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CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Clinical Study ProtocolSponsor:GlaxoSmithKline Biologicals SARue de l’institut 89, 1330 Rixensart, BelgiumPrimary Studyvaccine(s)/product(s) andnumber(s)GlaxoSmithKline (GSK) Biological investigationalrespiratory syncytial virus (RSV) maternal vaccine(GSK3888550A)Other Studyvaccine(s)/product(s)eTrack study number andAbbreviated TitlePlaceboInvestigational New Drug(IND) number18434EudraCT number2018-001340-62Date of protocolFinal Version 2: 13 August 2018TitleA study to evaluate the safety, reactogenicity andimmunogenicity of GSK Biologicals’ investigationalunadjuvanted RSV maternal vaccine compared toplacebo when administered to healthy non-pregnantwomen.Detailed TitleA Phase 1/2 randomised observer-blind placebocontrolled study to evaluate the safety, reactogenicityand immunogenicity of different dose levels of GSKBiologicals’ investigational unadjuvanted RSVmaternal vaccine (GSK3888550A) compared toplacebo when administered to healthy non-pregnantwomen aged 18-45 years.Co-ordinating author(s)!PPDContributing authors!!!PPD208068 (RSV MAT-001)!!!!!, Science Writer, Study Delivery Lead, Study Delivery LeadPPD, Clinical Research andDevelopment Lead (CRDL)PPD, Lead StatisticianPPDStudy StatisticianPPD, Oversight Data ManagerPPD, Clinical Readout Team LeadPPD, Clinical Readout Team 45d98d2013-AUG-201811
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22 eTrack study number andAbbreviated Title208068 (RSV MAT-001)Investigational New Drug(IND) number18434EudraCT number2018-001340-62Detailed TitleA Phase 1/2 randomised observer-blind placebocontrolled study to evaluate the safety, reactogenicityand immunogenicity of different dose levels of GSKBiologicals’ investigational unadjuvanted RSVmaternal vaccine (GSK3888550A) compared toplacebo when administered to healthy non-pregnantwomen aged 18-45 years.Contributing authors!!(Cont )!!!!!!PPD, Clinical Trial Supply Manager, Senior Scientist,Immunology PlatformPPD, Clinical Laboratory Sciences(CLS) Study Manager, Business & Decisions LifeSciences Contractor for GSK BiologicalsPPD, Safety PhysicianPPD, Safety ScientistPPD, Safety ScientistPPD, Regulatory AffairsPPD, Clinical & Epidemiology ProjectLead (CEPL)PPDGSK Biologicals’ Protocol DS v 15.02018 GlaxoSmithKline group of companies or its 7845d98d2013-AUG-201822
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Protocol Sponsor Signatory ApprovaleTrack study number andAbbreviated Title208068 (RSV MAT-001)IND number18434EudraCT number2018-001340-62Date of protocolFinal Version 2: 13 August 2018Detailed TitleA Phase 1/2 randomised observer-blind placebocontrolled study to evaluate the safety, reactogenicityand immunogenicity of different dose levels of GSKBiologicals’ investigational unadjuvanted RSVmaternal vaccine (GSK3888550A) compared toplacebo when administered to healthy non-pregnantwomen aged 18-45 years.Sponsor signatoryOuzama Henry, Clinical and Epidemiological ProjectLead (CEPL), US RDCSignatureDateFor internal use only- ted On - 153a6ad96b43badb3a17cb1987ba867845d98d20 7.0 8/20/2018 2:27:19 PM - -------------------------- 2013-AUG-201833
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Protocol Investigator AgreementI agree: To conduct the study in compliance with this protocol, any future protocolamendments or protocol administrative changes, with the terms of the clinical trialagreement and with any other study conduct procedures and/or study conductdocuments provided by GlaxoSmithKline (GSK) Biologicals. To assume responsibility for the proper conduct of the study at this site. That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and allapplicable regulatory requirements. To ensure that all persons assisting me with the study are adequately informed aboutthe GSK Biologicals’ study vaccine(s)/product(s) and other study-related duties andfunctions as described in the protocol. To acquire the reference ranges for laboratory tests performed locally and, if requiredby local regulations, obtain the laboratory’s current certification or QualityAssurance procedure manual. To ensure that no clinical samples (including serum samples) are retained onsite orelsewhere without the approval of GSK Biologicals and the express written informedconsent of the subject and/or the subject’s legally acceptable representative. To perform no other biological assays on the clinical samples except those describedin the protocol or its amendment(s). To co-operate with a representative of GSK Biologicals in the monitoring process ofthe study and in resolution of queries about the data. That I have been informed that certain regulatory authorities require the sponsor toobtain and supply, as necessary, details about the investigator’s ownership interest inthe sponsor or the investigational vaccine(s)/product(s), and more generally abouthis/her financial ties with the sponsor. GSK Biologicals will use and disclose theinformation solely for the purpose of complying with regulatory requirements.Hence I: Agree to supply GSK Biologicals with any necessary information regardingownership interest and financial ties (including those of my spouse and dependentchildren). Agree to promptly update this information if any relevant changes occur during thecourse of the study and for one year following completion of the study. Agree that GSK Biologicals may disclose any information it has about suchownership interests and financial ties to regulatory authorities. Agree to provide GSK Biologicals with an updated Curriculum Vitae and otherdocuments required by regulatory agencies for this 5d98d2013-AUG-201844
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22eTrack study number andAbbreviated Title208068 RSV MAT-001)IND number18434EudraCT number2018-001340-62Date of protocolFinal Version 2: 13 August 2018Detailed TitleA Phase 1/2 randomised observer-blind placebocontrolled study to evaluate the safety, reactogenicityand immunogenicity of different dose levels of GSKBiologicals’ investigational unadjuvanted RSVmaternal vaccine (GSK3888550A) compared toplacebo when administered to healthy non-pregnantwomen aged 18-45 years.Investigator nameSignatureDateLeiter der klinischenPrüfung name, function andtitleSignatureDateFor internal use only- ted On - 153a6ad96b43badb3a17cb1987ba867845d98d20 7.0 8/20/2018 2:27:19 PM - -------------------------- 2013-AUG-201855
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Sponsor Information1.SponsorGlaxoSmithKline Biologicals,Rue de l’institut 89, 1330 Rixensart, Belgium2.Sponsor Medical Expert for the StudyRefer to the local study contact information document.3.Sponsor Study MonitorRefer to the local study contact information document.4.Sponsor Study Contact for Reporting of a Serious Adverse Event:Refer to the local study contact information document.GSK Biologicals Central Back-up Study Contact for Reporting SAEs: refer to protocolSection 8.4.2.5.GSK Biologicals’ Central Safety Physician On-Call Contact information forEmergency UnblindingGSK Biologicals Central Safety Physician and Back-up Phone contact: refer toprotocol Section 8d2013-AUG-201866
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22SYNOPSISDetailed TitleA Phase 1/2 randomised observer-blind placebo controlledstudy to evaluate the safety, reactogenicity andimmunogenicity of different dose levels of GSK Biologicals’investigational unadjuvanted RSV maternal vaccine(GSK3888550A) compared to placebo when administered tohealthy non-pregnant women aged 18-45 years.IndicationActive immunization of pregnant women during the thirdtrimester of pregnancy to prevent respiratory syncytial virus(RSV) associated lower respiratory tract infection (LRTI) ininfants by transfer of maternal antibodies.Rationale for thestudy and studydesign Rationale for the study:The purpose of this study is to evaluate the safety,reactogenicity and immunogenicity of three dose levels(30 µg, 60 µg and 120 µg) of the investigational RSVmaternal vaccine antigen compared to placebo administered asa single intramuscular injection. Rationale for the study design:To assess the impact of the investigational RSV maternalvaccine in terms of safety, reactogenicity and immuneresponse, four treatment groups will be evaluated.Healthy, non-pregnant women aged 18 - 45 years will beenrolled, a population of the same gender and age of thevaccine’s target population Rationale for the use of placebo:The placebo group is included as a control for both thesafety/reactogenicity and the immunogenicity assessments.Objective(s)Primary To evaluate the safety and reactogenicity of three doselevels (30, 60, 120 µg) of the RSV maternalinvestigational vaccine administered as a singleintramuscular injection, as compared to placebo up to 1month post vaccination (Day 31).Secondary To evaluate the safety of three dose levels (30, 60, 120µg) of the RSV maternal investigational vaccinecompared to placebo up to 6 months post vaccination(Day d98d2013-AUG-201877
CONFIDENTIAL 208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22To evaluate the humoral immune response to three doselevels (30, 60, 120 µg) of the RSV maternalinvestigational vaccine compared to placebo up to 3months post vaccination (Day 91).TertiaryStudy designSynopsis Table 1Study GroupsRSV MAT 30RSV MAT 60RSV MAT 120Placebo To further evaluate the humoral immune response to theRSV maternal vaccine. Experimental design: Phase I/II, observer-blind,randomised, controlled, multi-centre, multi-country withfour parallel groups. Duration of the study: Epoch 001: Screening Visit (Day -7 to Day 1) Epoch 002: Active Vaccination phase starting atVisit 1 (Day 1) and concluding at, and including,Visit 3 (Day 31) Epoch 003: Long-term follow-up starting after Visit3 (Day 31) and concluding at Contact 1 (Day 181) Primary completion Date (PCD): Visit 3 (Day 31) or lastvisit of Epoch 002 End of Study (EoS): Last testing results released ofhuman biological samples collected at Visit 5 (Day 91) orLast Subject Last Visit (LSLV, i.e. last Contact 1),whichever comes last Study groups:Study groups and epochs foreseen in the studyNumber ofsubjects 125 125 125 125Age (Min - Max)18 - 45 years18 - 45 years18 - 45 years18 - 45 d98d2013-AUG-201888Epoch 001xxxxEpochsEpoch 002xxxxEpoch 003xxxx
CONFIDENTIALSynopsis Table 2Treatment nameRSVPreF3 30RSVPreF3 60RSVPreF3 120ControlSynopsis Table 3208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Study groups and treatment foreseen in the studyVaccine/ProductnameRSVPreF3 low doseRSVPreF3 middoseRSVPreF3 highdoseNaClRSV MAT 30 Study GroupsRSV MAT 60 RSV MAT 120Placebo Control: placebo control Vaccination schedule: Single intramuscular injection atVisit 1 (Day 1) Treatment allocation: Subjects will be randomised using acentralized randomisation system on internet (SBIR) atVisit 1 (Day 1). The randomisation algorithm will use aminimization procedure accounting for age (18 - 32 yearsor 33 - 45 years) and centre Blinding:Blinding of study epochsStudy EpochsEpoch 001Epoch 002Epoch 003BlindingN/Aobserver-blindsingle-blind ** The study will be conducted in an observer-blind fashionthrough Day 91. After this day, the study will continue in asingle-blind fashion. For more details about blinding seeSection[s] 1.5.6, 5.3, 10.11.1. Sampling schedule: Blood samples for haematology/biochemistry: willbe collected ( 5.5 mL) from all subjects at Screening,Visit 2 (Day 8), Visit 3 (Day 31) and any UnscheduledVisit(s). Blood samples for humoral immunogenicity: will becollected ( 30 mL) from all subjects at Screening,Visit 2 (Day 8), Visit 3 (Day 31), Visit 4 (Day 61) andVisit 5 (Day 91). Type of study: self-contained Data collection: Electronic Case Report Form (eCRF) Safety 867845d98d2013-AUG-201899
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22As this will be the first time that the RSV maternal vaccine willbe administered in humans, the study will enrol subjects in twosteps (Step 1 will enroll 60 subjects in the United States [US]only and Step 2 will enroll 440 subjects across multiplecountries). Subjects will be randomised to all dose levels fromthe start. Both blinded and unblinded safety monitoring will beperformed, as described below.The Safety Review Team (SRT) will review blinded data on aregular basis throughout the study, and an internal SafetyReview Committee (iSRC) will review unblinded data atspecific study timepoints. (Refer to section[s] 8.10.1 and 8.10.2for more details on the safety monitoring for this study).During Step 1, until the first 30 subjects have been vaccinated,vaccination will be limited to 10 subjects/ per day across allsites. These subjects will be vaccinated sequentially and at least60 minutes apart.Subsequent vaccinations will continue without limitation to thenumber of subjects vaccinated per day or time lag betweenvaccination of consecutive subjects.Screening and enrolment of Step 2 subjects will only beinitiated if the iSRC review of Day 31 data results in arecommendation to proceed with Step 2.Number of subjects Approximately 500 healthy women will be enrolled( 125/group).Endpoint(s)Primary Occurrence of any adverse events (AEs) from vaccinationduring a 30-day follow-up period, for all subjects in allgroups: Occurrence of each solicited local and generalsymptom during a 7-day follow-up period. Occurrence of any unsolicited AE during a 30-dayfollow-up period. Occurrence of Serious AEs during a 30-day follow-upperiod. Occurrence of any haematological (Leukocytes,Neutrophils, Lymphocytes, Eosinophils, Haemoglobin,Platelets) and biochemical (alanine aminotransferase[ALT], aspartate aminotransferase [AST], creatinine,blood urea nitrogen [BUN]) laboratory abnormalitiesat Day 8 and Day 8d2013-AUG-20181010
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Secondary Occurrence of SAEs from vaccination up to Day 91 and upto Day 181 for all subjects, in all groups. Humoral immune response to the investigational vaccine atDay 8, Day 31, Day 61 and Day 91 for all subjects in eachinvestigational RSV vaccine group RSV-A neutralising antibody (Nab) titres; RSVPreF3 immunoglobulin G (IgG) antibodyconcentrationsTertiary Additional humoral response which may include but notlimited to, RSVPreF3 specific IgG1 subclass antibodyconcentrations, RSV-B neutralising antibody titres,antibody competing for binding to specific epitopes onRSVPreF3 and antibody concentrations to residual host cellproteins in the RSVPreF3 7845d98d2013-AUG-20181111
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22TABLE OF CONTENTSPAGESPONSOR INFORMATION .6SYNOPSIS.7LIST OF ABBREVIATIONS .19GLOSSARY OF TERMS .23TRADEMARKS . 281.INTRODUCTION. 291.1.Background .291.2.Current Management of RSV Disease in Infants. 291.3.Maternal Immunization. 301.4.GlaxoSmithKline (GSK) Biologicals’ Investigational RSV maternalvaccine . 311.5.Rationale for the study and study design . 311.5.1.Rationale for the study . 311.5.2.Rationale for the study design. 311.5.3.Rationale for dose selection.321.5.4.Rationale for the use of placebo . 321.5.5.Safety considerations. 321.5.6.Study blinding . 331.6.Benefit: Risk Assessment . 331.6.1.Risk Assessment . 341.6.2.Benefit Assessment . 351.6.3.Overall Benefit: Risk Conclusion. 352.OBJECTIVE(S) . 362.1.Primary objective . 362.2.Secondary objectives. 362.3.Tertiary objective . 363.STUDY DESIGN OVERVIEW . 364.STUDY COHORT. 394.1.Number of subjects/centres . 394.2.Inclusion criteria for enrolment . 394.3.Exclusion criteria for enrolment. 405.CONDUCT OF THE STUDY . 435.1.Regulatory and ethical considerations, including the informedconsent process.435.2.Subject identification and randomisation. 445.2.1.Subject identification. 445.2.2.Randomisation of treatment .445.2.2.1.Randomisation of supplies. 445.2.2.2.Treatment allocation to the subject 8d2013-AUG-20181212
208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Study group and treatmentnumber allocation . 44Method of blinding . 45General study aspects . 45Outline of study procedures . 46Detailed description of study procedures . 485.6.1.Study procedure timings .485.6.2.Informed consent . 485.6.3.Subject number allocation and Registration in SBIR“subject planning” module.485.6.4.Check inclusion and exclusion criteria . 485.6.5.Collect demographic data .495.6.6.Medical history. 495.6.7.Physical examination . 495.6.8.Pregnancy test. 495.6.9.Check contraindications, warnings and precautions tovaccination. 495.6.10. Assess pre-vaccination body temperature . 505.6.11. Study group and treatment number allocation.505.6.12. Blood sampling for safety or immune responseassessments. 505.6.13. Study Vaccine administration. 505.6.14. 60 minutes post-vaccination observation . 515.6.15. Distribution of Subject Card .515.6.16. Check and record concomitant medication/vaccination andintercurrent medical conditions . 515.6.17. Recording of AEs, SAEs and pregnancies . 515.6.18. Extension/Booster study .525.6.19. Day 181 Contact . 525.6.20. Study conclusion. 52Biological sample handling and analysis . 535.7.1.Use of specified study materials . 535.7.2.Biological samples . 545.7.3.Laboratory assays . 545.7.4.Biological samples evaluation . 565.7.4.1.Haematology/Blood Chemistry . 565.7.4.2.Immunological read-outs . 565.7.5.Immunological correlates of protection. 56STUDY VACCINES ADMINISTRATION. 576.1.Description of study vaccine . 576.2.Storage and handling of study vaccine . 576.3.Dosage and administration of study vaccine . 586.4.Replacement of unusable vaccine .586.5.Contraindications to vaccination . 596.6.Concomitant medications/products and concomitant vaccinations. 596.6.1.Recording of concomitant medications/products andconcomitant vaccinations.596.6.2.Concomitant medications/products/vaccines that may leadto the elimination of a subject from Per Protocol analyses . 606.7.Intercurrent medical conditions that may lead to elimination of asubject from Per Protocol 867845d98d2013-AUG-20181313
CONFIDENTIAL208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 227.HEALTH ECONOMICS .608.SAFETY . 618.1.Safety definitions . 618.1.1.Definition of an adverse event. 618.1.2.Definition of a serious adverse event . 628.1.3.Solicited adverse events .638.1.3.1.Solicited local (injection-site) adverse events. 638.1.3.2.Solicited general adverse events .638.1.4.Clinical laboratory parameters and other abnormalassessments qualifying as adverse events or seriousadverse events . 638.2.Events or outcomes not qualifying as adverse events or seriousadverse events (pregnancy). 648.3.Detecting and recording adverse events, serious adverse eventsand pregnancies . 658.3.1.Time period for detecting and recording adverse events,serious adverse events and pregnancies . 658.3.2.Post-Study adverse events and serious adverse events . 668.3.3.Evaluation of adverse events and serious adverse events. 678.3.3.1.Active questioning to detect adverse eventsand serious adverse events. 678.3.3.2.Assessment of adverse events . 678.3.3.2.1. Assessment of intensity . 678.3.3.2.2. Assessment of causality . 698.3.3.3.Assessment of outcomes. 708.3.3.4.Medically attended visits. 708.4.Reporting of serious adverse events, pregnancies and other events . 708.4.1.Prompt reporting of serious adverse events, pregnanciesand other events to GSK.708.4.2.Contact information for reporting serious adverse eventsand pregnancies . 718.4.3.Completion and transmission of SAE reports to GSK. 718.4.3.1.Back-up system in case the electronicreporting system does not work . 728.4.4.Completion and transmission of pregnancy reports to GSK . 728.4.5.Updating of SAE and pregnancy information after removalof write access to the subject’s eCRF . 728.4.6.Regulatory reporting requirements for serious adverseevents.728.5.Follow-up of adverse events, serious adverse events, andpregnancies .738.5.1.Follow-up during the study.738.5.2.Follow-up after the subject is discharged from the study. 738.5.3.Follow-up of pregnancies.738.6.Treatment of adverse events . 738.7.Unblinding. 748.8.Emergency unblinding . 748.9.Subject card.758.10. Holding rules and safety monitoring .758.10.1. Safety review team (SRT).758.10.2. Internal Safety Review Committee (iSRC) Evaluation . d2013-AUG-20181414
CONFIDENTIAL8.10.3.8.10.4.9.208068208068 (RSV(RSV MAT-001)MAT-001)ProtocolProtocol FinalFinal VersionVersion 22Holding rules. 76Risk assessment. 77SUBJECT COMPLETION AND WITHDRAWAL. 789.1.Subject completion . 789.2.Subject withdrawal. 789.2.1.Subject withdrawal from the study . 789.3.Screening Failures. 799.4.Extension study .7910. STATISTICAL METHODS. 8010.1. Primary endpoints.
respiratory syncytial virus (RSV) maternal vaccine (GSK3888550A) Other Study vaccine(s)/product(s) Placebo eTrack study number and Abbreviated Title 208068 (RSV MAT-001) Investigational New Drug (IND) number 18434 EudraCT number 2018-001340-62 Date of protocol Final Version 2: 13 August 2018 Title A study to evaluate the safety, reactogenicity and
