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Clinical Trial Protocol Doc Clinical Trial Protocol Doc. No.: c02214385-09 EudraCT No.: 2013 003201 26 BI Trial No.: 1160.186- - BI Investigational Pradaxa®, dabigatran etexilate Product(s): Title: A prospective Randomised, open label, blinded endpoint (PROBE) study to Evaluate DUAL antithrombotic therapy with dabigatran etexilate (110mg and 150mg b.i.d.) plus clopidogrel or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 – 3.0) plus clopidogrel or ticagrelor and aspirin in patients with non valvular atrial fibrillation (NVAF) that have undergone a percutaneous coronary intervention (PCI) with stenting (RE-DUAL PCI) Clinical Phase: IIIb Trial Clinical Monitor: Phone: Fax: Co-ordinating Investigator: Phone: Fax: Status: Final Protocol (Revised Protocol (based on global Amendments 1, 2 and 3)) Version and Date: Version: 4.0 Date: 21 July 2016 Page 1 of 150 Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. TITLE PAGE Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 2 of 150 CLINICAL TRIAL PROTOCOL SYNOPSIS Name of company: Tabulated Trial Protocol Boehringer Ingelheim Name of finished product: Pradaxa® Name of active ingredient: Dabigatran Protocol date: Trial number: Revision date: 26 March 2014 1160.186 21 July 2016 Title of trial: A prospective Randomised, open label, blinded endpoint (PROBE) study to Evaluate DUAL antithrombotic therapy with dabigatran etexilate (110mg and 150mg b.i.d.) plus clopidogrel or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 – 3.0) plus clopidogrel or ticagrelor and aspirin in patients with non valvular atrial fibrillation (NVAF) that have undergone a percutaneous coronary intervention (PCI) with stenting. (RE-DUAL PCI) Co-ordinating Investigator: Trial sites: Multi-centre trial Clinical phase: IIIb Objectives: The main objective is to compare a dual antithrombotic regimen of 110mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (110mg DE-DAT) and 150mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor (150mg DE-DAT) with a triple antithrombotic therapy (TAT) of warfarin plus clopidogrel or ticagrelor plus aspirin (warfarin-TAT) in patients with non valvular atrial fibrillation (NVAF) that undergo a PCI with stenting. The study aims to show non-inferiority of each dose of DE-DAT when compared to Warfarin-TAT in terms of safety. Safety is determined by bleeding events, assessed using the modified International Society of Thrombosis and Haemostasis (ISTH) classification of Major Bleeding and Clinically Relevant Non- Major Bleeding Events (CRNMBE). Methodology: This is a prospective, randomised, open label, blinded endpoint (PROBE), active comparator (warfarin) trial. The study will employ a time to event analysis and all patients will remain on study treatment until the last patient entered has completed at least six months of treatment. The patients will be stratified by age (<80 or ≥80 years old) and region (EU/ROW or USA). No. of patients: total entered: 2502* Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 3 of 150 Name of company: Tabulated Trial Protocol Boehringer Ingelheim Name of finished product: Pradaxa® Name of active ingredient: Dabigatran Protocol date: Trial number: Revision date: 26 March 2014 1160.186 21 July 2016 each treatment: 834* * These are approximations. As this is an event driven trial the actual number of patients entered may increase or decrease based on actual event rates. Sites will be notified when recruitment ends. Diagnosis : Patients with NVAF that undergo a successful PCI with stenting (elective or due to an acute coronary syndrome (ACS)). Main criteria 1. Male or female patients aged ≥18 years for inclusion: 2. Patients with NVAF that have been receiving oral anticoagulant treatment (either with warfarin, another VKA or other novel oral anticoagulant) or treatment naïve prior to PCI 3. Patient with NVAF presenting with: ACS that was successfully treated by PCI and stenting (either BMS or DES) or Stable Coronary Artery Disease with at least one lesion eligible for PCI that was successfully treated by elective PCI and stenting (either BMS or DES ) Test products: Dabigatran etexilate dose: 110mg and 150mg (b.i.d.) mode of admin.: Oral Comparator products: Warfarin dose: 1mg, 3mg and 5mg mode of admin.: Oral Duration of treatment:The minimum duration of study treatment is six months Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 4 of 150 Name of company: Tabulated Trial Protocol Boehringer Ingelheim Name of finished product: Pradaxa® Name of active ingredient: Dabigatran Protocol date: Trial number: Revision date: 26 March 2014 1160.186 21 July 2016 Criteria for efficacy: The primary endpoint for this trial is a safety endpoint, please see below. The secondary efficacy endpoints (all time to first event) are: A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE) and unplanned revascularisation by PCI/CABG A combined endpoint of thrombotic events or death (DTE: all death + MI + stroke/SE) Individual outcome events: All death (Cardiovascular death, Non-cardiovascular death, Undetermined), MI Stroke SE Stent Thrombosis Composite endpoint of death + MI + stroke Unplanned revascularisation by PCI/CABG Criteria for safety: The primary endpoint for this trial is time to first ISTH Major or Clinically Relevant Non-Major Bleeding Event. Statistical methods: The stratified Cox proportional hazards regression model will be used to analyse time- to-event endpoints. To control the Type I error rate at a one-sided 0.025 level, a hierarchical procedure for multiple testing will be used to test the safety hypotheses. Additional testing for safety and efficacy endpoints will also be included in this hierarchical procedure. Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 5 of 150 FLOW CHART Follow Screen Random 3 Final Trial Periods Treatment EOT2 up ing1 isation1 Visit4 Visit 1 2 3 4 5 6 7 85 9, 11 10, 125 9706 980 990 Baseline Days since Randomisation -5 to 0 0 Months since Randomisation 1 3 6 9 12 15 18, 24 21, 27 6-30 EOT + 4 weeks (+7 days) Time window (days) 0 7 14 14 14 14 14 14 14 Informed Consent7 X Check Eligibility XX Demographics X Medical History X Physical Examination X8 X Vital Signs (PR/BP) XX9 XXX X X X Weight X X X X X ECG10 X X X X X Haematology Laboratory Evaluations11 X12 XXXXXX X X Chemistry Laboratory Evaluations11 X12 XX X X X Creatinine Clearance13 X12 XXX XXX X X Pregnancy Test14 X XXX XX X XX Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 6 of 150 Follow Screen Random 3 Final Trial Periods Treatment EOT2 up ing1 isation1 Visit4 Visit 1 2 3 4 5 6 7 85 9, 11 10, 125 9706 980 990 Baseline Days since Randomisation -5 to 0 0 Months since Randomisation 1 3 6 9 12 15 18, 24 21, 27 6-30 EOT + 4 weeks (+7 days) Time window (days) 0 7 14 14 14 14 14 14 14 Troponin11 X X INR/Warfarin dose adjustment15 X every 2 weeks – monthly 16 Randomisation via IRT X Dispense Trial Medication X XXXX X First Admin of Trial Medication X17 Drug Accountability X18 XXXX X X Bleeding Assessment XXXXXXXXXXXX Concomitant Therapy XXXXXXXXXXXXX Reporting of Outcome Events In an expedited fashion – reporting timelines the same as for SAEs Adverse Events XXXXXXXXXXXXX Termination of Trial Medication X19 End of Patient Participation X20 X20 Proprietary confidential information. 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. Boehringer Ingelheim 21 Jul 2016 BI Trial No.: 1160.186 Doc. No.: c02214385-09 Trial Protocol Version 4.0 Page 7 of 150 1 Screening and randomisation will occur after successful PCI. 2 End of treatment (EOT) procedures to be completed by all patients at the time of study drug discontinuation. For patients who discontinue early, the EOT visit should be performed instead of the scheduled trial visit at time of discontinuation. 3 For patients that complete all scheduled visits or discontinue treatment early, follow up visit to be conducted four weeks after EOT. 4 For patients that discontinue treatment early, the final visit will take place at the time trial conclusion is declared. 5 To be conducted by telephone. 6 This event driven trial is expected to take place over 30 months, however, the trial can conclude earlier if an adequate number of events is reported sooner.
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