FII 2013 HygieneAIC 2014
Univ.‐ Prof.Dr.med.FrankM.BrunkhorstCenterforClinicalStudies(CCS)
JenaUniversityHospital
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
Arten von klinischen Studien
Wegscheider K. 2. Wissenschaftliches Diskussionsforum zur Nutzenbewertung im Gesundheitswesen, Berlin, 21. Oktober 2008
Ways to find “truth” …
Bremen 2015Brussels 2015
CenterforClinicalStudies(CCS)JenaUniversityHospital
FII 2013 HygieneAIC 2014
Statisticalconclusions,notindividual Statisticalconclusionsarenotpreciseinnature
(„Confidenceintervalsvsp‐values“).
Studyconclusions may notbe validinother settings(external validity)
Studyconclusions may notbe validincertain subgroups
Studyconclusionsnotvalidforever(„creeping“)
Limitations of clinical studies
Wegscheider K. 2. Wissenschaftliches Diskussionsforum zur Nutzenbewertung im Gesundheitswesen, Berlin, 21. Oktober 2008Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
Limitations of clinical studies
Wegscheider K. 2. Wissenschaftliches Diskussionsforum zur Nutzenbewertung im Gesundheitswesen, Berlin, 21. Oktober 2008Bremen 2015
Chance
Heterogenicity
Unsuitable outcome
External validity
Differentialmissings
Lackof blinding
Hiddenbias
Overt bias
unknown
Meta‐Analysis RCT
Cohort‐study
Case‐controlstudy Registry
Qualitativestudy
‐
‐
‐
‐
Brussels 2015
Source
FII 2013 HygieneAIC 2014
Randomizedcontrolledtrialsdeliveronlyapartofinformation,whichpatientsandphysiciansneedfordecisionmaking OtherstudytypesmustbeaddedandmaybemoreimportantfortheindividualdecisionthanquantifyingefficacybyRCTs
Conclusions
Wegscheider K. 2. Wissenschaftliches Diskussionsforum zur Nutzenbewertung im Gesundheitswesen, Berlin, 21. Oktober 2008Bremen 2015Brussels 2015
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Register
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Nogivenintervention(non‐interventionalstudy)
Norandomization
Precisedefinedtargetpopulation
Representativeortotalinclusionofthetargetpopulation
Active,standardizeddataassessment
Registrys
AG Memorandum Register für die Versorgungsforschung Gesundheitswesen 2010; 72(11): 824-839Bremen 2015Brussels 2015
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Notprimarilydesignedforproofofefficacy,
Descriptionofepidemiologicalinteractionsanddifferences Supportofqualityassessmentand–improvementmeasures Supportoffurtherandnewclinicalresearchprojects Evaluationandmonitoringofpatientsafety Evaluationofefficacyunderreal–lifeconditions Oeconomicevaluation Minimumquantityresearch Supportinhealthcareservicesresearch
Registrys
Brussels 2015
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„Sciencetellsuswhatwecando;Guidelineswhatweshoulddo;
Registrieswhatweareactuallydoing.„
LukasKappenbergerMDHeartRhythmSocietyPolicyConference
WashingtonDC2005
8
Take home message
Bremen 2015Brussels 2015
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Australian Clinical Quality Registers
http://www.registries.org.au/Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014 10* AAgency for Healthcare Research and Quality; U.S. Department of Health and Human Services, www.ahrq.gov
CytoSorb Registry – fulfils operatingprinciples of clinical quality registries *
Cleardefinition of purposes aiming atimproving thequality of health care
Datacollection focussed onessentialfeatures ofmedicinal product use
Datacomprise objective,reliable and reproducibleitems
Datacontribution by individualparticipants employsstandardized procedures
Datacover alargeproportion of the eligible population Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014 11* AAgency for Healthcare Research and Quality; U.S. Department of Health and Human Services, www.ahrq.gov
CytoSorb Registry – fulfils operatingprinciples of clinical quality registries *
Datacapture is performed closely to the place andtimeof product use
Dataare uniformly specified and readily comparable
Health careprocedures of product use have establishedlinksto outcomes
Registryincorporates in‐built data validation andmanagement processes
Arobustquality assurance planwarrants continuousdata accuracy control
Bremen 2015Brussels 2015
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Registrycustodianship and ownership is contractuallystipulated
Thirdparty access to data requires Steering Committeeand IRBapproval
Investigators are obliged to adhere to ethic standards
Dataacquisition complies with nationalregulations onprivacy protection
CytoSorb Registry – complies with ethics and privacy protection standards*
* Agency for Healthcare Research and Quality; U.S. Department of Health and Human Services, www.ahrq.govBremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
http://www.cytosorb-registry.orgBremen 2015Brussels 2015
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Principal Investigator Prof.Dr.FrankM.Brunkhorst,JenaUniversityHospital,CenterforClinicalStudies
Projectmanagement
Manja Schein, Jena University Hospital, Center for Clinical Studies
BiometryDr.UlrikeSchumacherJenaUniversityHospital,CenterforClinicalStudies
Datamanagement
ViolaBahr,JenaUniversityHospital,CenterforClinicalStudies
SteeringCommittee Prof.Dr.FrankM.Brunkhorst,JenaUniversityHospitalProf.Dr.JanKielstein,HannoverMedicalSchoolProf.Dr.AndreasMeier‐Hellmann,HeliosClinic ErfurtProf.KarlTräger,UlmUniversityHospitalFrankBorn,Munich UniversityHospitalN.N.
ScientificAdvisoryBoardProf.MervinSinger,LondonProf.JohnKellum,Pittsburgh
CytoSorb Registry - Responsibilities
Bremen 2015Brussels 2015
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Title Registry on CytoSorb Use in Intensive Care Unit Patients
Shorttitle CytoSorb Registry
Population Patients subject to extracorporeal blood purification with CytoSorb®
Indications 1.) Severe sepsis / septic shock2.)Scheduledcardiovascularsurgerywithcardiopulmonarybypass2a.)preemptiveapplicationduringsurgery2b.)postoperativeapplicationinICU3.) Other conditions (e.g. liver failure, acute pancreatitis, major trauma, burns,ARDS)
Design Prospective multi‐center registry, based on systematic data acquisition
Aim Collection,evaluation,anddisseminationofdataonCytoSorbuseunderreal‐lifeconditions
Endpoints Effects of CytoSorb use on:‐ Organintegrity and function (SOFA‐ Score)‐Mechanical ventilation (days)‐ Biomarkersof inflammation ‐ ICUand hospital stay‐ ICUand in‐hospitalmortality ‐ Renalreplacement therapy (days)‐ Safety ‐ Vasopressor use (days)
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Synopsis (1)CytoSorb Registry – Synopis 1
Bremen 2015Brussels 2015
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Inclusioncriteria ‐ CytoSorb use‐ Age ≥ 18
Exclusioncriteria ‐ none
Participatingcenters ‐ ca.30atinception‐ IncreasingrecruitmentinGermany,AustriaandSwitzerlandduringthe
study‐ Possibleexpansiontoothercountries
Timelines Start 01.01.2015
Duration 3 years, with an option of extension
Tentativerecruitment Approx. 1,000 new patients per year
Intermediateassessment Semi‐annually
Evaluation annually
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CytoSorb Registry – Synopis 2
Bremen 2015Brussels 2015
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Baseline Visit1 Treatment Visit2 FollowupInclusion criteria xIndication xDemographics xOriginandlocalizationofinfection xCo‐morbiditiesaffectingAPACHEII/SAPSII xAPACHEII/SAPSIIscore xSOFAscore x xRelevantdiagnostictests x xCytoSorb®applicationdata(duration,anticoagulation,bloodpumpflowrate,vasopressors,corticoids)
x
Renalreplacementtherapy x x xComplications xDaysinICUandhospital xMortalityinICUandhospital xDaysonmechanicalventilation xDaysonrenalreplacementtherapy xDaysonvasopressors xAssessmentoftherapeuticeffect(Likert‐scale) x
17Visit 1: up to 24h before CytoSorb® application; Visit 2: 24h after end of CytoSorb® application; Follow up: Discharge from hospital
CytoSorb Registry (1) – severe sepsis
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014Brussels 2015
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Baseline Visit 1 Treatment Visit 2 Follow upInclusion criteria check xIndication check xDemographics xCo‐morbidities affecting APACHE II / SAPS II xEuroSCORE xRelevant diagnostic tests x xCytoSorb® application data (duration, anticoagulation, blood pump flow rate, vasopressors, corticoids)
x
Renal replacement therapy (type, filter) xSurgery report xSOFA score xAPACHE II / SAPS II score xComplications xDays in ICU and hospital xMortality in ICU and hospital xDays on mechanical ventilation xDays on renal replacement therapy xDays on vasopressors xAssessment of therapeutic effect (Likert‐scale) x
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Visit 1: up to 24h before CytoSorb® application; Visit 2:24h over the second postoperative day; Follow‐up: Discharge from hospital
CytoSorb Registry (2) – preemptive use in elective cardiovascular surgery
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
Baseline Visit 1 Treatment Visit 2 Follow upInclusion criteria xIndication xDemographics xCo‐morbidities affecting APACHE II / SAPS II xAPACHE II / SAPS II score xSOFA score x xEuroSCORE xSurgery report xRelevant diagnostic tests x xCytoSorb® application data (duration, anticoagulation, blood pump flow rate, vasopressors, corticoids)
x
Renal replacement therapy (type, filter) xComplications xDays in ICU and hospital xMortality in ICU and hospital xDays on mechanical ventilation xDays on renal replacement therapy xDays on vasopressors xAssessment of therapeutic effect (Likert‐scale) x
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Visit 1: 24h before CytoSorb® application; Visit 2: 24h after end of CytoSorb® application; Follow up: Discharge from hospital
CytoSorb Registry (3) – after cardiovascular surgery
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
Baseline Visit 1 Treatment Visit 2 Follow upInclusion criteria xIndication xDemographics xCo‐morbidities affecting APACHE II / SAPS II xAPACHE II / SAPS II score xSOFA score x xRelevant diagnostic tests x xCytoSorb® application data (duration, anticoagulation, blood pump flow rate, vasopressors, corticoids)
x
Renal replacement therapy (type, filter) xComplications xDays in ICU and hospital xMortality in ICU and hospital xDays on mechanical ventilation xDays on renal replacement therapy xDays on vasopressors xAssessment of therapeutic effect (Likert scale) x
21Visit 1:up to 24h before CytoSorb® application; Visit 2: 24h after end of CytoSorb® application; Follow up: Discharge from hospital
CytoSorb Registry (4) – use in other indications
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
MainAnalysisPopulation:useinseveresepsisandsepticshock/postoperativeuseincardiovascularsurgery
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24hpre 24hpost…CytoSorbapplication(s)…
SOFApre
Observedin‐hospitalmortality
SOFApost
APACHEII/SAPSII‐predicted
in‐hospitalmortality
Comparisonwitht‐test,linear/quadratic
modelling
Comparisonwithlogisticregressionmodel
time
discharge
Allowanceforcovariatesasforinstance:baselineSOFA;daysonmechanicalventilation;daysonrenalreplacementtherapy;daysonvasopressors
Subgroupanalysisforusageindicationgroups
Descriptiveanalysisofallvariables
CytoSorb Registry – Primary analysis
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
DataManagementwith OpenClinica (https://www.openclinica.com/)OpenClinica istheworldwidefastestgrowingclinicaltrialsoftware,usedfordatacapture,validationandquerymanagement
DataisenteredincentersviaRDE(RemoteDataEntry)andtransferredtotheCenterforClinicalStudiesinJenaviaasecurecommunicationprotocol(https)
OpenClinica supportsGoodClinicalPractice(GCP)andregulatoryguidelinessuchas21CFRPart11(electronicrecordsandelectronicsignatures)
Thesoftwareenablesdifferentiateduserrolesandprivileges Thesoftwarepermitscomprehensiveaudittrailstorecords,aswellasmonitoraccess
anddatachanges
AnalysiswithSASSAS(StatisticalAnalysisSystem)Instituteworksextensivelywithgovernmentagencies Meetsaccessibilitystandardsandcomplieswithallrelevantregulationsforsoftware
anddatasubmissions
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CytoSorb Registry – Data management & analysis
Bremen 2015Brussels 2015
FII 2013 HygieneAIC 2014
Get started ! (1)
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Ethics&informedconsentformsContractsPasswordandaccesstoe‐CRF
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Thank you for your attention !
http://www.zks.uniklinikum-jena.de/
Jena Center of Clinical StudiesBremen 2015Brussels 2015