Novartis Institutes for BioMedical Research QVM149 Clinical Trial Protocol CQVM149B2209 A randomized, double-blind, repeat dose cross-over study to assess the bronchodilator effects of once daily QVM149 following morning or evening dosing for 14 days compared to placebo in patients with asthma Document type: Clinical Trial Protocol EUDRACT number: 2017-000644-17 Version number: v00 (Original Protocol) Clinical Trial Phase: II Release date: 08-Mar-2017 Property of Novartis Confidential May not be used, divulged, published or otherwise disclosed without the consent of Novartis Novartis Confidential Page 2 Clinical Trial Protocol (Version 00) Protocol No. CQVM149B2209 Site Operations Manual (SOM) A Site Operations Manual (SOM) accompanies this protocol, providing the operational details for study conduct. Note: The SOM will not form part of the Clinical Study Report. Notification of serious adverse events Dear Investigator, You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized below. Refer to Section 9.2 of the Clinical Trial Protocol for SAE criteria and additional requirements. See also page 2 of the Site Operations Manual for further details on the method of reporting a SAE. Complete SAE report Submit SAE report to Novartis Chief Medical Office and Patient Safety (CMO&PS) within 24 hours after awareness of the SAE Notify the Novartis Medical Lead The fax number(s) and email address(es) are located in the Site Operations Manual. Novartis Confidential Page 3 Clinical Trial Protocol (Version 00) Protocol No. CQVM149B2209 Table of contents Site Operations Manual (SOM)...........................................................................................2 Notification of serious adverse events.................................................................................2 Table of contents.................................................................................................................3 List of tables........................................................................................................................7 List of figures......................................................................................................................7 List of abbreviations............................................................................................................8 Glossary of terms...............................................................................................................11 Protocol summary..............................................................................................................13 1 Introduction.......................................................................................................................16 1.1 Background............................................................................................................16 Corporate Confidential Information 1.3 Clinical data...........................................................................................................19 1.3.1 Human safety and tolerability data.......................................................19 1.3.2 Human pharmacokinetic data................................................................20 1.3.3 Human pharmacodynamic data.............................................................20 1.4 Study purpose........................................................................................................21 2 Objectives and endpoints...................................................................................................21 2.1 Primary objective(s)...............................................................................................21 2.2 Secondary objective(s)...........................................................................................21 Corporate Confidential Information 3 Investigational plan...........................................................................................................23 3.1 Study design...........................................................................................................23 3.2 Rationale for study design.....................................................................................27 3.3 Rationale for dose/regimen, route of administration and duration of treatment....28 3.4 Rationalefor choice of comparator.......................................................................31 Corporate Confidential Information 3.6 Risks and benefits..................................................................................................31 3.6.1 Blood sample volumes..........................................................................34 4 Population..........................................................................................................................34 4.1 Inclusion criteria....................................................................................................35 4.2 Exclusion criteria...................................................................................................36 5 Restrictionsfor studypatients...........................................................................................40 5.1 Contraception requirements...................................................................................40 5.2 Prohibited treatment...............................................................................................40 Novartis Confidential Page 4 Clinical Trial Protocol (Version 00) Protocol No. CQVM149B2209 5.3 Dietary restrictions and smoking...........................................................................42 5.4 Other restrictions ...................................................................................................42 6 Treatment...........................................................................................................................42 6.1 Study treatment......................................................................................................42 6.1.1 Investigational and control drugs ..........................................................42 6.1.2 Additional study treatment....................................................................43 6.2 Treatment arms ......................................................................................................43 6.3 Treatment assignment and randomization .............................................................43 6.4 Treatment blinding.................................................................................................44 6.5 Treating the patient ................................................................................................45 6.6 Permitted dose adjustments and interruptions of study treatment .........................46 6.7 Emergency breaking of assigned treatment code ..................................................46 6.8 Treatment exposure and compliance .....................................................................47 6.9 Recommended treatment of adverse events ..........................................................47 6.10 Rescue medication.................................................................................................47 6.11 Concomitant treatment...........................................................................................47 7 Study completion and discontinuation ..............................................................................48 7.1 Study completion and post-study treatment ..........................................................48 7.2 Discontinuation of study treatment........................................................................48 7.3 Withdrawal of informed consent ...........................................................................50 7.4 Lost to follow-up ...................................................................................................50 7.5 Study stopping rules ..............................................................................................50 7.6 Early study termination by the sponsor .................................................................50 8 Procedures and assessments ..............................................................................................51 8.1 Assessment schedule .............................................................................................51 8.2 Informed consent procedures.................................................................................56 8.3 Patient screening....................................................................................................57 8.4 Patient demographics/other baseline characteristics .............................................57 8.4.1 Alcohol test, Drug screen, Urine cotinine.............................................57 8.4.2 Reversibility ..........................................................................................57 8.5 Efficacy / Pharmacodynamics ...............................................................................57 8.5.1 Spirometry.............................................................................................57 8.5.2 Peak expiratory flow .............................................................................57 8.6 Safety .....................................................................................................................58 8.6.1 Physical examination ............................................................................58 8.6.2 Vital signs..............................................................................................58