Protocol - GB44332 - ASTEGOLIMAB - v4 PDF

PROTOCOL PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ASTEGOLIMAB IN PATIENTS WITH CHRONIC...

PROTOCOL PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ASTEGOLIMAB IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE PROTOCOL NUMBER: GB44332 STUDY NAME: ARNASA VERSION NUMBER: 4 TEST COMPOUND: Astegolimab (RO7187807) STUDY PHASE: Phase III EU TRIAL NUMBER: 2022-502234-70-00 IND NUMBER: 129,714 NCT NUMBER: NCT05595642 SPONSOR’S NAME F. Hoffmann-La Roche Ltd AND LEGAL Grenzacherstrasse 124 REGISTERED 4070 Basel, Switzerland ADDRESS: APPROVAL: See electronic signature and date stamp on the final page of this document. CONFIDENTIAL This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, including Genentech, Inc. in the United States. The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without written authorization from Roche except to the extent necessary to obtain informed consent from persons to whom the drug may be administered. AstegolimabF. Hoffmann-La Roche Ltd Protocol GB44332, Version 4  PROTOCOL HISTORY Protocol Version Date Final 4 See electronic date stamp on final page. 3 26 May 2023 2 9 November 2022 1 16 September 2022 AstegolimabF. Hoffmann-La Roche Ltd 2/Protocol GB44332, Version 4  PROTOCOL AMENDMENT, VERSION 4: RATIONALE GB44332 has been amended to include language preferred as part of the harmonized multinational Clinical Trials Regulation (CTR) process. Substantive changes to the protocol, along with a rationale for each change, are summarized below.  To align with the most recent Investigator’s Brochure (IB) version 8, the IB data cutoff date was updated and patient exposure data was amended accordingly (Section 2.3.2 and Appendix 4).  Clarification was added regarding the Sponsor-contracted professional mobile nursing service and their training (Sections 6.1 and 8.2).  For clarification, a sentence referencing the Statistical Analysis Plan (SAP) was removed (Section 9.3).  It was clarified that for the primary endpoint, no sensitivity analyses are planned for the missing data (Section 9.3.2.3).  Section describing interim analyses has been removed as there are no planned interim analyses (previously Section 9.4). Additional minor changes have been made to improve clarity and consistency. Substantive new information appears in italics. This amendment represents cumulative changes to the original protocol. AstegolimabF. Hoffmann-La Roche Ltd 3/Protocol GB44332, Version 4  TABLE OF CONTENTS PROTOCOL AMENDMENT ACCEPTANCE FORM............................................ 9 1. PROTOCOL SUMMARY............................................................... 10 1.1 Synopsis.................................................................................. 10 1.2 Study Schema......................................................................... 15 1.3 Schedule of Activities and Sample Collection Schedule.......... 16 2. BACKGROUND............................................................................ 23 2.1 Background on Chronic Obstructive Pulmonary Disease........ 23 2.2 Background on Astegolimab.................................................... 24 2.3 Background on Interleukin-33 and ST2................................... 24 2.3.1 Summary of Nonclinical Studies.............................................. 25 2.3.2 Summary of Clinical Studies.................................................... 26 2.4 Study Rationale and Benefit-Risk Assessment........................ 26 3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS.......................... 28 4. STUDY DESIGN........................................................................... 33 4.1 Overview of Study Design........................................................ 33 4.1.1 Open-Label Extension Study GB43374................................... 34 4.1.2 Safety Follow-Up Period and Assessments after Study Treatment Discontinuation....................................................... 35 4.1.3 Independent Data Monitoring Committee................................ 35 4.2 Rationale for Study Design...................................................... 36 4.2.1 Rationale for Study Population................................................ 36 4.2.2 Rationale for Biomarker Assessments..................................... 36 4.2.3 Rationale for Control Group..................................................... 37 4.3 Justification for Dose and Schedule......................................... 37 4.4 End of Study Definition............................................................ 38 4.5 Duration of Participation.......................................................... 38 5. STUDY POPULATION.................................................................. 38 5.1 Inclusion Criteria...................................................................... 38 5.2 Exclusion Criteria..................................................................... 40 5.3 Lifestyle Considerations........................................................... 42 5.3.1 Contraception Requirements................................................... 42 AstegolimabF. Hoffmann-La Roche Ltd 4/Protocol GB44332, Version 4  5.4 Screen Failures........................................................................ 42 6. STUDY TREATMENT, OTHER TREATMENTS RELEVANT TO THE STUDY DESIGN, AND CONCOMITANT THERAPY...... 43 6.1 Study Treatment Administered................................................ 43 6.1.1 Standard of Care COPD Maintenance Therapy....................... 44 6.2 Preparation, Handling, Storage, and Accountability................. 45 6.3 Treatment Assignment and Blinding........................................ 46 6.3.1 Treatment Assignment............................................................. 46 6.3.2 Blinding.................................................................................... 46 6.4 Study Treatment Compliance.................................................. 47 6.5 Dose Modification.................................................................... 47 6.6 Continued Access to Study Treatment after the End of the Study....................................................................................... 48 6.7 Treatment of Overdose............................................................ 48 6.8 Concomitant Therapy.............................................................. 48 6.8.1 Rescue Therapy...................................................................... 48 6.8.2 Systemic Corticosteroids......................................................... 49 6.8.3 COPD Therapy and Concomitant Therapy Restrictions.......... 49 6.8.4 Cautionary Therapy................................................................. 51 6.8.4.1 Herbal Therapies..................................................................... 51 7. DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT DISCONTINUATION OR WITHDRAWAL............ 51 7.1 Discontinuation of Study Treatment......................................... 51 7.2 Participant Discontinuation or Withdrawal from the Study....... 52 7.3 Participants Lost to Follow-Up................................................. 52 8. STUDY ASSESSMENTS AND PROCEDURES........................... 53 8.1 Informed Consent Forms and Screening Log.......................... 53 8.2 Medical History, Baseline Conditions, Concomitant Medication, and Demographic Data......................................... 53 8.2.1 Smoking History....................................................................... 54 8.2.2 Smoking Cessation for Current Smokers................................. 54 8.2.3 Radiographic Assessments..................................................... 55 8.3 Efficacy Assessments.............................................................. 55 AstegolimabF. Hoffmann-La Roche Ltd 5/Protocol GB44332, Version 4  8.3.1 COPD Exacerbation Assessment............................................ 55 8.3.2 Spirometry............................................................................... 55 8.3.2.1 Pre-Bronchodilator Spirometry................................................. 56 8.3.2.2 Post-Bronchodilator Spirometry............................................... 56 8.3.3 Clinical Outcome Assessments............................................... 56 8.3.3.1 Saint George’s Respiratory QuestionnaireCOPD................. 57 8.3.3.2 Modified Medical Research Council Dyspnea Scale................ 57 8.3.3.3 EXACT Questionnaire and E-RS:COPD Subset...................... 57 8.3.3.4 EuroQoL 5-Dimension Questionnaire...................................... 57 8.4 Safety Assessments................................................................ 58 8.4.1 Physical Examinations............................................................. 58 8.4.2 Vital Signs................................................................................ 58 8.4.3 Electrocardiograms.................................................................. 58 8.4.4 Clinical Safety Laboratory Tests.............................................. 59 8.4.5 Pregnancy Testing................................................................... 60 8.5 Adverse Events, Serious Adverse Events, and Other Safety Reporting...................................................................... 60 8.5.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information.................................. 60 8.5.2 Method of Detecting Adverse Events and Serious Adverse Events...................................................................................... 61 8.5.3 Follow-Up of Adverse Events and Serious Adverse Events.... 61 8.5.4 Regulatory Reporting Requirements for Serious Adverse Events...................................................................................... 61 8.5.5 Pregnancy................................................................................ 62 8.5.6 Cardiovascular and Death Events........................................... 62 8.5.7 Anticipated Events Not Qualifying for Expedited Reporting..... 62 8.5.8 Adverse Events of Special Interest.......................................... 63 8.5.9 Medical Device Complaints...................................................... 63 8.5.10 Medical Monitors and Emergency Medical Contacts............... 63 8.6 Pharmacokinetics.................................................................... 64 8.7 Pharmacodynamics................................................................. 65 8.8 Genetics.................................................................................. 65 8.9 Biomarker Assessments.......................................................... 65 AstegolimabF. Hoffmann-La Roche Ltd 6/Protocol GB44332, Version 4  8.10 Immunogenicity Assessments................................................. 66 8.11 Additional Assessments and Procedures Requiring Separate Consent or Performed Only at Participating Sites.... 66 8.11.1 Optional Physical Activity Monitoring (Participants Providing Separate Consent)................................................... 66 8.11.2 Samples for Research Biosample Repository (Participants Providing Separate Consent at Participating Sites)....................................................................................... 67 8.11.2.1 Overview of the Research Biosample Repository.................... 67 8.11.2.2 Approval by the Institutional Review Board or Ethics Committee............................................................................... 67 8.11.2.3 Sample Collection.................................................................... 67 8.11.2.4 Data Protection, Use, and Sharing.......................................... 68 8.11.2.5 Consent to Participate in the Research Biosample Repository................................................................................ 69 8.11.2.6 Withdrawal from the Research Biosample Repository............. 69 8.11.2.7 Monitoring and Oversight......................................................... 70 9. STATISTICAL CONSIDERATIONS.............................................. 70 9.1 Statistical Hypotheses............................................................. 70 9.1.1 Sample Size Determination..................................................... 70 9.2 Analysis Sets........................................................................... 71 9.3 Statistical Analyses.................................................................. 71 9.3.1 General Considerations........................................................... 72 9.3.2 Primary Endpoint..................................................................... 72 9.3.2.1 Primary Estimand.................................................................... 72 9.3.2.2 Main Analytical Approach for Primary Endpoint....................... 73 9.3.2.3 Sensitivity Analyses for Primary Endpoint............................... 73 9.3.3 Estimation Methods for the Secondary Endpoints................... 74 9.3.3.1 Secondary Endpoints............................................................... 74 9.3.3.2 Safety Analyses....................................................................... 74 9.3.4 Exploratory Analyses............................................................... 75 9.3.4.1 Summaries of Conduct of Study.............................................. 75 9.3.4.2 Summaries of Demographics and Baseline Characteristics.... 75 9.3.4.3 Pharmacokinetic Analyses....................................................... 75 AstegolimabF. Hoffmann-La Roche Ltd 7/Protocol GB44332, Version 4  9.3.4.4 Immunogenicity Analyses........................................................ 76 9.3.4.5 Biomarker Analyses................................................................. 76 9.3.4.6 China Subpopulation Analyses................................................ 76 10. REFERENCES.............................................................................. 78 LIST OF TABLES Table 1 Schedule of Activities.................................................................. 16 Table 2 Schedule of Intensive Pharmacokinetic and Pharmacodynamic Biomarker Sampling for Patients in Mainland China........................................................................... 22 Table 3 Primary and Secondary Objectives and Corresponding Estimands................................................................................... 28 Table 4 Other Secondary and Exploratory Objectives and Endpoints..... 31 Table 5 Study Treatment Description....................................................... 43 Table 6 COPD Therapy and Concomitant Therapy Restrictions.............. 49 Table 7 Analysis Data Sets...................................................................... 71 LIST OF FIGURES Figure 1 Study Schema............................................................................. 15 LIST OF APPENDICES Appendix 1 Regulatory, Ethical, and Study Oversight Considerations........... 82 Appendix 2 Clinical Safety Laboratory Tests................................................. 89 Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-Up, and Reporting......................................... 90 Appendix 4 Safety Plan: Management of Identified and Potential Risks..... 106 Appendix 5 Collection of Pregnancy Information......................................... 114 Appendix 6 Reporting Requirements for Medical Device Complaints.......... 117 Appendix 7 Clinical Outcome Assessment Instruments............................... 119 Appendix 8 Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events.......................................... 135 Appendix 9 Anaphylaxis Precautions........................................................... 165 Appendix 10 Genetics: Use and Analysis of DNA for Mandatory Samples... 166 Appendix 11 Investigational Medicinal Product and Non-Investigational Medicinal Product Designations (for Use in European Economic Area and United Kingdom)....................................... 167 Appendix 12 Protocol Amendment History.................................................... 168 Appendix 13 Abbreviations............................................................................ 170 AstegolimabF. Hoffmann-La Roche Ltd 8/Protocol GB44332, Version 4  PROTOCOL AMENDMENT ACCEPTANCE FORM PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ASTEGOLIMAB IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE PROTOCOL NUMBER: GB44332 STUDY NAME: ARNASA VERSION NUMBER: 4 TEST COMPOUND: Astegolimab (RO7187807) SPONSOR NAME: F. Hoffmann-La Roche Ltd I agree to conduct the study in accordance with the current protocol. Principal Investigator's Name (print) Principal Investigator's Signature Date Please retain the signed original of this form for your study files. Please return a copy of the signed form as instructed by the Contract Research Organization (CRO). Astegolimab—F. Hoffmann-La Roche Ltd 9/Protocol GB44332, Version 4 1. PROTOCOL SUMMARY 1.1 SYNOPSIS PROTOCOL TITLE: A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ASTEGOLIMAB IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE REGULATORY IND Number: 129,714 AGENCY IDENTIFIER EU Trial Number: 2022-002705-23502234-70-00 NUMBERS: NCT Number: NCT05595642 STUDY RATIONALE The purpose of this study is to assess the efficacy and safety of astegolimab compared with placebo in participants with chronic obstructive pulmonary disease (COPD) who are former or current smokers and have a history of frequent exacerbations. OBJECTIVES AND ENDPOINTS Primary and selected secondary objectives for the study are expressed using the estimand framework in accordance with the International Conference on Harmonization E9 (R1) statistical principles for clinical trials (FDA 2020) in Section 3. Primary Objective Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria, and received at least one dose of study drug  Endpoint: annualized rate of moderate and severe COPD exacerbations over the 52-week treatment period – A moderate COPD exacerbation is defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) that lead to treatment (duration  3 days) with systemic corticosteroids (oral, IV, or IM) at a dose of  10 mg/day prednisolone equivalent and/or antibiotics – A severe COPD exacerbation is defined as new or increased COPD symptoms that lead to hospitalization (duration  24 hours) or lead to death  Treatment: – Experimental: astegolimab 476 mg SC Q2W Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: RR for annualized rate of moderate and severe COPD exacerbations Astegolimab—F. Hoffmann-La Roche Ltd 10/Protocol GB44332, Version 4  Secondary Objectives Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria, and received at least one dose of study drug  Endpoint: time to first moderate or severe COPD exacerbation during the 52-week treatment period  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: HR for time to first COPD exacerbation  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria, and received at least one dose of study drug  Endpoint: – Absolute change from baseline in HRQoL at Week 52, as assessed through the SGRQ-C total score – Absolute change from baseline in post-bronchodilator FEV1 (liters) at Week 52 – Absolute change from baseline in E-RS:COPD total score at Week 52  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy – Discontinuation from study prior to Week 52: treatment policy strategy  Population-level summary: difference in mean absolute change at Week 52 Astegolimab—F. Hoffmann-La Roche Ltd 11/Protocol GB44332, Version 4  Secondary Objectives Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria, and received at least one dose of study drug  Endpoint: proportion of participants with improvement in HRQoL, defined as a decrease from baseline of  4 points in SGRQ-C total score, at Week 52  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: difference in proportion  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria, and received at least one dose of study drug  Endpoint: annualized rate of severe COPD exacerbations over the 52-week treatment period  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: RR for annualized rate of severe COPD exacerbations COPD  chronic obstructive pulmonary disease; E-RS:COPD  Evaluating Respiratory Symptoms in COPD; FEV1  forced expiratory volume in 1 second; HR  hazard ratio; HRQoL  health-related quality of life; IM  intramuscular; mITT  modified intent-to-treat; Q2W  every 2 weeks; Q4W  every 4 weeks; RR  rate ratio; SGRQ-C  St. George’s Respiratory Questionnaire-COPD. OVERALL DESIGN This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of astegolimab in combination with standard of care (SOC) compared with placebo in combination with SOC, in participants with COPD who are former or current smokers and have a history of frequent exacerbations. Approximately 1290 participants with COPD are expected to be enrolled globally. Following a screening period of at least 7 days and to up to 4 weeks, participants will be randomized in a 1:1:1 ratio to 1 of 3 treatment arms to receive blinded treatment with either astegolimab or placebo. Randomization will be stratified by smoking status at screening (former smoker vs. current smoker) and region. The first dose of study drug (astegolimab or placebo) will be administered on Day 1; treatment will continue through Week 50, followed by a 12-week safety follow-up period. The treatment regimens for each arm are as follows: Astegolimab—F. Hoffmann-La Roche Ltd 12/Protocol GB44332, Version 4   Astegolimab 476 mg SC every 2 weeks (Q2W)  Astegolimab 476 mg SC every 4 weeks (Q4W) To ensure that all study participants undergo the same visit schedule, participants randomized to the Q4W dosing arm will alternate between injections of astegolimab and placebo Q2W (beginning with astegolimab on Day 1), thus receiving astegolimab Q4W.  Placebo SC Q2W Participants will return to the clinic Q2W through the treatment completion visit at Week 52. The primary endpoint analyses will be conducted using the 52-week treatment period data for all participants. Several key aspects of the study design and study population are summarized below. Phase: Phase 3 Population Type: Adult patients of any gender Control Method: Placebo Population Diagnosis Chronic obstructive or Condition: pulmonary disease Interventional Parallel group Population Age: 4080 years Model: Test Compound{s}: Astegolimab Site Distribution: Multi-site and multi- region Active Comparator: Not applicable Study Intervention Randomization and Assignment Method: stratification Number of Arms: 3 Number of Participants Approximately 1290 to Be Enrolled: participants STUDY TREATMENT Astegolimab and placebo will be supplied by the Sponsor as a sterile liquid in 2.25 mL pre-filled syringes with a needle safety device, providing 238 mg/1.7 mL of astegolimab or placebo. For information on the astegolimab and placebo formulation, see the pharmacy manual and/or Astegolimab Investigator's Brochure. Study drug administration must occur after all other procedures have been completed at the visit, unless specifically indicated otherwise. Study drug will be administered by trained medical personnel. Each dose of study drug (astegolimab or placebo) will be administered as 2 SC injections (for a total of 3.4 mL), with each injection administered on a different side of the abdomen (i.e., right or left). See the pharmacy manual for details on study drug preparation and administration. All participants will be observed for at least 30 minutes after each dose and longer (approximately 60 minutes) in the event of an injection-site reaction, as determined by the investigator. If a participant develops any signs or symptoms to suggest a systemic hypersensitivity reaction or anaphylactic event, longer observation may be warranted as per the opinion of the investigator. There must be a minimum of 8 days between doses. In the event a dosing visit would occur within 8 days of a subsequent or previous dosing visit (e.g., due to an out-of-window visit), the study drug may not be administered. Instead, the next dose of study drug should be administered at the subsequent scheduled visit within the protocol-defined visit window to ensure that the 8-day minimum dosing interval is maintained. DURATION OF PARTICIPATION The total duration of study participation for each individual is expected to be approximately 15 months. Astegolimab—F. Hoffmann-La Roche Ltd 13/Protocol GB44332, Version 4 COMMITTEES Independent Committees: Independent Data Monitoring Committee Other Committees: Not applicable Astegolimab—F. Hoffmann-La Roche Ltd 14/Protocol GB44332, Version 4 1.2 STUDY SCHEMA Figure 1 Study Schema COPD  chronic obstructive pulmonary disease; OLE  open-label extension; Q2W  every 2 weeks; Q4W  every 4 weeks. a To ensure that all study participants undergo the same visit schedule, participants randomized to the Q4W dosing arm will alternate between injections of astegolimab and placebo Q2W thus receiving astegolimab Q4W. b Participants will enter the safety follow-up period and undergo end of study assessments 12 weeks after their last dose of study drug, as detailed in Section 4.1.2. c Participants enrolled in this study may have the opportunity to participate in OLE Study GB43374, if eligible, as detailed in Section 4.1.1. Astegolimab—F. Hoffmann-La Roche Ltd 15/Protocol GB44332, Version 4 1.3 SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION SCHEDULE Table 1 Schedule of Activities Treatment Period EOS/ Treat Safety Compl/ Follow- Screen a Disc b Up b V3V7 V9V13 V15V19 V2126 c, d, e c, d, e c, d, e c, d, e V2 (every (every (every (every Visit (V) V1 (Day 1) 2 wk) V8 2 wk) V14 2 wk) V20 2 wk) V27 e V28 V29 Week  4 to  1 0 210 12 1422 24 2634 36 3848 50 52 62 Protocol ( 7 (Window) Reference ( 3 days) days) Informed consent 8.1 x Demographic data 8.2 x Medical history and baseline 8.2 x conditions Smoking history 8.2.1 x x x x x x x Smoking cessation 8.2.2 x counseling f Vital signs 8.4.2 x x x x x x x x x x x x Height  x Weight  x x Complete physical 8.4.1 x examination Limited physical examination 8.4.1 x x x x x x Chest X-ray g 8.2.3 x Astegolimab—F. Hoffmann-La Roche Ltd 16/Protocol GB44332, Version 4 Table 1: Schedule of Activities (cont.) Treatment Period EOS/ Treat Safety Compl/ Follow- Screen a Disc b Up b V3V7 V9V13 V15V19 V2126 c, d, e c, d, e c, d, e c, d, e V2 (every (every (every (every Visit (V) V1 (Day 1) 2 wk) V8 2 wk) V14 2 wk) V20 2 wk) V27 e V28 V29 Week  4 to  1 0 210 12 1422 24 2634 36 3848 50 52 62 Protocol ( 7 (Window) Reference ( 3 days) days) SGRQ-C 8.3.3.1 x x x x x A7–2 mMRC 8.3.3.2 x x x x A7–4 EQ-5D-5L 8.3.3.4 x x x x x eDiary h 8.3.3.3 x x x x x (EXACT, E-RS:COPD) A7–3 Single ECG 8.4.3 x x x x x x x Pre-bronchodilator 8.3.2.1 x x spirometry i Post-bronchodilator 8.3.2.2 x x x x x x spirometry i Concomitant medications 6.8 x x x x x x x x x x x x Astegolimab—F. Hoffmann-La Roche Ltd 17/Protocol GB44332, Version 4 Table 1: Schedule of Activities (cont.) Treatment Period EOS/ Treat Safety Compl/ Follow- Screen a Disc b Up b V3V7 V9V13 V15V19 V2126 c, d, e c, d, e c, d, e c, d, e V2 (every (every (every (every Visit (V) V1 (Day 1) 2 wk) V8 2 wk) V14 2 wk) V20 2 wk) V27 e V28 V29 Week  4 to  1 0 210 12 1422 24 2634 36 3848 50 52 62 Protocol ( 7 (Window) Reference ( 3 days) days) Adverse events 8.5 Appendix 3 x x x x x x x x x x x Appendix 4 COPD exacerbation 8.3.1 x x x x x x x x x x x assessment Adherence with background  x x x x x x x x x x x COPD treatment Chemistry Appendix 2 Weeks 4 x x x x x x x and 8 only Hematology Appendix 2 Weeks 4 x x x x x x x and 8 only HIV and/or TB testing 5.2 xj Urinalysis Appendix 2 x Pregnancy Test (WOCBP) k 8.4.5 x x x x x x x x x x x x Appendix 2 Astegolimab—F. Hoffmann-La Roche Ltd 18/Protocol GB44332, Version 4 Table 1: Schedule of Activities (cont.) Treatment Period EOS/ Treat Safety Compl/ Follow- Screen a Disc b Up b V3V7 V9V13 V15V19 V2126 c, d, e c, d, e c, d, e c, d, e V2 (every (every (every (every Visit (V) V1 (Day 1) 2 wk) V8 2 wk) V14 2 wk) V20 2 wk) V27 e V28 V29 Week  4 to  1 0 210 12 1422 24 2634 36 3848 50 52 62 Protocol ( 7 (Window) Reference ( 3 days) days) Serum PK sample l 8.6 Week 4 x x x x x x only Serum ADA sample 8.10 Week 4 x x x x x x only Serum samples for 8.9 Week 4 x x x x x x biomarkers l only Plasma samples for 8.9 Week 4 x x x x x x biomarkers only Blood sample for specified 8.9 DNA SNP analysis x (mandatory) Blood sample for RBR 8.11.2 x (optional) m Study drug administration n 6.1 x x x x x x x x x Astegolimab—F. Hoffmann-La Roche Ltd 19/Protocol GB44332, Version 4 Table 1: Schedule of Activities (cont.) Treatment Period EOS/ Treat Safety Compl/ Follow- Screen a Disc b Up b V3V7 V9V13 V15V19 V2126 c, d, e c, d, e c, d, e c, d, e V2 (every (every (every (every Visit (V) V1 (Day 1) 2 wk) V8 2 wk) V14 2 wk) V20 2 wk) V27 e V28 V29 Week  4 to  1 0 210 12 1422 24 2634 36 3848 50 52 62 Protocol ( 7 (Window) Reference ( 3 days) days) Physical Activity Monitoring (For consenting participants at participating sites only) o Physical activity measure 8.11.1 x x x x Physical activity monitor 8.11.1 x Week 10 Week 22 x dispensation ADA  anti-drug antibody; Compl  completion; COPD  chronic obstructive pulmonary disease; CT  computed tomography; Disc  discontinuation; eCRF  electronic Case Report Form; eDiary  electronic diary; EOS  end of study; E-RS:COPD  Evaluating Respiratory Symptoms in COPD; EXACT  EXAcerbations of Chronic Pulmonary Disease Tool; FEV  forced expiratory volume; FVC  forced vital capacity; mmRC  modified Medical Research Council Dyspnea Scale; OLE  open-label extension; PK  pharmacokinetic; PRO  participant-reported outcome; RBR  Research Biosample Repository; Screen  screening; SGRQ-C  St. George’s Respiratory Questionnaire-COPD; SNP  single nucleotide polymorphism; TB  tuberculosis; V  visit; wks  weeks; WOCBP  women of childbearing potential. Notes: Visit windows for V3V29 should be calculated in relation to the first dosing day (Day 1, V2 [Week 0]). On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. a A minimum screening period of 7 days prior to randomization is required. See Section 5.4. b See Section 4.1.2. c Unless otherwise specified, visits and assessments should occur every 2 weeks on even-numbered weeks (e.g., Week 4 [V4], Week 6 [V5], Week 8 [V6], etc.). Astegolimab—F. Hoffmann-La Roche Ltd 20/Protocol GB44332, Version 4 Table 1: Schedule of Activities (cont.) d For participants at participating sites who have provided written informed consent to participate in mobile nursing visits, this visit (with the exception of Week 4 [V4] and Week 8 [V6]) may be performed by a trained nursing professional at the participant's home or another suitable location. e For participants who discontinue study treatment prematurely, these visits (with the exception of Week 4 [V4] and Week 8 [V6]) may be performed via telephone to collect changes in health status and concomitant medications, if any. If the visit is conducted via telephone, vital signs do not need to be collected. f For participants who are current smokers. g Chest X-ray must be performed unless results are available for chest X-ray or chest CT scan performed within 6 months of screening. h eDiary training and/or distribution must be performed prior to the specified timepoints, to allow completion of the diary for 7 days. i Except for Visit 1, participants must withhold inhaled bronchodilator use within the specified window. Participants can perform spirometry at the screening visit even if the morning inhalers were used that morning. j HIV and/or TB testing conducted where required by local regulations. HIV and/or TB testing does not need to be repeated if performed within 3 months prior to screening. k All women of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed locally at subsequent visits prior to study drug administration. If a urine pregnancy test result is positive, it must be reported immediately, and study drug will not be administered that day. The positive urine pregnancy test result must be confirmed by a serum pregnancy test. See Section 8.5.5 for reporting requirements for a participant with a positive pregnancy test. l For approximately the first 60 patients enrolled in mainland China, additional PK and biomarker assessments are required as per Table 2. m The RBR sample is optional and should only be obtained from participants who sign the separate RBR ICF. Not applicable for a site that has not been granted approval for RBR sampling. n A minimum 8-day interval between study drug administrations is required (see Section 6.1 for details). o The physical activity monitor will be worn for a minimum of 1 week and up to 2 weeks during the monitoring period. Training and instructions on dispensing the device, information for participants, and data collection will be provided. Astegolimab—F. Hoffmann-La Roche Ltd 21/Protocol GB44332, Version 4 Table 2 Schedule of Intensive Pharmacokinetic and Pharmacodynamic Biomarker Sampling for Patients in Mainland China Visit (V) a Timepoint b Sample Type 2-a 3 days after V2 ( 1 day)  Serum PK and biomarker sample 2-b 7 days after V2 ( 1 day)  Serum PK and biomarker sample 2-c 10 days after V2 ( 1 day)  Serum PK and biomarker sample 26 V26 (see Table 1)  Serum PK and biomarker sample 26-a 7 days after V26 ( 1 day)  Serum PK and biomarker sample 28-a c 28 days after V28 ( 14 days)  Serum PK and biomarker sample COPD  chronic obstructive pulmonary disease; OLE  open-label extension; PK  pharmacokinetic; V  visit. Notes: Intensive PK and biomarker samples will be collected in early enrolled patients in mainland China, targeting approximately 60 patients. Once sufficient numbers of participants are enrolled, subsequent participants in mainland China will follow the PK schedule as specified in Table 1. Intensive PK samples are in addition to the standard PK samples specified in Table 1. PK and biomarker samples are to be collected prior to dosing, when applicable, and at approximately the same time each day. For patients at participating sites who have provided written informed consent to participate in mobile nursing visits, visits may be performed by a trained nursing professional at the patient's home or another suitable location. a PK and biomarker sampling visits that are between regular study visits are given a letter suffix. These timepoint designations are not reflected in the schedule of activities in Table 1. b Visit windows should be calculated in relation to the first dosing day (Day 1 of Week 0 [V2]). c For patients enrolling in OLE Study GB43374, Visit 28-a should not be conducted. Astegolimab—F. Hoffmann-La Roche Ltd 22/Protocol GB44332, Version 4 2. BACKGROUND 2.1 BACKGROUND ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD) was the third leading cause of death globally in 2019, causing approximately 6% of the world’s total deaths (World Health Organization [WHO] Factsheet 2020). The WHO estimates that 65 million people currently have moderate to severe COPD (WHO 2021). Development of COPD is attributed to long-term exposure to inhaled cigarette smoke or noxious particles such as smoke from biomass fuels. Although cigarette smoking has traditionally been the single most important risk factor for COPD, there is consistent evidence that non-smokers can also develop COPD (Lamprecht et al. 2011). The risk of COPD increases with age and COPD usually occurs in patients aged 40 years or older; the prevalence is greater among men than women (Landis et al. 2014). Chronic obstructive pulmonary disease is characterized by persistent respiratory symptoms and airflow limitation caused by airway and/or alveolar abnormalities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2021). The chronic airflow limitation is caused by a mixture of small airways diseases and parenchymal destruction (emphysema), which may be associated with narrowing of small airways and decreased lung elastic recoil (GOLD 2021). Clinically, the characteristic symptoms of COPD can include dyspnea, cough, and sputum production. Chronic obstructive pulmonary disease is a heterogeneous and progressive disease, with progression being strongly associated with airway-wall thickening and airflow limitation. The GOLD has introduced a classification of airflow limitation severity based on measurements of the forced expiratory volume in 1 second (FEV1) and by the ratio of FEV1 to the forced vital capacity (FVC). This assessment has been widely accepted as a key marker for disease progression (Hogg et al. 2004; Celli et al. 2008; GOLD 2021). Another key marker of disease activity is COPD exacerbation, defined as an acute worsening of respiratory symptoms that result in additional therapy (GOLD 2021). While there exists some variability in the definition of exacerbation severity, severity is often classified as mild (increase in respiratory symptoms controllable by an increase of usual medication), moderate (requiring treatment with systemic corticosteroids and/or antibiotics), or severe (requiring hospitalization) (Solem et al. 2013; GOLD 2021). An increasing frequency of COPD exacerbations is associated with a decline in lung function, reduced quality of life, and death (Miravitlles et al. 2004; Halpin et al. 2012). Although the frequency of exacerbations increases with the severity of disease (Halpin et al. 2012), exacerbations affect individuals even with moderate COPD. Prior history of exacerbation, rather than airflow limitation, is the single best predictor for risk of future exacerbations (Hurst et al. 2010). Chronic obstructive pulmonary disease exacerbations are not only a major cause of morbidity and mortality, but also account for the greatest proportion of total COPD healthcare costs (AbuDagga et al. 2013; Solem et al. 2013). Astegolimab—F. Hoffmann-La Roche Ltd 23/Protocol GB44332, Version 4 Current treatment options for COPD include non-pharmacologic and pharmacologic measures. Smoking cessation is a vital intervention for patients who continue to smoke and has the greatest potential impact on the natural course of COPD. Pulmonary rehabilitation similarly represents an important intervention for people with COPD, yet application remains low due to a variety of factors, including transportation, cost, and access. Pharmacologic treatment options include inhaled bronchodilators (-agonists and anticholinergics), inhaled and systemic corticosteroids, azithromycin, and phosphodiesterase inhibitors (GOLD 2021). Despite these treatment options, slowing of disease progression and prevention of COPD exacerbations are still unmet needs (Patalano et al. 2014; Diette et al. 2015). Alternative and more effective therapeutic approaches that will relieve symptoms in patients and alter the disease trajectory are urgently needed (Cazzola et al. 2016). 2.2 BACKGROUND ON ASTEGOLIMAB Astegolimab (also known as RO7187807 or MSTT1041A) is a fully human, IgG2 monoclonal antibody that binds with high affinity to the interleukin (IL)-33 (IL-33) receptor, ST2, thereby blocking the signaling of IL-33, an inflammatory cytokine of the IL-1 family and member of the “alarmin” class of molecules. Astegolimab has subnanomolar affinity and potency, is active in blood, and lacks agonistic activity. Refer to the Astegolimab Investigator's Brochure for details on nonclinical and clinical studies. 2.3 BACKGROUND ON INTERLEUKIN-33 AND ST2 Interleukin-33 is considered an “alarmin” or a damage-associated molecular pattern molecule that is constitutively expressed on epithelial cells and released upon cell injury or stress from exposure to exogenous stimuli such as allergens, toxins, or infections. Interleukin-33 is a member of the IL-1 family of cytokines (Sims and Smith 2010) with potential as a target in the treatment of asthma, COPD, and atopic dermatitis. High levels of IL-33 are found in stromal cells, particularly at barrier surfaces such as the lung and gastrointestinal tract. Within the lung, IL-33 is detected in multiple cell types, including epithelial cells, endothelial cells, and fibroblasts (Liew et al. 2016). Interleukin-33 bioavailability is tightly regulated, and under homeostatic conditions, this protein is sequestered in the nuclei of these cells. Cellular damage caused by injury, mechanical stress, or death leads to the release of bioactive IL-33 into circulation, where it initiates and propagates innate and adaptive immune responses. The receptor for IL-33, ST2, is expressed on multiple cell types implicated in pulmonary inflammation and disease, including mast cells, eosinophils, basophils, innate lymphoid cells, T lymphocytes, macrophages, and endothelial cells. Interleukin-33 is also linked to the function of type-2 innate lymphocytes that accumulate in the lung and promote T helper type 2 (Th2) cell inflammation, even in the absence of Astegolimab—F. Hoffmann-La Roche Ltd 24/Protocol GB44332, Version 4 antigen stimulation (Scanlon and McKenzie 2012). In some settings, IL-33 will also promote type 1 responses, such as interferon (IFN)- production from natural killer (NK) cells or NK T cells. As such, IL-33 may be involved in multiple inflammatory pathways implicated in COPD. Interleukin-33 activates these various immune cells through its receptor ST2, also known as IL-1 receptor-like 1 (IL-1RL1) (Nabe 2014). The binding of IL-33 to ST2 promotes association with the shared IL-1 family subunit, IL-1RAcP, to form the active IL-33 receptor. Intracellular signaling induced by IL-33 promotes expression of inflammatory genes. A secreted soluble form of ST2 (sST2) arises from alternative splicing, is elevated in settings of inflammation, and acts as a decoy to bind and inhibit released IL-33 (Hayakawa et al. 2007). Excess extracellular IL-33 is highly inflammatory in pulmonary tissue and is capable of triggering local inflammation that can lead to airway hyper responsiveness (AHR) and mucus production, important components of exacerbations. Airway administration of IL-33 in mice leads to an infiltration of inflammatory cells in bronchoalveolar lavage fluid, including eosinophils and neutrophils, as well as elevated IL-5, IL-13, eotaxin, and thymus and activation-regulated chemokine (also known as TARC/CCL17) (Louten et al. 2011). Given the diverse nature of signals that lead to IL-33 release and the wide range of target cells, IL-33 is implicated in a number of pathological pathways. Interleukin‑33 release can trigger acute exacerbations and/or disease progression in asthma, COPD, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. Interleukin-33 activity is elevated following viral infections, and inhibition of this pathway reduces virus-induced exacerbations in rodent models of asthma and COPD (Werder et al. 2018; Ravanetti et al. 2019). Mice deficient in ST2 or IL-33 exposed to cigarette smoke have decreased inflammatory responses in response to subsequent respiratory viral infections, without compromising anti-viral host defense (Kearley et al. 2015). The absence of the IL‑33 pathway significantly reduced viral-induced leukocyte migration into the lung, inflammatory cytokine expression, and subsequent pulmonary pathology. For these reasons, inhibiting ST2 is hypothesized to confer clinical benefit to patients with COPD by limiting excessive inflammatory sequelae. 2.3.1 Summary of Nonclinical Studies The toxicology program was designed to support IV and SC administration of astegolimab in clinical studies. Astegolimab has been shown to have a favorable overall nonclinical safety profile. In 28-day and 6-month repeat-dose toxicity studies, no adverse effects were observed in cynomolgus monkeys following biweekly IV or SC administration at doses up to 300 mg/kg (the highest dose tested). There were no adverse findings at the injection sites, as evidenced by macroscopic and microscopic analysis following SC administration at doses up to 300 mg/kg. In an ex vivo human Astegolimab—F. Hoffmann-La Roche Ltd 25/Protocol GB44332, Version 4 tissue cross-reactivity study, biotin-labeled astegolimab staining was not observed in any human tissues evaluated by immunohistochemistry. Refer to the Astegolimab Investigator's Brochure for details on nonclinical studies. 2.3.2 Summary of Clinical Studies As of the data cutoff of 10 February 2023, 653 patients with asthma (Study GB39242), 726 patients with COPD (645/726 from the ongoing/blinded Studies GB43311 and GB44332), 1 patient with chronic rhinosinusitis with nasal polyps (Amgen Study 20110236), 410 patients with severe coronavirus disease 2019 (COVID-19) pneumonia (Study GA42469), 65 patients with atopic dermatitis (Study GS40965), and 145 healthy subjects (Amgen Studies 20110235, 20110236, and 20130177) have been enrolled into astegolimab clinical studies. A total of approximately 583 patients and 109 healthy subjects have been exposed to at least 1 dose of astegolimab in the completed studies. Refer to the Astegolimab Investigator's Brochure for details on clinical studies. 2.4 STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT Chronic obstructive pulmonary disease is recognized as a progressive, heterogeneous disease. Chronic obstructive pulmonary disease exacerbations represent the largest burden in terms of healthcare utilization, patient morbidity, and risk of mortality (Anzueto 2010). Therefore, interventions that target the reduction of COPD exacerbations are expected to have the most benefit for patients with COPD. Despite a large unmet need, there are currently limited options for pharmacotherapy specifically targeted at reducing exacerbations. Chronic obstructive pulmonary disease exacerbations can be attributed to a variety of underlying factors, including bacterial, viral, eosinophilic, or pollution-related. As detailed in Section 2.2, excess extracellular IL-33 is highly inflammatory in pulmonary tissue and is capable of triggering local inflammation that can lead to AHR and mucus production, important components of exacerbations. The role of the IL-33/ST2 axis in COPD remains uncertain. However, a mouse model demonstrated increased IL-33 expression following viral infection, and lung tissues from patients with very severe COPD had significant increases in both IL33 mRNA and IL-33 protein levels when compared with lung tissue from patients without COPD, thus suggesting IL-33 may play a role in the consequent inflammatory response and possible susceptibility to secondary viral infection in obstructive lung disease (Byers et al. 2013). Therefore, targeting the IL-33/ST2 axis might reduce COPD exacerbations. Astegolimab, an anti-ST2 monoclonal antibody that acts as a pure, competitive antagonist to block IL-33 signaling, is hypothesized to have the potential to treat COPD by reducing exacerbations without inhibiting the development of protective adaptive immunity and viral clearance (Kearley et al. 2015). Nonclinical and clinical studies have demonstrated that astegolimab has a well-tolerated safety profile, and clinical studies of Astegolimab—F. Hoffmann-La Roche Ltd 26/Protocol GB44332, Version 4 astegolimab have demonstrated reductions in asthma and COPD exacerbations. Therefore, astegolimab has potential for efficacy to treat COPD, supporting further clinical development. To date, there are no identified risks associated with astegolimab. Although not observed in the 1 ongoing or 6 completed clinical trials to date, as with all protein therapies, there is the possibility that administration of astegolimab may lead to the development of anti-astegolimab antibodies, which could lead to adverse events and/or decreased exposure. To date, the immunogenicity rates observed with astegolimab have ranged from 3%27% (in the 5 completed clinical studies in which anti-drug antibody [ADA] data is available), and there has been no correlation with clinical findings or adverse events. Monoclonal antibodies such as astegolimab carry a potential risk of hypersensitivity reactions and anaphylaxis or hypersensitivity-like reactions. Nevertheless, in completed astegolimab studies, rates of hypersensitivity and anaphylaxis or hypersensitivity-like reactions attributed to study drug have been much less than 1%, with only 1 patient in an astegolimab arm having experienced hypersensitivity across all studies to date. The intended mechanism of action of astegolimab suggests inhibitory effects on immune responses mediated by Th2 cells, leading to the possibility of a decrease in the protective response to infection, particularly helminthic infections. Despite this possibility, no imbalance in infections, including helminthic infections, has been seen to date across the clinical trials. Finally, in mouse models of cardiovascular disease, a protective role for IL-33/ST2 has been described; mice genetically deficient in ST2 had more left ventricular hypertrophy, more fibrosis, and impaired survival relative to their wild-type littermates in an experimentally induced acute left ventricular pressure overload model. However, the translatability of those findings to humans remains unknown, and in addition, studies with conflicting data exist (Demyanets et al. 2011; Abston et al. 2012; Martin et al. 2015). Safety pharmacology studies in cynomolgus monkeys found no biologically significant cardiovascular effects of astegolimab. In the completed Phase II studies with astegolimab, none of the reported potential major adverse cardiovascular events (MACE) were considered related to study drug. No cases of potential MACE were reported in the three completed Phase I astegolimab studies. In the setting of the COVID-19 pandemic, patients with comorbidities, including those with COPD, are a more vulnerable population. Having COPD is known to increase the risk of severe illness from COVID-19. Astegolimab was evaluated in Study GA42469 in patients with severe COVID-19 pneumonia and was not found to adversely impact the severity of COVID-19. Based on the mechanism of action of astegolimab and preliminary analysis of Study GA42469, it is anticipated that astegolimab will not increase the risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or facilitate a worse outcome in participants with COVID-19. The pattern of adverse events observed with astegolimab in Study GA42469 is consistent with Astegolimab—F. Hoffmann-La Roche Ltd 27/Protocol GB44332, Version 4 patterns expected in a population of patients with severe COVID-19 pneumonia. Therefore, astegolimab is not expected to increase the risk from SARS-CoV-2 in participants with COPD. Nonclinical and clinical studies have demonstrated that astegolimab has a well-tolerated safety profile and strong rationale supporting its potential benefit in patients with COPD who have frequent exacerbations, supporting further clinical development in this indication. The potential risks for astegolimab will be mitigated by safety monitoring and enrollment criteria that limit participation of patients with a history of unstable cardiac disease, recent myocardial ischemia, or severe heart failure. Detailed information on astegolimab is provided in the Astegolimab Investigator's Brochure. See Appendix 4 for information on anticipated risks for astegolimab and risk mitigation measures, including guidelines for managing adverse events associated with astegolimab. More detailed information about the known and expected benefits and risks and reasonably expected adverse events of astegolimab may be found in the Astegolimab Investigator’s Brochure. 3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS This study will evaluate the efficacy and safety astegolimab compared with placebo in participants with COPD who are former or current smokers and have a history of frequent exacerbations. Table 3 presents the primary and secondary objectives for the study expressed using the estimand framework in accordance with the International Council for Harmonisation (ICH) E9(R1) statistical principles for clinical trials (U.S. Food and Drug Administration [FDA] 2020). Table 4 presents the remaining objectives and corresponding endpoints. Table 3 Primary and Secondary Objectives and Corresponding Estimands Primary Objective Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria (Sections 5.1 and 5.2), and received at least one dose of study drug Astegolimab—F. Hoffmann-La Roche Ltd 28/Protocol GB44332, Version 4 Table 3 Primary and Secondary Objectives and Corresponding Estimands (cont.) Primary Objective Estimand Definition  Endpoint: annualized rate of moderate and severe COPD exacerbations over the 52-week treatment period – A moderate COPD exacerbation is defined as new or increased COPD symptoms (e.g., dyspnea, sputum volume, and sputum purulence) that lead to treatment (duration  3 days) with systemic corticosteroids (oral, IV, or IM) at a dose of  10 mg/day prednisolone equivalent and/or antibiotics – A severe COPD exacerbation is defined as new or increased COPD symptoms that lead to hospitalization (duration  24 hours) or lead to death  Treatment: – Experimental: astegolimab 476 mg SC Q2W Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: RR for annualized rate of moderate and severe COPD exacerbations Secondary Objectives Estimand Definition  To evaluate the efficacy of Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria (Sections 5.1 and 5.2), and received at least one dose of study drug  Endpoint: time to first moderate or severe COPD exacerbation during the 52-week treatment period  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: HR for time to first COPD exacerbation Astegolimab—F. Hoffmann-La Roche Ltd 29/Protocol GB44332, Version 4 Table 3 Primary and Secondary Objectives and Corresponding Estimands (cont.) Secondary Objectives Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria (Sections 5.1 and 5.2), and received at least one dose of study drug  Endpoint: – Absolute change from baseline in HRQoL at Week 52, as assessed through the SGRQ-C total score – Absolute change from baseline in post-bronchodilator FEV1 (liters) at Week 52 – Absolute change from baseline in E-RS:COPD total score at Week 52  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: difference in mean absolute change at Week 52  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria (Sections 5.1 and 5.2), and received at least one dose of study drug  Endpoint: proportion of participants with improvement in HRQoL, defined as a decrease from baseline of  4 points in SGRQ-C total score, at Week 52  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: difference in proportion Astegolimab—F. Hoffmann-La Roche Ltd 30/Protocol GB44332, Version 4 Table 3 Primary and Secondary Objectives and Corresponding Estimands (cont.) Secondary Objectives Estimand Definition  To evaluate the efficacy of  Population: participants with COPD who are former or astegolimab compared with current smokers and have a history of frequent placebo exacerbations, as defined by the inclusion and exclusion criteria (Sections 5.1 and 5.2), and received at least one dose of study drug  Endpoint: annualized rate of severe COPD exacerbations over the 52-week treatment period  Treatment: – Experimental: astegolimab 476 mg SC Q2W – Experimental: astegolimab 476 mg SC Q4W – Control: placebo SC Q2W  Intercurrent events and handling strategies: – Early discontinuation from study treatment: treatment policy strategy  Population-level summary: RR for annualized rate of severe COPD exacerbations COPD  chronic obstructive pulmonary disease; E-RS:COPD  Evaluating Respiratory Symptoms in COPD; FEV1  forced expiratory volume in 1 second; HR  hazard ratio; HRQoL  health-related quality of life; IM  intramuscular; mITT  modified intent-to-treat; Q2W  every 2 weeks; Q4W  every 4 weeks; RR  rate ratio; SGRQ-C  St. George’s Respiratory Questionnaire-COPD; Table 4 Other Secondary and Exploratory Objectives and Endpoints Secondary Objectives Corresponding Endpoints To evaluate the safety of  Incidence and severity of all TEAEs, including SAEs, astegolimab compared with placebo AESIs, and TEAEs leading to death or discontinuation TEAEs severity will be determined according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (HHS 2017) (hereafter referred to as the DAIDS Toxicity Grading Scale), with slight modifications for clarity and for alignment with internal practices (see Appendix 8)  Change from baseline in selected vital signs  Change from baseline in selected clinical laboratory test results and ECGs  To characterize the astegolimab PK  Serum concentration of astegolimab at specified profile timepoints  To evaluate the immune response  Prevalence of ADAs at baseline and incidence of to astegolimab ADAs during the study Astegolimab—F. Hoffmann-La Roche Ltd 31/Protocol GB44332, Version 4 Table 4 Other Secondary and Exploratory Objectives and Endpoints (cont.) Exploratory Objectives Corresponding Endpoints  To evaluate the efficacy of  Change in COPD symptoms as measured by the astegolimab compared with placebo E-RS:COPD total score at Week 24  Change in E-RS:COPD individual domain scores (breathlessness, cough and sputum, and chest symptoms) from baseline at Week 24 and 52  Change in EXACT individual domain scores (tired or weak, sleep disturbance, and scared or worried) from baseline at Week 24 and 52  Proportion of participants with HRQoL improvement, defined as a decrease from baseline of  4 points in SGRQ-C total score, at Week 12 and Week 24  Proportion of participants with symptom improvement, defined as a decrease of  2 points from baseline in E-RS:COPD total score, at Week 24 and Week 52  Absolute change from baseline in post-bronchodilator FEV1 (liters) at Weeks 12, 24, and 36  Annualized rate of moderate COPD exacerbations over the 52-week treatment period  Duration of hospital stay for severe COPD exacerbations  Proportion of severe COPD exacerbations requiring hospital readmission within 30 days  Absolute change from baseline in daily step count at Weeks 12, 24, and 52  Absolute change from baseline in time in moderate and vigorous physical activity at Weeks 12, 24, and 52  To evaluate potential relationships  Relationship between serum concentration or PK between drug exposure and the parameters for astegolimab and efficacy endpoints efficacy and safety of astegolimab  Relationship between serum concentration or PK parameters for astegolimab and safety endpoints  To evaluate potential relationships  Relationship between selected covariates and serum between selected covariates and concentration or PK parameters for astegolimab exposure to astegolimab  To evaluate potential effects of  Relationship between ADA status and efficacy, safety, ADAs PK or biomarker endpoints Astegolimab—F. Hoffmann-La Roche Ltd 32/Protocol GB44332, Version 4 Table 4 Other Secondary and Exploratory Objectives and Endpoints (cont.) Exploratory Objectives Corresponding Endpoints  To identify and/or evaluate  Relationship between biomarkers in blood, plasma, biomarkers that are predictive of and serum (listed in Section 8.9) and efficacy, safety, response to astegolimab PK, immunogenicity, or other biomarker endpoints (i.e., predictive biomarkers), are early surrogates of efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), can provide evidence of astegolimab activity (i.e., PD biomarkers), or can increase the knowledge and understanding of disease biology and drug safety or pharmacokinetics  To evaluate health status utility  Change from baseline in EuroQol EQ-5D-5L scores of participants treated with index-based and VAS scores at Week 52 astegolimab compared with placebo ADA  anti-drug antibody; AESI  adverse event of special interest; COPD  chronic obstructive pulmonary disease; DAIDS  Division of AIDS; E-RS:COPD  Evaluating Respiratory Symptoms in COPD; EXACT  EXAcerbations of Chronic Pulmonary Disease Tool; FEV1  forced expiratory volume in 1 second; HHS  Health and Human Services; HRQoL  health-related quality of life; PD  pharmacodynamics; PK  pharmacokinetic; SAE  serious adverse event; SGRQ-C  St. George’s Respiratory Questionnaire-COPD; TEAE  treatment-emergent adverse event; VAS  Visual Analog Scale. 4. STUDY DESIGN 4.1 OVERVIEW OF STUDY DESIGN This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of astegolimab in combination with standard of care (SOC; defined in Section 6.1.1) compared with placebo in combination with SOC, in participants with COPD who are former or current smokers and have a history of frequent exacerbations. Approximately 1290 participants with COPD are expected to be enrolled globally. Following a screening period of at least 7 days and to up to 4 weeks, participants will be randomized in a 1:1:1 ratio to 1 of 3 treatment arms to receive blinded treatment with either astegolimab or placebo. Randomization will be stratified by smoking status at screening (former smoker vs. current smoker) and region. Astegolimab—F. Hoffmann-La Roche Ltd 33/Protocol GB44332, Version 4 The first dose of study drug (astegolimab or placebo) will be administered on Day 1; treatment will continue through Week 50, followed by a 12-week safety follow-up period. The treatment regimens for each arm are as follows:  Astegolimab 476 mg SC every 2 weeks (Q2W)  Astegolimab 476 mg SC every 4 weeks (Q4W) To ensure that all study participants undergo the same visit schedule, participants randomized to the Q4W dosing arm will alternate between injections of astegolimab and placebo Q2W (beginning with astegolimab on Day 1), thus receiving astegolimab Q4W.  Placebo SC Q2W Participants will return to the clinic Q2W through the treatment completion visit at Week 52. The primary endpoint analyses will be conducted using the 52-week treatment period data for all participants. If a separate open-label extension (OLE) study, Study GB43374, is open and available in their respective country, all participants enrolled in this study and who have completed the Week 52 visit will be given the option to either participate in OLE Study GB43374, if eligible (see Section 4.1.1), or enter the safety follow-up period (see Section 4.1.2). If OLE Study GB43374 is not opened, all participants who complete the Week 52 visit, including those participants receiving continued blinded treatment after Week 52, will enter the safety follow-up period. All participants will undergo a safety follow-up visit 12 weeks after their final dose of study drug (regardless of the length of treatment received). Participants who do not meet the criteria for participation in this study (screen failure) may qualify for 2 re-screening opportunities (for a total of 3 screenings per participant) at the investigator's discretion (see Section 5.4). The investigator will record reasons for screen failure in the screening log. A study schema is provided in Section 1.2 (see Figure 1). A schedule of activities is provided in Section 1.3 (see Table 1). 4.1.1 Open-Label Extension Study GB43374 A separate OLE study for Study GB43311 will be opened subject to approval by local Institutional Review Boards (IRBs) or Ethics Committees (ECs) and relevant health authorities. Participants who complete the study treatment period through the Week 52 treatment completion visit will be given the option to enter OLE Study GB43374 and receive treatment with open-label astegolimab, if eligible and provided that the OLE Study GB43374 is open in their respective country. Participants who are ineligible for or choose not to enroll in OLE Study GB43374 will enter the safety follow-up period in this study (see Section 4.1.2). Astegolimab—F. Hoffmann-La Roche Ltd 34/Protocol GB44332, Version 4 Participants who discontinue study drug prematurely will not be eligible to participate in OLE Study GB43374 and will enter the safety follow-up period (see Section 4.1.2). 4.1.2 Safety Follow-Up Period and Assessments after Study Treatment Discontinuation Participants who complete the study treatment period through the Week 52 treatment completion visit and do not enter OLE Study GB43374 will enter the safety follow-up period and undergo end of study assessments 12 weeks after the final dose of study drug. Participants who discontinue study drug prematurely during the 52-week treatment period should be asked to continue with all scheduled study assessments, with the exception of study drug administration and optional assessments (if applicable), through the end of the study. For these participants, telephone visits may replace certain in-clinic visits. Specific details are outlined in Table 1. Participants who discontinue study drug prematurely during the 52-week treatment period and are unwilling to complete the study assessments should return to the clinic for a treatment discontinuation visit within 14 ( 7) days of the event and will then enter the safety follow-up period, with end of study assessments 12 weeks after the final dose of study drug. Participants who are unwilling to complete the safety follow-up period should return to the clinic for a treatment discontinuation visit as soon as possible and no later than 30 days after their final dose (see Table 1 for additional details). 4.1.3 Independent Data Monitoring Committee An independent Data Monitoring Committee (iDMC) will monitor safety data on an ongoing basis. Members of the iDMC will be external to the Sponsor and will follow a charter that outlines the iDMC roles and responsibilities. The iDMC will meet at regular intervals to review unblinded safety data prepared by an external independent Data Coordinating Center (iDCC). In addition, ad hoc reviews may be requested by the iDMC or the Sponsor at any time to address potential safety concerns. Safety monitoring reviews conducted by the iDMC will include unblinded evaluation of all adverse events, serious adverse events, adverse events of special interest, major protocol deviations, ECGs, and relevant laboratory data. The iDMC may recommend stopping the study early for safety reasons; however, the iDMC may not recommend stopping the study early for reasons of positive efficacy. Any outcomes of these reviews that affect study conduct will be communicated in a timely manner to the investigators for notification of their respective IRBs/ECs. Astegolimab—F. Hoffmann-La Roche Ltd 35/Protocol GB44332, Version 4 Full details of the roles, responsibilities, membership, scope of activities, meeting schedule, and communication plan will be provided in the iDMC Charter. 4.2 RATIONALE FOR STUDY DESIGN 4.2.1 Rationale for Study Population Frequent exacerbations significantly impact symptoms, health-related quality of life, physical function, disease progression, healthcare utilization, and mortality in COPD (Anzueto 2010). Patients with COPD who have 2 or more moderate to severe exacerbations within a 12-month period are at the greatest continued risk of future exacerbations (Han 2017). Therefore, it is in this group of patients that the most benefit is expected from a reduction in exacerbations. History of prior exacerbations is a stronger predictor of future exacerbation risk than severity of airflow obstruction, inflammatory markers, and functional or clinical markers (Hurst 2010). While the frequency of exacerbations increases with severity of airflow obstruction, a significant proportion of patients with moderate airflow obstruction experience a high frequency of exacerbations (Decramer 2009). This study will enroll participants with moderate to very severe airflow obstruction who have a history of frequent exacerbations (defined as 2 or more exacerbations in the prior 12 months). 4.2.2 Rationale for Biomarker Assessments Chronic obstructive pulmonary disease is a heterogeneous disease and IL-33 and sST2 expression has been shown to vary among patients. Therefore, all participants may not be equally likely to benefit from treatment with astegolimab. Biomarker assessments, before and at various timepoints after treatment, will be used to provide evidence of the biologic activity of astegolimab in participants, identify biomarkers that may be predictive of response to astegolimab, define pharmacokinetic (PK) and/or pharmacodynamic (PD) relationships, advance the understanding of the mechanism of action of astegolimab in patients, support selection of a recommended dose regimen, and increase the knowledge and understating of disease biology. Exploratory biomarker analysis may include, but will not be limited to, analysis of eosinophils, IL-33 pathway markers (e.g., sST2), and inflammatory mediators (e.g., C-reactive protein). A blood s