Stat Analysis Plan Blinding And Unblinding Plan A Phase 3 .
Stat Analysis Plan Blinding and Unblinding PlanA Phase 3, Multicenter Study with a 36-Week Open-Label Period Followed by a RandomizedDouble-Blind Withdrawal Period from Week 36 to Week 104 to Evaluate the Long-TermEfficacy and Safety of Ixekizumab (LY2439821) 80 mg Every 2 Weeks in Biologic DiseaseModifying Antirheumatic Drug–Naive Patients with Active Psoriatic ArthritisNCT02584855Approval Date: 27-Oct-2017
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Page 11. Blinding and Unblinding Plan for Protocol I1F-MC-RHBF:A Phase 3, Multicenter with a 36-Week Open-Label PeriodFollowed by a Randomized Withdrawal Period from Week36 to Week 104 to Evaluate the Long-Term Efficacy andSafety of Ixekizumab (LY2439821) 80 mg Every 2 Weeksin Biologic Disease-Modifying Antirheumatic Drug-NaïvePatients with Active Psoriatic ArthritisConfidential InformationThe information contained in this blinding and unblinding plan is confidential and theinformation contained within it may not be reproduced or otherwise disseminated withoutthe approval of Eli Lilly and Company or its subsidiaries. This document and its associatedattachments or appendices are subject to United States Freedom of Information ActExemption 4.Ixekizumab (LY2439821)I1F-MC-RHBF is a Phase 3, multicenter study with a 36-week initial open-label treatmentperiod examining the effect of ixekizumab 80 mg every 2 weeks (Q2W) in patients withactive psoriatic arthritis (PsA) who are conventional disease-modifying (cDMARD)inadequate responders (IRs) and biologic disease-modifying (bDMARD) naïve followed bya randomized, double-blind withdrawal period from Week 36 to Week 104 examining theeffect of ixekizumab 80 mg Q2W compared to that of Placebo.Eli Lilly and CompanyIndianapolis, Indiana USA 46285Protocol I1F-MC-RHBFPhase 3Version Number1.02.03.0Document HistoryBrief Description of ChangeOriginal Blinding and Unblinding PlanUpdated for the Open-Label Treatment Period to remain unblindedUpdated to add flexible wording around the occurrence of the two interimanalysesApproval Date: 27-Oct-2017 GMTEli Lilly and Company 2014ConfidentialPage 1 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Page 22. Objective of This DocumentThe objective of the blinding and unblinding plan is to serve as a source for operational details,roles, and responsibilities around delivering data, either datasets or tables, figures, and listings(TFLs) in either a blinded or unblinded fashion per the objectives of the protocol.As described in the Study I1F-MC-RHBF (RHBF) protocol and statistical analysis plan, the firstinterim database lock may occur after the last patient completes Visit 19 (Week 64) or the earlytermination visit (ETV). At this time, the analysis using only data from the open-label treatmentperiod will be performed. This interim analysis may be planned when all enrolled patients havehad the chance to complete the open-label treatment period (Period 2). The second interimdatabase lock may occur when all patients complete Week 104 or discontinue study treatmentprior to the end of the randomized double-blind withdrawal period . At this time, unblinding willoccur and the primary analysis will be performed.A final database lock will occur after the Post-Treatment Follow-Up Period (Period 4) iscompleted, when no further unblinding is needed.The purpose of RHBF blinding and unblinding plan is to detail procedures in place to minimizebias while preparing for or conducting any summary or analysis of Study RHBF for datareviews, development safety update report (DSUR), periodic safety update report (PSUR), triallevel safety reviews (TLSR), documents for the PsA submission and regulatory updates, and forthe two potential interim analysis database locks, which may be used for the interim clinicalstudy report (CSR).Eli Lilly and Company 2014ConfidentialPage 2 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Page 33. Creating the Blind: General Blinding RequirementsSpecific to This StudyFor Study RHBF, the following data must be blinded to patients, sites and study team membersbefore the randomized double-blind withdrawal period database is locked: Treatment assignment from interactive web-response system (IWRS)LY2439821 serum concentrations and immunogenicity data from Lilly Generic LabSystem (GLS) collected during the randomized double-blind withdrawal period.Treatment assignment and dose adjustments are both blinded and unblinded in the interactiveweb-response system (IWRS). The data extract tool (DEX) is use to extract either the blinded orthe unblinded IWRS data. Following the randomized withdrawal period interim lock, the datamovement group (DMG) extracts the unblinded IWRS data and subsequently transfers the datato SAS drug development (SDD) system. Only the personnel from the functions listed below areunblinded to the treatment assignment and dose adjustments before the second interim databaselocks: IWRS Global supporteCTS Randomization/Dispensing AssociateAll roles with Clinical Trial (CT) Supply Planning OrganizationDMG AssociatesThe ixekizumab serum concentrations and immunogenicity data could potentially unblind thedosing regimen during the randomized double-blind withdrawal period to sites and study teammembers; therefore, the investigator sites will not have access to the data prior to the therandomized withdrawal period interim lock. The study team will not have access to the datacollected during the randomized double-blind withdrawal period prior to the interim databaselock following the randomized double-blind withdrawal period. These laboratory analytesduring the randomized double-blind withdrawal period must be blinded for all transfers of theselaboratory data prior to the randomized withdrawal period interim lock. Clinical LaboratoryOperations (CLO) sets up blinding flags to the ixekizumab serum concentrations andimmunogenicity analytes in the GLS data for the data collected during the randomized doubleblind withdrawal period. Subsequently the DMG applies these flags to the data collected duringthe randomized double-blind withdrawal period during the data transfer. After the randomizedwithdrawal period interim lock, these laboratory analytes results will be unblinded (meaning theDMG will not apply the blinding flag) when transferring the GLS data. Subsequently, thetransferred data is stored in SAS drug development (SDD) either in a blinded or unblinded area,as appropriate. Only the personnel listed below are unblinded to these laboratory analytes resultsbefore the interim database lock: CLO unblinded Lab AssociatesDMG AssociatesEli Lilly and Company 2014ConfidentialPage 3 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Page 4If unintentional unblinding occurs, When a subject’s treatment group is unexpectedly unblinded during the randomizeddouble-blind withdrawal period and the unblinding occurs at a site, notify the monitor orsite manager.When a subject’s treatment group is unexpectedly unblinded during the randomizeddouble-blind withdrawal period and the unblinding occurs at a location other than thesite, the person who identifies the unblinding notifies his or her immediate supervisor orMedical Quality representative in accordance with the requirements described in theDeviation Management (SEQSQ104-001) procedure.The procedure for the emergency unblinding is described in the protocol.The unintentional unblinding and the emergency unblinding, if they occur, will be documentedin the CSR.After the randomized withdrawal period interim lock, study team members will be unblinded.There is no blinding restriction for the final database lock at the time the Post-Treatment FollowUp Period is completed. Sites and patients unblinding to treatment assignment will occur afterthe study is complete.Eli Lilly and Company 2014ConfidentialPage 4 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Page 54. Details of Maintaining the BlindThe details of data blinding before the randomized withdrawal period interim lock is presented inTable 1. After interim database lock, these data will be unblinded to generate the final standarddata tabulation model (SDTM), analysis data model (ADaM) datasets, and TFLs for interimanalyses, interim CSR and subsequent disclosures.Table 1.Data to be Blinded(Source)Randomizedtreatment assignmentand dose adjustments(IWRS)Details of Data Blinding Before the Randomized Withdrawal PeriodDatabase LockBlinded Data FormatDeliverable TypeRaw data and all subsequentdeliverables based on the rawdata (SDTM, ADaM, TFLs, orcustomized datasets/reports)Test transfers before the interimlocks, DSURs and PSURs beforeinterim lock, TLSRs, documentsfor the PsA submission, otherregulatory transfers before thesecond interim lockTest transfers before the interimlocks, DSURs and PSURs beforeboth interim locks, TLSRs,documents for the PsAsubmission, other regulatorytransfers before the secondinterim lockTest transfers before the interimlocks, DSURs and PSURs beforeboth interim locks, TLSRs,documents for the PsAsubmission, other regulatorytransfers before the secondinterim lockLY2439821 serumconcentrations (GLS)collected during therandomized doubleblind withdrawalperiodRaw data and all subsequentdeliverables based on the rawdata (SDTM, ADaM, TFLs, orcustomized datasets/reports)Immunogenicity data(GLS) collectedduring therandomized doubleblind withdrawalperiodRaw data and all subsequentdeliverables based on the rawdata (SDTM, ADaM, TFLs, orcustomized datasets/reports)How Data beBlindedScrambled dataBlinded. Include theword ‘BLINDED’instead of the actualresultMissing dataTable 2 provides the details of blinded and unblinded data transfers, including the functions todeliver the data and the locations of the data for the deliverables.Eli Lilly and Company 2014ConfidentialPage 5 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3Table 2.BlindingStatusBlindedPage 6Blinded and Unblinded Data Transfers and LocationsDataFormatRaw dataFunctionto DeliverDataainVentivDMGDeliverableTypeCLUWE LocationOtherLocationTest transfersbefore secondinterim lock\\statsclstr\lillyce\qa\ly2439821\i1f mc rhbf\intrmn\data\raw\shared\Source: GLS,IWRS,Inform, ePRODSURs/PSURs/Documents for the PsAsubmission/otherregulatorytransfersbefore theinterim lockfollowing sTFLsLillyStatisticsCustomizeddatasets orreportsLillyStatisticsEli Lilly and Company 2014TestTransfersbeforeinterim lockfollowing theRDBWPTLSRsTestTransfersbefore secondinterim lockTestTransfersbeforeinterim lockfollowing theRDBWPDSURs/PSURs/Documents for the PsAsubmission/otherNote: n indicates the sequence number ofthe test transfer\\statsclst\lillyce\prd\ly2439821\i1f mc rhbf\regulatory mmmyyyy\data\raw\shared\Source: GLS,IWRS,Inform, ePRONote: mmmyyyy indicates the month andyear of transfer, same below.\\statsclstr\lillyce\prd\ly2439821\i1f mcrhbf\safety reviewn\data\raw\shared\Source: GLS,IWRS,Inform, ePRONote: n indicates the sequence number ofTLSR, same below.\\statsclstr\lillyce\qa\ly2439821\i1f mc yce\prd\ly2439821\i1f mcrhbf\safety 1\i1f mc yce\qa\ly2439821\i1f mc \ly2439821\regulatory mmmyyyy\data\analysis\customConfidentialPage 6 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3BlindingStatusDataFormatFunctionto re theinterim lockfollowing theRDBWPTLSRsUnblindedRaw eports arestored 1\i1f s for the PsAsubmissionotherregulatorytransfers afterinterim lockfollowing theRDBWP andbefore 1f mcrhbf\regulatory mmmyyyy\data\raw\shared\Source: GLS,IWRS,Inform, ePROSource: GLS,IWRS,Inform, ePROInterim\\statsclstr\lillyce\prd\ly2439821\i1f llyce\prd\ly2439821\i1f lyce\prd\ly2439821\i1f llyce\prd\ly2439821\i1f lyce\prd\ly2439821\i1f rd\ly2439821\i1f \ly2439821\\regulatory tatisticsInterimFinalCustomizeddatasetsEli Lilly and Company e\prd\ly2439821\i1f mc rhbf\safety reviewn\data\observed\shared\customFinalADaMCLUWE LocationPage 7DSURs/PSURs/Documents for the prd\ly2439821\i1f mcrhbf\final\data\raw\shared\ConfidentialSource: GLS,IWRS,Inform, ePROPage 7 of 8
I1F-MC-RHBF Blinding and Unblinding Plan, Version 3BlindingStatusDataFormatFunctionto DeliverDataaDeliverableTypeCLUWE LocationPage 8OtherLocationtransfers afterinterim lockfollowing theRDBWP andbefore finallockRDBWP Randomized Double-Blind Withdrawal Perioda The personnel in the function to deliver the data will have access in CLUWE to check containers before transfer.Eli Lilly and Company 2014ConfidentialPage 8 of 8
Oct 27, 2017 · As described in the Study I1F-MC-RHBF(RHBF) protocol and statisticalanalysis plan, the first interim database lock may occurafter the last patient completes Visit 19(Week 64) or the early termina
incorporated in one SWECO Separator, providing simultaneous separation into five fractions. Less Blinding. Vibro-Energy action holds most screen blinding to an acceptable minimum. However, certain materials have inherent blinding characteristics. For unusual situations, SWECO has developed accessories to eliminate blinding. Greater Capacity.
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