th April 2017 IRAS Project number: 202042 REC Reference ... study... · Chief Investigator: ... Disease Ethics Ref: 17/SC/0152 IRAS project ID 202042 ... 17/SC/0152 Chief Investigator:

Study Protocol version 2, 25th April 2017 IRAS Project number: 202042 REC Reference number: 17/SC/0152 Chief Investigator: Professor Marian Knight Next stage in Evidence-based paediatric surgical Treatment Strategies 2 - Hirschsprung's Disease (NETS2HD): A nationwide cohort study investigating the impact of choice of surgical intervention on core outcomes at six to seven years of age in children with Hirschsprung's Disease.

ClinicalResearchProtocolTemplateversion13.0 CONFIDENTIAL©Copyright:TheUniversityofOxfordandOxfordUniversityHospitalsNHSFoundationTrust2016 Page1of30

Study Title: Next stage in Evidence-based paediatric surgical Treatment Strategies 2 - Hirschsprung'sDisease(NETS2HD):AnationwidecohortstudyinvestigatingtheimpactofchoiceofsurgicalinterventiononcoreoutcomesatsixtosevenyearsofageinchildrenwithHirschsprung'sDisease.

Internal Reference Number / Short title:NETS2HD- Six-year outcomes in infants with Hirschsprung’sDisease

EthicsRef:17/SC/0152

IRASprojectID202042

DateandVersionNo:Versiontwo,25thofApril2017

ChiefInvestigator: ProfessorMarianKnight

NationalPerinatalEpidemiologyUnit

UniversityofOxford

OldRoadCampus

Oxford

OX37LF

Investigators: MrBenjaminAllin,NationalPerinatalEpidemiologyUnit

ProfJenniferKurinczuk,NationalPerinatalEpidemiologyUnit

MrTimothyBradnock,RoyalHospitalforChildren,Glasgow

MrGregorWalker,RoyalHospitalforChildren,Glasgow

MrSimonKenny,AlderHeyChildren’sHospital

Sponsor: UniversityofOxford

Funder: NationalInstituteforHealthResearch

ChiefInvestigatorSignature:

Therearenopotentialconflictsofinteresttodeclare

ConfidentialityStatement

Thisdocument contains confidential information thatmustnotbedisclosed toanyoneother than theSponsor,theInvestigatorTeam,HRA,hostorganisation,andmembersoftheResearchEthicsCommittee,unlessauthorisedtodoso.



TABLEOFCONTENTS

1. SYNOPSIS...............................................................................................................................................4

2. ABBREVIATIONS....................................................................................................................................4

3. BACKGROUNDANDRATIONALE............................................................................................................5

3.1. Hirschsprung’sDisease................................................................................................................6

3.2. Long-termoutcomes....................................................................................................................8

4. OBJECTIVESANDOUTCOMEMEASURES...............................................................................................8

5. STUDYDESIGN.......................................................................................................................................9

5.1. Summary......................................................................................................................................9

5.2. StudySize...................................................................................................................................10

5.3. CostsandResources..................................................................................................................10

5.4. ProjectManagement.................................................................................................................10

5.5. PublicParticipation....................................................................................................................10

6. PARTICIPANTIDENTIFICATION............................................................................................................11

6.1. StudyParticipants......................................................................................................................11

6.2. InclusionCriteria........................................................................................................................11

6.3. ExclusionCriteria.......................................................................................................................11

6.4. Recruitment...............................................................................................................................11

Sharinginformationwithparentsofpotentiallyeligibleparticipants................................................11

Eligibilityscreeningandinitialcontact................................................................................................12

6.5. Consenttoparticipate...............................................................................................................13

6.6. Requirementsofstudyparticipants...........................................................................................13

6.7. Discontinuation/WithdrawalofParticipantsfromStudy..........................................................14

6.8. DefinitionofEndofStudy..........................................................................................................14

7. STATISTICSANDANALYSIS..................................................................................................................14

7.1. TheNumberofParticipants.......................................................................................................16

8. DATAMANAGEMENT..........................................................................................................................16

8.1. AccesstoData............................................................................................................................16

8.2. DataRecordingandRecordKeeping..........................................................................................16

Dataentry............................................................................................................................................16



Datacollection-ClinicianReportedOutcomesArm...........................................................................17

Datacollection-ParentReportedOutcomesArm..............................................................................17

Linkageofclinicianandparentreporteddata....................................................................................17

DataStorage........................................................................................................................................18

Dataavailability,timelineofuse,andremoval...................................................................................19

9. QUALITYASSURANCEPROCEDURES...................................................................................................21

10. ETHICALANDREGULATORYCONSIDERATIONS..............................................................................21

10.1. DeclarationofHelsinki...............................................................................................................21

10.2. GuidelinesforGoodClinicalPractice.........................................................................................21

10.3. Approvals...................................................................................................................................21

10.4. Reporting...................................................................................................................................22

10.5. ParticipantConfidentiality.........................................................................................................22

10.6. ExpensesandBenefits...............................................................................................................22

10.7. Justificationforeligibilityscreeningbymembersofstaffoutsideoftheusualclinicalteam....22

10.8. Justificationforlong-termstorageofdata...................................Error!Bookmarknotdefined.

11. FINANCEANDINSURANCE.............................................................................................................24

11.1. Funding......................................................................................................................................24

11.2. Insurance...................................................................................................................................25

12. PUBLICATIONPOLICY.....................................................................................................................25

13. REFERENCES...................................................................................................................................26

14. APPENDIXA:STUDYFLOWCHART................................................................................................29

15. APPENDIXC:AMENDMENTHISTORY............................................................................................30



1. SYNOPSIS

StudyTitle Next stage in Evidence-based paediatric surgical Treatment Strategies 2:Hirschsprung's Disease (NETS2HD) - A nationwide cohort study assessingcoreoutcomesatsixyearsofageinchildrenwithHirschsprung'sDisease.

Internal ref. no. / shorttitle

NETS2HD-SixyearoutcomesininfantswithHirschsprung’sDisease

StudyDesign NationalCohortstudygatheringdataonhealthandqualityoflifeoutcomesusingparentandcliniciancompletedquestionnaires

StudyParticipants Children diagnosed with Hirschsprung’s Disease between 1st of October2010, and 31st of March 2012, who were less than six months of age atdiagnosis,andwhosedatawereusedintheBritishAssociationofPaediatricSurgeonsCongenitalAnomaliesSurveillanceSystemHirschsprung’sDiseasestudy

PlannedSampleSize 305

PlannedStudyPeriod 01/06/2017-31/05/2018

Objectives OutcomeMeasures

Primary

To investigate whether choice ofdefinitive pull-through procedure isassociated with differences in coreoutcomesatsixtosevenyearsofage

Faecal incontinenceat sixyearsofage.

Secondary

Todescribecoreoutcomesatsixyearsof age for a nationwide cohort ofinfantswithHirschsprung’sDisease.To investigate whether any diseasefactors, such as length of affectedcolon, and mode of presentationaffect core outcomes at six years ofage.To investigate whether pre-operativefactors, such as birth-weight andgestational age affect core outcomesatsixyearsofage.

Secondary outcomes are theremaining nine outcomesidentified in the NETS1HD CoreOutcomeSet.

2. ABBREVIATIONS



BAPS BritishAssociationofPaediatricSurgeons

BAPS-CASS BritishAssociationofPaediatricSurgeonsCongenitalAnomalySurveillanceSystem

CI ChiefInvestigator

CRF CaseReportForm

CRN ClinicalResearchNetwork

CTRG ClinicalTrials&ResearchGovernance,UniversityofOxford

DCF DataCollectionForm

GCP GoodClinicalPractice

GP GeneralPractitioner

HD Hirschsprung’sDisease

HRA HealthResearchAuthority

ICF InformedConsentForm

LA LaparoscopicallyAssistedApproach

NHS NationalHealthService

NIHR NationalInstituteforHealthResearch

NPEU NationalPerinatalEpidemiologyUnit

NRES NationalResearchEthicsService

OA OpenApproach

PI PrincipalInvestigator

PIL Participant/PatientInformationLeaflet

R&D NHSTrustR&DDepartment

REC ResearchEthicsCommittee

SOP StandardOperatingProcedure

TA PurelyTrans-AnalApproach

3. BACKGROUNDANDRATIONALE

Three approaches to the definitive Hirschsprung’s Disease operation now exist; the ‘open approach’(OA), the ‘laparoscopically-assisted approach’ (LA) [1], and the ‘purely trans-anal approach’ (TA) [2].



There is variation in practice between different surgical centres, and no evidence-basedmanagementguidelinesexist[3,4].

Proposedbenefits to the laparoscopicallyassistedapproachover theopenapproach include improvedcosmesis, reduced operative time, length of stay, and risk of intra-abdominal adhesions[5-7].Assessments of benefit for the purely trans-anal approach have mainly been made using short-termmarkersofsuccesssuchasoperativetime,orbowelfunctionpriortotheageatwhichaninfantcanbeexpected to be continent [8, 9]. It has been suggested that over the long-term, the purely trans-analapproach may be associated with poorer outcomes than the open or laparoscopically assistedapproaches[10-13].Withthetrendtowardsincreasedutilisationofthepurelytrans-analapproach[3,4],it is important thatwe assess its impact on valid, patient centred outcomes over the longer-term. Asthereiscurrentlyinsufficientevidenceonwhichtobasearandomisedcontrolledtrial,populationbasedcohortstudiesshouldinsteadbeperformed.

TheBritishAssociationofPaediatricSurgeonsCongenitalAnomaliesSurveillanceSystem,(BAPS-CASS)isanestablishedschemethroughwhichdatahavebeencollectedonoutcomesinanumberofconditionsrequiring early surgery. This systemhas beendesigned to informevidence-based practice in a settingwhere recruitment to clinical trials has traditionally been challenging. By assessing the impact ofdifferent interventions on outcomes at 28 days of life and again at one year of age, the BAPS-CASScollaborationhaspublishedanevolvingbodyofevidencetoinformcurrentpractice.Theimpactofearlysurgeryhoweveroften laststhroughoutapatient’s life,andexpansionoftheBAPS-CASSframeworktoincorporateassessmentofoutcomesinthelatterstagesofchildhoodandonintoadulthoodisessential.

This study will therefore use the national anonymous cohort of infants with Hirschsprung’s Diseaseidentified through BAPS-CASS as the sampling frame to identify patients and seek consent from theirparentstogatherdataonlong-termoutcomesinthecondition.

3.1. Hirschsprung’sDisease

TheincidenceofHirschsprung’sDiseaseisestimatedataround1in4500livebirths[14].Itisaconditioncharacterised by colonic aganglionosis, where the intestine’s intrinsic nervous system (the myentericplexus) has failed to fully develop, resulting in the infant being unable to spontaneously open theirbowels. Varying amounts of the bowel can be affected, ranging from the classic ‘short segment’affecting only the rectum and sigmoid colon, to total colonic Hirschsprung’s Disease affecting theentirety of the colon. Prognosis is generally considered to be better for those with shorter affectedsegmentsofbowel[15].

There are classically three modes of presentation for infants with Hirschsprung’s Disease. Neonatalpresenters are those who present shortly after birth with delayed passage of meconium, abdominaldistension and vomiting. Chronic presenters are thosewho present at a later agewith symptoms ofchronic constipation. Enterocolitis presenters are then those who present in either age group with



abdominaldistension,fever,anddiarrhoeasecondarytobacterialtranslocationoccurringasaresultofthe functional obstruction caused by the aganglionic segment of bowel[16]. Initial treatment ofHirschsprung’s disease always involves decompression of the obstructed bowel, usually with rectalwashouts. For infants presentingwith enterocolitis, antibiotics and intravenous fluid resuscitation areneededinadditiontorectalwashouts.

Definitive treatmentofHirschsprung’sDiseasehoweveralmostalwaysrequiresoperative intervention.SincethefirstsuccessfulsurgicaltreatmentofaninfantwithHirschsprung’sDisease[17],therehasbeensignificant evolution in the management strategies used. In uncomplicated infants, there has been aprogression towardsperforming the repairasa single-stage,minimally invasiveprocedure[3,7].Threemain approaches to the repair now exist: the ‘open approach’ (OA), the ‘laparoscopically assistedapproach’ (LA) [18],andthe ‘purely trans-analapproach’ (TA)[19].Threemainanastomotic techniquesalsoexist,theSwenson[17],whereanobliqueanastomosisisformedbetweentheganglioniccolonandaganglionicrectalremnant,theDuhamel[20],whereanend-sideanastomosisbetweenganglioniccolonand rectal remnant is precededby a retro-rectal dissection, and finally, the Soave [21],where colonicdissection proceeds in a sub-serosal plane prior to prolapsing of the ganglionic colon through theremainingrectalmuscularcuffandanastomosistotheanus.Thereiscurrentlywidevariationinpracticebetweendifferentsurgicalcentres[3,4].

Allthreeanastomotictechniques,aswellasallthreeapproachestotheprocedureareincommonuse.Proposed benefits to LA over OA are that it reduces the risk of forming intra-abdominal adhesions,improves cosmesis, and reducesoperative time, lengthof stay and financial cost [5-7]. It is suggestedthatTAfurtherimprovestheseoutcomes[8,22].However,long-termbenefitstoTAarelessclear,withhigherlong-termratesoffaecalincontinencesuggested[10,11].Thisishowever,stilldebated[12,13].

A furtherproposeddrawback to TA is the inability to accurately identify the transitionpoint betweenganglionicandaganglionicbowelprior tostarting the rectaldissection[7].With tenper-centof infantshavingnoradiologically identifiedtransitionzone,andapproximatelyeightper-centhavingatransitionzone identifiedoperatively that is proximal to that suggestedonpre-operative imaging[23], there is asignificantriskofattemptingTAoninfantswithaproximaltransitionzone(long-segmentHirschsprung’sDisease). Ithasbeensuggestedthat infantswithaproximal transitionzoneshouldnotundergoTA,astheiroutcomesareproposedtobebetterifotherapproachesareused[24,25].

AlthoughthevastmajorityofinfantswillhavetheirdefinitiveHirschsprung’s‘pull-through’performedasaone-stageoperation,therearestillsomewhowillundergoastagedprocedure.Thisinvolvesformationofadefunctioningloopenterostomyinordertodecompressthebowel,followedbylatterpull-throughprocedure, and then reversal of the stoma. Some surgeons employ the staged procedure as theirstandard operation, whilst some will use it only in infants who are unwell or who have significantintestinaldilatation.

Post-operatively,most infantswill be started early on enteral feedswithout theneed for intravenousnutrition,andmostwillbedischargedwithinaweekoftheoperation[26].Long-termoutcomeshowever



are very variable. Complications include ongoing constipation, long-term incontinence, recurrententerocolitis, adhesional small bowel obstruction, and need for further operations. The impact of thechoiceofearlysurgicalinterventioncanthereforebelonglasting.

3.2. Long-termoutcomes

Whilst paediatric surgeons know that infants with Hirschsprung’s Disease frequently have difficultiesover the longer–term,most research todatehas focussedon short-termoutcomemeasures, hospitalmetrics or surrogate markers of success[27]. There are many reasons for the short-term focus, butprimarilyitisduetothefactthatHirschsprung’sDiseasehasalowincidence,makingitimpossibleforasingle centre study to recruit sufficient infants to answer clinically relevant questions over a sensibleperiodoftime.Moststudiesthereforeeitherrepresentsmall,butcontemporaneouscohortsofpatients,orlarger,buthistoricalcohorts,collectedovertime-periodswheretherehavebeenmultiplechangesinpractice[27].Theretrospectivenatureofthemajorityofthesestudies[28]meansthatlimiteddata-pointsare available to researchers, and hence analysis focuses on those that are easily identified from caserecords, as opposed to thosewhich are relevant to patients, their families, or service provision. Tworecently conducted systematic reviews comparing the purely trans-anal pull-through with thelaparoscopicallyassistedpull through identifiedthat there is insufficienthighqualitydatatomakeanymeaningfulcommentonwhetherthereisbenefittooneorotherinterventionoverthelongerterm[26,27].

4. OBJECTIVESANDOUTCOMEMEASURES

Objectives OutcomeMeasures

PrimaryObjective

To investigate whether choice ofdefinitive pull-through procedureaffects core outcomes at six tosevenyearsofage

The primary outcome will be faecal incontinence, defined as per theNETS1HDcoreoutcomesetas“involuntarypassageof faecalmatter inaninappropriateplace”. Severitywill begradedusingamodificationof theKrickenbergcriteria.

SecondaryObjectives

Secondary objectives are todescribe core outcomes at sixyears of age in infants with

SecondaryoutcomeswillbetheremainingnineoutcomesintheNETS1HDcoreoutcomeset.

Theseare:

• Mortality,withcauseclassifiedasduetoo Complications of treatment, excluding Hirschsprung's



Hirschsprung’s Disease, andinvestigate whether any of thefollowing factors affect coreoutcomes at six years of age ininfants with Hirschsprung’sDisease?

• Lengthofaffectedbowel• How they presented at

firstdiagnosis• Whether a stoma (a piece

of bowel pulled outthrough the abdominalwall to relievepressureonthe gut) was createdbefore their definitiveoperation

AssociatedEnterocolitis(HAE)o HAEo Anassociatedanomalyoro Other

• Voluntarybowelmovementswithoutneed forenemas,or rectalorcolonicirrigation

• Psychological stress and quality of life for the individual withHirschsprung’sDisease,asmeasuredusing thePedsQL (standardvalidatedinstrument)

• Urinaryincontinencethatisconstant,causingsocialproblems,orrequiringcatheterisation.

• Bowel function asmeasured by the Paediatric Incontinence andConstipationScore(PICS)

• Unplanned re-operation.Unplanned isdefinedas anyprocedurenot consideredpartof routinepost-interventionpractice for thedefinitive operation the child underwent. The scope of includedprocedures is limited to any procedure performed as a directresultof thediagnosisor treatmentof the child'sHirschsprung'sDisease,oranyepisodeofgeneralanaesthesiathatisrequiredasa direct result of the diagnosis or treatment of the child’sHirschsprung'sDisease,regardlessofwhetherornotanoperativeprocedure isundertaken (e.g.Examinationunderanaesthesia,ormanualevacuation).

• NeedforapermanentstomaasadirectresultofthediagnosisortreatmentofHirschsprung'sDisease,includingwherethedecisionfor a stoma has been made out of patient preference or forcontinence management. Permanent is defined as any stomawhichwascreatedwithouttheintentionofreversingit.

• Diagnosis of HAE where a decision was made to admit andinstigatetreatment,orwhereascoreof10ormorewasachievedonPastoretal'sDelphiscoreforHAE[29].

5. STUDYDESIGN

5.1. Summary

This will be a prospective, nationwide cohort study investigating the impact of choice of surgicalinterventiononcoreoutcomesatsixtosevenyearsofageinanalreadyestablishedcohortof305infantswithHD.Therewillbetwoarmstothestudy,aparentreportedoutcomesarm,andaclinicianreportedoutcomesarm.Anonymousdataonlywillbecollectedfromclinicians.Resultswill informmanagementguidelinesforinfantswithHD.SeeattachedfileStudyflowdiagramforoverviewofstudyprocesses.



5.2. StudySize

The study size is governed by the size of the cohort of infantswithHirschsprung’sDisease previouslyidentifiedthroughBAPS-CASSandwillthusincludeupto305childrenandtheirparents.

5.3. CostsandResources

BenjaminAllin,aNETS2HDresearcher,hasapersonalgrantfromtheNationalInstituteforHeathResearchaspartofaDoctoralResearchFellowship.Thiswillfundtheprincipalresearchstaffandresources.

5.4. ProjectManagement

Day-to-daymanagement of the projectwill be carried out by aManagementGroup consisting of theChief Investigator (Professor Marian Knight), Dr Benjamin Allin, the Project Co-ordinator, the DataManager,theProjectProgrammer,theStatisticianandotherexternalmembersasconsiderednecessaryfortheproject.

Oversight of the studies direction and implementation will be maintained by the Study SteeringCommittee,whichwillcompriseProfessorMarianKnight,DrBenjaminAllin,ProfessorMariaQuigley,MrTimothy Bradnock (Consultant Surgeon), Mr Gregor Walker (Consultant Surgeon), Mr Simon Kenny(Consultant Surgeon), Ms Gemma Jordan (Parent Representative), and Ms Rebecca Craven (ParentRepresentative).

5.5. PublicParticipation

The research questions and design of this study has been informed through consultation andcollaborationwithaparentaladvisorygroupcontainingfamiliesofchildrenrequiringearlysurgery.Theoutcomes to be investigated have been identified through a robust Delphi process involving keystakeholder groups, including people with Hirschsprung’s Disease, and parents of children withHirschsprung’s Disease. Parents of children with Hirschsprung’s Disease, people with Hirschsprung’sDisease, and representativesof theHirschsprung’sandMotilityDisordersSupportNetworkhavebeeninvolved in development of the study materials and methodology, in particular, the participantinformationleaflet,consentformanddatacollectionform,andtherecruitmentandconsentingprocess.Two parents of children with Hirschsprung’s Disease have been appointed to the Study SteeringCommittee.



6. PARTICIPANTIDENTIFICATION

6.1. StudyParticipants

Childrenwillbeeligible to takepart in thestudy if theywerepreviously reportedanonymously to theBritish Association of Paediatric Surgeons Congenital Anomalies Surveillance System (BAPS-CASS) ashavingbeendiagnosedwithHirschsprung’sDiseaseat less thansixmonthsofage,betweenthe1stofOctober2010and31stofMarch2012.RecordsofeligiblechildrenheldbytheBAPS-CASSdatacollectioncentreswillbeusedto identifythese infants.Thereare305children inthiscohort. Infantswhohavediedpriortosixyearsofagewillnotbeincludedintheparentreportedoutcomesarmofthestudy.

6.2. InclusionCriteria

Anyinfantwho:

• WasdiagnosedwithHirschsprung’sDisease in theUK and IrelandbetweenOctober 2010 andMarch2012.

• Wassixmonthsofageorlessatthetimeofdiagnosis• WasreportedaspartoftheBAPS-CASSHirschsprung’sDiseasestudy

6.3. ExclusionCriteria

• Childrennotmeetingtheinclusioncriteria.• Childrenwhomeettheinclusioncriteria,butwhodiedpriortoturningsixyearsofagewillnot

beincludedintheparentreportedoutcomesarmofthestudy.

6.4. Recruitment

Sharinginformationwithparentsofpotentiallyeligibleparticipants

BaseduponfeedbackfromaParentAdvisoryGroupestablishedbytheNationalPerinatalEpidemiologyUnit,informationrelatingtotheexistenceoftheNETS2HDstudywillbesharedwithparentsofpotentiallyeligible children, through trusted sources, prior to formal eligibility screening or approach forparticipationinthestudy.Theintentionofsharinginformationrelatingtotheexistenceofthestudyinanadhocmanner through trusted sources is to reassureparents that their child’s treatinghospital is



involved in the study, and that the hospital, and relevant parent support groups endorse the study’sconduct.Thisinformationwillbesharedinthefollowingfiveways:

• Achild’smainpointofcontactwith their treatinghospital is throughtheir specialistcolorectalnurse.ThesenurseswillbegiveninformationabouttheNETS2HDstudy,andaskedtoexplainitspresencetoparentsofchildrenwhomaybeeligibletoparticipate.Theywillnotbeinvolvedinseeking consent for sharing of contact details, or seeking consent to participate in the study.Nurseswillbegivenashortformparentinformationleaflettosharewithparents(seeattachedfilePISShortformV1).

• Print and/or electronic posterswill bedisplayed in theoutpatientdepartments andpaediatricsurgicalwardsofparticipatinghospitals(seeattachedfileHospitalposterV2)

• Asummary information leaflet forfamiliesofpotentiallyeligible infantswillbeavailable intheoutpatientdepartmentsandpaediatricsurgicalwardsofparticipatinghospitals.Thiswillbethesameshortformparentinformationleafletgiventoparentsofpotentiallyeligibleinfantsbythespecialistcolorectalnurses.

• TheNETS2HDwebsite• Websites for theHirschsprung'sandMotilityDisordersSupportNetwork, theCHAMPSAppeal,

andtheBreakawayfoundation.

Eligibilityscreeningandinitialcontact

This will be a National Institute for Health Research (NIHR) portfolio study, and therefore eligible forNIHRClinicalResearchNetwork (CRN)support.NIHRCRNresearchnurses,andmembersof thechild’sclinical team will use hospitals’ BAPS-CASS registers to identify infants who meet the inclusion andexclusioncriteria.Ifthereisinsufficientcapacityforparticipantidentificationcentrestoidentifyinfantsusingonlythesestaff,thensupportwillbeprovidedbyDrBenjaminAllin,theNETS2HDresearcherwhoisworkingundertheauspicesofaresearchpassport.Allparticipantidentificationwilltakeplacefromthephysical building of the child’s initial reporting hospital, and will be supervised by the site lead (aconsultantpaediatricsurgeon).ThesesamestaffmemberswillusetheNHSDigital(EnglandandWales),CommunityHealth Index (Scotland),HSCN (Northern Ireland)andhospital records to confirma child’ssurvivalstatus.AnapplicationhasbeenmadetotheConfidentialityAdvisoryGroupforapprovaltousemembersofstaffoutsideoftheclinicalteamforeligibilityscreening(seesection11.7formoredetails).

InitialcontactwithparentsofchildrenwhoarepotentiallyeligibleforinclusionintheNETS2HDstudywillbemadebyeitheranNIHRCRNresearchnurseworkingatthechild'sreportinghospital,oramemberofthechild’susualclinicalteam.WherethereisinsufficientcapacityfortheNIHRCRNresearchnurseoramemberofthechild'sclinicalteamtomaketheinitialcontact,thiswillbedonebyDrBenjaminAllin.Allcontact between thesemembers of the study team (including Dr Benjamin Allin), and the parents ofpotentiallyeligiblechildrenwillbemadefromthechild’streatinghospital,andwillbemadeunderthesupervisionof the site investigator. First contactwill bemadeby telephone,unless contact cannotbemadeonthreeoccasions,whena letterwillbesent.Thisfirstcontactwillbeusedforthepurposesofexplainingthestudyandseekingconsentforcontinuedsharingofthechild’scontactdetailsoutsideof



theirusualclinicalteam.Itwillnotbeusedforseekingconsenttoparticipateinthestudy.Onlyparentsofchildrenwhoarestillalivewillbecontacted.Verbalconsentforon-goingsharingofcontactdetailswillberecordedinwritingbythememberofstaffobtainingconsent.

IfparentsverballyconsenttotheircontactdetailsbeingsharedwithstaffintheNPEUforthepurposesofcontactingthemregardingparticipationintheNETS2HDstudy,thenthechild’snameandNHSnumber,andparentaltelephonenumberandaddresswillbesentinanencryptedfileviasecuretransfertostaffintheNPEUwheretheywillbeenteredintoanencrypteddatabaseonsecureNPEUservers.ThechildwillbeassignedaNETS2HDcaseIDnumber.

6.5. Consenttoparticipate

Followingconsentforcontinuedsharingoftheircontactdetails,parentswillbesenteitherelectronically(if they indicate this is their preference, and provide a valid email address), or viamail, a study packcontaining:

• Invitationletter• Patientinformationleaflet• ContactdetailsforNETS2HDstudystaff• Consentform

Parentswillbegiven theopportunity todiscuss the study furthervia telephonedirectlywith researchstaffpriortogivingconsenttoparticipateiftheywish.Inordertoansweranyquestionstheymayhave,researchstaffbasedintheNationalPerinatalEpidemiologyUnitwillcontactparentstwoandfourweeksafter receipt of the pack if they have not yet indicatedwhether theywish to participate. Consent toparticipatecanbeindicatedthroughcompletionofeitherthepaperorelectronicconsentforms.Parentsofeligiblechildrencanindicatetheydonotwishtoparticipatebyreturningablankconsentforminthefreepostenvelope, informingstudystaffduring telephonecontact,orbysimplynotcompletinganyofthestudydocumentation. Itwillbemadecleartoparents inthestudymaterialsthatnon-participationwill not affect the care their child receives, and that they neednot give a reason for choosing to notparticipate.Parentswillbeaskedwhethertheyconsenttobeingcontactedinthefuturewithregardstotheirchild’sdatabeingusedinaresearchdatabase.Thiswillberecordedandtheircontactdetailswillbeused accordingly, either only for discussion of the NETS2HD study, or for future contact in regards todevelopmentofaHirschsprung’sDiseaseresearchdatabase.

6.6. Requirementsofstudyparticipants



Participation in thestudywill requireparentsofeligiblechildren tocompleteonestudyquestionnairewhichwillbesenttothemontheirchild’ssixthbirthdayorthedateofconsenttoparticipate,whicheveris the later.Twoweeksafter receiptof thestudyquestionnaire,parentswillbecontactedby researchstaffintheNPEUiftheyhavenotcompletedthequestionnaire,orindicatedthattheywishtowithdrawfromthestudy.Thisprocesswillberepeatedatfourweekspostreceiptofthequestionnaire.

Pleaseseesectionninerelatingtodatamanagementforfurther informationrelatingtodatacollectionandstorageprocedures.TheparentalquestionnairecanbefoundinattachedfileParentalDCF.

6.7. Discontinuation/WithdrawalofParticipantsfromStudy

Eachparticipanthastherighttowithdrawfromthestudyatanytime.Inaddition,theInvestigatormaydiscontinue a participant from the study at any time if the Investigator considers it necessary for anyreasonincluding:

• Ineligibility (either arising during the study or retrospectively having been overlooked atscreening)WithdrawalofConsent

• Losstofollowup

ThereasonforwithdrawalwillberecordedintheCRF.

6.8. DefinitionofEndofStudy

Datawillbecollectedfrom01/06/2017-31/05/2018.Atthetimeofdatacollection,infantswillbesixtosevenyearsofage,withthelastinfantturningsixpriortothe31stofMarch2018.Theadditionalthreemonthsofdatacollectionfrom31stofMarchto31stofJunewillallowtimeforconsentofthelastinfants,abstractionoftheirdata,andchasingofanyqueries.

7. STATISTICSANDANALYSIS

The primary outcome measure for this study is faecal incontinence. This will be defined as per theNETS1HDCoreOutcomeSetas"Involuntarypassageoffaecalmatterinaninappropriateplace".SeverityoffaecalincontinencewillbegradedusingamodifiedversionoftheKrickenbeckclassification–Grade1–occasional(oncetotwiceperweek),withorwithoutensuingsocialproblems,Grade2–everydaybutwithoutsocialproblems,andGrade3–constant,withsocialproblems.

SecondaryoutcomesaretheremainingoutcomesfromtheNETS1HDCoreOutcomeSet.Theseare:



• Mortality,withcauseclassifiedasduetoo Complicationsoftreatment,excludingHirschsprung'sAssociatedEnterocolitis(HAE)o HAEo Anassociatedanomalyoro Other

• Voluntarybowelmovementswithoutneedforenemas,orrectalorcolonicirrigation• Psychological stress and quality of life for the individual with Hirschsprung’s Disease, as

measuredusingthePedsQL(standardvalidatedinstrument)• Urinaryincontinencethatisconstant,causingsocialproblems,orrequiringcatheterisation.• BowelfunctionasmeasuredbythePaediatricIncontinenceandConstipationScore(PICS)• Unplannedre-operation.Unplannedisdefinedasanyprocedurenotconsideredpartofroutine

post-intervention practice for the definitive operation the child underwent. The scope ofincludedproceduresislimitedtoanyprocedureperformedasadirectresultofthediagnosisortreatment of the child's Hirschsprung's Disease, or any episode of general anaesthesia that isrequired as a direct result of the diagnosis or treatment of the child’sHirschsprung'sDisease,regardless of whether or not an operative procedure is undertaken (e.g. Examination underanaesthesia,ormanualevacuation).

• Needforapermanentstomaasadirect resultof thediagnosisor treatmentofHirschsprung'sDisease, includingwherethedecisionforastomahasbeenmadeoutofpatientpreferenceorforcontinencemanagement.Permanentisdefinedasanystomawhichwascreatedwithouttheintentionofreversingit.

• DiagnosisofHAEwhereadecisionwasmadetoadmitandinstigatetreatment,orwhereascoreof10ormorewasachievedonPastoretal'sDelphiscoreforHAE[29].

Descriptive information will be presented for key birth demographics. Proportions and 95%confidence intervals will be calculated for the cohort as a whole, and for each of the operativegroupsforeachofthefollowingcoreoutcomes.

• Faecalincontinence• Mortality• Voluntarybowelmovementswithoutneedforenemasorrectalorcolonicwashouts• Urinaryincontinence• Unplannedre-operation• Permanentstoma• Hirschsprung’sassociatedenterocolitis

Mediansandinterquartilerangeswillbecalculatedforthecohortasawholeandforeachoperativegroupforeachofthefollowingcoreoutcomes:

• Qualityoflife,asmeasuredbythePedsQLscore• Bowelfunction,asmeasuredbythePICSscore



As a causal relationship is being investigated between choice of definitive procedure and faecalincontinenceat6yearsofage,aregressionanalysismodelwillbebuiltbaseduponpriorknowledgeof likelyconfoundingfactors.ADirectAcyclicGraph(DAG)(seeattachedfiledaggity-model-6.pdf)was developed using Daggity[30] in order to identify factors that should be adjusted for in thismodel.BasedupontheresultsoftheDAG,thefollowingfactorswillbeadjustedfor:

• Birthweight• AgeatpresentationwithHirschsprung’sDisease• Presenceofenterocolitisatfirstpresentation• Developmentofpre-operativeenterocolitis• Pre-operativestomaformation• Weightatoperation• Methodofrectaldissection• Lengthofaffectedsegmentofcolon

7.1. TheNumberofParticipants

Thereare305 infants in theoriginalBAPS-CASSHirschsprung’sDiseasecohort.These infantswill formthestudysamplesize.

Assuming an incidence of faecal incontinence of 35% in infants undergoing LA[31],with 43% ofinfants undergoing the LA, and 15% TA, this study would have 80% power at the 5% level ofsignificance todetecta relativeriskof 1.8orabove,or0.35orbelowwhencomparing to infantswithHDundergoingTA.

8. DATAMANAGEMENT

8.1. AccesstoData

PersonaldatawillonlybeaccessiblebymembersoftheNETS2HDstudyteamwithalegitimateneedtocontact participants. Responsible members of the University of Oxford or NHS Trusts may be givenaccesstodataformonitoringand/orauditofthestudytoensurewearecomplyingwithregulations.

8.2. DataRecordingandRecordKeeping

Dataentry



ClinicianreportedoutcomeswillbeentereddirectlyintoOpenClinica.Parentreporteddatawilleitherbedirectlyentered intoOpenClinicausing theParticipateexpansion,orwill be recordedonapaperdatacollectionform,dependentonparentalpreference.Whereapaperdatacollectionformhasbeenused,thiswill be returned to staff at theNPEU,where datawill be double entered intoOpenClinica. Pre-specifiedacceptabledataentriesandrangeswillbeusedtoidentifytheinputofpotentially incorrectlyentereddata

Datacollection-ClinicianReportedOutcomesArm

NIHR CRN research nurses and members of the child’s usual clinical team will be responsible forextractionofdatafromexistinghospitalrecords,includingclinicletters,operativenotesandradiologicalinvestigations.Alldataextractionwilltakeplacefromthephysicalbuildingofthechild’sinitialreportinghospital, and will be supervised by the site lead. Anonymous data will be directly entered intoOpenClinicahostedonsecureNPEUservers,andwillbeassociatedwiththechild’sBAPS-CASScaseID.

Datacollection-ParentReportedOutcomesArm

Ontheirchild’ssixthbirthday,orthedateofconsenttoparticipate,whichever is later,parentswillbesent a paper data collection form, or link to an electronic data collection form according to theirpreference.Wheretheyoptforanelectronicform,theywillenterdatadirectlyintoOpenClinicaonthesecureNPEU servers.Where they opt for a paper data collection form, thesewill be returned to theNPEU,wheretheywillbedoubleenteredinthesecuredatabasebyNETS2HDstudystaff.Noparticipantidentifiable data will be collected on the data collection forms. Outcomes will be reported using thechild’sNETS2HDcaseID.Noparticipantidentifiableinformationwillbestoredintheoutcomesdatabase.

Linkageofclinicianandparentreporteddata

Toachievetheprimaryobjectiveofthestudy,itisessentialthatparentandclinicianreportedoutcomescan be linked to data relating to this cohort of children that were collected by the BAPS-CASSHirschsprung’sDiseasestudieswhenthechildrenwere28daysofageandoneyearofage.Achievingthisrequireslinkingachild’sBAPS-CASScaseIDtotheirNETS2HDcaseID.Therefore,afterconsenthasbeenobtained for participation in the NETS2HD study, the NIHR CRN research nurse based in the child’sreportinghospitalwillbeaskedtotransfertostaffintheNPEUtheBAPS-CASScaseIDthatisassociatedwithachild’sNHSnumber.Thistransferwillbedoneinanencryptedfileviasecuretransfersystem.Staffin theNPEUwill add theBAPS-CASS case ID to the child’s existing registration record containing theirname,NHSnumber,parentalcontactdetails,andNETS2HDcaseID.ThisinformationwillallbestoredontheNPEUsecureserversinadatabaseseparatefromanyclinicalinformation.



DataStorage

PersonaldataprovideddirectlybyparentswillbeenteredontoasecureareaoftheNationalPerinatalEpidemiology Unit (NPEU) computer system. This will be stored separately from the informationprovided in the questionnaires. All analysis will take place on fully anonymised datasets only. ThesecurityofthedatawillbemaintainedbystorageonasecureNPEUnetworkaccessibleonlybythekeyresearchers and responsiblemembers of theUniversity ofOxfordwhomay require access to data toensurecompliancewithregulations.

Completed paper questionnaires will be stored in locked filing cabinets and, once entered onto adatabase,compliancewillbemaintainedbystorageonasecureNPEUnetwork,accessibleonlybythekeyresearchersandresponsiblemembersoftheUniversityofOxfordwhomayrequireaccesstodatatoensurecompliancewithregulations.

Personaldatawillhavebeenprovidedbyparentswithconsentonthebasisthatwemaycontactthemregardinguseoftheirchild’sdataindevelopmentofaHirschsprung’sdiseaseresearchdatabase.

Wewillnotretainanypersonaldataforparentswhohavechosennottoconsenttoparticipationorhavewithdrawnfromthestudy.

AlldatawillbestoredinastudyspecificdatabasehostedonthesecureserversoftheNationalPerinatalEpidemiologyUnit,withsecuritymaintainedthroughimplementationofNationalPerinatalEpidemiologyUnitstandardoperatingprocedures.,specifically:

Physicalsecurity:

Physicalaccesstothebuildingiscontrolledbyswipecardandamannedreceptionforvisitors.FurtherswipeaccessisrequiredtoaccesstheNPEUsectionofthebuilding. Accessforvisitors isviatheNPEUreceptionandvisitorsareallocatedavisitorbadge.

Paper records containing sensitive and/or personal data are kept in locked filing cabinets in officesdedicatedforagivenresearchproject;theseofficesarekeptlockedwhenvacant.

Virtualsecurity:

Anypersonalorsensitivedigitaldata,suchaspatientidentifiabledata,iskeptontheNPEU’sencryptednetwork drive. This drive is controlled by eDirectory and access permissions are granted to data foridentified,authorisedandauthenticatedusers.TheNPEUadoptsapolicywherenosensitiveorpersonaldataleavestheunitonremovabledevicesunlessconsultationhasbeenhadwiththeunit’sDirectorandwouldonlybeenapprovedforexceptionalcircumstanceswherethedataneedstobetransferredandanalternativesecureelectronictransfermechanismcannotbeenabled.



All security is supported by the NPEU policies and these are regularly reviewed and audited inaccordancetotheNHSInformationGovernanceToolkit(IGT).InformationSecurityisdiscussedateverymonthlyseniormanagementgroupmeetingandisanagendaitemfortheNPEUtri-annualstaffmeeting,wherethelatestupdatesandvulnerabilitiesarereportedandstafftrainingisprovided.RandomcheckscanbecarriedoutbytheHeadofITandInformationSecurityatanytime.

The NPEU has been awarded level 3 status with 100% score on the NHS IGToolkit (EE133863-8J017-NPEU). TheNHSIGTaligns itself tothecontrolsof ISO27001and ISO27002. TheNPEUhaspoliciestosupport the NPEU’s operations in a safe, secure and controlled environment. Policies are reviewedbienniallyanddistributedtostaffbyanelectronicsystem(PRISMS)whichcan,ifrequired,testusersontheir knowledge for a given policy and/or SOP. The NPEU adopts a riskmanagement andmitigationapproach.

NHS IGToolkit: EE133863-8J017-NPEU; version13, level3witha scoreof100%withan improvementplaninplace.

UniOxDataprotectionregistrationnumber:Z575783X

Dataavailability,timelineofuse,andremoval

Once parental contact details have been obtained by a National Institute for Health Research (NIHR)ClinicalResearchNetwork (CRN) researchnurse, reportingclinician,orDrBenjaminAllin, thesewillbekept securely within the reporting hospital. Only the child’s NHS number, name date of definitiveoperationorstomaformationifdefinitiveprocedurehasnotbeenperformed,andparent’snamesandtelephonenumberswillbeavailabletopeopleoutsideoftheclinicalteam(NETS2HDstudyteam)priortoconsentbeingobtained.

Firstattemptatcontactviatelephonewiththeparentsofeligiblechildrenwillbemadewithin72hoursof obtaining the contact details. A further two attempts at contact will bemadewithin oneweek ofobtainingthecontactdetails.Ifnocontactismade,anattemptwillbemadetomakecontactinwrittenformatwithintwoweeksofobtainingcontactdetails.EachoftheseattemptsatcontactwillbemadeinordertoobtainconsenttocontinuedsharingofcontactdetailswithmembersoftheNETS2HDstudyteam.Ifconsentisgivenitwillberecordedinwritingbytheteammemberwhomadecontactwiththeparents.Alackofresponsefromparentswithinamonthofpostingofthewrittencommunicationwillbeassumedtoindicatetheydonotgivetheirconsentforon-goingsharingoftheircontactdetails.Inthisscenario,orwhereconsentisnotgivenforsharingofcontactdetailsfollowingcontactwiththerecruitingmemberofstaff, all contactdetailswill be removed from the local records, and replacedwitha record indicatingthatconsenttosharingofcontactdetailshasnotbeenobtained.

Whereconsenttosharingofcontactdetails isgiven,thesedetailswillbesharedwithNETS2HDresearchstaffintheNPEUwhowillsendaparticipantinformationpacktoparentsoftheeligiblechild.Thispackwillcontainaninvitationletter,patientinformationleaflet,contactdetailsforNETS2HDstudystaffanda



consent form. If no indication has been given by parents of whether theywish to participate at twoweeksandfourweeksafterreceiptoftheparticipantinformationpack,theywillbecontactedbystudystafftoascertainwhethertheywishtoparticipate.Ifconsenthasnotbeengivenforparticipationwithintwo months of posting of the study information pack, all contact details will be removed from thedatabaseheld in theNPEU, and replacedwith a record indicating that consent toparticipatewasnotobtained.

Throughusingtheabovemethodstoobtainconsent,andremovalofcontactdetailswhereconsenthasnotbeenobtained,theNETS2HDstudywillmovetowardsasituationwherethereisnolongeranypatientidentifiabledatabeingusedwithoutconsent.Thelongesttime-periodthatpatientidentifiabledatamaybeheldwithoutexplicitconsentis14weeks.Thiswouldbeforaninfantwhoseparentswerecontactedin writing two weeks after the initial attempt at telephone contact, and who then gave consent tosharing of contact details onemonth later, but who did not then respond to any of the attempts toobtainconsenttoparticipateinthestudy,leadingtoremovaloftheircontactdetailstwomonthsafterpostingofthestudyinformationpack.



9. QUALITYASSURANCEPROCEDURES

Theday-to-daymanagementof the studywill be undertakenby the studymanagement group,whichcomprisesthestudyresearcher,ProgrammeManager,StudyProgrammerandSeniorinvestigator.

Overall conduct of the studywill be overseen by the Study Steering Committee,which comprises theresearcherandseniorinvestigatorinadditiontothreeconsultantpaediatricsurgeonsandtwoparentsofchildrenwithHirschsprung’sDisease.Thesteeringcommitteewillmeet threemonthly throughout thedesign,implementationandanalysisofthestudy,andwillbeincontactelectronicallyandviatelephonemorefrequentlyasrequired.Theywillmonitorrecruitment,scrutiniseacceptabilityofthestudydesign,andanalyseanyadversefeedbackfromparticipantsorthosewhodissenttoparticipateinthestudy.

Progressof thestudywillalsobemonitored in theweeklymeetingsbetweenProfessorMarianKnightand Dr Benjamin Allin that form the supervisionmeetings for Dr Allin that are incorporated into theDoctoral Research Fellowship training and supervision program. Similarly, the study progress will bemonitored at the monthly supervision meetings that include Professor Jenny Kurinczuk as well asProfessorMarianKnightandDrBenjaminAllin.

10. ETHICALANDREGULATORYCONSIDERATIONS

10.1. DeclarationofHelsinkiThe Investigator will ensure that this study is conducted in accordance with the principles of theDeclarationofHelsinki.

10.2. GuidelinesforGoodClinicalPracticeTheInvestigatorwillensurethatthisstudyisconductedinaccordancewithrelevantregulationsandwithGoodClinicalPractice.

10.3. ApprovalsThe protocol, informed consent form, participant information sheet and any proposed advertisingmaterialwill be submitted to the sponsor, an appropriate Research Ethics Committee (REC), HRA andhost institution(s) forwrittenapproval.Approval isalsobeingsought fromtheConfidentialityAdvisoryGroup.

The Investigator will submit and, where necessary, obtain approval from the above parties for allsubstantialamendmentstotheoriginalapproveddocuments.



10.4. ReportingTheCIshallsubmitonceayearthroughoutthestudy,oronrequest,anAnnualProgressreporttotheREC Committee, HRA (where required) host organisation and Sponsor. In addition, an End of Studynotificationandfinalreportwillbesubmittedtothesameparties.

10.5. ParticipantConfidentiality

The study staff will ensure that the participants’ anonymity is maintained. The participants will beidentifiedonlybyaparticipantIDnumberonallstudydocuments.

Screening,handlinganderasureof identifiablepersonal informationofpotentiallyeligiblechildrenwillonlybeundertakeninthemannerdescribed.Anycontactdetailsorparticipantidentifiableinformationwereceivewillbestoredsecurely,separatefromtheresearchinformation.Allanalysiswilltakeplaceonfullyanonymiseddatasetsonly.

Completed paper questionnaires will be stored in locked filling cabinets and, once entered onto adatabase; the security of the data will be maintained by storage on a secure University networkaccessibleonlyby thekey researchersand responsiblemembersof theUniversityofOxfordwhomayrequire access to data to ensure compliancewith regulations. Access by any other individuals for thepurposesofanyother studywillonlybeallowedafter reviewby theNETS2HDSteeringCommitteeandfurtherreferencetoaResearchEthicsCommittee.

It is possible thatdirectquotes from free text areasof thequestionnairemaybeused inpublicationsrelatedtothequestionnairestudy.Nosuchquoteswillbeabletobetracedtoanyindividual.

ThestudywillcomplywiththeDataProtectionAct,whichrequiresdatatobeanonymisedassoonasitispracticaltodoso.

10.6. ExpensesandBenefits

Therearenointendedpaymentsorotherbenefitstoparticipants.

10.7. Justification for eligibility screening bymembers of staff outside of the usualclinicalteam

Onlyanonymousdatawerecollected for theBAPS-CASS study (EthicsRef:12/SC/0416),and thereforeonly the sites which collected the data, and not researchers have access to children’s and parent'scontact details. We conducted a previous study (AIMESGS, Ethics Reference Number 14/LO/1949) in



which we asked clinicians at sites to confirm eligibility and then post out long-term follow-upquestionnairestoparentsofchildrenwithadifferentcondition,whoseanonymousdatahadalsobeenincludedinapreviousBAPS-CASSstudy.Only50%ofsitesmanagedtoidentifyeligiblechildrenandpostoutthequestionnairesduetoissueswithstaffcapacity,andonly10%ofquestionnaireswerereturnedbyparents.At one sitewhereparentswere contactedpersonally by the research teamby telephone,responserateswerehigher.Reasonsforfailureofthisstudytorecruithavebeeninvestigatedindetailwith reportingclinicians,andalsowithmembersof theparentadvisorygroup.The reasons for failurewerebrokendownintotwobroadareas:

1. Insufficient time for clinical staff to identify eligible children, post studymaterials to themandcontactthemtoensurereceiptandunderstandingofmaterials.

2. Parentsfeelingdisconnectedfromthestudyduetoalackofrecentcontactwithhealthcareprofessionals,andlackofinformationaboutthestudy/opportunitytodiscussthestudypriortoreceivingthequestionnaire.

TherecruitmentandconsentingprocessusedfortheNETS2HDstudyhasthereforebeendevelopedbaseduponthisfeedback,withthefollowingchangessuggested:

1. Useofresearchnursesandwherenecessary,DrBenjaminAllin,theNETS2HDstudyresearcherinadditiontoreportingclinicianstoidentifyeligiblechildren.Thiswillreducetheworkloadonbusyclinicians,andensurethestudycanbesuccessfullycarriedoutevenindepartmentswherethereareinsufficientclinicianstomakeidentificationofeligiblechildrenfeasible.

2. Firstcontactwithparentsofeligiblechildrenbeingmadeviatelephoneasopposedtomailedinformationinordertoallowdiscussionofthestudypriortostudymaterialsbeingreceivedbyparents.

3. First contactwith parents of eligible children simply being to obtain consent to continuedsharingoftheircontactdetails,asopposedtobeingtoobtainconsentforparticipationinthestudy.

4. Providing information about the NETS2HD study at participating hospitals, to ensure thatparentsofeligiblechildrenareawareitistakingplace,andthattheirhospitalistakingpart.Thiswillalsopromptparentstoaskformoreinformationfromtheircliniciansiftheybelievetheirchildmaybeeligibletoparticipate.

Basedupon thisanalysisof the limitationsof theAIMESGS study,wepropose that initial contactwithchildrenwhoarepotentiallyeligibleforinclusionintheNETS2HDstudywillbemadebyeitheraNationalInstitute for Health Research (NIHR) Clinical Research Network (CRN) research nurse working at thechild's treating hospital, or a member of the child’s usual clinical team. Where there is insufficientcapacity for theNIHRCRN researchnurseor amemberof the child's clinical team tomake the initialcontact,weproposethatthiswillbedonebyDrBenjaminAllin,theNETS2HDresearcher,workingundertheauspicesofaresearchpassport, fromtherelevantsite.Allcontactbetweenthesemembersofthe



study team, including Dr Benjamin Allin, and the parents of potentially eligible childrenwill bemadefromthechild’streatinghospital,andwillbemadeunderthesupervisionofthesite investigator.Firstcontactwillbemadebytelephone,unlesscontactcannotbemadeonthreeoccasions,whenaletterwillbesent.Thisfirstcontactwillbeusedforthepurposesofexplainingthestudyandseekingconsentforcontinueduseof the child’s contactdetails outsideof their usual clinical team. Itwill notbeused forseekingconsenttoparticipateinthestudy.

IfDrBenjaminAllinisrequiredtoassistwithidentificationofeligiblechildren,hewillonlyhaveaccesstothat information required to identify the child, confirm eligibility and contact their parents. Thisinformation will be limited to the child’s NHS number, name, date of definitive operation or stomaformationifdefinitiveprocedurehasnotbeenperformed,andparent’snamesandtelephonenumbers.Site investigators will be appointed in each participating hospital, and will have responsibility forensuringthatonlyessentialdataareaccessed.All identificationofpotentiallyeligiblechildrenwilltakeplaceattherecruitinghospital.

Thismethodoffirstcontacthasbeendevelopedwiththecloseinvolvementofparentgroups,andtheyreportedthatsharingoftheabovedetailswitharesearchnurseand/orDrBenjaminAllinworkingwithinthe above framework was a step they were happy to take if it improved the chances of the studyachievingitsobjectives.Quotesfromparentsinclude:

“Asaparent Idon’t think Iwouldmind ifyouhadaccess tomycontactdetails, I thinkpeoplehaveageneral assumption that clinicians will treat personal information with respect. I’m not sure theynecessarilyworryaboutthedistinctionbetweenhospitalsaslongasitisexplainedwhyitisnecessary.”

And

“As a parent I don't have concerns about confidential contact information being passed outside ourimmediateclinicalteam”.

And

“Themainthingisthatyougetagoodresponserateandthatthere'sadequateresourcestofollowupwithparentsandgivethemanopportunitytoaskquestions”.

11. FINANCEANDINSURANCE

11.1. Funding



This study is fundedby theNational Institute forHealthResearch (NIHR)aspartofDoctoralResearchFellowshipawardedtoMrBenjaminAllin.

11.2. Insurance

TheUniversityofOxfordmaintainsPublicLiabilityandProfessionalLiabilityinsurancewhichwilloperateinthisrespect.

12. PUBLICATIONPOLICY

Thefindingsofthisstudywillbepresentedatspecialistconferences,suchastheBAPSAnnualCongress.Resultingworkwillalsobesubmittedforpublicationinpeer-reviewedjournals.Findingswillalsobefedbacktoaparentaladvisorygroupandthence,totherelevantpatientandparentgroups.

The Investigatorswillbe involved in reviewingdraftsof themanuscripts, abstracts,press releasesandanyotherpublicationsarisingfromthestudy. AuthorswillacknowledgethatthestudywasfundedbytheNationalInstituteforHealthResearch(NIHR).AuthorshipwillbedeterminedinaccordancewiththeICMJEguidelinesandothercontributorswillbeacknowledged.



13. REFERENCES

1. GeorgesonKE,FuenferMM,HardinWD:Primary laparoscopicpull-through forHirschsprung'sdisease in infants and children. JournalofPediatricSurgery1995,30(7):1017-1021;discussion1021-1012.

2. De la Torre-Mondragon L, Ortega-Salgado JA: Transanal endorectal pull-through forHirschsprung'sdisease.JournalofPediatricSurgery1998,33(8):1283-1286.

3. BradnockTJ,WalkerGM:EvolutioninthemanagementofHirschsprung'sdiseaseintheUKandIreland: a national survey of practice revisited. Annals of the Royal College of Surgeons ofEngland2011,93(1):34-38.

4. KecklerSJ,YangJC,FraserJD,AguayoP,OstlieDJ,HolcombGW,3rd,StPeterSD:Contemporarypractice patterns in the surgical management of Hirschsprung's disease. Journal of pediatricsurgery2009,44(6):1257-1260;discussion1260.

5. One-stage Soavepull-through forHirschsprung'sdisease:A comparisonof the transanal andopen approaches[http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed5&NEWS=N&AN=2000199114]

6. Primarypull-throughforHirschsprung'sdisease:Comparisonofopenandlaparoscopic-assistedprocedures[http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed8&NEWS=N&AN=2008003612]

7. Transanal pull-through for Hirschsprung disease[http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed7&NEWS=N&AN=2005188897]

8. Rangel SJ, de Blaauw I: Advances in pediatric colorectal surgical techniques. Seminars inpediatricsurgery2010,19(2):86-95.

9. Langer JC: Laparoscopic and transanal pull-through for Hirschsprung disease. Seminars inPediatricSurgery2012,21(4):283-290.

10. El-Sawaf MI, Drongowski RA, Chamberlain JN, Coran AG, Teitelbaum DH: Are the long-termresults of the transanal pull-through equal to those of the transabdominal pull-through? Acomparison of the 2 approaches for Hirschsprung disease. Journal of pediatric surgery2007,42(1):41-47;discussion47.

11. Zhang SC, Bai YZ, Wang W, Wang WL: Clinical outcome in children after transanal 1-stageendorectalpull-throughoperation forHirschsprungdisease.Journalofpediatricsurgery2005,40(8):1307-1311.

12. Van Leeuwen K, Geiger JD, Barnett JL, Coran AG, Teitelbaum DH: Stooling and manometricfindings after primary pull-throughs in Hirschsprung's disease: Perineal versus abdominalapproaches.Journalofpediatricsurgery2002,37(9):1321-1325.

13. Till H, HeinrichM, Schuster T, D VS: Is the anorectal sphincter damaged during a transanalendorectal pull-through (TERPT) for Hirschsprung's disease? A 3-dimensional, vectormanometric investigation. European journal of pediatric surgery : official journal of AustrianAssociationofPediatricSurgery[etal]=ZeitschriftfurKinderchirurgie2006,16(3):188-191.

14. Ahola JA,KoivusaloA,SairanenH, JokinenE,RintalaRJ,PakarinenMP: Increased incidenceofHirschsprung's disease in patients with hypoplastic left heart syndrome--a common neuralcrest-derivedetiology?Journalofpediatricsurgery2009,44(7):1396-1400.



15. NeuvonenMI, Kyrklund K, Lindahl HG, Koivusalo AI, Rintala RJ, PakarinenMP:A population-based, complete follow-up of 146 consecutive patients after transanal mucosectomy forHirschsprungdisease.Journalofpediatricsurgery2015,50(10):1653-1658.

16. Comparative review of functional outcomes post surgery for Hirschsprung's disease utilizingthe paediatric incontinence and constipation scoring system[http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed11&NEWS=N&AN=2012746393]

17. Swenson O, Bill AH, Jr.: Resection of rectum and rectosigmoid with preservation of thesphincter for benign spastic lesions producing megacolon; an experimental study. Surgery1948,24(2):212-220.

18. GeorgesonKE,FuenferMM,HardinWD:Primary laparoscopicpull-through forHirschsprung'sdisease in infants and children. Journalofpediatric surgery1995,30(7):1017-1021;discussion1021-1012.

19. De la Torre-Mondragon L, Ortega-Salgado JA: Transanal endorectal pull-through forHirschsprung'sdisease.Journalofpediatricsurgery1998,33(8):1283-1286.

20. DuhamelB:AnewoperationforthetreatmentofHirschsprung'sdisease.Archivesofdiseaseinchildhood1960,35:38-39.

21. Soave F: HIRSCHSPRUNG'S DISEASE: A NEW SURGICAL TECHNIQUE. Archives of disease inchildhood1964,39:116-124.

22. Langer JC: Laparoscopic and transanal pull-through for Hirschsprung disease. Seminars inpediatricsurgery2012,21(4):283-290.

23. ProctorML, Traubici J, Langer JC,GibbsDL, Ein SH,DanemanA, KimPC:Correlation betweenradiographictransitionzoneandlevelofaganglionosisinHirschsprung'sdisease:Implicationsforsurgicalapproach.Journalofpediatricsurgery2003,38(5):775-778.

24. Hoehner JC, Ein SH, Shandling B, Kim PC: Long-termmorbidity in total colonic aganglionosis.Journalofpediatricsurgery1998,33(7):961-965;discussion965-966.

25. De La Torre L, Langer JC: Transanal endorectal pull-through for Hirschsprung disease:technique, controversies, pearls, pitfalls, and an organized approach to themanagement ofpostoperativeobstructivesymptoms.Seminarsinpediatricsurgery2010,19(2):96-106.

26. Chen Y, Nah SA, Laksmi NK, Ong CC, Chua JH, Jacobsen A, Low Y: Transanal endorectal pull-throughversustransabdominalapproachforHirschsprung'sdisease:asystematicreviewandmeta-analysis.Journalofpediatricsurgery2013,48(3):642-651.

27. Thomson D, Allin B, Long AM, Bradnock T, Walker G, Knight M: Laparoscopic assistance forprimary transanal pull-through in Hirschsprung's disease: a systematic review and meta-analysis.BMJopen2015,5(3):e006063.

28. AllinBSRAN,Campion-Smith T, FloydE, Kimpton J, SwarbrickK,WilliamsE, KnightM. :Whatevidence is there to support clinical practice in paediatric surgery? A systematic reviewdescribingthestudydesignsusedinpaediatricsurgicalresearch.In.:UniversityofOxford;2014.

29. Pastor AC, Osman F, Teitelbaum DH, Caty MG, Langer JC: Development of a standardizeddefinition for Hirschsprung's-associated enterocolitis: a Delphi analysis. Journal of pediatricsurgery2009,44(1):251-256.

30. Benito van der ZanderML, Johannes Textor:Constructing separators and adjustment sets inancestralgraphs. In:30thConferenceonUncertaintyinArtificialIntelligence:2014:AUAIPress;2014.



31. Thomson D, Allin B, Long A, Bradnock T, Walker G, Knight M: Laparoscopic assistance forprimary transanal pull-through in Hirschsprung’s disease: a systematic review and meta-analysis.In:UnpublishedSystematicReview.2014.



14. APPENDIXA:STUDYFLOWCHART

SeefileStudyFlowDiagramV2.pptx



15. APPENDIXC:AMENDMENTHISTORY

AmendmentNo.

ProtocolVersionNo.

Dateissued

Author(s)ofchanges DetailsofChangesmade

Listdetailsofallprotocolamendmentsherewheneveranewversionoftheprotocolisproduced.ThisisnotnecessarypriortoinitialRECsubmission.

th April 2017 IRAS Project number: 202042 REC Reference ... study... · Chief Investigator: ... Disease Ethics Ref: 17/SC/0152 IRAS project ID 202042 ... 17/SC/0152 Chief Investigator:

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