1b8cdd352f47f834354f173d8704c27f 2021._Lancet_Respir_Med._Long_term_safety.pdf 45ab346c864451779360c6897fe5a13143e5dd9a 2021._Lancet_Respir_Med._Long_term_safety.pdf 077f2df88ff979fd4d36804128c74291a36ce31a0c702ddd6ad3cbe6106265a7 2021._Lancet_Respir_Med._Long_term_safety.pdf Title: Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study Subject: The Lancet Respiratory, Corrected proof doi:10.1016/S2213-2600(21)00322-2 Keywords: Author: Michael E Wechsler MD Creator: Elsevier Producer: Acrobat Distiller 6.0 for Windows CreationDate: Mon Sep 27 16:47:07 2021 CEST ModDate: Fri Sep 2 10:50:24 2022 CEST Custom Metadata: yes Metadata Stream: yes Tagged: no UserProperties: no Suspects: no Form: AcroForm JavaScript: no Pages: 63 Encrypted: no Page size: 595.276 x 799.37 pts Page rot: 0 File size: 1608712 bytes Optimized: yes PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ 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(2023-03-16) LastModified: 2023-08-08 01:34:23 CEST Size: 1608712 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf Profile: Linearized PDF PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: en-US Outlines: Item: Title: Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study Children: Item: Title: Introduction Item: Title: Methods Children: Item: Title: Study design and participants Item: Title: Procedures Item: Title: Outcomes Item: Title: Statistical analysis Item: Title: Role of the funding source Item: Title: Results Item: Title: Discussion Item: Title: Acknowledgments Item: Title: References Item: Title: 1-s2.0-S2213260021003222-mmc1.pdf Children: Item: Title: 20TLRM2742_cover.pdf Item: Title: 20TLRM2742_Wechsler_appendix.pdf Children: Item: Title: Wechsler TRAVERSE prim ms_LRM appendix_Sept 16 Item: Title: rdct-lts12551-amended-protocol02 Children: Item: Title: AMENDED CLINICAL TRIAL PROTOCOL 02 Item: Title: 1 FLOW CHARTS Children: Item: Title: 1.1 GRAPHICAL STUDY DESIGN Item: Title: 1.2 Study flow chart for patients ENROLLED PRIOR TO aMENDMENT 04 Item: Title: 1.3 Study flow chart for patients ENROLLED after AMENDMENT 04 Item: Title: 2 TABLE OF CONTENTS Item: Title: 3 LIST OF ABBREVIATIONS Item: Title: 4 INTRODUCTION AND RATIONALE Children: Item: Title: 4.1 INTRODUCTION Item: Title: 4.2 RATIONALE Item: Title: 5 STUDY OBJECTIVES Children: Item: Title: 5.1 PRIMARY Item: Title: 5.2 SECONDARY Item: Title: 6 STUDY DESIGN Children: Item: Title: 6.1 DESCRIPTION OF THE PROTOCOL Item: Title: 6.2 DURATION OF STUDY PARTICIPATION Children: Item: Title: 6.2.1 Duration of study participation for each patient Item: Title: 6.2.2 Determination of end of clinical trial (all patients) Item: Title: 6.3 INTERIM ANALYSIS Item: Title: 6.4 STUDY COMMITTEES Children: Item: Title: 6.4.1 Data monitoring committee Item: Title: 7 SELECTION OF PATIENTS Children: Item: Title: 7.1 INCLUSION CRITERIA Item: Title: 7.2 EXCLUSION CRITERIA Children: Item: Title: 7.2.1 Exclusion criteria related to study methodology Item: Title: 7.2.2 Exclusion criteria related to the active comparator and/or mandatory background therapies Item: Title: 7.2.3 Exclusion criteria related to the current knowledge of sanofi compound Item: Title: 8 STUDY TREATMENTS Children: Item: Title: 8.1 INVESTIGATIONAL MEDICINAL PRODUCT Children: Item: Title: 8.1.1 Dupilumab Item: Title: 8.1.2 Preparation of investigational product Item: Title: 8.1.3 Dose schedule Item: Title: 8.2 NONINVESTIGATIONAL MEDICINAL PRODUCT(S) Children: Item: Title: 8.2.1 Inhaled corticosteroid and controller therapies Children: Item: Title: 8.2.1.1 Enrollment V1/V2 visit (combined with the end-of-treatment visit of parent study) Item: Title: 8.2.1.2 Open-label treatment period Item: Title: 8.2.1.3 Post-treatment period Item: Title: 8.2.2 Albuterol or levalbuterol reliever medication Children: Item: Title: Table 1 ­ Conversion from Salbutamol/Albuterol Nebulizer Solution to Puffs Item: Title: Table 2 ­ Conversion from Levosalbutamol/Levalbuterol Nebulizer Solution to Puffs Item: Title: 8.3 BLINDING PROCEDURES Children: Item: Title: 8.3.1 Methods of blinding Item: Title: 8.4 METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP Item: Title: 8.5 PACKAGING AND LABELING Item: Title: 8.6 STORAGE CONDITIONS AND SHELF LIFE Item: Title: 8.7 RESPONSIBILITIES Children: Item: Title: 8.7.1 Treatment accountability and compliance Item: Title: 8.7.2 Return and/or destruction of treatments Item: Title: 8.8 CONCOMITANT MEDICATION Children: Item: Title: 8.8.1 Prohibited concomitant medication Item: Title: 8.8.2 Permitted concomitant medication Item: Title: 8.8.3 Cytochrome P450 (CYP) precaution Item: Title: 9 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT Children: Item: Title: 9.1 PRIMARY ENDPOINT Item: Title: 9.2 SECONDARY ENDPOINTS Children: Item: Title: 9.2.1 Safety and tolerability Children: Item: Title: 9.2.1.1 Vital signs Item: Title: 9.2.1.2 Physical examination Item: Title: 9.2.1.3 Electrocardiogram (ECG) variables Item: Title: 9.2.1.4 Clinical laboratory tests Item: Title: 9.2.2 Efficacy Children: Item: Title: 9.2.2.1 Forced expiratory volume in 1 second (FEV1) Item: Title: 9.2.2.2 ACQ-5 (Asthma Control Questionnaire, 5-question version) Item: Title: 9.2.2.3 Severe asthma exacerbation events Item: Title: 9.2.2.4 Asthma Quality of Life Questionnaire with standardized activities (AQLQ[S]) Item: Title: 9.2.2.5 EuroQol 5 dimensions questionnaire, 3-level version (EQ-5D-3L) Item: Title: 9.2.2.6 Health care resource utilization Item: Title: 9.2.2.7 Disease-specific, daily efficacy assessments Item: Title: 9.2.2.8 Prescribed oral corticosteroids (OCS) dose for patients from the EFC13691 study Item: Title: 9.3 OTHER ENDPOINTS Children: Item: Title: 9.3.1 Pharmacokinetics and anti-dupilumab antibodies Children: Item: Title: 9.3.1.1 Sampling time Item: Title: 9.3.1.2 Pharmacokinetics handling procedure Children: Item: Title: Table 3 ­ Summary of handling procedures for dupilumab Item: Title: 9.3.1.3 Bioanalytical method Children: Item: Title: Table 4 ­ Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody Item: Title: 9.3.1.4 Pharmacokinetics parameters Item: Title: 9.3.2 Pharmacogenetic assessment Item: Title: 9.3.3 Pharmacodynamic variables Children: Item: Title: 9.3.3.1 Whole blood biomarkers Item: Title: 9.3.3.2 Serum biomarkers and archival serum preparation Item: Title: 9.3.4 Quality of life / health economic variables / other endpoints (optional) Item: Title: 10 STUDY PROCEDURES Children: Item: Title: 10.1 VISIT SCHEDULE Children: Item: Title: 10.1.1 For patients enrolled prior to Amendment 04 Children: Item: Title: 10.1.1.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1) Item: Title: 10.1.1.2 Visit 3 (Week 2) Item: Title: 10.1.1.3 Visit 4 (Month 1, Week 4) Item: Title: 10.1.1.4 Visit 5 (Week 6) Item: Title: 10.1.1.5 Visit 6 (Month 2, Week 8) Item: Title: 10.1.1.6 Visit 7 (Week 10) Item: Title: 10.1.1.7 Visit 8 (Month 3, Week 12) Item: Title: 10.1.1.8 Visit 9 (Month 4, Week 16) Item: Title: 10.1.1.9 Visit 10 (Month 5, Week 20); Item: Title: 10.1.1.10 Visit 11 (Month 6, Week 24) Item: Title: 10.1.1.11 Visit 12 (Month 9, Week 36) Item: Title: 10.1.1.12 Visit 13 (Month 12, Week 48) Item: Title: 10.1.1.13 Visit 14 (Month 15, Week 60); Item: Title: 10.1.1.14 Visit 15 (Month 18, Week 72) Item: Title: 10.1.1.15 Visit 16 (Month 21, Week 84) Item: Title: 10.1.1.16 Visit 17 (End-of-Treatment: Month 24, Week 96) Item: Title: 10.1.1.17 Visit 18 (End-of-Study: Month 27, Week 108) Item: Title: 10.1.2 For patients enrolled after Amendment 04 Children: Item: Title: 10.1.2.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1) Item: Title: 10.1.2.2 Visit 3 (Week 2) Item: Title: 10.1.2.3 Visit 4 (Month 1, Week 4) Item: Title: 10.1.2.4 Visit 5 (Week 6) Item: Title: 10.1.2.5 Visit 6 (Month 2, Week 8) Item: Title: 10.1.2.6 Visit 7 (Week 10) Item: Title: 10.1.2.7 Visit 8 (Month 3, Week 12) Item: Title: 10.1.2.8 Visit 9 (Month 4, Week 16) Item: Title: 10.1.2.9 Visit 10 (Month 5, Week 20) Item: Title: 10.1.2.10 Visit 11 (Month 6, Week 24) Item: Title: 10.1.2.11 Visit 12 (Month 9, Week 36) Item: Title: 10.1.2.12 Visit 17 (End-of-Treatment: Month 12, Week 48) Item: Title: 10.1.2.13 Visit 18 (End-of-Study: Month 15, Week 60) Item: Title: 10.2 DEFINITION OF SOURCE DATA Item: Title: 10.3 HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION Children: Item: Title: 10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) Item: Title: 10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) Item: Title: 10.3.3 List of criteria for permanent treatment discontinuation Item: Title: 10.3.4 Handling of patients after permanent treatment discontinuation Item: Title: 10.3.5 Procedure and consequence for patient withdrawal from study Item: Title: 10.4 OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING Children: Item: Title: 10.4.1 Definitions of adverse events Children: Item: Title: 10.4.1.1 Adverse event Item: Title: 10.4.1.2 Serious adverse event Item: Title: 10.4.1.3 Adverse event of special interest Item: Title: 10.4.2 General guidelines for reporting adverse events Children: Item: Title: Table 5 ­ Adverse event/laboratory abnormality reporting timelines Item: Title: 10.4.3 Instructions for reporting serious adverse events Item: Title: 10.4.4 Guidelines for reporting adverse events of special interest Item: Title: 10.4.5 Guidelines for management of specific laboratory abnormalities Children: Item: Title: Table 6 ­ Summary of adverse event reporting instructions Item: Title: 10.5 OBLIGATIONS OF THE SPONSOR Item: Title: 10.6 SAFETY INSTRUCTIONS Children: Item: Title: 10.6.1 Hypersensitivity Item: Title: 10.6.2 Severe injection site reactions Item: Title: 10.6.3 Infections Item: Title: 10.6.4 Elevated liver function tests Item: Title: 10.7 ADVERSE EVENTS MONITORING Item: Title: 11 STATISTICAL CONSIDERATIONS Children: Item: Title: 11.1 DETERMINATION OF SAMPLE SIZE Item: Title: 11.2 DISPOSITION OF PATIENTS Item: Title: 11.3 ANALYSIS POPULATIONS Children: Item: Title: 11.3.1 Efficacy populations Item: Title: 11.3.2 Safety population Item: Title: 11.3.3 Pharmacokinetics population Item: Title: 11.3.4 Anti-drug antibody population Item: Title: 11.4 STATISTICAL METHODS Children: Item: Title: 11.4.1 Extent of study treatment exposure and compliance Children: Item: Title: 11.4.1.1 Extent of investigational medicinal product exposure Item: Title: 11.4.1.2 Compliance Item: Title: 11.4.2 Analyses of efficacy endpoints Item: Title: 11.4.3 Analyses of safety data Children: Item: Title: 11.4.3.1 Adverse events Item: Title: 11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables Children: Item: Title: 11.4.4.1 Pharmacokinetic analysis - (drug concentration analyses) Item: Title: 11.4.4.2 Anti-drug antibodies analysis Item: Title: 11.4.4.3 Pharmacodynamics Item: Title: 11.4.5 Analyses of patient reported outcomes (health-related quality of life / health economics variables) Item: Title: 11.5 INTERIM ANALYSIS Item: Title: 12 ETHICAL AND REGULATORY CONSIDERATIONS Children: Item: Title: 12.1 ETHICAL AND REGULATORY STANDARDS Item: Title: 12.2 INFORMED CONSENT Item: Title: 12.3 INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE Item: Title: 13 STUDY MONITORING Children: Item: Title: 13.1 RESPONSIBILITIES OF THE INVESTIGATOR(S) Item: Title: 13.2 RESPONSIBILITIES OF THE SPONSOR Item: Title: 13.3 SOURCE DOCUMENT REQUIREMENTS Item: Title: 13.4 USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST Item: Title: 13.5 USE OF COMPUTERIZED SYSTEMS Item: Title: 14 ADDITIONAL REQUIREMENTS Children: Item: Title: 14.1 CURRICULUM VITAE Item: Title: 14.2 RECORD RETENTION IN STUDY SITES Item: Title: 14.3 CONFIDENTIALITY Item: Title: 14.4 PROPERTY RIGHTS Item: Title: 14.5 DATA PROTECTION Item: Title: 14.6 INSURANCE COMPENSATION Item: Title: 14.7 SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES Item: Title: 14.8 PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A SITE Children: Item: Title: 14.8.1 By the Sponsor Item: Title: 14.9 CLINICAL TRIAL RESULTS Item: Title: 14.10 PUBLICATIONS AND COMMUNICATIONS Item: Title: 15 CLINICAL TRIAL PROTOCOL AMENDMENTS Children: Item: Title: 15.1 BY THE INVESTIGATOR Item: Title: 16 BIBLIOGRAPHIC REFERENCES Item: Title: 17 APPENDICES Children: Item: Title: Appendix A. List of prohibited live, attenuated vaccines Item: Title: Appendix B. Examples of commonly used asthma controller therapies Item: Title: Appendix C. Examples(1) of CYP substrates with narrow therapeutic range Item: Title: Appendix D. General guidance for the follow-up of laboratory abnormalities by sanofi Item: Title: Appendix E. Asthma Quality of Life Questionnaire AQLQ(S) Item: Title: Appendix F. Asthma Control Questionnaire, 5-question Version (ACQ-5) Item: Title: Appendix G. EuroQUAL Questionnaire (EuroQol 5 dimensions questionnaire, 3-Level Version [EQ-5D-3L]) Item: Title: Appendix H. Definition of Anaphylaxis Item: Title: Appendix I. 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Identity Supplement: 0 FontDescriptor: FontName: TimesNewRomanPS-ItalicMT Flags: Nonsymbolic FontBBox: -498, -216, 1333, 694 FontFile2: true XMP: application/pdf doi:10.1016/S2213-2600(21)00322-2 Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study Michael E Wechsler MD Linda B Ford MD Jorge F Maspero MD Ian D Pavord FMedSci Alberto Papi MD Arnaud Bourdin MD Henrik Watz MD Mario Castro MD Natalia M Nenasheva MD Yuji Tohda MD David Langton FRACP Guido Cardona MD Christian Domingo MD Hae Sim Park MD Kenneth R Chapman MD Xuezhou Mao PhD Yi Zhang PhD Asif H Khan MPH Yamo Deniz MD Paul J Rowe MD Upender Kapoor MD Faisal A Khokhar MD Leda P Mannent MD Marcella Ruddy MD Elizabeth Laws PhD Nikhil Amin MD Megan Hardin MD The Lancet Respiratory, Corrected proof doi:10.1016/S2213-2600(21)00322-2 Elsevier Ltd journal The Lancet Respiratory Copyright © 2021 Elsevier Ltd. All rights reserved. 2213-2600 10.1016/S2213-2600(21)00322-2 http://dx.doi.org/10.1016/S2213-2600(21)00322-2 2010-04-23 true 10.1016/S2213-2600(21)00322-2 elsevier.com sciencedirect.com P 6.5 10.1016/S2213-2600(21)00322-2 noindex 2010-04-23 true sciencedirect.com elsevier.com Elsevier 2021-09-27T20:17:07+05:30 2022-09-02T10:50:24+02:00 2022-09-02T10:50:24+02:00 True Acrobat Distiller 6.0 for Windows False uuid:24c65432-6962-455a-b6c2-3865b083a644 uuid:bc829b75-cc20-416f-ad82-ab6687390c15 Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 517, 654, 541, 679 Page: Sequence: 2 Page: Sequence: 3 Page: Sequence: 4 Page: Sequence: 5 Page: Sequence: 6 Page: Sequence: 7 Page: Sequence: 8 Page: Sequence: 9 Page: Sequence: 10 Page: Sequence: 11 Page: Sequence: 12 Page: Sequence: 13 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 533, 316, 552, 307 Annotation: Subtype: Link Rect: 79, 307, 110, 299 Annotation: Subtype: Link Rect: 35, 298, 110, 290 Page: Sequence: 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