Clinical trial NCT04353661
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Genentech, Inc.
Start date: 2021-11-16; Completion date: 2023-06-29
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will test whether daily use of azithromycin will reduce the rate of exacerbations and improve lung ventilation and perfusion assessed by XE-MRI. The sensitivity of XE-MRI to detect COPD progression will be compared with standard clinical assessment measures including standard lung function tests, 6 minute walk test, and patient reported quality of life.

Detailed description:

Arms: arm 1: Participants will receive azithromycin and SOC theraphy for 52 weeks. arm 2: Participants will receive SOC theraphy for 52 weeks. arm 3: Participants will receive SOC theraphy for 52 weeks.
Interventions: intervention 1: Azithromycin intervention 2: HP xenon (¹²⁹XE)
Intervention descriptions: intervention 1: Azithromycin will be administered orally. intervention 2: HP xenon (¹²⁹XE) will be administered at specified timepoints and the total dose bag volume should target 20% of the patient's forced vital capacity followed by a breath hold of up to 15 seconds

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
¹²⁹XE MRI Assessment Of Disease Progression In Patients With 
Chronic Obstructive Pulmonary Disease Treated With Standard-of-
Care Medications With Or Without Daily Open-Label Azithromycin 
Treatment To Prevent Acute Exacerbation 
NCT Number: 
NCT04353661 
Document Date: 
Protocol Version 5: 29-June-2022 
 
 


CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
129Xe MRIGenentech, Inc. 
Protocol GE42063, Version 5 
PROTOCOL 
TITLE: 
129XE MRI ASSESSMENT OF DISEASE 
PROGRESSION IN PATIENTS WITH CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE TREATED 
WITH STANDARD-OF-CARE MEDICATIONS WITH 
OR WITHOUT DAILY OPEN-LABEL 
AZITHROMYCIN TREATMENT TO PREVENT 
ACUTE EXACERBATION 
PROTOCOL NUMBER: GE42063 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-000852-36 
IND NUMBER 
148058 
NCT NUMBER: 
NCT04353661 
INTERVENTIONS: 
Hyperpolarized 129Xenon MRI  
Azithromycin 
MEDICAL MONITOR: 
, M.D., M.A.S. 
SPONSOR: 
Genentech, Inc. 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 


129Xe MRIGenentech, Inc. 
2/Protocol GE42063, Version 5 
PROTOCOL HISTORY 
 
Protocol 
Associated Country- or Region-Specific Protocols 
Version 
Date Final 
Country or Region 
Version 
Date Final 
5 
See electronic date 
stamp on title page. 
U.K. 
4 
See electronic date 
stamp on title page. 
4 
15 March 2022 
U.K. 
3 
15 March 2022 
3 
06 August 2021 
U.K. 
2 
06 August 2021 
2 
11 December 2020 
U.K. 
1 
11 December 2020 
1 
11 June 2020 
 
 
 
 


129Xe MRIGenentech, Inc. 
3/Protocol GE42063, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
 
Protocol GE42063 has been amended primarily to remove hearing assessment 
requirements and to implement clarifications.  Changes to the protocol, along with a 
rationale for each change, are summarized below: 
• 
Hearing audiometry requirements for Cohort A have been removed and replaced 
with alternative hearing disturbance mitigation strategies that more closely align with 
clinical practice in patients with chronic obstructive pulmonary disease who start 
azithromycin (Sections 4.1.2, 4.5.5, and 5.1.2.7; Appendix 1). 
• 
Administration of hyperpolarized xenon-129 gas (HP 129Xe) has been revised to 
align with the study imaging manual (Section 4.3.2.2).  
• 
Management of patients who experience adverse events (including onset or 
worsening of hearing loss) and the reasons for treatment discontinuation have been 
updated to reflect current safety profiles related to study treatment (Sections 4.5.5, 
4.6.1, 5.1.2.7, and 5.1.3.3; Appendix 1). 
• 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.22.6). 
• 
The URL for the Roche Global Policy on Sharing of Clinical Study Information has 
been updated (Section 9.6). 
• 
Guidance for sites to ensure patients have received a bronchodilator prior to 
performing the HP 129Xe magnetic resonance imaging scan has been added 
(Appendix 1). 
 
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. 


129Xe MRIGenentech, Inc. 
4/Protocol GE42063, Version 5 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND ............................................................................ 20 
1.1 
Background on COPD ............................................................. 20 
1.2 
Background on Azithromycin Treatment for COPD and 
129Xe MRI Imaging ................................................................... 20 
1.3 
Study Rationale and Benefit-Risk Assessment ........................ 22 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 22 
2.1 
Efficacy Objectives .................................................................. 23 
2.1.1 
Primary Efficacy Objective ....................................................... 23 
2.1.2 
Secondary Efficacy Objective .................................................. 23 
2.1.3 
Exploratory Efficacy Objective ................................................. 23 
2.2 
Safety Objective ....................................................................... 24 
2.3 
Exploratory Biomarker Objective ............................................. 24 
3. 
STUDY DESIGN ........................................................................... 24 
3.1 
Description of the Study ........................................................... 24 
3.2 
End of Study and Length of Study ........................................... 26 
3.3 
Rationale for Study Design ...................................................... 27 
3.3.1 
Rationale for Patient Populations ............................................. 27 
3.3.2 
Rationale for Azithromycin and Control Groups ....................... 28 
3.3.3 
Rationale for Biomarker Assessments ..................................... 29 
3.3.4 
Rationale for Non-Standard Clinical Outcome Assessment 
(129Xe MRI) .............................................................................. 29 
4. 
MATERIALS AND METHODS ...................................................... 30 
4.1 
Patients .................................................................................... 30 
4.1.1 
Inclusion Criteria ...................................................................... 30 
4.1.2 
Exclusion Criteria ..................................................................... 31 
4.2 
Method of Treatment Assignment and Blinding ....................... 33 
4.3 
Study Interventions and Treatments Relevant to the Study 
Design ..................................................................................... 33 


129Xe MRIGenentech, Inc. 
5/Protocol GE42063, Version 5 
4.3.1 
Study Treatment Formulation and Packaging .......................... 33 
4.3.1.1 
Azithromycin ............................................................................ 33 
4.3.1.2 
Hyperpolarized 129Xe ................................................................ 33 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 33 
4.3.2.1 
Azithromycin ............................................................................ 34 
4.3.2.2 
Hyperpolarized 129Xe ............................................................... 34 
4.3.3 
Standard-of-Care Therapy ....................................................... 34 
4.3.4 
Medical Devices ....................................................................... 34 
4.4 
Concomitant Therapy and Additional Restrictions ................... 35 
4.4.1 
Permitted Therapy ................................................................... 35 
4.4.2 
Prohibited Therapy .................................................................. 36 
4.5 
Study Assessments ................................................................. 37 
4.5.1 
Informed Consent Forms and Screening Log .......................... 37 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medications, and Demographic Data ....................................... 37 
4.5.3 
Physical Examinations ............................................................. 37 
4.5.4 
Vital Signs ................................................................................ 38 
4.5.5 
Hearing Assessment ................................................................ 38 
4.5.6 
Tobacco Use ............................................................................ 38 
4.5.7 
Height and Weight ................................................................... 38 
4.5.8 
Chest X-Rays ........................................................................... 38 
4.5.9 
Spirometry and Forced Oscillometry ........................................ 38 
4.5.10 
Gas Exchange-Diffusion Capacity of the Lung for Carbon 
Monoxide Assessment ............................................................. 39 
4.5.11 
High-Resolution Computed Tomography ................................. 39 
4.5.12 
Hyperpolarized 129Xe MRI ........................................................ 40 
4.5.13 
Acute Exacerbations of COPD................................................. 40 
4.5.14 
Urgent COPD-Related Health Care Utilization......................... 40 
4.5.15 
Six-Minute Walk Test ............................................................... 40 
4.5.16 
BODE Index ............................................................................. 41 
4.5.17 
Sputum Induction ..................................................................... 41 
4.5.18 
Laboratory, Biomarker, and Other Biological Samples ............ 41 
4.5.19 
Electrocardiograms .................................................................. 42 
4.5.20 
Clinical Outcome Assessments ............................................... 43 


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4.5.20.1 
St. George’s Respiratory Questionnaire for COPD Patients .... 43 
4.5.20.2 
Modified Medical Research Council Dyspnea Scale ................ 44 
4.5.21 
Optional Blood Samples .......................................................... 44 
4.5.22 
Optional Samples for Research Biosample Repository ........... 45 
4.5.22.1 
Overview of the Research Biosample Repository .................... 45 
4.5.22.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 45 
4.5.22.3 
Sample Collection .................................................................... 45 
4.5.22.4 
Confidentiality .......................................................................... 46 
4.5.22.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 46 
4.5.22.6 
Withdrawal from the Research Biosample Repository ............. 47 
4.5.22.7 
Monitoring and Oversight ......................................................... 47 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 47 
4.6.1 
Study Treatment Discontinuation ............................................. 47 
4.6.2 
Patient Discontinuation from the Study .................................... 48 
4.6.3 
Study Discontinuation .............................................................. 49 
4.6.4 
Site Discontinuation ................................................................. 49 
5. 
ASSESSMENT OF SAFETY ......................................................... 49 
5.1 
Safety Plan .............................................................................. 49 
5.1.1 
Risks Associated with 129Xe ..................................................... 50 
5.1.1.1 
General Anesthesia ................................................................. 50 
5.1.1.2 
Hypoxemia ............................................................................... 50 
5.1.2 
Risks Associated with Azithromycin ......................................... 51 
5.1.2.1 
Hypersensitivity ........................................................................ 51 
5.1.2.2 
Hepatotoxicity .......................................................................... 51 
5.1.2.3 
Ergot Derivatives ..................................................................... 51 
5.1.2.4 
Superinfection .......................................................................... 51 
5.1.2.5 
Clostridium Difficile Associated Diarrhea ................................. 51 
5.1.2.6 
Myasthenia Gravis ................................................................... 52 
5.1.2.7 
Tinnitus or Hearing Loss .......................................................... 52 
5.1.2.8 
Elevated Liver Enzymes .......................................................... 52 
5.1.2.9 
Hypersensitivity: Rash, Pruritus, Tongue, or Facial 
Swelling ................................................................................... 52 


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5.1.2.10 
Prolongation of QT Interval ...................................................... 53 
5.1.3 
Management of Patients Who Experience Adverse Events ..... 53 
5.1.3.1 
Dose Modifications .................................................................. 53 
5.1.3.2 
Treatment Interruption ............................................................. 53 
5.1.3.3 
Management Guidelines .......................................................... 53 
5.1.3.4 
Management of Increases in QT Interval ................................. 54 
5.2 
Safety Parameters and Definitions .......................................... 55 
5.2.1 
Adverse Events ........................................................................ 55 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 56 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 56 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 57 
5.3.1 
Adverse Event Reporting Period .............................................. 57 
5.3.2 
Eliciting Adverse Event Information ......................................... 57 
5.3.3 
Assessment of Severity of Adverse Events ............................. 57 
5.3.4 
Assessment of Causality of Adverse Events............................ 58 
5.3.5 
Procedures for Recording Adverse Events .............................. 59 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 59 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ............. 60 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 60 
5.3.5.4 
Abnormal Laboratory Values ................................................... 60 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 61 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 62 
5.3.5.7 
Deaths ..................................................................................... 62 
5.3.5.8 
Preexisting Medical Conditions ................................................ 63 
5.3.5.9 
Lack of Efficacy or Worsening of COPD .................................. 63 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 63 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 64 
5.4.1 
Emergency Medical Contact .................................................... 64 
5.4.2 
Reporting Requirements for Serious Adverse Events, 
Adverse Events of Special Interest .......................................... 64 


129Xe MRIGenentech, Inc. 
8/Protocol GE42063, Version 5 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 64 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 65 
5.4.3 
Reporting Requirements for Pregnancies ................................ 65 
5.4.3.1 
Pregnancies in Female Patients .............................................. 65 
5.4.3.2 
Abortions.................................................................................. 65 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 66 
5.5 
Follow-Up of Patients after Adverse Events............................. 66 
5.5.1 
Investigator Follow-Up ............................................................. 66 
5.5.2 
Sponsor Follow-Up .................................................................. 66 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 66 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 67 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 67 
6.1 
Determination of Sample Size ................................................. 67 
6.2 
Summaries of Conduct of Study .............................................. 68 
6.3 
Summaries of Treatment Group Comparability or 
Demographic and Baseline Characteristics ............................. 68 
6.4 
Efficacy Analyses ..................................................................... 69 
6.4.1 
Primary Efficacy Endpoints ...................................................... 69 
6.4.2 
Secondary Efficacy Endpoint ................................................... 69 
6.4.3 
Exploratory Efficacy Endpoints ................................................ 69 
6.5 
Safety Analyses ....................................................................... 69 
6.6 
Exploratory Analysis of Patient-Reported Outcome 
Measures ................................................................................. 70 
6.7 
Exploratory Biomarker Analyses .............................................. 70 
6.8 
Interim Analyses ...................................................................... 70 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 71 
7.1 
Data Quality Assurance ........................................................... 71 
7.2 
Electronic Case Report Forms ................................................. 71 
7.3 
Source Data Documentation .................................................... 72 
7.4 
Use of Computerized Systems ................................................ 72 
7.5 
Retention of Records ............................................................... 72 


129Xe MRIGenentech, Inc. 
9/Protocol GE42063, Version 5 
8. 
ETHICAL CONSIDERATIONS ...................................................... 73 
8.1 
Compliance with Laws and Regulations .................................. 73 
8.2 
Informed Consent .................................................................... 73 
8.3 
Institutional Review Board or Ethics Committee ...................... 74 
8.4 
Confidentiality .......................................................................... 75 
8.5 
Financial Disclosure ................................................................. 75 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 76 
9.1 
Study Documentation .............................................................. 76 
9.2 
Protocol Deviations .................................................................. 76 
9.3 
Management of Study Quality .................................................. 76 
9.4 
Site Inspections ....................................................................... 76 
9.5 
Administrative Structure ........................................................... 76 
9.6 
Dissemination of Data and Protection of Trade Secrets .......... 77 
9.7 
Protocol Amendments ............................................................. 78 
10. 
REFERENCES.............................................................................. 79 
 
 
LIST OF TABLES 
Table 1 
Management Guidelines ............................................................. 54 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 58 
Table 3 
Causal Attribution Guidance ....................................................... 59 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 26 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ................................................................. 83 
Appendix 2 
 St. George’s Respiratory Questionnaire for COPD Patients ...... 88 
Appendix 3 
 Modified Medical Research Council Dyspnea Scale .................. 95 
Appendix 4 
 Six-Minute Walk Test ................................................................. 96 
Appendix 5 
 WHO Toxicity Grading Scale ..................................................... 97 
Appendix 6 
 Borg Category Ratio 10 Scale ................................................ 101 
Appendix 7 
 Hearing Handicap Inventory in the Elderly−Screening 
Questionnaire ............................................................................ 103 


 
129Xe MRIGenentech, Inc. 
10/Protocol GE42063, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
129XE MRI ASSESSMENT OF DISEASE PROGRESSION 
IN PATIENTS WITH CHRONIC OBSTRUCTIVE 
PULMONARY DISEASE TREATED WITH STANDARD-
OF-CARE MEDICATIONS WITH OR WITHOUT DAILY 
OPEN-LABEL AZITHROMYCIN TREATMENT TO 
PREVENT ACUTE EXACERBATION 
PROTOCOL NUMBER: GE42063 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-000852-36 
IND NUMBER 
148058 
NCT NUMBER: 
NCT04353661 
INTERVENTIONS: 
Hyperpolarized 129Xenon MRI 
Azithromycin 
MEDICAL MONITOR: 
, M.D., M.A.S. 
SPONSOR: 
Genentech, Inc. 
 
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 your local study monitor. 


 
129Xe MRIGenentech, Inc. 
11/Protocol GE42063, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
129XE MRI ASSESSMENT OF DISEASE PROGRESSION IN 
PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE TREATED WITH STANDARD-OF-CARE MEDICATIONS 
WITH OR WITHOUT DAILY OPEN-LABEL AZITHROMYCIN 
TREATMENT TO PREVENT ACUTE EXACERBATION 
PROTOCOL NUMBER: 
GE42063 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-000852-36 
IND NUMBER: 
148058 
NCT NUMBER: 
NCT04353661 
INTERVENTIONS: 
Hyperpolarized 129Xenon MRI  
Azithromycin 
PHASE: 
Phase IIa 
INDICATION: 
Chronic obstructive pulmonary disease 
SPONSOR: 
Genentech, Inc. 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate magnetic resonance imaging with inhaled hyperpolarized (HP) 
xenon-129 gas (129Xe MRI) as a prognostic and diagnostic tool in patients with chronic 
obstructive pulmonary disease (COPD) treated with either azithromycin (AZM) plus standard-
of-care COPD medications (long-acting β agonists [LABAs] and/or long-acting muscarinic 
antagonists [LAMAs], with or without inhaled corticosteroid [ICS] therapy) (AZM + SOC) or 
standard-of-care COPD medications alone (SOC).  Specific objectives and corresponding 
endpoints for the study are outlined below. 
 
EFFICACY OBJECTIVES 
Primary Efficacy Objective 
The primary efficacy objective for this study is to characterize the relationship between 129Xe 
MRI metrics and clinical outcome in patients treated with AZM + SOC versus SOC on the basis 
of the following endpoint: 
• 
Change in 129Xe MRI ventilation defect percent (VDP) from baseline to Week 24 compared 
with rate of moderate or severe COPD exacerbations over 48 weeks 
A moderate COPD exacerbation is defined as new or increased COPD symptoms 
(e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days 
that lead to treatment with systemic corticosteroids and/or antibiotics. 
A severe COPD exacerbation is defined as new or increased COPD symptoms 
(e.g., dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days 
that lead to hospitalization or death. 
 


 
129Xe MRIGenentech, Inc. 
12/Protocol GE42063, Version 5 
Secondary Efficacy Objective  
The secondary efficacy objective for this study is to characterize the relationship between 129Xe 
MRI metrics and clinical outcome in patients treated with AZM + SOC versus SOC on the basis 
of the following endpoint: 
• 
Change in 129Xe MRI VDP from baseline to Week 24 and Week 48 compared with absolute 
change in pre-bronchodilator forced expiratory volume in 1 second (FEV1; liters) from 
baseline to Week 24 and Week 48, respectively 
 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to characterize the relationship between 129Xe 
MRI metrics and clinical outcome in patients treated with AZM + SOC versus SOC on the basis 
of the following endpoint: 
• 
Change in 129Xe MRI metrics (VDP, barrier defect percent, and/or RBC defect percent) from 
baseline to Week 24 and (as appropriate) Week 48 compared with the following: 
– 
Change in dyspnea, as assessed by the Baseline and Transition Dyspnea Indexes 
(BDI/TDI), from baseline to Week 24 
– 
Change in high-resolution computed tomography (HRCT) metrics (parametric response 
mapping-functional small airway disease [PRMfSAD] and parametric response 
mapping-emphysema [PRMEmph]) from baseline to Week 24 (if applicable) and Week 48, 
respectively  
– 
Change in oscillometry endpoints (including, but not limited to, R5, R20, R5−20, X5, 
resonance frequency, and reactance area), from baseline to Week 24 
– 
Absolute change in carbon monoxide diffusing capacity from baseline to Week 24 and 
Week 48, respectively 
– 
Change in six-minute walk test (6MWT) distance from baseline to Week 24 and 
Week 48, respectively 
– 
Change in health-related quality of life, as assessed by the overall score of the 
St. George’s Respiratory Questionnaire for COPD, from baseline to Week 24 and 
Week 48, respectively 
 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of 129Xe MRI procedures and of 
AZM + SOC compared with SOC on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to the World 
Health Organization toxicity scale 
• 
Change from baseline in targeted vital signs 
• 
Change from baseline in targeted clinical laboratory test results 
• 
Change from baseline in ECG data 
 
EXPLORATORY BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify biomarkers that may provide 
evidence of changes in disease progression or may increase the knowledge and understanding 
of disease biology (e.g., association between chronic bronchitis and imaging measures), on the 
basis of the following endpoints: 
• 
Relative change from randomization visit in biomarker levels in sputum or blood at 
Weeks 12, 24, and 48 
• 
Relationship between biomarkers in sputum or blood and other biomarker endpoints 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a multicenter, open-label, parallel group, randomized study designed to assess the 
sensitivity of HP 129Xe MRI metrics as measures of disease progression in patients with COPD 


 
129Xe MRIGenentech, Inc. 
13/Protocol GE42063, Version 5 
treated with SOC medications with or without daily azithromycin treatment.  129Xe MRI will be 
evaluated as a diagnostic tool that may provide useful images of the functioning of the lung for 
determining changes in lung function and structure.  Approximately 120 patients with a 
diagnosis of COPD will be enrolled in the study across two cohorts (defined by severity of 
disease) and three arms.  Patients will be followed for 52 weeks, during a 48-week open-label 
treatment period followed by a 4week safety follow-up period, with assessments performed at 
baseline and at Weeks 6, 12, 24, and 48.  129Xe MRI images will be compared with standard 
lung function assessments, including 6MWT to assess functional status, quantitative HRCT to 
assess lung structure, and questionnaires to assess shortness of breath and quality of life.  
Patients will be enrolled in the following cohorts: 
• 
Cohort A:  Approximately 100 patients with COPD Global Initiative for Chronic Obstructive 
Lung Disease Stage 2–4 (GOLD 2−4), with or without chronic bronchitis, and history of 
≥2 acute exacerbations (AEx) within a 12-month period in the prior 24 months will be 
randomly assigned in a 1:1 ratio to the following treatment arms: 
AZM + SOC:  azithromycin (250 mg once a day [QD]) plus other SOC therapy 
consisting of LABAs and/or LAMAs, with or without ICS therapy  
SOC:  SOC therapy consisting of LABAs and/or LAMAs, with or without ICS therapy 
Randomization will be stratified by region (United States vs. United 
Kingdom/Canada) and by the number of exacerbations in the prior 12 months 
(2 vs. ≥ 3).    
• 
Cohort B:  Approximately 20 patients with COPD GOLD Stage 1 (GOLD 1), with or without 
chronic bronchitis, and history of ≥ 1 AEx within a 12-month period in the prior 24 months 
will be enrolled as an observational cohort into the following arm:  
SOC:  SOC therapy consisting of LABAs and/or LAMAs, with or without ICS therapy 
 
Patients who are unable to complete the assessments or meet eligibility requirements during 
the screening period (from 1 to 28 days) will be permitted to be re-screened once for a total of 
two times.  Patients who re-screen ≤ 6 weeks after Informed Consent Form completion must 
repeat only the assessments that triggered the screen failure.  Patients who re-screen 
> 6 weeks after Informed Consent Form completion are required to repeat the consent process 
and all screening assessments except for lung X-rays or HRCT. 
The first dose of study drug for applicable patients in Cohort A will be self-administered on the 
same day as randomization (Visit 2, Day 1) after completion of all scheduled assessments.  
Thereafter, dosing will be repeated once daily during a 48-week treatment period.  Patients will 
continue on stable doses of their SOC therapy, which must include a long-acting bronchodilator 
inhaler medication (LABAs and/or LAMAs) with or without additional ICS medication throughout 
the 48-week treatment period and subsequent 4-week safety follow-up period.    
The first assessment of the 129Xe MRI intervention will be performed at Visit 2 (Week 0) for all 
patients randomized to Cohort A and Cohort B and then repeated at Visit 3 (Week 6), Visit 4 
(Week 12), Visit 5 (Week 24), and Visit 7 (Week 48).  Safety, efficacy, and patient-reported 
outcome measures will be assessed throughout the treatment period, as specified in the 
protocol.  Patients in Cohort A will be evaluated for safety for an additional 4 weeks following 
completion of the treatment period.   
One or more interim analyses may be executed at the Sponsor’s discretion. 
NUMBER OF PATIENTS 
Approximately 7 sites will participate to enroll approximately 120 patients with a diagnosis of 
COPD across two cohorts.  Approximately 100 patients with COPD (GOLD 2–4) will be 
randomized to Cohort A; patients with chronic bronchitis (n ≤ 60) and without chronic bronchitis 
(n ≥ 40) will be randomized across treatment arms.  Approximately 20 patients (GOLD 1) will be 
enrolled in the Cohort B substudy. 


 
129Xe MRIGenentech, Inc. 
14/Protocol GE42063, Version 5 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age ≥40 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
Signed Informed Consent Form (signed before any study procedures are performed) 
• 
Current or former smokers with ≥10 pack years 
• 
mMRC dyspnea score ≥ 1 
• 
Post-bronchodilator FEV1/forced vital capacity <0.70 at screening (Visit 1) or randomization 
(Visit 2) 
• 
For patients enrolled in Cohort A:  GOLD Stage 2−4 COPD with a history of 
≥ 2 moderate/severe exacerbations within a 12-month period in the 24 months prior to 
screening 
• 
For patients enrolled in Cohort B:  GOLD Stage 1 COPD with a history of 
≥ 1 moderate/severe exacerbations within a 12-month period in the 24 months prior to 
screening 
• 
Receiving SOC background drug therapy as per GOLD or British Thoracic Society (BTS) 
guidance for COPD for 12 weeks prior to screening (Visit 1) 
• 
On an eligible bronchodilator medication (LABA and/or LAMA) ± ICS therapy for ≥ 12 weeks 
prior to screening (Visit 1) 
• 
Chest X-ray or CT scan within 6 months prior to screening (Visit 1), or during the screening 
period (prior to randomization [Visit 2]), that confirms the absence of clinically significant 
lung disease besides COPD 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraception during the study period (all 
patients) and for 28 days after the final dose of azithromycin (patients enrolled in Cohort A 
receiving azithromycin) 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing intrauterine 
devices; copper intrauterine devices; male or female condom with or without 
spermicide; and cap, diaphragm, or sponge with spermicide. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not adequate methods of contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of allergy or hypersensitivity to azithromycin 
• 
Significant known respiratory disorders other than COPD that, in the view of the 
investigator, will affect the trial 
• 
A COPD exacerbation and/or pneumonia within the 4 weeks prior to screening (Visit 1) 


 
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• 
FEV1 percent predicted less than 25% 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study period (all 
patients) or within 28 days after the final dose of azithromycin (patients enrolled in Cohort A 
receiving azithromycin) 
Women of childbearing potential must have a negative serum pregnancy test result at 
screening. 
• 
Participation in an interventional clinical trial within 4 weeks of screening (Visit 1) or receipt 
of any investigational medicinal product (IMP) within 30 days or 5 half-lives, whichever is 
longer 
• 
Use of systemic corticosteroids within 4 weeks (oral or IV) or 12 weeks (intramuscular) prior 
to screening 
• 
Active tuberculosis requiring treatment within 12 months prior to Visit 1  
Patients who have completed treatment for tuberculosis at least 12 months prior to 
Visit 1 and have no evidence of recurrent disease are permitted. 
• 
Receiving treatment considered to be palliative (life expectancy <12 months) 
• 
Myocardial infarction, unstable angina, or stroke within 12 months prior to screening 
(Visit 1) 
• 
Clinically significant ECG changes, which in the opinion of investigator warrants further 
investigation or with a QTc interval > 450 ms 
• 
History of congenital or documented QT prolongation 
• 
Currently receiving treatment with other active substance at doses known to prolong QT 
interval such as antiarrhythmic of Classes Ia and III, cisapride, and terfenadine 
• 
Electrolyte disturbance (e.g., clinically significant hypokalemia or hypomagnesemia) 
• 
Clinically relevant bradycardia, cardiac arrhythmia, or severe cardiac insufficiency 
• 
History of myasthenia gravis 
• 
For patients in Cohort A:  Known significant hearing impairment as indicated by a score 
of ≥ 26 on the Hearing Handicap Inventory in the Elderly−Screening Questionnaire or as 
determined by the investigator 
• 
Impaired hepatic function 
• 
Severe renal insufficiency (estimated glomerular filtration rate < 10 mL/min) 
• 
Concomitant use of ergot derivatives 
• 
Bloodborne infection (e.g., HIV, hepatitis B or C) 
• 
History of Clostridium difficile diarrhea  
• 
Ventricular cardiac arrhythmia in the past 30 days 
• 
Claustrophobia, inner ear implants, aneurysm or other surgical clips, metal foreign bodies in 
eye, pacemaker or other contraindication to MRI scanning 
Patients with any implanted device that cannot be verified as MRI compliant will be 
excluded. 
• 
Unable to fit into 129Xe vest coil used for MRI 
• 
Deemed unlikely to be able to comply with instructions during imaging 
• 
Evidence, in the opinion of the investigator, of alcohol, drug, or solvent abuse within the 
prior 12 months 
• 
Medical or psychological conditions which, in the opinion of the investigator, might create 
undue risk to the patient or interfere with the patient’s ability to comply with the protocol 
requirements 
• 
Diagnosis of malignancy within 5 years of Visit 1 (except for excised localized non-
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END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  The 
LPLV is expected to occur approximately 52 weeks after the last patient is randomized into the 
study.  This timeframe includes a 48-week treatment period and a 4-week safety follow-up 
period for Cohort A.  The LPLV for Cohort B is expected to occur approximately 48 weeks after 
the last patient is randomized into the cohort. 
LENGTH OF STUDY 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 30 months. 
Total duration of patient participation in Cohort A of the study, from date of randomization 
(Visit 2, Day 1) through the 48-week treatment period and 4-week safety follow-up period, is 
approximately 52 weeks.  Total duration of patient participation in Cohort B of the study, from 
date of randomization (Visit 2, Day 1) through the 48-week observation period, will be 
approximately 48 weeks. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMPs for this study are azithromycin and HP 129Xe.  All patients will continue their COPD 
therapy as recommended in published COPD guidelines or BTS guidelines.  Required COPD 
inhaler therapy, consisting of LABA and/or LAMA with or without ICS therapy, is considered a 
non-IMP for this study. 
Patients in Cohort A randomized to treatment intervention will receive generic azithromycin 
250 mg taken orally QD.  Patients will receive a 3-month supply of azithromycin 250-mg tablets 
at Visit 2 (baseline), Visit 4 (Week 12), Visit 5 (Week 24), and Visit 6 (Week 36) at the study 
site.  Patients randomized to receive azithromycin will receive a maximum of 336 doses with a 
tablet strength of 250 mg.  All patients will be provided with a diary to track daily study treatment 
and the date of any AEx events. 
HP xenon (129Xe) will be administered at specified timepoints and the total dose bag volume 
should target 20% of the patient’s forced vital capacity followed by a breath hold of up to 
15 seconds.  Subsequent 129Xe doses will only be administered once the patient is ready to 
proceed.  Patients will be monitored by a qualified medical professional for the duration of the 
xenon dose and post-procedural period, as well as the MRI.  Refer to the study imaging 
manual for details. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
Required COPD inhaler therapies, consisting of LABA and/or LAMA with or without ICS therapy, 
are considered non-IMPs for this study. 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
Details of the analysis are available in the Statistical Analysis Plan, including sensitivity 
analysis.  At a minimum, VDP change at 24 weeks can predict rate of moderate/severe COPD 
exacerbation over 48 weeks, controlling for treatment assignment.  The initial model will be a 
negative binomial model for exacerbation rate using the intent-to-treat population.  As this is an 
exploratory study, sensitivity analysis is performed for the purpose of confirming signal.  If signal 
is not found using the primary analysis, sensitivity analysis will not be performed. 
DETERMINATION OF SAMPLE SIZE 
Power calculations for this exploratory study require many assumptions due to lack of available 
literature on the 129Xe MRI metrics.  Further details than those provided in the protocol, 
including code to generate these calculations, are available in the Statistical Analysis Plan.  All 
calculations were done in R version 3.5.0.  The focus of this trial is on estimation, not 
hypothesis testing. 
The main objective of this study is establishing if 129Xe MRI metrics (VDP) are a more sensitive 
measure of lung function decline and can predict the rate of moderate/severe exacerbation.  
Approximately 100 patients in Cohort A will be enrolled in this study.  A sample size of 100 will 
enable enough exacerbations to anchor the evaluation of the performance of VDP. 
This study is powered (at 77%) to detect a treatment effect due to exacerbation, depending on 
assumptions.  Power calculation was done based on a negative binomial with over-dispersion 


 
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of 1.3, with 5% alpha, assuming a mean exacerbation frequency of 2 and observed for 
48 weeks.  A one-sided test was used and 10% drop-out rate.  A further assumption on the 
azithromycin effect size was needed to establish powera 35 % reduction rate ratio was used.   
This study is powered, depending on assumptions, for the secondary efficacy objectives.  To 
test the sensitivity of VDP metric relative to FEV1 (coefficient of variation test), a sample size of 
100 provides just under 90% power to establish improved coefficient of variation relative to 
FEV1 (assumes coefficient of variation of 180% and using a simulation-based power calculation 
run with MSLR and a p-value of 0.05.) 
This study is well powered to test the secondary efficacy objective of establishing the 
relationship between HRCT metrics and the VDP metric.  With a sample size of 100, and 
assuming a true correlation of 0.25 between the metrics, the study has approximately 75% 
power to determine if a correlation exists (assuming a multivariate normal with correlation of 
0.25 and PRMfSAD mean of 26.6% and SD of 11.6%, and VDP mean of 4.37 and SD of 1.89). 
INTERIM ANALYSES  
An interim analysis may be performed to assess for changes in VDP and/or other 129Xe MRI 
metrics relative to other clinical assessments, at the Sponsor’s discretion. 
Given the exploratory nature of this study, the Sponsor may choose to conduct additional 
interim efficacy analyses.  The decision to conduct an optional interim analysis and the timing of 
the analysis will be documented in the Sponsor's trial master file prior to the conduct of the 
interim analysis.  The interim analysis will be performed and interpreted by the Sponsor’s study 
team personnel. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
6MWT 
six-minute walk test 
AECOPD 
acute exacerbations of chronic obstructive pulmonary disease 
AEx 
acute exacerbations 
ATS 
American Thoracic Society 
AX 
reactance area 
AZM + SOC 
azithromycin and standard of care therapy 
BDP 
barrier defect percent  
Borg CR10 Scale 
Borg Category-Ration 10 Scale 
BTS 
British Thoracic Society 
C. difficile 
Clostridium difficile 
CDAD 
Clostridium difficile associated diarrhea 
COPD 
chronic obstructive pulmonary disease 
COPD-CB 
chronic obstructive pulmonary disease with chronic bronchitis 
CRO 
contract research organization 
CRP 
c-reactive protein 
CT 
computed tomography 
DDI 
drug-drug interaction 
DLCO 
carbon monoxide diffusing capacity 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FOT 
forced oscillometry technique 
FVC 
forced vital capacity  
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HHIE-S 
Hearing Handicap Inventory in the Elderly−Screening 
Questionnaire 
HIPAA 
Health Insurance Portability and Accountability Act 
HP 
hyperpolarized 
HP 129Xe MRI 
hyperpolarized xenon magnetic resonance imaging 
HRCT 
high-resolution computed tomography 
ICH 
International Council for Harmonisation 
ICS 
inhaled corticosteroids 


 
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Abbreviation 
Definition 
IM 
intramuscular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRC 
Independent Review Charter 
IxRS 
interactive voice or web-based response system 
LABA 
long-acting β-agonist 
LAMA 
long-acting muscarinic antagonist 
LPLV 
last patient, last visit 
mMRC 
Modified Medical Research Council 
MRI 
magnetic resonance imaging 
N2O 
nitrous oxide 
PD 
pharmacodynamic 
PRMEmph 
parametric response mapping-emphysema 
PRMfSAD 
parametric response mapping-functional small airway disease  
PRO 
patient-reported outcome 
QD 
once a day 
QTc 
corrected QT interval 
QTcF 
QT interval corrected through use of Fridericia's formula 
RBR 
Research Biosample Repository 
RDP 
Red blood cell defect percent 
SAP 
Statistical Analysis Plan 
SGRQ-C 
St. George’s Respiratory Questionnaire-COPD  
SMC 
Safety Monitoring Committee 
SNP 
single nucleotide polymorphism 
SOC 
standard of care 
SpO2 
oxygen saturation 
ULN 
upper limit of normal 
VDP 
ventilation defect percent  
WHO 
World Health Organization 
  
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON COPD  
Chronic obstructive pulmonary disease (COPD) has been defined as a clinical syndrome 
characterized by chronic respiratory symptoms, structural pulmonary abnormalities 
(airways disease and/or emphysema), and lung function impairment (primarily airflow 
limitation that is poorly reversible).  The characteristic symptoms of COPD are dyspnea, 
cough, and sputum production (Global Initiative for Chronic Obstructive Lung Disease 
[GOLD 2019]).  The GOLD staging system expresses COPD severity, as reflected by 
symptoms, history of worsening, requirements for hospital stay, and spirometric 
measures of lung function and includes stages:  GOLD 1 (mild), GOLD 2 (moderate), 
GOLD 3 (severe), and GOLD 4 (very severe). 
COPD is a significant cause of morbidity and mortality worldwide (GOLD 2019).  In 
contrast to other chronic diseases, COPD is increasing in prevalence and is projected to 
be the third-leading cause of death and disability worldwide by 2030 (GOLD 2019).  
Worldwide estimation of the overall prevalence of Stage ≥ 2 (moderate) COPD is 10.1% 
(Buist et al. 2007).  COPD is caused by long-term exposure to inhaled noxious gases 
and particles.  Cigarette smoke accounts for more than 90% of cases in developed 
countries.  COPD usually occurs in patients over the age of 40 years and is more 
common in men.  
The costs to society for treating COPD are high, accounting for approximately 3.4% of 
the total health care budget of the European Union.  In the United States, medical costs 
for treatment of COPD were $32.1 billion in 2010 and are estimated to increase to 
$49 billion by 2020 (Ford et al. 2015).  Acute exacerbations of COPD (AECOPD) are 
responsible for a large portion of the economic burden, morbidity, and mortality of the 
disease and are attributed to more than 500,000 hospitalizations and 100,000 deaths in 
the United States each year.   
COPD is a heterogeneous disease, and there are currently no clear methods to identify 
patients with a high risk of acute exacerbations (AEx), particularly in mild COPD.  For 
example, although patients with a history of exacerbations and/or reduced forced 
expiratory volume (FEV1) are considered at higher risk for future adverse outcomes and 
subsequent disease progression (Donaldson and Wedzicha. 2006; Agusti et al. 2010; 
GOLD 2019), patients with mild disease also have AEx (Han et al. 2017).  To date, the 
strongest predictor of exacerbation risk is a prior history of exacerbation.   
1.2 
BACKGROUND ON AZITHROMYCIN TREATMENT FOR COPD 
AND 129XE MRI IMAGING 
The current, guideline-driven treatment options to prevent AECOPD include inhaled 
corticosteroids (ICSs) with or without oral macrolides such as azithromycin; however, 
these treatments are not effective for all patients.  Development of novel therapies to 
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exacerbations.  Due to the low frequency of AEx in patients, interventional trials that use 
AEx rate as a primary endpoint require a large number of patients and a long period of 
assessment (i.e., monitoring for 1 year or more).  More detailed phenotyping of all 
patients with COPDincluding those at high risk of severe exacerbation according to 
physiological, biological, genetic, and imaging phenotypes (Kirby et al. 2014; Lowe et al. 
2019)may provide new therapeutic windows of opportunity for targeted treatment. 
Several relevant research clinical trials have been published supporting the clinical 
benefit of long-term macrolide treatment in reducing the rate of AECOPD (Albert et al. 
2011; Simpson et al. 2014; Lijuan et al. 2018; Vermeersch et al. 2019).  The COPD 
GOLD 2019 guidelines propose prophylactic macrolide therapy with azithromycin or 
erythromycin to reduce the risk of exacerbations in patients with moderate or severe 
COPD prone to exacerbations.  However, long-term macrolide treatment could increase 
the occurrence of adverse events and increase macrolide resistance (Taylor et al. 2015; 
GOLD 2019 guidelines).  While daily azithromycin decreases AECOPD, the response to 
therapy is unpredictable, even in patients within the same GOLD stage (Han et al. 2014).  
This is largely related to variable structural damage in different lung units that impair not 
only ventilation, but also gas exchange.  It is necessary to identify these physiological 
derangements of COPD (i.e., clinical phenotypes) so the pharmacological responses 
and clinical outcomes can be predicted with more precision. Currently, no single 
assessment modality provides a comprehensive regional evaluation of lung structure, 
ventilation, and gas exchange.   
Magnetic resonance imaging (MRI) using hyperpolarized (HP) xenon‐129 gas (129Xe) is 
an emerging technology capable of 3D mapping of ventilation and gas distribution in the 
alveolar space and its uptake in interstitial barrier tissues (“barrier uptake”), as well as its 
transfer to red blood cells (Driehuys 2012; Joseph 2019).  Recent studies comparing 
healthy smokers, patients with COPD, and non-smokers support the potential of 129Xe 
MRI to identify multiple physiological lung changes using a single breath-hold (Qing 
2019).  This allows for discrimination between healthy subjects and healthy smokers 
prior to loss of lung function assessed by FEV1 and could become a powerful new 
measure of early-stage lung disease (Qing et al. 2019; Ruppert 2019). Importantly, this 
assessment may offer improved sensitivity compared with an AEx endpoint allowing for 
shorter duration clinical trials. 
Few studies have shown any impact of chronic azithromycin treatment on clinically 
relevant measures of COPD such as FEV1, or quality of life associated with prophylactic 
treatment with azithromycin.  COPD manifests in a spatially heterogeneous manner, with 
areas of normal lung in close proximity to areas of small airways disease, fibrosis, and 
emphysema.  Thus, detection of progression and response to therapy requires local 
assessment of lung structure and function, with the ability to monitor these regions over 
time.  Currently, no single established assessment modality provides a comprehensive 
regional evaluation of both ventilation and gas exchange.  Although high-resolution 
computed tomography (HRCT) is integral to the diagnosis of COPD/emphysema, it is 


 
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poorly suited to monitor therapeutic response.  Computed tomography (CT) scans detect 
structural abnormalities, but the earliest harbinger of changing disease status is lung 
function.  Additionally, CT scans and HRCT scans require use of ionizing radiation.  The 
ability to image both lung function and structure may now be addressed by HP 129Xe 
MRI.    
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
129Xe MRI is capable of 3D-mapping ventilation and gas distribution in the alveolar space 
and its uptake in interstitial barrier tissues (“barrier uptake”), as well as its transfer to red 
blood cells (“RBC transfer”).  Because 129Xe, like oxygen, must traverse the interstitial 
barrier to reach capillary blood, 129Xe signal in RBCs is exquisitely sensitive to barrier 
thickness.  129Xe in RBCs has a unique frequency shift, allowing it to reveal interstitial 
thickening of only a few microns.  This high sensitivity to altered blood-gas-barrier in 
regions of small airways disease and emphysema makes 129Xe MRI uniquely suited to 
study COPD without the use of potentially harmful ionizing radiation.  This has the 
potential to accelerate clinical trials for COPD by visualizing the therapeutic response on 
the timescale of months versus years. 
This study aims to assess whether change from baseline in 129Xe MRI metrics for 
ventilation defect percent (VDP), barrier defect percent (BDP), and/or RBC defect 
percent (RDP) at 24 weeks can predict rate of exacerbation over a 48-week period, 
and whether baseline 129Xe MRI metrics are prognostic for AEx rate and/or predictive of 
clinical benefit from daily treatment with azithromycin. 
Azithromycin use has been shown to reduce AECOPD, but carries some risk to patients 
(Taylor et al. 2015).  These include a small risk for QT-interval prolongation, hearing 
loss, and the development of antibacterial resistance.  Nonetheless, with adequate 
safety monitoring (see Section 5.1), reduced risk for recurrent exacerbations may benefit 
patients’ overall quality of life and long-term outcomes. 
An assessment has been conducted to determine whether the coronavirus disease 2019 
pandemic has any impact on the benefit-risk assessment of this study including, but not 
limited to, the patient population under study and study treatments (azithromycin and 
hyperpolarized 129Xe).  The safety monitoring and management guidelines and risk 
mitigation measures provided in the study are considered adequate. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate 129Xe MRI as a prognostic and diagnostic tool in patients with 
COPD treated with either azithromycin plus standard-of-care COPD medications 
(long-acting β agonists [LABAs] and/or long-acting muscarinic antagonists [LAMAs], 
with or without ICS therapy) (AZM + SOC) or standard-of-care COPD medications alone 
(SOC).  Specific objectives and corresponding endpoints for the study are outlined 
below. 


 
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2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to characterize the relationship between 
129Xe MRI metrics and clinical outcome in patients treated with AZM + SOC versus SOC 
on the basis of the following endpoint: 
• 
Change in 129Xe MRI VDP from baseline to Week 24 compared with rate of 
moderate or severe COPD exacerbations over 48 weeks 
A moderate COPD exacerbation is defined as new or increased COPD 
symptoms (e.g., dyspnea, sputum volume, and sputum purulence) for at least 
2 consecutive days that lead to treatment with systemic corticosteroids and/or 
antibiotics. 
A severe COPD exacerbation is defined as new or increased COPD symptoms 
(e.g., dyspnea, sputum volume, and sputum purulence) for at least 
2 consecutive days that lead to hospitalization or death. 
 
2.1.2 
Secondary Efficacy Objective  
The secondary efficacy objective for this study is to characterize the relationship 
between 129Xe MRI metrics and clinical outcome in patients treated with AZM + SOC 
versus SOC on the basis of the following endpoint: 
• 
Change in 129Xe MRI VDP from baseline to Week 24 and Week 48 compared with 
absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 24 and 
Week 48, respectively 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to characterize the relationship 
between 129Xe MRI metrics and clinical outcome in patients treated with AZM + SOC 
versus SOC on the basis of the following endpoint: 
• 
Change in 129Xe MRI metrics (VDP, BDP, and/or RDP) from baseline to Week 24 
and (as appropriate) Week 48 compared with the following: 
– 
Change in dyspnea, as assessed by the Baseline and Transition Dyspnea 
Indexes (BDI/TDI), from baseline to Week 24 
– 
Change in HRCT metrics (parametric response mapping-functional small 
airway disease [PRMfSAD] and parametric response mapping-emphysema 
[PRMEmph]) from baseline to Week 24 (if applicable; see Section 4.5.11 and 
Appendix 1) and Week 48, respectively  
– 
Change in oscillometry endpoints (including, but not limited to, R5, R20, R5−20, 
X5, resonance frequency [Fres], and reactance area [AX]), from baseline to 
Week 24 
– 
Absolute change in carbon monoxide diffusing capacity (DLCO) from baseline to 
Week 24 and Week 48, respectively 


 
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– 
Change in six-minute walk test (6MWT) distance from baseline to Week 24 and 
Week 48, respectively 
– 
Change in health-related quality of life, as assessed by the overall score of the 
St. George’s Respiratory Questionnaire for COPD (SGRQ-C), from baseline to 
Week 24 and Week 48, respectively  
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of 129Xe MRI procedures and 
of AZM + SOC compared with SOC on the basis of the following endpoints: 
• 
Incidence and severity of adverse events, with severity determined according to the 
World Health Organization (WHO) toxicity scale 
• 
Change from baseline in targeted vital signs 
• 
Change from baseline in targeted clinical laboratory test results 
• 
Change from baseline in ECG data 
 
2.3 
EXPLORATORY BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify biomarkers that may 
provide evidence of changes in disease progression or may increase the knowledge and 
understanding of disease biology (e.g., association between chronic bronchitis and 
imaging measures), on the basis of the following endpoints: 
• 
Relative change from randomization visit in biomarker levels in sputum or blood at 
Weeks 12, 24, and 48 
• 
Relationship between biomarkers in sputum or blood and other biomarker endpoints 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY  
This is a multicenter, open-label, parallel group, randomized study designed to assess 
the sensitivity of HP 129Xe MRI metrics as measures of disease progression in patients 
with COPD treated with SOC medications with or without daily azithromycin treatment.  
MRI with inhaled HP 129Xe gas (129Xe MRI) will be evaluated as a diagnostic tool that 
may provide useful images of the functioning of the lung for determining changes in lung 
function and structure.  Approximately 120 patients with a diagnosis of COPD will be 
enrolled in the study across two cohorts (defined by severity of disease) and three arms.  
Patients will be followed for 52 weeks, during a 48-week open-label treatment period 
followed by a 4-week safety follow-up period, with assessments performed at baseline 
and at Weeks 6, 12, 24, and 48.  129Xe MRI images will be compared with standard lung 
function assessments, including 6MWT to assess functional status, quantitative HRCT to 
assess lung structure, and questionnaires to assess shortness of breath and quality of 
life.  Patients will be enrolled in the following cohorts: 


 
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• 
Cohort A:  Approximately 100 patients with COPD GOLD Stage 2–4 (GOLD 2−4), 
with or without chronic bronchitis, and history of ≥2 AEx within a 12-month period in 
the prior 24 months will be randomly assigned in a 1:1 ratio to the following 
treatment arms: 
– 
AZM + SOC:  azithromycin (250 mg QD) plus other SOC therapy consisting of 
LABAs and/or LAMAs, with or without ICS therapy  
– 
SOC:  SOC therapy consisting of LABAs and/or LAMAs, with or without ICS 
therapy 
Randomization will be stratified by region (United States vs. United 
Kingdom/Canada) and by the number of exacerbations in the prior 
12 months (2 vs. ≥ 3).    
• 
Cohort B:  Approximately 20 patients with COPD GOLD Stage 1 (GOLD 1), with or 
without chronic bronchitis, and history of ≥1 AEx within a 12-month period in the 
prior 24 months will be enrolled as an observational cohort into the following arm:  
– 
SOC:  SOC therapy consisting of LABAs and/or LAMAs, with or without ICS 
therapy 
 
Patients who are unable to complete the assessments or meet eligibility requirements 
during the screening period (from 1 to 28 days) will be permitted to be re-screened once 
for a total of two times.  Patients who re-screen ≤ 6 weeks after Informed Consent Form 
completion must repeat only the assessments that triggered the screen failure.  Patients 
who re-screen  > 6 weeks after Informed Consent Form completion are required to repeat 
the consent process and all screening assessments except for lung X-rays or HRCT. 
The first dose of study drug for applicable patients in Cohort A will be self-administered 
on the same day as randomization (Visit 2, Day 1) after completion of all scheduled 
assessments.  Thereafter, dosing will be repeated once daily during a 48-week 
treatment period.  Patients will continue on stable doses of their SOC therapy, which 
must include a long-acting bronchodilator inhaler medication (LABAs and/or LAMAs) 
with or without additional ICS medication throughout the 48-week treatment period and 
subsequent 4-week safety follow-up period.    
The first assessment of the 129Xe MRI intervention will be performed at Visit 2 (Week 0) 
for all patients randomized to Cohort A and Cohort B and then repeated at Visit 3 (Week 
6), Visit 4 (Week 12), Visit 5 (Week 24), and Visit 7 (Week 48).  Safety, efficacy, and 
PRO measures will be assessed throughout the treatment period, as specified in 
Appendix 1.  Patients in Cohort A will be evaluated for safety for an additional 4 weeks 
following completion of the treatment period.   
One or more interim analyses may be executed at the Sponsor’s discretion.  
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 


 
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Figure 1 Study Schema 
 
AEx = acute exacerbations; CB = chronic bronchitis; COPD = chronic obstructive pulmonary 
disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease;  QD = once a day; 
R = randomization; SFU = safety follow up; SOC = standard of care. 
 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) 
occurs.  The LPLV is expected to occur approximately 52 weeks after the last patient is 
randomized into the study.  This timeframe includes a 48-week treatment period and a 
4-week safety follow-up period for Cohort A.  The LPLV for Cohort B is expected to 
occur approximately 48 weeks after the last patient is randomized into the cohort. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 30 months. 
Total duration of patient participation in Cohort A of the study, from date of 
randomization (Visit 2, Day 1) through the 48-week treatment period and 4-week safety 
follow-up period, is approximately 52 weeks.  Total duration of patient participation in 
Cohort B of the study, from date of randomization (Visit 2, Day 1) through the 48-week 
observation period, will be approximately 48 weeks. 


 
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3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Patient Populations 
There is a high unmet need and limited therapeutic options for patients with intermittent 
AECOPD and persistent dyspnea, despite adherence with guidelines-based SOC 
therapy.  The definition of COPD exacerbation used in this study is consistent with 
published guidelines that define a patient population with unmet medical need.  Patients 
having exacerbations despite treatment with ICS and bronchodilator therapy are at 
increased risk for future exacerbations and adverse health outcomes.  A dyspnea score 
of 1 or more, as defined by the Modified Medical Research Council (mMRC), during 
screening identifies a patient population with incomplete control of symptoms. 
All patients considered for participation in the 48-week azithromycin treatment in 
Cohort A will have a physician diagnosis of COPD for at least 12 months prior to 
screening and meet GOLD Stage 2–4 criteria.  Patients will be required to have 
optimal guideline-based SOC treatment (daily for a minimum of 12 weeks prior 
to randomization).  All patients eligible for Cohort A will have a history of 
≥ 2 moderate/severe COPD exacerbations within a 12-month period in the 24 months 
prior to screening.   
A separate substudy (Cohort B) will enroll an observational cohort of patients with mild 
COPD (GOLD 1) and will be required to have optimal guideline-based SOC treatment 
for a minimum of 12 weeks prior to randomization.  Patients must have a history of 
≥ 1 moderate/severe AEx within a 12-month period in the 24 months prior to screening 
and meet all other eligibility criteria.  The rationale for this substudy is based on results 
from large observational studies of COPD that indicate substantial instability in the rate 
of AEx from year to year, regardless of prior AEx history (Han et al. 2017).  This 
instability potentially limits the clinical value of requiring a threshold of ≥ 2 incidents of 
AEx in the previous year (Han et al. 2017) as the basis for treatment decisions or patient 
selection for clinical trials.  Furthermore, a large natural history study that explored the 
association between AECOPD and the change in FEV1 over a 5-year follow-up period 
provided convincing data that confirmed a relationship between exacerbations and FEV1 
loss.  Additionally, this same study indicated that the impact of AEx on FEV1 loss is 
greater in patients with mild COPD (GOLD 1) than in patients with moderate to severe 
COPD (GOLD 2 or 3) (Dransfield et al. 2017).  Collectively, these studies suggest that a 
threshold of ≥ 2 AEx in the prior year provides limited utility in identifying individual 
patients at increased risk of AEx, or classifying individuals for treatment decision making 
and for the basis of patient selection for future clinical trials assessing novel treatments.  
Therefore, the analysis of patients with mild COPD will help clarify the relationship 
between lung structure/function and disease status/progression.  Initial studies in small 
cohorts of healthy smokers and patients with COPD suggest that 129Xe MRI has 
increased sensitivity to detect changes in lung physiology and structure relative to 
standard clinical measures, including pulmonary function tests (Ruppert 2019). 


 
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Patients with GOLD 1 COPD enrolled in Cohort B will be required to be on stable 
background therapy for a minimum of 12 weeks prior to screening.  This cohort of 
patients will be monitored for changes in disease status and progression based on an 
assessment of changes in 129Xe MRI metrics relative to the rate of AEx and other 
standard clinical measures, including lung function activity and PROs. 
3.3.2 
Rationale for Azithromycin and Control Groups 
The selected dose of azithromycin planned for this study is 250 mg/QD.  This dosing is 
supported by the safety and efficacy demonstrated in several research clinical trials and 
current GOLD guidelines (Albert et al. 2011; Simpson et al. 2014; Cui et al. 2018). 
The COPD GOLD 2019 guidelines state that treatment with azithromycin (250 mg/QD 
or 500 mg three times per week) or erythromycin (500 mg two times per day) for 1 year 
in patients prone to exacerbations reduces the risk of exacerbations compared with 
usual care.  These dosing recommendations are based on results from several 
placebo-controlled research clinical trials (Albert et al. 2011; Simpson et al. 2014; 
Vermeersch et al. 2019).  Potential side effects include an increased incidence of 
bacterial resistance, prolongation of corrected QT interval (QTc), and impaired hearing, 
which can be monitored in the clinic.  Several relevant clinical trial reports support the 
clinical benefit of long-term macrolide treatment in reducing the rate of AECOPD (Albert 
et al. 2011).  Azithromycin was chosen over other macrolides (e.g., clarithromycin or 
erythromycin) based on the benefit−risk profile established in several placebo-controlled 
clinical trials (Cui et al. 2018) and the limited drug-drug interaction (DDI) profile.  In 
contrast to clarithromycin and erythromycin, azithromycin is not metabolized by 
cytochrome P450 enzymes, specifically cytochrome P450 3A4 (CYP3A4), involved with 
the metabolism of the largest number of medications (i.e., calcium channel blockers, 
statins).   
In Cohort A, a control group consisting of patients treated only with stable SOC 
medications will be monitored over the 48-week treatment period to assess for 
differences in COPD AEx events, pulmonary function, dyspnea symptoms, 6MWT, 
biomarkers, and safety compared to patients who receive azithromycin plus SOC 
(AZM + SOC).  In Cohort A, patients in both the control and azithromycin arm will 
continue to receive SOC medication that includes daily long-acting bronchodilator 
medication with or without ICS.  The use of a control group is necessary to assess the 
differences in 129Xe MRI metrics, exacerbations, pulmonary function, symptoms, and 
safety compared with patients who receive to azithromycin.  In Cohort B, all patients will 
undergo the same study assessments as patients in Cohort A.  All patients will continue 
to receive SOC for COPD and other allowable medical conditions (with some 
restrictions; refer to Section 4.4).  


 
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3.3.3 
Rationale for Biomarker Assessments 
Biomarker assessments, before and at various timepoints after azithromycin treatment, 
will be used to provide evidence of the biologic activity of azithromycin in patients with 
and without chronic bronchitis, and increase the knowledge and understanding of 
disease biology.  Exploratory biomarker analysis may include, but will not be limited to, 
analysis of eosinophils, neutrophils, c-reactive protein (CRP), sputum mucins, 
transcriptomic changes in blood samples, and imaging measures (e.g., PRMfSAD). 
A blood sample will be collected for DNA extraction to enable identification of genes 
related to chronic bronchitis in COPD that may be associated with disease progression 
or can increase the knowledge and understanding of disease biology. 
3.3.4 
Rationale for Non-Standard Clinical Outcome Assessment 
(129Xe MRI) 
MRI using inhaled HP 129Xe gas (129Xe MRI) will be assessed as a new imaging 
assessment tool that can provide useful images of the functioning of the lung to 
determine change in lung function and structure; 129Xe MRI provides images of the 
functioning lung.  
More sensitive imaging approaches are vital to monitor the progression of COPD as 
COPD manifests itself in a spatially heterogeneous manner. In the COPD lung, areas of 
normal lung are located in close approximation to areas of emphysema and small airway 
(obstructive) disease.  Therefore, it is expected that potential therapeutic responses to 
slow or halt progression would be regional, thus supporting the need for a sensitive tool 
that allows for the detection of localized changes on structure and function over time.  
Advances in 3D pulmonary MRI to image both function and structure now make this 
possible.  HP noble gases, such as 3He and 129Xe (after a single breath mixed with 4He 
or N2), provide a way to visualize pulmonary ventilation 3-dimensionally.  For inhaled 3He 
and 129Xe, increased nuclear polarization overcomes their low density compared to 
tissues and permits imaging their distribution in the airways and airspaces. This can be 
used to measure apparent diffusion coefficients that estimate gas displacement, as well 
as to detect structural abnormities in the small airways.  
For 129Xe, the fractional solubility of xenon gas in biological tissues has additional 
applications for measuring gas exchange, alveolar surface area, and capillary blood 
volume.  Because 129Xe, like oxygen, must traverse the interstitial barrier to reach 
capillary blood, 129Xe signal in RBCs is exquisitely sensitive to barrier thickness and 
surface area.  129Xe in RBCs has a unique frequency shift, allowing it to reveal loss of 
surface area manifested as BDP and RDP.  The exquisite sensitivity to increased 
blood-gas-barrier thickness makes 129Xe MRI uniquely suited to study pulmonary 
function, lung perfusion, and alveolar-to-capillary tissue barrier without ionizing radiation.  
This has the potential to accelerate clinical trials for COPD by literally visualizing the 
therapeutic response on the timescale of months versus years.  


 
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HP 129Xe MRI has been shown to be safe and well-tolerated in several Phase I clinical 
trials (Kirby et al. 2012).  The safety and sensitivity of HP 129Xe MRI has been evaluated 
in patients with chronic lung disease, including idiopathic pulmonary fibrosis, asthma, 
COPD, and pulmonary vascular disease, at one or more of clinical academic centers 
selected to participate in this trial (Driehuys et al. 2012; Kirby et al. 2012; Svenningsen 
et al. 2013; Qinga et al. 2014; Ebner et al. 2017; Martin et al. 2017; Stewart et al. 2017; 
Qing et al. 2019; Weatherley et al. 2019).  These studies have enrolled in excess of 
200 patients and healthy volunteers and demonstrated that inhalation of up to four 
1 L doses of HP 129Xe was well-tolerated, generated no notable changes in measured 
physiologic parameters, and resulted in no serious adverse events or withdrawals.  
Patients in this study will be exposed to five 1 L doses of HP 129Xe, and the selected 
clinical academic centers participating in this trial have the technical experience and 
infrastructure to conduct this study. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 7 sites will participate to enroll approximately 120 patients with a 
diagnosis of COPD across two cohorts.  Approximately 100 patients with COPD 
(GOLD 2–4) will be randomized to Cohort A; patients with chronic bronchitis (n ≤ 60) and 
without chronic bronchitis (n ≥ 40) will be randomized across treatment arms.  
Approximately 20 patients (GOLD 1) will be enrolled in the Cohort B substudy.  
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age ≥40 years at time of signing Informed Consent Form 
• 
Ability to comply with the study protocol, in the investigator's judgment 
• 
Signed Informed Consent Form (signed before any study procedures are 
performed) 
• 
Current or former smokers with ≥ 10 pack years 
• 
mMRC dyspnea score ≥ 1 
• 
Post-bronchodilator FEV1/forced vital capacity (FVC) <0.70 at screening (Visit 1) or 
randomization (Visit 2) 
• 
For patients enrolled in Cohort A:  GOLD Stage 2−4 COPD with a history of 
≥ 2 moderate/severe exacerbations within a 12-month period in the 24 months prior 
to screening 
• 
For patients enrolled in Cohort B:  GOLD Stage 1 COPD with a history of 
≥ 1 moderate/severe exacerbations within a 12-month period in the 24 months prior 
to screening 
• 
Receiving SOC background drug therapy as per GOLD or British Thoracic Society 
(BTS) guidance for COPD for 12 weeks prior to screening (Visit 1) 


 
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• 
On an eligible bronchodilator medication (LABA and/or LAMA) ± ICS therapy for 
≥ 12 weeks prior to screening (Visit 1) 
• 
Chest X-ray or CT scan within 6 months prior to screening (Visit 1), or during the 
screening period (prior to randomization [Visit 2]), that confirms the absence of 
clinically significant lung disease besides COPD 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use adequate contraception during the study period (all 
patients) and for 28 days after the final dose of azithromycin (patients enrolled in 
Cohort A receiving azithromycin) 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
The following are examples of adequate contraceptive methods:  bilateral tubal 
ligation; male sterilization; hormonal contraceptives; hormone-releasing 
intrauterine devices; copper intrauterine devices; male or female condom with 
or without spermicide; and cap, diaphragm, or sponge with spermicide. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of allergy or hypersensitivity to azithromycin 
• 
Significant known respiratory disorders other than COPD that, in the view of the 
investigator, will affect the trial 
• 
A COPD exacerbation and/or pneumonia within the 4 weeks prior to screening 
(Visit 1) 
• 
FEV1 percent predicted less than 25% 
• 
Pregnant or breastfeeding, or intending to become pregnant during the study period 
(all patients) or within 28 days after the final dose of azithromycin (patients enrolled 
in Cohort A receiving azithromycin) 
Women of childbearing potential must have a negative serum pregnancy test 
result at screening. 


 
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• 
Participation in an interventional clinical trial within 4 weeks of screening (Visit 1) or 
receipt of any investigational medicinal product (IMP) within 30 days or 5 half-lives, 
whichever is longer 
• 
Use of systemic corticosteroids within 4 weeks (oral or IV) or 12 weeks 
(intramuscular [IM]) prior to screening 
• 
Active tuberculosis requiring treatment within 12 months prior to Visit 1  
Patients who have completed treatment for tuberculosis at least 12 months 
prior to Visit 1 and have no evidence of recurrent disease are permitted. 
• 
Receiving treatment considered to be palliative (life expectancy <12 months) 
• 
Myocardial infarction, unstable angina, or stroke within 12 months prior to screening 
(Visit 1) 
• 
Clinically significant ECG changes, which in the opinion of investigator warrants 
further investigation or with a QTc interval > 450 ms 
• 
History of congenital or documented QT prolongation 
• 
Currently receiving treatment with other active substance at doses known to prolong 
QT interval such as antiarrhythmic of Classes Ia and III, cisapride, and terfenadine 
• 
Electrolyte disturbance (e.g., clinically significant hypokalemia or hypomagnesemia) 
• 
Clinically relevant bradycardia, cardiac arrhythmia, or severe cardiac insufficiency 
• 
History of myasthenia gravis 
• 
For patients in Cohort A:  Known significant hearing impairment as indicated by 
a score of ≥ 26 on the Hearing Handicap Inventory in the Elderly−Screening 
Questionnaire (HHIE-S) or as determined by the investigator 
• 
Impaired hepatic function 
• 
Severe renal insufficiency (estimated glomerular filtration rate [eGFR] < 10 mL/min) 
• 
Concomitant use of ergot derivatives 
• 
Bloodborne infection (e.g., HIV, hepatitis B or C) 
• 
History of Clostridium difficile (C. difficile) diarrhea  
• 
Ventricular cardiac arrhythmia in the past 30 days 
• 
Claustrophobia, inner ear implants, aneurysm or other surgical clips, metal foreign 
bodies in eye, pacemaker or other contraindication to MRI scanning 
Patients with any implanted device that cannot be verified as MRI compliant will 
be excluded. 
• 
Unable to fit into 129Xe vest coil used for MRI 
• 
Deemed unlikely to be able to comply with instructions during imaging 
• 
Evidence, in the opinion of the investigator, of alcohol, drug, or solvent abuse within 
the prior 12 months 


 
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• 
Medical or psychological conditions which, in the opinion of the investigator, might 
create undue risk to the patient or interfere with the patient’s ability to comply with 
the protocol requirements 
• 
Diagnosis of malignancy within 5 years of Visit 1 (except for excised localized 
non-melanoma skin cancer in remission) 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Patients will be randomized to the treatment arms through the interactive 
voice/web-based response system (IxRS).  After written informed consent has been 
obtained, patients in Cohort A will be randomized in a 1:1 ratio to one of two open-label 
treatment arms (azithromycin, 250 mg/QD plus daily SOC medications or daily SOC 
medications).  Patients in Cohort B will continue to receive daily SOC medications.   
Permuted block randomization will be performed centrally for Cohort A and stratified by 
region (United States or United Kingdom/Canada) and prior exacerbation history (2, ≥ 3).  
During the open-label treatment period, the IxRS will make study treatment kit 
assignments.   
In Cohort A, the number of COPD patients with chronic bronchitis (COPD-CB) will be 
capped at  ≤ 65. 
4.3 
STUDY INTERVENTIONS AND TREATMENTS RELEVANT TO 
THE STUDY DESIGN 
The IMPs for this study are azithromycin and HP 129Xe.  All patients will continue their 
COPD therapy as recommended in published COPD guidelines (GOLD 2019) or BTS 
guidelines (NICE 2018).  Required COPD inhaler therapies, consisting of LABA and/or 
LAMA with or without ICS therapy, are considered non-IMPs for this study.   
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Azithromycin 
Azithromycin will be supplied by the Sponsor in the approved 250-mg tablet dosage 
form.  For information on the azithromycin formulation, see the Summary of Product 
Characteristics for azithromycin. 
4.3.1.2 
Hyperpolarized 129Xe 
129Xe is created by passing a gas mixture of xenon, helium, and nitrogen through the 
Hyperpolarizer.  The gas mixture will be provided by the clinical site and will be 
hyperpolarized at the clinical site.  For information on the gas mixture, see the study 
imaging manual. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.  Details on treatment 
administration (e.g., dose and timing) should be noted on the Study Drug Administration 
electronic Case Report Form (eCRF).  Guidelines for treatment interruption or 


 
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discontinuation for patients who experience adverse events are provided in 
Section 5.1.3. 
4.3.2.1 
Azithromycin 
Patients in Cohort A randomized to treatment intervention will receive generic 
azithromycin 250 mg taken orally (PO) QD.  Patients will receive a 3-month supply of 
azithromycin 250-mg tablets at Visit 2 (baseline), Visit 4 (Week 12), Visit 5 (Week 24), 
and Visit 6 (Week 36) at the study site.  Patients randomized to receive azithromycin will 
receive a maximum of 336 doses with a tablet strength of 250 mg.  All patients will be 
provided with a diary to track daily study treatment and the date of any AEx events. 
4.3.2.2 
Hyperpolarized 129Xe  
HP xenon (129Xe) will be administered at specified timepoints and the total dose bag 
volume should target 20% of the patient’s forced vital capacity followed by a breath 
hold of up to 15 seconds.  Subsequent 129Xe doses will only be administered once the 
patient is ready to proceed.  Patients will be monitored by a qualified medical 
professional for the duration of the xenon dose and post-procedural period, as well as 
the MRI.  Refer to the study imaging manual for details. 
HP 129Xe MRI scans will be acquired according to procedures described in the study 
imaging manual.  Scans will be centrally processed and analyzed per the Independent 
Review Charter (IRC).  129Xe MRI scans will be made available to each participating 
clinical site when the study has been completed and database has been locked.  The 
study imaging manual and IRC are provided to ensure image acquisition and processing 
is standardized across all clinical sites.  
4.3.3 
Standard-of-Care Therapy 
All patients will continue the required COPD inhaler therapy for this study that includes 
bronchodilator medication consisting of LABA and/or LAMA with or without ICS therapy.  
Refer to the local prescribing information for the formulation, packaging, and handling of 
these medications.  Patients may not be on systemic (oral, IV, or IM) corticosteroids, 
biologics, or experimental therapeutics for the treatment of COPD.  All patients will be 
provided with a diary to track daily study treatment and the date of any AEx events. 
4.3.4 
Medical Devices 
In this study, the hyperpolarizer and the MRI machines are considered medical devices.  
Both devices are provided by the site and are not manufactured by or for the Sponsor.  
The hyperpolarizer and MRI machines are to be operated according to standard 
institutional practices. 


 
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4.4 
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS  
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 7 days prior to screening 
(for medications not intended for the treatment of COPD) or 12 weeks prior to screening 
(for medications intended for the treatment of COPD) to the study 
completion/discontinuation visit.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications electronic Case Report Form 
(eCRF). 
Medications known to interact with azithromycin (see prescribing information or 
summary of product characteristics), in addition to digoxin and cyclosporine, should be 
used with caution.  
Azithromycin should not be taken concurrently with ergot derivatives or simultaneously 
with antacids. 
4.4.1 
Permitted Therapy  
All patients will continue their COPD therapy as recommended in published COPD 
guidelines (GOLD 2019 or BTS [NICE 2018]) and adhere to the following: 
• 
Patients must be on stable therapy for at least 12 weeks prior to screening (Visit 1).  
There should be no anticipated changes in bronchodilator medication during the 
study.   
 
Patients are permitted to use the following therapies during the study: 
• 
Inhaled bronchodilator and ICS therapy 
Patients may be on more than one bronchodilator with or without ICS therapy. 
• 
Required COPD inhaler therapy for this study:  Bronchodilator medication consisting 
of LABA and/or LAMA 
• 
Additional background COPD therapy during the trial (e.g., phosphodiesterase-4 
inhibitors and theophylline), but should remain stable from the start of screening 
(Visit 1) through completion of the study 
 
From the start of screening (Visit 1) through completion of the study, the doses of 
bronchodilator medications and ICSs should remain stable.  If changes to the 
background COPD medications are unavoidable, the patient may be switched to another 
brand or formulation that is equivalent to the medication that the patient was receiving at 
study entry.  All changes to a patient’s background medications should be documented 
in the COPD Targeted Concomitant Medications eCRF. 




 
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4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medications, and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, medication 
allergies, smoking history, and use of alcohol and drugs of abuse will be recorded at 
screening.  In particular, sites should record whether the patient has any history of 
anaphylaxis, cancer, cardiovascular disease, eosinophilic disease, inflammatory or 
autoimmune disease, and surgeries with metal implants. Any history of smoking should 
be entered on the Tobacco Use History eCRF.  
Demographic data will include age (date of birth), sex, and self-reported race/ethnicity.    
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should 
be recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified visits 
during the treatment period and as clinically indicated.  Limited physical examination 
includes head, ears, eyes, nose, throat, cardiovascular, respiratory, and dermatologic 
examinations. Changes from baseline abnormalities should be recorded in patient notes.  
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 


 
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4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the patient is in a seated position (resting for at least 
5 minutes), temperature, and oxygen saturation.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent 
visits, record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.  
4.5.5 
Hearing Assessment 
Patients in Cohort A will complete the HHIE-S (Appendix 7) and be queried on any onset 
hearing loss, worsening hearing loss, or hearing disturbances at specified timepoints. 
Any patient in Cohort A randomized to azithromycin reporting onset or worsening 
hearing loss, reporting hearing disturbances, or demonstrating any decline in the 
interpretation of the HHIE-S score during the study will permanently discontinue 
azithromycin and be referred for formal audiology testing.  Any patient who 
permanently discontinues azithromycin should be asked to continue all other study 
assessments, with the exception of azithromycin administration, through the end of the 
study. 
4.5.6 
Tobacco Use 
At each study visit, the patient will be asked about their tobacco use.  Any changes in 
tobacco use since screening (Visit 1) will be recorded in the eCRF. 
4.5.7 
Height and Weight 
Height and weight will be measured at visits according to the schedule of activities (see 
Appendix 1).  Weight will be determined to the nearest 0.1 kg.  For body weight 
measurements, the patient will wear street clothes without any shoes, outerwear, or 
accessories. 
4.5.8 
Chest X-Rays 
A chest X-ray must be performed during screening (between Visit 1 and Visit 2), unless 
a chest X-ray or CT scan has been obtained within 6 months prior to screening (Visit 1) 
and is available for review by the investigator.  The X-ray may be performed locally, but 
must be reviewed by the investigator prior to randomization at Visit 2. 
4.5.9 
Spirometry and Forced Oscillometry 
Spirometry, including the procedure for bronchodilator testing, which is based on the 
American Thoracic Society (ATS) and the European Respiratory Society (ERS) 
Consensus Statement (Graham et al. 2019) and forced oscillometry technique (FOT), 
will be conducted as per the study pulmonary function manual.  Spirometry measures 
will include pre- and post-bronchodilator FEV1 and FVC (volume in liters) per 
Appendix 1.  The percentage of predicted FEV1 and percentage of predicted FVC will 


 
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be derived from these volume measurements using the equations derived from the 
third National Health and Nutrition Examinations Survey (Hankinson et al. 1999).  
Inhaled bronchodilator therapies that may affect spirometry must be withheld until 
pre-bronchodilator spirometry measurements are completed.  Patients must be made 
aware that inhaled bronchodilator use is prohibited within a specified window prior to 
each clinic visit, with the exception of the screening visit (Visit 1), as follows: 
• 
Twice-daily LABA and twice-daily LAMA:  within 12 hours prior to spirometry 
• 
Once-daily LABA and once-daily LAMA:  within 24 hours prior to spirometry 
• 
Short-acting β-agonist/ipratropium:  within 4 hours prior to spirometry  
 
Pre-bronchodilator spirometry should not be performed during the screening visit (Visit 
1) if the patient did not withhold bronchodilator medications during the specified time 
period prior to the screening assessment.  The remaining screening assessments should 
be completed as indicated in Appendix 1.  
FOT will be conducted as per the study pulmonary function manual, which is based on 
the ERS Task Force on Respiratory Impedance Measurements (Oostveen et al. 2003).  
FOT measures will include resistance at low frequency, 5 Hz (R5), resistance change 
(R5-20), AX, and reactance difference inspiration − expiration (∆X5). 
FOT assessments should be performed shortly before completing the pulmonary 
function testing assessments. 
4.5.10 
Gas Exchange-Diffusion Capacity of the Lung for Carbon 
Monoxide Assessment 
DLCO will be conducted as per the study pulmonary function manual, which is based 
on the 2017 ATS/ERS guidance (Graham et al. 2017). 
4.5.11 
High-Resolution Computed Tomography  
Good-quality pulmonary quantitative HRCT scans (one at full inspiration and one 
at expiration) performed per the imaging acquisition guidelines provided in the 
study-specific imaging manual will be obtained at baseline.  Alternatively, an acceptable 
set of scans performed ≤ 6 months prior to screening and in accordance with study 
image acquisition guidelines can be used for eligibility determination.   
Follow-up HRCT scans will be performed at specified timepoints (see Appendix 1).  
Ideally, two follow-up HRCT scans will be performed at both Week 24 (Visit 5) and Week 
48 (Visit 7).  However, if local IRB approves only one follow-up HRCT timepoint, then the 
HRCT scans should be collected at Week 0 (Visit 2) and Week 48 (Visit 7).  Details 
regarding image acquisition will be provided in the imaging manual. 


 
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4.5.12 
Hyperpolarized 129Xe MRI 
129Xe MRI will be performed at each study visit as indicated in the schedule of activities 
(see Appendix 1).  Details for standardization of image acquisition will be provided in the 
imaging manual. 
To confirm that the 129Xe MRI image acquisition procedure has been harmonized across 
all clinical research sites, approximately 2 volunteers will be tested at each site prior to 
randomizing the first patient with COPD.  Each volunteer will complete two MRI test 
sessions within an 8-hour timeframe.  The test scans from the volunteers will be 
analyzed centrally per the study-specific imaging manual. Details regarding test scans 
will be provided in the imaging manual. 
Patients and volunteers will be monitored by a qualified medical professional for the 
duration of the 129Xe dose and post-procedural period, as well as during the MRI. 
4.5.13 
Acute Exacerbations of COPD 
All patients will be provided with a diary to track daily study treatment and the date(s) of 
any AEx events.  Patients will be required to bring their diaries to study visits.  Patients 
will be asked if they have experienced an AEx during the last month at each study visit.   
The investigator will ask directed questions to assess whether the patient experienced 
any adverse events and any protocol-defined COPD exacerbations since the last study 
visit. 
Given that COPD exacerbations are the key primary endpoint in this study, a dedicated 
eCRF will be used to record information regarding protocol-defined exacerbation events.  
A COPD exacerbation must also be reported as an adverse event (or serious adverse 
event as applicable) as per Section 5.2.  Sites should update the COPD Targeted 
Concomitant Medications eCRF with all medications used for treatment. 
4.5.14 
Urgent COPD-Related Health Care Utilization 
At each study visit after randomization, the investigator will ask directed questions to 
assess whether the patient has required any urgent COPD-related health care since 
the last study visit.  Urgent COPD-related health care utilization includes any 
hospitalizations, emergency department visits, and acute care visits (i.e., unplanned 
clinic visits).  A dedicated eCRF will be used to record information regarding any 
COPD-related hospitalizations, emergency department visits, and/or acute care visits. 
4.5.15 
Six-Minute Walk Test  
The 6MWT will be conducted as per the study 6MWT procedural manual that is based 
on the 2002 ATS guidelines for the 6MWT (ATS Statement 2002). 
For safety reasons, all patients should be clinically stable prior to performing any 
study-related 6MWT.  Supplemental oxygen flow rate will be recorded before every 


 
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6MWT.  Heart rate, SpO2, and the Borg Category-Ratio 10 (CR10) Scale (Appendix 6) 
will be recorded immediately before and after the procedure.  The Borg CR10 Scale is 
a 1-item assessment that can be used to measure a variety of perceptions and 
experiences (i.e., perceived exertion, chest pain, dyspnea, and fatigue) (Borg and 
Borg 2010).  The Borg CR10 Scale ranges from 0 (Nothing at all) to 10 (Absolute 
maximum/Highest possible).   
4.5.16 
BODE Index 
The BODE index is a composite score of other assessments collected in the study. 
Body mass index (B), obstruction (O) as measured by FEV1, dyspnea (D) as measured 
by the mMRC scale, and exercise endurance (E) as measured by the 6MWT will be 
assessed as described under the separate sections for each assessment.  The standard 
scoring system will be followed (Celli et al. 2004). 
4.5.17 
Sputum Induction 
Sputum induction will be performed per the study procedure manual.  Patients will be 
pre-medicated with a bronchodilator and then inhale an aerosolized saline solution 
delivered by an ultrasonic nebulizer to facilitate forcible coughs and sputum 
expectoration.  Peak expiratory flow and FEV1 will be monitored during sputum induction 
for safety.  Induced sputum will be processed immediately according to the lab manual 
at the clinical sites to obtain raw and sputolysin-treated sputum samples, as well as 
sputum cell pellets prepared in a special RNA-protecting solution.   
4.5.18 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)  
• 
Chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, 
calcium, phosphorus, magnesium, total and direct bilirubin, total protein, albumin, 
ALT, AST, LDH, alkaline phosphatase, creatine phosphokinase, and uric acid 
• 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
• 
Urinalysis, if clinically indicated as determined by the investigator, including dipstick 
(pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination 
(which may include sediment, RBCs, WBCs, casts, crystals, epithelial cells, 
bacteria) 
 


 
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Samples for the following laboratory tests will be sent to the Sponsor or a designee for 
analysis: 
• 
Serum and plasma samples for exploratory research on biomarkers 
• 
Sputum samples for mucin measurements and for exploratory research on 
biomarkers  
 
Exploratory biomarker research may include, but will not be limited to, analysis of 
eosinophils, neutrophils, sputum mucins, RNA expression from blood, and single 
nucleotide polymorphisms (SNPs) of selected genes (e.g., FAM13A, ATF6, and other 
genes related to COPD).  Research will not be aimed at distinguishing germline 
mutations from somatic mutations. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.22), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exception: 
• 
Blood, serum, plasma, and sputum samples collected for biomarker research will be 
destroyed no later than 10 years after the final Clinical Study Report has been 
completed.   
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on germline mutations, will be subject 
to the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.19 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 


 
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performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  The following should be recorded in the appropriate eCRF: time of 
day of recording, heart rate, RR interval, QRS interval, PR duration, uncorrected QT 
interval, and QT interval corrected through use of Fridericia’s formula (QTcF) based on 
the machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If considered 
appropriate by the Sponsor, ECGs may be analyzed retrospectively at a central 
laboratory. 
If at a particular postdose timepoint the mean QTcF is > 500 ms and/or > 60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 
successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator. The investigator should also 
evaluate the patient for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.20 
Clinical Outcome Assessments 
The SGRQ-C and mMRC will be completed in their entirety by the patient.  Each PRO 
will be collected on paper at the site.  Data Collection Methods for Clinical Outcome 
Assessments PRO instruments will be self-administered at the clinic at specified 
timepoints during the study (see Appendix 1).  At the clinic, instruments will be 
administered before the patient receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified.  Copies of each questionnaire are provided in 
Appendix 2 and Appendix 3. 
4.5.20.1 
St. George’s Respiratory Questionnaire for COPD Patients 
The impact of COPD on health and well-being, as measured by the SGRQ-C (Meguro 
et al. 2007), will be assessed by asking patients to recall their COPD-related 
experiences and to respond to 40 questions included within three domains: symptoms 
(7 items), activity (13 items), and impacts (20 items).  The SGRQ-C does not specify 
a recall period, with the exception of the item that assesses chest trouble.  This item 
has a recall period of the past year.  Lower scores of the SGRQ-C indicate better 
health-related quality of life.  A copy of the assessment is provided in Appendix 2. 


 
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4.5.20.2 
Modified Medical Research Council Dyspnea Scale 
The mMRC scale assesses dyspnea (Bestall et al. 1999).  Patients rate how much their 
breathlessness impacts their mobility.  The mMRC is a 5-item scale.  A score of “0” 
(zero) represents the least impairment due to dyspnea and a score of “4” indicates 
greatest impairment due to dyspnea.  There is no recall period for the mMRC.  The 
mMRC is administered at the site on paper.  The mMRC is completed at Visit 1 and 
Visit 2 to determine whether the patient is eligible for this study.  The mMRC is also 
completed throughout the treatment period as a component of the BODE index, as 
specified in Appendix 1.  A copy of the scale is available in Appendix 3. 
4.5.21 
Optional Blood Samples  
Consenting patients will undergo optional blood samples for DNA extraction to enable 
SNP array to identify variants that are predictive of response to study drug, are 
associated with progression to a more severe disease state, are associated with 
acquired resistance to study drug, are associated with susceptibility to developing 
adverse events, can lead to improved adverse event monitoring or investigation, or can 
increase the knowledge and understanding of disease biology and drug safety.  
Research will be aimed at exploring inherited characteristics.  The samples may be sent 
to one or more laboratories for analysis. 
The Informed Consent Form will contain a separate section that addresses optional 
blood samples.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional blood samples.  The investigator should document 
whether or not the patient has given consent to participate and (if applicable) the date(s) 
of consent, by completing the appropriate eCRF. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
SNP array is a method that sequences specific subsets of the genome, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events.  Data will 
be analyzed in the context of this study but may also be explored in aggregate with data 
from other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 
Samples may be used for exploratory biomarker research as described in 
Section 4.5.18.  For sampling procedures, storage conditions, and shipment instructions, 
see the laboratory manual.  Refer to Section 4.5.18 for details on duration of sample 
storage, use of samples after patient withdrawal, confidentiality standards for data, and 
availability of data from biomarker analyses.  


 
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4.5.22 
Optional Samples for Research Biosample Repository 
4.5.22.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
• 
To study the association of biomarkers with efficacy or disease progression 
• 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
• 
To increase knowledge and understanding of disease biology and drug safety 
• 
To study drug response 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.22.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's Institutional Review Board/Ethics Committee (IRB/EC) and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for RBR 
sampling, this section of the protocol (Section 4.5.22) will not be applicable at that site. 
4.5.22.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to COPD or other respiratory 
diseases or drug safety: 
• 
Leftover blood, serum, sputum, and any derivatives thereof (e.g., DNA, RNA, 
proteins, peptides)  
 
The above samples may be sent to one or more laboratories for analysis of germline 
or somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researchers’ understanding of disease pathobiology.  WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop adverse events. 


 
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Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.22.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.22.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 


 
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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.22.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global.rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.22.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice (GCP) 
by a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation  
Patients must permanently discontinue study treatment if they experience any of the 
following: 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 


 
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• 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
• 
Any Grade 4 adverse event that the investigator determines to be related to study 
treatment 
This excludes COPD exacerbations, unless they meet one of the other criteria 
for study treatment discontinuation. 
• 
Pregnancy 
• 
Development of C. difficile diarrhea (for patients in Cohort A randomized to 
azithromycin) 
• 
Any onset hearing loss, worsening hearing loss, hearing disturbance, or decline in 
the interpretation of the HHIE-S score (for patients in Cohort A randomized to 
azithromycin) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced. 
Patients will return to the clinic for scheduled study visits after the final dose of study 
drug (see Appendix 1 for additional details). 
4.6.2 
Patient Discontinuation from the Study 
All patients will return to the clinic for final clinical assessments at Week 48.  Patients in 
Cohort B will be discontinued after completing assessment at Week 48 Visit.  Patients in 
Cohort A will be discontinued from the study after a final safety follow-up assessment 
performed by telephone at Week 52. 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
• 
Patient withdrawal of consent 
• 
Study termination or site closure 
• 
Adverse event 
• 
Loss to follow-up 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 


 
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For Cohort A, participants will be considered to have completed the trial if they complete 
trial treatment through Visit 7 (Week 48; end-of-treatment visit) and complete Visit 8 
(Week 52; safety follow-up visit, which is conducted by telephone). 
For Cohort B, participants will be considered to have completed the trial if they continue 
to participate in the trial through Visit 7 (Week 48). 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients 
• 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY   
5.1 
SAFETY PLAN 
Azithromycin is an approved agent to treat patients with a bacterial infection, and the 
safety profile for both acute and chronic dosing is well characterized in the drug 
manufacturer’s prescribing information.  The use of HP 129Xe MR imaging is an 
investigational diagnostic tool.  While there is clinical experience with 129Xe MRI in 
studies with healthy volunteers, COPD patients, and patients with other chronic lung 
diseases, its safety profile has not been fully characterized.  
The safety plan for this study is designed to ensure patient safety and includes specific 
eligibility criteria, a Safety Monitoring Committee (SMC), and specific pharmacovigilance 
monitoring assessments, as detailed below.  
A SMC will be used to carefully review the accumulating safety data.  The SMC will 
consist of Sponsor representatives from the following functions: clinical science, drug 


 
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safety, biostatistics, and statistical programming and analysis (SPA), and the principal 
investigator or delegate from each participating clinical study site.  The SMC will 
regularly monitor the safety of the patients in the study and review cumulative data 
approximately every 6 months.   
The anticipated important safety risks are outlined below. 
5.1.1 
Risks Associated with 129Xe 
5.1.1.1 
General Anesthesia 
Xenon is a general anesthetic when breathed continuously at concentrations > 70% for 
extended periods of time.  Patients may experience transient effects including dizziness, 
tingling or numbness of the extremities, nausea, smelling of flowers, or a feeling of 
well-being and euphoria.   
Adverse effects may include those listed below and will be monitored closely by 
medically trained staff throughout the imaging session. 
• 
Sense of analgesia (dizziness, light-headedness, numbness, euphoria, sleepiness, 
and tingling in extremities) 
• 
Altered heart rate 
• 
Altered gas exchange, SpO2  
 
5.1.1.2 
Hypoxemia 
The effect of xenon on the respiratory tract has been the subject of many animal studies.  
Results showed moderately increased airway resistance with high xenon concentrations 
(70%) in pigs and dogs with or without methacholine-induced bronchoconstriction 
(Calzia et al. 1999a), but no effects were seen at a lower xenon concentration (50%) in 
dogs (Zhang et al. 1995).  In a study in pigs (Baumert et al. 2005), where the resistance 
was corrected for gas viscosity and density, it was concluded that the increase in airway 
pressure observed in xenon anesthesia can be attributed entirely to its high density and 
viscosity, and that xenon does not exert any major effects on airway diameter. 
Diffusion hypoxia manifests as a reduction in alveolar oxygen partial pressure and 
occurs when the administration of the gas mixture is discontinued and room air is 
breathed.  This phenomenon is seen in anesthesia with nitrous oxide (N2O) and depends 
on lipid solubility of the gas.  As the solubility of xenon is higher than that of N2, this 
could theoretically occur after exposure to xenon gas.  A study in pigs has been 
performed to address this question and the arterial partial oxygen pressure was 
measured during nitrogen wash-in (30% O2 and 70% N2) after an initial 30-minute 
ventilation period with either 70% xenon and 30% O2, or 70% N2O and 30% O2.  The 
changes in arterial partial oxygen pressure were much less in the xenon-treated pigs as 
compared to that of the N2O group, demonstrating that diffusion hypoxia is much less 
likely with xenon than with N2O, probably due to the low blood solubility of the noble gas 
(Calzia et al. 1999a). 


 
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5.1.2 
Risks Associated with Azithromycin 
Summary data from Phase III and Phase IV trials indicate that azithromycin is generally 
well tolerated.  The most common adverse events observed were gastrointestinal 
disorders followed by central nervous system (hearing loss) disorders, and all were 
typically mild to moderate.  Decreased hearing has been reported at low frequency and 
was reversible.  Prolongation of QT interval and cases of torsades de pointes have been 
reported, with greater incidence in elderly patients. 
5.1.2.1 
Hypersensitivity 
As with erythromycin and other macrolides, serious allergic reactions including 
angioneurotic edema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous 
Pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms 
(DRESS) have been reported.  Some of these reactions with azithromycin have resulted 
in recurrent symptoms and required a longer period of observation and treatment. 
5.1.2.2 
Hepatotoxicity 
Since the liver is the principal route of elimination for azithromycin, the use of 
azithromycin should be undertaken with caution in patients with significant hepatic 
disease.  Cases of fulminant hepatitis potentially leading to life-threatening liver failure 
have been reported with azithromycin.  Some patients may have had preexisting hepatic 
disease or may have been taking other hepatotoxic medicinal products. 
In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia 
associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver 
function tests/investigations should be performed immediately.  Azithromycin 
administration should be stopped if liver dysfunction has emerged. 
5.1.2.3 
Ergot Derivatives 
In patients receiving ergot derivatives, ergotism has been precipitated by 
co-administration of some macrolide antibiotics.  There are no data concerning the 
possibility of an interaction between ergot and azithromycin; however, because of the 
theoretical possibility of ergotism, azithromycin and ergot derivatives should not be 
co-administrated. 
5.1.2.4 
Superinfection 
As with any antibiotic preparation, observation for signs of superinfection with 
non-susceptible organisms including fungi is recommended. 
5.1.2.5 
Clostridium Difficile Associated Diarrhea 
Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly 
all antibacterial agents, including azithromycin, and may range in severity from mild 
diarrhea to fatal colitis.  Strains of C. difficile producing hypertoxin A and B contribute to 
the development of CDAD.  Hypertoxin-producing strains of C. difficile cause increased 
morbidity and mortality, as these infections can be refractory to antimicrobial therapy and 


 
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may require colectomy.  Therefore, CDAD must be considered in patients who present 
with diarrhea during or subsequent to the administration of any antibiotics.  Careful 
medical history is necessary since CDAD has been reported to occur over 2 months 
after the administration of antibacterial agents.  Patients who develop C. difficile diarrhea 
during the study will be discontinued from treatment. 
5.1.2.6 
Myasthenia Gravis 
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia 
syndrome have been reported in patients receiving azithromycin therapy. 
5.1.2.7 
Tinnitus or Hearing Loss 
Hearing disturbances including hearing loss, deafness and/or tinnitus, and reports of 
taste/smell perversion and/or loss have been reported in postmarketing surveillance and 
in randomized controlled trials assessing benefit/risk profile of azithromycin to prevent 
AEx in COPD (Albert et al. 2011). 
Patients in Cohort A will complete the HHIE-S (see Appendix 7) to assess perceived 
hearing disability.  Those with known significant hearing impairment at screening will 
be excluded.  Patients who are randomized to the azithromycin arm complaining of 
worsening tinnitus, onset hearing loss, or worsening hearing loss will permanently 
discontinue azithromycin and be referred for formal audiology testing. 
5.1.2.8 
Elevated Liver Enzymes 
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic 
failure have been reported, some of which have resulted in death.  The combination of 
transaminase elevations and elevated bilirubin without evidence of obstruction is 
generally recognized as an important predictor of severe liver injury that could lead to 
death or the need for liver transplants in some patients.  Discontinue azithromycin 
immediately if signs and symptoms of hepatitis occur. 
Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with 
azithromycin in all patients, then every 12 weeks thereafter.  Dosage modifications or 
interruption may be necessary for liver enzyme elevations.  These guidelines should be 
followed for any patient who may initiate azithromycin treatment, whether as prevention 
or rescue therapy. 
5.1.2.9 
Hypersensitivity: Rash, Pruritus, Tongue, or Facial Swelling 
The only contraindication listed in the E.U. Summary of Product Characteristics for 
azithromycin is giving it to patients with known hypersensitivity to macrolide antibiotics. 


 
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5.1.2.10 
Prolongation of QT Interval 
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac 
arrhythmia and torsades de pointes, have been seen with treatment with macrolides, 
including azithromycin.  Cases of torsades de pointes have been spontaneously 
reported during postmarketing surveillance in patients receiving azithromycin.  
Physician/Principal Investigators should consider the risk of QT prolongation, which can 
be fatal when weighing the potential risks and benefits of azithromycin for patients have 
one or more contraindications 
• 
Known prolongation of the QT interval, a history of torsades de pointes, congenital 
long QT syndrome, bradyarrhythmias or uncompensated heart failure 
• 
Co-medications known to prolong the QT interval 
• 
Ongoing proarrhythmic conditions such as uncorrected hypokalemia or 
hypomagnesemia, clinically significant bradycardia, and in patients receiving 
Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) 
antiarrhythmic  
 
ECG testing will be performed during the screening and baseline visits to exclude 
patients with known risk associated with QT prolongation.  ECG testing should be 
repeated every 6 months to monitor for any significant changes in the QT interval 
months.   
5.1.3 
Management of Patients Who Experience Adverse Events 
5.1.3.1 
Dose Modifications 
Reduction in dosing for adverse events is not permitted.  Patients who experience 
certain adverse events considered to be related to study drug should be discontinued 
from treatment as described in Section 4.6.1.  
5.1.3.2 
Treatment Interruption 
Study treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  If study treatment has been withheld for two or 
more consecutive dosing visits because of toxicity, the patient should be discontinued 
from study treatment.  However, if the adverse event(s) that led to withholding dosing 
shows clear evidence of improvement in the investigator’s judgment, treatment may be 
resumed; the Medical Monitor may be consulted as appropriate. 
5.1.3.3 
Management Guidelines 
Guidelines for management of specific adverse events are outlined in Table 1.   


 
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Table 1 
Management Guidelines 
Event 
Action to Be Taken 
Hepatotoxicity 
ALT or AST > 3 × ULN in combination 
with total bilirubin > 2 × ULN or clinical 
jaundice 
• 
Immediately discontinue study treatment. 
• 
Elevations of AST or ALT of > 5 × ULN should be 
reported as adverse event(s) of special interest to 
the Sponsor in an expedited manner (see 
Section 5.3.3).  
• 
A hepatology consult is recommended. 
Hearing Disturbances 
Any reported onset hearing loss, 
worsening hearing loss, or hearing 
disturbance  
• 
Discontinue study treatment.  
• 
Refer for formal audiology testing. 
QT Prolongation 
Sustained (at least two ECG 
measurements > 30 minutes apart) 
QTcF that is > 500 ms and > 60 ms 
longer than the baseline value 
• 
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment (see 
Section 5.1.3.4).a 
Sustained absolute QTcF that is 
> 515 ms 
• 
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment (see 
Section 5.1.3.4).a 
An episode of torsades de pointes or a 
new ECG finding of clinical concern 
• 
Unless there is a clear alternative cause other than 
study drug, discontinue study treatment (see 
Section 5.1.3.4).a 
ULN = upper limit of normal. 
a In rare circumstances, it may be acceptable to resume azithromycin, provided that any ECG 
abnormalities have resolved and the patient is appropriately monitored, following discussion 
with the Medical Monitor.  Clinical judgment should be applied.  
 
5.1.3.4 
Management of Increases in QT Interval 
Azithromycin should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes: 
• 
Sustained absolute (at least two ECG measurements > 30 minutes apart) QTcF that 
is > 500 ms and > 60 ms longer than the baseline value 
• 
Sustained absolute QTcF that is > 515 ms 
• 
An episode of torsades de pointes or a new ECG finding of clinical concern 


 
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• 
Of note, if there is a new intraventricular conduction block, the increase in QRS 
complex duration should be subtracted from the QTcF change, because this 
represents an increase in QTcF unrelated to alterations in repolarization.  Also of 
note, it is not uncommon to record arrhythmias such as non-sustained ventricular 
tachycardia, supraventricular tachycardia, pauses, or atrial fibrillation in healthy 
volunteers receiving placebo during periods of extended ECG monitoring.  
Therefore, it is critical that expert cardiology advice be sought to confirm any ECG 
changes and to ascertain the likelihood of a drug-induced arrhythmia versus the 
background occurrence of this arrhythmia.  In such a situation, saving all available 
ECG data is highly suggested. 
• 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended to 
help in the management of such patients. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, 
including serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation patient administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can, therefore, be any of the 
following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.9 for more 
information) 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 


 
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5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to WHO 
Toxicity Grading Scale; see Section 5.3.3); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6) 
 


 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.1.3 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.3−5.5.  The 
investigator is also responsible for reporting medical device complaints. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study randomization, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.3.2 for instructions for reporting serious adverse events). 
After randomization, all adverse events will be reported until 28 days after the final dose 
of azithromycin. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.5. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The WHO toxicity grading scale (see Appendix 5) will be used for assessing adverse 
event severity.  Table 2 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale. 


 
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Table 2 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale 
Grade 
Severity 
1 
Mild; transient or mild discomfort (< 48 hours); no medical intervention or 
therapy required 
2 
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required 
3 
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible 
4 
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable 
WHO = World Health Organization. 
Notes:  Developed by the Division of Microbiology and Infectious Diseases. 
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see Section 5.2.2). 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 3): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 3 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 


 
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5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.3.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 


 
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• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × upper limit of normal [ULN] associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 or 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 


 
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Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × ULN) in combination with either an elevated 
total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.3.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.2.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.3.2).  This 
includes death attributed to progression of COPD. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of COPD, “Chronic Obstructive Pulmonary 
Disease progression" should be recorded on the Adverse Event eCRF.   
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.5. 


 
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5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of COPD 
Medical occurrences or symptoms of deterioration that are anticipated as part of COPD 
should be recorded as an adverse event if judged by the investigator to have 
unexpectedly worsened in severity or frequency or changed in nature at any time during 
the study.  When recording an unanticipated worsening of COPD on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated worsening of Chronic Obstructive Pulmonary 
Disease"). 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
• 
Hospitalization for respite care 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 


 
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5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (defined in Section 5.2.2; see Section 5.4 for details on 
reporting requirements) 
• 
Adverse events of special interest (defined in Section 5.2.3, see Section 5.4.2 for 
details on reporting requirements) 
• 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs/ECs, drug 
manufacturers, and health authorities based on applicable legislation. 
5.4.1 
Emergency Medical Contact 
Medical Monitor Contact Information 
Genentech Medical Monitor: 
Medical Monitor:  
, M.D., M.A.S. (Primary) 
Telephone Nos.: 
+1 650-225-2331 (United States) 
 
 (United States) 
 
Genentech Medical Monitor: 
Medical Monitor:  
, M.D. (Secondary) 
Telephone Nos.: 
+1 650-866-7684 (United States) 
 
+1 650-826-9469 (United States) 
 
5.4.2 
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 


 
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5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of 
special interest will be reported until 28 days after the final dose of study treatment.  
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 
via the electronic data capture (EDC) system.  A report will be generated and sent to 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur > 28 days after the final dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 28 days after the final dose of azithromycin.  A paper Clinical Trial Pregnancy 
Reporting Form should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Pregnancy should not be recorded on the Adverse Event 
eCRF.  The investigator should discontinue study treatment and counsel the patient, 
discussing the risks of the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy.  Any serious adverse 
events associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event eCRF.  In addition, the investigator will submit a paper 
Clinical Trial Pregnancy Reporting Form when updated information on the course and 
outcome of the pregnancy becomes available.   
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4). 


 
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If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.  
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study treatment.  These events should be reported through use of the Adverse Event 


 
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eCRF.  However, if the EDC system is not available, the investigator should report these 
events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Azithromycin 
Single drug covered by prescribing information: 
Azithromycin E.U. Summary of Product Characteristics 
129Xe MRI 
Drug device combination covered by combination 
Investigator’s Brochure:  
HP 129Xe and MRI Investigator's Brochure 
HP = hyperpolarized; MRI = magnetic resonance imaging. 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
A SMC will monitor the incidence of the above-listed anticipated events during the study.  
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
Power calculations for this exploratory study require many assumptions due to lack of 
available literature on the 129Xe MRI metrics.  Further details than those provided in the 
protocol, including code to generate these calculations, are available in the Statistical 
Analysis Plan (SAP).  All calculations were done in R version 3.5.0.  The focus of this 
trial is on estimation, not hypothesis testing. 


 
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The main objective of this study is establishing if 129Xe MRI metrics (VDP) are a more 
sensitive measure of lung function decline and can predict the rate of moderate/severe 
exacerbation.  Approximately 100 patients in Cohort A will be enrolled in this study.  A 
sample size of 100 will enable enough exacerbations to anchor the evaluation of the 
performance of VDP. 
This study is powered (at 77%) to detect a treatment effect due to exacerbation, 
depending on assumptions.  Power calculation was done based on a negative binomial 
with over-dispersion of 1.3 (COPD BEAT data), with 5% alpha, assuming a mean 
exacerbation frequency of 2 and observed for 48 weeks.  A one-sided test was used and 
10% drop-out rate.  A further assumption on the azithromycin effect size was needed to 
establish powera 35 % reduction rate ratio was used (Seemungal et al. 2008).   
This study is powered, depending on assumptions, for the secondary efficacy objectives.  
To test the sensitivity of VDP metric relative to FEV1 (coefficient of variation test), a 
sample size of 100 provides just under 90% power to establish improved coefficient of 
variation relative to FEV1 (assumes coefficient of variation observed in Weatherly 
et al. 2019 of 180% and using a simulation-based power calculation run with MSLR and 
a p-value of 0.05.) 
This study is well powered to test the secondary efficacy objective of establishing the 
relationship between HRCT metrics and the VDP metric.  With a sample size of 100, and 
assuming a true correlation of 0.25 between the metrics, the study has approximately 
75% power to determine if a correlation exists (assuming a multivariate normal with 
correlation of 0.25 and PRMfSAD mean of 26.6% and standard deviation of 11.6% [Bhatt 
et al. 2016]).  Assumptions of operating characteristics of 129Xe MRI metric, VDP, come 
from Smith et al. 2018 (mean = 4.37, SD = 1.89). 
Exploratory endpoints of RDP and BDP were not evaluated in terms of power.  They are 
purely exploratory and there is no literature on which to base a power calculation. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY OR 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, COPD-CB) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented overall and by treatment group. 


 
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6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all patients, with patients 
grouped according to their assigned treatment. 
6.4.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are detailed in Section 2.1.1. 
Details of the analysis are available in the SAP, including sensitivity analysis.  At a 
minimum, VDP change at 24 weeks can predict rate of moderate/severe COPD 
exacerbation over 48 weeks, controlling for treatment assignment.  The initial model will 
be a negative binomial model for exacerbation rate using the intent-to-treat (ITT) 
population.  As this is an exploratory study, sensitivity analysis is performed for the 
purpose of confirming signal.  If signal is not found using the primary analysis, sensitivity 
analysis will not be performed. 
6.4.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is detailed in Section 2.1.2. 
Details of the analysis are available in the SAP, including sensitivity analysis around 
alternative timepoints.  Establishing greater sensitivity of 129Xe MRI metrics (VDP) will 
rely on a coefficient of variation test.  Establishing correlation of 129Xe MRI metrics (VDP) 
with HRCT metrics will rely on testing the correlation metric.  
6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints for this study are detailed in Section 2.1.3. 
Details of the analysis are available in the SAP, including sensitivity analysis around 
alternative timepoints.  Establishing greater sensitivity of 129Xe MRI metrics (RDP and 
VDP), will rely on a coefficient of variation test.  Establishing correlation of 129Xe MR 
imaging metrics (RDP and VDP) with other metrics will rely on testing the correlation 
metric.  Prognostic biomarker assessment will be done via linear modeling for primary 
129Xe MRI endpoints (RDP, VDP, and BDP).  
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all patients who received at least one dose 
of study drug during the 48-week open-label treatment period, with patients grouped 
according to treatment received (AZM + SOC or SOC).  
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs (see 
Section 2.2). 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 


 
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All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to the WHO toxicity grading scale.  All adverse events, serious adverse 
events, adverse events leading to death, adverse events of special interest, and adverse 
events leading to study treatment discontinuation that occur on or after the first dose of 
study treatment (i.e., treatment emergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, and severity grade.  For events of varying 
severity, the highest grade will be used in the summaries.  Deaths and cause of death 
will be summarized. 
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized.  
6.6 
EXPLORATORY ANALYSIS OF PATIENT-REPORTED 
OUTCOME MEASURES 
The PRO measures for this study are as follows: 
• 
SCRQ-C change from baseline to Week 24 and Week 48 
• 
Change in cough and sputum as measured by visual analogue score for dyspnea, 
cough sputum production (100 mm) from baseline to Week 24 and Week 48 
 
6.7 
EXPLORATORY BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies.  Exploratory biomarker objectives and endpoints are described in Section 2.3. 
Pharmacodynamic (PD) biomarkers (e.g., eosinophils, neutrophils, sputum mucins, and 
serum CRP) may be assessed to determine pharmacological activity of azithromycin in 
patients with and without chronic bronchitis.  Data will be summarized by absolute levels 
of the biomarker, as well as absolute and relative changes from levels at randomization 
visit, for each treatment group.  Additional PD analyses will be conducted as appropriate. 
Additional exploratory analyses to understand molecular pathways will evaluate the 
relationship at baseline and longitudinally between biomarkers in sputum, blood (serum, 
plasma, and RNA from blood) or other biomarker endpoints. 
6.8 
INTERIM ANALYSES 
An interim analysis may be performed to assess for changes in VDP and/or other 129Xe 
MRI metrics relative to other clinical assessments, at the Sponsor’s discretion. 


 
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Given the exploratory nature of this study, the Sponsor may choose to conduct 
additional interim efficacy analyses.  The decision to conduct an optional interim analysis 
and the timing of the analysis will be documented in the Sponsor's trial master file prior 
to the conduct of the interim analysis.  The interim analysis will be performed and 
interpreted by the Sponsor’s study team personnel. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
eCRF and paper patient reported questionnaires including SGRQ-C and mMRC are the 
primary data collection instruments and are treated as source data. All source data will 
be entered into the EDC system by site staff. 
The Sponsor will provide support for data management of this study, including quality 
checking of the data in the EDC.  Data entered manually will be collected via EDC 
through use of eCRFs.  Sites will be responsible for data entry into the EDC system.  In 
the event of discrepant data, the Sponsor will request data clarification from the sites, 
which the sites will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 


 
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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-
related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 


 
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the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 


 
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The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated 
or revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7). 


 
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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC authority requirements and the policies and 
procedures established by their IRB/EC, and archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any collaborating site 
or location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  The 
Sponsor will identify potential risks associated with critical trial processes and data and 
will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
Genentech, a member of the Roche group, is the Sponsor of this study.  A contract 
research organization (CRO) may provide clinical operations oversight, including, but not 
limited to, project management, site management, data quality support, safety reporting, 
and regulatory activities as specified in the study management plans.  The Sponsor will 


 
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provide CRO oversight, develop the database and randomization scheme, and conduct 
statistical programming and analysis.  EDC will be utilized for this study.  
An IxRS will be used to assign patient numbers, randomize patients into the study 
through use of a dynamic hierarchical algorithm, and manage site drug supply. 
An SMC will be used in this study to provide oversight of safety (see Section 5.1). 
Samples for blood and urine chemistry including pregnancy tests will be analyzed at the 
local laboratory.  Samples for PD biomarkers, tests will be sent to the Sponsor for 
analysis. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 


 
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78/Protocol GE42063, Version 5 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Baumert JH, Hecker KE, Hein M, et al. Effects of xenon anaesthesia on the circulatory 
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Buist AS, McBurnie MA, Vollmer WM, et al. International variation in the prevalence of 
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Joseph G. Joseph G. Mammarappallil4, EM, et al. Identification of gas exchange 
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NICE Guideline Updates Team (UK) (editors). Chronic obstructive pulmonary disease in 
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Care Excellence (UK); 2018 Dec. 
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Qinga J, Mugler JP III, Altes TA, et al. Assessment of lung function in asthma and COPD 
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dissolved-phase MRI. NMR Biomed 2014;27:1490−1501. 
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early-stage lung disease in smokers. Acad Radiol 2019;26:335−6. 
Seemungal TA, Tom M A, Wilkinson MA, et al. Long-term erythromycin therapy is 
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Am J Respir Crit Care Med 2008;178:1139–47.  
Simpson JL, Powell H, Baines KJ, et al. The effect of azithromycin in adults with stable 
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Smith L, Marshall H, Aldag I, et al. Longitudinal assessment of children with mild cystic 
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Taylor SP, Sellers E, Taylor BT. Azithromycin for the Prevention of COPD 
Exacerbations: The Good, Bad, and Ugly. Am J Med. 2015;128:1362.e1−6. 
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World Health Organization. The Global Burden of Disease [resource on the Internet]. 
2017 [cited: 12 December 2017]. Available 
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nitrous oxide. Can J Anaesth 1995;42:547−53. 
 
 


 
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Appendix 1  
Schedule of Activities 
 
Screening 
Treatment Period 
End 
of Tx 
Safety 
Follow-Up a 
ET b 
UV 
Visit No. 
1 
2 c 
3 
4 
5 
6 d 
7 
8 e 
 
 
Week 
(Window, days) –28 to –1 
0 
(± 4) 
6 
(± 4) 
12 
(± 7) 
24 
(± 7) 
36 
(± 7) 
48 
(± 7) 
52 
(± 7) 
 
 
Informed consent f 
x 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
Demographic data g 
x 
 
 
 
 
 
 
 
 
 
General medical history and baseline conditions h 
x 
 
 
 
 
 
 
 
 
 
Smoking history 
x 
 
 
 
 
 
 
 
 
 
Tobacco use 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Vital signs i 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
Complete physical examination 
x 
 
 
 
 
 
 
 
 
 
Limited physical examination j 
 
x 
x 
x 
x 
x 
x 
 
x 
x 
Single ECG k 
x 
x 
 
 
x 
 
x 
 
x 
 
HHIE-S l 
x 
 
 
x 
x 
 
x 
 
 
 
Pregnancy test m 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
Annual COPD exacerbation rate n 
x 
 
 
 
 
 
 
 
 
 
SGRQ-C o 
 
x 
 
x 
x 
 
x 
 
x 
x 


Appendix 1: Schedule of Activities 
  
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Screening 
Treatment Period 
End 
of Tx 
Safety 
Follow-Up a 
ET b 
UV 
Visit No. 
1 
2 c 
3 
4 
5 
6 d 
7 
8 e 
 
 
Week 
(Window, days) –28 to –1 
0 
(± 4) 
6 
(± 4) 
12 
(± 7) 
24 
(± 7) 
36 
(± 7) 
48 
(± 7) 
52 
(± 7) 
 
 
mMRC Dyspnea p 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
Hematology q 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Chemistry r 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
Urinalysis s 
x 
x 
 
 
x 
 
x 
 
x 
x 
Pre-bronchodilator spirometry t 
x 
x 
 
 
x 
 
x 
 
 
 
Post-bronchodilator spirometry  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
Forced oscillometry technique  
 
x 
x 
x 
x 
 
x 
 
x 
x 
DLCO/KCO  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
129Xe MRI session u 
 
x 
x 
x 
x 
 
x 
 
x 
 
X-ray v 
x 
 
 
 
 
 
 
 
 
x 
HRCT w 
 
x 
 
 
(x) 
 
x 
 
 
 
6-minute walk test x 
 
x 
 
 
x 
 
x 
 
 
 
Serum for biomarkers  
 
x 
 
x 
x 
 
x 
 
x 
x 
Plasma for biomarkers 
 
x 
 
 
 
 
 
 
 
 
Sputum for biomarkers y 
 
x 
 
x 
x 
 
x 
 
 
x 
Blood for RNA analysis  
 
x 
 
 
 
 
x 
 
x 
 
Blood for specific DNA SNP analysis (optional) z 
 
x 
 
 
 
 
 
 
 
 


Appendix 1: Schedule of Activities 
  
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Screening 
Treatment Period 
End 
of Tx 
Safety 
Follow-Up a 
ET b 
UV 
Visit No. 
1 
2 c 
3 
4 
5 
6 d 
7 
8 e 
 
 
Week 
(Window, days) –28 to –1 
0 
(± 4) 
6 
(± 4) 
12 
(± 7) 
24 
(± 7) 
36 
(± 7) 
48 
(± 7) 
52 
(± 7) 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AEx 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Health care utilizations aa 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events bb 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug Rx (3-month supply) cc 
 
x 
 
x 
x 
x 
 
 
 
 
Patient diary review dd 
 
 
x 
x 
x 
x 
x 
 
 
 
6MWT = six-minute walking test; AEx = acute exacerbations; BORG CR10 Scale = Borg Category-Ratio 10 Scale; COPD = chronic obstructive 
pulmonary disease; CT = computed tomography; DLCO = carbon monoxide diffusing capacity; ET = early termination; FEV1 = forced expiratory 
volume; HHIE-S = Hearing Handicap Inventory in the Elderly−Screening Questionnaire; HRCT = high-resolution computed tomography; IRB = 
Institutional Review Board; KCO = carbon monoxide transfer coefficient; mMRC = Modified Medical Research Council; MRI = magnetic resonance 
imaging; PRO = patient-reported outcome; Rx = prescription; SGRQ-C = St. George’s Respiratory QuestionnaireCOPD; SNP = single nucleotide 
polymorphism; SOA = Schedule of Activities; SOC = standard of care; SpO2 = oxygen saturation; Tx = treatment; UV = unscheduled visit. 
a Safety follow-up will take place via telephone interview for adverse events, health care utilization, and change in medications. 
b The ET visit applies to patients who discontinue study drug prematurely.  
c All baseline assessments at Visit 2 must be completed prior to the first dose of study drug (azithromycin).  Azithromycin will only be dispensed to 
patients randomized to study drug in Cohort A. 
d Patients in Cohort B will be assessed by telephone call from site staff.  Assessments limited to changes in concomitant medications, AEx, health 
care utilizations, and adverse events occurring between Week 24 and Week 36. 
e Limited to patients in Cohort A only. 
f Written informed consent for participation in the study must be obtained before performing any study-specific tests or evaluations. 
g Demographic data will include age (date of birth), sex, and self-reported race/ethnicity.   


Appendix 1: Schedule of Activities 
  
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h Medical history, including clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, medication allergies, smoking history, and use of alcohol and drugs of abuse, will be recorded at screening.  In particular, sites should 
record whether the patient has any history of anaphylaxis, cancer, cardiovascular disease, eosinophilic disease, inflammatory or autoimmune 
disease or surgeries with metal implants. Any history of smoking should be entered on the Tobacco Use History eCRF. 
i Vital signs include respiratory rate, pulse rate, systolic and diastolic blood pressure while the patient is in a seated position (resting for at least 
5 minutes), temperature, and oxygen saturation. 
j Limited physical examination includes head, ears, eyes, nose, throat, cardiovascular, respiratory, and dermatologic examinations. 
k ECGs must be performed prior to any scheduled spirometry measurements, vital sign measurements, or blood draws. 
l Required hearing questionnaires are limited to Cohort A. 
m All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at specified 
subsequent visits.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
n Annual COPD exacerbation rate is determined by a continuous 12-month period within the 24 months prior to screening where a COPD 
exacerbation is defined by symptomatic worsening of COPD requiring use of systemic corticosteroids and/or antibiotics for at least 3 days, a 
single depot injectable dose of corticosteroids will be considered. 
o PRO questionnaires must be administered prior to the completion of other non-PRO assessments and before the patient receives any disease 
status information or study drug during that visit. 
p mMRC (Appendix 3) must be administered prior to the completion of other non-PRO assessments and before the patient receives any disease 
status information or study drug during that visit. 
q Includes hemoglobin, hematocrit, platelet count, WBC count, RBC count, and differential count (neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, other cells). 
r Includes sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, total 
protein, albumin, ALT, AST, LDH, alkaline phosphatase, creatine phosphokinase, and uric acid. 
s If clinically indicated as determined by the investigator.  Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic 
examination (which may include sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
t Pre-bronchodilator spirometry.  Except for Visit 1, patients must withhold inhaled bronchodilator use within the specified window (see 
Section 4.5.9).  The pre-bronchodilator spirometry measurements should not be performed during the screening visit (Visit 1) if the patient did 
not withhold bronchodilator medications during the specified time period prior to the screening assessment.  For safety reasons, spirometry may 
be omitted if the patient is having an acute COPD exacerbation event at the time of the scheduled visit. 


Appendix 1: Schedule of Activities 
  
129Xe MRIGenentech, Inc. 
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u Sites should ensure that the patient receives a bronchodilator (either daily SOC medication or short-acting bronchodilator on visits where 
pre-bronchodilator spirometry is performed) prior to performing the 129Xe MRI assessment. 
v A chest X-ray must be performed or scheduled at Visit 1 unless a chest X-ray or CT scan has been obtained within 6 months prior to Visit 1 and 
is available for review by the investigator.  The X-ray may be performed locally but must be reviewed by the investigator prior to randomization at 
Visit 2.  If a chest X-ray (or CT scan) is not available in the 6 months preceding Visit 1 or a chest X-ray cannot be completed during screening, 
the patient will not be eligible for the study. 
w An HRCT should be performed at baseline (Visit 2) unless an acceptable set of inspiratory and expiratory scans have been performed within 
6 months of screening per imaging manual guidelines.  Follow-up sets of scans at Weeks 24 and 48 will be performed as indicated in the SOA if 
acceptable by site IRB; if determined to be unacceptable by site IRB, a single follow-up set of scans at Week 48 is acceptable.   
x For safety reasons, the 6MWT may be omitted if the patient is unable or unwilling to perform the test. Heart rate, SpO2, and the Borg CR10 Scale 
(Appendix 6) will be recorded immediately before and immediately after the procedure. 
y Sputum induction will be performed per the study procedure manual.  Subjects will be pre-medicated with a bronchodilator and then inhale an 
aerosolized saline solution delivered by an ultrasonic nebulizer to facilitate forcible coughs and sputum expectoration.  Peak expiratory flow and 
FEV1 will be monitored during sputum induction for safety.  Induced sputum will be processed immediately according to the lab manual at the 
clinical sites to obtain raw and sputolysin treated sputum samples, as well as sputum cell pellets prepared in a special RNA-protecting solution.   
z Blood samples for DNA are optional and should only be obtained from patients who provide written informed consent to participate. 
aa The investigator will ask directed questions to assess whether the patient has required any urgent COPD-related health care since the last 
study visit.  Urgent COPD-related health care utilization includes any hospitalizations, emergency department visits, and acute care visits 
(i.e., unplanned clinic visits).  See Section 4.5.14 for additional details. 
bb All adverse events, including serious adverse events and adverse events of special interest.  Patients in Cohort A randomized to azithromycin 
will additionally be queried on any onset or worsening hearing loss or hearing disturbances.  
cc 3-month drug supply limited to Cohort A.  Completion of all Visit 2 baseline assessments required to be completed prior to dispensing first dose 
of azithromycin. 
dd  Patients will be instructed to complete a diary that will be reviewed at study visits. 
 
 


 
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Appendix 2  
St. George’s Respiratory Questionnaire for COPD Patients 
 


 
Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
129Xe MRIGenentech, Inc. 
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Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
129Xe MRIGenentech, Inc. 
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Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
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Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
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Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
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Appendix 2: St George’s Respiratory Questionnaire for COPD Patients 
 
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Appendix 3  
Modified Medical Research Council Dyspnea Scale 
. 
 


 
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Appendix 4  
Six-Minute Walk Test 
The Six-Minute Walk Test (6MWT) will be conducted as per the study 6MWT Procedural 
Manual that is based on the 2002 American Thoracic Society (ATS) guidelines for the 
Six-Minute Walk Test (ATS Statement 2002). 
Absolute contraindications to the 6MWT include unstable angina or myocardial infarction 
during the previous month. 
Relative contraindications to participation in the 6MWT include: 
• 
Resting heart rate > 120 per minute 
• 
Systolic blood pressure > 180 mmHg 
• 
Diastolic blood pressure > 100 mmHg 
 
Supplemental oxygen flow rate will be recorded before every 6MWT.  Heart rate, oxygen 
saturation (SpO2), and the Borg Category Ratio 10 (CR10) Scale will be recorded 
immediately before and after the procedure. 
6MWT procedures will occur with the patient receiving the O2 flow rate as determined by 
the screening oxygen titration protocol.  Patients that are prescribed a different oxygen 
requirement either at rest or with exercise should be placed on the flow rate determined 
during the titration protocol.  SpO2 should be measured before all study-related 6MWTs 
after the patient has been at rest for 5 minutes while receiving their titrated O2 
requirement.  Any patient who has an SpO2 of < 85% after 5 minutes should not undergo 
the procedure during that visit.  
SpO2 should not be monitored during the 6MWT procedure.  Patients should 
immediately stop the 6MWT procedure if any of the following occur: 
• 
Chest pain 
• 
Light headedness 
• 
Intolerable dyspnea 
• 
Leg cramps 
• 
Staggering 
• 
Diaphoresis 
• 
Pale or ashen appearance 
• 
Mental confusion or headache 


 
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Appendix 5  
WHO Toxicity Grading Scale 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
HEMATOLOGY 
Hemoglobin 
9.5−10.5 g/dL 
8.0−9.4 g/dL 
6.5−7.9 g/dL 
< 6.5 g/dL 
Absolute neutrophil count 
1000−1500/mm3 
750−999/mm3 
500−749/mm3 
<500/mm3 
Platelets 
75,000−99,000/mm3 
50,000−74,999/mm3 
20,000−49,000/mm3 
<20,000/mm3 
PT 
1.01−1.25 × ULN 
1.26−1.5 × ULN 
1.51−3.0 × ULN 
>3 × ULN 
aPPT 
1.01−1.66 × ULN 
1.67−2.33 × ULN 
2.34−3 × ULN 
> 3 × ULN 
Fibrinogen 
0.75−0.99 × LLN 
0.50−0.74 × LLN 
0.25−0.49 × LLN 
< 0.25 × LLN 
Fibrin split product 
20−40 µg/mL 
41−50 µg/mL 
51−60 µg/mL 
> 60 µg/mL 
Methemoglobin 
5%−9.9% 
10.0%−14.9% 
15.0%−19.9% 
> 20% 
LIVER ENZYMES 
AST (SGOT) 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
ALT (SGPT) 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
GGT 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
ALP 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
Amylase 
1.1−1.5 × ULN 
1.6−2.0 × ULN 
2.1−5.0 × ULN 
> 5.1 × ULN 
CHEMISTRIES 
Hyponatremia 
130−135 mEq/L 
123−129 mEq/L 
116−122 mEq/L 
< 116 or mental status changes or 
seizures 
Hypernatremia 
146−150 mEq/L 
151−157 mEq/L 
158−165 mEq/L 
> 165 mEq/L or mental status 
changes or seizures 
Hypokalemia 
3.0−3.4 mEq/L 
2.5−2.9 mEq/L 
2.0−2.4 mEq/L or intensive 
replacement Rx required or 
hospitalization required 
< 2.0 mEq/L or paresis or ileus or 
life-threatening arrhythmia 
Hyperkalemia 
5.6−6.0 mEq/L 
6.1−6.5 mEq/L 
6.6−7.0 mEq/L 
> 7.0 mEq/L or life-threatening 
arrhythmia 
Hypoglycemia 
55−64 mg/dL 
40−54 mg/dL 
30−39 mg/dL 
<30 mg/dL or mental status changes 
or coma 
Hyperglycemia 
(note if fasting) 
 
 
251−500 mg/dL 
> 500 mg/dL or ketoacidosis or 
seizures 
Hypocalcemia 
(corrected for albumin) 
8.4−7.8 mg/dL 
7.7−7.0 mg/dL 
6.9−6.1 mg/dL 
< 6.1 mg/dL or life-threatening 
arrhythmia or tetany 


 
Appendix 5: WHO Toxicity Grading Scale 
  
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ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Hypercalcemia 
(correct for albumin) 
10.6−11.5 mg/dL 
11.6−12.5 mg/dL 
12.6−13.5 mg/dL 
> 13.5 mg/dL life-threatening 
arrhythmia 
Hypomagnesemia 
1.4−1.2 mEq/L 
1.1−0.9 mEq/L 
0.8−0.6 mEq/L 
< 0.6 mEq/L or life-threatening 
arrhythmia 
Hypophosphatemia 
2.0−2.4 mg/dL 
1.5 −1.9 mg/dL or 
replacement Rx 
required 
1.0 −1.4 mg/dL intensive 
Rx or hospitalization 
required 
< 1.0 mg/dL or life-threatening 
arrhythmia 
Hyperbilirubinemia 
1.1−1.5 × ULN 
1.6−2.5 × ULN 
2.6−5 × ULN 
> 5 × ULN 
BUN 
1.25−2.5 × ULN 
2.6−5 × ULN 
5.1−10 × ULN 
> 10 × ULN 
Creatinine 
1.1 × 1.5 × ULN 
1.6−3.0 × ULN 
3.1−6 × ULN 
> 6 × ULN or required dialysis 
URINALYSIS 
Proteinuria 
1+ or  
< 0.3% or  
<3 g/L or  
200 mg−1 g loss/day 
2 −3 + or  
0.3%−1.0% or 
3−10 g/L or  
1−2 g loss/day 
4+ or 
> 1.0% or 
> 10 g/L or 
2−3.5 g loss/day 
nephrotic syndrome or  
> 3.5 g loss/day 
Hematuria 
Microscopic only 
Gross, no clots 
Gross+ clots 
Obstructive or required transfusion 
CARDIAC DYSFUNCTION 
Cardiac rhythm 
 
Asymptomatic, 
transient signs, no 
Rx required 
Recurrent/persistent; 
no Rx required 
Requires treatment 
Hypertension 
Transient inc. > 20 mm; 
no Rx 
Recurrent, chronic,  
> 20 mm, Rx required 
Requires acute Rx; 
no hospitalization 
Requires hospitalization 
Hypotension 
Transient orthostatic 
hypotension, no Rx 
Symptoms correctable 
with oral fluids Rx 
Requires IV fluids; 
no hospitalization 
required 
Requires hospitalization 
Pericarditis 
Minimal effusion 
Mild/moderate 
asymptomatic 
effusion, no Rx 
Symptomatic effusion; pain; 
EKG changes 
Tamponade; pericardiocentesis or 
surgery required 


 
Appendix 5: WHO Toxicity Grading Scale 
  
129Xe MRIGenentech, Inc. 
99/Protocol GE42063, Version 5 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Hemorrhage, blood loss 
Microscopic/occult 
Mild, no transfusion 
Gross blood loss; 
1−2 units transfused 
Massive blood loss; 
> 3 units transfused 
RESPIRATORY 
Cough 
Transient; no Rx 
Treatment associated 
cough; local Rx 
Uncontrolled 
 
Bronchospasm, acute 
Transient; no Rx 
< 80%−70% FEV1 
(or peak flow) 
Requires Rx 
normalizes with 
bronchodilator; FEV1 
50%−70% (or peak 
flow) 
No normalization with 
bronchodilator; FEV1 
25%−50% (or peak flow 
retractions) 
Cyanosis: FEV1 < 25% (or peak 
flow) or intubated 
GASTROINTESTINAL 
Stomatitis 
Mild discomfort; 
no limits on activity 
Some limits on 
eating/drinking 
Eating/talking very limited 
Requires IV fluids 
Nausea 
Mild discomfort; 
maintains reasonable 
intake 
Moderate discomfort; 
intake decreased 
significantly; some 
activity limited 
Severe discomfort; 
no significant intake; 
activities limited 
Minimal fluid intake 
Vomiting 
Transient emesis 
Occasional/moderate 
vomiting 
Orthostatic hypotension or 
IV fluids required 
Hypotensive shock or hospitalization 
required for IV fluid therapy 
Constipation 
Mild 
Moderate 
Severe 
Distensions with vomiting 
Diarrhea 
Transient 3−4 loose 
stools/day 
5−7 loose stools/day 
Orthostatic hypotension or 
> 7 loose stools/day or 
required IV fluids 
Hypotensive shock or hospitalization 
for IV fluid therapy required 
NEURO & NEUROMUSCULAR 
Neuro−cerebellar 
Slight incoordination 
dysdiadochokinesis 
Intention tremor, 
dysmetria, slurred 
speech; nystagmus 
Locomotor ataxia 
Incapacitated 
Mood 
Mild anxiety or 
depression 
Moderate anxiety or 
depression and 
therapy required 
Severe anxiety or 
depression or mania; needs 
assistance 
Acute psychosis; incapacitated, 
requires hospitalization 


 
Appendix 5: WHO Toxicity Grading Scale 
  
129Xe MRIGenentech, Inc. 
100/Protocol GE42063, Version 5 
ITEM 
Grade 1 Toxicity 
Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
Neuro control 
Mild difficulty 
concentrating; 
no Rx; mild 
confusion/agitation; 
ADL unaffected 
Moderate 
confusion/agitation 
some limitation of 
ADL; minimal Rx 
Severe confusion/agitation 
needs assistance for ADL; 
therapy required 
Toxic psychosis; hospitalization 
Muscle strength 
Subjective weakness; 
no objective 
symptoms/signs 
Mild objective 
signs/symptoms; 
no decrease in 
function 
Objective weakness 
function limited 
Paralysis 
OTHER PARAMETERS 
Fever: oral, > 12 hours 
37.7°C −38.5°C or 
100.0°F −101.5°F 
38.6°C −39.5°C or 
101.6°F −102.9°F 
39.6°C −40.5°C or 
103°F −105°F 
> 40°C or > 105°F 
Headache 
Mild, no Rx therapy 
Transient, moderate; 
Rx required 
Severe; responds to initial 
narcotic therapy 
Intractable; required repeated 
narcotic therapy 
Fatigue 
No decrease in ADL 
Normal activity 
decreased 25%−50% 
Normal activity 
decreased > 50% can’t 
work 
Unable to care for self 
Allergic reaction 
Pruritus without rash 
Localized urticaria 
Generalized urticaria; 
angioedema 
Anaphylaxis 
Local reaction 
Tenderness or 
erythema 
Induration < 10 cm or 
phlebitis or 
inflammation 
Induration > 10 cm or 
ulceration 
Necrosis 
Mucocutaneous 
Erythema; pruritus 
Diffuse, 
maculopapular rash, 
dry desquamation 
Vesiculation, moist 
desquamation, or ulceration 
Exfoliative dermatitis, mucous 
membrane involvement or erythema, 
multiforme or suspected Stevens-
Johnson or necrosis requiring 
surgery 
ADL = activities of daily living; FEV1= forced expiratory volume in 1 second; LLN= lower limit of normal; Rx= treatment; ULN= upper 
limit of normal. 


 
129Xe MRIGenentech, Inc. 
101/Protocol GE42063, Version 5 
Appendix 6  
Borg Category Ratio 10 Scale 
 
 


 
Appendix 6: Borg Category Ratio 10 Scale 
 
129Xe MRIGenentech, Inc. 
102/Protocol GE42063, Version 5 
 
 


 
129Xe MRIGenentech, Inc. 
103/Protocol GE42063, Version 5 
Appendix 7  
Hearing Handicap Inventory in the Elderly−Screening 
Questionnaire 
 
 
 
 


Signature Page for Prot GE42063 (COPD Xenon MRI) v5 - Published
System identifier: RIM-CLIN-444954
Approval Task
Company Signatory
29-Jun-2022 22:24:25 GMT+0000