clinical study protocol preventing cholestasis in … · 2017-11-15 · o immune mediated hemolytic...
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page1of39
CLINICALSTUDYPROTOCOL
PREVENTINGCHOLESTASISINPREMATUREINFANTSUSINGSMOFLIPID®
Version1.10/98.311.20121ConfidentialityStatementTheinformationcontainedinthisdocument,especiallyunpublisheddata,isthepropertyofthesponsorofthisstudy.Itisthereforeprovidedtoyouinconfidenceasaninvestigator,potentialinvestigator,orconsultant,forreviewbyyou,yourstaff,andanIndependentEthicsCommitteeorInstitutionalReviewBoard.ItisunderstoodthatthisinformationwillnotbedisclosedtootherswithoutwrittenauthorizationfromtheDepartmentofPediatrics,MedicalUniversityViennaexcepttotheextentnecessarytoobtaininformedconsentfromthosepersonstowhomthestudydrugmaybeadministered.
Testdrug(IMP)andPharmaceuticalCompany
SMOFlipid®FreseniusKabiAG,BadHomburg,Germany
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page2of39
Protocolauthors AndreasRepa,MD
InvestigatorsAndreasRepa,MDNadjaHaiden,MDRenateFuiko,PhD
Documenttype Clinicalstudyprotocol
Studyphase PhaseIV
Documentstatus Version1.1
Date 92.311.20121
Numberofpages 38
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page3of39
1. SPONSOR,INVESTIGATOR,MONITORANDSIGNATURESSponsor/orrepresentative(OEL)(AMG§§2a,31,32) MedicalUniversityofVienna,AustriaO.Univ.Prof.Dr.ArnoldPollak________________ ___________Signature(OEL) DateInvestigator(AMG§§2a,35,36) PDDr.med.univ.NadjaHaiden,DepartmentofPediatrics,MedicalUniversityofVienna,Austria _________________ ___________Signature DateMonitor/orRepresentativeofCRO(AMG§§2a,33,34) KoordinierungszentrumfürKlinischeStudien(PD.Dr.JohannesPleiner)_________________ ___________Signature DateStatistician Mag.IreneSteiner_________________ ___________Signature DateClinicalTrialsCenters:MedicialUniversitiyofVienna,Austria
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page4of39
2. PROTOCOLSYNOPSISTITLE PreventingCholestasisinPrematureInfantsUsingSMOFLipid®OBJECTIVES PrimaryObjective
• To compare a mixed parenteral lipid emulsion containing fish oil(SMOFlipid®)withasoybeanoilbased lipidemulsion (Intralipid®) for itseffectontheoccurrenceofparenteralnutritionassociatedcholestasis inextremelylowbirthweightinfants
SecondaryObjectives• To assess the impact of SMOFLipid® on the long term neurocognitive
developmentofextremelowbirthweightinfantsat12and24monthsofcorrectedage
DESIGN/PHASE Prospective,randomized,double-blind,phaseIVstudy.STUDYPLANNEDDURATION Firstpatient
Firstvisit
1stmonth
LastpatientFirstvisit
36months
LastpatientLastvisit
62months
CENTER(S)/COUNTRY(IES)
Singlecenter,Austria(Medical University Vienna, Austria; Department of Neonatology, PediatricIntensiveCareandNeuropediatrics,UniversityChildren´sHospital,)
PATIENTS/GROUPS 200patientsin2groups100patientspergroupBlockrandomizationratio1:1,stratificationbysexandweight(intwogroups:<750gramvs.≥750gram).Incaseoftwins,randomizationwillbeappliedtothefirstborn;thetwinwillbeassignedtotheothertreatmentgroup.Tripletsorhigherwillbeexcluded.
INCLUSIONCRITERIA • Infants born with a birth weight ≤ 1000 Gram (= extreme low birthweightinfants)
• Admissiontotheneonatalwardinthefirst24hoursoflife• Informed consent obtained and randomized on study drug the first 5
daysoflifeEXCLUSIONCRITERIA • Tripletsorhigher
• Conjugatedbilirubin>1.5mg/dlbeforeinclusiontothestudy• Conditions associated with cholestasis independent of parenteral
nutrition:o Inbornerrorsofmetabolismo ViralInfections(cytomegalyvirus,HIV,HepatitisB,C)o Immunemediatedhemolyticdiesease(e.g.Rhesusincompatibility)o Cysticfibrosiso Primarycholestaticdiseasesoftheliver
STUDYPERIODS • OperationalPhase:Theoperationalphaseofthestudywilllastforthreeyears(months1-39)andstartwiththeinclusionofthefirstpatienttothetrialandwillendwiththelastpatient’sdischargefromhospital.
• Follow Up: The follow up phase will last start with the first includedpatientreachingtheageof12monthscorrectedageandwillendat24monthsofcorrectedgestationalageofthelastincludedpatient(months15-62)
INVESTIGATIONALDRUG SMOFLIPID®:initialdose:1g/kg/day targetdose:3g/kg/day
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page5of39
COMPARATIVEDRUG/CONTROLCONDITION
INTRALIPID®initialdose:1g/kg/day targetdose:3g/kg/day
CONCOMITANTMEDICATION In case of of cholestasis (i.e. conjugated bilirubin two times > 1.5 mg/dl),ursodeoxycolicacidat20-30mg/kg/dayisthetreatmentofchoice.In case of severe cholestasis (i.e. conjugated bilirubin > 6 mg/dL) andelevationofliverenzymes(3timesovernormal)arescuetherapyusingpurefishoil(Omegaven®)at0.5-1g/kg/daywillbeallowed.
EFFICACYENDPOINT Incidence of parenteral nutrition associated cholestasis (PNAC), defined asconjugatedbilirubin>1.5mg/dlmeasuredontwoconsecutiveoccasionsbybloodsamplingperformedatleastevery10+/-4days.Basedonapresentincidenceof25%usingthecomparativedrugatthestudycenter(unpublisheddata2007-9)anabsolutedifferenceof15%betweenthegroups(25%vs.10%incidence)wasconsideredclinicallysignificant.
TOLERABILITY/SAFETYENDPOINTS
-
PHARMACOKINETIC/PHARMACODYNAMICENDPOINTS
-
QUALITYOFLIFE/PHARMACOECONOMICENDPOINTS
-
STATISTICALMETHODOLOGY PrimaryEndpointPNAC(definitionseeefficacyendpoint)Nullandalternativehypotheses:H0:ThepercentageofPNACingroup1(investigationaldrug)equalsgroup2(comparativedrug)H1:ThepercentageofPNACingroup1(investigationaldrug)doesnotequalgroup2(comparativedrug)SamplesizecalculationAsamplesizeestimationusingaχ2-testindicatedthat200infants(100/group)arerequiredtodetecta15%diference(10%ingroup1vs.25%ingroup2)withapowerof80%andatwo-sidedsignificancelevelof0.05.Theestimateddropoutrateis22%.Therefore,asamplesizeof122patientspergroupisplanned.Forsamplesizeestimation,datawereassumedtobeindependent.StatisticalmethodologyMainanalysisset(s)Aχ2-testwillbeusedforanalysisoftheprimaryoutcomePNAC.Additionally,theeffectoftreatmentandotherrelevantinfluencefactors(i.e.durationofparenteralnutrition,birthweight,necrotizingenterocolitis)ontheprimaryendpointwillbeanalyzedusingalogisticregressionmodelwithstepwiseselection.Incaseoftwins,theanalysiswillbecarriedout1)asmentionedabove,butonlyincludingthefirstbornand2)bycalculatinga
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page6of39
generalizedlinearmodelwithmotherasrandomfactor.OtherendpointsBailey Scales of InfantDevelopment II at 12 and24months:Differences inthe scores of psychomotor development and neurocognitive development,respectively, between the groups will be analyzed by repeated measuresANOVAs, also accounting for confounder factors (e.g. birth weight, …). Incaseoftwins,theanalysiswillbecarriedout1)asmentionabove,butonlyincludingthefirstbornand2)bycalculatingamixedmodelwithmotherandchildasrandomfactor. Incaseof toomanydropouts,descriptivestatisticswillbecarriedout.ForGrossMotor functionmeasurements at 12 and 24months, descriptivestatisticswillbeconducted.
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page7of39
3. LISTOFABBREVATIONSELBW ExtremeLowBirthWeightICH InternationalConferenceonHarmonizationILE IntravenousLipidEmulsionGCP GoodClinicalPracticeDHA DocosahexaenoicAcidDOH DeclarationofHelsinkiLC-PUFA LongChainPolyunsaturatedFattyAcidsPN ParenteralNutritionPNAC ParenteralNutritionAssociatedCholestasis
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4. TABLEOFCONTENTSCLINICALSTUDYPROTOCOL 1PREVENTINGCHOLESTASISINPREMATUREINFANTSUSINGSMOFLIPID® 11. SPONSOR,INVESTIGATOR,MONITORANDSIGNATURES 32. PROTOCOLSYNOPSIS 43. LISTOFABBREVATIONS 74. TABLEOFCONTENTS 8TABLE1.VISITANDASSESSMENTSCHEDULE 105. BACKGROUNDINFORMATION 115.1 BACKGROUND 115.2 STUDYRATIONALE 146. STUDYOBJECTIVES 146.1 PRIMARYOBJECTIVE 146.2 SECONDARYOBJECTIVES 157. STUDYDESIGN 157.1 STUDYPOPULATION 157.1.1 SUBJECTPOPULATION 157.1.2 INCLUSIONCRITERIA 157.1.3 EXCLUSIONCRITERIA 157.1.4 STUDYDURATION 167.1.5 WITHDRAWALANDREPLACEMENTOFSUBJECTS 167.1.6 PREMATURETERMINATIONOFTHESTUDY 178. METHODOLOGY 178.1 STUDYMEDICATION 178.1.1 DOSAGEANDADMINISTRATION 178.1.2 STUDY-DRUGUP-ANDDOWNTITRATION 188.1.3 STUDYDRUGINTERRUPTIONORDISCONTINUATION 188.1.4 STUDYDRUGPREMATUREPERMANENTDISCONTINUATION 188.1.5 STUDY-DRUGDELIVERY&DRUGSTORAGECONDITIONS 188.1.6 STUDYDRUGPACKAGINGANDLABELING 198.1.7 IMPADMINISTRATION&HANDLING 198.1.8 DRUGACCOUNTABILITY 198.1.9 PROCEDURESTOASSESSSUBJECTSCOMPLIANCE 19208.1.10 CONCOMITANTMEDICATION 208.2 RANDOMIZATIONANDSTRATIFICATION 208.3 BLINDING 208.3.1 EMERGENCYPROCEDUREFORUNBLINDING 21208.3.2 UNBLINDINGATTHEENDOFTHESTUDY. 21208.4 BENEFITANDRISKASSESSMENT 21208.5 STUDYPROCEDURES 22218.5.1 GENERALRULESFORTRIALPROCEDURES 22218.5.2 SCREENINGINVESTIGATION 22218.5.3 END-OF-STUDY(EOS)EXAMINATION 22218.5.4 LABORATORYTESTS 22219. SAFETYDEFINITIONSANDREPORTINGREQUIREMENTS 25249.1 ADVERSEEVENTS(AES) 2524
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9.1.1 SUMMARYOFKNOWNANDPOTENTIALRISKSOFTHESTUDYDRUG 25249.1.2 DEFINITIONOFADVERSEEVENTS 26259.2 SERIOUSADVERSEEVENTS(SAES) 26259.2.1 HOSPITALIZATION–PROLONGATIONOFEXISTINGHOSPITALIZATION 27269.2.2 SAESRELATEDTOSTUDY-MANDATEDPROCEDURES 27269.2.3 SUSPECTEDUNEXPECTEDSERIOUSADVERSEREACTIONS(SUSARS) 279.3 SEVERITYOFADVERSEEVENTS 28279.4 RELATIONSHIPTOSTUDYDRUG 28279.5 REPORTINGPROCEDURES 29289.5.1 REPORTINGPROCEDURESFORSAES 30299.5.2 REPORTINGPROCEDURESFORSUSARS 30299.5.3 ANNUALSAFETYREPORT 3010. FOLLOW-UP 313010.1 FOLLOW-UPOFSTUDYPARTICIPANTSINCLUDINGFOLLOW-UPOFADVERSEVENTS 313010.2 TREATMENTAFTERENDOFSTUDY 313011. STATISTICALMETHODOLOGYANDANALYSIS 313011.1 ANALYSISSETS 313011.2 SAMPLESIZECONSIDERATIONS 313011.3 RELEVANTPROTOCOLDEVIATIONS 323111.4 STATISTICALANALYSISPLAN 323111.5 MISSING,UNUSEDANDSPURIOUSDATA 323111.6 ENDPOINTSANALYSIS 323111.6.1 PRIMARYENDPOINTANALYSIS 323111.6.2 SECONDARYENDPOINTANALYSIS 3211.6.3 SAFETYANDTOLERABILITYENDPOINTS 333211.6.4 BASELINEPARAMETERSANDCONCOMITANTMEDICATIONS 333211.7 INTERIMANALYSIS 333211.8 SOFTWAREPROGRAM(S) 333212. DOCUMENTATIONANDDATAMANAGEMENT 333212.1 DOCUMENTATIONOFSTUDYRESULTS 333212.1.1 CASEREPORTFORM(CRF) 3312.1.2 DATACOLLECTION 343312.2 SAFEKEEPING 343312.3 QUALITYCONTROLANDQUALITYASSURANCE 353412.3.1 PERIODICMONITORING 353412.3.2 AUDITANDINSPECTIONS 353412.4 REPORTINGANDPUBLICATION 353412.4.1 PUBLICATIONOFSTUDYRESULTS 3513. ETHICALANDLEGALASPECTS 363513.1 INFORMEDCONSENTOFSUBJECTS 363513.2 ACKNOWLEDGEMENT/APPROVALOFTHESTUDY 363513.2.1 CHANGESINTHECONDUCTOFTHESTUDY 363513.3 INSURANCE 373613.4 CONFIDENTIALITY 373613.5 ETHICSANDGOODCLINICALPRACTICE(GCP) 373614. APPENDICES 383715. REFERENCES 3837
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TABLE1.VISITANDASSESSMENTSCHEDULE
PERIODS Name SCREENING TREATMENT FOLLOW-UP
Duration months 2years
VISITS Number 1 2 3 4 5 6 7 8 9 10 11
Name Screening Randomization
Control1 Control2 Control3 Control4 Control5 Control6 Control7 EndofStudy
Follow-up
Time Day0 Day0-2 Week2 Week4 Week6 Week8 Week10 Week12 Week16 Week18 Month16and28
(± 4days)
(± 4days)
(± 4days)
(± 4days)
(± 5days) (± 7days)
(± 7month)
(± 1month)
(± 5days)
InformedConsent X
Inclusion/ExclusionCriteria X
MedicalHistory X X X
PhysicalExamination X X X
Bodyweightandheight X X X X X X X X X XConcomitant/Changeinmedication X X X X X X X X X
VitalSigns(BP,PR) X X X X X X X X X XLabTests(Bilirubin,liverfunction) X X X X X X X X X
Visualevokedpotentials X(36wks
GA)
CerebralFunctionMonitoring X X X X X X X X
CerebralUltrasound X X X X X X X X X AdverseEvents(IVH,NEC,ROP,BPD) X X X X X X X X PsychomotorDevelopmentalTests X
Ophtalmologicexam X X X X X X X XAdverseEvents(IVH,NEC,ROP,BPD) X X X X X X X X
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page11of39
5. BACKGROUNDINFORMATION
5.1 Background5.1.1Parenteralnutritionassociatedcholestasis(PNAC)
Sincethefirstdescriptionofparenteralnutritionassociatedliverdisease1itiswellestablishedthat
patientsreceivingparenteralnutrition(PN)areatriskfordevelopinghepaticcomplications.In
neonatesandinfants,liverinjuryischaracterizedbyanearlyoccurrenceofintrahepaticcholestasis-
i.e.parenteralnutritionassociatedcholestasis(PNAC)-characterizedbyariseinserumconjugated
bilirubin2.Inseverecaseslivercelldamageandevenprogressiveliverdysfunctionwithanincidence
ofhepaticfailureofupto17%isdescribed3.
5.1.2.Extremelowbirthweightinfants
Preterminfantswithextremelowbirthweight(ELBW)<1000gramareoftendependentonlong
termPNduetointoleranceofenteralfeedings4.Additionallytheyfrequentlyacquirenosocomial
infectionsandareatriskfordevelopingnecrotizingenterocolitis,asevereinflammatorydiseaseof
theintestinewithconsiderablelongtermmorbiditysuchasshortgutsyndrome.Prematurity,long
termPN,nosocomialinfections,necrotizingenterocolitisandshortgutsyndromeareallarerisk
factorsforthedevelopmentofPNAC.ThereforeELBWinfantsareathighrisktodevelopthis
complication2.
5.1.3.ParenterallipidsaspathogenicfactorinPNAC
Besidesfactorsrelatedtoprematurityanditscomplicationsorshortgutsyndrome,PNACis-as
alreadyproposedbythecondition’sname-closelylinkedtoaspectsofPN.Hypercaloricfeedswith
anexcessofglucosecanresultinchroniccholestasis5.Mostimportanthowever,intravenouslipid
emulsions(ILE)seemtobeimplicatedinthedevelopmentofPNAC.Higherparenterallipid
administrationhasbeendocumentedtobecorrelatedwithcholestasisinpediatricpatients6aswell
asverylowbirthweightinfants7.
5.1.4.Soybeanoilbasedintravenouslipidemulsions
Untilnowadays,standardofcareforsupplyinglipidsinPNofpreterminfantsandsickneonatesare
ILEbasedonsoybeanoil(Intralipid®)2.Someofthecomponentsofsoybeanoilarebelievedtobe
implicatedinthepathogenesisofPNAC.Theirhighcontentofω-6polyunsaturatedlongchainfatty
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
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acidsmayexertpro-inflammatoryeffectsandplantsterolsfromsoymayreducebileflowandboth
factorswerelinkedtothedevelopmentofPNAC8.
5.1.5.Fishoilbasedintravenouslipidemulsions
Inrecentyears,ILEscontainingfishoilwereproposedfortreatmentofPNACinpediatricpatients
mainlysufferingfromshortgutsyndrome.Tworesearchgroupsconsecutivelydescribedthe
successfultreatmentofseverePNACinneonatesusingOmegaven®9,10anILEcomposedexclusively
offishoil.Therationalebehindthepositiveeffectsobservedisbuiltontheirhighcontentofω-3
fattyacidswhichactanti-inflammatoryandarethoughttoimprovebileflow11.However,whether
fishoiloronlyreplacementofsoybeanoilbasedILEinPN6causedtheimprovementinthese
patients,cannotbeconcluded.Prospectivetrialsarerequiredtosubstantiatetheevidence8.
5.1.6.PreventingPNACinELBWinfants
InviewoftheirhighrisktodevelopPNAC,ELBWinfantscouldprofitfromaprophylactic
intervention.BasedonthepromisingresultsinthetreatmentofPNAC,ILEsbasedonfishoilseem
attractivecandidates.However,anILEbasedon100%fishoillikeOmegaven®maydelivernot
enoughω-6fattyacidsandthereforecannotbeusedastheexclusiveILEsfornutritionofELBW
infants8.
WithabroaderpanelofILEsavailabletoday,amixtureoffishoilwithsoybeanoil,mediumchain
triglyceridesandoliveoil(SMOFlipid®)hasrecentlyemerged.Aprospectivestudyinatotalof60
preterminfantsshowedthatPNwithSMOFlipid®inducedlowerserumγ-glutamyltransferaselevels
comparedtocontrolsreceivingasoybeanoilbasedILE,suggestingafavourableinfluenceon
cholestasisandliverfunction12.Aprospectiverandomizedtrialin28pediatricpatientsdemonstrated
areductionintotalbilirubinlevelsusingSMOFlipd®comparedtoasoybeanoilbasedILE13.
ImportantlySMOFlipid®isregisteredforPNofpreterminfants,whichmakesadirectcomparisonof
Intralipid®andSMOFlipid®inthesevulnerablepatientsethicallyacceptable14.
5.1.7.Fishoilandneurocognitivedevelopment
LongChainpolyunsaturatedfattyacids(LC-PUFA)arebothstructuralandfunctionallipidsplayingan
importantroleingrowthanddevelopmentofthefetusandthenewborn.Inparticularthe22:6ω3-
LC-PUFAdocosahexaenoicacid(DHA)isdeemedtobecrucialforanormaldevelopmentofthefetal
brain.Inutero,highamountsofDHAcrosstheplacentainthelasttrimester.Afterbirthmother’s
milkisthemostimportantsource15.
Preterminfants–astheirendogenouscapacitytosynthesizeDHAfromprecursorfattyacidsis
limited–dependonexogenoussupply16.Inthiscontext,preterminfantsaccumulateadeficitofup
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PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33
Date19.3.2012 Version1.1 Page13of39
to44%comparedtoinuteroaccretionrates16.InviewofthedocumentedcorrelationofDHAdeficit
andlowbirthweight16ELBWinfantsareatparticularrisk,astheydependPNforseveralweeksand
DHAisabsentinthetraditionalsoybeanoilbasedILEs.AstheonlysourceofDHAforthepreterm
infantismother’smilkorpretermformuaandnotILEs,theprolongedtimeuntilfullenteralfeedsare
establishedinthesepatientsseemsparticularlycritical.
ThereforeanILElikeSMOFlipid®containgfishoilthatprovidesDHAwouldreducethisdeficitand
maythereforeconferpotentialbenefitsfortheneurocognitivedevelopment.
5.1.8.CurrentStatusofresearchonfishoilandparenteralnutritionassociatedcholestasisin
preterminfants
TherearecurrentlynostudiespublishedonafishoilcontainingILEforprophylaxisofPNAC.
ThereisgrowingsupportiveevidencefortreatmentofestablishedPNACusingILEbasedonfishoilin
pediatricpatientsfromtwoobservationalandoneprospectiveclinicaltrial,buttherearenodata
frompreterminfants.
ThegrowingbeliefinatherapeuticeffectoffishoilcontainingILEsonPNACisbasedonthe
publishedexperienceofcliniciansfromBostonaroundMarkPuder11andTorontoaroundPaulWales9.TheybothdescribedneonateswithsevereshortgutsyndromeandPNACthatdramatically
improvedafterreplacingsomeofthe100%soybeanoilbasedILE“Intralipid®”witha100%fish-oil
basedILE(Omegaven®)(Toronto)orcompletelyswitchingovertoafishoilbasedILE(Boston).The
Bostongroupreportedaresolutionofcholestasisin45-61%(publishedcases:60)10,17.TheToronto
groupreportedarateofresolutionof63%(publishedcases:22)18.Poolingthesecasestogether,a
meanof53.6%(44/82)ofpatientsshowedreversalofcholestasis.Forcomparison,historicalcohorts
ofcomparablepatientswhoreceivedthesoybeanoilbasedIntralipid®forPN,showedresolutionof
cholestasisonlyin5-33%duringthediseasecourse(publishedcases:47)10,17.
TheonlyprospectivetrialusingamixedILEcontaningfishoil(SMOFlipid®)inpediatricpatients
reportedasignificantreductionoftotalbilirubinlevelscomparedwiththesoybeanoilbasedILE
Intralipid®13.
TheonlyprospectivestudyperformedinapopulationofpreterminfantswasperformedbyTomsits
etal12.Inhealthypreterminfants(birthweights1000–2500gramm)theydemonstratedgood
clinicaltoleranceandlowerγ-glutamyltransferaselevelsusingSMOFlipid®comparedtostandard
carewithIntralipid®.Thoughliverfunctionwasonlyasecondaryoutcomeparameterofthestudy
andtheobservationalperiodwastooshorttoassessanyeffectonPNAC,thisfindingsupportsa
prophylacticeffectofSMOFlipid®onliverfunction,underliningtheneedforfurtherinvestigations.
5.1.9.CurrentStatusofresearchonfishoilandneurodevelopmentofpreterminfants
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Therearecurrentlynostudiesonlongtermneurodevelopmentofpreterm–inparticularELBW-
infantsafterusingafishoilcontainingILE.
ThereareprospectivetrialsonenteralsupplementationwithLC-PUFAcontainingDHAfromfishoilin
preterminfantsandduringpregnancywithmixedresults15,19.
ClinicalstudiesinpreterminfantsfocusedonenteralsupplementationofLC-PUFAs(includingDHA)
fromfishoilinformulafeedings.Inthiscontext,aCochraneReviewin2008bySimmeret.al19
concludedthatcurrentlythereisnoconvincingevidenceofasustainedimprovementof
neurodevelopmentbyLC-PUFAsupplementation.However,asthemeanbirthweightofpreterm
infantsenrolledinthesestudieswasconsistently>1000gram(1074–1980)theauthorsstressed
thatELBWinfantsshouldbeinvestigated19.Inthiscontext,thereisindirectevidencefromtwo
prospectiverandomizedtrials,thatsupplementationofpregnantwomenwithfishoilconvertsa
beneficialeffectonlaterneurodevelopmentoftheirchildren15.Inlinewiththeevidencefromthese
trials,usinganILEcontainingfishoilforparenteralnutritionofELBWinfantscouldclosethegapuntil
ELBWinfantsarefullynourishedwithmother’smilkorformula(supplementedwithLC-PUFA).A
reductionoftheDHAdeficittheseinfantsnormallyaccumulate16mayconferabenefitto
neurodevelopment.
5.2 StudyrationalePrimaryendpoint:
ELBWinfantsareathighriskfordevelopmentofparenteralnutritionassociatedcholestasis(PNAC).
Thereisgrowingevidenceforapositiveeffectoffishoilbasedintravenouslipidemulsions(ILE)for
thetreatmentofPNAC.PrimaryuseofafishoilcontainingILEforPNmaypreventthedevelopment
ofPNAC.
SecondaryEndpoint:
ELBWinfantsaccumulateadeficitofω3-LC-PUFA(especiallyDHA),whichareimportantfor
neurodevelopment.AnILEcontainingfishoilprovidesthesefattyacidsandwouldreducethedeficit
inELBWinfants,whichmayimprovetheirneurocognitivedevelopment.
6. STUDYOBJECTIVES
6.1 PrimaryObjective
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ToinvestigatewhetherELBWinfantstreatedwithtwodifferentILEs(investigationaldrug:
SMOFlipid®,comparativedrug:Intralipid®)differintheoccurrenceofPNAC(conjugatedbilirubin>
1.5mg/dl,measuredontwoconsecutiveoccasions).
6.2 SecondaryObjectives
ToinvestigatewhetherELBWinfantstreatedwithtwodifferentILEs(investigationaldrug:
SMOFlipid®,comparativedrug:Intralipid®)differintheirneurodevelopment(BaileyScalesofInfant
DevelopmentII)at12and24monthsofcorrectedgestationalage
7. STUDYDESIGN
7.1 Studypopulation
7.1.1 SubjectpopulationPopulation:Extremelowbirthweight(ELBW)infants
Recruitment:About90ELBWinfantsareadmittedtoouruniteachyearinthefirst24hoursoflife.
Weexpecttorecruit90%(81patients/ayear)tothestudy.
DropOuts:Basedonamortalityof22%in2010(KlebermaszK.,unpublisheddata)andaconservative
calculation,weexpect18/81patientstodropout,leaving63patientsayearforanalysisofthe
primaryoutcome.Wedonotexpectanyotherreasonsfordropout.
Lossestofollowup:63patientsareexpectedtobedischargedfromhospitaleachyear.Basedona
followuprateof60%afterdischargein2009(FuikoR,unpublisheddata),weexpectabout38/63
patientstobeavailableforanaylsisofthesecondaryoutcomeeachyear.Intheendweexpectto
lose80/200patientstofollowup.
7.1.2 Inclusioncriteria-Infantswithabirthweight≤1000Gram
-Admissiontotheneonatalwardinthefirst24hoursoflife
-Randomizationontherespectivestudydruginthefirst5daysoflife
7.1.3 Exclusioncriteria
Tripletsorhigher
Conjugatedbilirubin>1.5mg/dlbeforeinclusiontothestudy
Conditionsassociatedwithcholestasisindependentofparenteralnutrition:
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-Inbornerrorsofmetabolism
-ViralInfections(cytomegalyvirus,HIV,HepatitisB,C)
-Immunemediatedhemolyticdiesease(e.g.Rhesusincompatibility)
-Diagnosisofcysticfibrosis
-Primarycholestaticdiseasesoftheliver
7.1.4 Studyduration
Theinterventionalphasestartswithrandomizationonthestudydruginthefirst5daysoflifeand
endswithdiscontinuationofPN,typicallyafter6weeks(mean44days+/-SD34days,personal
data).
Thefollowupphaseendsat24months(2years)ofcorrectedgestationalage.
7.1.5 WithdrawalandreplacementofsubjectsCriteriaforwithdrawalPrematurediscontinuationfromthestudyistobeunderstoodwhenthesubjectdidnotundergoEndofStudy(EOS)examinationand/orallpivotalassessmentsduringthestudy.Subjectsmustbewithdrawnunderthefollowingcircumstances:
• attheirparent´srequestatanytime• iftheinvestigatorfeelsitwouldnotbeinthebestinterestofthesubjecttocontinue• ifthesubjectviolatesconditionslaidoutintheconsentform/informationsheetor
disregardsinstructionsbythestudypersonal• ifthesubjectistransferredtoanotherhospitalbeforeparenteralnutritionisdiscontinued• ifthestudydrugwasnotprovided<80%oftimeasplanedperprotocol• Ifanexclusioncriterionismet,afterinclusiontothestudy• deathbeforedayoflife28
Inallcases,thereasonwhysubjectsarewithdrawnmustberecordedindetailintheCRFandinthesubject’smedicalrecords.Shouldthestudybediscontinuedprematurely,allstudymaterials(complete,partiallycompletedandemptyCRFs)willberetained.Follow-upofpatientswithdrawnfromthestudyIncaseofprematurediscontinuationafterstudydrugintake,theinvestigationsscheduledfortheEOSvisitwillbeperformed7+/-4daysafterstudydrugdiscontinuation.Thesubjectswillbeadvisedthatparticipationintheseinvestigationsisvoluntary.Furthermore,theymayrequestthatfromthe
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timepointofwithdrawalnomoredatawillberecordedandthatallbiologicalsamplescollectedinthecourseofthestudywillbedestroyed.ReplacementpolicyPatientswithdrawnfromthestudy<28days(outcomecannotbecalculated)willbereplacedandthenextfreesubjectnumberwillbeallocated.Dropsoutswillbeincludedinthesamplesize.Ifpatientsarewithdrawnfromthestudyandtheoutcomecanbecalculated,(morethantwobloodsamplestaken),theywillbeconsideredintheintentiontotreatanalysis(seechapter10)
7.1.6 PrematureterminationofthestudyThesponsorhastherighttoclosethisstudyatanytime.TheIECandthecompetentregulatoryauthoritymustbeinformedwithin15daysofearlytermination.Thetrialorsingledosestepswillbeterminatedprematurelyinthefollowingcases:
• Ifadverseeventsoccurwhicharesoseriousthattherisk-benefitratioisnotacceptable.• Ifthenumberofdropoutsissohighthatpropercompletionofthetrialcannotrealisticallybe
expected.
8. METHODOLOGY
8.1 StudymedicationActiveagentandcharacteristics:InvestigationalProductTradenameoftheagent: SMOFlipid200mg/mlEmulsionzurInfusionManufacturer: FreseniusKabiAustriaGmbHDrugsupply: FreseniusKabiAustriaGmbHStorageInstructions: Donotfreeze,donotstore>25°Celsius,protectfromlightRouteofadministration: IntravenousComparatorTradenameoftheagent: Intralipid20%-EmulsionzurInfusionManufacturer: FreseniusKabiAustriaGmbHDrugsupply: FreseniusKabiAustriaGmbHStorageInstructions: Donotfreeze,donotstore>25°Celsius,protectfromlightRouteofadministration: Intravenous
8.1.1 DosageandadministrationInitialdose: 1g/kg/d(=5ml/kg/d)
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Maintenancedose: 3g/kg/d(=15ml/kg/d)Routeofadministration: IntravenousDuration: Aslongasparenteralnutritionisneeded
8.1.2 Study-drugup-anddowntitrationAccordingtoastepwiseincreaseorreductionofenteralfeedingsaproportionalincreaseorreductionofparenteralnutritionwillperformedincludingareductionofthestudydrug/comparator.Thestudydrug/comparatorwillbefinishedassoonasfullenteralfeedsarereachedandPNisstopped(at140-160ml/kg/doftotalfluidvolumedependingonthefluidneedsoftheinfant).
8.1.3 StudydruginterruptionordiscontinuationTheinvestigatormusttemporarilyinterruptorpermanentlydiscontinuethestudydrugifcontinuedadministrationofthestudydrugisbelievedtobecontrarytothebestinterestsofthepatient.TheinterruptionorprematurediscontinuationofstudydrugmightbetriggeredbyanAE,adiagnosticortherapeuticprocedure,anabnormalassessment(e.g.,laboratoryabnormalities),orforadministrativereasons,inparticularwithdrawalofthepatient’sconsent.Hypertriglceridemia:Thestudydrugwillbeinterruptedfor24hoursattriglyeridelevels>400mg/dlordowntitratedattriglyceridelevelsof251-400mg/dl.Controlmeasurementsoftriglycridelevelswillbeperformedinthenext24-72hourstocontrolforsuccessfulnormalizationoftriglyceridelevelsunderparenteralnutrition.ThereasonforstudydruginterruptionorprematurepermanentdiscontinuationmustbedocumentedintheCRF.
8.1.4 StudydrugprematurepermanentdiscontinuationStudydrugprematurepermanentdiscontinuationduetoanadverseeventIfthereasonforprematurepermanentdiscontinuationofstudytreatmentisanAE,thepatientshouldhavea“PrematureEndofStudy(EOS)”visitwithalltheassessmentsperformedbeforethestudydrugdiscontinuation,wheneverpossible.StudydrugprematurepermanentdiscontinuationduetoanotherreasonthanadverseeventIfthereasonforprematurepermanentdiscontinuationofstudytreatmentisnotanAE,thepatientshouldbewithdrawnfromthestudy(withdrawalofconsent)andhavetheendofstudy(EOS)visitwithalltheassessmentsperformedbeforethestudydrugdiscontinuation,wheneverpossible.
8.1.5 Study-drugdelivery&drugstorageconditionsThestudydrugwillbedeliveredfromthesupplyingcompanytothehospital´spharmacyinvestigatorsandstoredatroomtemperatureundercontrolledconditions(22°C+/-3°C)inalockedroomcabinett.
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Amin/maxthermometerwillbeusedtocontrolfortemperatureinthestorageroom.Fulldocumentationofdelivery,storageanddispositionwillbemaintained.
8.1.6 StudydrugpackagingandlabelingThestudydrugsaredeliveredinsterileglasscontaninersof100mlbythemanufacturerandwillbere-labelledatthestudysiteasdescribedinsection8.3.Storageisdescribedinsection8.1.5.Forapplicationtostudysubjects,thestudydrugswillbebroughttotheneonatalwardsbyamemberoftheblindingteam.ForIVapplication,thestudydrugswillbetransferredfromthere-labelledcommercialcontainerstoperfusorsyringesconnectedtoperfuorslinessuitableforIVapplicationoftheILE.Perfusorsyringeswillbelabelled(seesamplelabels1and2below).PreparationforIVapplicationwillbedoneinalaminarairhoodundersterileconditionsbytrainedintensivecarenurses,formingpartoftheblindingteam.Perfusorsyringeswillbelabelledbytheblindingteamusingtheprovidedlabels.SampleLabelNumber1SampleLabelNumber1 SampleLabelNumber2
8.1.7 IMPadministration&handlingTheIMPorcomparatormustnotbefrozenorstored>25°C,applicationisperformedinlightprotectedperfusorsyringesandperfusorlines.ApplicationmaybeperformedIVviacentralandperipheralvenouscatheters.TheIMPorcomparatormustnotbemixedwithanyotherdrugbesidesthecommerciallyavailablevitaminsolutions“SoluvitN”and“Vitalipid”(FreseniusKabiAustriaGmbH).
8.1.8 DrugAccountabilityDrugAccountabilitywillberecordedaton-goingbasisonpaperform/sourcedata,DrugdispensinghavetobeenteredintotheCRF.FurthermorethecorrectintakeofIMPoranyvariationsconcerningthatwillberecordedintheCRFateachvisitduringtreatmentperiod
8.1.9 Procedurestoassesssubjectscompliance
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WhethertheIMPorcomparatorwhereadministeredcorrectlywillbefollowedfromthedocumentationintheelectronicpatientdocumentarysystemusedattheneonatalICU.
8.1.10 ConcomitantmedicationThewell-beingofthepatienthasthefirstpriority,andmodificationsofconcomitanttreatmentduringthetrialareallowedasnecessary.Theyshouldbedocumentedinthepatient’srecords.Incaseofofcholestasis(i.e.conjugatedbilirubintwotimes>1.5mg/dl),
Ursodeoxycolicacidat20-30mg/kg/dayisthetreatmentofchoice. Omegaven®isallowedasasaddonat1g/kg/d,ifconj.ugatedbilirubin>6mg/dl,0,5-1g/kg/d
8.2 RandomizationandstratificationOnday0,patientsarerandomizedtooneofthetwostudygroupsandthestudymedicationisprovided.Studysubjectswillbeblockrandomized(ratio1:1)andstratifiedaccordingtosexandbirthweight(intwogroups:<750gramvs.≥750gram)usinganonlinerandomizationprogrammeprovidedbytheCenterforMedicalStatistics,Informatics,andIntelligentSystemsoftheMedicalUniversityofVienna.Incaseoftwins,randomizationwillbeappliedtothefirstborn;thetwinwillbeassignedtotheothertreatmentgroup.
8.3 BlindingBlindingofsubjects,investigatorsandoutcomeassessorswillbeperformedasfollows:BlindingRFirstre-labellingofthestudydrugcontainers(seesamplelabel1and2below)willbeperformedbytwomembersoftheablindingteamof2personsnotinvolvedinthestudycollectionofdata,ortreatmentofstudysubjectspatientsorpreparationofthestudydrugsforIVapplicationafterallocationtooneofthetwostudygroups.ThepersonleadingtheblindingteamwillbeMag.AlexandraKreissl.Thestudydrugsarekeptinglasscontainersof100mlandwillbere-labelledwithsamplesasindicated(seesamplelabel1and2below)andstoredasdescribed(section8.1.5).Second,Ffordeliverytostudysubjectspatientsthestudydrugswillbebroughttransferredtothewardsbyamemberoftheblindingteam,wherethepreparationforIVapplicationwillbedoneinalaminarairhoodbyamemberoftheblindingteamasdescribedinfromthecommercialcontainerstoperfusorsyringesconnectedtoperfuorslinessuitableforIVapplicationoftheILEandlabelledaccordingtosection8.1.7.Asintensivecarenursesinvolvedincaretakingofthepatientsformpartoftheblidingteam,nursingcaregiversarenotblinded.MedicaldoctorsprescribingthedailyamountsoftheIMPremainblinded.SampleLabelNumber1 SampleLabelNumber2:
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SampleLabelNumber1SampleLabelNumber2:ThestudydrugwillbetransferredfromthecommercialcontainerstoperfusorsyringesconnectedtoperfuorslinessuitableforIVapplicationoftheILEandlabelledaccordingtosection8.1.7.Preparationofthestudydrugwillbedoneinalaminarairhoodundersterileconditionsbytheblindingteam.
8.3.1 EmergencyprocedureforunblindingIfunblindingofastudyparticipantisrequiredduetoanemergency,thecodecanbebrokenbytheInvestigator.Codebreakingwillbefullydocumented.
8.3.2 Unblindingattheendofthestudy.Codeswillbebrokenaftertheclose-outMonitoringVisitandthecleaningofthedatabase.
8.4 Benefitandriskassessment
8.4.1Benefitforthepatient
Ifthehypothesisiscorrect,participatingpatientsreceivingthestudymedicationwillbenefitfroma
reducedriskofdevelopingliverinjuryduetolongtermparenteralnutrition.Theywillbenefitfroma
improvedlongtermneurodevelopment.
8.4.2Riskforthepatient
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Thedrugunderinvestigationfulfilledthecriteriaforregistrationforapplicationinpreterminfants.
Therefore,riskforpatientsreceivingthestudydrugshouldnotbehighercomparedtostandardcare.
Intheworstcaseweexpectthattherewillbenobenefit.
8.5 Studyprocedures
8.5.1 Generalrulesfortrialprocedures
• Allstudymeasureslikebloodsamplingandmeasurements(ultrasoundetc.)havetobedocumentedwithdate(dd:mmm:yyyy).
• Incaseseveralstudyproceduresarescheduledatthesametimepoint,thereisnospecificsequencethatshouldbefollowed.
• Thedatesofallproceduresshouldbeaccordingtotheprotocol.Thetimemarginsmentionedinthestudyflowchartareadmissible.Ifforanyreason,astudyprocedureisnotperformedwithinscheduledmarginsaprotocoldeviationshouldbenoted,andtheprocedureshouldbeperformedassoonaspossibleorasadequate.
• Ifitisnecessaryfororganizationalreasons,itisadmissibletoperformprocedureswhicharescheduledforonevisitattwodifferenttimepoints.Allowedtimemarginsshouldtherebynotbeexceeded.
8.5.2 ScreeninginvestigationAtscreening,thepatient´sdemographicdataandlabresults(seeSection7.1.2and7.1.3Inclusion
andExclusionCriteria)willbeevaluatedforeligibilitytothestudy.
8.5.3 End-of-study(EOS)examinationAtdischargeofthepatientfromhospital,patientsundergotheend-of-studyexaminationthatentails
Weight,crownheellength,headcircumferenceandabasicbloodtest(redandwhitebloodcount,
liverfunctiontests,electrolytes)performedinclinicalroutineinallELBWinfants.
8.5.4 LaboratoryTestsBloodcountsandcompletebloodchemistryisroutinelyperperformedaccordingtothelocal
standardofcareattheunitatleastevery10+/-4daysuntildischargefromhospital.Noadditional
bloodsamplingoranalyseswillbeperformedinstudysubjectsincomparisontostandardofcareof
ELBWinfants.
Alllaboratoryparametersofinterestforthestudyroutinelyperformedare:
denomination Variable timeofmeasurement
Conjugatedbilirubin mg/dL every7-14duntildischarge
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ALAT U/L every7-14duntildischarge
ASAT U/L every7-14duntildischarge
γ-glutamyltransferase U/L every7-14duntildischarge
Alkalinephosphatase U/L every7-14duntildischarge
Triglycerides mg/dL every7-14duntildischarge
Additionalparametersusedforthestudy
Alladditionalparametersofinterestaredocumentedorproducedroutinelyduringthepatient’s
admissiontotheunitorfollow-upaccordingtothelocalstandardofcare.Noadditional
interventionswillneedtobeperformed.
denomination Variable timeofmeasurement
Basicdemographicdata
Sex m/f atbirth
Gestationalage days atbirth
Twin yes/no atbirth
Modeofdelivery caesarean/spontaneousatbirth
Prenatalsteroidsforlungmaturation yes/no atbirth
Birthweight gram,ZScore atbirth
Birthcrownheellength cm,ZScore atbirth
Birthheadcircumference cm,ZScore atbirth
Smallforgestationalage yes/no atbirth
Apgarscoresat1,5and10minutes 0-10 atbirth
UmbilicalarterypHatbirth range6.7–7.6 atbirth
Growthandnutritionparameters
Timeonparenteralnutrition days atdischarge
Totalamountofparenterallipids gram atdischarge
Enteralnutritionin1stfirstweekoflife ml/day day0-6
Weightatdischarge gram,ZScore atdischargefromhospital
Crownheellengthatdischarge gram,ZScore atdischargefromhospital
Headcircumferenceatdischarge gram,ZScore atdischargefromhospi
Death>28days yes/no dayoflife28-discharge
(Deathbefore28days=dropout)
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Ifdeath dayoflife dayoflife28-discharge
Neonatal(preterm)morbidities
IntraventricularhemorrhageGrad3/4 yes/no atdischarge
Cysticperiventricularleucomalacia yes/no atdischarge
Chroniclungdisease yes/no atdischarge
Receivedsteroidsforchroniclungdisease yes/no atdischarge
Treatmentforpulomanryhypertension yes/no atdischarge
(Sildenafil,iNO)
Cultureprovensepsis yes/no atdischarge
NecrotizingenterocolitisBell´sStage≥IIa yes/no atdischarge
Focalintestinalpeforation yes/no atdischarge
Abdominalsurgery yes/no atdischarge
IbuprofenforPDA yes/no atdischarge
SurgicalligationofPDA yes/no atdischarge
HighestROPGrade 0-5 atdischarge
ROPtreatedwithlaser yes/no atdischarge
ROPtreatedwithantiVEGF yes/no atdischarge
Otherparameters
Lengthofhospitalstay days atdischarge
Ageatdischarge days atdischarge
Otherinvestigations
Cerebralfunctionmonitoring %continouospattern weekly
Visualevokedpotentials N2latencyinms at37-40wksgestationalage
Assessmentofneurodevelopmentaloutcome
BaileyScalesofInfantDevelopmentII metric(points) at12and24monthsof
Grossmotordevelopment 0-5points correctedgestationalage.
Opthalmologicexamsatfollowup
Visualfixation yes/no at12and24monthsof
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Trackingmovements yes/no correctedgestationalage.
Strabism yes/no
Refractionmeasuredbyskiascopy metric(dioptres)
Binocularvisualization(LangStereotest) pos/neg at24monthsof
correctedgestationalage
9. SAFETYDEFINITIONSANDREPORTINGREQUIREMENTS
9.1 Adverseevents(AEs)
9.1.1 SummaryofknownandpotentialrisksofthestudydrugUndesirableeffectsobservedduringtheadministrationoffatemulsions:
Common(≥1/100to<1/10)
Uncommon(≥1/1000to<1/100)
Rare(≥1/10000to<1/1000)
Veryrare(<1/10000)
Respiratory,thoriacicandmediastinaldisorders
Dyspnoea
Gastrointestinaldisorders
Lackofappetite,nausea,vomiting
Vasculardisorders Hypotension,hypertension
Generaldisordersandadministrationsiteconditions
Slightincreaseinbodytemperature
Chills Hypersensitivity-reactions(e.g.anaphylacticoranaphylactoidreactions,skinrash,urticaria,flush,headache),heatorcoldsensation,paleness,cyanosis,painintheneck,back,bones,chestandloins
Reproductivesystemdisorders
Priapism
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9.1.2 DefinitionofadverseeventsAnAEisanyuntowardadversechangefromthesubject'sbaselinecondition,i.e.,anyunfavorableandunintendedsignincludinganabnormallaboratoryfinding,symptomordiseasewhichisconsideredtobeclinicallyrelevantbythephysicianthatoccursduringthecourseofthestudy,whetherornotconsideredrelatedtothestudydrug.Adverseeventsinclude:
• Exacerbationofapre-existingdisease.• Increaseinfrequencyorintensityofapre-existingepisodicdiseaseormedicalcondition.• Diseaseormedicalconditiondetectedordiagnosedafterstudydrugadministrationeven
thoughitmayhavebeenpresentpriortothestartofthestudy.• Continuouspersistentdiseaseorsymptomspresentatbaselinethatworsenfollowingthe
startofthestudy.• Lackofefficacyintheacutetreatmentofalife-threateningdisease.• Eventsconsideredbytheinvestigatortoberelatedtostudy-mandatedprocedures.• Abnormalassessments,e.g.,ECGandphysicalexaminationfindings,mustbereportedasAEs
iftheyrepresentaclinicallysignificantfindingthatwasnotpresentatbaselineorworsenedduringthecourseofthestudy.
• LaboratorytestabnormalitiesmustbereportedasAEsiftheyrepresentaclinicallysignificantfinding,symptomaticornot,whichwasnotpresentatbaselineorworsenedduringthecourseofthestudyorledtodosereduction,interruptionorpermanentdiscontinuationofstudydrug.
Adverseeventsdonotinclude:• Pre-plannedinterventionsoroccurrenceofendpointsspecifiedinthestudyprotocolarenot
consideredAE´s,ifnotdefinedotherwise(eg.asaresultofoverdose)• Medicalorsurgicalprocedure,e.g.,surgery,endoscopy,toothextraction,transfusion.
However,theeventleadingtotheprocedureisanAE.Ifthiseventisserious,theproceduremustbedescribedintheSAEnarrative.
• Pre-existingdiseaseormedicalconditionthatdoesnotworsen.• Situationsinwhichanadversechangedidnotoccur,e.g.,hospitalizationsforcosmetic
electivesurgeryorforsocialand/orconveniencereasons.• Overdoseofeitherstudydrugorconcomitantmedicationwithoutanysignsorsymptoms.
However,overdosemustbementionedintheStudyDrugLog.
9.2 SeriousAdverseEvents(SAEs)ASeriousAdverseEvent(SAE)isdefinedbytheInternationalConferenceonHarmonization(ICH)guidelinesandWHOGCPguidelinesasanyAEfulfillingatleastoneofthefollowingcriteria:
• Resultsindeaths.• Life-threatening–definedasaneventinwhichthesubjectwas,inthejudgmentofthe
investigator,atriskofdeathatthetimeoftheevent;itdoesnotrefertoaneventthathypotheticallymighthavecauseddeathhaditbeenmoresevere.
• Requiringsubject'shospitalizationorprolongationofexistinghospitalization–inpatienthospitalizationreferstoanyinpatientadmission,regardlessoflengthofstay.
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• Resultinginpersistentorsignificantdisabilityorincapacity(i.e.,asubstantialdisruptionofaperson’sabilitytoconductnormallifefunctions).
• Congenitalanomalyorbirthdefect.• Ismedicallysignificantorrequiresinterventiontopreventatleastoneoftheoutcomeslisted
above.Life-threateningreferstoaneventinwhichthesubjectwasatriskofdeathatthetimeoftheevent.Itdoesnotrefertoaneventthathypotheticallymighthavecauseddeathifitweremoresevere.Importantmedicaleventsthatmaynotimmediatelyresultindeath,belife-threatening,orrequirehospitalizationmaybeconsideredasSAEswhen,baseduponappropriatemedicaljudgment,theymayjeopardizethesubjectandmayrequiremedicalorsurgicalinterventiontopreventoneoftheoutcomeslistedinthedefinitionsabove.
9.2.1 Hospitalization–ProlongationofexistinghospitalizationHospitalizationisdefinedasanovernightstayinahospitalunitand/oremergencyroom.Anadditionalovernightstaydefinesaprolongationofexistinghospitalization.HospitalizationascriteriumforSAEclassificationseverylimitedinthisstudy.Inthisstudy,patientsarehospitalizedfromstudystartuntilendoftreatment.Hospitalization–prolongationofexistinghospitalizationshouldbeappliedascriteriumforSAEclassificationonlyincaseofAEsdirectlyleadingtoaprolongationofhospitalization.ThecriteriumshouldnotbeappliedAEsoccurringduringtheroutinehospitalization.ThefollowingisnotconsideredanSAEandshouldbereportedasanAEonly:
• Treatmentonanemergencyoroutsubjectbasisforaneventnotfulfillingthedefinitionofseriousnessgivenaboveandnotresultinginhospitalization.
ThefollowingreasonsforhospitalizationsarenotconsideredAEs,andthereforenotSAEs:• Hospitalizationsforcosmeticelectivesurgery,socialand/orconveniencereasons.• Standardmonitoringofapre-existingdiseaseormedicalconditionthatdidnotworsen,e.g.,
hospitalizationforcoronaryangiographyinasubjectwithstableanginapectoris.• Electivetreatmentofapre-existingdiseaseormedicalconditionthatdidnotworsen,e.g.,
hospitalizationforchemotherapyforcancer,electivehipreplacementforarthritis.
9.2.2 SAEsrelatedtostudy-mandatedproceduresSuchSAEsaredefinedasSAEsthatappeartohaveareasonablepossibilityofcausalrelationship(i.e.,arelationshipcannotberuledout)tostudy-mandatedprocedures(excludingadministrationofstudydrug)suchasdiscontinuationofsubject'sprevioustreatmentduringawashoutperiod,orcomplicationofamandatedinvasiveprocedure(e.g.,bloodsampling,heartcatheterization),orcaraccidentonthewaytothehospitalforastudyvisit,etc.
9.2.3 Suspectedunexpectedseriousadversereactions(SUSARs)
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SUSARsareallseriousadversereactionswithsuspectcausalrelationshiptothestudydrugthatisunexpected(notpreviouslydescribedintheSmPC-SummaryofProductCharacteristicsorInvestigator’sbrochure)andserious.
9.3 SeverityofadverseeventsTheseverityofclinicalAEsisgradedonathree-pointscale:mild,moderate,severe,andreportedonspecificAEpagesoftheCRF.IftheseverityofanAEworsensduringstudydrugadministration,onlytheworstintensityshouldbereportedontheAEpage.IftheAElessensinintensity,nochangeintheseverityisrequired.IfanAEoccursduringawashoutorplaceborun-inphaseandafterwardsworsensduringthetreatmentphase,anewAEpagemustbefilledinwiththeintensityobservedduringstudydrugadministration.MildEventmaybenoticeabletosubject;doesnotinfluencedailyactivities;theAEresolvesspontaneouslyormayrequireminimaltherapeuticintervention;ModerateEventmaymakesubjectuncomfortable;performanceofdailyactivitiesmaybeinfluenced;interventionmaybeneeded;theAEproducesnosequelae.SevereEventmaycausenoticeablediscomfort;usuallyinterfereswithdailyactivities;subjectmaynotbeabletocontinueinthestudy;theAEproducessequelae,whichrequireprolongedtherapeuticintervention.Amild,moderateorsevereAEmayormaynotbeserious.Thesetermsareusedtodescribetheintensityofaspecificevent(asinmild,moderate,orseveremyocardialinfarction).However,asevereeventmaybeofrelativelyminormedicalsignificance(suchassevereheadache)andisnotnecessarilyserious.Forexample,nausealastingseveralhoursmayberatedassevere,butmaynotbeclinicallyserious.Feverof39°Cthatisnotconsideredseveremaybecomeseriousifitprolongshospitaldischargebyaday.Seriousnessratherthanseverityservesasaguidefordefiningregulatoryreportingobligations.
9.4 RelationshiptostudydrugForallAEs,theinvestigatorwillassessthecausalrelationshipbetweenthestudydrugandtheAEusinghis/herclinicalexpertiseandjudgmentaccordingtothefollowingalgorithmthatbestfitsthecircumstancesoftheAE:Unrelated
• Mayormaynotfollowareasonabletemporalsequencefromadministrationofthestudyproduct
• Isbiologicallyimplausibleanddoesnotfollowknownresponsepatterntothesuspectstudydrug(ifresponsepatternispreviouslyknown).
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• Canbeexplainedbytheknowncharacteristicsofthesubject’sclinicalstateorothermodesoftherapyadministeredtothesubject.
• Unlikely• Mayormaynotfollowareasonabletemporalsequencefromadministrationofthestudy
product• Isbiologicallynotveryplausible• Maybeexplainedbytheknowncharacteristicsofthesubject’sclinicalstateorothermodes
oftherapyadministeredtothesubject.Possiblerelated
• Followsareasonabletemporalsequenceformadministrationofthestudydrug.• Mayfollowaknownresponsepatterntothestudydrug(ifresponsepatternispreviously
known).• Couldnotbereasonablyexplainedbytheknowncharacteristicsofthesubject’sclinicalstate
orothermodesoftherapyadministeredtothesubject,ifapplicable.• Probable• Followsareasonabletemporalsequenceformadministrationofthestudydrug.• Followsaknownresponsepatterntothestudydrug(ifresponsepatternispreviously
known).• othercausesfortheeventareunlikely
Definitelyrelated
• Followsareasonabletemporalsequenceformadministrationofthestudydrug.• Followsaknownresponsepatterntothestudydrug(ifresponsepatternispreviously
known).• Nootherreasonablecauseispresent.
9.5 ReportingproceduresAspecialsectionisdesignatedtoadverseeventsinthecasereportform.Thefollowingdetailsmusttherebybeentered:
• Typeofadverseevent• Start(dateandtime)• End(dateandtime)• Severity(mild,moderate,severe)• Serious(no/yes)• Unexpected(no/yes)• Outcome(resolved,ongoing,ongoing–improved,ongoing–worsening)• Relationtostudydrug(unrelated,possiblyrelated,definitelyrelated)
Adverseeventsaretobedocumentedinthecasereportforminaccordancewiththeabovementionedcriteria.
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9.5.1 ReportingproceduresforSAEsIntheeventofserious,theinvestigatorhastouseallsupportivemeasuresforbestpatienttreatment.Awrittenreportisalsotobepreparedandmadeavailabletotheclinicalinvestigatorimmediately.Thefollowingdetailsshouldatleastbeavailable:
• Patientinitialsandnumber• Patient:dateofbirth,sex,ethicalorigin• Thesuspectedinvestigationalmedicalproduct(IMP)• Theadverseeventassessedasserious• Shortdescriptionoftheeventandoutcome
Ifapplicable,theinitialreportshouldbefollowedbytheFollowupreport,indicatingtheoutcomeoftheSAE.
9.5.2 ReportingproceduresforSUSARsItmustberememberedthattheregulatoryauthorities,andincaseofSUSARswhichcouldpossiblyconcernthesafetyofthestudyparticipants,alsotheInstitutionalReviewBoard/IndependentEthicsCommittee(IRB/IEC)aretobeinformed.Suchreportsshallbemadebythestudymanagementandthefollowingdetailsshouldbeatleastavailable:
• Patientinitialsandnumber• Patient:dateofbirth,sex,ethicalorigin• Nameofinvestigatorandinvestigatingsite• Periodofadministration• Thesuspectedinvestigationalmedicalproduct(IMP)• Theadverseeventassessedasseriousandunexpected,andforwhichthereisareasonable
suspectedcausalrelationshiptotheIMP• Concomitantdiseaseandmedication• Shortdescriptionoftheevent:
• Description• Onsetandifapplicable,end• Therapeuticintervention• Causalrelationship• Hospitalizationofprolongationofhospitalization• Death,life-threatening,persistentorsignificantdisabilityorincapacity
ElectronicreportingshouldbetheexpectedmethodforreportingofSUSARstothecompetentauthority.Inthatcase,theformatandcontentasdefinedbyGuidance(28)shouldbeadheredto.ThelatestversionofMedDRAshouldbeapplied.Lowerlevelterms(LLT)shouldbeused.
9.5.3 AnnualSafetyReportTheAnnualSafetyReportwillbeprovidedbytheprincipalinvestigatoratleastonceayear.ThisreportwillalsobepresentedannuallytotheIndependentEthics(IEC)andtothecompetentauthoritiesbythesponsor.
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10. FOLLOW-UP
10.1 Follow-upofstudyparticipantsincludingfollow-upofadverseventsAllstudyparticipantswillbefollowedupto24monthsofcorrectedgestationalagetoassessneurodevelopment,growthparametersandophthalmologicexams(visualdevelopment(accordingtothestandardsofourfollow–upoutpatientclinicforextremelyprematureinfants.SAEsincludingdeathwillbemonitored.Adverseeventswillbefolloweduntiltheyhavebeencompletelyresolvedorstabalizedaccordingtotheinvestigatorsdiscretion.
10.2 TreatmentafterendofstudyThereisnotreatmentaftertheendofthestudy
11. STATISTICALMETHODOLOGYANDANALYSIS
11.1 AnalysissetsTwodifferentanalysissetsaredefined:(Modified)IntentiontotreatsetThisanalysissetincludesallsubjectswheretheoutcomecanbecalculated(morethantwobloodsamplestaken),eventhoughthesubjectwasnotobservedthefull18weeks.Per-protocolsetThisanalysissetcomprisesallsubjectswhowereobservedthefull18weeks,receivedthestudydrugasplannedanddidnotviolatetheprotocolinawaythatmightaffecttheevaluationoftheeffectofthestudydrugontheprimaryobjective,i.e.,withoutmajorprotocolviolations.
11.2 SamplesizeconsiderationsDatainvestigatingtheincidenceofPNACinourunitshowedanincidenceof25%from2007-9(unpublisheddata).Weconsideredadifferenceof15%betweenthegroups(incidenceofPNAC:25%forIntralipidand10%forSMOFlipid,respectively)asaclinicallyrelevanteffect.Asamplesizeestimationbasedonaχ2-testindicatedthat200infants(100/group)arerequiredtodetectadifferenceof15%betweenthegroupswithapowerof80%andasignificancelevelof0.05.The
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estimateddropoutrateis22%.Therefore,asamplesizeof122patientspergroupisplanned.Forsamplesizeestimation,datawereassumedtobeindependent.
11.3 RelevantprotocoldeviationsProtocoldeviationswillhavetobedocumentedandshouldbediscussedwiththeSponsor.Allprotocoldeviationswillbelistedinthestudyreportandreportedtothesponsor.
11.4 StatisticalanalysisplanAstatisticalanalysisplan(SAP)willprovidefulldetailsoftheanalyses,thedatadisplaysandthealgorithmstobeusedfordataderivations.TheSAPfurthermorewillincludedefinitionsofmajorandminorprotocoldeviationsandthelinkofdeviationstotheanalysisset,whichalsowillbecoveredinthefinalstudyreport.Proceduresofreportinganydeviationsfromtheoriginalstatisticalplan(anydeviationsfromtheoriginalstatisticalplanshouldbedescribedandjustifiedintheprotocoland/orinthefinalreport,asappropriate.TheSAPshouldpreferablybeaseparatedocument.Intheprotocolthisdocumentshouldbereferenced.AlternativelytheSAPcouldbefullyincludedinthestudyprotocol.
11.5 Missing,unusedandspuriousdataIflessthantwobloodsamplesofapatientweretaken,theoutcomecannotbecalculatedandtherefore,thispatientwillbeexcludedfromtheanalysis.Theanalysiswillbecarriedoutperprotocol.Iftheoutcomeofapatientcanbecalculated(morethantwobloodsamplestaken)butthepatientwaswithdrawnfromthestudybeforeweek18,analysiswillbecarriedout1)byintentiontotreatanalysis,withthedurationoftreatmentasadditionalcovariableand2)perprotocol.
11.6 Endpointsanalysis
11.6.1 PrimaryendpointanalysisAχ2-testwillbeusedforanalysisoftheprimaryoutcomePNAC.Additionally,theeffectoftreatmentandotherrelevantinfluencefactors(i.e.durationofparenteralnutrition,birthweight,amountofenteralfeedsinthefirstweekoflife)ontheprimaryendpointwillbeanalyzedusingalogisticregressionmodelwithstepwiseselectionIncaseoftwins,theanalysiswillbecarriedout1)asmentionedabove,butonlyincludingthefirstbornand2)bycalculatingageneralizedlinearmodelwithmotherasrandomfactor.
11.6.2 SecondaryendpointanalysisBaileyScalesofInfantDevelopmentIIat12and24months:Differencesinthescoresofpsychomotordevelopmentandneurocognitivedevelopment,respectively,betweenthegroupswillbeanalyzedby
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repeatedmeasuresANOVA,alsoaccountingforconfounders(e.g.birthweight,IVHGrade3/4,cysticperiventricularleucomalacia,NEC).Incaseoftwins,theanalysiswillbecarriedout1)asmentionabove,butonlyincludingthefirstbornand2)bycalculatingamixedmodelwithmotherandchildasrandomfactor.Incaseoftoomanydropouts,descriptivestatisticswillbecarriedout.ForGrossMotorfunctionmeasurementsat12and24months,descriptivestatisticswillbeconducted.
11.6.3 SafetyandtolerabilityendpointsHypertriglyceridemia:Peaklevelinmg/dl
11.6.4 BaselineparametersandconcomitantmedicationsThefollowingparameterswillbeinvestigated:Sex(m/f)Ageatbirth(gestationalweeks+days)Twin(yes/no)Modeofdelivery(caesareansection/spontaneousdelivery)Receivedanyprenatalsteroidsforlungmaturation(yes/no).Weight(gram)atbirthLength(cm)atbirthHeadcircumference(cm)atbirthSmallforgestationalage(<10.percentilebirthweight,yes/no)Apgarscoresat1,5and10minutes(0-10)UmbilicalarterypHComcomitantmedicationsandchangesinconcomitantmedicationwillbedocumentedbytheInvestigator.
11.7 InterimanalysisNointerimanalysisplanned.
11.8 Softwareprogram(s)SAS9.2MicrosoftExcel
12. DOCUMENTATIONANDDATAMANAGEMENT
12.1 DocumentationofstudyresultsAsubjectscreeningandenrollmentLogwillbecompletedforalleligibleornon-eligiblesubjectswiththereasonsforexclusion.
12.1.1 Casereportform(CRF)
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Foreachsubjectenrolled,regardlessofstudydruginitiation,apaperCRFmustbecompletedandsignedbytheinvestigatororadesignatedsub-investigator.Thisalsoappliestothosesubjectswhofailtocompletethestudy.Ifasubjectwithdrawsfromthestudy,thereasonmustbenotedontheCRF.Casereportformsaretobecompletedonanongoingbasis.CRFentriesandcorrectionswillonlybeperformedbystudysitestaff,authorizedbytheinvestigator.Ina“Paper-CRF”allformsshouldbecompletedandmustbelegible.Errorsshouldbecrossedoutbutnotobliterated,thecorrectioninserted,andthechangeinitialedanddatedbytheinvestigator,co-investigatororstudynurse.Theentrieswillbecheckedbytrainedpersonnel(Monitor)andanyerrorsorinconsistencieswillbecheckedimmediately.ThemonitorwillcollectoriginalcompletedandsignedCRFsattheendofthestudy.AcopyofthecompletedandsignedCRFswillremainonsite.CompletedCRFswillbepassedtotheStatisticianforfurtheranalysis.
12.1.2 DataCollectionDatacollectedatallvisitsareenteredintoaninteractiveform.TheCRFswillbesourcedocumentsverifiedfollowingguidelinesestablishedbeforestudyonsetasdetailedintheMonitoringPlan.
12.2 SafekeepingTheinvestigatorwillmaintainadequateandaccuraterecordstoenabletheconductofthestudytobefullydocumentedandthestudydatatobesubsequentlyverified(accordingtoICH-GCP“essentialdocuments”).Thesedocumentswillbeclassifiedintotwodifferentcategories:investigator'sfile,andsubjectclinicalsourcedocuments.Theinvestigator'sfilewillcontaintheprotocol/amendments,EudraCTforms,CRFs(eCRFprintout),standardoperationprocedures(SOPs),dataclarificationandqueryforms,EC/IRBandHealthAuthorityapprovalwithcorrespondence,informedconsent,drugrecords,staffcurriculumvitaeandauthorizationforms,screeningandenrollmentlogs,andotherappropriatedocuments/correspondenceasperICH/GoodClinicalPractice(GCP)andlocalregulations.Subjectclinicalsourcedocumentsinclude,butarenotlimitedtosubjecthospital/clinicrecords,physician’sandnurse’snotes,appointmentbook,originallaboratoryreports,ECG,X-ray,pathologyandspecialassessmentreports,consultantletters,etc.Thesetwocategoriesofdocumentsmustbekeptonfilebytheinvestigatorforaslongasneededtocomplywithnationalandinternationalregulations(inAustria15yearsafterdiscontinuingclinicaldevelopmentorafterthelastmarketingapproval).Ifsourcedocumentsarenotdurableaslongasneeded(e.g.ECGprintouts)theymustbepreservedasacopy.NostudydocumentshouldbedestroyedwithoutpriorwrittenapprovalfromtheDepartmentof……Whensourcedocumentsarerequiredforthecontinuedcareofthesubject,appropriatecopiesshouldbemadeforstoringoutsideofthesite.
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12.3 QualityControlandQualityAssurance
12.3.1 PeriodicMonitoringAccordingtoGCPatleast3monitoringvisitsarescheduled.Aninitiationvisit,oneroutinevisitandacloseoutvisitafterthelastpatienthasfinishedthestudyordatabaselock.ThedesignatedmonitorwillcontactandvisittheinvestigatorregularlyandwillbeallowedtohaveaccesstoallsourcedocumentsneededtoverifytheentriesintheCRFsandotherprotocol-relateddocumentsprovidedthatsubjectconfidentialityismaintainedinagreementwithlocalregulations.Itwillbethemonitor'sresponsibilitytoinspecttheCRFsatregularintervalsaccordingtothemonitoringplanthroughoutthestudy,toverifytheadherencetotheprotocolandthecompleteness,consistencyandaccuracyofthedatabeingenteredonthem.Themonitoringstandardsrequirefullverificationforthepresenceofinformedconsent,adherencetotheinclusion/exclusioncriteria,documentationofSAEsandtherecordingofthemainefficacy,safety,andtolerabilityendpoints.ThemonitorwillbeworkingaccordingtoSOPsandwillprovideamonitoringreportaftereachvisitfortheSponsor.Dependingonthequalityofthedata,additionalmonitoringvisitsmaybenecessaryaccordingtothesponsor’sdiscretion.Theinvestigatorwillresolvediscrepanciesofdata.MonitoringwillbeperformedbyKoordinierungszentrumfürKlinischeStudienonaregularbasisandwillfollowadetailedMonitoringPlan.
12.3.2 AuditandInspectionsUponrequest,theinvestigatorwillmakeallstudy-relatedsourcedataandrecordsavailabletoaqualifiedqualityassuranceauditormandatedbythesponsorortocompetentauthorityinspectors.Themainpurposesofanauditorinspectionaretoconfirmthattherightsandwelfareofthesubjectshavebeenadequatelyprotected,andthatalldatarelevantforassessmentofsafetyandefficacyoftheinvestigationalproducthaveappropriatelybeenreportedtothesponsor.
12.4 ReportingandPublication
12.4.1 PublicationofstudyresultsThefindingsofthisstudywillbepublishedbythesponsor(investigators)inascientificjournalandpresentedatscientificmeetings.Themanuscriptwillbecirculatedtoallco-investigatorsbeforesubmission.Confidentialityofsubjectsinreports/publicationswillbeguaranteed.
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13. ETHICALANDLEGALASPECTS
13.1 InformedconsentofsubjectsFollowingcomprehensiveinstructionregardingthenature,significance,impactandrisksofthisclinicaltrial,apatient´scaregiver(motherorfather)mustgivewrittenconsenttoparticipationinthestudy.Duringtheinstructionthetrialparticipantsaretobemadeawareofthefactthattheycanwithdrawtheirconsent–withoutgivingreasons–atanytimewithouttheirfurthermedicalcarebeinginfluencedinanyway.Inadditiontothecomprehensiveinstructionsgiventothetrialparticipantsbytheinvestigator,thetrialparticipantsalsoreceiveawrittenpatientinformationsheetincomprehensiblelanguage,explainingthenatureandpurposeofthestudyanditsprogress.Thepatientsmustagreetothepossibilityofstudy-relateddatabeingpassedontorelevantauthorities.Thepatientsmustbeinformedindetailoftheirobligationsinrelationtothetrialparticipantsinsuranceinordernottojeopardizeinsurancecover.
13.2 Acknowledgement/approvalofthestudyTheinvestigator(oradesignatedCRO)willsubmitthisprotocolandanyrelateddocumentprovidedtothesubject(suchassubjectinformationusedtoobtaininformedconsent)toanEthicsCommittee(EC)orInstitutionalReviewBoard(IRB).Approvalfromthecommitteemustbeobtainedbeforestartingthestudy.TheclinicaltrialshallbeperformedinfullcompliancewiththelegalregulationsaccordingtotheDrugLaw(AMG-Arzneimittelgesetz)oftheRepublicofAustria.AnapplicationmustalsobesubmittedtotheAustrianCompetentAuthorities(BundesamtfürSicherheitimGesundheitswesen(BASG)representedbytheAgencyforHealthandFoodSafety(AGESPharmMed)andregisteredtotheEuropeanClinicalTrialDatabase(EudraCT)usingtherequiredforms.Thetimelinesfor(silent)approvalsetbynationallawmustbefollowedbeforestartingthestudy.
13.2.1 ChangesintheConductoftheStudy ProtocolamendmentsProposedamendmentsmustbesubmittedtotheappropriateCAandECs.SubstantialamendmentsmaybeimplementedonlyafterCA/ECapprovalhasbeenobtained.AmendmentsthatareintendedtoeliminateanapparentimmediatehazardtosubjectsmaybeimplementedpriortoreceivingCA/ECapproval.However,inthiscase,approvalmustbeobtainedassoonaspossibleafterimplementation.StudyTerminationIfthesponsorortheinvestigatordecidestoterminatethestudybeforeitiscompleted,theywillnotifyeachotherinwritingstatingthereasonsofearlytermination.Interminatingthestudy,thesponsorandtheinvestigatorwillensuretheadequateconsiderationisgiventotheprotectionofthe
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subjectinterests.Theinvestigator,sponsoror(designatedCROonbehalfofthesponsor)willnotifytherelevantCAandEC.DocumentationwillbefiledintheTrialMasterandInvestigatorFiles.ClinicalStudyReport(CSR)Withinoneyearafterthefinalcompletionofthestudy,afullCSRwillbepreparedbythesponsorandsubmittedtotheECandthecompetentauthority.TheInvestigatorwillbeaskedtoreviewandsignthefinalstudyreport.
13.3 InsuranceDuringtheirparticipationintheclinicaltrialthepatientswillbeinsuredasdefinedbylegalrequirements.Theinvestigatoroftheclinicaltrialwillreceiveacopyoftheinsuranceconditionsofthe'patientsinsurance'.Thesponsorisprovidinginsuranceinordertoindemnify(legalandfinancialcoverage)theinvestigator/centeragainstclaimsarisingfromthestudy,exceptforclaimsthatarisefrommalpracticeand/ornegligence.Thecompensationofthesubjectintheeventofstudy-relatedinjurieswillcomplywiththeapplicableregulations.Detailsontheexistingpatientsinsurancearegiveninthepatientinformationsheet.PatientswillbeinsuredbytheZürich-Versicherung(Nr.07229622-2)accordingtotheAustrianlaw. Pleaseindicateinsurancedetails!
13.4 ConfidentialityTheinformationcontainedinthisdocument,especiallyunpublisheddata,isthepropertyofthesponsor.Itisthereforeprovidedtoyouinconfidenceasaninvestigator,potentialinvestigator,orconsultant,forreviewbyyou,yourstaff,andanEthicsCommitteeorInstitutionalReviewBoard.Itisunderstoodthatthisinformationwillnotbedisclosedtootherswithoutwrittenauthorizationfromthesponsor.
13.5 EthicsandGoodClinicalPractice(GCP)Theinvestigatorwillensurethatthisstudyisconductedinfullconformancewiththeprinciplesofthe"DeclarationofHelsinki"(asamendedatthe56thWMAGeneralAssembly,Tokyo,Japan,2008)andwiththelawsandregulationsofthecountryinwhichtheclinicalresearchisconducted.Theinvestigatoroftheclinicaltrialshallguaranteethatonlyappropriatelytrainedpersonnelwillbeinvolvedinthestudy.AllstudiesmustfollowtheICHGCPGuidelines(June1996)and,ifapplicable,theCodeofFederalRegulations(USA).InothercountriesinwhichGCPGuidelinesexist,theinvestigatorswillstrictlyensureadherencetothestatedprovisions.ThereforethisstudyfollowstheEUDirectiveembeddedintheAustriandrugact.
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14. APPENDICESAppendix1.InformedConsentForm(Version1.0;Date8.11.11)Appendix2.Summaryofproductcharacteristics
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