REALIGN NEJM 01Sept2013 Protocol And TSAP Appendix Revised
ProtocolThis trial protocol has been provided by the authors to give readers additional information about their work.Protocol for: Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369:1206-14. DOI: 10.1056/NEJMoa1300615
This supplement contains the following items:1.Study protocol with summary of changes.REͲALIGN main trial (Boehringer Ingelheim study number 1160.113): Protocol version 6, as of 28 Jan 2013 REͲALIGN extension trial (Boehringer Ingelheim study number 1160.138): Protocol version 4, as of 28 Jan 2013 Summary of changes: Section 11 of each of the protocols contains a summary of all changes and highlights differences compared to the original protocol. 2.Statistical analysis plans, summary of changes.REͲALIGN main trial (Boehringer Ingelheim study number 1160.113): Trial statistical analysis plan (TSAP) version 4, as of 18Feb 2013 REͲALIGN extension trial (Boehringer Ingelheim study number 1160.138): Trial statistical analysis plan (TSAP) version 2, as of 8Feb 2013 Summary of changes: These revised versions of the trial statistical analysis plan contain a history table in section 10, which represents a summary of all changes.
Clinical Trial ProtocolDoc. No.: U11-1819-06EudraCT No.:2010-022685-27BI Trial No.:1160.113BI InvestigationalProduct:Pradaxa , dabigatran etexilate, BIBR 1048BSTitle:A Randomised, phase II study to Evaluate the sAfety andpharmacokinetics of oraL dabIGatran etexilate in patients after heartvalve replacemeNt(RE-ALIGN)Clinical Phase:IITrial ClinicalMonitor:Dr. Ruth Harper, PhDBoehringer Ingelheim LtdEllesfield AvenueBracknellBerkshire, RG12 8YSPhone: 44-1344-741474Fax: 44-1344-741657Co-ordinatingInvestigators:Dr John Eikelboom MDMcMaster UniversityHamilton Health Sciences237 Barton StreetEast Hamilton,Ontario, L8L 2X2CanadaProf Frans Van de WerfUniversity of LeuvenDepartment of Cardiovascular MedicineHerestraat 493000 LeuvenBelgiumPhone: 1- 905-527-4322Fax: 1- 905-297-3785Phone : 32 16 342111Fax: 32 16 342100Status:Final Protocol (Revised Protocol (based on Global Amendments 1,2, 3, 4 and 5)Version and Date:Version:6Date: 28 January 2013Page 1 of 206Proprietary confidential information. 2013 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 IngelheimBI Trial No.: 1160.113Trial Protocol (Version 6)28 January 2013Page 2 of 206CO-ORDINATING INVESTIGATOR SIGNATURETrial Title: A Randomised, phase II study to Evaluate the sAfety andpharmacokinetics of oraL dabIGatran etexilate in patients after heart valvereplacemeNt(RE-ALIGN)Trial Number: 1160.113Protocol Version 6I herewith certify that I agree to adhere to the trial protocoland to all documents referenced in the trial protocol.Name: Dr J EikelboomSignature:Signed signature page is located in the electronic Clinical Trial Master FileAffiliation: McMaster UniversityHamilton Health Sciences237 Barton StreetEast HamiltonOntarioL8L 2X2CanadaDate:
Boehringer IngelheimBI Trial No.: 1160.113Trial Protocol (Version 6)28 January 2013Page 3 of 206CO-ORDINATING INVESTIGATOR SIGNATURETrial Title: A Randomised, phase II study to Evaluate the sAfety andpharmacokinetics of oraL dabIGatran etexilate in patients after heart valvereplacemeNt(RE-ALIGN)Trial Number: 1160.113Protocol Version 6I herewith certify that I agree to adhere to the trial protocoland to all documents referenced in the trial protocol.Name: Prof F Van de WerfSignature:Signed signature page is located in the electronic Clinical Trial Master FileAffiliation: University of LeuvenDepartment of Cardiovascular MedicineHerestraat 493000 LeuvenBelgiumDate:
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 4 of 206Trial Protocol (Version 6)LOCAL SIGNATURES(PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) This page is not part of the protocol itself. Clinical Monitor Local optional, delete if not applicable :DateNameFull nameOrganisation/Department Add other signatories if applicable. I herewith certify that I agree to adhere to the trial protocol and to all documentsreferenced in the trial protocol.Principal Investigator (site):DateNameFull nameOrganisation/DepartmentSigned signature page is located in the electronic Clinical Trial Master File
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 5 of 206Trial Protocol (Version 6)CLINICAL TRIAL PROTOCOL SYNOPSISTabulatedTrial ProtocolName of company:Boehringer IngelheimName of finished product:Pradaxa ,, dabigatran etexilateName of active ingredient:DabigatranProtocol date:13 June 2011Title of trial:Trial number:1160.113Revision date:28 January 2013A Randomised, phase II study to Evaluate the sAfety and pharmacokineticsof oraL dabIGatran etexilate in patients after heart valve al sites :Dr John Eikelboom MDMcMaster UniversityHamilton Health Sciences237 Barton StreetEast Hamilton,Ontario, L8L 2X2CanadaMulti-centre trialProf Frans Van de WerfUniversity of LeuvenDepartment of Cardiovascular MedicineHerestraat 493000 LeuvenBelgiumClinical phase:IIObjectives:To validate the dosing algorithm for dabigatran etexilate in patients receiving amechanical heart valve.Methodology:This is a prospective, randomised, open label, blinded endpoint (PROBE), activecomparator (warfarin) trial.Due to the suspension of the Population A arm additional patients will not berecruited into this group at this time. To date 199 Population A patients and 53Population B patients have been recruited.Following implementation of Urgent Safety Memo 3 (28 November 2012),discontinuation of the study (including Population B), no further patients willbe recruited and all patients will be discontinued from study treatment. approximately 200 Ҁ of patients should have received a mechanical bileafletheart valve during the current hospital stay the remaining patients should have received a mechanical bileaflet mitral valvein the past (more than three months prior to randomisation).It is designed to evaluate the trough plasma concentrations of dabigatran and thesafety of dabigatran etexilate. The comparator will be warfarin at different targetinternational normalisation ratios (INRs) as recommended by clinical guidelines.For patients at low thromboembolic risk guidelines suggest an INR of 2.5 (range2.0-3.0) and for patients at intermediate to high thromboembolic risk guidelinessuggest a higher target INR of 3.0 (range 2.5-3.5).No. of patients:
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 6 of 206Trial Protocol (Version 6)TabulatedTrial ProtocolName of company:Boehringer IngelheimName of finished product:Pradaxa ,, dabigatran etexilateName of active ingredient:DabigatranProtocol date:13 June 2011Trial number:1160.113total entered:Minimum 405each treatment:Minimum 270 dabigatran etexilateMinimum 135 warfarinRevision date:28 January 2013Additional patients may be recruited to increase the amount of clinical data. Amaximum number of 650 patients will not be exceeded.Due to study termination these numbers were not reached.Diagnosis :Elective mechanical heart valve replacement.Main criteriafor inclusion:Patients aged 18 years and 75 years, either undergoing implantation of amechanical valve during the current hospital stay or having undergone implantationmore than three months prior to randomisation.Patients receiving a coronary artery bypass graft (CABG) concomitantly to the valvereplacement may be included.Test products :Dabigatran etexilatedoses:150mg, 220mg and 300mg twice daily (b.i.d.)mode of admin. :OralComparator products:Warfarindose:1mg, 3mg and 5mgmode of admin. :OralDuration of treatment:12 weeksCriteria for efficacy:NoneCriteria for safety:Primary endpoint:Total dabigatran concentration at trough.Statistical methods:Analysis of variance, linear logistic regression, descriptive statistics and graphicalmethods.
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 7 of 206Trial Protocol (Version 6)FLOW CHARTSFrom the time of implementation of Protocol Version 5 (and associated urgent safety memodated 11 October 2012) only patients in Population B will continued in the study untilimplementation of urgent safety memo (dated 28 November 2012), when all remainingpatients in the study were discontinued. The following Flow charts FlowChart 1represented the actions required for Population B during this interim period. Thisflow chart is now obsolete and Flow Chart 2 should be followed.those patients alreadyrecruited into Population A or discontinued from Population B.FLOW CHART 1FOR ONGOING POPULATION B PATIENTSThe flow chart detailed below is the original flow chart for the study to date (as detailed inProtocol Version 4 (10 September 2012), with the amendments to be implemented in thisprotocol version highlighted in yellow.With the implementation of urgent safety memo 28 November 2012, no patients are tocontinue in the study and the tasks in this table are no longer relevant.Trial PeriodsScreening &Randomisation3VisitDays since Randomisation412Baseline-14 to -20Weeks sinceRandomisationTime window (days)0Informed Consent/Subject3InformationXCheck EligibilityXDemographicsXMedical HistoryXPhysical ExaminationXVital Signs (PR/BP)XECG5Safety 213-1/ 2 3 7 7 7 74XXXXXXXXXXXXInclusion/Exclusion CriteriaPregnancy TestEOTTreatmentXXXXXX
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 8 of 206Trial Protocol (Version 6)FLOW CHART 1 CONTINUEDTrial PeriodsScreening &Randomisation3VisitDays since Randomisation412Baseline-14 to -20Weeks sinceRandomisationTime window (days)Creatinine Clearance7 100XBlood sample for central7 12Hemoclot /measurement11X13X11 13Pharmacokinetics (HPLC7 12MS/MS)XBlood sample for assay7 12 18validationX11 13INR/Warfarin dose7 19adjustmentXRandomisation via IXRSX21Dispense Trial MedicationXFirst Admin of TrialMedicationX456989912481213-1/ 2 3 7 7 7 71111X1111X1111 16XXTermination of TrialMedication11X1111XX20every 2 - 4 g AssessmentAdverse Events11 15X21Drug AccountabilityConcomitant TherapyXX11 15 16XX15X11 14 1711X15 16XX11X14XX11X24Gastrointestinal SymptomRating ScaleFollowup23Possible Dabigatran nd of Patient ParticipationEchocardiography/TEE Sub27study (see Appendix 10.9)X28XEnd of treatment (EOT) procedures to be completed by all patients. For patients who discontinue early, the EOT visitshould be performed instead of the scheduled trial visit at time of discontinuation.For patients completing the study per protocol and wishing to continue into the long term observation study (1160.138),the information from this EOT visit will form Visit 1 for the long term observation study (1160.138).2Performed for any patient who discontinues study treatment early or does not want to continue to the long termobservation study (1160.138).
Boehringer IngelheimBI Trial No.: 1160.1133Trial Protocol (Version 6)28 January 2013Page 9 of 206All patients must sign an informed consent consistent with ICH-GCP guidelines prior to any trial-related procedures.4For patients who wish to participate in the long term observation study (1160.138).5If additional ECGs are performed during the course of the trial as part of patient normal care and demonstrate a changefrom baseline or a new pathology develops this should be documented in the eCRF. Copies of all ECGs documented willbe provided to the Sponsor.6Standard safety lab panel (haematology and chemistry, including renal function and liver function tests (LFTs)) will becollected at each visit.An additional safety lab (including haematology and LFT) may be taken at any time in case haemolysis or haemolyticanaemia is suspected.All analyses will be performed by the central laboratory (except INR). For details see Appendix 10.5.7Additional safety laboratory and CrCl samples should be taken (for all patients) if the patient experiences any outcomeevent (see Section 5.2.2.1 for definitions of outcome events).For patients receiving dabigatran etexilate:Additional samples for central Hemoclot (diluted thrombin time), PK (HPLC-MS/MS) and assay validation should also becollectedFor patients receiving warfarin:An additional INR measurement (local laboratory) should be takenPlease refer to Section 6.2.2.3.1 for details89Hepatitis B and C serology will be performed at screening visit only if patient is considered to belong to an “at risk” group.Required for all women of child bearing potential – serum pregnancy test will be performed at central laboratory.101112Renal function: creatinine clearance (CrCl) will be calculated based on serum creatinine using the Cockroft-Gaultequation.To be collected at same time as sample is collected for a Hemoclot test.For patients receiving dabigatran etexilate only, samples to be taken at trough at each visit with the exception of onetrough sample and an additional peak sample taken at Visit 5.Additional samples will be taken if the patient’s thromboembolic risk status should change from low to moderate-high (orvice versa) during the course of the study.131415The baseline sample must be taken prior to first intake of study medication.The blood samples for Hemoclot and HPLC-MS/MS measurement (USA only) taken at Visit 4 (two weeks 3 days)must be taken in the morning when the dabigatran plasma concentration is at trough levels (last drug intake must haveoccurred the evening before blood sampling). The dose allocation for the remainder of the treatment period is determinedby this sample. If the patient attends for the sampling at a time when the dabigatran level is not at trough, or the last drugintake has not occurred the evening before, the sample will not be taken and the visit will need to be re-scheduled twodays later. If a patient has a plasma concentration of 250ng/mL despite already having been allocated to 150mgdabigatran etexilate b.i.d. or a concentration of 50ng/mL despite already having been allocated 300mg dabigatranetexilate b.i.d. a repeat sample should be taken within 10 days for confirmation prior to excluding the patient from furtherdabigatran etexilate treatment.These samples will not result in dose adjustment. However, if a patient is found to have a plasma concentration of 50ng/mL at Visit 6 or EOT, the patient will be discontinued from study treatment and switched to non study VKA.
Boehringer IngelheimBI Trial No.: 1160.11316Trial Protocol (Version 6)28 January 2013Page 10 of 20617One trough sample and an additional sample to be taken when the dabigatran level is at a peak (two hours 30minutesfollowing drug administration). Peak samples should be taken following the intake of the study medicine the patient wasallocated prior to Visit 5. Any change in dose at Visit 5 should be implemented AFTER this peak sample has been taken.18FOR PATIENTS IN USA ONLY:The sample taken at Visit 4 and any confirmatory retest, must be sent in an expedited fashion to the central laboratory foranalysis – these are the samples that will be used to confirm/assign the dose for the rest of the study. See Footnote 16.It is planned to validate a diagnostic assay (e.g. coagulation assay) for the determination of dabigatran plasma levels inheart valve patients. Analysis of these samples will not occur until after the study has been completed.19All patients will have a baseline INR. Follow-up INRs will be performed only in those patients randomised to warfarin. AllINR measurements conducted locally.20At least two-weekly INR measurements in patients who are commencing warfarin for first time – all other patients at leastmonthly. More frequently if required.21Patients who have received surgery for mitral bileaflet heart valve implantation in the past (at least 3 months priorto randomisation) and are currently taking a Vitamin K Antagonist (VKA):Patients randomised to warfarin can start study warfarin if the INR is within the target range of 2.5-3.5.Patients randomised to dabigatran can start study drug if INR is 2.5 (patients at intermediate- high thromboembolic risk).22232425Dispense medication for long term observation study 1160.138.Dose adjustment for patients receiving dabigatran etexilate will be determined based upon the results of the Hemoclot test/HPLC-MS/MS (US patients only), taken at Visit 4 (2 weeks 3 days), performed at the central laboratory. Anychange in study dose should be made AFTER the visit, to ensure the peak PK sample reflects the dose the patient had beentreated on UNTIL Visit 5 (i.e., Visit 5 medication should only be dispensed to the patient at the end of Visit 5 with thefirst dose to be taken in the evening following Visit 5).One TEE to be conducted in all patients who are on treatment at time of implementation of Protocol Version 5 – if a TEEis not possible every effort to conduct at least a TTE must be made. All TEEs should be performed as soon as practicallypossible, preferably within two weeks of implementation of Protocol Version 5. If a patient discontinues subsequent toimplementation of Protocol Version 5, then an additional TEE within two weeks of discontinuation is required.A second TEE (TTE if TEE is not possible) may be required if there is evidence of thrombus identified (see Section6.2.2.3)262728For patients who discontinue early from the study or do not wish to continue into the long term observation study.Patients switching to a non study VKA from dabigatran etexilate may continue on study medication after this visit for 2-3days to assist bridging.Optional substudy – Patient must undergo additional informed consent prior to participation.One TEE conducted on or before EOT visit (time window – 14 days).
Boehringer IngelheimBI Trial No.: 1160.11328 January 2013Page 11 of 206Trial Protocol (Version 6)FLOW CHART 2FOR ALL POPULATION A PATIENTS AND FOR POPULATION B PATIENTS WHODISCONTINUE TREATMENT EARLY AS A RESULT OF IMPLEMENTATION OFTHE URGENT SAFETY MEMOS (11 OCTOBER 2012 AND 28 NOVEMBER 2012),OR WHO HAVE DISCONTINUED STUDY TREATMENT WITHIN THE PAST SIXMONTHSPrior to implementation of Protocol Version 5, all patients followed the flow chart detailedabove (without the changes highlighted for Protocol Version 5). With implementation ofProtocol Version 5 and subsequently urgent safety memo dated 28 November 2012, allpatients who have been randomised into the study under Population A will be discontinuedfrom study drug treatment and the following follow-up procedures will be performed. Theseprocedures will also be followed for patients who have discontinued early from the studytreatment (either in Population A or B) in the six month period prior to implementation ofthe urgent safety memo (11 October 2012) or who chose to discontinue study treatmentfollowing implementation of Protocol Version 5 (see Sections 3.3.4.2.1 and 6.2.3.2).VisitsEOTWeeks relative to discontinuationWith implementationof Urgent safetymemoTime window (days)Physical ExaminationXVital Signs (PR/BP)XFollow up1Follow up21Follow up31EOT 1 weekEOT 1 monthEOT 6 months 7 14 14X2ECGXSafety Laboratory EvaluationsPregnancy Test34X5X467Creatinine ClearanceXBlood sample for central8Hemoclot /measurementXPharmacokinetics (HPLC-MS/MS)889Blood sample for assay validationINR7X7X4 10XDispense non study anticoagulationXEchocardiography11X12Drug AccountabilityXGastrointestinal Symptom RatingScaleXXBleeding AssessmentXXXXConcomitant TherapyXXXXXXXX13Adverse Events
Boehringer IngelheimBI Trial No.: 1160.113Trial Protocol (Version 6)VisitsWeeks relative to discontinuation28 January 2013Page 12 of 206EOTWith implementationof Urgent safetymemoFollow up1Follow up21Follow up31EOT 1 weekEOT 1 monthEOT
Trial statistical analysis plan (TSAP) version 4, as of 18Feb 2013 . Hamilton Health Sciences 237 Barton Street East Hamilton, Ontario, L8L 2X2 Canada . (28 November 2012),
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The series--now titled ASM Handbook--continues to evolve and expand to serve the changing needs of metallurgy professionals throughout the world. One example of this evolution is the release this year of the ASM Handbook on CD-ROM. This year also marks the 50th anniversary of the classic 1948 edition of Metals Handbook--the last "regular" edition to be contained in one volume. The 1948 edition .
