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Clinical Investigation Plan – PORTICO ICPRB CodeProject AcronymProject VersionVersion Date: CV-12-054-EU-PV: PORTICO I: 5.0: 14JUL2016PORTICO I STUDYInternational Long-term Follow-up Study of PatientsImplanted with a PORTICO ValveClinical Investigation Plan eSt. Jude Medical Coordination Center BVBAThe Corporate VillageDa Vincilaan 11- box F1B-1935 ZaventemBelgiumTel: 32 2 774 69 37Fax: 32 2 774 69 46Prof L. SøndergaardRigshospitalet Copenhagen UniversityHospitalKardiologisk Klinik BBlegdamsvej 92100 CopenhagenDenmarkTel: 45 35452018Prof F.Maisano, MDFESC Head of Cardiovascular SurgeryUniversity Hospital ZurichRamistrasse 100Zurich CH-8091SwitzerlandTel: 41 (0)44 255 33 81Prof S. Worthley, M.B., B.S., Ph.D, F.R.A.C.P,R.A.C.C., F.C.S.A.N.Z.Dept CardiologySt Andrews Hospital350 South Terrace AdelaideSA, 5000AustraliaTel: 61 8 8223 4288Dr. J. RodesInstitut Universitaire De Cardiologie Et DePneumologie de Québec (ICUPQ)2725 ch Sainte-Foy,Québec, QCG1V 4G5CanadaTel: 1 418 656 8711All rights reserved. No portion of this work may be reproduced in whole or in part without the express written permission of SJM International, Inc.Portico Valve will be referred as Portico Valve in the rest of the document.CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 1 of 92CL1000269
Clinical Investigation Plan – PORTICO ICoordinating InvestigatorSIGNATURE PAGECIP PORTICO IInternational Long-term Follow-up Study of PatientsImplanted with a PORTICO ValveVersion 5.014JUL2016Reference #:I have read and agree to adhere to the clinical investigational plan and all regulatory requirementsapplicable in conducting this clinical study.Coordinating InvestigatorPrinted name:Signature:Date:CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 2 of 92CL1000269
Clinical Investigation Plan – PORTICO IAmendmentN Revision ionaleDetailsFirst release of the CIPGlobal modification of the CIP : To allow collection of any otherdata acquired as part of patient’snative aortic valve assessment notcaptured by default in the casereport forms (CRF). To address comments received froml’Agence nationale de sécurité dumédicament et des produits de santé(ANSM) in France regardingdevice deficiencies.Global Modification of the CIP: To include two additional countries(Canada and Australia) toparticipate into the clinicalinvestigation and to adjustsubsequently the approximatenumber of sites.To include an additionalexclusion criterion.Global modification of the CIP: To include additional assessmentsand recommendations stronglyadvised by Steering Committeemembers. To clarify 1 exclusion criterion andcertain study activities required bythe protocol in order to avoidmisinterpretation and to ensure allrequired examinations areperformed.Global modification of the CIP: To integrate all local revisions(Australia, Canada, France andOther EU version) into one Globalversion. To update the protocol to matchroutine practice for TAVI patientfollow-up.CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialSee summaryof changes (inCIP V2.0)See summaryof changes (inCIP V3.0)See summaryof changes (inCIP V4.0)See summaryof changes (inCIP V5.0)Page 3 of 92CL1000269
Clinical Investigation Plan – PORTICO ITable of Contents1234567Summary of changes. 71.1Rationale for revision . 7Synopsis . 102.1Clinical investigation flow charts . 12Contacts . 14Background . 15Clinical study design. 175.1Purpose . 175.2Objectives . 175.2.1Primary Objective . 175.2.2Secondary Objective . 175.3Endpoints . 175.3.1Primary Endpoint. 175.3.2Secondary Endpoints . 175.4Population . 185.5Device description . 185.6Geographical device considerations . 195.6.1For EU sites: . 195.6.2For Australian and Canadian sites: . 195.6.3Investigational device accountability for Australian and Canadian sites: . 195.7Hospital heart team . 205.8Patient screening. 205.9Point of enrollment . 205.10 Inclusion and Exclusion Criteria . 215.10.1 Inclusion Criteria . 215.10.2 Exclusion Criteria . 215.10.3 Additional considerations . 23Procedures. 246.1Clinical investigation flow chart. 246.1.1Cohort A (Prospective) . 246.1.2Cohort B . 246.2Clinical investigation activities and visits . 266.2.1.Enrollment Visit . 336.2.2.Baseline Visit (Cohort A only) . 346.2.3.Portico Valve Implant visit - Index procedure (Cohort A only) . 346.2.4.Pre-Discharge visit (Cohort A only) . 366.2.5.30 Day follow-up visit (Cohort A only) . 366.2.6.1 Year follow-up visit (Cohort A only) . 376.2.7.2 Year follow-up visit . 376.2.8.3 Year follow-up visit . 386.2.9.4 Year follow-up visit . 386.2.10. 5 Year follow-up visit . 396.2.11. Unscheduled Visit . 396.2.12. Description of activities performed by Sponsor Representatives . 396.2.13. Description of post-investigational provision of medical care . 40Clinical Investigation Conduct . 417.1Statements of Compliance . 417.1.1.Adherence to the Clinical Investigation Plan . 417.1.2.Repeated non-compliance. 427.2Informed Consent Process . 427.2.1.General Process . 42CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 4 of 92CL1000269
Clinical Investigation Plan – PORTICO I7.2.2.Patient unable to read or write . 437.3Adverse Event, Adverse Device Effect, Device Deficiency . 437.3.1.Definitions (ISO 14155:2011) . 437.3.2.Procedure for assessing, recording and reporting adverse events, adverse device effects, seriousadverse events, serious adverse device effects and device deficiencies. 457.4Patient Death . 467.4.1.Procedure for recording and reporting Patient Death . 467.5Criteria and procedures for patient withdrawal or discontinuation . 477.6Document and data control . 487.6.1.Traceability of documents and data . 487.6.2.Definition of source data . 487.6.3.Recording of data . 487.6.4.Review of data (source data verification) . 487.7Monitoring . 487.7.1.Designated Monitors. 497.7.2.Monitoring Plan . 497.7.3.National Competent Authority (NCA)/ National Regulatory Authority (NRA) Inspections . 497.8Investigation Termination . 497.8.1.Investigation Conclusion . 508Risks and Benefits of the clinical investigation . 518.1Anticipated clinical benefits . 518.2Anticipated Adverse Events and Adverse Device Effects . 518.3Possible interactions with concomitant medical treatments . 518.4Steps that will be taken to control or mitigate the risks . 518.5Risk-to-Benefit Rationale . 519Statistical considerations. 529.1Analysis population . 529.2Sample size estimation . 529.2.1Cohort A . 529.2.2Cohort B . 529.3Primary endpoint analysis . 529.4Secondary endpoint analysis . 539.5Interim reporting. 5310 Data Management . 5410.1 Data Management Plan. 5411 Document Retention . 5512 Amendments to Clinical Investigation Plan . 5613 Publication Policy . 5714 Investigation Organization . 5814.1 Investigation Management/Sponsor . 5814.1.1 Sponsor Responsibilities. 5814.2 Clinical Investigators . 5914.2.1 Investigator’s responsibilities . 5914.2.2 Clinical Coordinating Investigators . 6014.2.3 Source Data and Patient Files . 6014.3 Boards . 6114.3.1 Steering Committee . 6114.3.2 Clinical Event Committee . 6114.4 Outsourcing of duties and functions . 6114.4.1 Power of Attorney . 6115 Bibliography . 63CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 5 of 92CL1000269
Clinical Investigation Plan – PORTICO IList of AppendiciesAppendix A: Abbreviations . 65Appendix B: Declaration of Helsinki . 67Appendix C: Data Collection Method . 72Appendix D: VARC 2 Endpoints Definitions 19. 74Appendix E: Surgical Risk Assessment Tools . 82Appendix F: Frailty Assessment . 83Appendix G: ATS Guidelines (25) for the Six Minute Walk Test . 84Appendix H: Structured Interview for the Modified Rankin Scale (mRS) . 88Appendix I: Peri-procedural instructions . 89Appendix J: Instruction for paced rhythm assessment in patients with a TAVI related implantation ofpermanent pacemaker . 90Appendix K: Explant, Return, and Analysis of Valve. 91Appendix L: Instructions for device return - Large and Small Kits . 92CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 6 of 92CL1000269
Clinical Investigation Plan – PORTICO I1 Summary of changes1.1Rationale for revisionThe primary purpose of this revision is to create a single global Portico I Clinical Investigation Plan (CIP),compiling the EMEA, French, Australian and Canadian CIP versions into a single global version. Minorgeographical differences will be outlined as necessary in the appropriate sections. A detailed Summary ofChanges comparing each of the previous CIP versions is separately available. Additional modifications havebeen made to align the study assessments and data collection with current practice.Modification 1Local CIP versions (EMEA Revision 4.0 17DEC2013 France Revision 3.1 27JAN2014, Australian Revision4.1 28JAN2014, and Canadian Revision 4.1 22JAN2014) are consolidated into one global CIP version. Forthis reason both Clinical Coordinating Investigators, Prof L.SØndergaard (EU), Prof F. Maisano (EU), andboth National Principal Investigators, Prof S. Worthley (AU) and Dr. Rhodes (CA), are listed with theirrespective addresses including their signatures. Specific local requirements are provided in the global protocolin their respective sections.Modification 2The 6 Month visit was removed throughout the CIP because a visit at this interval is not done in routinepractice. This includes the removal of all separate assessments at 6 months and their corresponding eCRFs.Modification 3The Secondary Endpoints have been modified to align with VARC 2 defined events. The rate of all-causemortality, cardiovascular mortality, myocardial infarction, stroke (disabling and non-disabling), bleeding (lifethreatening, major and minor), acute kidney injury, vascular access complications (major and minor) through30 days following index procedure, new or worsened conduction disturbances and cardiac arrhythmias will beevaluated at 30 days and annually through 5 years post implant. Prosthetic valve function and clinical benefitendpoints will be evaluated at 30 days and annually through 5 years post implant.Modification 4The Secondary Endpoint “Evaluation of the TAVI-related resource utilization up to 5-years post-implant” hasbeen changed to “Evaluation of the TAVI-related resource utilization until discharge”. This includes asimplified hospital resources utilization section on the case report form.Modification 5The Secondary Endpoint “Evaluation of the device implantability characteristics” (deliverability,retrievability, and repositionability, placement accuracy and deployment) is removed. Separate characteristicson deliverability, retrievability, and repositionability, placement accuracy will still be collected.Modification 6The Secondary Endpoint “Reporting of the VARC 2 event rates for a sub-population comprising the nonproctored cases only” has been removed.Modification 7The Secondary Endpoint “Impact of annulus sizing method (MSCT versus Echocardiography or otherimaging modalities) on patient’s outcomes” has been removed.Modification 8The data collection for the Secondary Endpoint “Evaluation of impact of anesthesia on patient’s outcome” hasbeen reduced. The type of anesthesia will still be collected.CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 7 of 92CL1000269
Clinical Investigation Plan – PORTICO IModification 9The time points for reporting on the Secondary Endpoint “Interim reporting of all-cause mortality on a subsetof patients compared with an appropriate external comparator” has been changed from 6 months and 1year to30 days and 1 year.Modification 10The window for the echo Baseline measurement has been changed from within 45 days of index procedure towithin 6 months of index procedure.Modification 11The Inclusion Criterion has underlined verbiage in addition:“Subject has senile degenerative aortic valve stenosis confirmed by echocardiographically derived criteria: An initial aortic valve area (AVA) of less than or equal to ( ) 1.0 cm2 (or indexed EOA less than orequal to ( ) 0.6 cm2/m2)AND A mean gradient greater than ( )40 mmHg or jet velocity greater than ( )4.0 m/s or Doppler VelocityIndex less than ( )0.25.If the mean gradient is 40 mmHg and left ventricular ejection fraction (LVEF) 55%, then the site may aswell perform a dobutamine stress echo to see if the mean gradient increases to 40 mmHg.”(Baseline measurement taken by echo within 6 months of index procedure.)Modification 12The Exclusion Criterion “Patient needs an embolic protection device” was removed.Modification 13The time point requirements for the frailty assessments (e.g. 5 meters walking time, grip strength with handheld dynamometer, wasting and malnutrition assessment (including blood sample to obtain serum albuminvalue)) and cognitive impairment or dementia assessment (via the mini-mental state examination (MMSE))have been reduced. These tests will be assessed at Enrollment/Baseline, 30d and 1Year only.Modification 14The time point requirements for the Modified Rankin Scale (mRS) have been reduced. The mRS will beconducted Enrollment/Baseline, Pre-Discharge, 30 days, 1Year and (if possible) 90 days after anyneurological event (stroke, TIA, encephalopathy).Modification 15The requirement to assess a 12 Lead ECG beyond the 1 year follow-up has been removed. In addition theuploading of the required 12 Lead ECG at Enrollment/Baseline, Pre-discharge, 30 days and 1 year has beenremoved. An ECG may still be requested in the case of potential cardiac related AE.Modification 16The requirement to provide Baseline CT Scan (if routinely performed), angiography and echocardiographyexams at the predefined visits to Sponsor has been removed. These recording will only be provided to Sponsorupon Sponsor request . Echocardiography will be routinely provided to the Core Laboratory for analysis.Modification 17The requirement to complete and sign a record of the heart team’s recommendation for each patient enrolledin the study has been removed. The Heart team recommendation, including the presence of physicians, can bedocumented according to the sites standard procedure and available for periodic site monitoring.Modification 18The Steering Committee will consist of 4 members: Prof. L. SØndergaard (EU), Prof. F. Maisano (EU), Prof.S. Worthley (AU) and Dr. Rhodes (CA).Modification 19CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 8 of 92CL1000269
Clinical Investigation Plan – PORTICO IThe protocol section on the Internal Safety Committee is removed because an external committee will beused.Modification 20The 6 month Echo requirement has been removed.The requirement to use a separate echocardiographic guideline has been removed. Routine echocardiogramscan be used to complete the reduced datafields on the echocardiogram study Case Report Forms (CRFs).Modification 21Patients that undergo an implant attempt but did not receive a Portico Valve Implant will be followed forresolution of any procedure or Portico system related AEs. The patient should then be withdrawn from theclinical investigation.Modification 22Annual follow-up visits beginning at year 2 may be conducted at outside hospitals and reported to the studysite provided the study site follows local laws and appropriately obtains the necessary source documents tocomplete the study Case Report Forms (CRFs).Modification 23Appendix J title has been changed from Instruction towards Recommendation for paced rhythm assessment inpatients with a TAVI related implantation of permanent pacemaker.Other modificationsMinor corrections of typos and grammatical errors having no impact on the content of the protocol have alsobeen made.CV-12-054-EU-PV PORTICO I CIP V5.0 20160714 (4)SJM ConfidentialPage 9 of 92CL1000269
Clinical Investigation Plan – PORTICO I2 :International long-term follow-up study of patients implanted with a PORTICOvalve.PORTICO IThe purpose of this clinical investigation is to further assess the performance andsafety profile of the Portico TAVI System in patients with severe symptomaticaortic stenosis.The primary objective of this clinical investigation is to assess the 1 year all-causemortality of patients with severe symptomatic aortic stenosis, implanted with aPortico Valve as per current guidelines.1 The secondary objective of this clinicalinvestigation is to assess the 30 day and long-term performance and safety profileof the Portico valve in patients with severe symptomatic aortic stenosis.The primary endpoint is all-cause mortality at 1 year post implantThe secondary Endpoints are: Evaluation of the VARC-219 defined event* rates at 30 days, 1 year, 2 years, 3years, 4 years and 5 years post implant.o All-Cause Mortalityo Cardiovascular Mortalityo Myocardial Infarctiono Stroke (disabling and non-disabling) Evaluation of the VARC-219 defined event* rates at 30 days from the indexprocedureo Vascular access site complication (major and minor)o Bleeding (life-threatening, major and minor)o Acute kidney injury New or worsened conduction disturbances and cardiac arrhythmias (includingpacemaker implantation rate at 30 days and new-onset atrial fibrillation (AF)) Prosthetic valve function at 30 days, 1 year, 2 years, 3 years, 4 years and 5years post implant. (Prosthetic valve stenosis and prosthetic valveregurgitation). Clinical benefit endpoints as measured with NYHA classification and 6MWT,at 30 days, 1 year, 2 years, 3 years, 4 years and 5 years post implant, andQOL (EQ-5D questionnaire) until 1 year post implant.Design: Evaluation of the TAVI-related resource utilization through hospitaldischarge (e.g. index
See summary of changes (in CIP V4.0) 4 V5.0 22JUN2016 Global modification of the CIP: To integrate all local revisions (Australia, Canada, France and Other EU version) into one Global version. To update the protocol to match routine practice for TAVI patient follow-up. See summary of changes (in CIP V5.0)
