Noteto investigators:
The following protocol templatewas derived fromGood Clinical Practice (GCP)Guidelines– aninternational ethicaland scientificquality standard for designing, conducting, recording, and reporting trials thatinvolvetheparticipationof humansubjects. It isintended to provide a basic framework for organizing your researchplan.
The completeGCP guidelines can be found at: Scrolldownthepageto find:ICH E6:Good Clinical Practice: Consolidated Guidance. Whenyouopenthedocument–the cover pagewill say “Guidance for Industry”. Do notbe confused bythis. Applicationof GCP standards to clinical research is notlimited toresearch conducted by (or for)industry.
PROTOCOL
ARegistryofPatients with
PrimaryImmunodeficiencyDisorders
Version: 1.04H
August 2015
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Nameandaddress ofthesponsor ofthestudy
United StatesImmunodeficiencyNetwork(USIDNET)
110 West Road, Suite 300 Towson, MD 21204
Nameandaddress ofthepersonauthorizedto signtheprotocol andamendments
RamsayFuleihan, M.D.
United StatesImmunodeficiencyNetwork(USIDNET)
110 West Road, Suite 300 Towson, MD 21204
Nameandaddress ofstudy monitor
Tara Caulder – Project Director
United StatesImmunodeficiencyNetwork(USIDNET)
110 West Road, Suite 300 Towson, MD 21204
Name, title, address andtelephonenumber(s)ofthemedical expert for the trial
Ramsay L.Fuleihan, M.D.
United StatesImmunodeficiencyNetwork(USIDNET)
110 West Road, Suite 300 Towson, MD 21204
443.632.2556
773.327.1701
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1.0 BACKGROUND...... 10
1.1INVESTIGATIONALAGENT...... 12
1.2PRE-REGISTRYDATA...... 12
1.3RISK/BENEFITS...... 14
1.4PURPOSE...... 14
1.5TRIALCONDUCT...... 14
1.6POPULATION...... 14
1.7LITERATURE...... 15
2.0 TRIAL OBJECTIVES...... 15
3.0 TRIAL DESIGN...... 16
3.1USIDNETS COLLABORATIONWITHTHECENTERFOR INTERNATIONALBLOODAND MARROWTRANSPLANTRESEARCH(CIBMTR)...... 18
3.2PRIMARYSTUDYENDPOINTS/SECONDARYENDPOINTS...... 19
3.3DURATION ...... 19
3.4DISCONTINUATION...... 19
3.5DATAIDENTIFICATION...... 19
4.0 SELECTION AND WITHDRAWAL OFSUBJECTS...... 19
4.1INCLUSIONCRITERIA...... 20
4.2EXCLUSIONCRITERIA...... 20
4.3SUBJECTWITHDRAWAL...... 20
4.4ENROLLMENT/RECRUITMENTMETHODS...... 20
5.0 ASSESSMENT OFSAFETY...... 21
5.1ADVERSEEVENTREPORTING...... 21
5.2DEFINITIONS...... 21
5.3ADVERSEEVENTFOLLOW-UP...... 21
6.0 STATISTICAL METHODS...... 22
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6.1DATAMANAGEMENTANDSTATISTICALANALYSIS...... 22
6.2DEVIATIONREPORTING...... 22
7.0 QUALITY CONTROLANDQUALITY ASSURANCE...... 23
8.0 ETHICAL CONSIDERATIONS...... 23
9.0 DATA HANDLING ANDRECORDKEEPING...... 23
10.0 FINANCE AND INSURANCE...... 25
APPENDIX
1.0 CORE FORM …………………………………………………………………………25
2.0 FILL DATA COLLECTION FORM……………………………………………………38
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List ofAbbreviations
AEAdverseEvent
CFRCodeof Federal Regulations
CGDChronic granulomatous disease
CIBMTRCenter forInternationalBlood and Marrow Transplant Research
CRFCaseReport Form
CVDCommon variable immunodeficiency
DGSDiGeorgesyndrome
DHHSDepartment ofHealth and Human Services ESIDEuropean SocietyforImmunodeficiency FDA Food and DrugAdministration
FWAFederal Wide Assurance
GCPGood Clinical Practice
ICHInternational Conferenceon Harmonisation
IDFImmunodeficiencyFoundation
IPEXImmunodysregulation, Polyendocrinopathy, Enteropathy, X linked(IPEX) Syndrome
IRBInstitutional ReviewBoard
LADLeukocyte adhesion deficiency
NIAIDNationalInstitute ofAllergyandInfectious Disease
NICHDNationalInstituteof Child Health and HumanDevelopment
NIH NationalInstitutes of Health PHI Personal HealthInformation PI PrincipalInvestigator
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PIDDPrimaryimmune deficiencydiseases SCISevere combined immunodeficiency USIDNET United StatesImmunodeficiencyNetwork WAS Wiskott– Aldrich syndrome
XHIGMX-linked hyperIgM
XLAX-linked agammaglobulinemia
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1.0 Background
Primaryimmune deficiencydiseases (PIDD)represent a class ofdisorders inwhich there is an intrinsic defect in thehuman immunesystem(ratherthan immune disorders that are secondaryto infection, chemotherapy, or someother external agent).In some cases, the bodyfails to produce anyor enough antibodies tofight infection.In other cases, the cellulardefensesagainstinfection failto work properly.There aremorethan 200 different primaryimmune deficiencydiseases currentlyrecognized bythe International Union of Immunological Societies, most of which are thought to be due to genetic mutations.
Medical recognition of primaryimmune deficiencydiseaseis only 60years old. Although thesedisordersmayhave existed in antiquity, itwas not until thedevelopment of antibiotics that infections could be controlled longenough torecognizetherewasan underlyingdefect in the immunesystem. Also, theparallel development of gammaglobulinin World WarIIprovideda replacement therapyforthe antibody deficiencyforms of immune deficiency.
Successful treatments have been developed for many forms of immune deficiency. The most profound immune defects are collectively known as severe combined immunodeficiency (SCID), in which both antibody production and cellular immunity are absent. If untreated, SCID is fatal early in life due to infectious complications; however, if diagnosed promptly, SCID can be cured by transplantation of blood-forming stem cells from a tissue-matched healthy donor. Like almost all forms of immune deficiency, early diagnosis is a key to optimal treatment, and infants identified as having SCID at a very young age because of awareness of an affected relative have superior survival and outcomes. Unfortunately the great majority of SCID cases are sporadic and not recognizable at birth, but a biomarker for normal T cell development, T cell receptor excision circles (TRECs), were suggested in 2005 as a simple analyte to screen all infants to flag problems with T cell development. Insert paragraph re: NBSBeginning in 2008, pilot programs were undertaken to assay TRECs in the dried blood spot samples already universally obtained to screen newborns for rare inborn conditions such as metabolic diseases, hypothyroidism and hemogobinopathies. SCID newborn screening with the TREC assay has proven sensitive and specific. In 2010 the DHHS Secretary recommended addition of SCID screening with TRECs for all state newborn screening panels, and as of 2015 over two thirds of United States born infants are being screened. In addition to detecting SCID, the TREC test also identifies infants with low T cells due to a variety of causes, some well recognized and others not yet fully understood. Conditions with low T cells found by TREC screening and/or by family history are the first immune defects amenable to pre-symptomatic, unbiased diagnosis to reveal the incidence as well as the full range of underlying causes and responses to treatment.
Although primaryimmunedeficiencydiseases areoften described asraredisorders, the truepopulation prevalenceof thesediseases, eitherindividuallyor in theaggregate, is not wellestablished.Themajorhealth surveysconducted bythegovernment inthe United States, the National HealthInterview Surveyand theNational Health and Nutrition Examination Survey,donot collect information on primaryimmune deficiencydiseases. No comprehensive population surveyhas even been undertaken bythe federal government to estimatethe prevalenceor thepopulation characteristics ofthesediseases in theUnited States. Hence, although thesediseases areclinicallydescribed in the
medicalliterature, thereis no comprehensive portraitavailable ofthe patient with primaryimmune deficiencydisease.
In 1992 theNationalInstitute ofAllergyandInfectious Disease (NIAID)alongwith NationalInstitutes of Health (NIH)contracted with theImmuneDeficiencyFoundation (IDF) to developa Registryof patients with Chronicgranulomatousdisease(CGD). With the success of that initial registry, NIAIDexpanded the contract in 1998to include eight different immunodeficiencydisorders including (in addition to CGD): X-linked agammaglobulinemia(XLA), Common variable immunodeficiency(CVID), X-linked hyperIgM (X-HIGM),Leukocyte adhesion deficiency(LAD), Severecombined immunodeficiency(SCID), DiGeorgesyndrome(DGS) and the Wiskott-Aldrich syndrome(WAS).
TheRegistryat that timewas designed to be primarilyaphysicianRegistrywith all contact between the Registryand thepatient being carried out through thesubmitting physician. TheRegistrywas de-identifiedwith thepatients assigned aunique code number. However, the patient’s initials and fulldate ofbirth weremaintained in the record to help identifyand eliminate duplicate registrations of thesamepatient by different physicians.The contract forcontinuingoperation oftheseRegistries was includedwhen NIAIDand NationalInstituteof Child Health and HumanDevelopment (NICHD) decided to change theirmechanismforfundingresearch in theprimaryimmunodeficiencydiseases and developed aconsortiumapproachwith agroupofinvestigators banded togetherinto an immunodeficiencydiseasenetwork. TheIDF assembled agroup of prominent investigators in this fieldunder thenameUnited StatesImmunodeficiencyNetwork (USIDNET)whoseproposal was selected byNIAIDforoperation ofthe new research consortiumthat began inOctober2003.
In 2006 theSteeringCommitteewas developedand the duties ofthe committeemembers areto review and periodicallyupdate thedata collection forms fortheir specific sub- Registry. Themembers act as an advisorycommitteeto reviewand approve requeststo use thedata contained inthat sub-Registry. The committeeis also used to recruit colleagues to submit patients forthe Registryandto develop research protocols that can be addressed usingthe Registrydata orpatient/physician list.Lastly, the committeeis usedto act as apublication committeeto prepareperiodic reports, or recruit authors to prepare reports, on the data being collected on specific disorderscovered intheirsub- Registry.
Duringthetime theSteeringCommitteeof theUSIDNETwas developed, the members decided that the futuresuccess of theRegistrywould begreatly enhanced if USIDNET joined forces with the European Societyfor Immunodeficiency(ESID) that has also established aRegistrysimilarly containing about 1,500 patients. ESID has developed an electronicweb-based data entrysystem that permitseasyregistration ofpatient data and thecapacityto
enterfollow-up data on thepatients over thecourseof timeto assist determination ofnatural diseasehistoryand the outcome ofvarious treatment procedures. Together thesedatabasesshould provide the research communitywith a very powerful new tool to facilitatestudyof theseindividuallyraredisorders.
DiseaseSpecificWorkingGroups (DSWGs):Takingalead from theformat of theESID Patient Registry, the USIDNEThas formed 11 DiseaseSpecificWorking Groups (DSWGs)to determinewhat datashould be collected. DSWGs arecomposed of aChair, aCo-chairand 2-5 othermembers who areespeciallyinterested in theindividual defects. TheUSIDNET Disease Specific Working Groups areoverseen bytheSteering Committee.These committees designed the CoreCaseReport Form (forallPIDD patients) and separate diseasespecific forms. Usingthe Core Form, alldataon patients areentered,even thosewith unknown defects, as thesemaybecome identifiablewith time and this datawillbepreserved.Thesemembers realizethepatient Registryis an amazingresourceand are determined to help itgrow. Themembers of theDisease Specific WorkingGroups have6 main responsibilities:
1. Periodicdata validationsto identifyanyoutliers orerrors.
2. Review research protocols relatedto thedisease.
3. Assess the composition of the Disease Specific WorkingGroup
4. Brainstorm for potential in-house research efforts that could be addressed bythe
Registry.
5. Reviewwith themain centers forspecific patientpopulation and ensurethat patient recruitingefforts havebeen maximized.
6. Review and revise the DiseaseSpecificWorking Groupforms.
1.1Investigational Agent
TheRegistryhas no investigational agent.
1.2Pre-RegistryData
Advances in theunderstandingof thesedisordershavebeen madebysomeinstitutions aroundthe world. Theseinstitutions wereable to accumulate patients to begin studying the rangeof symptoms that patientsexhibit.
With the completion oftheHuman GenomeProject, sudden increases of immunodeficiencydisorders definedbymutations in unique genes weredescribed. Researchers believethatthereareatotal of over 120 distinct genedefects. Although still individuallyrare, the aggregatefrequencyof patients presenting with a geneticdisorder
ofimmunitynowapproachesthe frequencyof patients with common genetic diseases such as, CysticFibrosis. It has been recognized that thedefinition ofthe phenotypic rangeof presentations of thesemultiple disorders, as wellas their natural history, could begreatlyaided bythe establishment ofaRegistry. TheRegistrycombinesthe observations of manyindividual investigators andphysiciansacross thecountryand world.
Previous studies donewith theRegistryinformation wereusuallycollaborativein nature with theRegistryserving as a mechanismto identifyphysicians caring forpatients with a particular disease – and theinvestigator then contactingthose physicians to establish a research collaboration.
Theoriginal 8 Registriescontain data on 2,060 patients distributed as shown below:
Chronic granulomatous disease / 394Commonvariable immunodeficiencydisease / 606
DiGeorgeanomaly / 325
HyperIgMsyndrome / 118
Leukocyte adhesiondefect / 0
Severe combinedimmunodeficiencydisease / 147
Wiskott- Aldrich syndrome / 186
X-linked agammaglobulinemia / 284
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1.3Risk/Benefits
There areno known potential risks to thepatients who wish to enrollin thepatient Registry. Dueto primaryimmunodeficiencydiseases being rare, no onephysician sees enough patients to be ableto form a representativepictureof thesediseases.Byallowing patient medical information to be combined with that of thousands ofotherpatients, each participatingpatient will be helpingtoestablish avaluable comprehensivedatabasefor researchers.
1.4Purpose
Thepurpose of this studyis to build a nationalregistryof data from subjects with primary immune deficiencydiseases, and in some cases, thosesubjects who arecarriers ofgenes that lead to immunedefectsor who have been identified as having low lymphocytes.Thedatacollected willincludedemographic, immunologic and health data onalargegroup of patients to discover thefrequencyofcertain complications (autoimmunity, cancer, hepatitis, etc.), theageof thesubjects, relationship between immune function and outcomes, race/orethnicity, andcause of death if known. The research studywillprovide data on anumberofsubjects with these rare immunodeficiencydisorders to a nationaldatabase; thegoal is to discoverbasic outcome data, ethnic andracial characteristics, kinds of complications, etc., of theseimmune defects. TheRegistrywillprovide aminimum estimateof theprevalenceofeach disorder in theUnited States, a comprehensive clinical pictureof each disorder, anditwillprovide a resource for clinical and laboratoryresearch.
1.5TrialConduct
This studywillbe conducted in compliancewith:
TheWorld Medical Association, Declaration ofHelsinki 2000.
TheNational Health andMedical Research Council’s National Statement on
Ethical Conduct in HumanResearch(2007).
Theprotocol approved bytheInstitutional Review Board and accordingto Good Clinical Practicestandards. No deviation from theprotocol will be implemented withoutthe prior reviewand approval of theIRB except whereitmaybe necessaryto eliminate animmediate hazard to a research subject. In suchcase, the deviation will be reported to theIRB as soon as possible.
This is a longitudinalstudyandwillhavemultiple sites conductingthe trial. Allsites that arerequired to obtain approval from theirIRBmust do so priorto initiatingthe start up of the trial.If asitedoes not have anIRB, the sitemayrequest to operate under themain site’s (USIDNET Towson, MD) FWA number.
1.6Population
TheRegistrywillcollect datato represent allpatient populations withknown or suspectedprimaryimmune deficiencydiseases. USIDNET willalso, as appropriate, collect data on carriers of immune defects and infants who have been identified as having low lymphocytes by population-based screening or other means, as thesemayreveal additional important immunologic orclinical data.
Thegoal is to discover basic outcomedata,ethnicand racial characteristics, kinds of complications, etc; oftheseimmune defects.
1.7Literature
Chronic GranulomatousDisease - SeeWinkelstein, Marino, Johnston et al., " Chronic GranulomatousDisease: Report on aNational Registryof 368 Patients ", Medicine, Vol. 79, No.3,May2000, p.155-69.
HyperIgM Syndrome-SeeWinkelstein, Marino, Ochs et al.,"TheX-linked Hyper-IgM Syndrome: Clinical andImmunologicFeatures of 79 Patients", Medicine, Vol. 82, No. 6, Nov. 2003, p.373-83.
2.0 TrialObjectives
Thepatient Registryis designed to obtain longitudinal data on alargenumber ofpatients withknown or suspected primaryimmunodeficiencydiseases, and in some cases,geneticcarriers ofthese defectsand infants who have been identified as having low lymphocytes by population-based screening or other means in order to:
Learn more about thephenotypic variations seen in alargenumber ofindividual patients with thesamemoleculardiagnosis.
Determinethe natural historyof thesegeneticdisorders ofimmunityand establish genotype-phenotypecorrelations.
Learneffects of various treatment protocols used in thesepatients overthecourse oftime includingunexpected side effects that maybeunique to aparticular diagnosticgroup.
Toevaluatemeasures ofqualityof lifein patients with thesedisorders and correlate thesewithgenotypeand treatment history
To promote collaborativeresearch amongst interested investigators byidentifying alarger pool of potentialresearch subjects than would be available to these investigators at their owninstitutions.
To identifypatients with a specific diagnosis forpotential participationin multi- institutional clinical trialsdesignedfordiagnosis or therapyof their specific disease.
•Learn more about individuals identified as having low lymphocytes early in life, found either by population-based screening or by other means, to understand (i) the true incidence of SCID and other disorders with low T cells, (ii) the natural history of non-SCID T lymphopenic conditions, and (iii) the significance of having T cells that are below the normal range early in life. While all such infants are suspected to have an immune deficiency, some may recover or normalize over time.
3.0 TrialDesign
Thedesign of this Registryinvolvesa “Core”setofdata that will be collected on all patients being enrolled inthe Registryirrespectiveof their diagnosis(Appendix1.0). When the patient’s specific diagnosis isrecorded,asubsequent Disease SpecificData EntryForm will be seamlesslyjoined to theCoreForm duringthe web data entrysession. Included in these forms aresections fordiagnosticcriteriaandgrade, and adescription of the clinical spectrum of thediseaseseen in patients with that diagnosis. TheseDisease SpecificDataForms are designed tocollect datathat is morespecificfortheparticular diagnosis of thepatient andincludes things such as laboratorydiagnostic teststhat are important forthat disease, geneticmutation analysis forthegene(s)involved with that diagnosis, and treatmentrelated items that aremorespecific to that diagnosis.
Infants who have been identified as having low lymphocytes by population-based screening or other means will be enrolled into the Registry through the “Following Infants with Low Lymphocytes” (FILL) project. Parents will give consent to have their children’s information entered into the Registry either by a physician at an IRB-approved USIDNET enrolling site or by USIDNET staff, who will obtain the information from the treating physicians upon request of parents. FILL-specific data collection forms have been designed to capture both the “Core” set of data as well as specific data at multiple time points to reveal the spectrum of causes and the natural history of such infants.
Experiencewith theprevious Registrysuggested several keys to help participation:
Theinterestsof theparticipatingacademicinvestigators must be protected ifthey are goingto be willingtoregister their patients and provide useful data --they need toget somethingpositivein return fortheir efforts.
Keep the data entryprocess as user friendlyas possible.
Providesuggested responses(usingpull-down menus is onewayto achievethis level of beinguser-friendly).
Ask enough specificquestions to permit the “rule-out” ofamisdiagnosis.
Provision of data entryassistanceto centers that follow alarger number of patients willhelp encouragetheirparticipation.
In addition to clinician entered data, an avenue for patient-entered data exists through the PI CONNECT project. Patients who create an electronic personal health record (ePHR) on the Immune Deficiency Foundation’s website can consent to have their data shared with the Registry. The relevant data from the ePHR will be stored in the Registry, and it will trigger an alert for USIDNET staff to validate the data and obtain further clinical information where necessary. Patient-entered data will be flagged as such and thereby distinguished from clinician entered data in any results returned to investigators.
Foraccess to the data contained in theRegistry, an interested investigatormustsubmita request outliningtheexperimental question being asked and the specific datarequested. This request willthen bereviewed byadesignatedUSIDNETstaff member, the Steering Committee and where appropriate, the disease specific working group. Upon approval, and if the data isavailable in the Registry,a report willbegenerated bythedatabase technical manager to answer thequery. If the request involves data that is not found in the databasein sufficientdetail, the SteeringCommittee mayallow therequesting investigator to havea list of physicians who havesubmitted patients matchingthe search criteria. Theinvestigatorwould then be responsible for contactingthose physiciansand establishingaresearchcollaboration to completeacquisition ofthe data needed forthe study.
Onlythis formal requestprocess will allow accessto theRegistrydataandonlythe data requested will be provided. Browsingthrough thedatabasewillnot be permitted. However asubmittingphysician willhave access to allof thedata that he/shesubmitted on apatient and will be able to provide periodicup-dates.
The traditional physician-consented enrollment will continue using three options:
OPTION ONE, the subject’s identitywillnot bestored in the Registry. Thesubject’s name, date ofbirth andmailingand/or emailaddress will be used bythe investigatorat the sitebut will notbe entered in theRegistryorgiven to the studysponsor.A code numberwillbe assignedto his/herinformationin the Registry, but onlytheinvestigator at thesitewillknow it. TheRegistrySteeringCommitteemaydirect theRegistrystaffto send reports containinginformation about the subject’s diseaseto theinvestigator. The Registrycommitteemayalso permitinformation about proposals to studynew testsor
treatmentsto besent to theinvestigator. Thesubject will notbe contacteddirectlybytheRegistrystaff because thesubject will be de-identified.
OPTION TWO, the subject’s name, fulldateof birth and mailingand/oremail address willbe recorded bythe RegistryStaff and kept inadatabasethat is separate from any information about the subject’s condition. Thesubject’s specificmedical information will be assigned acodenumber when itis includedin theRegistry. Theonlylink between the subject’s name and themedical information in theRegistrywillbethe codenumber. The investigatorand studystaff mayperiodicallyupdatethe subject’s information to include changes in his/her condition ortreatment as well as changes in his/her nameor contact information. Investigators reviewingthe subject’s medical information contained in the Registrydatabasewillnot have access toasubjects’ identifyinginformation.
UnderOPTION TWO-A, communication between the Registryand the subject will be carried out bytheinvestigator. TheRegistrystaffwillsend allinformation to the investigatorand he/she will then transmit that information to thesubject. This may includenew information about theirdisease, new treatments, or futureresearch opportunities. TheonlycircumstancewheretheRegistrystaff might contact thesubject directlywould bein thecasethat the subject has moved and/or ended contact with the original investigator or theoriginal investigator has retired or for someother reasoncan no longerbe contacted bythe Registrystaff.