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Study Protocol and Amendments As Applicable  Obtaining Signed Informed Consent  Investigator Reporting Requirements (E.G

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Study Protocol and Amendments As Applicable  Obtaining Signed Informed Consent  Investigator Reporting Requirements (E.G 2016 N270529_06 C ONFIDENTIA L The GlaxoS mith Kline group of co mpanies 205722 TI T L E P A G E Di visi o n: W orl d w ide Develop ment Infor mation Type: Protocol A mend ment Titl e: A rando mised double -bli n d (s p o ns or o p e n), pl a c e b o c o ntr oll e d, si n gl e as c e n di n g d os e, First Ti m e i n H u m a n st u d y i n p arti ci p a nts wit h mil d t o m o d er at e ast h m a t o ass ess s af et y, t ol er a bilit y , i m munogenicity, phar macokinetics and phar macodyna mics of GS K3511294 ad ministered subcutaneousl y. Co mpound Nu mber: GS K3511294 Develop ment Phase: I Effective Date: 0 7- J A N -2019 Protocol A mend ment Nu mber: 0 6 A ut hor (s) : P P D P P D P P D Copy ri g ht 2 0 1 8 t h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni es. All ri g hts r es er v e d. Unauthorised cop yi n g or us e of t his i nf or m ati o n is pr o hi bit e d. 1 2016N270529_06 CONFIDENTIAL The GlaxoSmithKline group of companies 205722 Revision Chronology GlaxoSmithKline Date Version Document Number 2016N270529_00 2017-JUN-13 Original 2016N270529_01 2017-JUN-21 Amendment No. 1 To correct errors in the Secondary Medical Monitor’s email address and in the inflammatory marker tests to be performed at screening. 2016N270529_02 2017-AUG-04 Amendment No. 2 To amend the pharmacokinetic stopping criterion and clarify that saline for placebo will be an EU licensed product sourced locally by trial sites, in response to comments from the Medicines and Healthcare Products Regulatory Agency. 2016N270529_03 2017-SEP-04 Amendment No. 3 To correct errors and make minor clarifications. 2016N270529_04 2018-FEB-02 Amendment No. 4 To amend the timeframe for collection of PEF measurements. To clarify that demography, height, weight and BMI will be collected at the pre-screening visit if this visit is required. Alignment of ECG collection timeframe. Clarify timeframe for review of safety data from sentinel participants. Clarify that sentinel participants will be used at each escalating dose level. To remove the necessity for evidence of airway hyperresponsiveness, airflow variation (peak flow rate or FEV1) or reversible airflow obstruction at inclusion. Added live vaccines to prohibited concomitant medications list. Added Right Bundle Branch Block as an exclusion criteria. Clarification of the study halting criteria. Clarification that each participants consent must be available, as well as obtained, before they are entered into the study. Added an exclusion criteria regarding vulnerable participants. Clarify the definition of a pre-screening failure. Added in country specific requirements for Germany, concerning the addition of Hepatitis B core antibody test screening and to increase the in-patient period to 8-days post dosing. Clarified that the PK sample information is located in the appropriate lab manual and not the study reference manual. To ensure there is no un-blinding that can occur for Eosinophil counts due to availability of other components and their contributions to WBC count. 2 2016N270529_06 CONFIDENTIAL The GlaxoSmithKline group of companies 205722 GlaxoSmithKline Date Version Document Number 2016N270529_05 2018-JUN-18 Amendment No. 5 A raw QT interval change from baseline as one of the criteria for limiting dose escalation and for increased monitoring of individual participants has been included in error. QTcF has been chosen as the most appropriate corrective measure of QT for this study and this is now reflected throughout. Accordingly, one of the required criteria for limiting further dose escalation and increased monitoring of individuals is now a change in QTcF from baseline of > 60 msec. To remove the requirement for reversibility testing at pre- screening/screening, as evidence of reversibility is no longer a requirement for inclusion as per the previous amendment. Consequently, participants who would not be a screen failure under the entry criteria in the current version of the protocol may be rescreened. Furthermore, participants that were not a screen failure but could not be dosed during the screening window due to logistical reasons may also be rescreened. To extend the PK sampling period in the 2 mg and 10 mg cohorts, to better characterise the PK profile of GSK3511294. To clarify that local labs are required for all sentinel participants at the 48 hour time point to enable dosing of the rest of the cohort. As the German in-patient stay is longer than the UK, local labs prior to discharge from the clinical site are required on Day 8 and not at 48 hours post dosing (Day 3). Minor corrections of typos throughout. 2016N270529_06 2019-JAN-07 Amendment No. 6 Inclusion of additional interim analyses to better assess blood eosinophil count return towards baseline profiles at the highest dose levels investigated and better inform dose and dosing regimen to move forward into the next phase of development. The earliest additional interim analysis is planned no earlier than once data is available at the 26-week time point after dosing Cohort 4 (planned 100 mg dose). 3 P P D P P D 2016 N270529_06 C ONFIDENTIA L 205722 M E DI C A L M ONIT OR/SP ON S OR INF OR M A T I O N P A G E Medical Monitor/S A E Contact Inf or matio n: R ol e Na me D a y Ti m e P h o n e Aft er -h o ur s F a x Sit e A d dr e s s N u m b er a n d e m ail P h o n e/ C ell/ Nu mber address Pager Nu mber Pri m ary P P D P P D P P D G S K M e dic al Gunnels Wood M o nit or Road Stevenage H ertf or ds h ir e S G 1 2 N Y U K Secondary P P D P P D P P D G S K M e dic al Gunnels Wood M o nit or Road Stevenage H ertf or ds hir e S G 1 2 N Y U K S A E c o nt act M e dic al m o nit or as a b ov e i nf or m atio n Sponsor Legal R egistere d A d dress: GlaxoS mith Kline Research & Develop ment Li mited 980 Great West Road Bre ntf or d Mi d dl es e x, T W 8 9 G S U K I n s o m e c o u ntri es, t h e cli ni c al tri al s p o ns or m a y b e t h e l o c al Gl a x o S mit h Kli n e Affili at e Co mpany ( or d esi g n e e). If a p pli c a bl e, t h e d et ai ls of t h e alt er n ati v e S p o ns or a n d c o nt a ct p ers o n i n t h e t errit or y will b e pr o vi d e d t o t h e r el e v a nt r e g ul at or y a ut h orit y as p art of t h e cli ni c al tri al a p pli c ati o n. Regulatory Agency I d e ntif y ing Nu mber(s): 2016 -004256-30 5 2016N270529_06 CONFIDENTIAL 205722 INVESTIGATOR PROTOCOL AGREEMENT PAGE For protocol number: 205722 I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study. Investigator Name: Investigator Address: Investigator Phone Number: Investigator Signature Date 6 2016N270529_06 CONFIDENTIAL 205722 TABLE OF CONTENTS PAGE 1. PROTOCOL SYNOPSIS FOR STUDY 205722......................................................11 2. INTRODUCTION....................................................................................................15 2.1. Study Rationale ..........................................................................................15 2.2. Brief Background ........................................................................................15 3. OBJECTIVES AND ENDPOINTS...........................................................................18 4. STUDY DESIGN ....................................................................................................19 4.1. Overall Design ............................................................................................19 4.2. Treatment Arms and Duration.....................................................................20 4.3. Dose Escalation..........................................................................................21 4.4. Type and Number of Participants................................................................22 4.5. Design Justification and Choice of Population ............................................22 4.6. Dose Justification........................................................................................23 4.7. Benefit:Risk Assessment ............................................................................26 4.7.1. Risk Assessment .........................................................................27 4.7.2. Benefit Assessment .....................................................................33 4.7.3. Overall Benefit:Risk Conclusion...................................................33 5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33 5.1. Inclusion Criteria.........................................................................................34 5.2. Exclusion Criteria........................................................................................36 5.3. Pre-screening/Screening/Baseline/Run-in Failures .....................................39 5.4. Study Withdrawal Criteria ...........................................................................39 5.4.1. Individual participant withdrawal from the study ...........................39 5.4.1.1. Lost to follow-up .........................................................39 5.4.2. Criteria for follow up of potential Type III Hypersensitivity/ Immune Complex Disease...........................................................40 5.4.3.
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