CLINICAL STUDY PROTOCOL PREVENTING CHOLESTASIS … · (SMOFlipid®) with a soybean oil based lipid...

PreventingCholestasisinPrematureInfantsUsingSMOFLipid®/SMOFLipid®MedicalUniversityofVienna,DepartmentofPediatricsEUDRACTNr2011-005456-33

Date22.8.2013 Version1.3 Page1of38

CLINICALSTUDYPROTOCOL

PREVENTINGCHOLESTASISINPREMATUREINFANTSUSINGSMOFLIPID®

Version1.3/22.8.2013ConfidentialityStatementTheinformationcontainedinthisdocument,especiallyunpublisheddata,isthepropertyofthesponsorofthisstudy.Itisthereforeprovidedtoyouinconfidenceasaninvestigator,potentialinvestigator,orconsultant,forreviewbyyou,yourstaff,andanIndependentEthicsCommitteeorInstitutionalReviewBoard.ItisunderstoodthatthisinformationwillnotbedisclosedtootherswithoutwrittenauthorizationfromtheDepartmentofPediatrics,MedicalUniversityViennaexcepttotheextentnecessarytoobtaininformedconsentfromthosepersonstowhomthestudydrugmaybeadministered.



Testdrug(IMP)andPharmaceuticalCompany

SMOFlipid®FreseniusKabiAG,BadHomburg,Germany

Protocolauthors AndreasRepa,MD

InvestigatorsAndreasRepa,MDNadjaHaiden,MDRenateFuiko,PhD

Documenttype Clinicalstudyprotocol

Studyphase PhaseIV

Documentstatus Version1.2

Date 17.9.2012

Numberofpages 38



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



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• ForNeurodevelopmentaloutcomeinfollowupphase:Congenital

neurologicalmalformationsandchromosomalaberrationsSTUDYPERIODS • OperationalPhase:Theoperationalphaseofthestudywilllastforthree

years(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

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)ontheprimaryendpointwillbeanalyzedusingalogisticregressionmodelwith



stepwiseselection.Incaseoftwins,theanalysiswillbecarriedout1)asmentionedabove,butonlyincludingthefirstbornand2)bycalculatingageneralizedlinearmodelwithmotherasrandomfactor.OtherendpointsBaileyScalesof InfantDevelopment IIIat12and24months: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.



3. LISTOFABBREVATIONSELBW ExtremeLowBirthWeightICH InternationalConferenceonHarmonizationILE IntravenousLipidEmulsionGCP GoodClinicalPracticeDHA DocosahexaenoicAcidDOH DeclarationofHelsinkiLC-PUFA LongChainPolyunsaturatedFattyAcidsPN ParenteralNutritionPNAC ParenteralNutritionAssociatedCholestasis



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 188.1.2 STUDY-DRUGUP-ANDDOWNTITRATION 188.1.3 STUDYDRUGINTERRUPTIONORDISCONTINUATION 188.1.4 STUDYDRUGPREMATUREPERMANENTDISCONTINUATION 188.1.5 STUDY-DRUGDELIVERY&DRUGSTORAGECONDITIONS 198.1.6 STUDYDRUGPACKAGINGANDLABELING 198.1.7 IMPADMINISTRATION&HANDLING 198.1.8 DRUGACCOUNTABILITY 198.1.9 PROCEDURESTOASSESSSUBJECTSCOMPLIANCE 198.1.10 CONCOMITANTMEDICATION 208.2 RANDOMIZATIONANDSTRATIFICATION 208.3 BLINDING 208.3.1 EMERGENCYPROCEDUREFORUNBLINDING 218.3.2 UNBLINDINGATTHEENDOFTHESTUDY. 218.4 BENEFITANDRISKASSESSMENT 218.5 STUDYPROCEDURES 218.5.1 GENERALRULESFORTRIALPROCEDURES 218.5.2 SCREENINGINVESTIGATION 228.5.3 END-OF-STUDY(EOS)EXAMINATION 228.5.4 LABORATORYTESTS 229. SAFETYDEFINITIONSANDREPORTINGREQUIREMENTS 249.1 ADVERSEEVENTS(AES) 24



9.1.1 SUMMARYOFKNOWNANDPOTENTIALRISKSOFTHESTUDYDRUG 249.1.2 DEFINITIONOFADVERSEEVENTS 259.2 SERIOUSADVERSEEVENTS(SAES) 269.2.1 HOSPITALIZATION–PROLONGATIONOFEXISTINGHOSPITALIZATION 269.2.2 SAESRELATEDTOSTUDY-MANDATEDPROCEDURES 279.2.3 SUSPECTEDUNEXPECTEDSERIOUSADVERSEREACTIONS(SUSARS) 279.3 SEVERITYOFADVERSEEVENTS 279.4 RELATIONSHIPTOSTUDYDRUG 289.5 REPORTINGPROCEDURES 299.5.1 REPORTINGPROCEDURESFORSAES 299.5.2 REPORTINGPROCEDURESFORSUSARS 299.5.3 ANNUALSAFETYREPORT 3010. FOLLOW-UP 3010.1 FOLLOW-UPOFSTUDYPARTICIPANTSINCLUDINGFOLLOW-UPOFADVERSEVENTS 3010.2 TREATMENTAFTERENDOFSTUDY 3011. STATISTICALMETHODOLOGYANDANALYSIS 3011.1 ANALYSISSETS 3011.2 SAMPLESIZECONSIDERATIONS 3111.3 RELEVANTPROTOCOLDEVIATIONS 3111.4 STATISTICALANALYSISPLAN 3111.5 MISSING,UNUSEDANDSPURIOUSDATA 3111.6 ENDPOINTSANALYSIS 3211.6.1 PRIMARYENDPOINTANALYSIS 3211.6.2 SECONDARYENDPOINTANALYSIS 3211.6.3 SAFETYANDTOLERABILITYENDPOINTS 3211.6.4 BASELINEPARAMETERSANDCONCOMITANTMEDICATIONS 3211.7 INTERIMANALYSIS 3311.8 SOFTWAREPROGRAM(S) 3312. DOCUMENTATIONANDDATAMANAGEMENT 3312.1 DOCUMENTATIONOFSTUDYRESULTS 3312.1.1 CASEREPORTFORM(CRF) 3312.1.2 DATACOLLECTION 3312.2 SAFEKEEPING 3312.3 QUALITYCONTROLANDQUALITYASSURANCE 3412.3.1 PERIODICMONITORING 3412.3.2 AUDITANDINSPECTIONS 3512.4 REPORTINGANDPUBLICATION 3512.4.1 PUBLICATIONOFSTUDYRESULTS 3513. ETHICALANDLEGALASPECTS 3513.1 INFORMEDCONSENTOFSUBJECTS 3513.2 ACKNOWLEDGEMENT/APPROVALOFTHESTUDY 3513.2.1 CHANGESINTHECONDUCTOFTHESTUDY 3613.3 INSURANCE 3613.4 CONFIDENTIALITY 3613.5 ETHICSANDGOODCLINICALPRACTICE(GCP) 3714. APPENDICES 3715. REFERENCES 37



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 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 X34-37wks)

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 X

AdverseEvents X X X X X X X X



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



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



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



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



ToinvestigatewhetherELBWinfantstreatedwithtwodifferentILEs(investigationaldrug:

SMOFlipid®,comparativedrug:Intralipid®)differintheoccurrenceofPNAC(conjugatedbilirubin>

1.5mg/dl,measuredontwoconsecutiveoccasions).

6.2 SecondaryObjectives

ToinvestigatewhetherELBWinfantstreatedwithtwodifferentILEs(investigationaldrug:

SMOFlipid®,comparativedrug:Intralipid®)differintheirneurodevelopment(BaileyScalesofInfant

DevelopmentIII)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:



-Inbornerrorsofmetabolism

-ViralInfections(cytomegalyvirus,HIV,HepatitisB,C)

-Immunemediatedhemolyticdiesease(e.g.Rhesusincompatibility)

-Diagnosisofcysticfibrosis

-Primarycholestaticdiseasesoftheliver

Atfollowup:

-Congenitalneurologicalmalformationsandpatientswithchromosomalaberrationswillbe

excludedfromfollowupanalysis(exceptscreeningforadverseevents)

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(exceptneurologicalmalformation

andchromosomalaberrationwhichonlyleadstowithdrawalfromfollowupanalysisexceptscreeningforadverseevents)

• deathbeforedayoflife28

Inallcases,thereasonwhysubjectsarewithdrawnmustberecordedindetailintheCRFandinthesubject’smedicalrecords.Shouldthestudybediscontinuedprematurely,allstudymaterials(complete,partiallycompletedandemptyCRFs)willberetained.



Follow-upofpatientswithdrawnfromthestudyIncaseofprematurediscontinuationafterstudydrugintake,theinvestigationsscheduledfortheEOSvisitwillbeperformed7+/-4daysafterstudydrugdiscontinuation.Thesubjectswillbeadvisedthatparticipationintheseinvestigationsisvoluntary.Furthermore,theymayrequestthatfromthetimepointofwithdrawalnomoredatawillberecordedandthatallbiologicalsamplescollectedinthecourseofthestudywillbedestroyed.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)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&drugstorageconditionsThestudydrugwillbedeliveredfromthesupplyingcompanytotheinvestigatorsandstoredatroomtemperatureundercontrolledconditions(22°C+/-3°C)inalockedroom.Amin/maxthermometerwillbeusedtocontrolfortemperatureinthestorageroom.Fulldocumentationofdelivery,storageanddispositionwillbemaintained.

8.1.6 StudydrugpackagingandlabelingThestudydrugsaredeliveredinsterileglasscontaninersof100mlbythemanufacturerandwillbere-labelledatthestudysiteasdescribedinsection8.3.Storageisdescribedinsection8.1.5.Forapplicationtostudysubjects,thestudydrugswillbebroughttotheneonatalwardsbyamemberoftheblinidingteam.ForIVapplication,thestudydrugswillbetransferredfromthere-labelledcommercialcontainerstoperfusorsyringesconnectedtoperfuorslinessuitableforIVapplication.Perfusorsyringeswillbelabelled(seesamplelabels1and2below).PreparationforIVapplicationwillbedoneinalaminarairhoodundersterileconditionsbytrainedintensivecarenurses,formingpartoftheblindingteam.SampleLabelNumber1 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



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.bilirubin>6mg/dl,

8.2 RandomizationandstratificationOnday0,patientsarerandomizedtooneofthetwostudygroupsandthestudymedicationisprovided.Studysubjectswillbeblockrandomized(ratio1:1)andstratifiedaccordingtosexandbirthweight(intwogroups:<750gramvs.≥750gram)usinganonlinerandomizationprogrammeprovidedbytheCenterforMedicalStatistics,Informatics,andIntelligentSystemsoftheMedicalUniversityofVienna.Incaseoftwins,randomizationwillbeappliedtothefirstborn;thetwinwillbeassignedtotheothertreatmentgroup.

8.3 BlindingBlindingofsubjects,investigatorsandoutcomeassessorswillbeperformedasfollows:Firstre-labellingofthestudydrugcontainers(seesamplelabel1and2below)willbeperformedbytwomembersoftheblindingteamnotinvolvedinthecollectionofdata,treatmentofstudysubjectsorpreparationofthestudydrugsforIVapplication.Thestudydrugsarekeptinglasscontainersof100mlandwillbere-labelledwithsamplesasindicated(seesamplelabel1and2below)andstoredasdescribed(section8.1.5).Second,fordeliverytostudysubjectsthestudydrugswillbebroughttothewardsbyamemberoftheblindingteam,wherethepreparationforIVapplicationwillbedoneinalaminarairhoodbyamemberoftheblindingteamasdescribedinsection8.1.7.Asintensivecarenursesinvolvedincaretakingofthepatientsformpartoftheblidingteam,nursingcaregiversarenotblinded.MedicaldoctorsprescribingthedailyamountsoftheIMPremainblinded.SampleLabelNumber1 SampleLabelNumber2:



8.3.1 EmergencyprocedureforunblindingIfunblindingofastudyparticipantisrequiredduetoanemergency,thecodecanbebrokenbytheInvestigator.Codebreakingwillbefullydocumented.

8.3.2 Unblindingattheendofthestudy.Codeswillbebrokenafterdataanalysisoftheprimaryoutcome,thisisafterthelastpatienthasfinishedactivephase.Investigatorsinvolvedinasessmentofdatainthefollowupphase(secondaryoutcomeneurodevelopment)willremainblinded.

8.4 Benefitandriskassessment

8.4.1Benefitforthepatient

Ifthehypothesisiscorrect,participatingpatientsreceivingthestudymedicationwillbenefitfroma

reducedriskofdevelopingliverinjuryduetolongtermparenteralnutrition.Theywillbenefitfroma

improvedlongtermneurodevelopment.

8.4.2Riskforthepatient

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

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)

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 N2latencyinmsat34-37wksgestationalage

Assessmentofneurodevelopmentaloutcome

BaileyScalesofInfantDevelopmentIII metric(points) at12and24monthsof

Grossmotordevelopment 0-5points correctedgestationalage.

Opthalmologicexamsatfollowup

Visualfixation yes/no at12and24monthsof

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

Gastrointestinal Lackofappetite,



disorders nausea,vomitingVasculardisorders Hypotension,

hypertension

Generaldisordersandadministrationsiteconditions

Slightincreaseinbodytemperature

Chills Hypersensitivity-reactions(e.g.anaphylacticoranaphylactoidreactions,skinrash,urticaria,flush,headache),heatorcoldsensation,paleness,cyanosis,painintheneck,back,bones,chestandloins

Reproductivesystemdisorders

Priapism

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.

• 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)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).

• 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.

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.

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.Theestimateddropoutrateis22%.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 SecondaryendpointanalysisBaileyScalesofInfantDevelopmentIIIat12and24months:Differencesinthescoresofpsychomotordevelopmentandneurocognitivedevelopment,respectively,betweenthegroupswillbeanalyzedbyrepeatedmeasuresANOVA,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)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 Safekeeping



Theinvestigatorwillmaintainadequateandaccuraterecordstoenabletheconductofthestudytobefullydocumentedandthestudydatatobesubsequentlyverified(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.

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.

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,thesponsorandtheinvestigatorwillensuretheadequateconsiderationisgiventotheprotectionofthesubjectinterests.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,or



consultant,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.

14. APPENDICESAppendix1.InformedConsentForm(Version1.0;Date8.11.11)Appendix2.Summaryofproductcharacteristics

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