Clinical study protocol template - ClinicalTrials.gov

1 Global Clinical Development - General Medicine QAW039/fevipiprantClinical Trial protocol CQAW039A2316 / NCT03215758A 12-week, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of QAW039 when added to standard-of-care asthma therapy in patients with uncontrolled asthmaDocument type: Clinical Trial ProtocolEUDRACT number:2017-001273-16 Version number:00 (OriginalProtocol) Clinical trial phase:IIIR elease date:10- May-2017 Property of NovartisConfidentialMay not be used, divulged, published, or otherwise disclosedwithout the consent of NovartisClinical Trial protocol template Version (July 2016)NovartisConfidentialPage 2 Clinical Trial protocol (Version 00) protocol No. CQAW039A2316 Table of contentsTable of of of of of objectives and and related for study for dose/regimen, route of administration and duration of for choice ofcomparator .. and timing of interim analyses/design and and control assignment and randomization.

2 The numbering .. the study of study and additional for prescribing and taking study adjustments and interruptions of study medication ..32 NovartisConfidentialPage 3 Clinical Trial protocol (Version 00) protocol No. medication .. medication .. breaking of assigned treatment completion and completion and post- study of study of informed to follow-up .. study termination by the schedule and to be collected on screening demographics/other baseline exposure and (Pre-dose FEV1 ).. for daily asthma symptoms, and rescue medication of efficacy and (ECG).. and assessments of of safety Outcome Assessments (COAs)..5456577 Safety adverse of 4 Clinical Trial protocol (Version 00) protocol No. safety safety of study treatment errors including drug reactions review and database collection .. management and quality Monitoring demographics and other baseline of the primary variable(s).

3 Variable(s).. model, hypothesis, and method of of missing values/ of secondary variables .. analyses .. size for the secondary and ethical consent of the investigator and of study protocol and Control and Quality 5 Clinical Trial protocol (Version 00) protocol No. 1: Clinically notable laboratory values and vital 2: Liver event and laboratory trigger definitions and follow-up 3: Specific Renal Alert Criteria and 4: List of idiosyncratic drug reactions (IDRs) for 5: Spirometry for 6: Estimated equivalence of inhaled Appendix 7: Asthma Control Questionnaire (ACQ-5)..8920 Appendix 8: Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12)..9197 List of tablesTable 2-1 Objectives and related 5-1 Medications allowed under certain 5-2 Medications to be withheld prior to 5-3 Prohibited medication ..34 Table 6-1 Assessment 7-1 Guidance for capturing the study treatment errors including 9-1 Result of power simulations for the primary 9-2 Power simulations for secondary 14-1 Liver Event and Laboratory Trigger 14-2 Follow Up Requirements for Liver Events and Laboratory 15-1 Specific Renal Alert Criteria and 16-1 Definition of potential idiosyncratic drug of figuresFigure 3-1 study 9-1 Closed testing procedure for primary and secondary 6 Clinical Trial protocol (Version 00) protocol No.

4 CQAW039A2316 List of AbbreviationsAbbreviation Explanation:ACRalbumin-creatinine ratioACQasthma control questionnaireAE(s)adverse event(s)AlbalbuminALTalanine aminotransferaseANCOVA analysis of covarianceAQLQ+12 asthma quality of life questionnaire for 12 years and olderALPalkaline phosphataseASTaspartate aminotransferaseATCanatomical therapeutic chemicalATS/ERSA merican Thoracic Society/European Respiratory SocietyAVatrioventricularBMIbody m ass indexBTPS body temperature and pressure saturatedBUNblood urea nitrogen CFRCode of Federal Regulations CKcreatine kinaseCK-MBcreatine kinase isoenzyme MBCPOC ountry Pharma OrganizationCOAclinical outcome assessmentCRAclinical research associateCRFcase r eport/record form (paper or electronic)CROcontract research organizationCRTh2chemoattractant receptor-homologous molecule expressed on Th2 CTcomputed tomographyDARdosage administration recordDDEdirect data entryDNAdeoxyribonucleic acidDP2prostaglandin D2 receptor2 DPIdry powder inhalerDMCData Monitoring CommitteeDRESS drug reaction with eosinophilia and systemic symptomsDS&EDrug Safety & EpidemiologyECGelectrocardiogramEDCelect ronic data captureeGFRestimated glomerular filtration rateEMAE uropean Medicines AgencyePEFelectronic peak expiratory flowEUEuropean UnionFASfull analysis setFDAFood and Drug AdministrationNovartisConfidentialPage 7 Clinical Trial protocol (Version 00) protocol No.

5 CQAW039A2316 Abbreviation Explanation:FDCfixed dose combinationFEV1forced expiratory volume in 1 second -GTgamma-g lutamyltransferaseGCPgood Clinical practiceGINAG lobal Initiative for AsthmaGOLDG lobal Initiative For Chronic Obstructive Lung DiseaseH0null hypothesisHaalternative hypothesisHbA1chemoglobin A1c; glycosylated hemoglobinhCGhuman chorionic gonadotropinHFAhydrofluoroalkaneHRQOL health-related quality of lifehsCRPhigh sensitivityC- reactive proteinIBinvestigator brochureICHinternational conference on harmonization of technical requirements for registration of pharmaceuticals for human useICSinhaled corticosteroidIDRidiosyncratic drug reactionsIECindependent ethics committeeIgEimmunoglobulin EImmunoCAP specific IgE testINinvestigator notificationINRinternational normalized ratioIRBinstitutional review boardIRTinteractive response technologyITTintention-to-treatIUDintrau terine deviceIUSintrauterine systemLABA long-acting -agonistLAMA long-acting muscarinic antagonist LDHlactate dehydrogenaseLFTliver function testLTRA leukotriene receptor antagonistMARmissing at randomMedDRAmedical dictionary for regulatory activitiesMDImetered dose inhalerMDRD modification of diet in renal disease studyMIDminimal important differenceMMRM mixed model repeated

6 MeasuresMXRmulti-xenobiotic resistance proteinNYHANew York Heart AssociationNovartisConfidentialPage 8 Clinical Trial protocol (Version 00) protocol No. CQAW039A2316 Abbreviation Explanation:OAT3organic anion transporter 3 OATP1B3organic anion transporter P1B3OC/RDCO racle Clinical /Remote Data CapturePCRprotein-creatinine ratioPEFpeak expiratory flowPGD2prostaglandin D2P- gpp- glycoproteinPPSper- protocol setPROpatient reported outcomePTprothrombin timeQMquality managementQOLquality of lifeQTcFFridericia QT correction formulaRAST radioallergosorbent testSABA short-acting -agonistSAE(s)serious adverse event(s)SAFsafety analysis setsCrserum creatinineSCRscreeningSDstandard deviationSJSS tevens-Johnson syndromeSoCstandard of careSOPstandard operating procedureSUSAR suspected unexpected serious adverse reactionsTBLtotal bilirubinTDtreatment discontinuationTENS toxic epidermal necrolysisTh2T helper 2 UGTuridinediphosphate glucuronosyltransferaseULNupper limit of normalWoCwithdrawal of consentWHOW orld Health OrganisationUSUnited StatesNovartisConfidentialPage 9 Clinical Trial protocol (Version 00) protocol No.

7 CQAW039A2316 Glossary of termsControl drugDrugs(s) used as a comparator to reduce assessment bias, preserve blinding of investigational drug, assess internal study validity, and/or evaluate comparative effects of the investigational drugDosageDose of the study treatment given to the patient in a time unit ( 100 mg once a day, 75 mg twice a day)Electronic data capture (EDC)Electronic data capture (EDC) is the electronic acquisition of Clinical study data using data collection systems, such as Web- based applications, interactive voice response systems and Clinical laboratory includes the use of Electronic Case Report Forms (eCRFs) which are used to capture data transcribed from paper source forms used at the point of Direct Data Entry (DDE) refers to the capture of Clinical study data electronically, at the point of care. eSource Platform/Applications reduce the use of paper capture source data during Clinical visits. eSource combines source documents and case report forms (eCRFs) into one application, allowing for the real time collection of Clinical trial information to sponsors and other oversight authorities, as of patient entry into the study at which informed consent must be obtained ( prior to starting any of the procedures described in the protocol )Epoch/PeriodA portion of the study which serves a specific purpose.

8 Typical epoch/periods are: screening/recruitment, wash-out, treatment, and follow-upInvestigational drugThe drug whose properties are being tested in the study ; this definition is consistent with US CFR 21 Section and is synonymous with investigational new drug or investigational medicinal product. Part A single component of a study which contains different objectives or populations within that single study . Common parts within a study are: a single dose part and a multiple dose part, or a part in patients with established disease and in those with newly-diagnosed A unique number assigned to each patient upon signing the informed consent Randomization numberA unique identifierassigned to each randomized patient, corresponding to a specific treatment arm assignmentSource data/DocumentSource data refers to the initial record, document, or primary location from where data comes. The data source can be a database, a dataset, a spreadsheet or even hard-coded data, such as paper or drug/ treatmentAny single drug or combination of drugs administered to the patient as part of the required study procedures; includes investigational drug (s), placebo/comparator activedrug run-ins or background therapyNovartisConfidentialPage 10 Clinical Trial protocol (Version 00) protocol No.

9 CQAW039A2316 study treatment discontinuation (TD)When the patient permanently stops taking study treatment prior to the defined study treatment completion date VariableA measured value or assessed response that is determined in specific assessments and used in data analysis to evaluate the drug being tested in the studyWithdrawal of consent (WoC)Withdrawal of consent from the study is defined as when a patient does not want to participate in the study any longer, and does not want any further visits or assessments, and does not want any further study related contact, and does not allow analysis of already obtained biologic materialNovartisConfidentialPage 11 Clinical Trial protocol (Version 00) protocol No. CQAW039A2316 protocol summaryProtocol numberCQAW039A2316 Full titleA 12-week, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of QAW039 when added to standard-of-care asthma therapy in patients with uncontrolled asthmaBrief titleStudy of efficacy and safety of QAW039 when added to standard-of-care asthma therapyin patients with uncontrolled asthma Sponsor and Clinical phaseNovartis, Phase 3 Investigation typeDrugStudy typeInterventional Purpose and rationaleThe purpose of this study is to determine the efficacy and safety of QAW039 (150 mgonce daily), compared with placebo, when added to standard-of-care (SoC) asthma therapy in adult and adolescent ( 12 years) patients with uncontrolled asthma with respect to change from baseline in forced expiratory volume in 1 second (FEV1)

10 At the end of 12 weeks of o bjectiveTo demonstrate the efficacy of QAW039 150 mg once daily as measured by change from baseline in pre-dose FEV1 [in liters], compared with placebo, at the end of the 12-week active-treatment objectives1. To demonstrate the efficacy of QAW039 150 mg once daily, compared with placebo, on daytime asthma symptoms over the 12-week active-treatment To demonstrate the efficacy of QAW039 150 mg once daily, compared with placebo, on total daily short-acting -agonist (SABA) use over the 12-week active-treatment To demonstrate the efficacy of QAW039 150 mg once daily, compared with placebo, on change from baseline in Asthma Quality of Life Questionnairefor 12 years and older(AQLQ+12) scores at the end of the 12-week active-treatment To assess the safety of QAW039 150 mg once daily, compared with placebo, with respect to adverse events(AEs), electrocardiograms (ECGs), vital signsand laboratory designThis study uses a randomized, multicenter, double-blind, placebo-controlled, parallel-group study study population will include: Males and females aged 12 years.