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STroke secondary prevention with catheter ABLation and EDoxaban for patients with non-valvular atrial fibrillation: STABLED study- Company-led clinical study - Statistical Analysis PlanStatistical analysis manager: Toshiaki Otsuka, Department of Hygiene and Public Health, Nippon Medical School, Center for Clinical Research, Nippon Medical School HospitalVer.1.0 (prepared on January 29, 2018)Table of Contents TOC \o "1-2" \h \z \u 1.Purpose of Statistical Analysis Plan PAGEREF _Toc523388644 \h 62.Definition of Analysis Populations/Sets PAGEREF _Toc523388645 \h 62.1 Analysis set PAGEREF _Toc523388646 \h 62.2 Data handling PAGEREF _Toc523388647 \h 63.General matters regarding analysis PAGEREF _Toc523388648 \h 63.1 Software used for tabulated analysis PAGEREF _Toc523388649 \h 63.2 Significance level PAGEREF _Toc523388650 \h 73.3 Number of display digits PAGEREF _Toc523388651 \h 73.4 Location where statistical analyses are carried out PAGEREF _Toc523388652 \h 74.Statistical methodology details PAGEREF _Toc523388653 \h 74.1 Patient disposition PAGEREF _Toc523388654 \h 74.2 Follow-up status PAGEREF _Toc523388655 \h 74.3 Patient characteristics PAGEREF _Toc523388656 \h 74.4 Primary endpoint PAGEREF _Toc523388657 \h 84.5 Secondary endpoints PAGEREF _Toc523388658 \h 94.5.1 Incident rates of events PAGEREF _Toc523388659 \h 94.5.2 mRS score and NYHA classification at the end of the observation period PAGEREF _Toc523388660 \h 94.5.3 Rate of maintenance of sinus rhythm PAGEREF _Toc523388661 \h 104.5.4 Rate of continuation of edoxaban PAGEREF _Toc523388662 \h 104.5.5 Recurrence rate of ischemic stroke according to the presence or absence of edoxaban discontinuation PAGEREF _Toc523388663 \h 104.6 Safety PAGEREF _Toc523388664 \h 104.6.1 Adverse events, serious adverse events PAGEREF _Toc523388665 \h 104.6.2 Adverse reactions, serious adverse reactions PAGEREF _Toc523388666 \h 104.6.3 Laboratory test values PAGEREF _Toc523388667 \h 104.7 Subgroup analysis PAGEREF _Toc523388668 \h 105.Revising and Fixing the Statistical Analysis Plan PAGEREF _Toc523388669 \h 116.Target sample size PAGEREF _Toc523388670 \h 117.Revision history PAGEREF _Toc523388671 \h 12Summary of Clinical StudyStudy title:STroke secondary prevention with catheter ABLation and EDoxaban for patients with non-valvular atrial fibrillation: STABLED study- Company-led clinical study -Item name: Edoxaban tosilate hydrate (Lixiana? tablets; Daiichi Sankyo Co., Ltd., Tokyo, Japan)Target disease: Patients with non-valvular atrial fibrillation (NVAF) in sub-acute ischemic strokeObjectives: To investigate the efficacy and safety of catheter ablation (CA) with anticoagulant therapy using edoxaban in patients with NVAF and a history of recent ischemic stroke. In addition, the study aims to identify factors that affect the discontinuation of edoxaban with or without CA for NVAF, and to examine the prognosis of patients who discontinue edoxaban.Study design: Interventional, multicenter, randomized, open-label, standard medication therapy-controlled parallel-group comparative studyScheduled study period: January 2018 to December 2022(Enrollment period: January 2018 to December 2019)Target sample size:250 patientsInclusion criteria: [Inclusion criteria]1) Patients aged ≥20 and <80 years (at time of giving informed consent)2) Patients with NVAF3) Patients with a history of a prior ischemic stroke (with local neurological symptoms and imaging findings confirming the infarct area) within 6 months before enrollment4) Patients with a modified Rankin Scale (mRS) ≤3 (i.e. require some assistance in daily living but can walk without help. An assessment of walking ability shall mainly be conducted for walking on level ground, and the use of walking aids (cane, walker) shall not be included in walking assistance)Exclusion criteria: [Exclusion criteria] 1) Patients who have symptomatic paroxysmal atrial fibrillation and are resistant to medication therapy2) Patients with left atrial and left atrial appendage thrombus as confirmed by transthoracic echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) 3) Patients who are bleeding or have a tendency to bleed, who are at high risk of bleeding due to anticoagulation therapy. Or, patients who cannot undergo anticoagulation therapy for other reasons4) Patients who are suffering from severe renal disorder (Ccr <30 mL/min)5) Patients who have previously undergone CA or surgical interventions for NVAF6) Patients who have a treatment history with a left atrial appendage closure device 7) Patients with a left atrial diameter of ≥55 mm on transthoracic echocardiography 8) Patients with an ejection fraction of ≤35% on transthoracic echocardiography 9) If the duration of NVAF is clearly over 10 years 10) Patients who are pregnant or have a possibility of being pregnant 11) Patients who are unlikely to complete the study, e.g. complication with advanced malignant tumors 12) Patients who are currently participating or planning to participate in another interventional study13) If informed consent is not provided in writing by the study participant 14) Patients who are deemed inappropriate for this study by the investigator, etc.Study groups:1) Standard medication therapy (anticoagulation therapy* + administration of antiarrhythmic agents depending on the clinical condition)2) Standard medication therapy + CA* As a general rule, edoxaban tosilate hydrate (Lixiana? tablets)Primary endpoint:A composite of the following events during the observation period - Recurrence of ischemic stroke - Occurrence of systemic embolism - All-cause death - Hospitalization for heart failureSecondary endpoints: Recurrence of ischemic strokeSystemic embolismAll-cause deathCardiovascular deathHospitalization for heart failureAny bleedingOnset of intracranial hemorrhageComposite events (all-cause death, onset of stroke, systemic embolism, hospitalization for heart failure, and serious adverse event caused by CA).The rate of and related factors to discontinuation of edoxaban Recurrence of cerebral infarction in patients with or without discontinuation of edoxabanSafety endpoints1) Serious adverse events related to CA maneuver2) All adverse events not related to CA maneuver3) Drug reaction to edoxabanStatistical methods: Differences in the primary endpoint shall be examined with Kaplan-Meier curves using the log-rank test. If necessary, analyses based on models such as Cox regression models shall be carried out in order to assess the influence of covariates such as participant characteristics and baseline values.Study centers:Roughly 30 facilities in Japan (see the clinical study protocol for details)Purpose of Statistical Analysis PlanThis statistical analysis plan specifies the details of data handling and statistical analysis pertaining to "STroke secondary prevention with catheter ABLation and EDoxaban for patients with NVAF.Definition of Analysis Populations/Sets2.1 Analysis setMain analyses shall be performed according to the principle of Intention-To-Treat (ITT).2.1.1 Analysis population in accordance with the principle of Intention-To-Treat (ITT)The ITT population is defined as all participants enrolled in this study, who are allocated to either the standard medication group or the medication plus CA group, excluding those who fall under the following categories.1) Serious ICH-GCP non-compliance2) No data after randomization 2.2 Data handling2.2.1 Handling of missing valuesWith respect to missing data, no imputation with estimated values ??or calculated values shall be performed unless otherwise specified.2.2.2 Age Age is defined as the age at the time consent is obtained.2.2.3 Deviations from theoretical dateWith respect to deviations from the theoretical date of test data (date calculated from the date of allocation), laboratory test values are treated as those of the relevant month in a range of ±2 months at the point of 3 months, or ±3 months at the point of 12-60 months. However, when there are multiple test dates in the same target month, mean values of multiple test values shall be used.In addition, for test values at the time of study termination / completion, among all values obtained during the study period, those that are closest to the date of study termination / completion shall be adopted.2.2.4 Study groupsThe study groups are defined as the standard medication group and the medication plus CA group.General matters regarding analysis3.1 Software used for tabulated analysisSAS? System ver. 9.43.2 Significance level The significance level of testing for primary and secondary endpoints shall be set at 0.05 (two-sided). Other hypothesis testing shall be carried out at the significance level of 0.05 (two-sided) unless otherwise specified, with no multiplicity adjustment performed for the comparison of multiple items. 3.3 Number of display digitsAnalysis results shall be presented according to the following number of display digits.Mean, standard deviation, median: significant digits of data +1Minimum, maximum: the same number of digits as the significant digits of dataProportion: round off to one decimal placeHazard ratio, odds ratio: round off to two decimal placesP value: round off to three decimal places 3.4 Location where statistical analyses are carried outEP-CRSU Co., Ltd.Statistical methodology details4.1 Patient dispositionThe patient disposition table summarizing all patients enrolled shall be created. Tabulation items shall include the following. These shall be tabulated for all patients by study group and overall.Number of enrolled and allocated patientsNumber of patients included in the ITT population, the number of patients excluded from the ITT population and reasons for exclusion.4.2 Follow-up statusIn the ITT population, the following items shall be tabulated by study group.Summary statistics for the number of years of follow-up Number of patients followed up continuously for 3, 12, 24, 36, 48, and 60 months and their proportions 4.3 Patient characteristicsIn the ITT population, the number and proportion of patients shall be tabulated for categorical variables, and the number of patients, mean, standard deviation, maximum, minimum, and median values shall be calculated for continuous variables. Items to be tabulated include the following.Data are tabulated for all patients by study group and overall.Characteristics of study participants (at the time of enrollment)Age, sex, height, body weight, BMI, and CHADS2 scoreHistory and presence or absence of complications (hypertension, diabetes, dyslipidemia, liver disease, kidney disease, heart disease, vascular disease, cerebrovascular disease, chronic respiratory disease, malignant tumor, thyroid dysfunction, thromboembolism, digestive organ disease), Smoking habit, alcohol drinking habit, education history,NYHA classification, mRS score, NIHSS score, MMSE score, 12-lead electrocardiogram examination (rhythm), chest X-ray (cardiothoracic ratio), transthoracic echocardiography (left atrium diameter, EF), type of atrial fibrillation (paroxysmal, persistent, long-standing persistent)Concomitant medications (at the time of enrollment)Presence or absence of anticoagulant agents, presence or absence of antiplatelet agents, presence or absence of antiarrhythmic agents, presence or absence of antihypertensive agents, presence or absence of diabetes medications, presence or absence of lipid-lowering medications, presence or absence of dementia medications, presence or absence of anticancer agents, presence or absence of proton-pump inhibitorsBlood test (at the time of enrollment)WBC, RBC, Ht, Hb, Plt, PT-INR, APTT, T-bil, AST (GOT), ALT (GPT), ALP, Cr, Ccr, BUN, blood sugar, HbA1c, TG, T-cho, HDL, LDL, high-sensitivity CRP, BNP, NT-Pro BNP, D-dimer4.4 Primary endpointIn the ITT population, with regard to the following events, proportions of occurrence, incidence rates, and their 95% confidence intervals (CIs) shall be calculated for each study group. For new-onset events, Kaplan-Meier curves shall be constructed for each study group, and p-values shall be calculated using the long-rank test.Furthermore, multivariate Cox regression analysis shall be performed to calculate hazard ratios and their 95% CIs, as well as p-values, for the medication plus CA group relative to the standard medication group. In the multivariate analysis, models shall include CHADS2 score and type of atrial fibrillation, i.e. allocation factor as covariates.Events: A composite of the following events during the observation period. However, events occurring after the date of completion of the same anticoagulation therapy (including treatment performed prior to the date of consent) continued for 4 weeks (28 days) or more shall be subject to evaluation (or, the date of allocation for patients who have undergone 4 weeks or more of continued treatment at the time of allocation).Recurrence of ischemic strokeDevelopment of systemic embolismAll-cause deathHospitalization due to heart failure4.5 Secondary endpoints 4.5.1 Incident rates of events In the ITT population, with regard to the following events 1)-9) during the observation period, proportions of occurrence, incidence rates, and their 95% CIs shall be calculated for each study group. For new-onset events, Kaplan-Meier curves shall be constructed for each study group, and p-values shall be calculated using the long-rank test.Furthermore, multivariate Cox regression analysis shall be performed to calculate hazard ratios and their 95% CIs, as well as p-values, for the medication plus CA group relative to the standard medication group. In the multivariate analysis, models shall include CHADS2 score, i.e. allocation factor, and type of atrial fibrillation as covariates.Events: Each of the following events during the observation period. However, events occurring after the date of completion of the same anticoagulation therapy (including treatment performed prior to the date of consent) continued for 4 weeks (28 days) or more shall be subject to evaluation (or, the date of allocation for patients who have undergone 4 weeks or more of continued treatment at the time of allocation).1) Onset of stroke2) Recurrence of ischemic stroke3) All-cause death4) Cardiovascular death5) Hospitalization for heart failure6) All bleeding adverse events7) Development of intracranial hemorrhage8) Composite of events including all cause death, occurrence of systemic embolism, development of new stroke, hospitalization due to heart failure, serious adverse events related to CA procedures9) Discontinuation of edoxaban4.5.2 mRS score and NYHA classification at the end of the observation periodIn the ITT population, the proportion of patients with an mRS score of 0-2 and the proportion of patients with NYHA classification I at the end of the observation period shall be determined, and p-values shall be calculated using the chi-square test.4.5.3 Rate of maintenance of sinus rhythm In the ITT population, the rate of maintenance of sinus rhythm at 3, 12, 24, 36, 48, and 60 months shall be calculated for each study group.4.5.4 Rate of continuation of edoxabanIn the ITT population, the rate of continuation of edoxaban at 3, 12, 24, 36, 48, and 60 months shall be calculated for each study group.4.5.5 Recurrence rate of ischemic stroke according to the presence or absence of edoxaban discontinuationIn the ITT population, the recurrence rate of ischemic stroke after discontinuation / completion of edoxaban and its 95% CI shall be calculated for each treatment group and according to the presence or absence of edoxaban discontinuation.4.6 Safety4.6.1 Adverse events, serious adverse eventsFor each study group, proportions of occurrence of adverse events and serious adverse events and their 95% CIs shall be determined, and p-values shall be calculated by performing the chi-square test.Also, proportions of occurrence of adverse events related to CA and their 95% CIs shall be determined.4.6.2 Adverse reactions, serious adverse reactionsIn patients using edoxaban, proportions of occurrence of adverse events (adverse reactions) for which a causal relationship with edoxaban cannot be ruled out, proportions of occurrence of serious adverse reactions, and their 95% CIs shall be calculated for each study group.Also, in patients undergoing CA for the first time, proportions of adverse reactions related to the procedures and their 95% CIs shall be calculated.4.6.3 Laboratory test values With respect to the quantitative values of blood test values included in “4.3 Patient characteristics,” mean and standard deviation of each test value at enrollment, 3, 12, 24, 36, 48, and 60 months shall be calculated for each study group. In addition, with regard to values at 3, 12, 24, 36, 48, and 60 months, similar calculations shall be performed for the amount of change relative to enrollment.4.7 Subgroup analysisWith respect to the following factors, subgroup analysis shall be performed.Analysis set: ITT populationAssessment item: Primary endpointFactorsSex (Male / Female)Age (<65 years / ≥65 years)According to CHADS2 score (≤3 / ≥4)Type of atrial fibrillation (paroxysmal, persistent, long-lasting persistent)Revising and Fixing the Statistical Analysis Plan In, and any changes made to the Statistical Analysis Plan thereafter shall be recorded in the revision history to describe where and why the changes have been made. The final version shall be fixed before locking the database.Target sample size250 patients (125 in the standard medication group, and 125 in the medication plus CA group)<Rationale>The rate of occurrence of primary outcomes in the control group is estimated to be 13%/year. Assuming CA reduces the primary outcome by 50%, when the α error is set to 0.05 and the detection rate is set to 0.8, the required number of patients at 5 years is calculated to be 106 patients in each group, for a total of 212 patients. Assuming a dropout rate of 10%, 250 patients (125 patients in each group) has been set.Revision historyVersion [Date prepared]ChangeReasons for change0.1[2018/11/13]-Preparation of the first draft ................
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