of stroke or non-cns (Central Nervous System) systemic embolism. Study design: Prospective, international, multi-center, non-interventional, cohort study. Methodology: Patients were followed up for 1 year or until 30 days after end of rivaroxaban therapy in case of earlier permanent discontinuation The visit schedule was at the discretion of the attending investigator, however it was advised to documented patients status every 3 months Outcome measures were collected as adverse events and included major bleeding, all-cause mortality and thromboembolic events Major bleeding events, stroke, death, transient ischemic attack (TIA), non-cns systemic embolism, pulmonary embolism (PE), deep vein thrombosis, atrial thrombus, and myocardial infarction (MI) were centrally adjudicated Haemorrhagic strokes were recorded as both, stroke and intracranial bleeding. Haemorrhagic transformations of ischaemic stroke were also reported as intracranial haemorrhage Study center(s): Publication(s) based on the study (references): 111 investigational sites in 10 countries in the Asia Pacific region: Hong Kong (3), Indonesia (9), Malaysia (5), Philippines (7), South Korea (54), Taiwan (16), Thailand (6), Vietnam (4), Singapore (4), and Pakistan (3) None at the time of study report Study period: Study Start Date: 09 JAN 2013 (FPFV) Study Completion Date: 12 OCT 2015 (LPLV) Early termination: no Number of subjects: Planned: 2300 Analyzed: 2273
01-Jun-2017 Study no. 16371 Page: 3 of 7 Criteria for evaluation All clinical outcomes were collected as adverse events. Primary Outcome Measures: Adjudicated major bleeding events defined as overt bleeding associated with: o o o o a fall in haemoglobin (Hb) of 2 g/dl, or a transfusion of 2 units of packed red blood cells (RBCs) or whole blood, or occurrence at a critical site (intra-cranial, intra-spinal, intraocular, pericardial, intra-articular, intra-muscular with compartment syndrome, retroperitoneal), or death. AEs and SAEs. All-cause mortality. Secondary Outcome Measures: Symptomatic thromboembolic events (stroke, SE, TIA, MI) collected as SAEs or non-serious AEs. Non-major bleeding, collected as SAEs or non-serious AEs and defined as all bleeding events that do not fall in the category of major bleedings. Treatment satisfaction. Healthcare resource, number of healthcare professional visits and hospitalizations due to anticoagulation therapy. AE rates in the different AF risk factor categories. Persistence with rivaroxaban treatment. Reasons for any switch from or interruption of rivaroxaban treatment.
01-Jun-2017 Study no. 16371 Page: 4 of 7 Statistical methods: AEs were coded using MedDRA version 18.1. Statistical analyses were explorative and descriptive. Generally, summary tables were presented as either frequency tables or summary statistics. The main analysis population was the safety analysis set which contained all patients who took at least one dose of rivaroxaban. An AE was considered as treatment-emergent when it started on or after the day of the first dose of rivaroxaban and up to 2 days after the last dose. There were no substantial changes to the study protocol after the start of Substantial data collection. The latest protocol is dated 18 Sep 2013. protocol changes: Subject disposition and baseline Centers were requested to document each patient with NVAF treated to prevent stroke and systemic embolism in an anonymous patient log file regardless of the prescribed treatment. This led to 2910 patients being screened. 2273 patients were enrolled in the study. Demographics: Rivaroxaban (N = 2273) Age (years), mean ± SD 70.5 ± 10.57 Median (Q1 Q3) 72.0 (64.0 78.0) Age 75, n (%) 909 (40) First available Creatinine clearance, n (%) <15 ml/min 15 (0.7) 15 <30 ml/min 55 (2.4) 30 <50 ml/min 301 (13.2) 50 80 ml/min 543 (23.9) >80 ml/min 257 (11.3) Missing 1102 (48.5) Co-morbidities, n (%) Hypertension 1673 (73.6)
01-Jun-2017 Study no. 16371 Page: 5 of 7 Rivaroxaban (N = 2273) Diabetes mellitus 605 (26.6) Prior stroke/non-cns SE/TIA 746 ( 32.8%) Congestive HF 456 ( 20.1%) Prior MI 86 (3.8%) Mean CHADS2 score ± SD 2.3 ± 1.3 Mean CHA2DS2-VASc score ± SD 3.7 ± 1.8 Mean HAS-BLED score ± SD 2.1 ± 1.2 Treatment duration: The median (range) duration of treatment was 350 (1 785) days. The mean (SD) duration of treatment 296 (129) days Outcomes: Treatment-emergent event Events per 100-patient years (95% CI) Major bleeding event* Any Fatal Critical organ bleeding Intracranial Gastrointestinal Haemoglobin decrease 2 g/dl Transfusion of 2 units of packed red blood cells or whole blood 1.5 (1.0, 2.1) 0.2 (0.1, 0.6) 0.8 (0.4, 1.3) 0.7 (0.4, 1.2) 0.5 (0.2, 0.9) 0.1 (0, 0.4) 0.6 (0.3, 1.1) Non-major bleeding event 11.2 (9.7, 12.9) Any AE 50.3 (46.8, 54.0) Any SAE 15.6 (13.8, 17.5) All-cause mortality* 2.0 (1.4, 2.7) Symptomatic thromboembolic event (Stroke, non-cns SE, TIA, MI)* 2.6 (1.9, 3.4)
01-Jun-2017 Study no. 16371 Page: 6 of 7 Stroke/non-CNS SE* 1.9 (1.3, 2.6) Stroke* 1.7 (1.2, 2.5) Non-CNS SE* 0.1 (0.0, 0.4) TIA* 0.2 (0.1, 0.6) MI* 0.5 (0.2, 0.9) *Adjudicated Incidence proportion for haemorrhagic stroke = 0.4%; incidence proportion for ischaemic stroke = 0.9% AE, adverse event; CNS, central nervous system; MI myocardial infarction; SE, systemic embolism; TIA, transient ischaemic attack Treatment satisfaction: At final visit, the majority of patients were satisfied (976 patients, 42.9%) or very satisfied (403 patients, 17.7%). Healthcare resource usage: The majority of patients (1890, 83.2%) did not have any additional physician visits for rivaroxaban therapy. Among patients who did have physician visits, more than half had hospital physician visits (211 patients, 55.1%). AEs in AF risk factor categories: Rates of major bleeding events and stroke/se generally rose with increasing CHADS2 and CHA2DS2-VASc scores. Treatment persistence: 1505 patients (66.2%) remained persistent on treatment at 1 year after study start Reasons for switch of treatment: The most common reasons for a switch during or at end of the study was patient decision in 117 (5.1%) patients, patient convenience in 32 (1.4%) patients, supply issues due to health system in 30 (1.3%) patients or missing in 175 (7.7%) patients. Interruption of treatment: A total of 116 (5.1%) patients had 129 treatment interruptions. The most common reasons for interruption were AEs (bleeding) in 31 (24.0%) patients, surgery in 26 (20.2%) patients, and AEs (excluding bleeding) in 20 (15.5%) patients. Adverse event pattern: AEs were broadly distributed throughout several system organ classes. The review of AEs did not reveal any particular cluster of non-bleeding events, in particular serious and/or unexpected ones. The AEs with highest incidence were dizziness (63 patients, 2.8%), gingival bleeding (46 patients, 2.0%) and dyspnoea (36 patients, 1.6%).
01-Jun-2017 Study no. 16371 Page: 7 of 7 Overall conclusions The incidence rates of and patterns of (serious) adverse events, major and non-major bleeding and thromboembolic events did not indicate a higher than expected safety risk of rivaroxaban therapy in this indication. Death was reported in 1.6% of patients, consistent with the age and underlying conditions of this population. In conclusion, this non-interventional safety study data do not give rise to any new or unexpected safety concerns.
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 BAY59-7939 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