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056-F275, Clinical Investigation Plan Template, Version 2.0Page 1 of 115Clinical Investigation PlanClinical Investigation Plan/Study TitleStudy Product NameSTOP Persistent AFArctic Front Advance Cardiac CryoAblation CatheterFreezor MAX Cardiac CryoAblation CatheterSponsor/Local SponsorUnited States of AmericaMedtronic, Inc.8200 Coral Sea Street NEMounds View, MN 55112United States of AmericaCanadaMedtronic of Canada, Ltd.99 Hereford StreetBrampton, Ontario, L6Y 0R3CanadaEuropeMedtronic, Bakken Research Center B.V.Endeplosdomein 56229 GW MaastrichtThe NetherlandsJapanMedtronic Japan Co. Ltd.1-2-70 KonanMinato-ku, Tokyo 108-0075JapanDocument VersionLead Co-PrincipalInvestigator(s)/Coordinating Investigators4, 10NOV2016Hugh Calkins, MDAddress: Johns Hopkins, 1800 Orleans Street, ZayedTower 712R, Baltimore, MD 21287Telephone: 410-955-7405Fax: 410-614-1345Professional Position: Nicholas J. Fortuin Professor ofCardiology, Division of Cardiology, The Johns HopkinsUniversity School of Medicine. Professor of Medicine,Department of Medicine, Division of Cardiology, TheJohns Hopkins University School of Medicine. Professorof Pediatrics, Department of Pediatrics, Division ofPediatric Cardiology, The Johns Hopkins UniversitySchool of Medicine. Director of the Arrhythmia Service,Version 4, 10NOV2016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 2 of 115Clinical Electrophysiology Laboratory, andArrhythmogenic Right Ventricular Dysplasia Program,The Johns Hopkins HospitalVivek Reddy, MDAddress: Mt. Sinai Heart, One Gustave L Levy Place, Box1030, New York, NY 10029Telephone: 212-241-7114Fax: 646-537-9691Coordinating InvestigatorsProfessional Position: The Leona M. and Harry B.Helmsley Charitable Trust Professor of Medicine inCardiac ElectrophysiologyRobert Kowal, MDAddress: Cardiology Consultants of Texas, 621 NorthHall Street, Suite 4400, Dallas, TX 75226Telephone: 469-800-7400Fax: 469-800-7410Professional Position: Co-Medical Director, CardiacElectrophysiologyBaylor Scott and White Health CareVP and Medical Director, Best Care and ClinicalIntegrationBaylor Scott and White Quality AllianceWilbur Su, MDAddress: Banner-University Medical Group-Heart Center1300 North 12th Street, Suite 407, Phoenix, AZ 58006Telephone: 602-839-7393Professional Position: Clinical Assoc. Professor ofMedicine, University of Arizona, Chief of Cardiac EP,Banner-University Medical Center-Phoenix, Director ofEP Fellowship, Banner-University Medical CenterPhoenixConfidentiality StatementThe information contained in this document is confidential and the proprietary property of Medtronic. Anydistribution, copying, or disclosure without the prior written authorization of Medtronic is strictly prohibited.Persons to whom the information is disclosed must know that it is confidential and that it may not be furtherdisclosed by them.Version 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 3 of 1151. Version HistoryVersionSummary of ChangesRationaleAuthor(s)/Title1.0Not Applicable, NewDocumentNot Applicable, New DocumentDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. Statistician2.02.02.02.02.0Synopsis, Sections 7.1, 7.2and 18: Modified theprimary efficacy OPC andchanged the atypicalflutter treatment failure toany recurrence of atrialflutterFDA feedbackSynopsis, Sections 7.1, 7.214.16 and 18.3.2: Changedthe secondary safetyobjective to a primarysafety objective with apre-specified hypothesisFDA feedbackDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianSynopsis, Sections 7.1, 7.2and 18.5: Added anancillary objectiveDana Wigert, Sr. Prin. ClinicalResearch SpecialistSynopsis, Sections 7.1, 7.2and 18.5: Added andancillary objectiveDana Wigert, Sr. Prin. ClinicalResearch SpecialistSynopsis, Sections 7.1, 7.2and 18.5: RemovedDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianFred Kueffer, Pr. StatisticianFred Kueffer, Pr. Statisticianancillaryobjective2.0Synopsis, Sections 5, 8and 18: Study data fromthe Japanese centers willnot be included in thePMA-S submission, but willParticipation and enrollment inJapan is anticipated to startlater than the othergeographiesVersion 4, 10NOVO016ConfidentialDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. Statistician
056-F275, Clinical Investigation Plan Template, Version 2.0Page 4 of 115be included in a submissionto Japan Pharmaceuticalsand Medical DeviceAgency (PMDA)2.02.02.02.02.0Table 5: Noted thecomplication definitionmay vary from study tostudyClarificationDana Wigert, Sr. Prin. ClinicalResearch SpecialistSections 14 and 20.2:Added weekly andsymptom driven eventmonitoringFDA feedback and consistentwith the 2012 HRS ExpertConsensus Statement onCatheter and Surgical Ablationof AFDana Wigert, Sr. Prin. ClinicalResearch SpecialistSections 7.2.1, 14.7 and18.3: Modified theantiarrhythmic doseallowed after the blankingperiod to historicmaximumFDA feedbackDana Wigert, Sr. Prin. ClinicalResearch SpecialistSections 7.2.1 and 18: 12lead ECGs need todemonstrate at least 10seconds of an atrialarrhythmia to beconsidered a treatmentfailureAligns with standard practiceand FDA feedbackSection 8.2: Rationale wasupdatedConsistent with the addition ofa primary safety objectiveFred Kueffer, Pr. StatisticianFred Kueffer, Pr. StatisticianFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. Statistician2.02.0Section 14.1: Addedreview of symptomssuggestive of recurrentAF/AT/AFL to the studyprocedures and datacollection tableClarificationSection 14.4: Added Whenperformed, the TEE shouldbe occur within 1 day (onthe day of or within the dayprior to) the plannedablation procedureClarificationDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.02.02.02.02.02.02.02.0Page 5 of 115Section 14.5.5: RequireCTI ablation if typicalflutter has beendocumented or wasinduced. Recommendinduction if not in thedocumented history.FDA feedbackSections 7.2.1, 7.2.3,14.5.5, 14.8, 18.3, and18.5: removed thelimitation that only CTIablations are allowed in theright atriumAllows for treatment of preexisting right atrial arrhythmiasthat may contribute to theprimary objective if leftuntreatedDana Wigert, Sr. Prin. ClinicalResearch SpecialistSection 14.18: Added thata study deviation is notrequired if a subjectmisses a weekly TTMtransmission.Compliance percentage will bemanaged by the core labDana Wigert, Sr. Prin. ClinicalResearch SpecialistSection 17: Added thatassociated imagingstudies may be requested,if available, for all seriousadverse events withpossible relatedness tothe system or procedureTo support adverse eventadjudicationSection 18: Provideddetails regarding thedetermination of subjectsfor data analysisFDA feedbackSection 18.4: Provideddetails on the Hommelstepwise procedure forthe secondary objectivesFDA feedbackSection 18.5: Stated thatancillary objectives beendefined to provideadditional informationabout the performance ofthe Arctic Front AdvanceCardiac CryoAblationCatheter. No hypothesesare defined for regulatoryor labeling purposes.FDA feedbackDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianFred Kueffer, Pr. StatisticianFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.02.0Section 21.3: RemovedLtd reference.TypoPage 6 of 115Dana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. Statistician3.04.0Section 18.3.2: Revisedprimary safety hypothesisstatement and endpointdefinitionTypoSections 5, 8 and 18.2:Included additional detailsabout the sample size inrelation to Japanese dataand how Japanese data willbe reportedFDA feedbackDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianDana Wigert, Sr. Prin. ClinicalResearch SpecialistFred Kueffer, Pr. StatisticianVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 7 of 115Table of Contents1.Version History . 3Table of Contents. 72.Glossary . 113.Sponsor Contacts . 144.CROs/Core Laboratories . 155.Synopsis . 156.Introduction . 196.1.6.2.7.Background.19Purpose .22Objectives and Endpoints . 237.1. Objectives .237.1.1. Primary Objectives . 237.1.1.1. Primary Efficacy Objective . 237.1.1.2. Primary Safety Objective . 237.1.2. Secondary Objective . 237.1.3. Ancillary Objectives. 237.2. Endpoints .247.2.1. Primary Endpoints . 247.2.2. Secondary Endpoint . 257.2.3. Ancillary Endpoints. 258.8.1.8.2.9.Study Design . 26Duration.27Rationale .28Product Description . 289.1. General .289.1.1. Arctic Front Advance Cardiac CryoAblation Catheters. 299.1.2. Freezor MAX Cardiac CryoAblation Catheters . 299.1.3. FlexCath Advance Steerable Sheath . 299.1.4. Achieve Mapping Catheter . 309.1.5. CryoConsole . 309.1.6. Coaxial Umbilical. 309.1.7. Electrical Umbilical . 309.1.8. Manual Retraction Kit . 309.1.9. 309.1.10.Additional Study Devices . 319.2. Packaging .319.3. Product Receipt, Tracking and Storage .31Version 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 8 of 11510.Investigator/Investigational Center Selection . 3211.Center Activation . 3212.Selection of Subjects . 3312.1.12.2.12.3.12.4.Study Population.33Subject Enrollment .33Inclusion Criteria .33Exclusion Criteria .3413.Minimization of Bias . 3414.Study Procedures. 3514.1. Schedule of Events .3514.2. Role of the Sponsor .3714.3. Subject Consent.3714.4. Enrollment, Baseline and Pre-ablation .3914.5. Procedure .4014.5.1.Esophageal Visualization and Temperature Monitoring . 4014.5.2.Peri-procedural Anticoagulation . 4014.5.3.Diaphragm Movement . 4014.5.4.Balloon Pulmonary Vein (PV) Cryoablation . 4114.5.5.Other Ablations during Index Procedure . 4114.5.6.Cardioversion . 4114.5.7.Procedure Documentation . 4114.6. Hospital Discharge .4214.7. Medications .4214.7.1.Class I and III antiarrhythmic medication use after the 90 day post-procedureblanking period . 4314.8. Permissible Repeat Cryoablations.4314.9. Cardioversions .4314.10.Scheduled Follow-up Visits .4314.10.1. Six Week Phone Call. 4514.10.2. Three Month Office Visit . 4514.10.3. Six Month Office Visit . 4514.10.4. Twelve Month Office Visit . 4514.11.Unscheduled Office Visits .4514.12.Holter and TTM Management .4614.13.12 lead Electrocardiograms .4614.14.4614.15.Assessment of Efficacy .4614.16.Assessment of Safety .4714.17.Recording Data .4714.18.Deviation Handling .4714.19.Subject Withdrawal or Discontinuation .4815.Risks and Benefits . 4915.1.Potential Risks .49Version 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.015.2.15.3.15.4.16.Page 9 of 115Risk Minimization .51Potential Benefits .52Risk-Benefit Rationale .52Adverse Event and Device Deficiencies Assessment . 5216.1. Adverse Event and Device Deficiency Definitions .5316.2. Adverse Events .5516.3. Device Deficiencies .5616.4. Processing Updates and Resolution .5616.5. Reporting of Adverse Events and Device Deficiencies.5616.6. Subject Death.6316.6.1.Death Classification and Reporting . 6316.7. Product Complaint Reporting .6317.Data Review Committees . 6418.Statistical Design and Methods . 6518.1. General Considerations .6518.2. Analysis Timing .6518.2.1.PMA-S Submission . 6518.2.2.PMDA Submission. 6518.3. Primary Objectives .6518.3.1.Primary Efficacy Objective . 6518.3.2.Primary Safety Objective . 7018.4. Secondary Objective.7418.4.1.Secondary Objective: Quality of Life - Atrial Fibrillation Effect on QualiTy-of-life(AFEQT) and SF-12 Questionnaires . 7418.5. Ancillary Objectives .7618.5.1. 7618.5.2. 77. 7818.5.3.18.5.4. 7818.5.5. 7918.5.6. 7919.Ethics . 8019.1.20.Statement(s) of Compliance .80Study Administration . 8220.1. Monitoring .8220.2. Data Management .8220.3. Confidentiality .8320.4. CIP Amendments .8320.5. Record Retention .8420.5.1.Investigator Records . 8420.5.2.Investigator Reports . 8520.5.3.Sponsor Records. 8720.5.4.Sponsor Reports . 88Version 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 10 of 11520.6. Publication and Use of Information.9220.7. Suspension or Early Termination.9420.7.1.Early Termination or Suspension . 9420.7.2.Study-wide Termination or Suspension . 9420.7.3.Investigator/Center Termination or Suspension . 9420.7.4.Procedures for Termination or Suspension . 9520.7.4.1.Medtronic-Initiated and Regulatory Authority-Initiated. 9520.7.4.2.Investigator-Initiated . 9520.7.4.3.IRB/MEC Initiated . 9621.Warranty/Insurance Information . 9621.1.21.2.21.3.21.4.21.5.Warranty .96Insurance (US) .96Insurance (Canada) .96Insurance (Europe) .96Insurance (Japan) .9722.References . 9723.Appendices. 99Version 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 11 of 1152. GlossaryTable 1: GlossaryTermDefinitionAEAdverse eventAFAtrial fibrillationAADAntiarrhythmic drugACCAmerican College of CardiologyACTActivated clotting timeADEAdverse device effectAFLAtrial flutterAHAAmerica Heart AssociationATAtrial tachycardiaAFEQTAtrial fibrillation effect on quality-of-lifequestionnaireBMIBody mass indexCCelsiusCTComputed tomographyCVCurriculum vitaeCECClinical Events CommitteeCFEComplex fractionated electrogramsCFRCode of Federal RegulationsCIPClinical investigation planCRFCase report formCTAClinical trial agreementDCDirect currentVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 12 of 115DDDevice deficiencye.g.For exampleECGElectrocardiogramECASEuropean Cardiac Arrhythmia SocietyECRFElectronic case report formEHRAEuropean Heart Rhythm AssociationFFahrenheitFDFinancial disclosureFALForeseeable adverse event listFDAFood and Drug AdministrationFDAAAFood and Drug Administration Amendments ActGCPGood clinical practiceGEEGeneralized estimating equationHRHazard rationHRSHeart Rhythm SocietyHOMIHead of medical institutionIDIdentificationIDEInvestigational device exemptionIncIncorporatedIRBInstitutional review boardISOInternational Organization for StandardizationICMJEInternational Committee of Medical Journal EditorsLADLeft atrial diameterLVEFLeft ventricular ejection fractionMDDMedical device directiveVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 13 of 115MECMedical ethics committeeMHLWMinistry of Health, Labour and WelfareMedDRAMedical Dictionary for Regulatory ActivitiesNOACNovel oral anticoagulantNYHANew York Heart AssociationN2ONitrous OxideOPCObjective performance criteriaPVPulmonary veinPAFParoxysmal atrial fibrillationPCIPercutaneous coronary interventionPICPatient informed consentPVIPulmonary vein isolationPTCAPercutaneous transluminal coronary angioplastyPMDAPharmaceuticals and Medical Devices AgencyPMA-SPremarket Approval SupplementRFRadiofrequencyRIRight inferiorRSRight superiorSDStandard deviationSFShort formSAESerious adverse eventSAPStatistical analysis planSCDSudden cardiac deathSADESerious adverse device effectTEETransesophageal echocardiogramVersion 4, 10NOVO016Confidential
056-F275, Clinical Investigation Plan Template, Version 2.0Page 14 of 115TIATransient ischemic attackTTETransthoracic echocardiogramTTMTrans-telephonic monitoringUSUnited StatesUADEUnanticipated adverse device effectUSADEUnanticipated serious adverse device effect3. Sponsor ContactsRegional contact information is provided below. This information may be subject to change during the courseof the study. Periodic updates to study contact information will be sent to centers as needed.Table 2: Study Sponsor Contact InformationStudy ContactsWorldwide and US Clinical Study LeaderDana Wigert, Principal Clinical Research SpecialistDirect Phone: 763-526-2802Direct Fax: 763-367-1727Email: dana.wigert@medtronic.comEuropeDaniel Becker, Senior Clinical Research SpecialistDirect Phone: 49 215981490Direct Fax: 49 21598149100Email: daniel.becker@medtronic.comCanadaMary McCann, Senior Clinical Research SpecialistDirect Phone: 905-460-3639Direct Fax: 905-460-3998Email: shiko Ishiwatari, Senior Clinical Research SpecialistDirect Phone: 81-3 6776-0105Direct Fax: 81-3 6774-4705Email: yoshiko.ishiwatari@medtronic.comUS, CanadaBeth Ornell, Clinical Monitoring ManagerDirect Phone: 508-261-8000Email: beth.a.ornell@medtronic.comVersio
Director of the Arrhythmia Service, 056-F275, Clinical Investigation Plan Template, Version 2.0 Page 2 of 115 Version 4, 10NOVO016 . Cardiology Consultants of Texas, 621 North Hall Street, Suite 4400, Dallas, TX 75226 . Telephone: 469-800-7400 . . University of Arizona, Chief of Cardiac EP, Banner-University Medical Center-Phoenix, Director of
