Clinical trial NCT04133909
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD Mepolizumab Exacerbations MATINEE
Sponsor: GlaxoSmithKline
Start date: 2019-10-30; Completion date: 2024-08-08
Enrollment: 806 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, placebo-controlled, double-blind, parallel group study designed to confirm the benefits of mepolizumab treatment on moderate or severe exacerbations in chronic obstructive pulmonary disease (COPD) participants given as an add on to their optimized maintenance COPD therapy. The maximum duration of participant participation is approximately 109 weeks, consisting of 2 screening visits (up to 3 weeks), a run-in period (up to 2 weeks), and an intervention period of at least 52 weeks and up to 104 weeks. 800 participants will be randomized in a 1:1 ratio to receive mepolizumab 100 milligrams (mg) or placebo every 4 weeks for at least 13 doses (52 weeks treatment period) up to a maximum of 26 doses (104 weeks treatment period). The number of randomized participants may increase up to approximately 1400.

Detailed description:

Arms: arm 1: Participants with Chronic Obstructive Pulmonary Disease (COPD) received a 100 milligrams (mg) dose of mepolizumab as a subcutaneous injection every 4 weeks. Participants remained in the study for an assessment period of minimum of 52 weeks and a maximum of 104 weeks. arm 2: Participants with COPD received matching placebo as a subcutaneous injection every 4 weeks. Participants remained in the study for an assessment period of minimum of 52 weeks and a maximum of 104 weeks.
Interventions: intervention 1: Mepolizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Mepolizumab was a sterile liquid formulation. It was administered as a subcutaneous injection (100 milligrams per milliliter \[mg/mL\]) delivered once every 4 weeks using a pre-filled safety syringe. intervention 2: Placebo was a 0.9% sodium chloride solution. It was administered as a subcutaneous injection delivered once every 4 weeks using a pre-filled safety syringe.

Protocol documents:
Prot_000.pdf: 
TMF-13811028 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
208657 
 
Protocol Amendment 6 
 
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TITLE PAGE 
Protocol Title:  A multi-center, randomized, double-blind, parallel-group, placebo-
controlled study of mepolizumab 100 mg SC as add-on treatment in participants with 
COPD experiencing frequent exacerbations and characterized by eosinophil levels (Study 
208657) 
Protocol Number: 208657/ Amendment 6-STD 
Compound 
Number: 
SB240563 
Study Phase: IIIA  
Short Title:  Mepolizumab as Add-on Treatment IN participants with COPD 
characterized by frequent Exacerbations and Eosinophil Level  
Acronym: MATINEE 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s): 
IND: 006971 
EudraCT: 2018-001540-56 
Approval Date: 06-DEC-2021 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title:  A multi-center, randomized, double-blind, parallel-group, placebo-
controlled study of mepolizumab 100 mg SC as add-on treatment in participants with 
COPD experiencing frequent exacerbations and characterized by eosinophil levels (Study 
208657) 
Protocol Number: 208657/ Amendment 6-STD 
Compound 
Number: 
SB240563 
 
 
 
 
 
Robert Chan M.D. 
Clinical Development Leader – Mepolizumab 
Respiratory R&D 
 
Date 
 
The signed page is a separate document. 
 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment-6-STD 
06-Dec-2021 
TMF-13811028 
Amendment-5-STD 
16-Oct-2020 
2018N357924_05 
Amendment-4-STD 
13-Sep-2019 
2018N357924_04 
Amendment-3-STD 
18-Jul-2019 
2018N357924_03 
Amendment 2-CHI-1 
23-May-2019 
2018N357924_02 
Amendment 1-USA-1 
23-May-2019 
2018N357924_01 
Original Protocol 
15-Feb-2019 
2018N357924_00 
 
Amendment 6: 06-DEC-2021 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
 
Overall Rationale for Amendment 6: 
 
Non-pharmaceutical interventions (NPIs) taken to prevent COVID-19 transmission 
(e.g., masks, lockdowns, physical distancing) have led to an observed reduction in the 
rate of exacerbations among individuals with COPD. Given that the primary study 
outcome and eligibility criteria for this study are based on an exacerbation rate, the 
observed reduction in the rate of COPD exacerbations has affected (i) the collection of 
exacerbation data among enrolled participants and (ii) the recruitment of participants into 
the study, respectively.  
 
The rationale for this amendment is two-fold. First, based on the presumption that the 
COPD exacerbation rate is expected to progressively return to pre-COVID-19 levels 
following the lifting of NPIs, this amendment will extend the allowable treatment 
duration to beyond 52 weeks and up to 104 weeks to maximize the opportunity for 
collection of exacerbation data. Second, to further mitigate the effects of a 
lower-than-expected exacerbation rate and to maintain sufficient study power, this 
amendment will permit the study population to increase up to 1400 participants, if 
warranted, based on future blinded sample size re-evaluations.  
 
A summary of changes is described in the table below.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2 - Schema 
Schema was updated to reflect 
an extended treatment 
duration beyond 52 weeks and 
up to 104 weeks. 
Updates to the 
treatment duration 
necessitated a change 
in the study schema. 
Section 1.3 – Schedule of 
Activities (SoA) 
 
 
A second SoA table was 
added (Section 1.3.2) to 
reflect procedures for 
participants enrolled in an 
extended treatment duration 
beyond 52 weeks and up to 
104 weeks. 
An extended treatment 
duration maximizes the 
opportunity for data 
collection on 
exacerbations. 
An explanation was added 
under Section 1.3 to 
differentiate the two SoA 
tables (Section 1.3.1 and 
Section 1.3.2) and explain 
when ‘IP Conclusion’ and 
‘Study Conclusion’ dates will 
be communicated to the study 
sites. 
To highlight the 
difference between the 
two SoA tables and that 
study sites will be 
provided with 
information to plan 
each participant’s Exit 
Visit.  
Section 1.1 – Synopsis 
  
Section 4.1 – Overall 
Design 
 
Section 9 – Statistical 
Considerations 
Updates were made to the 
number of randomized 
participants, which can 
increase up to 1400 
(approximately 700 per 
group). 
 
Future blinded sample 
size re-evaluations may 
warrant an increase in 
the size of the study 
population to maintain 
sufficient study power. 
 
Section 1.1 – Synopsis 
  
Section 4.1 – Overall 
Design 
 
Section 4.2 – Scientific 
Rationale for Study Design 
 
Wherein treatment duration 
was discussed, updates were 
made to reflect the extension 
of the treatment duration to 
beyond 52 weeks and up to 
104 weeks.  
Changes were required 
to reflect the updated 
study design.  
Section 1.1 – Synopsis 
 
In the ‘Overall Design’, the 
first paragraph was updated to 
state the study treatment 
duration will be dependent on 
a number of factors discussed 
in Section 4.4. 
To reference the 
section of the protocol 
that provides details 
related to study 
treatment durations for 
participants. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.4 – End of Study 
Definition 
Section was updated to 
include ‘Completion of  
Intervention Period’ and 
‘Completion of Study’ 
definitions for participants 
enrolled for 52 weeks (Section 
4.4.1) and those enrolled 
beyond 52 weeks and up to 
104 weeks (Section 4.4.2). 
The ‘End of Study’ definition 
(Section 4.4.3) was updated to 
reference the SoA for 52 
weeks (Section 1.3.1).  
The updated study 
design (52 weeks 
versus beyond 52 
weeks) warranted a 
differentiation of these 
definitions. 
Section 1.3.1 – SoA for the 
First 52 Weeks 
Table footer ‘a’ was updated, 
specifically point [2] under 
the note, to clarify that for 
participants with no historical 
eosinophil count, the blood 
sample collected at Visit 1 
must be >14 days after Visit 
0. 
To further clarify the 
blood collection 
timepoint for 
participants with no 
documented historical 
eosinophil count. 
Table footer ‘j’ was expanded 
to additionally indicate that all 
medications and vaccines 
used at 
pre-screening/screening and 
during the study are to be 
recorded. 
To ensure that 
concomitant therapies 
are recorded. 
Table footer ‘r’ was updated. 
To clarify the 
assessment of AEs and 
SAEs throughout the 
study.  
‘EXACT/ER-S:COPD’ was 
replaced with ‘Daily 
Symptom Diary’ and the 
related table footer ‘t’ was 
updated. 
 
In addition to the 
EXACT instrument, 
daily symptom 
reporting includes other 
questions on 
symptoms, rescue 
medications, and night 
time awakenings 
(Section 8.1.3.3). 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3.1 – SoA for the 
First 52 Weeks 
Table footer ‘w’ was added. 
To clarify that all 
procedures listed for 
Week 52 in the first 
SoA table (Section 
1.3.1) apply only to 
participants enrolled 
for 52 weeks and not 
beyond. 
Table footer ‘x’ was added. 
To explain that 
‘reconsent’ only 
applies to participants 
enrolled prior to 
implementation of 
Protocol Amendment 6 
and who have agreed to 
extend study 
participation beyond 52 
weeks. 
Table footer ‘y’ was added. 
To reiterate when home 
healthcare can be used 
and what study 
procedures qualify for 
it. 
Table footer ‘z’ was added. 
To reiterate that 
participants will be 
monitored in clinic for 
1 hour after receiving 
the first 3 doses of 
study intervention. 
Table footer ‘aa’ was added.  
To state the 
permissibility of 
extension of visit 
windows for the 
screening/run-in period 
‘under exceptional 
circumstances’ with 
advance written 
permission from GSK’s 
Medical Monitor. 
Section 8.1.3.3 – Evening 
eDiary 
Section 8.1.3.3 was renamed 
‘Daily Symptom Diary’ and 
the types of symptom 
collections were bulleted 
upfront. 
The renaming of 
Section 8.1.3.3 
associates the symptom 
reporting with the 
SoAs. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 – Synopsis 
In the ‘Overall Design’, the 
‘note’ discussing the impact 
of COVID-19 was updated. 
 
To elaborate on the 
impact of COVID-19 
and public health 
measures on the study. 
Section 1.1 – Synopsis 
 
Section 4.1 – Overall 
Design 
A statement was added that 
the PK sub-study in China and 
the US is to be conducted in 
the first 52 weeks of the study 
treatment period only. 
To clarify when the PK 
sub-study is to be 
conducted. 
Section 1.1- Synopsis 
 
Section 4.1 – Overall 
Design 
The requirement for a 
minimum ICS dose of 
≥500 mcg/day fluticasone 
propionate or equivalent for 3 
months prior to Screening 
Visit 1 was reiterated. 
To reiterate the study 
eligibility criteria with 
respect to the minimum 
required dose of ICS. 
Section 5.1 – Inclusion 
Criteria 
In the first paragraph, the 
SRM was cited for further 
details on the inclusion 
criteria.  
To reiterate a relevant 
reference regarding 
interpretation of the 
inclusion criteria.  
Section 5.3.2 – 
Randomization Exclusion 
Criteria 
An additional randomization 
exclusion criterion was added 
(#6) related to 12-lead ECG. 
To ensure that 
participants with a 
prolonged QT interval 
at Visit 2 are not 
randomized into the 
study.  
Section 2.3.1 – Risk 
Assessment 
For the mitigation strategy of 
‘blinding eosinophil counts’, 
‘delegate’ was added for 
monthly patient follow-up 
[i.e., Investigators (or 
delegate)] and ‘specialized in 
COPD’ was removed. 
Patient follow-up will 
be with qualified 
personnel who may or 
may not be specialized 
in COPD care.  
Section 2.3.2 – Benefit 
Assessment 
In the third paragraph, the 
wording was changed to 
indicate that participants will 
be followed-up monthly rather 
than having to attend monthly 
visits.  
To acknowledge that 
study procedures may 
not be conducted in 
clinic but could be 
conducted with home 
healthcare.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.3 – Overall 
Benefit: Risk Conclusion 
A statement was added that 
participants will be receiving 
optimized maintenance COPD 
therapy throughout the study 
in addition to their 
randomized IP.  
To reiterate a key 
aspect of the study 
design regarding 
participant safety and 
well-being. 
Section 5.4 – Screen and 
Run-in Failures 
The bullet regarding SAE data 
collection for screen failures 
at Visit 0 and Visit 1 was 
updated. 
To clarify that, as per 
Section 8.3.1. and not 
related to China, prior 
to the start of study 
intervention, SAEs 
related to study 
participation or ‘any 
GSK product’ are to be 
collected from the time 
informed consent is 
signed. 
For run-in failures, the bullet 
regarding the collection of 
details on COPD medications 
in the 3 months prior to 
Screening Visit 1 was deleted. 
Because run-in failures 
do not receive any 
study intervention, 
these data are not 
necessary. 
The last paragraph regarding 
re-screening of participants 
was updated. 
To clarify that 
re-screening of both 
screen failure and 
run-in failure 
participants is 
permissible with 
written approval. 
Section 6.3 – Measures to 
Minimize Bias: 
Randomization and 
Blinding 
In the second paragraph, the 
mention of 13 doses of IP was 
removed. 
Doses of IP will be 
greater than 13 for 
participants enrolled 
beyond 52 weeks. 
Section 6.4 – Study 
Intervention Compliance 
In the second and third 
bullets, the wording was 
updated to also reflect 
monitoring of participants 
during a home visit, if 
applicable. 
To make the wording 
applicable to instances 
wherein home 
healthcare is used.  
Section 6.5 – Concomitant 
Therapy 
Inclusion of wording 
pertaining to COVID-19 
vaccines. 
To clarify the 
permissibility for 
participants to be 
vaccinated with 
authorized or approved 
COVID-19 vaccines. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 – Participant 
Discontinuation/Withdrawal 
from the Study 
A paragraph was added at the 
end regarding data handling if 
a participant withdraws from 
the study prior to their 
‘Completion of Study’ date. 
To indicate that 
participants will be 
considered as having 
missing data from the 
date of study 
withdrawal to the 
planned ‘Completion of 
Study’ date. 
‘Home healthcare, if 
applicable’ was included as an 
alternate to in-clinic visits for 
completion of specified visits 
for participants who have 
permanently discontinued IP 
but have not withdrawn 
consent. 
Home healthcare may 
be used by study 
participants. 
Sesction 8.2 – Safety 
Assessments  
In the first paragraph, a 
statement was added to 
indicate the safety 
assessments (vital signs, 
safety laboratories) that will 
be taken at less frequent 
intervals in the second versus 
first year of the study. 
The safety profile of 
mepolizumab in the IB 
justifies a less frequent 
assessment of safety 
measures after the first 
year of treatment. 
Section 9 – Statistical 
Considerations 
The first paragraph was 
updated to include 
‘annualized’ exacerbations; 
‘over 52 weeks’ was removed; 
and, ‘intercurrent’ was added 
to the statement “COVID-19 
pandemic-related 
‘intercurrent’ events”. 
To align with the 
updated study design 
and the wording in 
Section 9.4.1 (Efficacy 
Analyses) regarding 
strategies for 
‘intercurrent’ events. 
Section 9.2 – Sample Size 
Determination 
Regarding the statement on 
the estimated annualized rate 
of moderate/severe 
exacerbations in the placebo 
arm of 1.7, it was clarified 
that this was based on studies 
conducted prior to the 
COVID-19 pandemic. 
To provide a 
chronological context 
to the exacerbation rate 
originally used for the 
sample size calculation. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.2 – Sample Size 
Determination 
The paragraph related to 
blinded re-evaluations of the 
sample size was updated. 
To indicate that blinded 
re-evaluations of the 
sample size will be 
conducted to ensure its 
adequacy, and the 
sample size may 
increase up to a 
potential maximum of 
1400 participants. 
Section 9.2.1 – Sample Size 
Sensitivity 
Table 2 was updated to 
include lower annualized 
exacerbation rates (i.e., 0.9 
and 1.1). 
To provide information 
on the effect of 
annualized 
exacerbation rates 
lower than 1.3 on study 
power. 
Section 9.4 – Statistical 
Analyses 
In the first paragraph, it was 
added that additional analyses 
including the impact of 
COVID-19 on the study will 
be addressed in the RAP.  
To reiterate that the 
RAP will include all 
relevant statistical 
analyses. 
Section 9.4.1 – Efficacy 
Analyses 
Regarding secondary 
endpoints and the proportion 
of responders at Week 52, the 
effect of restrictions due to 
COVID-19 was clarified as 
being ‘on or before the 
Week 52 visit’. 
Since the study is 
continuing beyond 
Week 52, this 
clarification was 
needed. 
Section 10.1.3 – Informed 
Consent Process 
The bullet regarding 
re-screening was updated. 
 
A bullet on the requirement 
and timeline to re-sign a new 
ICF for participants extending 
their treatment duration to 
beyond 52 weeks was 
included. 
To clarify when 
rescreening and 
reconsenting are 
permissible or required, 
respectively. 
Section 10.4.5 – Reporting 
of SAE to GSK 
For ‘SAE Reporting to GSK 
via Electronic Data Collection 
Tool’, the bullet regarding 
review and verification of 
causality within 72 hours of 
SAE entry into eCRF was 
removed.  
To reflect GSK’s 
updated Monitoring 
SOP (VQD-SOP-
005639). 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.10.2 – Study 
Procedures During COVID-
19 Pandemic 
 
Section 1.3 – Schedule of 
Activities (SoA) 
The SoA Table 4 
(Assessments for clinic visits 
and home healthcare) was 
deleted and its mention 
removed. 
 
A row was included in the 
main SoA tables (Section 1.3) 
regarding home healthcare 
and procedures that qualify 
for it, including footer ‘y’ 
(Section 1.3.1) and footer ‘j’ 
(Section 1.3.2).  
 
In Section 10.10.2.1, ‘Study 
assessments performed 
through home healthcare’ was 
updated to cite SoA tables in 
Section 1.3. 
 
To decrease the 
duplication of 
information.  
The qualifying timepoints for 
home healthcare were 
corrected from Visit 3 
onwards to Visit 5 onwards. 
In accordance with the 
risk mitigation 
strategies (Section 
2.3.1), participants are 
to be monitored in 
clinic following the 
first 3 administrations 
of study product (i.e., 
Visits 2, 3, and 4).  
Section 11 –  References 
The reference regarding the 
IB for mepolizumab was 
removed. 
To ensure the study 
protocol does not cite 
an outdated IB. 
Section 2.3 – Benefit/Risk 
Assessment 
 
Section 6.1 – Study 
Intervention(s) 
Administered 
The citation to the IB was 
deleted and instead reference 
was made to the ‘current 
version of the IB’. 
Throughout protocol 
The term ‘subject’ was 
replaced with ‘participant’ 
where applicable. 
 
Minor editorial and document 
formatting revisions were 
made. 
To align with GSK’s 
protocol template. 
 
 
 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 16 
1.1. 
Synopsis ..................................................................................................... 16 
1.2. 
Schema ...................................................................................................... 20 
1.3. 
Schedule of Activities (SoA) ........................................................................ 21 
1.3.1. 
SoA for the First 52 Weeks .......................................................... 22 
1.3.2. 
SoA for Weeks 52 to 104 ............................................................. 30 
2. 
INTRODUCTION .................................................................................................... 34 
2.1. 
Study Rationale .......................................................................................... 34 
2.2. 
Background ................................................................................................ 35 
2.3. 
Benefit/Risk Assessment ............................................................................ 36 
2.3.1. 
Risk Assessment ......................................................................... 37 
2.3.2. 
Benefit Assessment ..................................................................... 43 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 43 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 43 
3.1. 
Pharmacokinetics Sub-study: China and US only ....................................... 46 
4. 
STUDY DESIGN .................................................................................................... 46 
4.1. 
Overall Design ............................................................................................ 46 
4.2. 
Scientific Rationale for Study Design .......................................................... 48 
4.3. 
Justification of Dose .................................................................................... 49 
4.4. 
End of Study Definition ............................................................................... 50 
4.4.1. 
Participants Enrolled for 52 Weeks .............................................. 50 
4.4.2. 
Participants Enrolled Beyond 52 Weeks ...................................... 50 
4.4.3. 
End of Study ................................................................................ 51 
5. 
STUDY POPULATION ........................................................................................... 51 
5.1. 
Inclusion Criteria ......................................................................................... 51 
5.2. 
Exclusion Criteria ........................................................................................ 54 
5.3. 
Randomization Criteria ............................................................................... 56 
5.3.1. 
Randomization Inclusion Criteria ................................................. 56 
5.3.2. 
Randomization Exclusion Criteria ................................................ 57 
5.4. 
Screen and Run-in Failures ........................................................................ 58 
6. 
STUDY INTERVENTION ........................................................................................ 59 
6.1. 
Study Intervention(s) Administered ............................................................. 59 
6.1.1. 
Medical Devices ........................................................................... 60 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 61 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 61 
6.4. 
Study Intervention Compliance ................................................................... 62 
6.5. 
Concomitant Therapy.................................................................................. 63 
6.5.1. 
Rescue Medicine ......................................................................... 64 
6.5.2. 
Permitted Medications and Non-Drug Therapies .......................... 64 
6.5.3. 
Prohibited Medications and Non-Drug Therapies ......................... 65 
6.6. 
Intervention after the End of the Study ........................................................ 66 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 66 
7.1. 
Discontinuation of Study Intervention .......................................................... 66 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 67 
7.1.1.1. 
Study Intervention Restart or Rechallenge after 
liver stopping criteria met ............................................ 69 
7.1.2. 
QTc Stopping Criteria .................................................................. 69 
7.1.3. 
Temporary Discontinuation .......................................................... 70 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 70 
7.3. 
Lost to Follow Up ........................................................................................ 71 
7.4. 
Reasons for IP Discontinuation and/or Study Withdrawal ........................... 71 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 71 
8.1. 
Efficacy Assessments ................................................................................. 74 
8.1.1. 
Moderate and Severe COPD Exacerbations ................................ 74 
8.1.1.1. 
Guidelines for Identifying Symptom Defined 
COPD Exacerbations ................................................. 75 
8.1.2. 
Exacerbation Treatment ............................................................... 75 
8.1.3. 
Health Related Quality of Life Assessments ................................ 76 
8.1.3.1. 
COPD Assessment Test (CAT) .................................. 76 
8.1.3.2. 
St. George’s Respiratory Questionnaire for 
COPD patients (SGRQ-C) .......................................... 76 
8.1.3.3. 
Daily Symptom Diary .................................................. 77 
8.1.3.4. 
Patient Global Rating of COPD Severity and 
Patient Global Rating of Change in COPD ................. 78 
8.1.3.5. 
Patient and Clinician Rated Response to 
Therapy ...................................................................... 78 
8.1.4. 
Spirometry and Bronchodilator Responsiveness Testing ............. 78 
8.1.4.1. 
Spirometry .................................................................. 78 
8.1.4.2. 
Bronchodilator Responsiveness Testing ..................... 79 
8.2. 
Safety Assessments ................................................................................... 79 
8.2.1. 
Physical Examinations ................................................................. 80 
8.2.2. 
Vital Signs .................................................................................... 80 
8.2.3. 
Electrocardiograms ...................................................................... 80 
8.2.4. 
Medical Problems and Concomitant Medications ......................... 81 
8.2.5. 
Pneumonia .................................................................................. 81 
8.2.6. 
Clinical Safety Laboratory Assessments ...................................... 81 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 82 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 82 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 83 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 83 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 83 
8.3.5. 
Pregnancy ................................................................................... 84 
8.3.6. 
Cardiovascular and Death Events ................................................ 84 
8.3.7. 
Medical Device Deficiencies ........................................................ 84 
8.3.7.1. 
Time Period for Detecting Medical Device 
Deficiencies ................................................................ 85 
8.3.7.2. 
Follow-up of Medical Device Deficiencies ................... 85 
8.3.7.3. 
Prompt Reporting of Medical Device 
Deficiencies to Sponsor .............................................. 85 


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8.3.7.4. 
Regulatory Reporting Requirements for 
Medical Device Deficiencies ....................................... 85 
8.3.8. 
Adjudication Committee ............................................................... 85 
8.4. 
Treatment of Overdose ............................................................................... 86 
8.5. 
Pharmacokinetics ....................................................................................... 86 
8.5.1. 
Optional pharmacokinetic sub-study in China and the US 
only: ............................................................................................. 86 
8.5.2. 
Sample preparation and shipment ............................................... 86 
8.5.3. 
Sample Analysis and Assay Method ............................................ 86 
8.6. 
Pharmacodynamics .................................................................................... 86 
8.7. 
Genetics ..................................................................................................... 86 
8.8. 
Biomarkers ................................................................................................. 87 
8.9. 
Immunogenicity Assessments ..................................................................... 87 
8.10. 
Health Outcomes Assessments .................................................................. 88 
8.10.1. 
Medical Resource Utilization and Health Economics ................... 88 
8.10.2. 
EuroQol questionnaire (EQ-5D-3L) .............................................. 88 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 89 
9.1. 
Statistical Hypotheses................................................................................. 89 
9.2. 
Sample Size Determination ........................................................................ 89 
9.2.1. 
Sample Size Sensitivity ................................................................ 90 
9.3. 
Populations for Analyses ............................................................................ 91 
9.3.1. 
Pharmacokinetics Sub-study........................................................ 92 
9.4. 
Statistical Analyses ..................................................................................... 92 
9.4.1. 
Efficacy Analyses ......................................................................... 92 
9.4.2. 
Safety Analyses ........................................................................... 95 
9.4.2.1. 
Extent of Exposure ..................................................... 95 
9.4.2.2. 
Adverse Events .......................................................... 95 
9.4.2.3. 
Clinical Laboratory Evaluations .................................. 95 
9.4.2.4. 
Other Safety Measures ............................................... 95 
9.4.2.5. 
Immunogenicity .......................................................... 96 
9.4.3. 
Other Analyses ............................................................................ 96 
9.4.3.1. 
Health Related Quality of Life and Health 
Outcomes ................................................................... 96 
9.4.3.2. 
Pharmacodynamic Analyses ...................................... 96 
9.5. 
Interim Analyses ......................................................................................... 96 
9.5.1. 
Data Monitoring Committee (DMC) .............................................. 96 
9.6. 
Pharmacokinetics Analyses (PK Sub-study) ............................................... 96 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 97 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 97 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 97 
10.1.2. 
Financial Disclosure ..................................................................... 97 
10.1.3. 
Informed Consent Process .......................................................... 98 
10.1.4. 
Data Protection ............................................................................ 98 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 98 
10.1.6. 
Data Quality Assurance ............................................................... 99 
10.1.7. 
Source Documents .................................................................... 100 
10.1.8. 
Study and Site Closure .............................................................. 100 
10.1.9. 
Publication Policy ....................................................................... 100 


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10.2. 
Appendix 2: Anaphylaxis Criteria .............................................................. 102 
10.3. 
Appendix 3: Clinical Laboratory Tests ....................................................... 103 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 105 
10.4.1. 
Definition of AE .......................................................................... 105 
10.4.2. 
Definition of SAE ........................................................................ 106 
10.4.3. 
Definition of Cardiovascular Events ........................................... 107 
10.4.4. 
Recording and Follow-Up of AE and SAE .................................. 107 
10.4.5. 
Reporting of SAE to GSK ........................................................... 109 
10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 111 
10.5.1. 
Definitions: ................................................................................. 111 
10.5.2. 
Contraception Guidance: ........................................................... 112 
10.5.3. 
Collection of Pregnancy Information: ......................................... 113 
10.6. 
Appendix 6: Genetics ................................................................................ 114 
10.7. 
Appendix 7: Liver Safety: Required Actions, Monitoring and Follow-
up Assessments ....................................................................................... 115 
10.8. 
Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies ................................ 118 
10.8.1. 
Definition of Medical Device AE and ADE .................................. 118 
10.8.2. 
Definition of Medical Device SAE, SADE and USADE ............... 119 
10.8.3. 
Definition of Device Deficiency ................................................... 119 
10.8.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies ............................................................................... 120 
10.8.5. 
Reporting of SAEs ..................................................................... 122 
10.8.6. 
Reporting of SADEs ................................................................... 123 
10.9. 
Appendix 9: Country-specific Requirements ............................................. 124 
10.10. Appendix 10:  COVID-19 Measures .......................................................... 125 
10.10.1. Overall Rationale For This Appendix .......................................... 125 
10.10.2. Study Procedures During COVID-19 Pandemic ......................... 125 
10.10.2.1. Home Healthcare ..................................................... 125 
10.11. Appendix 11: Protocol Amendment History ............................................... 127 
10.12. Appendix 12: Abbreviations and Trademarks ............................................ 141 
11. REFERENCES ..................................................................................................... 144 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A multi-center, randomized, double-blind, parallel group, placebo-
controlled study of mepolizumab 100 mg SC as add-on treatment in participants with 
COPD experiencing frequent exacerbations and characterized by eosinophil levels (Study 
208657) 
Short Title:  Mepolizumab as Add-on Treatment IN participants with COPD 
characterized by frequent Exacerbations and Eosinophil Level (MATINEE) 
Rationale:  Chronic Obstructive Pulmonary Disease (COPD) is characterized by 
persistent airflow limitation that is usually progressive and associated with an enhanced 
chronic inflammatory response, in the airways and the lung, to noxious particles or gases. 
While the disease course is marked by progressive deterioration in airflow it is 
punctuated by acute exacerbations of COPD (AECOPD) which contribute to the overall 
disease severity and which increase in frequency as the disease worsens [Vogelmeier, 
2017; Barnes, 2015].  In addition to the increased risk of morbidity and mortality 
associated with COPD exacerbations, these events place a significant economic burden 
on healthcare systems which is predicted to increase with the increasing global disease 
prevalence [Halpin, 2017; Perera, 2012; Toy, 2010].  
Mepolizumab has been studied in patients with COPD with limited or no treatment 
options [Pavord, 2017].  The initial Phase IIIA COPD mepolizumab program consisted of 
two 52-week multicenter, randomized, double blind, placebo-controlled studies, 
MEA117106 and MEA117113 [Pavord, 2017].  These studies compared treatment with 
mepolizumab to placebo when added to maximum inhaled standard of care (Inhaled 
corticosteroids [ICS] plus long-acting beta2-adrenergic receptor agonists [LABA] plus 
long-acting muscarinic receptor antagonists [LAMA]).  MEA117113 randomized 
participants with peripheral blood eosinophil counts of ≥150 cells/µL at Screening or 
≥300 cells/µL in the prior 12 months.  MEA117106 was stratified based on blood 
eosinophil levels at Screening and randomized participants who either met the same 
threshold as for MEA117113, designated the “high stratum”, or who had a blood 
eosinophil level <150 cells/µL at Screening and no evidence of blood eosinophil levels 
≥300 cells/µL in the year prior, designated the “low stratum”.  
Evidence from MEA117113 and MEA117106 demonstrated a consistent and clinically 
relevant impact of treatment with mepolizumab 100 mg SC compared with placebo on 
exacerbation reduction in participants with COPD who frequently exacerbate despite 
treatment with ICS-based inhaled triple maintenance therapy (ICS plus LABA plus 
LAMA). 
This study is designed to confirm the benefits of mepolizumab treatment on the primary 
outcome of moderate/severe exacerbations as well as to more robustly inform on 
outcomes which are less frequent such as exacerbations requiring emergency department 
(ED)/hospitalization as well as additional important health related quality of life data. 


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Based on the results of the MEA117113 and MEA117106 studies and feedback from 
health authorities, the inclusion criteria for this study have been modified to focus on a 
group of COPD participants with a documented historical blood eosinophil count of ≥150 
cells/μL in the 12 months prior to Screening Visit 0 (or at Screening Visit 1) and blood 
eosinophil counts of ≥300 cells/µL at Screening Visit 0 that are more likely to benefit 
from mepolizumab treatment.  
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
• To evaluate the efficacy of mepolizumab 
100 mg subcutaneous (SC) compared to 
placebo, given every 4 weeks in liquid 
formulation by safety syringe (SS) to 
COPD participants at high risk of 
exacerbations despite the use of optimized 
COPD maintenance therapy. 
 
• Annualized rate of moderate/severe 
exacerbations 
 
Secondary 
• To evaluate mepolizumab 100 mg SC 
compared to placebo given every 4 weeks 
in liquid formulation by SS on additional 
efficacy assessments, health related 
quality of life (HRQoL), health care 
utilization, and symptoms 
 
• Time to first moderate/severe exacerbation 
• Proportion of COPD assessment test (CAT) 
responders (≥2 unit reduction in CAT score 
from Baseline) at Week 52  
• Proportion of St. George's Respiratory 
Questionnaire (SGRQ) total score 
responders (measured using the St. 
George's Respiratory Questionnaire for 
COPD [SGRQ-C], and defined as ≥4 point 
reduction in SGRQ total score from 
Baseline) at Week 52 
• Proportion of Evaluating Respiratory 
Symptoms in COPD (E-RS: COPD) 
responders (≥2 unit reduction in total score 
from Baseline) at Week 52  
• Annualized rate of exacerbations requiring 
ED visit and/or hospitalization 


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Overall Design: 
This is a multi-center, randomized, placebo-controlled, parallel group, double-blind, trial 
evaluating mepolizumab 100 mg SC compared with placebo given every 4 weeks as a 
liquid formulation in a pre-filled safety syringe injection. The study treatment period will 
be a minimum of 52 weeks up to a maximum of 104 weeks. The study treatment duration 
for each participant will be determined based on a number of factors, which are detailed 
in the main body of the study protocol (Section 4.4). 
Study inclusion criteria require a blood eosinophil count of ≥300 cells/μL at Screening 
Visit 0 and a documented historical blood eosinophil count of ≥150 cells/μL in the 12 
months prior to Screening Visit 0. Historical blood eosinophil count used to meet 
inclusion criteria must not have been measured within 14 days of a COPD exacerbation. 
Participants with no documented historical blood eosinophil count of ≥150 cells/µL must 
meet this threshold at the Screening Visit 1 assessment.  Participants must have a history 
of regular use of ICS-based triple maintenance COPD therapy (as defined in Inclusion 
Criteria, Section 5.1) for at least 12 months prior to Screening Visit 1.  In addition, for at 
least 3 months immediately prior to Screening Visit 1, each participant must have a 
documented history of use of a specific ICS-based inhaled triple maintenance COPD 
regimen (ICS plus LABA plus LAMA) with a minimum inhaled corticosteroid at a dose 
of ≥500 mcg/day fluticasone propionate or equivalent.  Participants are also required to 
have a history of at least 2 moderate COPD exacerbations that were treated with systemic 
corticosteroids (intramuscular (IM), intravenous or oral) with or without antibiotics, or 1 
severe exacerbation requiring hospitalization in the 12 months prior to Screening Visit 1 
and one of the exacerbations has to have occurred while treated with ICS plus LABA 
plus LAMA.  All participants will continue optimized maintenance COPD therapy 
throughout the entire duration of the study regardless of intervention arm assignment. 
Note:  The COVID-19 pandemic has impacted the conduct of this clinical study by, for 
example, preventing participants from attending study visits at the study site during 
periods when the transmission of the virus is being managed with local/national 
government instruction to not leave home.  Where applicable country and local 
regulations and infrastructure allow, and at the discretion of the Investigator and consent 
of the participant, home healthcare may take place at a location other than the clinical 
study site, e.g., the participant’s home to perform study assessments.  In addition, the 
public health measures brought in to combat COVID-19 such as mask wearing, social 
distancing and lockdowns can potentially lead to a fall in non-COVID viral infections 
(e.g., respiratory syncytial virus, influenza) and pollution, which in turn reduce the 
overall COPD exacerbation rates of the study population. 
Disclosure Statement: 
This is a parallel group double-blind intervention study with 2 arms, one active 
mepolizumab and one placebo matching arm given to participants as an add on to their 
optimized maintenance COPD therapy. 


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Number of Participants: 
It is estimated that approximately 4000 participants will be screened to achieve 
approximately 800 randomized participants and an estimated total of 400 randomized 
participants per intervention group.  The number of randomized participants may increase 
up to approximately 1400 (approximately 700 per intervention group) following blinded 
sample size re-evaluation. 
Intervention Groups and Duration: 
Following the Run-in period, eligible participants will be randomized 1:1 to 
mepolizumab or placebo.  Interventional Product (IP) will be administered as a single SC 
injection given every 4 weeks.   
Excluding screening and run-in periods, participants will remain in the study for at least 
52 weeks and either up to 104 weeks or until a scheduled visit that aligns to the date the 
last randomized participant is scheduled to complete their Week 52 Exit Visit, whichever 
is sooner. The timing of the last randomized participant into the study will thus affect the 
timing of the Exit Visit for participants enrolled beyond 52 weeks. All participants will 
be expected to complete at least 52 weeks of the study. The last randomized participant 
will be scheduled to complete only 52 weeks of the study. 
 
The primary efficacy endpoint will include all moderate (require either systemic 
corticosteroids and/or antibiotics) and severe exacerbations (requiring hospitalization or 
resulting in death) reported after the first dose up to and including the last study visit 
(Exit Visit). 
Pharmacokinetic Sub-study:  China and US only 
An optional pharmacokinetic (PK) sub-study will be conducted in China and the US to 
assess potential ethnic differences in the PK of mepolizumab 100 mg, in liquid 
formulation, between non-Asian participants in the US and Chinese participants in China. 
PK blood samples will be collected from approximately 50 randomized participants from 
the US and approximately 50 randomized participants from China to ensure at least 20 
participants from each country provide PK information related to mepolizumab. This PK 
assessment will be conducted over the first 52 weeks of the study period only. 
Independent Adjudication Committee: 
An independent external adjudication committee for all serious adverse event (SAE) 
reports will be utilized in this study to ensure external objective medical review of these 
events in a blinded fashion. Additionally, Major Adverse Cardiac Events (MACE) 
(cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) will also be 
adjudicated in a blinded fashion by the independent external adjudication committee. 


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1.2. 
Schema 
 
 


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1.3. 
Schedule of Activities (SoA) 
Two SoA tables are shown below, which describe study procedures to be followed (i) for the first 52 weeks for all participants and for 
participants with an Exit Visit at Week 52 (Section 1.3.1) and (ii) for Week 52 to Week 104, for those enrolled in an extended treatment 
duration beyond 52 weeks (Section 1.3.2).  
The timing of the last randomized participant into the study (for a 52-week treatment period) will affect the timing of the Exit Visit for 
participants enrolled in an extended treatment duration beyond 52 weeks. As such, around the time the last participant is randomized into 
the study, the study team will communicate to study sites the dates for ‘IP Conclusion’ and ‘Study Conclusion’ as defined in Section 4.4. 
The Investigators will use these communicated dates to plan each participant’s Exit Visit.  
 


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1.3.1. 
SoA for the First 52 Weeks  
Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Eligibility Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reconsent x 
 
 
X  
 
 
Genetic sample 
Informed Consent d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology with 
differential e 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
/Randomization 
Criteria f 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/child 
bearing status 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Historical blood 
eosinophil counts 
X g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Medical history 
including 
cardiovascular (CV), 
CV risk factors, 
Hepatitis B and C, 
COVID-19,COPD 
and exacerbations. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening spirometry 
(including 
bronchodilator 
responsiveness 
testing) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parasite Screening h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgE 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary registration 
and training i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Eligibility and In Study Assessments 
Concomitant 
Medication 
Assessment j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination  
 
X k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X i 
 X i 
 X i 


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Protocol Amendment 6 
 
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Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Vital Signs and pulse 
oximetry l 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
ECG 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
mMRC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test m 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology with 
differential 
 
X n 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Clinical Chemistry 
including liver 
chemistry 
 
X 
X o 
X o 
X o 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Immunogenicity 
sample 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Blood Biomarker p 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Genetics sample q 
 
 
X 
 
 
Smoking Status  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Smoking Cessation 
Counselling 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Dispense Rescue 
medication  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


TMF-13811028 
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208657 
 
Protocol Amendment 6 
 
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Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Register Visit in the 
interactive web 
response system 
(IWRS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-bronchodilator 
Spirometry  
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Review of eDiary  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide medical 
problems and 
healthcare utilization 
worksheet 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Review medical 
problems and 
healthcare utilization 
worksheet 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Assessment 
r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review COPD 
symptoms summary 
report (based on 
eDiary)  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Administer 
Interventional 
Product 
 
 
X z 
X z 
X z 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
eDiary close out  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X s 
X 
Complete eCRF   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HRQoL: PRO and Health Outcomes Assessments 
Daily Symptom 
Diary t 
 
 
 
 
CAT  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
SGRQ-C 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
EQ-5D-3L 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Clinician rated 
response to therapy 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Patient rated 
response to therapy  
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
Patient global rating 
of COPD severity  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Patient global rating 
of change in COPD  
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 


TMF-13811028 
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Protocol Amendment 6 
 
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Protocol Activity 
Screening 
Visit 0 is 
3-21 days 
before 
Screening 
Visit 1aa 
 
Screening 
Visit 1/Run-in 
is ≥2 weeks 
(14-21) days  
before Visit 2aa 
 
 
 
Intervention Period and Exit Visit for the First 52 Weeks (visit window is 7 days) 
Early discontinuation 
/Withdrawal Visit 
(7 days)  
V0 a 
Screening 
Visit 1 a 
and start of  
2-wk Run-in  
V2 b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 Exit Visit 
V15 w 
Discontinue 
from IP 
Visit c 
Withdraw 
from study 
Visit c 
Study Week  
 
 
Wk 
0 
Wk 4 Wk 8 Wk 12 Wk16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 
Study Day  
 
 
1 
28 
56 
84 
112 
140 
168 
196 
224 
252 
280 
308 
336 
364 
 
 
Pharmacokinetics (PK) sub-study: US and China only 
PK sub-study u 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample v 
(PK sub-study only) 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Home healthcare 
for study 
procedures y 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a. Informed Consent must be obtained prior to initiating any study assessments.  Screening Visit 0 must be completed and eosinophil count from the hematology test 
must be obtained for review prior to initiating any Screening Visit 1 assessments.  Note: 1- For participants with a documented historical eosinophil count ≥150 
cells/µL, Screening Visit 1 is performed following confirmation that Screening Visit 0 blood eosinophil count meets the inclusion criteria of ≥300 cells/µL.  2- For 
participants with no documented historical eosinophil count ≥150 cells/ µL, a blood sample must be collected at Visit 1 which must be >14 days after Visit 0.  Refer 
to SRM for more details.  
b. Randomization Visit 2 is ≥2 weeks after Screening Visit 1 and must be performed at least 14 days after Screening Visit 1.  Results from Screening Visit 1 
procedures must be available for review of randomization criteria.  To be randomized, participants with no historical eosinophil count of ≥150 cells/µL in the 12 
months prior to Screening Visit 0, must have an eosinophil count of ≥150 cells/µL obtained at Screening Visit 1. 
c. If participant discontinues study interventional product (IP) and remains in the study, then the discontinuation from IP Visit must be conducted 4 weeks after IP 
discontinuation.  If the participant withdraws from the study after discontinuation of IP, then the Withdraw from Study Visit is conducted within 4 weeks after the 
decision to withdraw from the study is made.  If participant discontinues IP and withdraws from the study at the same time, a withdraw from study Visit must be 
conducted 4 weeks after IP discontinuation. 


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d. Informed Consent for optional genetics research must be obtained before collecting a sample.  China only:  Genetic Informed Consent will not be collected from 
participants in China. 
e. A mandatory hematology test is performed at Screening Visit 0 and will be analyzed by the designated central laboratory.  Eosinophil count must be available for 
review of Inclusion Criterion 2 (Section 5.1) and prior to initiating any Screening Visit 1 assessments.   Participants who do not meet the eosinophil inclusion 
criterion of  300 cells/L at Screening Visit 0 will be considered a screen failure. 
f. Inclusion and Exclusion criteria should be assessed at Screening Visit 0 and Screening Visit 1.  Randomization criteria should be assessed at Visit 2 prior to 
Randomization. 
g. Where several historical eosinophil counts are obtainable, the highest eosinophil count should be recorded in the eCRF for each of the following specified periods: 
≥1 to <6 months and 6 to12 months. In order to meet the Inclusion Criterion #2 (Section 5.1), a historical blood eosinophil measurement must meet the following: It 
must have been measured between 12 months and 1 month prior to Visit 0 and it must not have been measured within 14 days of a COPD exacerbation.  If, in 
either of the 2 specified periods, the only historical documented blood eosinophil count is associated with a COPD exacerbation, then this eosinophil count cannot 
be used for inclusion in the study but should be recorded in the eCRF. Refer to the SRM for more information.  
h. Parasitic Screening is only required in countries with high-risk or for participants who have visited high-risk countries in the past 6 months.  Site staff should use 
local laboratories for the parasitic test.  
i. Thorough eDiary training should be conducted at Screening Visit 1 and throughout the study on as-needed basis.  
j. Ensure maintenance COPD medications from the year prior to Screening Visit 1, all medications within the 3 months prior to Screening Visit 1 and all current 
medications are reviewed. Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the 
participant is receiving at the time of pre-screening/screening or receives during the study must be recorded. 
k. A complete physical exam including height and weight should be conducted at Screening Visit 1.  For Subsequent visits a complete physical exam including weight 
only should be conducted.  
l. Pulse oximetry at Screening Visit 1 only 
m. Pregnancy testing is only required for women of child bearing potential (WOCBP).  An assessment must be made at Screening Visit 1 to determine child bearing 
potential of each female study participant 
n. A hematology sample is only collected at Screening Visit 1 for participants with no historical eosinophil count of ≥150 cells/µL in the 12 months prior to Screening 
Visit 0.  Note: For hematology samples collected after Randomization the absolute and differential (%) values of eosinophils, lymphocytes, basophils, neutrophils 
and monocytes will be blinded to site staff and sponsor.  However, sites will be sent total white blood counts throughout the study. 
o. Participants who entered with stable chronic Hep B or Hep C, liver chemistry labs should be assessed monthly for the first 3 months (Screening Visit 1, Day 1, 
Week 4, Week 8, Week 12) then every 3 months (Week 24, Week 36, Week 48 and then at Week 52 (Exit Visit), or Early Withdrawal Visit); all other participants 
will have liver chemistry labs done every 3 months:  Screening Visit 1, Day 1, Week 12, Week 24, Week 36, Week 48 and then at Week 52 (Exit Visit) or Early 
Withdrawal Visit  
p. China only: Blood biomarker samples will not be collected from participants in China 


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q. The genetics sample can be collected at Visit 2 or any visit after. China only: Genetic blood samples will not be collected from participants in China. 
r. As per Section 8.3.1., all AEs and SAEs will be collected from the start of study intervention (Visit 2) until the Exit Visit/Study withdrawal visit. In addition, for the 
Screening and Run-in Periods that occur prior to the start of study intervention, SAEs (and not AEs) related to study participation or related to any GSK product 
must also be collected from the point that Informed Consent is signed. China only:  All SAEs must be collected from signing of Informed Consent. 
s. For participants who continue with phone visits only. 
t. The daily symptom diary will be comprised of 14 items from the EXACT instrument plus 5 additional questions on symptoms plus questions on rescue medication 
use and night time awakenings (Section 8.1.3.3). The symptom diary will be completed daily, in the evening, starting at Screening Visit 1 and up to Week 52. On 
the date of the Exit Visit, the evening diary for daily symptom reporting will not be completed. 
u. Informed Consent for the optional PK sub-study (in China and US only) must be obtained before collecting a sample.  Participation in the PK sub-study must also 
be recorded in the IWRS.  
v. PK samples should be obtained as described in the SoA and prior to dosing on dosing days. 
w. All procedures listed for Week 52 including the Exit Visit 15 apply to study participants enrolled for 52 weeks and not beyond. Importantly, no study intervention 
product is to be administered at Week 52 for these participants. For participants who have consented to participate in a study beyond 52 weeks, Week 52 
procedures are detailed in the SoA appearing in Section 1.3.2. 
x. Reconsent only applies to participants who enrolled in the study prior to Protocol Amendment 6 implementation and who have agreed to extend study participation 
beyond 52 weeks; these participants must re-sign a new ICF at, or prior to, completion of the Week 52 visit (Exit Visit 15). Participants enrolling after Protocol 
Amendment 6 is in place will follow usual Informed Consent procedures to enroll in the study for up to 104 Weeks. 
y. When clinic visits are impacted by restrictions imposed during the COVID-19 pandemic (e.g., quarantines, site closures, travel limitations), for participants unable 
to attend a site visit, home healthcare (home visits and telemedicine visits) may be used. Study procedures that can be conducted through home healthcare are 
those listed in the SoA table from Visit 5 and onwards (excluding the Exit Visit), with the exception of the following procedures normally conducted in the clinic: 
(i) pre-bronchodilator spirometry, (ii) clinician rated response to therapy, and (iii) physical examinations (see Section 10.10.2). Consent for home healthcare can be 
signed at any point during the study before home healthcare is used. There is no requirement to sign consent for home healthcare if it is not needed.  
z. As per Section 6.4, for the first 3 administrations of the study intervention (i.e., at Visit 2, Visit 3, and Visit 4), participants will be monitored in clinic for 1 hour after 
receiving the study intervention product.  
aa. Under exceptional circumstances (for example, as a consequence of COVID-19-related restrictions disrupting scheduled visits), the extension of visit windows for 
the screening/run-in period is permissible but only with advance written permission from the GSK Medical Monitor.  
 
 
 
 


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1.3.2. 
SoA for Weeks 52 to 104 
Protocol Activity 
 
 
 
Intervention Period and Exit Visit For Weeks 52 to 104 (visit window is ± 7 days) 
Early discontinuation 
/Withdrawal Visit 
(±7 days)  
V15 a 
V16  
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
Exit 
Visit 
V28 b 
Discontinue 
from IP 
Visit c 
Withdraw 
from 
study 
Visit c 
Study Week  
Wk 
52 a 
Wk 
56 
Wk 
60 
Wk 
64 
Wk 
68 
Wk 
72 
Wk 
76 
Wk 
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 
104 
 
 
Study Day  
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
728 
 
 
Additional Eligibility and in Study Assessments 
Concomitant 
Medication 
Assessment d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 X  
 X  
Vital Signs  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Urine Pregnancy Test f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology with 
differential 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Clinical Chemistry 
including liver 
chemistry  
X 
 
 
X g 
 
 
X 
 
 
X g 
 
 
 
X  
X  
X  
Immunogenicity 
sample 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Smoking Status  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Smoking Cessation 
Counselling 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Dispense Rescue 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Register Visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol Activity 
 
 
 
Intervention Period and Exit Visit For Weeks 52 to 104 (visit window is ± 7 days) 
Early discontinuation 
/Withdrawal Visit 
(±7 days)  
V15 a 
V16  
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
Exit 
Visit 
V28 b 
Discontinue 
from IP 
Visit c 
Withdraw 
from 
study 
Visit c 
Study Week  
Wk 
52 a 
Wk 
56 
Wk 
60 
Wk 
64 
Wk 
68 
Wk 
72 
Wk 
76 
Wk 
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 
104 
 
 
Study Day  
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
728 
 
 
Pre-bronchodilator 
Spirometry  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Review of eDiary  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide medical 
problems and 
healthcare utilization 
worksheet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Review medical 
problems and 
healthcare utilization 
worksheet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review COPD 
symptoms summary 
report (based on 
eDiary)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer 
Interventional Product 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
eDiary close out  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X h 
X 
Complete eCRF  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
HRQoL: PRO and Health Outcomes Assessments 
Daily Symptom Diary i 
X 
 
 
CAT  
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
SGRQ-C 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 


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Protocol Activity 
 
 
 
Intervention Period and Exit Visit For Weeks 52 to 104 (visit window is ± 7 days) 
Early discontinuation 
/Withdrawal Visit 
(±7 days)  
V15 a 
V16  
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
Exit 
Visit 
V28 b 
Discontinue 
from IP 
Visit c 
Withdraw 
from 
study 
Visit c 
Study Week  
Wk 
52 a 
Wk 
56 
Wk 
60 
Wk 
64 
Wk 
68 
Wk 
72 
Wk 
76 
Wk 
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 
104 
 
 
Study Day  
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
728 
 
 
EQ-5D-3L 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Clinician rated 
response to therapy 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Patient rated response 
to therapy  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Patient global rating of 
COPD severity  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Patient global rating of 
change in COPD  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
Home healthcare for 
study procedures j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a. Procedures listed for V15 at Week 52 only apply to study participants receiving treatment beyond 52 weeks (i.e., Week 52 to a maximum of Week 104). 
For these participants, a dose of intervention product must be taken at Week 52.  
b. Exit visit will be either at Week 104 or at a scheduled visit closest to the date (i.e., on or immediately before, but not after) the last randomized participant 
is scheduled to complete their Exit Visit at Week 52 (as per the SoA in Section 1.3.1), whichever is sooner. In the instance that the Exit Visit occurs sooner 
than Week 104, all predefined Exit Visit assessments are to be conducted in lieu of the predefined assessments for a scheduled visit. Importantly, the Exit 
Visit should occur 4 weeks after the last dose of study intervention product and no study intervention product is to be administered at the Exit Visit. 
c. If a participant discontinues study interventional product and remains in the study, then the discontinuation from IP Visit must be conducted 4 weeks after 
IP discontinuation.  If the participant withdraws from the study after discontinuation of IP, then the Withdraw from Study Visit is conducted within 4 weeks 
after the study withdrawal decision is made.  If a participant discontinues IP and withdraws from the study at the same time, a withdraw from study Visit 
must be conducted 4 weeks after IP discontinuation. 
d. Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the participant is receiving 
during the study must be recorded. 


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Protocol Activity 
 
 
 
Intervention Period and Exit Visit For Weeks 52 to 104 (visit window is ± 7 days) 
Early discontinuation 
/Withdrawal Visit 
(±7 days)  
V15 a 
V16  
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
Exit 
Visit 
V28 b 
Discontinue 
from IP 
Visit c 
Withdraw 
from 
study 
Visit c 
Study Week  
Wk 
52 a 
Wk 
56 
Wk 
60 
Wk 
64 
Wk 
68 
Wk 
72 
Wk 
76 
Wk 
80 
Wk 
84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 
104 
 
 
Study Day  
364 
392 
420 
448 
476 
504 
532 
560 
588 
616 
644 
672 
700 
728 
 
 
e. A complete physical exam including weight should be conducted. 
f. 
Pregnancy testing is only required for women of child bearing potential (WOCBP). 
g. Week 64 and Week 88 measurements do not apply to study participants who do not have stable chronic Hep B or Hep C. For those with stable chronic 
Hep B or Hep C, collections to be made every 3 months (Weeks 52, 64, 76, 88, 100, and the Exit Visit at Week 104). For all others, collections to be made 
every 6 months (Weeks 52, 76, 100, and the Exit Visit at Week 104).  
h. For participants who continue with phone visits only. 
i. 
From Week 52 to Week 104, the daily symptom diary will be comprised of 3 items from the EXACT instrument (not all 14 items) plus 5 additional questions 
on symptoms plus questions on rescue medication use and night time awakenings (Section 8.1.3.3). The symptom diary will be completed daily, in the 
evening, throughout the treatment period. At the Exit Visit, the evening diary for daily symptom reporting will not be completed. 
j. 
When clinic visits are impacted by restrictions imposed during the COVID-19 pandemic (e.g., quarantines, site closures, travel limitations), for participants 
unable to attend a site visit, home healthcare (home visits and telemedicine visits) may be used. Study procedures that can be conducted through home 
healthcare are those listed in the SoA table from V15 onwards (excluding the Exit Visit), with the exception of the following procedures normally conducted 
in the clinic: (i) pre-bronchodilator spirometry, (ii) clinician rated response to therapy, and (iii) physical examinations (see Section 10.10.2).  Consent for 
home healthcare can be signed at any point during the study before home healthcare is used. There is no requirement to sign consent for home healthcare 
if it is not needed.  
 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
While chronic obstructive pulmonary disease (COPD) is generally viewed as a disease 
driven by neutrophilic inflammation, up to 40% of COPD patients have an inflammatory 
pattern that includes elevated sputum eosinophils [Brightling, 2005; Saha, 2006].  In 
severe COPD patients, sputum eosinophils and Interleukin (IL)-5 levels are elevated to 
similar levels as those seen in severe asthmatics [Bafadhel, 2012a].  Notably, COPD 
patients with eosinophilic inflammation cannot be distinguished based on clinical features 
and lung function alone from those without eosinophilic inflammation [Saha, 2006].  
Furthermore, increased eosinophilic inflammation in COPD has been associated with 
increased risk of exacerbations [Vedel-Krogh, 2016].  COPD exacerbations are 
characterized by periods of acute worsening of symptoms, deterioration in lung function, 
and decreased health-related quality of life (HRQoL) [Vogelmeier, 2017] and potentially 
contribute to further permanent decrements in lung function.  Recent studies identified 
that increased eosinophilic airway inflammation occurred during COPD exacerbations 
[Bafadhel, 2011] and that peripheral eosinophils levels in the blood were used 
successfully as a surrogate marker to predict response to corticosteroid therapy [Bafadhel, 
2012b; Bafadhel, 2017].  A study by Siva et al [Siva, 2007] showed that a treatment 
strategy that aimed to reduce sputum eosinophils in COPD showed a significant reduction 
in severe exacerbations compared to a treatment strategy aimed towards symptom 
reductions alone. 
Based on the observation that airway eosinophilic inflammation is associated with COPD 
exacerbations [Bafadhel, 2011; Bafadhel, 2017], that a treatment regimen designed to 
reduce eosinophils will attenuate COPD exacerbations, and that airway levels of IL-5 and 
eosinophils are comparable in both severe eosinophilic asthma and in eosinophilic-
phenotype of COPD, the mepolizumab COPD program was designed to study a COPD 
patient population meeting a blood eosinophil threshold with a history of exacerbations 
despite receiving inhaled corticosteroid (ICS)-based triple maintenance therapy.  This 
clinical experience and the successful reduction of acute exacerbation of COPD 
(AECOPD) by IL-5 inhibition with mepolizumab [Pavord, 2017] suggests that the 
management of exacerbations can be tailored by therapy directed at a treatable trait. 
Mepolizumab is a humanised immunoglobulin G (IgG) antibody (IgG1, kappa) which 
binds to and inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are 
primarily expressed on eosinophils.  IL-5 is a major regulator of eosinophils and upon 
binding to the IL-5 receptor results in accumulation in tissues and modulation of 
eosinophil behaviour from maturation to survival.  Mepolizumab can reduce eosinophils 
in the periphery and in tissues. 
Two 52-week, randomized, placebo-controlled, double-blind, parallel-group, multi-center 
initial Phase IIIA studies, MEA117106 and MEA117113, evaluated the effect of 
mepolizumab, administered every 4 weeks through subcutaneous (SC) injection, on the 
rate of moderate/severe COPD exacerbations in participants with a history of COPD 
exacerbations despite receiving ICS-based triple maintenance therapy [Pavord, 2017].  
Studies MEA117106 and MEA117113 demonstrated that treatment with mepolizumab 


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led to improvements in exacerbations and other efficacy endpoints when compared with 
placebo.  In addition, in these studies, the safety profile of mepolizumab was similar to 
placebo and no new safety concerns were identified in this COPD patient population to 
those identified in the severe asthma program.  
The results from MEA117113 and MEA117106 demonstrate that while patients selected 
with an exacerbating phenotype and with a blood eosinophil count 150 cells/µL at 
Screening or 300 cells/µL in previous 12 months achieved a clinically relevant 
reduction in moderate/severe exacerbations, patients with a blood eosinophil count 300 
cells/µL (in previous 12 months or at Screening) are more likely to achieve greater 
benefit from mepolizumab.  Thus, a blood eosinophil count 300 cells/µL provides a 
clear threshold to identify patients that are more likely to benefit from mepolizumab. In 
this study, to ensure stability of eosinophil counts, an additional requirement is for a 
documented historical eosinophil count of ≥150 cells/µL in the 12 months prior to 
Screening Visit 0. Participants with no documented historical eosinophil count of ≥150 
cells/µL must meet this threshold at the Screening Visit 1 assessment prior to 
randomization. 
Therefore, this study will provide additional efficacy data on the benefits of mepolizumab 
treatment in a more refined patient population expected to benefit from treatment.  In 
addition to exacerbation data, this study will provide additional important HRQoL data 
for mepolizumab compared with placebo. 
2.2. 
Background 
COPD is a chronic progressive disease with rising morbidity and mortality and is 
currently the fourth leading cause of death in the world [WHO Report, 2008]; Lozano, 
2012].  The disease course is marked by progressive deterioration in airflow and increase 
in AECOPD frequency that contribute to the overall disease severity [Vogelmeier, 2017].  
In addition, a study by [Hurst, 2010] showed that the single best predictor of 
exacerbations was previous exacerbations.  
AECOPD are heterogeneous in nature with respect to their inflammatory component.  A 
study by Siva et al [Siva, 2007] showed that a treatment strategy that aimed to reduce 
sputum eosinophil counts in COPD showed a significant reduction in severe 
exacerbations compared with a treatment strategy aimed towards optimizing symptoms 
alone.  Subsequent studies found that increased eosinophilic airway inflammation 
occurred during COPD exacerbations [Bafadhel, 2011] and that blood eosinophil levels 
were used successfully as a surrogate for sputum eosinophil levels to predict response to 
corticosteroid therapy [Bafadhel, 2017].  Furthermore, the 2019 GOLD report 
recommends the use of blood eosinophil count as a biomarker for considering treatment 
of COPD with inhaled corticosteroids [GOLD, 2019]. Additionally, the results from the 
mepolizumab COPD initial phase IIIA studies indicate that blood eosinophil levels are a 
useful biomarker to tailor treatment and prevent exacerbations for those COPD patients 
with an eosinophilic phenotype defined by the level of blood eosinophil counts [Pavord, 
2017]. 


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The [GOLD, 2019] report advocates the use of one or more long-acting inhaled 
bronchodilators (long acting beta2 -agonist [LABA]) or (long acting muscarinic 
antagonist [LAMA]) in addition to ICS for patients with more advanced disease, high 
blood eosinophil count and high risk of exacerbations [GOLD, 2019]  
The concurrent use of these medications (i.e., ICS plus LABA plus LAMA) is often 
termed ‘triple inhaled maintenance therapy’ and is usually considered optimal for COPD 
patients at risk of exacerbations.  For patients who continue to exacerbate despite the use 
of triple inhaled therapy (approximately 40% of patients on inhaled triple therapy), there 
are limited additional maintenance treatment options.  Of these patients, approximately 
20% have eosinophil levels ≥300 cells/μL [Müllerova, 2017]. 
 
Overall, there are approximately 6.1% of COPD patients who have progressive disease 
that is not controlled with triple therapy, and blood eosinophil levels ≥300 cells/µL, who 
could benefit from the attenuation of eosinophilic inflammation by mepolizumab 
[Benson, 2018]. 
 
This population of patients is at higher risk of poor outcomes including a 2-fold increased 
risk of moderate/severe exacerbations and a 26% increase in mortality compared with the 
general COPD population [GlaxoSmithKline document number 2017N350371_00]. 
 
The mepolizumab COPD program addresses a key unmet need in patients at high risk for 
adverse outcomes.  The patient population for mepolizumab includes patients who 
continue to experience AECOPD despite optimized COPD therapy namely ICS-based 
triple inhaled maintenance therapy (see inclusion criteria Section 5.1).  There are limited 
or no additional therapeutic options [GOLD, 2019] for this target population with a high 
burden of disease despite intensive therapy. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of mepolizumab may be found in the current 
version of the Investigator’s Brochure (IB). 
 


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
Mepolizumab 
Risk of Systemic Reactions (Allergic [type 
I hypersensitivity] and Other systemic), 
including Anaphylaxis 
In the integrated initial Phase IIIA COPD 
trials MEA117106 and MEA117113, the 
incidence of systemic reactions was 2% in 
the mepolizumab All Doses group and 2% 
in the placebo group. 
Systemic reactions reported to date across 
the mepolizumab programme are 
summarised in the Investigator Brochure 
(IB) “Safety in Clinical studies” section 
under each indication studied and in 
Section 6 of the IB titled ‘Summary of Data 
and Guidance for the Investigator’  
 
Regular monitoring of serious adverse 
events (SAEs) by Medical Monitor; regular 
systematic review of adverse event 
(AE)/SAE data from ongoing studies by a 
GlaxoSmithKline (GSK) study team and/or 
safety review team.  
Customized AE and SAE case report form 
(CRF) utilized for collection of information 
for systemic reaction adverse events. 
Use of Joint National Institute of Allergy 
and Infectious Diseases (NIAID)/Food 
Allergy and Anaphylaxis Network (FAAN) 
2nd Symposium on Anaphylaxis to collect 
data on reports of anaphylaxis (see 
Appendix 2) 
Participants are monitored in clinic for 1 
hour after the first 3 administrations of 
study treatment and then according to 
monitoring policies for the center. 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
In the event of an acute severe reaction 
(e.g., anaphylaxis) following administration 
of study treatment, there must be 
personnel/staff onsite at the treatment 
facility who are appropriately trained in 
basic life support to manage the patient 
including administration of medications 
(e.g., epinephrine), and have access to a 
system that can promptly transport the 
patient to another facility for additional 
care if appropriate. 
Local Injection site reactions 
In the integrated Phase IIIA COPD trials 
MEA117106 and MEA117113, incidence 
of local injection site reactions was 3% in 
the mepolizumab All Doses group and 3% 
in the placebo group. 
Local injection site reactions reported to 
date across the mepolizumab program are 
summarized in the IB “Safety in Clinical 
studies” section under each indication 
studied and in Section 6 titled ‘Summary of 
Data and Guidance for the Investigator’ 
Regular monitoring of SAEs by Medical 
Monitor; regular systematic review of 
AE/SAE data from ongoing studies by 
GSK study team and/or safety review team. 
Customised AE and SAE case report form 
(CRF) utilised for collection of information 
for local injection site reaction adverse 
events. 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
Potential risk of immunogenicity 
Mepolizumab has low immunogenic 
potential. Overall, the immunogenicity 
results from clinical studies across the 
mepolizumab program demonstrate that the 
presence of anti-drug antibodies (ADAs) is 
not associated with any specific adverse 
events, anti-mepolizumab antibodies did 
not discernibly impact the 
pharmacokinetics (PK) or 
pharmacodynamics (PD) of mepolizumab 
in the majority of participants and there 
was no evidence of a correlation between 
antibody titers and change in eosinophil 
level.  
Immunogenicity data reported to date 
across the mepolizumab development 
program are summarized in the IB; See 
Section 5.4 ‘Clinical Immunogenicity’ and 
in Section 6 ‘Summary of Data and 
guidance for the investigator”. 
Blood samples will be collected for 
detection of both ADA and neutralizing 
antibodies (Nab). 
Potential risk for adverse cardiovascular 
(CV) effects 
In the integrated Phase IIIA COPD trials 
117106 and 117113, incidence of 
Investigator reported serious cardiac, 
vascular and thromboembolic events was 
5% in the mepolizumab All Doses group 
Regular monitoring of SAE by Medical 
Monitor; regular systematic review of 
AE/SAE data from ongoing studies by a 
GSK study team and/or safety review team. 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
and 4% in the placebo group.  The 
incidence of fatal and non-fatal serious 
adverse events adjudicated by the external 
independent Clinical End Point committee 
(CEC) in a blinded fashion to the CV 
category was 4% across all treatment 
groups. 
Cardiac events reported to date across the 
mepolizumab programme are summarised 
in the IB “Safety in Clinical studies” 
section under each indication studied.  
Electrocardiography (ECG) monitoring 
during the trial; 
As per GSK standard practice use of 
standardized CRFs to collect additional 
data on protocol-specified CV events (i.e., 
myocardial infarction, hospitalization for 
unstable angina and congestive heart 
failure, arterial thrombosis, pulmonary 
embolism and deep vein thrombosis); 
MACE events and all SAE reports will be 
adjudicated by external independent CEC 
in a blinded fashion. 
Potential risk for increase in infections - 
theoretical concern with biologics 
In the integrated Phase IIIA COPD trials 
117106 and 117113, incidence of events in 
the Infections and Infestation System 
Organ Class (SOC) was 51% in the 
mepolizumab All Doses group and 53% in 
the placebo group.  The incidence of events 
potentially representing opportunistic 
infections was 3% in the mepolizumab 
groups and 2% in placebo group.  There 
were no parasitic infections reported in 
these studies. Infections reported to date 
across the mepolizumab development 
Regular monitoring of SAE by Medical 
Monitor; regular systematic review of 
AE/SAE data from ongoing studies by a 
GSK study team and/or safety review team  
Participants with a known, pre-existing 
parasitic infestation within 6 months prior 
to Visit 1 are also excluded 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
program are summarized in the IB “Safety 
in Clinical studies” section under each 
indication studied, and in Section 6 titled 
‘Summary of Data and Guidance for the 
Investigator’. 
Potential risk for increase in malignancies - 
theoretical concern with biologics 
In the integrated initial Phase IIIA COPD 
trials 117106 and 117113, incidence of 
malignancy was 2% in the mepolizumab 
All Doses group and 2% in placebo group.   
Malignancies reported to date across the 
mepolizumab development program are 
summarized in the IB “Safety in Clinical 
studies” section under each indication 
studied. 
Regular monitoring of SAE by Medical 
Monitor; regular systematic review of 
AE/SAE data from ongoing studies by a 
GSK study team/safety review team  
 
Study Procedures 
Blinding eosinophil counts 
This study is a double-blind study which 
may be used to support approval for the use 
of mepolizumab in the reduction of 
moderate/severe COPD exacerbations. 
Unblinded eosinophil counts after the first 
administration of IP may compromise the 
integrity of the study. 
Patients will be seen monthly by 
Investigators (or delegate).  
After Randomization, neither the site staff 
nor GSK personnel will be sent results 
from the central laboratory for: absolute 
and differential values for eosinophils, 
lymphocytes, basophils, neutrophils and 
monocytes. However, sites will be sent 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
 
Mitigation Strategy 
total white blood counts throughout the 
study. 
 
 


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2.3.2. 
Benefit Assessment 
Study 208657 will investigate the efficacy and safety of mepolizumab in the reduction of 
moderate/severe COPD exacerbations in participants receiving intensive therapeutic 
intervention for COPD treatment recommended for this population with severe disease 
and high risk of AECOPD. 
Exacerbations are a major concern to COPD patients and lead to a worsening of the 
quality of life for patients. A reduction in frequency of moderate and severe 
exacerbations may improve a patient’s quality of life and may reduce hospitalizations. 
Participants in this study will be followed-up monthly and will continue optimized 
maintenance COPD therapy and therefore may benefit both from the additional assurance 
of medicine compliance and monitoring of their current maintenance therapy. 
Participants may also benefit from regular monitoring of their COPD symptoms and 
potential identification of exacerbations.  
Data obtained from this study will provide additional evaluation of the efficacy and 
safety of mepolizumab delivered as a pre-filled liquid formulation in a safety syringe. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Data from mepolizumab preclinical and clinical development demonstrate the ability of 
mepolizumab to inhibit IL-5, and consequently treat inflammatory conditions linked to an 
eosinophil signal, such as COPD patients predisposed to future exacerbations. To date, 
the safety profile of mepolizumab has been favourable. Furthermore, preclinical and 
clinical data to date have not identified any safety concerns that would preclude further 
investigation in COPD. Importantly, in addition to their randomized IP, all participants 
will be receiving optimized maintenance COPD therapy throughout the study. Therefore, 
further investigation of the efficacy and safety of mepolizumab is justified in study 
208657. 
3. 
OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary 
• To evaluate the efficacy of mepolizumab 
100 mg subcutaneous (SC) compared to 
placebo, given every 4 weeks in liquid 
formulation by safety syringe (SS) to 
COPD participants at high risk of 
exacerbations despite the use of 
optimized COPD maintenance therapy. 
 
• Annualized rate of moderate/severe 
exacerbations 
 
Secondary 
• To evaluate mepolizumab 100 mg SC 
compared to placebo given every 4 weeks 
 
• Time to first moderate/severe exacerbation 


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
4 4  
 
O bj e cti ve  
E n d p oi nt  
i n li q ui d for mul ati o n by S S o n a dditi o n al 
effic acy assess m e nts, he alth r el at ed 
q u ality of lif e ( H R Q o L), h ealt h c ar e 
utiliz ati o n, a nd sy m pt o ms  
•  Pr o p orti on of C O P D assess m e nt t est ( C A T) 
r es p o nd ers ( ≥2 u nit r ed uctio n i n C A T sc or e 
fr o m b as eli ne) at W eek 5 2  
•  Pr o p orti on of St. G e org e's R es pirat ory 
Q u esti on n aire ( S G R Q) t otal sc or e 
r es p o nd ers ( m e as ure d usi ng t he St. 
G e or g e's R es pirat ory Q uesti o n n aire  f or 
C O P D [ S G R Q -C] , an d d efine d as ≥4 p oi nt 
r e d ucti on i n S G R Q t ot al sc or e fr o m B aseli n e) 
at W e ek 5 2  
•  Pr o p orti on of Ev al uati ng R es pirat ory 
Sy m pt o ms i n C O P D ( E -R S: C O P D) 
r es p o nd ers ( ≥2 u nit r ed uctio n i n t otal sc or e 
fr o m B as eli ne) at W eek 5 2  
•  A n n ualiz e d r at e of exac er bati o ns r e quiri n g 
E m er g e ncy De p art m ent ( E D) visit a n d/ or 
h os pitaliz ati o n  
Ot h er  
•  T o f urt her i nv estig ate oth er e n dp oi nts 
 
•  C h a n ge fr o m B as eli ne i n  pr e -br o nc ho dil ator  
f orc e d ex pirat ory vol u m e i n o n e sec on d 
( F E V1) a nd forc e d vital c a pacity ( F V C) 
•  C A T r es p o nd ers at W e ek 24  
•  C A T c h a ng e fr o m b aseli n e at W e ek 2 4 a n d 
5 2  
•  S G R Q r es po n ders at W eek 2 4  
•  S G R Q c h an ge fr o m B as eli ne at W eek 2 4 
a n d 5 2  
C CI


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
4 5  
 
O bj e cti ve  
E n d p oi nt  
•  Pr o p orti on of Ev al uati ng R es pirat ory 
Sy m pt o ms i n C O P D ( E -R S: C O P D) 
r es p o nd ers at W e ek 2 4  
•  Pr o p orti on of E -R S: C O P D res p on d ers: su b -
sc al es of br e at hl ess n ess, co u gh a n d s p ut u m 
a n d ch est sy m pt o ms at W eek 2 4 a nd 5 2 
•  C h a n ge fr o m B as eli ne i n E -R S: C O P D T otal 
Sc or e at W e ek 2 4 a n d 5 2  
•  
 
 
S af et y O bje cti ve  
•  T o ev al uat e t he s afety of me p oliz u m ab i n 
p artici p a nts wit h C O P D  
 
•  I nci d e nc e of A Es /S A Es  i nclu di n g syst e mic 
r e acti o ns. 
•  I nci d e nc e of adj u dic at e d S A E  r e p orts a nd 
M A C E ev e nts ( C V de ath, no n -f atal 
my oc ar di al i nf arcti on, a n d n o n -f atal str ok e) 
•  Vit al si g ns incl u di ng bl oo d pr ess ur e  ( B P), 
b o dy t e m p er at ur e, p ulse r ate  
•  E C G ass ess m ents  
•  M ort ality ( all c a us e incl u di ng  r es piratory a nd 
c ar di ov asc ular c a uses of d eat h) 
•  Pr es e nce of a nti -dr ug a nti bo di es ( A D A) to 
m e p oliz u m a b  
•  H e m at ol o gical a nd cli nic al ch e mistry 
p ar a m eters  
H e alt h O ut c o m e E n d p oi nt s  
•  T o f urt her ev alu ate  t h e eff ect of 
m e p oliz u m a b 1 00 m g S C on h ealt h car e 
utiliz ati o n . 
 
•  H e alt hc ar e utiliz ati on f or C O P D i ncl u di ng 
h os pitaliz ati o n, E D, a n d p hysici a n 
offic e/cli nic visits  
 
C CI
C CI


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3.1. 
Pharmacokinetics Sub-study: China and US only 
Objective 
Endpoint 
• To evaluate the PK of mepolizumab 
100 mg in liquid formulation 
administered subcutaneously by SS 
in Chinese participants and to 
assess potential PK ethnic 
differences between non-Asian 
participants in the US and Chinese 
participants in China 
• Plasma mepolizumab concentrations 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities (SoA, Section 1.3), are essential and required for 
study conduct.  
This is a multi-center, randomized, placebo-controlled, double-blind, parallel group, trial 
evaluating mepolizumab 100 mg compared with placebo given every 4 weeks through SC 
injection of a liquid formulation delivered in a pre-filled safety syringe.  
It is estimated that approximately 4000 participants will be screened to achieve a target 
global randomization of approximately 800 randomized participants.  The number of 
randomized participants may increase up to approximately 1400 following blinded 
sample size re-evaluation (Section 9.2).  Eligible participants will be randomized 1:1 to 
mepolizumab 100 mg or placebo. 
During Screening Visit 0, a mandatory haematology blood sample is collected.  The 
Investigator or designee must review the results of the Visit 0 blood eosinophil count 
prior to initiating Screening Visit 1.  Participants with eosinophil count less than 300 
cells/L cannot proceed to Screening Visit 1 and will be considered a screen failure.  
Participants must also have a documented historical eosinophil count of ≥150/μL in the 
12 months prior to Screening Visit 0 and the historical eosinophil count must not have 
been measured during a COPD exacerbation.  Participants with no documented historical 
eosinophil count of ≥150 cells/µL must meet this threshold based on the Screening Visit 
1 assessment in order to return for Visit 2 (Inclusion Criteria, Section 5.1). 
Investigators are required to thoroughly review participants’ medical records to identify 
historical eosinophil counts.  It is only in the absence of documented records will 
eosinophils measurement at Screening Visit1 be considered.  
Participants who meet all the inclusion criteria and none of the exclusion criteria at 
Screening Visit 0 and Screening Visit 1 will enter a 2-week Run-in period. Excluding 
screening and run-in periods, study participants will remain in the study for at least 


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52 weeks (see SoA in Section 1.3.1) and up to a maximum of 104 weeks (See SoA in 
Section 1.3.2). More specifically, 
• For participants enrolled for 52 weeks (SoA in Section 1.3.1), their Exit Visit will 
occur at Week 52, 4 weeks after the last scheduled dose of IP. 
 
• For participants enrolled beyond 52 weeks (SoA in Section 1.3.2), their Exit Visit 
will be at Week 104 or until a scheduled visit that aligns to the date (i.e., that 
occurs on or before) the last randomized participant is scheduled to complete their 
Week 52 Exit Visit, whichever is sooner. The Exit Visit will occur 4 weeks after 
the last dose of IP. 
 
The timing of the last randomized participant into the study will affect the timing of the 
Exit Visit for participants enrolled beyond 52 weeks. All participants will be expected to 
complete at least 52 weeks of the study. The last randomized participant will be 
scheduled to complete only 52 weeks of the study. See Section 4.4 for additional details. 
In addition to the blood eosinophil inclusion criteria, participants must also have a history 
of regular maintenance use of ICS-based triple COPD standard of care treatment (as 
further defined in inclusion criteria Section 5.1) for at least 12 months prior to Screening 
Visit 1.  In addition, for at least 3 months immediately prior to Screening Visit 1, each 
participant must have a recorded history of use of an ICS-based inhaled triple regimen 
(ICS plus LABA plus LAMA) with a minimum inhaled corticosteroid at a dose of 
≥500 mcg/day fluticasone propionate or equivalent.  A detailed schematic is provided in 
the study reference manual (SRM) giving examples of ICS plus LABA plus LAMA 
therapy in the 12 months prior to Screening Visit 1. 
Participants are also required to have a history of at least 2 moderate COPD 
exacerbations that were treated with systemic corticosteroids (intramuscular (IM), 
intravenous, or oral) with or without antibiotics, or 1 severe exacerbation requiring 
hospitalization in the 12 months prior to Screening Visit 1 and one exacerbation must 
have occurred while the participant was receiving ICS plus LABA plus LAMA (Inclusion 
Criteria, Section 5.1).  All participants will receive optimized maintenance COPD therapy 
throughout the entire duration of the study regardless of treatment arm assignment.  In 
addition to ICS plus LABA plus LAMA, participants can enter the study with other 
COPD maintenance medications. 
The requirement for ICS plus LABA plus LAMA is predicated on the participant’s 
tolerance and safety to ICS and to long-acting inhaled bronchodilators.  However, it is 
recognized that maximal tolerated and safe therapy may not allow the use of a LAMA or 
LABA in combination with ICS in a given participant.  Where documentation of safety 
and tolerance does not allow the use of LABA or LAMA, participants will be allowed 
into the study on ICS plus LABA or ICS plus LAMA.  These circumstances must be 
reviewed and discussed with the Medical Monitor. 
It is also recognized that escalation or de-escalation of COPD maintenance medications 
may need to be individualized if clinically crucial for a participant.  The investigator will 


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discuss all cases with the Medical Monitor before initiating changes to a participant’s 
COPD maintenance medication regimen. 
The study interventional product, prepared in a pre-filled safety syringe, will be 
administered as a single SC injection given every 4 weeks at every study visit (except for 
the Exit Visit), beginning at the Randomization Visit (Visit 2).  The Exit Visit will occur 
4 weeks after the last administration of intervention product.  The primary efficacy 
endpoint will include exacerbations reported after the first dose up to and including the 
Exit Visit.  
Participants should understand and agree to complete an electronic diary (eDiary) 
throughout the study to be considered eligible.  The daily eDiary consists of questions to 
be answered each evening before bedtime.  The same eDiary will be used to capture 
patient reported outcomes (PROs) (see Section 8.1.3).  Site staff must therefore train 
participants on the proper use of the eDiary and completion of PROs at Visit 1. 
Compliance with completion of the daily eDiary will be captured during the Run-in 
period and throughout the study.  Participants must meet the eDiary compliance 
requirement for them to be eligible for randomization.   
Instream review of the eDiary data will monitor participant symptoms suggestive of an 
exacerbation and will also trigger prompts to encourage site staff to contact the patient for 
assessment and possible diagnosis of AECOPD.  
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SRM. The SRM will provide the site staff with 
administrative and detailed technical information that does not impact participant safety. 
Note:  The COVID-19 pandemic has impacted the conduct of this clinical study.  Where 
applicable country and local regulations and infrastructure allow, and at the discretion of 
Investigator and consent of the participant, home healthcare may take place at a location 
other than the clinical study site, e.g., the participant’s home to perform study 
assessments.  Refer to Appendix 10 and the SRM for details on COVID-19 pandemic 
measures and home healthcare for study assessments.  
Pharmacokinetic Sub-study:  China and US only 
An optional pharmacokinetic (PK) sub-study will be included in China and the US to 
assess potential ethnic differences in the PK of mepolizumab 100 mg, in liquid 
formulation, between non-Asian participants in the US and Chinese participants in China.   
PK blood samples will be collected from approximately 50 randomized participants from 
the US and approximately 50 randomized participants from China to ensure at least 20 
participants from each country provide PK information related to mepolizumab. This PK 
assessment will be conducted over the first 52 weeks of the study period only. 
4.2. 
Scientific Rationale for Study Design 
This study is designed to evaluate the efficacy and safety of mepolizumab 100 mg SC 
over a treatment period of at least 52 weeks and up to 104 weeks, in participants who 
exacerbate despite regular use of optimal therapy appropriate for severe COPD patients, 


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in the 12 months prior to Screening Visit 1.  Optimized standard of care (SoC) therapy 
must include a well-documented requirement for ICS-based triple COPD maintenance 
treatment (per inclusion criteria Section 5.1) for at least 12 months prior to Screening 
Visit 1.  Participants are also required to have a history of at least 2 moderate COPD 
exacerbations that were treated with systemic corticosteroid (intramuscular (IM), 
intravenous, or oral) with or without antibiotics, or 1 severe exacerbation requiring 
hospitalization in the 12 months prior to Screening Visit 1.  
All participants will receive optimized maintenance COPD therapy throughout the entire 
duration of the study regardless of intervention arm assignment.   
The 2-week Run-in period allows for the assessment of participant understanding and 
compliance with the daily eDiary to establish Baseline E-RS: COPD symptoms, and to 
allow adequate time for receipt of results from assessments collected at Screening Visit 1. 
A Screening blood eosinophil count threshold of ≥300 cells/μL at Screening Visit 0 has 
been selected since the mepolizumab initial phase IIIA studies have shown that patients 
with an eosinophil count ≥300 cells/μL are likely to achieve greater benefit from 
mepolizumab treatment. 
For participants with no documented historical eosinophil count of ≥150 cells/µL in the 
12 months prior Screening Visit 0, the greater than 14 day period between Screening 
Visit 0 and Screening Visit 1 allows for a repeated eosinophil count measurement at 
Screening Visit 1.  
The protocol objective is to collect data over the full study period, whether participants 
continue on IP or in the case of premature discontinuation from IP.  However, the 
decision to continue in the study after premature discontinuation from IP remains the 
prerogative of the participant.  Participants who agree to continue in the study after 
premature discontinuation from IP (for any reason) will continue to be contacted by the 
study site, either through in clinic visits or by phone as agreed with the participant, on a 
monthly basis (aligned to their study schedule) until the end of their planned 
participation, to enable capture of post-intervention information. 
4.3. 
Justification of Dose 
Evidence from the two initial phase IIIA studies demonstrated that in individuals with 
blood eosinophils ≥150 cells/µL at screening or ≥300 cells/µL in the prior year, a 100 mg 
SC dose provided a clinically relevant reduction in the primary endpoint of 
moderate/severe exacerbations of 18 to 20% compared with placebo.  This magnitude of 
reduction was consistent across studies (MEA117113 and MEA117106 High Stratum) 
and across the two doses investigated with an 18-20% reduction with 100 mg and 14% 
reduction with 300 mg [Pavord, 2017].  The absence of evidence of a greater reduction in 
the rate of moderate/severe exacerbations and prolonged time to first moderate/severe 
exacerbation with 300 mg SC, as well as the absence of evidence of an exposure-
response for those endpoints, support the rationale for a 100 mg SC therapeutic dose 
administered every 4 weeks in patients with COPD [Pavord, 2017]. 


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Furthermore, the safety profile following mepolizumab treatment was comparable to 
placebo, irrespective of dose. From the well-characterized blood eosinophil dose-
response established across multiple eosinophilic conditions, this dose represents 
approximately the dose providing the ID90 for blood eosinophil reduction.   
4.4. 
End of Study Definition 
The timing of the last randomized participant into the study will affect the timing of the 
Exit Visit for participants enrolled in an extended treatment duration beyond 52 weeks. 
As such, around the time the last participant is randomized into the study, the study team 
will communicate to study sites the dates for ‘IP Conclusion’ and ‘Study Conclusion’ as 
defined below. The Investigators will use these communicated dates to plan each 
participant’s Exit Visit.  
4.4.1. 
Participants Enrolled for 52 Weeks   
Completion of Intervention Period: A participant will be considered to have completed 
the study intervention period if he/she continues to receive IP up to and including the last 
scheduled IP dose at Week 48. 
Completion of Study: A participant will be considered to have completed the study if 
he/she continues to participate in the study until the scheduled Week 52 Exit Visit, 
regardless of whether the participant continued to receive IP during the treatment period. 
4.4.2. 
Participants Enrolled Beyond 52 Weeks 
Completion of Intervention Period: Whichever of the following [(i) or (ii)] is sooner, a 
participant will be considered to have completed the study intervention period if he/she: 
(i) 
Continues to receive IP up to and including the last scheduled IP dose at Week 
100. 
OR 
(ii) 
Continues to receive IP until a scheduled visit that aligns to the date the last 
randomized participant is scheduled to receive the last dose of IP at Week 48 
(hereafter referred to as the ‘IP Conclusion’ date). In this scenario, a 
participant will have completed the study intervention period if he/she 
continues to receive IP up to and including the scheduled visit that occurs on 
or immediately before the ‘IP Conclusion’ date. 
Completion of Study: Whichever of the following is sooner [(i) or (ii)] and regardless of 
whether the participant continued to receive IP during the treatment period, a participant 
will be considered to have completed the study if he/she: 
(i) 
Continues to participate in the study until the scheduled Exit Visit at Week 
104. 
OR 


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(ii) 
Continues to participate in the study until a scheduled visit that aligns to the 
date the last randomized participant is scheduled to complete the Week 52 
Exit Visit (hereafter referred to as the ‘Study Conclusion’ date). In this 
scenario, a participant will have completed the study if the participant 
continued in the study until a scheduled visit that occurs on or immediately 
before the ‘Study Conclusion’ date. 
4.4.3. 
End of Study 
The end of the study is defined as the date of the last scheduled visit, shown in the SoA 
for 52 weeks (Section 1.3.1.), for the last participant in the trial globally. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the below criteria apply. 
Further details pertaining to the Inclusion Criteria can be found in the SRM. 
Age 
1. Participant must be at least 40 years of age at Screening Visit 1  
Blood eosinophils 
2. A peripheral blood eosinophil count of ≥300 cells/μL from the hematology sample 
collected at Screening Visit 0 
 
AND 
 
A documented historical blood eosinophil count of ≥150/μL in the 12 months prior to 
Screening Visit 0 that meets the following: It must have been measured between 12 
months and 1 month prior to Visit 0, and it must not have been measured within 14 
days of a COPD exacerbation.  
Participants with no documented historical blood eosinophil count of ≥150 cells/µL 
must meet this threshold based on the Screening Visit 1 assessment in order to return 
for Randomization Visit 2. 
Type of Participant and Disease Characteristics 
3. COPD Diagnosis: Participants with a clinically documented history of COPD for at 
least 1 year in accordance with the definition by the American Thoracic 
Society/European Respiratory Society [Celli, 2004] 
4. Severity of COPD: Participants must present with the following: 
• A measured pre- and post-salbutamol FEV1/FVC ratio of <0.70 at Screening 
Visit 1 to confirm the diagnosis of COPD 


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• A measured post-salbutamol FEV1>20% and ≤80% of predicted normal 
values calculated using NHANES III reference equations [Hankinson, 1999; 
Hankinson, 2010] at Screening Visit 1. 
5. History of Exacerbations: Participants must have a well-documented history (e.g., 
medical record verification) in the 12 months prior to Screening Visit 1 of: 
• Two or more moderate COPD exacerbations that were treated with systemic 
corticosteroids (intramuscular (IM), intravenous, or oral) with or without 
antibiotics  
OR 
• At least one severe COPD exacerbation requiring hospitalization 
Note: At least one exacerbation must have occurred while the participant was taking 
inhaled triple therapy, ICS plus LABA plus LAMA unless documented intolerance or 
safety risk with either of the two long-acting bronchodilators.  If intolerance is 
documented, ICS plus LABA or ICS plus LAMA would be allowable after discussion 
with the Medical Monitor. 
Note: COPD exacerbation(s) related to laboratory confirmed COVID-19 infection 
must not be counted as COPD exacerbation(s) for inclusion in the study. 
6. Concomitant COPD therapy: Participants must have a well-documented 
requirement for optimized standard of care background therapy that includes ICS plus 
2 additional COPD medications (i.e., ICS-based triple therapy) for the 12 months 
prior to Screening Visit 1 and meets the following criteria: 
• Immediately prior to Screening Visit 1, minimum of 3 months of use of an a) 
inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate dose 
equivalent plus b) LABA and c) LAMA unless documentation of safety or 
intolerance issues related to LABA or LAMA. 
• For participants who are not continually maintained on ICS plus LABA plus 
LAMA for the entire 12 months prior to Visit 1 use of the following is 
allowed (but not in the 3 months immediately prior to Visit 1):  
a. inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate 
dose equivalent plus 
b. inhaled LABA or inhaled LAMA and 
c. Phosphodiesterase-4-inhibitors, methylxanthines, or scheduled daily 
use of short acting beta2-agonist (SABA) and/or short acting 
muscarinic antagonist (SAMA).  
Note: Where intolerance or safety risk is documented for either LAMA or LABA, 
ICS-based inhaled dual maintenance therapy, either ICS plus LABA or ICS plus 
LAMA, is allowed in the 12 months prior to Visit 1 and during the clinical trial but 
must be discussed with the Medical Monitor. 
Note: Participants must be willing to receive optimized maintenance COPD therapy 
for the duration of the study. 


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7. Smoking Status: Current or former cigarette smokers with a history of cigarette 
smoking of ≥10 pack-years at Screening (Visit 1) [number of pack years = (number of 
cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 
years, or 10 cigarettes per day for 20 years)]. Former smokers are defined as those 
who have stopped smoking for at least 6 months prior to Screening Visit 1.  
Note: Pipe and/or cigar use cannot be used to calculate pack-year history. 
Sex 
8. Male or female: Contraceptive use for women should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies. 
Female Participants:  
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
o Is not a woman of childbearing potential (WOCBP) 
OR 
o Is a WOCBP and using a contraceptive method that is highly effective, with a 
failure rate of <1%, as described in Appendix 5, during the intervention period 
and for at least 16 weeks after the last dose of study intervention.  The principal 
investigator (PI) should evaluate the effectiveness of the contraceptive method in 
relation to the first dose of study intervention. 
 
• 
A WOCBP must have a negative highly sensitive pregnancy urine test within 
24 hours before the first dose of study intervention. 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 5 
• 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk of inclusion of a woman with an early 
undetected pregnancy 
Informed Consent 
9. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
Other 
French participants: In France, a participant will be eligible for inclusion in this 
study only if either affiliated to or a beneficiary of a social security category. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Asthma: Participants with a past history or concurrent diagnosis of asthma are 
excluded regardless of whether they have active or inactive disease. 
 
2. Other respiratory disorders: The Investigator must judge that COPD is the primary 
diagnosis accounting for the clinical manifestations of the lung disease. Participants 
with α1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, 
excluded are participants with active tuberculosis, lung cancer, bronchiectasis, 
sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases 
or other active pulmonary diseases.  
3. COPD stability: Participants with pneumonia, COPD exacerbation, or lower 
respiratory tract infection within the 4 weeks prior to Screening Visit 1. 
4. Lung resection: Participants with lung volume reduction surgery within the 12 
months prior to Screening Visit 1. 
5. Pulmonary rehabilitation program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1.  
Participants who are in the maintenance phase of a pulmonary rehabilitation program 
are not excluded. 
6. Oxygen: Participants receiving treatment with oxygen more than 2 L/min at rest over 
24 hrs. For Participants receiving oxygen treatment, participants should demonstrate 
an oxyhemoglobin saturation greater than or equal to 89% while breathing 
supplemental oxygen. 
7. 12-lead ECG at Screening Visit 1: Participants with a QT interval, from the ECG 
conducted at Screening Visit 1, corrected with Fridericia’s formula (QTcF) >450 
msec (or QTcF >480 msec in participants with bundle branch block).  
• 
QTcF is the QT interval corrected for heart rate according to Fridericia’s formula 
that is selected for this study. It is either machine-read or manually over-read when 
not automatically machine read.  This specific formula must be used to determine 
eligibility and discontinuation for an individual participant. 
• 
Participants are excluded if an abnormal ECG finding from the 12-lead ECG 
conducted at Screening Visit 1 is considered to be clinically significant and would 
impact the participant’s participation during the study, based on the evaluation of the 
Investigator. 
Note:  Where a single ECG demonstrates a prolonged QTcF interval, obtain two more 
ECGs readings at a minimum of 2 minutes apart over a brief recording period (e.g., 5-10 
minutes), The average of the triplicate QTcF measurements should be used to determine 
eligibility 


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8. Unstable or life threatening cardiac disease:  Participants with any of the 
following would be excluded: 
• Myocardial infarction or unstable angina in the 6 months prior to Screening Visit 
1  
• Unstable or life threatening cardiac arrhythmia requiring intervention in the 3 
months prior to Screening Visit 1  
• New York Heart Association (NYHA) Class IV Heart failure   
9. Other diseases/abnormalities:  Participants with (historical or) current evidence of 
clinically significant, neurological, psychiatric, renal, hepatic, immunological, 
endocrine (including uncontrolled diabetes or thyroid disease) or hematological 
abnormalities that are uncontrolled. Significant is defined as any disease that, in the 
opinion of the Investigator, would put the safety of the participant at risk through 
participation, or which could affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study. 
10. Eosinophilic disease:  Participants with other conditions that could lead to elevated 
eosinophils such as Hypereosinophilic syndromes including Eosinophilic 
Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome), 
or Eosinophilic Esophagitis. 
11. Parasitic infection: Participants with a known, pre-existing parasitic infestation 
within 6 months prior to Screening Visit 1. 
12. Malignancy: A current malignancy or previous history of cancer in remission for 
less than 12 months prior to Screening Visit 1 (Participants that had localized 
carcinoma of the skin or cervix which was resected for cure will not be excluded). 
Note: for South Korea: Korean participants with a diagnosis of malignancy within 5 
years of Visit 1 are excluded.  
13. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency 
virus – HIV), other than that explained by the use of corticosteroids taken for COPD. 
14. Liver disease: Cirrhosis or current unstable liver disease per investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice. Stable non-
cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic 
gallstones, and chronic stable hepatitis B or C) is acceptable if the participant 
otherwise meets entry criteria. 
Prior/Concomitant Therapy 
15. Previous mepolizumab studies: Participants who have received interventional 
product in previous mepolizumab studies are excluded. 
16. Monoclonal antibodies: Participants who have received any monoclonal antibody 
within 5 half-lives of Screening Visit 1 
17. Investigational medications: Participants who have received an investigational drug 
within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug, 


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whichever is longer (this also includes investigational formulations of a marketed 
product). 
18. Oral corticosteroids: Participants who have received short term use of oral 
corticosteroids within 30 days of Visit 1 
Other Exclusions 
19. Hypersensitivity:  Participants with a known allergy or sensitivity to any of the 
study interventions, or components thereof, or drug or other allergy that, in the 
opinion of the Investigator or Medical Monitor, contraindicates participation in the 
study or intolerance to another monoclonal antibody or biologic including history of 
anaphylaxis to another biologic 
20. Non-compliance: Participants at risk of non-compliance, or unable to comply with 
the study procedures. Any infirmity, disability, or geographic location that would 
limit compliance for scheduled visits.  
21. Questionable validity of consent: Participants with, conditions that will limit the 
validity of informed consent to participate in the study, e.g uncontrolled psychiatric 
disease or intellectual deficiency. 
22. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Screening Visit 1. 
23. Affiliation with Investigator Site: Is an Investigator, sub-Investigator, study 
coordinator, employee of a participating Investigator or study site, or immediate 
family member of the aforementioned that is involved in this study. 
24. COVID-19: a- Participants that have a current active COVID-19 infection, either 
laboratory confirmed or according to the investigator's medical judgement. 
 
Note:  Participants who have confirmed or suspected COVID-19 infection may be 
re-screened 4 weeks or more after the resolution of the COVID-19 infection and only 
after written approval from the study Medical Monitor. 
 
b- Participants known to be in contact with active COVID-19 positive individuals 
within the past 14 days.  
 
Note:  Participants may be re-screened 14 days or more following the contact, during 
which the participant should remain symptom free, and only after written approval 
from the study Medical Monitor. 
5.3. 
Randomization Criteria 
5.3.1. 
Randomization Inclusion Criteria 
At Visit 2, those participants who continue to meet the inclusion/exclusion criteria and 
who meet the randomization inclusion/exclusion criteria will be randomized and 
commence the study intervention period until the target of approximately 800 
randomized participants is reached. 


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1. Blood eosinophil count:  Participants that do not have a historical blood 
eosinophil count that satisfies screening inclusion criterion 2 (Section 5.1) must 
have Screening Visit 1 blood eosinophil count ≥150 cells/µL. 
2. Electronic Diary Compliance: Compliance with completion of the e-diary 
defined as completion of all questions on 5 or more days out of the 7 days 
immediately preceding Visit 2.  
5.3.2. 
Randomization Exclusion Criteria 
1. COPD stability:  Participants who have pneumonia, exacerbation, lower respiratory 
infection during the Run-in period. 
Note:  Participants may be re-screened 4 weeks after their exacerbation is resolved 
and only after written approval to proceed with re-screening from the study Medical 
Monitor. 
2. Laboratory abnormality:  Evidence of clinically significant abnormality in the 
hematological or biochemical screen at Visit 1, as judged by the Investigator. 
3. Liver function test (LFT):  Participants who meet the following based on results 
from sample taken at Screening Visit 1: 
Alanine aminotransferase (ALT) >2x upper limit of normal (ULN) 
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
Cirrhosis or current unstable liver or biliary disease per Investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice. 
NOTES:  Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, 
asymptomatic gallstones, and chronic stable hepatitis B or C) is acceptable if the 
participant otherwise meets entry criteria 
4. Pregnancy: Participants who are pregnant or breastfeeding. Participants should not 
be randomized if they plan to become pregnant during the time of study participation. 
5. COVID-19: a- Participants that had an active COVID-19 infection during the Run-in 
period, either laboratory confirmed or according to the investigator's medical 
judgment. 
Note:  Participants may be re-screened 4 weeks or more after the resolution of the 
COVID-19 infection and only after written approval from the study Medical Monitor. 
b- Participants known to be in contact with active COVID-19 positive individuals 
within the past 14 days. 
Note:  Participants may be re-screened 14 days or more following the contact, during 
which the participant should remain symptom free, and only after written approval 
from the study Medical Monitor. 


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6. 12-lead ECG: Participants with a QT interval, from the ECG conducted at Visit 2, 
corrected with Fridericia’s formula (QTcF) >450 msec (or QTcF >480 msec in 
participants with bundle branch block).  
Note:  Where a single ECG demonstrates a prolonged QTcF interval, obtain two more 
ECGs readings at a minimum of 2 minutes apart over a brief recording period (e.g., 5-10 
minutes). The average of the triplicate QTcF measurements should be used to determine 
eligibility for randomization. 
 
5.4. 
Screen and Run-in Failures 
Screen failure: Screening Visit 0 and Screening Visit 1 
Screen failures are defined as participants who consent to participate in the study, have at 
least one Screening Visit 0 assessment but who are not subsequently randomized.   
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. 
Participants will be assigned a participant number at the time the informed consent is 
signed. 
A participant, who is assigned a participant number at Screening Visit 0 but does not 
have any Screening Visit 1 procedures, will be considered a Screen failure at Screening 
Visit 0. 
The study interactive web response system (IWRS) will be contacted to report screen 
failures at Screening Visit 0.  The following information will be collected for participants 
who are screen failures at Screening Visit 0: 
• Date of ICF signature 
• Demographic information including race, year of birth, gender and child bearing 
potential 
• Participant number 
• Reason for screen failure 
• Inclusion/Exclusion criteria 
• Hematology sample collection 
• Historical eosinophil collection 
• Investigator signature page 
• SAEs considered as related to study participation or related to any GSK product.  
China only: All SAEs will be collected. 
Participants who continue to Screening Visit 1 and have at least one assessment but who 
are not subsequently randomized will be considered screen failures at Screening Visit 1.  


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
5 9  
 
I n a d diti o n t o i nf or mati o n c ollecte d f or scree n fail ures at Scree ni n g Visit 0  (a b o ve) t h e 
f oll o wi n g i nf or mati o n will be c ollecte d f or scree n fail ures at Scree ni n g V isit 1 : 
•  Date of Scree ni n g Visit 1  
•  Reas o n f or scree n fail ure  
•  S A Es  c o nsi dere d as relat e d t o st u d y partici pati o n  or relate d t o a n y G S K pr o d uct .  
C hi n a o nl y:  All S A Es will be c ollecte d.  
 
T he I W R S will be c o ntacte d t o re p ort scree n fail ures  at Scree ni n g V isit 1 .   
R u n -i n f ail ure 
A n y p artici pa nt w h o c o m pletes Scree ni n g Visit 1 e nters t he R u n -i n peri o d a n d c o m pletes 
at least o ne Visit 2 pr oce d ure b ut is n ot ra n d o mize d is classifie d as a R u n -i n fail ure 
T he I W R S will be c o ntacte d t o re p ort R u n -i n fail ures.  I n a d diti o n t o t he i nf or mati o n 
a b o ve, t he f oll o wi n g i nf or mati o n wil l be c ollecte d f or R u n-i n fail ures: 
•  Date of Visit 2  
•  Reas o n f or R u n -i n f ail ure (e. g., C O P D e x acer bati o n, l o wer res pir at or y tract 
i nfecti o n [L R TI ], p n e u m o nia)  
 
A d diti o nal i nf or mati o n relate d t o data c ollecti o n f or, scree n fail ures  at Scree ni n g Visit 0  
or  Scree ni n g  Visit 1 , a n d R u n-i n fail ures ca n b e f o u n d i n t he e C R F c o m pleti o n 
g ui deli nes.  
Re -scree ni n g of scree n fail ure a n d r u n-i n f ail ure p artici pa nts will be per mitte d; h o we ver, 
a d va nce writte n a p pr o val t o pr ocee d  wit h r e -scree ni n g a p artici pa nt m ust be obtai ne d 
fr o m t he Me dical M o nit or.  
 
6.  
S T U D Y I N T E R V E N TI O N 
St u d y i nter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), 
place b o , or me di cal de vi ce (s) i nte n d e d t o be a d mi nistere d t o a st u d y p artici pa nt acc or di n g 
t o t he st u d y pr ot oc ol.  
6. 1.  
St u d y I nt er v e nti o n(s ) A d mi ni st er e d  
 
 
 
 
 
 
 F urt her details of d ose pre parati o n a n d a d mi nistrati o n ca n be 
f o u n d i n t he c urre nt versi o n of t he  I B a n d t he S R M.   
C CI


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
6 0  
 
T a bl e 1  
St u d y I nt er v e nti o n al pr o d u ct s  
A R M N a m e  
M e p oliz u m a b 1 00 m g  
Place b o   
I nt er v e nti o n 
N a m e  
M e p oliz u m a b 1 00 m g S C  
Place b o   
T y p e  
Bi ol o gic  
N/ A  
D o s e 
F or m ul ati o n  
U nit D o s e 
Str e n gt h( s)  
1 0 0 m g/ m L ; 1. 0 m L ( d eliv era bl e)  
1. 0  m L d eliv er abl e  
D o s a g e L e v el( s)  1 0 0 m g o nce every 4 w eeks  
Pl ac e bo o nc e ev ery 4 we eks  
R o ut e of 
A d mi ni str ati o n  
S C i nj ecti o n  
S C i nj ecti o n  
S o ur ci n g  
Pr ovi d e d c e ntrally by t he Spo ns or  
Pr ovi d e d c e ntrally by t he Spo ns or  
P a c ka gi n g a n d 
L a b elli n g  
 
St u dy I nterv e nti on will b e pr ovi d e d i n 
pr e -fill e d s afety syrin ge. Eac h pr e-
fill e d s af ety syri n g e will b e la b ell ed 
as r e q uir ed p er c o untry r e q uire m e nt.  
St u dy I nterv e nti on will b e pr ovi d e d i n 
pr e -fill e d s afety syrin ge. Eac h pr e-
fill e d s af ety syrin g e will b e la b ell ed 
as r e q uired p er c o untry r e q uire m e nt.  
6. 1. 1.  
M e di c al D e vi c e s  
•  I nstr u cti o ns f or use of t h e pre-fille d safet y s yri n ge are pr o vi de d i n t he S R M  
•  G S K me dical de vice i nci de nts, i ncl u di n g t h ose res ulti n g fr o m malf u ncti o ns of t he 
de vice, m ust be dete cte d, d oc u me nte d, a n d re p orte d b y t he I n vesti gat or t hr o u g h o ut t he 
st u d y (see Secti o n 8. 3. 7 ) 
•  T he G S K ma n ufact ure d me dical de vices ( or de vi ces ma n ufact ure d f or G S K b y a t hir d 
part y) pr o vi de d f or use i n t his st u d y are i njecti o n de vices:  
➢ A prefille d s yri n ge c o ntai ne d wit hi n a safet y s yri n ge. T h e de vices use d i n t he 
st u d y are re prese nt ati ve of t he de vices m ar kete d f or t he pr o d uct.  
➢ 
 
 
. 
 
C CI
C CI


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
6 1  
 
➢ 
 
 
. 
T he I nstr ucti o n f or us e (I F U) of t h ese i njecti o n de vic es are pr o vi de d i n t he S R M.  T he 
i nstr ucti o ns were de v el o pe d a n d o pti mise d as a res ult of f or mati ve h u ma n fact ors 
st u dies a n d are re prese nt ati ve of t h ose t hat are pla n ne d f or t he pr o d uct.  
6. 2.  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  
1.  T he I n vesti gat or or d esi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns 
ha ve bee n mai ntai ne d d uri n g tr a nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y 
discre pa n cies are re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n.  
F urt her details are pr o vi d e d i n t he S R M.  
2.  O nl y partici pa nts ra n d o miz e d i n t he st u d y ma y recei ve st u d y i nter ve nti o n a n d 
o nl y a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n.  All st u d y 
i nter ve nti o ns m ust be st ore d i n a sec ure, e n vir o n m e ntall y c o ntr olle d, a n d 
m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da n ce wit h t he la belle d st or a ge 
c o n diti o ns wit h access li mite d t o a ut h orize d site staff.  
3.  T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here 
a p plica ble) is r es p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, r ec o nciliati o n, a n d 
rec or d m ai nte na nce (i.e., recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
4.  F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y 
i nter ve nti o n are pr o vi de d i n t he S R M  
5.  U n der n or mal c o n diti o ns of ha n dli n g a n d a d mi nistrati o n, st u d y i nter ve nti o n is n ot 
e x pecte d t o p ose si g nifica nt safet y ris ks t o site staff .  Ta ke a de q u ate preca uti o ns 
t o a v oi d direct e ye or s ki n c o ntact a n d t he ge nerati o n of aer os ols or mists. I n t he 
case of u ni nte nti o nal o cc u pati o nal e x p os ure n oti f y t he m o nit or, Me dical M o nit or 
a n d/ or G S K st u d y c o ntact.  
6.  Preca uti o n will be ta ke n t o a v oi d direct c o ntact wit h t he st u d y i nter ve nti o n.  A 
Material Safet y D ata S he et ( M S D S) descri bi n g occ u pati o nal hazar ds a n d 
rec o m me n de d h a n dli n g preca uti o ns will be pr o vi de d t o t he i n vesti gat or. I n t he 
case of u ni nte nti o nal o cc u pati o nal e x p os ure n otif y t he m o nit or, Me dical M o nit or 
a n d/ or G S K st u d y c o ntact.  
6. 3.  
M e a s ur e s t o Mi ni mi z e Bi a s: R a n d o mi z ati o n a n d Bli n di n g  
All partici pa nts will be ce ntrall y ra n d o mize d usi n g a n I W R S bef or e t he st u d y is i nitiate d. 
L o g i n details a n d dir ecti o ns f or accessi n g t he I W R S will be pr o vi de d t o partici pati n g 
sites.  
At Visit 2 ( Da y 1) t h ose partici pa nts w h o meet t h e ra n d o mizati o n eli gi bilit y criteria will 
be ra n d o mize d i n a 1: 1 rati o t o recei ve o ne of t he f oll o wi n g i nter ve nti o ns e v er y 4 wee ks:  
•  Me p oliz u ma b 1 0 0 m g S C  
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• Placebo SC 
A unique Participant Number will be assigned to participants who have consented. This 
unique participant number will be used to identify the individual participant throughout 
the study and will not be re-assigned to any other participant. 
Participants will be assigned to study intervention in accordance with the randomization 
schedule. Once a Randomization number has been assigned to a participant, it cannot be 
reassigned to any other participant in the study. 
The Randomization schedule will be generated using a validated Randomization 
software.  Separate Randomization schedules will be created for each country. Equal 
numbers of participants will be allocated to each intervention arm. 
Details of how to use the IWRS to register and randomize participants will be provided in 
the SRM. 
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’s intervention assignment is warranted.  Participant safety must always be the 
first consideration in making such a determination.  If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention of the participant.  If a participant’s intervention assignment is unblinded 
GSK must be notified within 24 hrs after breaking the blind. The date and reason that the 
blind was broken must be recorded in the source documentation and case report form, as 
applicable. 
A participant must discontinue IP but may continue in the study if the participant’s 
intervention assignment is unblinded by the investigator or treating physician.  The event 
or condition which led to the unblinding will be recorded in the eCRF. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered at the study site by a designated member of the 
site staff. Drug dispensing/accountability logs will be maintained by a designated 
member of the site staff. 
 
• 
Participants are dosed under medical supervision at the site, they will receive 
mepolizumab 100 mg SC or matching placebo, provided in a pre-filled safety 
syringe, directly from the Investigator or designee.  The date and time of each dose 
administered in the clinic will be recorded in the participant’s source documents.  
The study interventional product and study participant identification will be 


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confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study intervention. 
• 
For the first three administrations participants will be monitored for 1 hour after 
receiving study interventional product. For subsequent administrations of 
interventional product, participants will be monitored according to the monitoring 
policies for the center or vendor for home visits.   
• 
In the event of an acute severe reaction (e.g., anaphylaxis) following administration 
of study treatment, there must be personnel/staff onsite at the treatment facility or at 
the participant’s home (if a home visit) who are appropriately trained in basic life 
support to manage the patient including administration of medications (e.g., 
epinephrine), and have access to a system that can promptly transport the patient to 
another facility for additional care if appropriate. 
• 
Administration of study intervention will be documented in the source documents 
and reported in the CRF. 
• 
NOTE: Where applicable refer to Appendix 10 and the SRM for details on COVID-
19 pandemic measures and home healthcare for study assessments and study 
intervention. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of pre-
screening/screening or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
It is permissible for participants to be vaccinated against COVID-19 with vaccines 
authorized or approved by the local regulatory authority; vaccination with an unapproved 
or unauthorized COVID-19 vaccine (i.e., a candidate vaccine) is not permissible.  


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6.5.1. 
Rescue Medicine 
Participants will be supplied with the short-acting bronchodilator salbutamol Metered 
Dose Inhaler (MDI) or nebules as rescue medication.  
Although the use of rescue short-acting bronchodilators is allowable at any time during 
the study, the use of rescue medications should be delayed, if possible, for at least 4 hours 
prior to spirometry testing (see Schedule of Activities, Section 1.3 and Section 8.1.4). 
6.5.2. 
Permitted Medications and Non-Drug Therapies 
The COPD medications listed below are permitted during the treatment period while the 
participant is on IP.  The requirements for study inclusion with regards to this medication 
list are described in detail by Study Inclusion Criterion 5: 
• If taken as standard of care therapy prior to Visit 1 the following are permitted: 
o inhaled corticosteroids  
o inhaled long-acting muscarinic antagonists  
o inhaled long-acting beta2-agonists 
o methylxanthines 
o phosphodiesterase-4 (PDE-4) inhibitor  
o oral corticosteroids (chronic use only)  
o leukotriene receptor antagonists (Singulair) 
• Oral or injectable corticosteroids (short course ≤14 days) only for the short term 
treatment of COPD exacerbations and/or pneumonia 
• Antibiotics (short course ≤14 days) for the short term treatment of COPD 
exacerbations and/or pneumonia 
• Mucolytics such as acetylcysteine 
• Long term oxygen therapy (LTOT).  To be eligible to enter the study participants who 
are on LTOT must be using at a flow rate of 2 L/minute at rest over 24 hours.  
However, oxygen therapy may be adjusted as deemed medically necessary at any time 
during the study. Oxygen therapy must be captured on the concomitant medication 
page of the eCRF.  Supplemental oxygen is recommended for patients who exhibit 
oxyhemoglobin desaturation with rest or exertion (e.g. SaO2 88%) while breathing 
room air. 
• Maintenance phase of pulmonary rehabilitation treatment (participants are not 
allowed to initiate treatment during the study). 
• Rescue medication for prn use e.g. salbutamol or ipratropium. 
The following non-COPD medications are permitted during the study (for example): 
• Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants) 


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• Topical and ophthalmic corticosteroids 
• Unplanned localized corticosteroid injections (e.g. intra-articular and epidural) 
• Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc).  
Administration of influenza and pneumonia vaccines should be considered based on 
clinical discretion of the Investigator and local/national guidelines.  Vaccines will be 
captured on the concomitant medication pages of the eCRF 
• Allergy immunotherapy 
• Antibiotics for short-term treatment (14 days) of acute infections. Long term 
treatment with antibiotics is not allowed 
• Systemic and ophthalmic beta-blockers 
• Smoking cessation treatments 
• Cough suppressants 
• Anti-depressants and anxiolytics 
• Continuous Positive Airway Pressure (CPAP) and Bi-Level Positive Airway Pressure 
(BiPAP) 
• 
Note: Immune-suppressants for conditions other than COPD are allowed if they have 
been stable for the 3 months prior Screening Visit 1 and after discussion with the 
study Medical Monitor. 
6.5.3. 
Prohibited Medications and Non-Drug Therapies 
Medications noted as part of exclusion criteria are prohibited for the duration of the 
treatment period. 
Eligible participants are expected to continue their Baseline maintenance COPD 
medications during the run-in period and throughout the intervention period.  Where 
spirometry is performed (See SoAs in Section 1.3.1and Section 1.3.2), participants will 
refrain from taking their morning dose of their maintenance COPD medications until 
instructed to do so by clinic personnel. 
Rescue medication (i.e. salbutamol or ipratropium) must also be withheld for at least 4 
hours before visits when spirometry is performed (see SoA Section 1.3 ), and prior to 
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COPD medications and non-drug therapies that are prohibited during the 
randomized phase of the study: 
• Acute phase of pulmonary rehabilitation (at any time during the study including 
Run-in) 
• Long term systemic antibiotic therapy (antibiotics used for ≤14 days for acute 
infections or for exacerbations or pneumonia are allowed).   
• Monoclonal antibodies 
• Chronic oral corticosteroids for non-COPD treatment 
Note:  Chronic macrolide therapy is permitted.  Participants taking chronic 
macrolides at Visit 1 should continue the macrolide throughout the duration of the 
study. 
• Experimental anti-inflammatory drugs (non-biologicals) or other investigational 
products (biologic or non-biologic) within either 30 days or five drug half-lives 
prior to Visit 1, whichever is longer. 
• Other investigational products (participants must have not received investigational 
products for 1 months or 5 half-lives prior to Visit 1, whichever is longer) 
• Radiation therapy is excluded for 12 months prior to Visit 1 and throughout the 
study 
6.6. 
Intervention after the End of the Study 
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.  No additional doses of mepolizumab 
treatment will be provided by GSK at the end of the study. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If a participant permanently discontinues interventional product before the 
end of the protocol specified randomized intervention period, every effort will be made 
by the Investigator to encourage the participant to remain in the study and to complete all 
remaining study visits.  Participants will be provided with the option to continue to have 
regularly scheduled in-clinic visits or to have regularly scheduled phone visits.  The 
Investigator must document the reason for discontinuation of IP in the eCRF.  The 
principal Investigator/ site staff should continue contact with the participant at the 
protocol designated visit time intervals to complete study assessments.  The required 
study assessments will depend on whether the participant is attending an in-clinic visit or 
a scheduled phone visit.  At a minimum, an assessment of exacerbations, AEs, SAEs, and 
concomitant medications will be completed.  Further details are provided in the SRM. 


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The Investigator should make every effort to have the participant return to the clinic 4 
weeks after the participant permanently discontinues IP in order to complete the 
Discontinuation from IP Visit.   
The primary reason for discontinuation from IP will be recorded in the eCRF.  
Participants should permanently discontinue IP, but not the study, if the following criteria 
are met: 
• Meets any of the protocol-defined liver chemistry stopping criteria, identified 
during the study or identified during routine standard of care assessments outside 
of the study (See Section 7.1.1 and Appendix 7)  
• ECG: Clinically significant abnormality identified during the study that meet the 
QTc stopping criteria described in Section 7.1.2 
• Pregnancy:  Positive pregnancy test (See Appendix 5) 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping criteria and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm below  
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  


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Liver Chemistry Stopping Algorithm 
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; 
SAE = serious adverse event; ULN = upper limit of normal


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Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for 
participants with ALT 3xULN but <8xULN and who do not meet any liver 
stopping criteria  
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal. 
Refer to Appendix 7: Liver Safety Required Actions and Follow up Assessments for 
required actions, monitoring and follow up assessments for any event that met liver 
stopping or liver monitoring criteria. 
7.1.1.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met, by 
any participant in this study, is not allowed. 
7.1.2. 
QTc Stopping Criteria 
• 
The QT correction Fridericia formula must be used for each individual participant to 
determine eligibility for and discontinuation from IP.  This formula may not be 
changed or substituted once the participant has been enrolled.   
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment intervention but not from the study: 
• 
QTcF >500 msec OR Uncorrected QT >600 msec 
• 
Change from baseline of QTcF >60 msec 


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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below: 
Baseline QTcF with Bundle Branch 
Block 
Discontinuation QTcF with Bundle 
Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
7.1.3. 
Temporary Discontinuation 
If a participant becomes infected (parasitic infection) whilst receiving study intervention 
and does not respond to anti-helminth treatment, temporary discontinuation of study 
intervention should be considered in consultation with GSK Medical Monitor. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may prematurely discontinue study intervention product and withdraw from 
the study at any time at his/her own request, or at any time at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons.  
Participants may withdraw from the PK sub-study and remain in the study. 
Participants who permanently discontinue IP are not required to withdraw from the study.  
If a participant must permanently discontinue IP, every effort should be made by the 
Investigator/site staff to keep the participant in the study to collect important efficacy and 
safety data.  Participants who have permanently discontinued IP and have not withdrawn 
consent may continue in the study to complete all remaining protocol specified visits by 
continued in-clinic visits (or home healthcare, if applicable) or by phone contact. 
For participants who discontinue IP but remain in the study, an IP discontinuation Visit 
should be conducted as shown in SoA.  See SoA (Section 1.3) for data to be collected at 
the time of IP discontinuation.  If for any reason those participants later withdraw from 
the study, a withdrawal from the study Visit should be conducted as shown in the SoA. 
Additional details will be given in the SRM. 
For participants who discontinue IP and withdraw from the study at the same time, the 
Withdrawal from study Visit should be conducted as per SoA.  
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
Any participant who withdraws from the study prior to their planned Completion of 
Study date (defined in Section 4.4) will be considered to have missing data from the date 
of study withdrawal up to their planned Completion of Study date. 


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7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
7.4. 
Reasons for IP Discontinuation and/or Study Withdrawal 
The primary reason for IP discontinuation and/or study withdrawal will be recorded in 
the eCRF.  When a participant withdraws consent, the Investigator must document the 
reason (if specified by the participant) in the eCRF.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoAs (Section 1.3).  
NOTE:Where applicable refer to Appendix 10 and the SRM for details on COVID-19 
pandemic measures and home healthcare for study assessments. 
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 


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• 
All Screening Visit 0 and Screening Visit 1 evaluations must be completed and 
reviewed to confirm that potential participants meet all eligibility criteria.  The 
investigator will maintain a Screening log and complete details in the eCRF data 
base to record details of all participants screened and to confirm eligibility or record 
reasons for Screening failure, as applicable.  
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
• 
The order of assessments at clinic visits is listed in the SRM 
Screening and Critical Baseline Assessments 
Screening Visit 0 
During Screening Visit 0, site staff must provide informed consent to the study 
participant.  Informed consent for an optional genetic sample, where permitted, is also 
provided at this visit. 
China and US only: Informed consent for the optional PK sub-study in China and the 
US can also be provided at this visit. 
 
A mandatory hematology blood sample is collected at this visit and will be used to assess 
Inclusion Criterion 2 (a blood eosinophil count of ≥300 cells/μL at Screening Visit 0). 
 
A participant number will be assigned at the time the informed consent form (ICF) is 
signed. No study related procedures may be performed until the ICF document has been 
signed by the participant. 
 
During Screening Visit 0, the following assessments are performed: 
• Demography including year of birth, gender, race, child bearing potential and 
ethnicity 
• COPD and all concomitant medications review 
• Hematology blood sample (for eosinophil count) is collected. 
• Review of inclusion/exclusion criteria 
• Historical blood eosinophils: Where several historical blood eosinophil counts are 
obtainable, the highest eosinophil count should be recorded in the eCRF for each 
of the following specified periods: ≥1 to <6 months and 6 to12 months. In order to 
meet the Inclusion Criteria #2 (Section 5.1), a historical blood eosinophil 
measurement must meet the following: It must have been measured between 12 
months and 1 month prior to Visit 0 and it must not have been measured within 14 
days of a COPD exacerbation. If, in either of the 2 specified periods, the only 
historical documented blood eosinophil count is associated with a COPD 
exacerbation, then this eosinophil count cannot be used for inclusion in the study 
but should be recorded in the eCRF. Refer to the SRM for more information.  
 
For Screening Visit 0, SAEs considered as related to study participation (including 
concomitant medications related to the SAEs) must be reported.  For China all SAEs will 
be reported after signing of ICF. 


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All clinic visits from Screening Visit 0 to Exit Visit must be registered in the IWRS and 
the relevant eCRF form completed. 
 
Critical procedures performed at Screening Visit 1 
Results from the hematology testing at Screening Visit 0 must be obtained before 
performing Screening Visit 1.  Participants who do not meet the inclusion criteria of ≥300 
eosinophil/µL cannot proceed to Screening Visit 1 and will be considered screen failures. 
The following critical assessments will be conducted at Screening Visit 1: 
• Medical history including COPD (including date of diagnosis and COPD type 
(emphysema or chronic bronchitis), COPD exacerbation history, smoking status, 
smoking cessation counselling, previous and/or current medical conditions.  
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening as well as family history of premature cardiovascular 
disease.  
• A hematology blood sample must be drawn from participants who do not have 
documentation of a historical blood eosinophil count ≥150 cells/µL in the 12 
months prior to Screening Visit 0.  
• Screening Visit 1 spirometry including pre- and post-albuterol/salbutamol 
responsiveness testing, (see Section 8.1.4.2) 
• Parasitic screening, total IgE as described in the SoA 
•   Concomitant medication review; COPD maintenance medications from the year 
prior to Screening Visit 1 and all other medications within the 3 months prior to 
Screening Visit 1. 
• Complete physical examination including height and weight 
• 12-Lead ECG 
• Modified Medical Research Council Grading System (mMRC): The participant’s 
degree of dyspnea to different levels of activity will be rated on the five point 
mMRC scale. The mMRC, administered by an interviewer, asks participants to 
rate how breathless they are on a 5-point Guttman scale.  
• Vital signs and pulse oximetry at this visit only 
• Urine pregnancy test if applicable 
• Clinical chemistry 
• Register and train participant on the use of eDiary.  Instruct participant to 
complete the daily evening eDiary from Screening Visit 1 and throughout the 
study 
• Review inclusion/exclusion criteria assessments 
• Review exacerbations, SAEs if related to study participation. (for China all SAEs 
will be reviewed) 
• Provide medical problems and healthcare utilization worksheet 
• Dispense rescue medication 
• Record Visit in the IWRS 


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Critical procedures performed at Visit 2 (Randomization, first study 
intervention Visit) 
The following critical assessments will be conducted at Visit 2: 
 
• Review AEs and SAEs  
• Review exacerbations during the Run-in period 
• COPD and Concomitant medication review  
• Review and assess compliance with completing the eDiary during the Run-in 
period 
• Vital signs and 12-Lead ECG 
• Review randomization inclusion and exclusion criteria (Section 5.3) 
• Urine pregnancy test, if applicable 
• Hematology, clinical chemistry, immunogenicity and blood biomarker 
• CAT, SGRQ-C, EQ-5D-3L, and patient global rating of COPD severity 
questionnaires in eDiary 
• Spirometry  
• Review COPD symptoms summary report through the vendor’s web-based portal 
• Provide and review medical problems and healthcare utilization worksheet 
• Dispense rescue medication 
• Optional genetics sample can be collected at Visit 2 or any visit after. 
• China and US only:  Optional PK sample is collected at this visit.  See SoA 
Section 1.3 for collection of other PK samples during the study. 
• Register and randomize participant in the IWRS 
• Administer study Interventional product as per SoA 
8.1. 
Efficacy Assessments 
8.1.1. 
Moderate and Severe COPD Exacerbations 
Moderate exacerbations are defined per protocol as clinically significant exacerbations 
that require treatment with oral/systemic corticosteroids and/or antibiotics. 
Severe exacerbations are defined per protocol as clinically significant exacerbations that 
require in-patient hospitalization (i.e., ≥24 hrs) or result in death. 
The decision to treat moderate exacerbations should be corroborated by review of data 
from the daily symptoms eDiary to confirm that the exacerbation was associated with 
deterioration of symptoms. 
For safety reasons alerts will be programmed into the eDiary to encourage the participant 
to contact the investigator if their COPD symptoms worsen. The site will also receive 
notification of the alert. An alert itself will not be classified as a moderate exacerbation 
unless it resulted in subsequent treatment for the worsening of symptoms meeting the 
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8.1.1.1. 
Guidelines for Identifying Symptom Defined COPD Exacerbations 
The following are symptoms used to ascertain an exacerbation of COPD:  
Worsening of two or more of the following major symptoms for at least two consecutive 
days: 
Dyspnea 
Sputum volume 
Sputum purulence (color) 
OR 
Worsening of any one major symptom together with any one of the following minor 
symptoms for at least two consecutive days: 
Sore throat 
Colds (nasal discharge and/or nasal congestion) 
Fever (oral temperature >37.5°C) without other cause 
Increased cough 
Increased wheeze 
Site staff will have access to a symptom summary report through a web-based portal. The 
symptoms summary report will indicate when symptoms meet the above criteria.  
If a participant is determined to have an exacerbation it should be treated per protocol as 
described in Section 8.1.2  
8.1.2. 
Exacerbation Treatment 
If in the opinion of the Investigator/treating physician, the exacerbation is severe enough 
to warrant the need for oral corticosteroids (with or without antibiotics) the following 
guidelines should be used. 
• The duration of treatment with oral corticosteroids should be ≤14 days (dose and type 
according to local practice)  
• The duration of treatment with oral corticosteroids should not exceed 14 days unless 
given approval by the Medical Monitor 
• Any course of oral corticosteroids started within 7 days of finishing a previous course 
will be considered as treatment for a single exacerbation 
If, in the opinion of the Investigator/treating physician, there is evidence of respiratory 
bacterial infection that warrants treatment with antibiotics the following guidelines 
should be followed: 
• The duration of treatment with antibiotics should be 7 to 14 days (dose and type 
according to local practice).  If first line antibiotic treatment fails and additional 


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antibiotics are used, the total duration of antibiotic treatment should not exceed 30 
days unless given approval by the Medical Monitor. 
• Any course of antibiotics started within 7 days of finishing a previous course will be 
considered as treatment for the original exacerbation (i.e. a single exacerbation). 
Note: Use of antibiotics for the treatment of upper or lower respiratory tract infection is 
not considered a COPD exacerbation unless worsening of COPD symptoms are 
documented by the Investigator in the participant’s medical notes. 
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  
Exacerbations should not be recorded in the AE section of the eCRF unless they meet the 
definition of an SAE. 
8.1.3. 
Health Related Quality of Life Assessments 
All Clinical Outcomes Assessment (COA) efficacy endpoint assessments completed at 
study visits will be completed using the eDiary.  Participants will complete the following 
PROs at study visits where indicated in the Schedule of Assessments (Section 1.3). 
Clinician rated response to therapy will also be collected on the eDiary. 
• The COPD Assessment Test  
• The St. George’s Respiratory Questionnaire for COPD Patients  
• Patient Global rating of COPD severity and Global Rating of change in COPD  
• Patient and Clinician rated response to therapy 
8.1.3.1. 
COPD Assessment Test (CAT) 
The CAT [Jones, 2009; Jones, 2012] is a short and simple patient completed 
questionnaire which has been developed for use in routine clinical practice to measure the 
health status of patients with COPD.  The CAT is an 8-item questionnaire suitable for 
completion by all patients diagnosed with COPD. When completing the questionnaire, 
participants rate their experience on a 6-point scale, ranging from 0 (no impairment) to 5 
(maximum impairment) with a scoring range of 0-40. Higher scores indicate greater 
disease impact. 
The CAT should be completed in the clinic at each scheduled in clinic visit, before any 
other visit procedures, as indicated in the SoA (Section 1.3)  
8.1.3.2. 
St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C) 
The SGRQ-C is a 40-item patient questionnaire, designed to measure health impairment 
by addressing the frequency of respiratory symptoms (questions 1-7) and the patient’s 
current state (questions 8-14).  Higher scores indicate greater impairment of health. The 
SGRQ-C is derived from the original SGRQ, and produces scores equivalent to the 
SGRQ instrument [Meguro, 2007].  The SGRQ-C is designed for supervised self-
administration which means that the participant should answer the questionnaire by 
themselves, but that site staff can provide support if required. It is appropriate to help 


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clarify a question but do not provide an answer.  If participants have difficulty reading 
questions may be read out loud.  The participant’s response should not be challenged. 
Participants must complete the questionnaire while in the clinic for their scheduled study 
visit. The SGRQ-C should be administered after CAT and before any other study 
procedures at Randomization (Visit 2) and at additional visits indicated in the Schedule 
of Assessment (Section 1.3).  
8.1.3.3. 
Daily Symptom Diary 
Using the eDiary, participants will complete a daily symptom diary (each evening) 
consisting of: 
• items from EXACT; 
• additional symptoms questions (related to symptoms of an exacerbation); 
• rescue medication use; and 
• night time awakenings 
Participants will be trained to use the eDiary at Visit 1 and will complete the eDiary 
throughout the study. 
EXAcerbations of Chronic Pulmonary Disease Tool – Patient Reported Outcomes 
(EXACT) and Evaluating Respiratory Symptoms in COPD (E-RS: COPD) 
The Exacerbation of Chronic Pulmonary Disease Tool-Patient Reported Outcomes 
(EXACT) is a 14-item participant reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of symptoms suggestive 
of an exacerbation of disease in patients with COPD. EXACT captures information on 
the severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the participant [Leidy, 2011]. 
The EXACT questions will be the first questions presented for completion each evening 
at bedtime in the eDiary.  
The daily recording of information allows an assessment of the underlying day to day 
variability of a participant’s symptoms and facilitates the detection of symptom 
worsening that may be indicative of a COPD exacerbation.  The total score for EXACT 
ranges from 0-100, higher scores indicate more severe symptoms.  The entire instrument 
is intended to be completed in about 3 minutes or less (typically the time required for 
completion decreases as the participant becomes more familiar with the tool and the 
eDiary). 
The Evaluating Respiratory Symptoms in COPD (E-RS: COPD) consists of 11 items 
from the 14 item EXACT instrument. E-RS: COPD is intended to capture information 
related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum 
production, chest congestion, and chest tightness.  The E-RS: COPD has a scoring range 
of 0-40, higher scores indicate more severe symptoms [Leidy, 2014]. 
Three subscales of the E-RS: COPD are used to describe different symptoms; 
breathlessness, cough and sputum, and chest symptoms [E-RS™: COPD, 2016]. 


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Additional symptoms questions 
In addition to the collection of EXACT, participants will also complete 5 additional daily 
diary questions to provide the information on other symptoms suggestive of an 
exacerbation:  sputum purulence (color), wheezing, sore throat, colds (nasal discharge 
and/or nasal congestion) and fever without other cause. 
These additional symptoms questions, combined with EXACT responses to questions on 
dyspnea, cough and sputum quantity will be used to trigger prompts to both site staff and 
patients about symptom changes, as described in Section 8.1.1.1, that may be indicative 
of an exacerbation. 
Rescue medication use 
The number of occasions of rescue medication use will also be captured in the daily 
eDiary. 
Night time awakenings 
Data regarding nighttime awakenings will also be captured in the daily eDiary. 
8.1.3.4. 
Patient Global Rating of COPD Severity and Patient Global Rating of 
Change in COPD 
Participants will complete the Global Rating of COPD Severity as per SoA (Section 1.3).  
This single global question will ask participants to rate their severity of COPD on a four 
point scale (mild, moderate, severe, very severe).  
Participants will complete a Global Rating of Change in COPD (overall disease) question 
at specified scheduled visits as per SoA, subsequent to randomization including the Exit 
Visit (or IP Discontinuation Visit).  Response options are on a 7 point Likert scale 
ranging from much better to much worse.  
8.1.3.5. 
Patient and Clinician Rated Response to Therapy 
The clinician will be asked to rate the response to therapy at the visits 
specified in SoA (Section 1.3). This is an overall evaluation of response to intervention, 
conducted separately by the Investigator using a rating scale.  A seven-point scale score 
is used with the following definitions: 1 = significantly improved; 2 = moderately 
improved; 3 = mildly improved; 4 = no change; 5 = mildly worse; 6 = moderately worse; 
and 7 = significantly worse. 
8.1.4. 
Spirometry and Bronchodilator Responsiveness Testing 
8.1.4.1. 
Spirometry 
Spirometry measurements will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All sites 
will use their own spirometry equipment.  All participants will have pre and post-
bronchodilator spirometry performed at Screening Visit 1 and pre-bronchodilator 
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the SoA (Section 1.3).  For FEV1 and FVC determinations, at least 3 acceptable 
spirometry efforts (with no more than 8) should be obtained.  Acceptable spirometry 
efforts should have a satisfactory start of test and end of test (i.e. a plateau in the volume-
time curve) and be free from artefacts due to cough, early termination, poor effort, 
obstructed mouthpiece, equipment malfunction, or other reasons [Miller, 2005].  
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort. 
Additional details about acceptable quality for spirometry testing are provided in the 
SRM. 
Spirometry must be performed as follows: 
Started between 6:00AM and 11:00 AM 
• After completing questionnaires at visits where these assessments are captured (as 
specified in the SoA)  
• After withholding salbutamol for 4 hrs 
• After withholding ipratropium for ≥4 hrs 
• After withholding the morning dose of maintenance COPD medications 
• Prior to IP dosing 
Participants should refrain from smoking for 1 hour prior to each pulmonary function 
test. 
Participants should abstain from drinking beverages with high levels of caffeine such as 
tea and coffee for 2 hrs prior to each pulmonary function test. 
A full description of the timing and conduct of spirometry procedures is provided in the 
SRM.   
8.1.4.2. 
Bronchodilator Responsiveness Testing 
At the Screening Visit 1, both pre- and post-salbutamol spirometry will be obtained to 
determine participant eligibility. 
Bronchodilator responsiveness testing will be completed as follows: 
• Following pre-salbutamol spirometry (a minimum of three acceptable spirometry 
efforts), the participant will self-administer 4 puffs of salbutamol MDI.  Three 
acceptable spirometry efforts will be obtained approximately 10 to 30 minutes 
after salbutamol administration. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. In consideration 
of the safety profile of mepolizumab in the IB, for participants continuing in the study 
beyond 52 weeks (as per the SoA in Section 1.3.2), vital signs and clinical safety 


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laboratory assessments are taken at less frequent intervals in the second year (Week 52 to 
104; Section 1.3.2) than in the first year (Week 0 to 52; Section 1.3.1). 
8.2.1. 
Physical Examinations 
Complete physical examinations will be performed at scheduled visits as noted in the 
SoA (Section 1.3). 
• A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.  
Height and weight will also be measured and recorded at Screening Visit 1.  For 
subsequent visits, only weight will be measured.  
• Investigators should pay special attention to historical clinical signs related to 
previous serious illnesses. 
8.2.2. 
Vital Signs 
• Oral or skin temperature, pulse rate and BP will be assessed. 
• Blood pressure and pulse measurements will be assessed in the resting state with a 
completely automated device. (Manual techniques will be used only if an 
automated device is not available).  
• Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones) and should be taken before blood collection for laboratory tests. 
8.2.3. 
Electrocardiograms 
• A single 12-lead ECG and rhythm strip will be obtained at scheduled visits as 
outlined in the SoA (see Section 1.3) using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals (if a 
machine read QTcF is unavailable, QTcF will be manually calculated).  All sites 
will use their own ECG equipment.  All results will be recorded after 
measurement of vital signs and prior to spirometry.  
• If a routine single ECG demonstrates a prolonged QT interval, obtain two more 
ECG readings over a brief recording period (e.g., 5-10 minutes), with each 
recording separated by at least 2 minutes.  The averaged QTcF values of the three 
ECG readings should be used to determine whether the patient should be 
discontinued from intervention product (but not from the study). Refer to Section 
7.1.2 for QTc withdrawal criteria and additional QTc readings that may be 
necessary.  These ECGs in question should be scanned and sent to the Medical 
Monitor. 
• All ECG measurements will be made with the participant in a supine position 
having rested in this position for approximately 5 minutes before each reading.  
• The Investigator, a designated sub-Investigator, or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG.  The Investigator 


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must provide his/her dated signature on the original paper tracing, attesting to the 
authenticity of the ECG machine interpretation.  
• If a clinically relevant arrhythmia, infarct pattern or conduction defect is 
documented at Screening, the PI will need to record in eCRF prior knowledge of 
the ECG pattern.  
8.2.4. 
Medical Problems and Concomitant Medications 
Participants will be instructed to record any medical problems and the medications used 
to treat them over each day in the medical problems and health care utilization worksheet. 
These entries will be reviewed by the site staff at each study visit and recorded in the 
eCRF as AEs and concomitant medications as appropriate. 
8.2.5. 
Pneumonia 
All pneumonias should be confirmed by the presence of new infiltrate on chest X-ray and 
captured on the AE/SAE page of the eCRF.  
Investigators and site staff should remain vigilant for the possible development and 
diagnosis of pneumonia as the clinical features of such infections overlap with the 
symptoms of COPD exacerbations.  For all suspected cases of pneumonia, Investigators 
should confirm the diagnosis by obtaining a chest X-ray or documentation of the result of 
a chest X-ray performed outside of the clinic site.  Appropriate therapy should be 
initiated for confirmed pneumonia.  Confirmation by chest X-ray should occur within 48 
hours of suspected pneumonia. 
8.2.6. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  Tests must be performed by the designated central 
laboratory. 
• 
The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF.  The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than 
expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of treatment should be 
repeated until the values return to normal or Baseline or are no longer considered 
significantly abnormal by the Investigator or Medical Monitor.  
• 
If such values do not return to normal/Baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Medical 
Monitor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 3, must be 
conducted in accordance with the laboratory manual and the SoA. 


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• 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the Investigator (e.g., SAE or AE) the results 
must be recorded in the participant’s eCRF.  Refer to the SRM for appropriate 
processing and handling of samples to avoid duplicate and/or additional blood draws.   
A blood sample for hematology will be collected at scheduled study visits, including 
premature discontinuation of IP.  After Randomization, neither the site staff nor GSK 
personnel will be sent results from the central laboratory for: absolute and differential 
values for eosinophils, lymphocytes, basophils, neutrophils and monocytes. However, 
sites will be sent total white blood counts throughout the study.  This must also be 
applied to hematology results received from a local laboratory. 
Routine non-fasting clinical chemistry including serum glucose and serum potassium 
levels will be performed as per SoA.  In the event of premature discontinuation from IP 
or from the study a sample should be collected at the IP Discontinuation/study 
Withdrawal Visit as specified in the SoA (Section 1.3).  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 4. 
COPD exacerbations should not be recorded in the AE section of the eCRF unless they 
meet the definition of an SAE. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention  (see Section 
7.1). 
The following AEs of special interest will have customized AE and SAE pages in the 
eCRF: 
• Systemic reactions 
• Local injection site reactions 
In addition, the information as to whether an event met the diagnostic criteria for 
anaphylaxis as outlined by the Second Symposium on Anaphylaxis [Sampson, 2006] and 
in Appendix 2 will be collected on the AE and SAE eCRF pages. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
China only:  In China, all SAEs will be recorded from the time the consent form is 
signed until the Exit Visit/Study Withdrawal Visit at the time points specified in the 
SoA (Section 1.3). 


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• 
All SAEs will be collected from the start of study intervention until the Exit 
Visit/Study Withdrawal Visit at the time points specified in the SoA (Section 1.3).  
However, any SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to any GSK product will be recorded from the time a participant 
consents to participate in the study.  
• 
All AEs will be collected from the start of study intervention until the Exit 
Visit/Study withdrawal visit at the time points specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of intervention product but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF not the AE section. 
• 
All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hrs, as indicated in Appendix 4. The 
Investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the intervention product or study 
participation, the Investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4 
• 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-
ended and non-leading verbal questioning of the participant is the preferred method 
to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs and non-serious AEs of special 
interest as defined in (Section 8.3), will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 4. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 


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requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 16 weeks after the last dose. 
• If a pregnancy is reported, the Investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.3.6. 
Cardiovascular and Death Events 
For any CV events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific CV and Death sections of the CRF will be required to be 
completed.  These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information should be 
recorded in the specific CV section of the CRF within one week of receipt of a CV Event 
data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.3.7. 
Medical Device Deficiencies 
Medical devices are being provided for use in this study.  To fulfil regulatory reporting 
obligations worldwide, the Investigator or designee is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during 
the study with such devices.  
The definition of a Medical Device Deficiency can be found in Appendix 8. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 4 of the protocol. 


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8.3.7.1. 
Time Period for Detecting Medical Device Deficiencies 
• 
Medical device deficiencies that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical 
device is used.  
• 
If the investigator learns of any device deficiencies at any time after a 
participant has been discharged from the study, and such device deficiency is 
considered reasonably related to a medical device provided for the study, the 
investigator will promptly notify the sponsor. 
• 
The method of documenting Medical Device Deficiencies is provided in 
Appendix 8. 
8.3.7.2. 
Follow-up of Medical Device Deficiencies  
• 
Follow-up applies to all participants, including those who discontinue study 
intervention or the study. 
• 
The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the  deficiency. 
• 
New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator. 
8.3.7.3. 
Prompt Reporting of Medical Device Deficiencies to Sponsor 
• 
Medical Device Deficiency will be reported to the sponsor within 24 hours after 
the investigator determines that the event meets the protocol definition of a 
device deficiency. 
• 
The Medical Device Deficiency Report Form will be sent to the sponsor by e-
mail. If e-mail is unavailable, then fax should be utilized. 
• 
The sponsor will be the contact for the receipt of device deficiency reports. 
Details are provided in the SRM. 
8.3.7.4. 
Regulatory Reporting Requirements for Medical Device Deficiencies 
• 
The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies. 
• 
The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC. 
8.3.8. 
Adjudication Committee 
Independent external adjudication committees for all SAE reports and all potential 
MACE adverse events (CV death, non-fatal myocardial infarction [MI], non-fatal stroke) 


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will be utilized in this study to ensure external objective medical review of these events 
in a blinded fashion. The committee members will remain blinded to study intervention 
assignment.  The adjudication plans are described in the charter, which is available upon 
request. 
8.4. 
Treatment of Overdose 
The dose of mepolizumab considered to be an overdose has not been defined. There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. However, the Investigator should use clinical judgement in treating 
the symptoms of a suspected overdose, inform the Medical Monitor and record the 
overdose in the eCRF. 
8.5. 
Pharmacokinetics 
8.5.1. 
Optional pharmacokinetic sub-study in China and the US only:  
Pharmacokinetic blood samples for the determination of mepolizumab plasma 
concentration will be collected at the timepoints indicated in the SoA (Section 1.3), from 
participants who sign the optional PK informed consent.  Samples should be obtained 
prior to dosing on dosing days. The actual date and exact time of each blood sample 
collection will be documented in the eCRF and on the sample requisition form provided 
by the Central Laboratory.  Additionally, the date and time of IP injection will be 
recorded in the eCRF. 
8.5.2. 
Sample preparation and shipment  
Details of PK sample preparation and shipment are described in the SRM. 
8.5.3. 
Sample Analysis and Assay Method 
Plasma analysis will be performed under the control of GSK- In Vitro / In Vivo 
Translation (IVIVT), the details of which will be included in the SRM.  Concentrations of 
mepolizumab will be determined in plasma samples using the approved bioanalytical 
methodology.  Raw data will be archived at the bioanalytical site.  Quality control 
samples will be assayed with each batch of samples in order to assess the day-to-day 
performance of the assay. 
8.6. 
Pharmacodynamics 
Blood eosinophil counts will be recorded as part of the standard hematological 
assessments performed at the visits specified in the SoA (Section 1.3) 
8.7. 
Genetics 
China only:  Genetic blood samples will not be collected from participants in China. 
A 6 mL whole blood sample for deoxyribonucleic acid (DNA) isolation will be collected, 
where permitted, from participants who have consented to participate in the genetics 


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analysis component of the study. Participation is optional.  Participants who do not wish 
to participate in the genetic research may still participate in the study. 
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the laboratory 
manual. 
8.8. 
Biomarkers 
China only:  Blood biomarkers samples will not be collected from participants in China. 
• 
Collection of samples for biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from participants, 
where permitted, in this study as specified in the SoA: 
➢ Blood 
• 
In addition, with the participant’s consent and where permitted, samples will be 
stored and analysis may be performed on biomarkers thought to play a role in 
mepolizumab response, with COPD or related diseases, or to evaluate their 
association with observed clinical responses to mepolizumab. 
• 
Additional whole blood and serum samples will be collected and may be used for 
future analyses. 
• 
Samples may be stored for a maximum of 15 years (or according to local 
regulations) following the last participant’s last Visit for the study at a facility 
selected by the sponsor to enable further analysis of biomarker responses to 
mepolizumab. 
8.9. 
Immunogenicity Assessments  
Antibodies to mepolizumab will be evaluated in blood samples collected from all 
participants according to the SoA. Additionally, blood samples should also be collected at 
the final treatment Visit from participants who discontinued intervention product or were 
withdrawn from the study. These samples will be tested by the sponsor or sponsor’s 
designee. 
Samples will be screened for antibodies binding to mepolizumab and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to mepolizumab and/or further characterize the immunogenicity 
of mepolizumab. 
The detection and characterization of antibodies to mepolizumab will be performed using 
a validated assay method by or under the supervision of the sponsor. All samples 
collected for detection of antibodies to mepolizumab will also be evaluated for 
mepolizumab serum concentration to enable interpretation of the antibody data. 
Antibodies may be further characterized and/or evaluated for their ability to neutralize the 
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Further details regarding sample collection and processing may be found in the SRM and 
lab manual. 
8.10. 
Health Outcomes Assessments 
8.10.1. 
Medical Resource Utilization and Health Economics 
Health Care resource utilization, associated with unscheduled medical encounters, will be 
recorded by participants in a worksheet and collected in the eCRF by the Investigator and 
study-site staff for all participants throughout the study. Protocol-mandated procedures, 
tests, and encounters are excluded.  
The data collected about unscheduled use of health care resources may be used to 
conduct exploratory economic analyses and will include: 
• Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient) 
• Duration of hospitalization (total days or length of stay, including duration by 
wards [e.g., intensive care unit, high dependency and usual care]) 
• Number and type of diagnostic and therapeutic tests and procedures 
• Outpatient medical encounters and treatments (including physician or emergency 
room visits, tests and procedures, and medications). 
• 
Home visits (day and night time) 
 
• Long term oxygen therapy 
The resource utilization worksheet used by the participant to record all COPD-related 
health care contacts experienced since the last visit will be collected and reviewed by the 
Investigator or designee at the visits indicated in Section 1.3. The Investigator or 
designated staff should ask the participant if any of the health care contacts that are 
recorded on the worksheet were due to a COPD exacerbation. The Investigator can refer 
to his/her records to verify or supplement information given by the participant, if 
necessary. If any unscheduled healthcare contact is due to a COPD exacerbation, then the 
Investigator should ensure completion of the COPD Exacerbation section of the eCRF. 
Details regarding completion of the Healthcare Utilization worksheet are located in the 
SRM. 
8.10.2. 
EuroQol questionnaire (EQ-5D-3L)  
The EQ-5D-3L questionnaire will be completed via eDiary by participants at 
randomization and at scheduled visits as indicated in the SoA (Section 1.3). 
The EQ-5D-3L is a standardised instrument for use as a measure of health utility. It is 
designed for self-completion and is cognitively simple, taking only a few minutes to 
complete. The EQ-5D-3L is a two-part self-assessment questionnaire. The first part 


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consists of five items covering five dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each dimension is measured by a five-point 
Likert scale (no problems, slight problems, moderate problems, severe problems, and 
extreme problems).  Respondents are asked to choose one level that reflects their “own 
health state today” for each of the five dimensions. Respondents can be then classified 
into one of 243 distinct health states. The second part is a vertical response scale (EQ-
VAS) that has endpoints labelled “best imaginable health state” and “worst imaginable 
health state anchored at 100 and 0, respectively. Respondents are asked to indicate how 
they rate their own health by drawing a line from an anchor box to that point on the EQ-
VAS which best represents their own health on that day.  EQ-5D-3L health states are 
converted to a single summary index by applying a formula that essentially attaches 
weights to each of the levels in each dimension. The formula is based on the valuation of 
EQ-5D health states from general population samples. 
9. 
STATISTICAL CONSIDERATIONS 
The primary estimand is the difference between mepolizumab 100 mg SC and placebo as 
add-on treatment in the rate of annualized exacerbations in participants with COPD 
experiencing frequent exacerbations and characterized by eosinophil levels, regardless of 
IP discontinuation or changes in background medication/starting a prohibited medication, 
in the absence of COVID-19 pandemic related intercurrent events. 
9.1. 
Statistical Hypotheses 
This study is designed to test the superiority of mepolizumab 100 mg SC vs placebo, the 
significance test will be considered statistically significant at the two-sided 5% alpha 
level (one-sided 2.5%). 
9.2. 
Sample Size Determination 
The primary analysis is based on comparing the annualized rate of moderate/severe 
exacerbations in participants treated with mepolizumab 100 mg SC vs. placebo. 
The null hypotheses used to test the superiority of mepolizumab 100 mg compared to 
placebo will be: 
H0: μi = μp  
where μi is the annualized exacerbation rate on the mepolizumab 100 mg SC arm and μp 
is the annualized exacerbation rate on the placebo arm.  
The (one-sided) alternative hypothesis is that the annualized exacerbation rate is lower on 
the mepolizumab arm:  
Ha: μi< μp 
The estimated annualized rate of moderate/severe exacerbations in the placebo arm was 
1.7 exacerbations (based on exacerbation data observed from studies MEA117113 and 
MEA117106 [High Stratum], which were conducted prior to the COVID-19 pandemic). 


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Based on a true population reduction of 23% in the annualized rate of moderate/severe 
exacerbations following treatment with mepolizumab 100 mg SC compared to placebo, it 
was estimated that 400 participants per arm (800 participants in total) are required to 
provide 90% power to detect a statistically significant reduction at the 2-sided 5% level 
of significance. The smallest observed effect which is predicted to result in a statistically 
significant difference between mepolizumab 100 mg SC compared to placebo is 15%.  
To account for the loss of patient years’ data from participants who withdraw early from 
the trial and no longer provide any data (on- or off-treatment), the sample size includes an 
additional 44 patients to account for approximately 5.5% of patient-years data being 
missing, this being the level of missing data encountered in study MEA117113.  
The sample size estimate is based on the number of moderate/severe exacerbations per 
year following a negative binomial distribution [Keene, 2007].  The estimate of 1.7 
moderate/severe exacerbations per year in the placebo arm and of 0.55 for the dispersion 
parameter are based on data observed from studies MEA117113 and MEA117106 (High 
Stratum). Overall in this study, a total of approximately 800 participants will be 
randomized with a randomization ratio of 1:1 placebo: mepolizumab 100 mg SC.   
Blinded re-evaluations of the sample size will be carried out prior to randomizing the 
800th participant to assess whether, based on the overall annualized rate of 
moderate/severe exacerbations and the level of dispersion seen within the available data, 
the initial planned sample size of 800 randomized participants would continue to provide 
90% power for this study.  The sample size re-estimation will follow the method 
described in [Friede, 2010].  A negative binomial distribution will be fitted to the blinded 
exacerbations from the available data with participant follow-up time as an offset, and 
estimates obtained for the overall exacerbation rate and the dispersion (shape) 
parameter.  These estimates will be used to re-calculate the sample size that would be 
required to provide 90% power.  If the re-estimated sample size is less than or equal to 
the currently planned 800 randomized participants, the study will continue as planned; 
otherwise the study sample size may be increased to that indicated by the re-estimation, 
with a potential maximum increase to 1400 participants. Further blinded re-evaluations 
will be conducted to monitor whether the sample size continues to be appropriate given 
the emerging event rate. The total sample size will be between 800 as originally planned 
up to a potential maximum of 1400 participants. 
9.2.1. 
Sample Size Sensitivity 
The sample size in Section 9.2 is based on an assumed exacerbation rate of 1.7 
exacerbations per year in the placebo group and an expected reduction of 23% in this rate 
for participants treated with mepolizumab. If the true placebo exacerbation rate or the 
expected reduction with mepolizumab differ from these assumptions then, at the given 
sample size, there will be an effect on the power of the study. Table 2 illustrates the effect 
on the power for the treatment comparison (based on 756 participants, excluding the 
additional 44 participants to account for early study withdrawals), and a dispersion 
parameter k=0.55. 


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Table 2 
Effect of placebo rate and expected rate reduction with 
mepolizumab on the power of the study 
% reduction 
in annualized 
exacerbation 
rate with 
mepolizumab 
Placebo: Annualized Exacerbation Rate  
 
0.9 
 
1.1 
 
1.3 
 
1.5 
 
1.7 
 
1.9 
Study Powera 
21% 
67 
73 
78 
81 
84 
86 
22% 
72 
77 
81 
85 
87 
90 
23% 
76 
81 
85 
88 
90 
92 
a. Power estimate based on a 52-week follow-up for each participant 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
All Participants Enrolled 
(ASE) 
All participants for whom a record exists on the study database. 
This population will be used for summarizing reasons for screen 
and run-in failures. 
Modified Intent-to-Treat 
(mITT) 
All randomized participants who receive at least one dose of trial 
medication. Primary population for analysis of efficacy endpoints 
data by randomized treatment arm. 
Safety 
All randomized participants who receive at least one dose of trial 
medication. Analysis of safety endpoints by actual treatment 
received for more than 50% of treatment administrations.  
Per-Protocol (PP) 
All participants in the mITT population not identified as protocol 
deviators with respect to criteria that are considered to impact the 
primary efficacy endpoint. Population for supplementary analysis 
of primary endpoint. 


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9.3.1. 
Pharmacokinetics Sub-study 
Population 
Description 
PK 
All participants enrolled in the PK sub-study who received at least 
one dose of trial medication and for whom at least one 
pharmacokinetic sample was obtained, analysed and was 
measurable. Population for the PK sub-study analysis. 
 
9.4. 
Statistical Analyses 
All analyses will be carried out using all available data and will be detailed in the 
Reporting and Analysis Plan (RAP), including details on additional analyses to assess the 
impact of COVID-19 on this study. 
9.4.1. 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary estimand is defined by the following attributes:  
Population: Participants with COPD experiencing frequent exacerbations and 
characterized by eosinophil levels 
Treatment comparison: Mepolizumab vs. placebo (both as add-on treatment to 
standard of care) 
Variable: Number of moderate or severe exacerbations 
Summary Measure : Ratio of the frequency of exacerbations in the 
mepolizumab treatment arm to the frequency in the placebo arm. Exacerbation 
rates will be expressed as an annualized exacerbation rate p.a. 
Strategies for intercurrent events: 
A treatment policy strategy will be used for the intercurrent events of 
discontinuation of study medication, use of medication prohibited by the 
protocol, and investigational product interruption of 2 or more doses, when 
these intercurrent events are not associated with disruptions or restrictions 
imposed due to the COVID-19 pandemic. 
A hypothetical strategy will be considered when these intercurrent events have 
occurred as a result of disruptions or restrictions (e.g. lockdown measures, 
social distancing) imposed due to the COVID-19 pandemic. Full details will be 
provided in the RAP. 
The target population for the estimand is as defined by the study 
inclusion/exclusion criteria and therefore the modified Intent-to-Treat population 
will be the primary population for efficacy analyses. 
Participants who prematurely discontinue study treatment (for any reason) will 
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Endpoint 
Statistical Analysis Methods 
investigator/site staff to encourage the participant to remain in the study for 
continued collection of efficacy and safety data.   
Exacerbations reported by participants from the start of treatment up to the Exit 
Visit will be included in the primary analysis 
The primary analysis of the rate of moderate/severe exacerbations will use a 
negative binomial model, including both on-treatment and, where available, off-
treatment exacerbation data.  Any remaining missing data will be considered 
missing at random (MAR).  This model will include covariates of smoking status 
(current vs previous smoker), number of exacerbations in previous year, 
baseline disease severity (as % predicted post-bronchodilator FEV1) and 
geographic region. The rate of moderate/severe exacerbations will be analysed 
using a negative binomial regression model. 
Sensitivity analyses to the assumption regarding missing data will be performed 
using multiple imputation methods based on pattern mixture models. These 
sensitivity analyses will include an off-treatment imputation approach based on 
the off-treatment data collected from participants who continue in the study 
following early discontinuation of randomized treatment and a tipping point 
analysis.  Further details will be provided in the RAP. 
Full details of the analysis methods to be used will be provided in the RAP. 
Secondary 
For all secondary endpoints the target population, treatment comparison and 
strategies for intercurrent events will be the same as for the primary estimand. 
For the evaluation of the time to the first moderate/severe exacerbation, the 
summary comparison between treatments will be the hazard ratio.  
Analysis of this variable will use a Cox’s proportional hazards model allowing 
for covariates of smoking status (current vs previous smoker), number of 
exacerbations in previous year, baseline disease severity (as % predicted post-
bronchodilator FEV1) and geographic region. Missing values will be considered 
as censored at random (non-informative censoring). Summaries and graphs of 
the Kaplan-Meier estimates of the proportion of participants with a 
moderate/severe exacerbation over time will be produced. 
The proportion of CAT score responders at Week 52 will be evaluated, and 
participants with missing values at Week 52 not associated with disruptions or 
restrictions imposed due to the COVID-19 pandemic on or before the Week 52 
visit, will be included in the analysis as a non-responder. Sensitivity analyses to 
the assumption regarding missing data will be performed using multiple 
imputation methods based on pattern mixture models. Analysis will be 
performed using a logistic regression model adjusting for baseline CAT score, 
smoking status and geographic region. 
The proportion of SGRQ Total score responders at Week 52 will be evaluated, 
and participants with missing values at Week 52 not associated with disruptions 


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or restrictions imposed due to the COVID-19 pandemic on or before the 
Week 52 visit, will be included in the analysis as a non-responder. Sensitivity 
analyses to the assumption regarding missing data will be performed using 
multiple imputation methods based on pattern mixture models. Analysis will be 
performed using a logistic regression model adjusting for baseline SGRQ total 
score, smoking status and geographic region. 
The proportion of E-RS: COPD responders at Week 52 will be evaluated, and 
participants with missing values at Week 52 not associated with disruptions or 
restrictions imposed due to the COVID-19 pandemic on or before the Week 52 
visit, will be included in the analysis as a non-responder. Sensitivity analyses to 
the assumption regarding missing data will be performed using multiple 
imputation methods based on pattern mixture models. Analysis will be 
performed using a logistic regression model adjusting for baseline score, 
smoking status and geographic region. 
The estimand for exacerbations that resulted in an ED visit or hospitalization 
will be the same as for the primary endpoint and analysis will use the same 
methods as for the primary endpoint. 
Other 
See Section 3 for a list of all other endpoints.  Full details of any analyses to be 
performed on these endpoints will be provided in the RAP. 
 
The treatment comparison of interest for the primary and secondary endpoints is 
mepolizumab 100 mg SC vs placebo in the mITT population.  A hierarchical testing 
procedure will be used to provide strong control of Type I error for multiplicity arising 
from the primary and multiple secondary endpoints.  This will be carried out using a step-
down closed testing procedure where inference for an endpoint in the predefined 
hierarchy will be dependent on statistical significance having been achieved for the 
previous endpoints in the hierarchy.  
For example, for the primary endpoint, mepolizumab will be compared to placebo at a 
two-sided α=0.05 (one-sided α=0.025).  The next endpoint in the hierarchy (i.e. the first 
secondary endpoint) will be tested only if the test for the primary endpoint is significant 
at the one-sided 2.5% level. Testing will continue down the hierarchy for the remaining 
endpoints in an equivalent manner only if the previous endpoint in the hierarchy achieves 
statistical significance.   
The hierarchy of the primary and secondary endpoints to be tested is as follows: 
1. Annualized rate of moderate/severe exacerbations (primary endpoint) 
2. Time to first moderate/severe exacerbation 


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3. Proportion CAT [Jones, 2009] score responders at Week 52 
4. Proportion of SGRQ [Meguro, 2007] Total score responders at Week 52 
5. Proportion of E-RS: COPD responders at Week 52 [Leidy, 2011; Leidy, 2014; [E-
RS™: COPD, 2016] 
6. Annualized rate of exacerbations requiring ED and/or hospitalization 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Summaries of data will include data from scheduled assessments only, all data will be 
reported according to the nominal visit for which it was recorded (i.e. no visit windows 
will be applied). Data from unscheduled visits will be included in “overall” and “any 
post-Baseline” summaries.  Further details will be provided in the RAP. 
9.4.2.1. 
Extent of Exposure 
The number of participants administered interventional product, the number of treatments 
administered, and the number of days over which treatment was administered will be 
summarised.  
9.4.2.2. 
Adverse Events 
Adverse Events will be coded using the standard GlaxoSmithKline MedDRA and will be 
grouped by system organ class (SOC).  AEs will be summarised by frequency and 
percentage of participants, by SOC and preferred term within each treatment group.  
Separate summaries will be presented for all AEs, drug-related AEs, SAEs, AE’s leading 
to permanent discontinuation of interventional product or withdrawal from study, any 
AEs of special interest and adjudicated events. 
9.4.2.3. 
Clinical Laboratory Evaluations  
Hematology (including blood eosinophils) and clinical chemistry data will be 
summarized at each scheduled assessment. The proportion of values outside of the 
normal reference range and those meeting the criteria for potential clinical significance 
will also be summarised.  Further details will be provided in the RAP. 
9.4.2.4. 
Other Safety Measures 
Other scheduled safety assessments such as vital signs data (including pulse rate, systolic 
and diastolic blood pressure) and ECG data (including categorised QTcF values) will be 
summarized at each scheduled assessment. Further details will be provided in the RAP.  


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9.4.2.5. 
Immunogenicity 
Immunogenicity data related to the presence of antibodies to mepolizumab will be 
summarised using appropriate descriptive statistics.  Further details will be provided in 
the RAP. 
9.4.3. 
Other Analyses 
9.4.3.1. 
Health Related Quality of Life and Health Outcomes  
Details of the summary of additional health related quality of life and health outcomes 
related data will be given in the RAP. 
9.4.3.2. 
Pharmacodynamic Analyses 
Blood eosinophils ratio to Baseline will be analysed using mixed model repeated 
measures adjusting for Screening, smoking status, geographic region, visit by Screening 
interaction and visit by treatment group interaction. Data will be log-transformed (loge) 
prior to analysis.  
9.5. 
Interim Analyses 
No formal interim analyses of efficacy data are planned for this study. See Section 9.2.1 
for details regarding blinded sample size evaluation. 
9.5.1. 
Data Monitoring Committee (DMC) 
Not applicable 
9.6. 
Pharmacokinetics Analyses (PK Sub-study) 
For participants included in the PK sub-study, blood samples will be collected to 
determine mepolizumab plasma concentrations at visits specified in the SoA table 
(Section 1.3).  Sparse blood sampling is being implemented in this PK sub-study. 
Mepolizumab plasma concentrations will be evaluated by population PK methods using 
the established population PK model developed based on previous mepolizumab data 
collected during mepolizumab clinical development.  The analysis will be conducted 
using appropriate software and will provide individual predicted plasma concentrations as 
well as individual predicted post-hoc apparent clearance estimates from which potential 
ethnic differences in mepolizumab exposure between Chinese participants in China and 
non-Asian participants in the US will be explored using a confidence interval approach. 
Evaluation of similarity in exposure will be guided by the confidence interval excluding 
at least a two-fold difference.  If deemed necessary population PK parameter estimates 
for the Chinese population will be estimated. 
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by group. Further details will be provided in the separate PK 
sub-study RAP. The PK sub-study results will be reported separately from the main CSR. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory 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. 


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant and answer all questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
In rare instances and with agreement from the Medical Monitor following 
consultation, a participant can be rescreened. In such circumstances, they are 
required to sign a new ICF. 
• 
Participants who enrolled in the study prior to Protocol Amendment 6 
implementation and who have agreed to extend study participation beyond 52 
weeks must re-sign a new ICF at, or prior to, the completion of the Week 52 
Visit (Exit Visit 15).  
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 


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reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that 
can help advance medical science or improve patient care. This helps ensure the 
data provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
10.1.6. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  


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• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.  
10.1.7. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in the SRM. 
10.1.8. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
10.1.9. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 


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as individual site 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. 


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10.2. 
Appendix 2: Anaphylaxis Criteria 
Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria 
do not make a distinction based on underlying mechanism. These criteria are summarized 
as follows: 
1) Acute onset of an illness (minutes to several hrs) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following: 
a) Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)  
b) Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
2) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hrs): 
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b) Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a) Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP 
b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s Baseline 
Reference 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson Jr FN, Bock AS, Branum A et 
al. Second symposium on the definition and management of anaphylaxis: summary 
report—Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006; 117:391-3 
 


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10.3. 
Appendix 3: Clinical Laboratory Tests 
• 
The tests detailed in Table 3 will be performed by the central laboratory  
Local laboratory results are only allowed for parasitic screening.  The investigator should 
decide what type of laboratory test, if any, is necessary. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• 
Pregnancy Testing  
• Refer to Section 5.1 Inclusion Criteria for Screening pregnancy criteria. 
• 
Pregnancy testing (urine) be conducted prior to each dose of study intervention and 
at Study Exit/Early Withdrawal Visit (4 weeks after the last dose). Note that for 
female participants pregnancy occurring within 16 weeks after the last dose should 
be reported. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
Table 3 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cells (RBC) 
Count 
Hemoglobin 
Hematocrit 
Red Cell Distribution 
Width (RDW) 
Mean Platelet Volume 
(MPV) 
Clinical 
Chemistry1 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
International 
normalized ratio 
(INR) 
Total and direct 
bilirubin 


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Laboratory 
Assessments 
Parameters 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
(non-fasting] 
Calcium 
Alkaline 
phosphatase 
Albumin 3 
Other 
Screening 
Tests 
• total IgE 
• Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)2 
• Parasitic Screening (only required in countries with high-risk or for 
participants who have visited high-risk countries in the past 6 months). 
Sites should use local laboratories.  
NOTES: 
1. 
Details of liver chemistry stopping criteria (Section 7.1.1)  and required actions and follow-up assessments 
after liver stopping or monitoring event are given in Appendix 7. All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
2. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC. 
3. 
China and US only:  For participants participating in the PK sub-study Albumin will be tested at Visit 2 only 
 
After randomization to end of study neither the site staff nor GSK personnel will be sent 
results from the central laboratory for absolute and differential values for eosinophils, 
lymphocytes, basophils, neutrophils and monocytes, until the study has been unblinded. 
However, sites will be sent total white blood counts throughout the study. 


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10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.4.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 


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• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.4.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
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Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. (See Section 7.1 and Appendix 7 for additional events defined as SAEs). 
10.4.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
10.4.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE CRF page. 


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• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
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• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.4.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in SRM. 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
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• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in SRM. 
 


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10.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.5.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 


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10.5.2. 
Contraception Guidance: 
• CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided 
that the partner is the sole sexual partner of the woman of childbearing potential and 
the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a. 
Contraceptive use by women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction) 
 


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10.5.3. 
Collection of Pregnancy Information: 
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study and up to 16 weeks after the last 
dose of study intervention.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant’s pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 4. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
intervention  


T M F -1 3 8 1 1 0 2 8  
C O N FI D E N TI A L  
 
 
 
2 0 8 6 5 7  
 
Pr ot o c ol A m e n d m e nt 6  
 
1 1 4  
 
1 0. 6.  
A p p e n di x 6 : G e n eti c s 
U S E/ A N A L Y SI S O F D N A  
C hi n a o nl y: N o ge netic sa m ples will be c ollecte d fr o m partici pa nts i n C hi na.  
•  Ge netic variati o n ma y i m pact a partici pa nt’s res p o nse t o treat me nt, s usce pti bilit y, 
se verit y a n d pr o gressi o n of disease. Varia ble res p o nse t o me p oliz u ma b ma y be d u e 
t o ge n etic deter mi na nts t hat i m pact dr u g a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e x creti o n; mec ha nis m of acti o n of t he dr u g; diseas e eti ol o g y; a n d / or m olec ular 
s u bt y pe of t h e disease b ei n g treate d. T heref ore, w here l ocal re g ulati o ns a n d I R B/I E C 
all o w, a bl o o d sa m ple will be c ollecte d f or D N A a nal ysis.  
•  D N A sa m ples will be use d f or res earc h rel ate d t o me p oliz u ma b i n C O P D.  
 
 
 
 
  
•  
 
 
 
. 
•  
T he s p o ns or will st ore t he  D N A sa m ples i n a s ec ure st ora ge s p ace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y.  
•  
T he sa m ples will be ret ai ne d w hile res earc h o n me p oliz u ma b f or t he treat me nt of 
C O P D c o nti n ues b ut n o l o n ger t ha n 1 5 years after t he last partici pa nt last visit or 
ot her peri o d as p er l ocal re q uire me nts  
 
C CI
C CI


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10.7. 
Appendix 7: Liver Safety: Required Actions, Monitoring and 
Follow-up Assessments  
Liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria  
ALT-absolute ALT  8xULN 
ALT Increase 
ALT  5xULN but <8xULN persists for 2 weeks 
ALT  3xULN but <5xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 ALT   3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention  
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• Do not restart/rechallenge participant with 
study treatment since restart/rechallenge is 
not allowed per protocol.  Permanently 
discontinue study intervention and continue 
participant in the study for any protocol 
specified follow up assessments  
 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
•  Obtain blood sample for 
pharmacokinetic (PK) analysis, within 4 
weeks after last dose5 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia This 
blood sample will be sent to the central 
laboratory to maintain the blind while 
study is ongoing. Results will be provided 
only if unblinding of a participant’s 


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MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 
perform liver event follow up assessments 
within 24 hours 
• Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) 
and perform liver event follow up 
assessments within 24-72 hours  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
treatment assignment is required. Also 
note that the mechanism of action of 
mepolizumab leads to lowering of 
eosinophils. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page 
 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
 
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5 which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving anticoagulants 
 


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3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)    
4. Includes: Hepatitis A immunoglobulin M (IgM) antibody; HbsAg and HbcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody.  In those with underlying chronic hepatitis B at study entry quantitative 
hepatitis B DNA and hepatitis delta antibody.  If hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal , 2005]. 
5. PK sample may not be required for participants known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et al. Pharmacokinetics of Acetaminophen-
Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P et al.  Quantification of Hepatitis Delta Virus RNA in Serum 
by Consensus Real-Time PCR Indicates Different Patterns of Virological Response to Interferon Therapy in Chronically 
Infected Patients.  J Clin Microbiol. 2005;43(5):2363–2369.  
 
Liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
ALT 5xULN and <8xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3xULN and <5xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
 
 
• Notify the GSK Medical Monitor within 24 hours 
of learning of the abnormality to discuss 
participant safety.  
• Participant can continue study intervention   
• Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above 
• If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within Baseline. 


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10.8. 
Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device 
Studies 
• The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and European Medical Device Regulation (MDR) 2017/745 for 
clinical device research. 
• Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices. 
• The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study (see Section 6.1.1 for the 
list of GSK medical devices).  
 
10.8.1. 
Definition of Medical Device AE and ADE 
Medical Device Incident Definition 
• 
 An AE is any untoward medical occurrence, in a clinical study participant, or 
other persons e.g., Investigator, study site staff, nurse etc.,  temporally associated 
with the use of study intervention whether or not considered related to the 
investigational medical device. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of an investigational 
medical device. This definition includes events related to the investigational 
medical device or comparator and events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or 
inadequate instructions for use, deployment, or operation, or any malfunction of 
the investigational medical device as well as any event resulting from use error or 
from intentional misuse of the investigational medical device. 
 


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10.8.2. 
Definition of Medical Device SAE, SADE and USADE 
 A Medical Device SAE is any serious adverse event that: 
a. Led to death 
b. Led to serious deterioration in the health of the participant, that either resulted 
in: 
• A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant was at risk of death at the 
time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
•  A permanent impairment of a body structure or a body function. 
•  Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
• Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function  
 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect 
SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the benefit/risk assessment (see 
Section 2.3). 
10.8.3. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
 A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer. 
 


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10.8.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies 
AE, SAE and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK/AE/SAE/device 
deficiency form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 
Assessment of Intensity 
• The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following 
categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; both AEs and SAEs can be assessed as severe. 


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• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe. 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or 
Instruction Direction For Use (IDFU) or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE/SAE/device deficiency 
• The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by GSK to elucidate the nature and/or causality of the 
AE/SAE/device deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or 
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• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.8.5. 
Reporting of SAEs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section). 
• Contacts for SAE reporting can be found in SRM. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in SRM. 


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10.8.6. 
Reporting of SADEs 
SADE Reporting to GSK  
NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency. 
• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
• Contacts for SAE reporting can be found in SRM. 
 


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10.9. 
Appendix 9: Country-specific Requirements 
Participants in China will not participate in the genetic (Appendix 6) or biomarker 
(Section 8.8) research. 
Serious AEs (Section 8.3) in China will be recorded from the time the informed consent 
form is signed until the Exit Visit/Study Withdrawal Visit at the time points specified in 
the SoA (Section 1.3). 
In China, the Centre of Drug Evaluation (CDE) requested the inclusion in the protocol of 
a PK sub-study to assess potential ethnic differences in the PK of mepolizumab 100 mg 
in liquid formulation, administered subcutaneously by a safety syringe, between Chinese 
and non- Chinese participants.  Therefore, a PK sub-study comparing Chinese 
participants in China with non-Asian participants in the US was included. 
 


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10.10. 
Appendix 10:  COVID-19 Measures 
10.10.1. 
Overall Rationale For This Appendix 
The COVID-19 pandemic may impact the conduct of this study.  Challenges may arise 
from disruptions or restrictions imposed due to the COVID-19 pandemic (e.g., from 
quarantines, site closures, travel limitations, interruptions to the supply chain for the 
interventional product or from other considerations such as if site personnel or study 
participants become infected with COVID-19).  These challenges may lead to difficulties 
in meeting protocol-specified procedures, including administering the interventional 
product, or adhering to protocol-mandated clinic visits and laboratory testing.  
This protocol appendix outlines measures that are applicable for sites and participants 
when clinic visits are impacted by the COVID-19 pandemic special circumstances.  This 
appendix applies to study Visit 5 and onwards.  The purpose of the appendix is to provide 
information on the measures to be taken to protect participants’ safety, welfare and rights, 
and promote data integrity.  
10.10.2. 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the COVID-19 pandemic, sites should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when considering the need for a participant to attend the site for a visit.  
For the duration of these special circumstances, home healthcare visits (home visits and 
telemedicine visits; see below) may be implemented for scheduled visits from Visit 5 and 
onwards for participants unable to attend a site visit due to COVID-19 related 
restrictions.  For such visits every effort should be made to adhere to protocol-specified 
assessments and procedures.  Missing protocol data/visits due to COVID-19 should be 
noted in participant notes and recorded as a COVID-19 protocol deviation. 
 
10.10.2.1. Home Healthcare 
Home healthcare is defined as:  
• visits at the participant’s home, and  
• telemedicine visits. 
Where applicable country and local regulations and infrastructure allow, home health 
care can be performed at the discretion of the investigator and following the participant 
signing of an informed consent form specific for home healthcare.  
Home visits at the participant’s home 
These are performed at the participant’s home by a qualified home healthcare personnel 
(e.g., nurse) when the participants is unable to attend a site visit due to COVID-19 
restrictions and the Investigator deems that a site visit is not necessary.  See the SRM for 
details. 


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Telemedicine visits 
These are defined as online (virtual) visits which use secure video conferences, phone 
calls, or a web portal and/or mobile application as a way of communicating with and 
monitoring the participant’s progress and safety.  Telemedicine visits are conducted by an 
investigator or designee and may be done in combination with a home visit by a qualified 
personnel/ nurse. 
The study investigator is responsible for ensuring that the identification, management, 
and reporting of COPD exacerbations, AEs and SAEs are completed in accordance with 
the protocol and applicable regulations.  AEs are first reported by participants to the 
investigator/site staff or may be identified during interactions with the participants via 
telemedicine visits.  In addition, healthcare personnel who are visiting participants at 
home may identify AEs as well and report them to the investigator for evaluation.  
The participant should be informed of the home healthcare plan and any potential risks 
associated with home visits and telemedicine.  The participant must sign an informed 
consent form specific to home healthcare. 
 
IRB/Ethics committee should be informed of the introduction of home healthcare in the 
study.  The committee should approve the home healthcare plan and the process should 
be documented in study files. 
 
Study Intervention 
The home healthcare personnel is responsible for administering the study IP (at the 
discretion of the investigator) according to procedures detailed in the protocol.  See 
Section 6, Study Intervention and the pharmacy manual in the SRM. 
 
Study assessments performed through home healthcare 
All assessments from Visit 5 and onwards stated in the SoA tables in Section 1.3.1 and 
1.3.2 can be performed through home healthcare with the exception of the Exit Visit, and 
the below procedures, which must be performed in clinic: 
 
o Pre-bronchodilator spirometry;  
o Clinician rated response to therapy; and 
o Physical examinations 
 


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10.11. 
Appendix 11: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
The overall rationale and the summary of changes tables for previous amendments are 
listed below. 
Amendment 1-USA-1: 23-May-2019 
Overall Rationale for Amendment 1-USA-1:  
Amendment 1-USA-1 was created to include an optional pharmacokinetic (PK) sub-study 
to assess potential ethnic differences in the PK of mepolizumab 100 mg in liquid 
formulation, administered subcutaneously by a safety syringe, between non-Asian 
participants in the US and Chinese participants in China. Summary of changes are 
described in the table below. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Added information  
that an optional PK sub-
study is included  
Align the Synopsis with the 
rest of the protocol 
Section 1.3: Schedule of 
activities 
Updated Section to 
include informed consent 
for the PK sub-study and 
schedule of PK blood 
samples collection 
To align the schedule of 
activities with other 
Sections of protocol 
Section 3: Objectives and 
endpoints 
Added the PK sub-study 
objectives and endpoints 
Assess potential ethnic 
differences in PK between 
non-Asian participants in 
the US and Chinese 
participants in China. 
Section 4: Overall design 
Added information that 
an optional PK sub-study 
is included 
Explain that a PK sub-study 
is included in the study 
design 
Section 7.2: Participant 
Discontinuation/Withdrawal 
from the Study 
Added information that a 
PK sample will be 
collected at the IP 
Discontinuation and 
Withdrawal Visits 
Provide clarity on collection 
of PK sample  
Section 8.5: 
Pharmacokinetics 
Added a pharmacokinetic 
section to describe PK 
samples collection, 
samples analysis and 
assay method 
Provide clarity and 
information on the PK sub-
study. 
Section 9.3.1: 
Added information about 
the PK population  
Provide information on the 
PK population to be 
analysed 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Added information  
that an optional PK sub-
study is included  
Align the Synopsis with the 
rest of the protocol 
Section 1.3: Schedule of 
activities 
Updated Section to 
include informed consent 
for the PK sub-study and 
schedule of PK blood 
samples collection 
To align the schedule of 
activities with other 
Sections of protocol 
Pharmacokinetics sub-study 
Section 9.4.3.3: PK 
analyses 
Added description of the 
PK data analysis 
Provide information on the 
PK analysis 
Appendix 3: Clinical 
laboratory tests, Table 3 
Added Albumin to the 
clinical chemistry tests 
Clarify that Albumin test is 
a required test for the PK 
sub-study only 
 
Amendment 2-CHI-1: 23-May-2019 
Overall Rationale for Amendment 2-CHI-1:  
This protocol amendment was created to include an optional pharmacokinetic (PK) sub-
study to assess potential ethnic differences in the PK of mepolizumab 100 mg in liquid 
formulation, administered subcutaneously by a safety syringe, between non-Asian 
participants in the US and Chinese participants in China. 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Added information  
that an optional PK sub-
study is included in the 
protocol 
Align the Synopsis with the 
rest of the protocol 
Section 1.3: Schedule of 
activities (SoA) 
Updated Section to 
include:   Informed 
consent for the PK sub-
study and schedule of PK 
blood samples collection 
 
Deleted row for the 
genetic informed consent 
 
Deleted rows for the 
collection of biomarker 
and genetic samples 
To align the schedule of 
activities with other 
Sections of protocol 
Section 3: Objectives and 
endpoints 
Added the PK sub-study 
objectives and endpoints 
Assess potential ethnic 
differences in PK between 
non-Asian participants in 
the US and Chinese 
participants in China. 
Section 4: Overall design 
Added information that 
an optional PK sub-study 
is included 
Explain that a PK sub-study 
is included in the study 
design 
Section 7.2: Participant 
Discontinuation/Withdrawal 
from the Study 
Added information that a 
PK sample will be 
collected at the IP 
Discontinuation and 
Withdrawal Visits  
 
Provide information on 
collection of PK samples  
Section 8: Study 
assessments and procedures 
Deleted text related to the 
genetic consent form and 
sample 
Ensure consistency of the 
protocol 
As genetic samples are not 
collected from Chinese 
participants  
Section 8.3.1: Time period 
and frequency for collecting 
AE and SAE Information 
 
Added text to clarify that 
SAEs will be collected 
from the time of signing 
the informed consent 
To comply with specific 
requirements for China 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5: 
Pharmacokinetics 
Added a pharmacokinetic 
section to describe PK 
samples collection, 
samples analysis and 
assay method 
Provide clarity and 
information on the PK sub-
study. 
Section 8.7: Genetics 
Deleted text from Section  Provide information that 
genetic samples are not 
collected from Chinese 
participants 
Section 8.8: Biomarkers 
Deleted text from Section Provide information that 
biomarker samples are not 
collected from Chinese 
participants 
Section 9.3.1 
Pharmacokinetics sub-study 
Added information about 
the PK population  
Provide information on the 
PK population to be 
analysed 
Section 9.4.3.3: PK 
analyses 
Added description of the 
PK data analysis 
Provide information on the 
PK analysis 
Appendix 3: Clinical 
laboratory tests, Table 3 
Added Albumin to the 
clinical chemistry tests 
Clarify that Albumin test is 
a required test for the PK 
sub-study only 
Appendix 6: Genetics 
Deleted text related to 
genetic test 
Ensure consistency of the 
protocol  
Section 10.9: Country-
specific requirements 
Added information on 
China specific 
requirements 
Ensure consistency with the 
protocol 
 
Amendment 3: 18-Jul-2019 
Overall Rationale for Amendment 3:  
This protocol amendment was created to make changes to Study design; integration of 
protocol amendment 1-USA-1 and protocol amendment 2-CHI-1 including a 
pharmacokinetics sub-study in China and the US; correction of typographical errors.  
Protocol changes are described in the table below.  
 


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Section # and Name Description of Change 
Brief Rationale 
Section 1.1: 
Synopsis 
Removed requirement of ≥300 
cells/µL in the 12 months prior 
Screening Visit 1 
 
Updated the number of 
screened participants to 
approximately 1600 
 
Added information that number 
of participants may increase to 
1000 maximum after sample 
size re-evaluation  
 
Added information about PK 
sub-study in China and the US 
only 
Align the synopsis with the rest 
of the protocol 
 
 
 
 
 
Align the synopsis with 
Section 9: Statistics 
 
 
Integrate country specific 
amendment for China and the 
US into this global amendment 
Section 1.2: 
Schema 
Changed Pre-screening Visit to 
Screening Visit 0 
Align Schema with other 
Sections of the protocol  
Section 1.3: 
Schedule of 
activities (SoA) 
Updated Section to include:  
Re-naming the Pre-screening 
Visit 0 to Screening Visit 0  
 
Provided details on the 
hematology test at Screening 
Visit 0 
 
Added PK informed consent 
and scheduled PK sample 
collection  
 
Removed post-bronchodilator 
Spirometry during the 
intervention period 
 
Clarified that no genetic or 
biomarker samples will be 
collected from participants in 
China. 
 
Update the SoA foot-note 
 
Align Section with study 
design and other Sections of 
protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Align with the changes in the 
SoA 
Section 3: 
Objectives and 
endpoints 
Other endpoints: Removed 
post-bronchodilator spirometry  
 
Added the PK sub-study 
objectives and endpoints 
Change in study design 
 
 
Integrate China and the US 
country specific amendment 
into this global amendment 
 


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Section # and Name Description of Change 
Brief Rationale 
Section 4: Study 
design 
Added requirement for 
eosinophil count of ≥300 
cells/µL at Screening Visit 0. 
Removed historical 
requirement of ≥300 cells/µL 
in the 12 months prior 
Screening Visit 1.  
 
Clarified that number of 
participants may increase to 
1000 maximum after sample 
size re-evaluation  
 
Added information about PK 
sub-study in China and the US  
 
Change in study design 
 
 
 
 
 
Alignment with the statistical 
Section 
Section 5.1: 
Inclusion criteria 
Added a new inclusion 
criterion: Blood eosinophil 
count of ≥300 cells/μL from 
the hematology sample 
collected at Screening Visit 0. 
Changed predicted FEV1 
reference range from Quanjer 
to NHANES III 
Change in study design 
Section 5.2: 
Exclusion criteria 
Further clarified that 
Participants with a past history 
or concurrent diagnosis of 
asthma are excluded regardless 
of whether they have active or 
inactive disease. 
Further clarification of 
exclusion criterion 1 
Section 5.4: Screen 
and Run-in failures 
Clarified that re-screening of 
participants is permitted only 
after written approval to 
proceed with re-screening from 
the Medical Monitor 
Clarification about re-
screening  
Section 8: Study 
assessments and 
procedures 
Updated Section in alignment 
with SoA Section 1.3.  
 
Added text in Section 8.3.1 to 
clarify that in China SAEs will 
be collected from the time of 
signing the informed consent 
 
 
 
To comply with specific 
requirements for China 


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Section # and Name Description of Change 
Brief Rationale 
Section 8.5: 
Pharmacokinetics 
Added a pharmacokinetic 
section specific to China and 
the US, to describe PK samples 
collection, samples analysis 
and assay method. 
Provide clarity and information 
on the PK sub-study. 
Sections 8.7: 
Genetics and 8.8: 
Biomarkers 
Clarified that genetic and 
biomarker samples will not be 
collected from participants in 
China. 
To comply with specific 
requirements for China 
Section 9.3.1: 
Pharmacokinetics 
sub-study 
Added information about the 
PK population  
Provide information on the PK 
population to be analysed 
9.6: 
Pharmacokinetics 
Analyses (PK Sub-
study) 
Added Section to describe 
analysis of the PK sub-study. 
 
Appendix 3: 
Clinical laboratory 
tests, Table 3 
Added Albumin to the clinical 
chemistry tests 
Clarify that Albumin test is a 
required test for the PK sub-
study in China and the US only 
Appendix 6: 
Genetics 
Clarified that no genetic 
samples will be collected from 
participants in China 
Integrate China country 
specific amendment in this 
global amendment  
Section 10.9: 
Country-specific 
requirements 
Added information on China 
specific requirements 
Ensure consistency with the 
protocol 
Appendix 10: 
protocol 
amendment history  
Added Appendix to describe 
protocol amendment history for 
China and the US 
Describe country specific 
protocol amendment for China 
and the US 
 
Amendment 4: 13-Sep-2019 
 
Overall Rationale for Amendment 4: 
This protocol amendment was created to make changes to Study design and correct some 
typographical errors.  Protocol changes are described in the table below. 
 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
Section 1.1: 
synopsis 
Added information that based on the results 
from the 2 previously completed COPD studies 
and feedback from health authorities, the study 
patient population must have a documented 
historical blood eosinophil count of ≥150 
cells/μL in the 12 months prior to Screening 
Visit 0 and a blood eosinophil counts of ≥300 
cells/µL at Screening Visit 0. Participants with 
no documented historical blood eosinophil 
count of ≥150 cells/µL must meet this 
threshold at the Screening Visit 1 assessment 
 
Clarified that participants must have at least 2 
COPD exacerbations that were treated with 
systemic corticosteroids with or without 
antibiotics, or 1 severe exacerbation requiring 
hospitalization in the 12 months prior to 
Screening Visit 1  
The number of participants estimated to be 
screened is 2286 
Clarify change 
in study design 
Section 1.2: 
Schema 
The duration between Visit 0 and Visit 1 was 
changed to >14 days. Footnote was updated 
Ensure 
consistency 
with other 
Sections of the 
protocol 
Section 1.3: 
Schedule of 
activities 
Updated Section to increase the duration 
between Visit 0 and Visit 1 to >14 days.  
 
Added a row for historical blood eosinophil 
count 
 
Updated foot note to clarify that only 
participants with no historical eosinophil count 
in the 12 months prior Screening Visit 0 will 
have a hematology sample collected at 
Screening Visit 1.  
 
Clarified that where several historical blood 
eosinophil counts are obtainable, the highest 
eosinophil count not associated with a COPD 
exacerbation should be recorded in the eCRF 
for each of the following specified periods: ≥1 
to <6 months and 6 to 12 months. In order to 
meet the Inclusion Criteria #2 (Section 5.1), a 
historical blood eosinophil measurement must 
Ensure 
alignment with 
the protocol 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
meet the following: It must have been 
measured between 12 months and 1 month 
prior to Visit 0 and it must not have been 
measured within 14 days of a COPD 
exacerbation. If, in either of the 2 specified 
periods, the only historical documented blood 
eosinophil count is associated with a COPD 
exacerbation, then this eosinophil count cannot 
be used for inclusion in the study but should be 
recorded in the eCRF 
Section 2.1: Study 
rationale 
Updated Section to clarify that to ensure 
stability of eosinophil counts participants must 
have 2 eosinophil measurements. One historical 
and one at Screening Visit 0. Participants with 
no documented historical eosinophil count of 
≥150 cells/µL must meet this threshold at the 
Screening Visit 1 assessment 
Clarified 
rationale for 
the 
requirement of 
2 blood 
eosinophil 
measurements 
Section 4.1: 
Overall design 
Added information that participants must also 
have a documented historical eosinophil count 
of ≥150/μL in the 12 months prior to Screening 
Visit 0 and historical eosinophil count must not 
have been measured during a COPD 
exacerbation.  Participants with no documented 
historical eosinophil count of ≥150 cells/µL 
must meet this threshold at the Screening Visit 
1 
Clarified that participants must have at least 2 
moderate COPD exacerbations that were 
treated with systemic corticosteroids 
(intramuscular (IM), intravenous, or oral) with 
or without antibiotics, or 1 severe exacerbation 
requiring hospitalization in the 12 months prior 
to Screening Visit 1 
Clarify 
changes in 
study design 
and ensure 
alignment with 
other Sections 
of the protocol 
Section 4.2: 
Scientific rationale 
for study design 
Clarified that duration between Screening V0 
and Screening V1 was increased to >14 to 
allow a repeated measurement of eosinophil 
count at Visit 1 
Ensure 
alignment with 
other Sections 
of protocol 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
Section 5.1: 
Inclusion Criteria 
Updated Inclusion Criteria # 2: Participants 
must have: A peripheral blood eosinophil count 
of ≥300 cells/μL from the hematology sample 
collected at Screening Visit 0 and a 
documented historical eosinophil count of 
≥150/μL in the 12 months prior to Screening 
Visit 0 that was measured between 12 months 
and 1 month prior to Visit 0, and that was not 
measured within 14 days of a COPD 
exacerbation.  
Participants with no documented historical 
blood eosinophil count of ≥150 cells/µL must 
meet this threshold at the Screening Visit 1 
Updated inclusion criterion # 5: Two or more 
moderate COPD exacerbations that were 
treated with systemic corticosteroids 
(intramuscular (IM), intravenous, or oral) with 
or without antibiotics etc. 
Change in 
study design to 
include 2 blood 
eosinophil 
counts, one 
historical and 
one at 
Screening 
Section 5.3.1: 
Randomization 
inclusion criteria 
Added a new Randomization inclusion 
criterion: Participants that do not have a 
historical blood eosinophil count that satisfies 
screening Inclusion Criterion 2 (Section 5.1) 
must have a Screening Visit 1 blood eosinophil 
count ≥150 cells/µL 
Alignment 
with other 
Sections of 
protocol 
Section 8: Study 
assessments and 
procedures; critical 
procedures 
performed at 
Screening Visit  
Further emphasized that in case several 
historical eosinophil counts are obtainable, the 
highest eosinophil count should be recorded in 
the eCRF for each of the following periods: ≥1 
to <6 months and 6 to12 months. In addition, to 
satisfy the inclusion criterion #2, a historical 
blood eosinophil measurement must meet the 
following: It must have been measured between 
12 months and 1 month prior to Visit 0 and it 
must not have been measured within 14 days of 
a COPD exacerbation.   
Clarified that a hematology sample is only 
collected at Screening Visit 1 for participants 
who do not have a historical eosinophil count 
meeting the Inclusion Criteria 
Alignment 
with Section 
1.3 
Typographical 
errors 
IVRS changed to IWRS throughout the 
protocol. Other typographical errors were 
corrected. 
 
 


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Amendment 5: 16-OCT-2020  
Overall Rationale for Amendment 5 
This protocol amendment was created to make changes to the study following the 
COVID-19 pandemic, to introduce home healthcare to perform study assessments, update 
details of the primary estimand and strategies for handling intercurrent events, add clarity 
to some sections of the protocol, and to correct typographical errors and inconsistencies.  
Protocol changes are described in the table below. 
Section # and 
Name 
Description of Change 
Brief 
Rationale 
Section 1.1: 
Synopsis 
 
 
 
 
 
 
 
 
 
Added text related to home healthcare 
 
 
 
 
 
 
 
 
Updated the approximate number of 
participants to be screened 
 
Clarify that 
home 
healthcare is 
included in the 
study as 
mitigation 
during 
COVID-19 
restrictions 
 
Updates based 
on observed 
screen failure 
rate 
Section 1.2: 
Schema 
Updated the range of days for Visit 0 and Visit 
1 to align with Section 1.3 
Ensure 
consistency 
between 
Sections 
Section 1.3: 
Schedule of 
activities (SoA) 
Updated SoA, removed study day and study 
week  
 
Updated the number of days between V0 and 
Visit 1 
 
Updated medical history to include Hepatitis B 
and C and COVID-19 
 
Removed Hepatitis B and C tests from SoA  
 
Removed collection of used rescue medication 
Updated footnotes to add clarity.  
Ensure  
Clarity and 
consistency 
across the SoA 
 
 
 
 
Align with new 
GSK guidance 
on Hepatitis B 
and C testing 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
Section 4.1: Study 
design 
 
 
Added text related to home healthcare 
 
 
 
 
 
 
 
 
 
Updated the approximate number of 
participants to be screened 
 
Clarify that 
home 
healthcare is 
included in the 
study as 
mitigation 
during 
COVID-19 
restrictions 
 
 
Updates based 
on observed 
screen failure 
rate 
 
Section 5.1: 
Inclusion Criteria 
Inclusion criterion 5: Added a note related to 
COVID-19 and COPD exacerbations  
Clarify that 
COPD 
exacerbations 
related to 
COVID-19 
infection must 
not be counted 
as COPD 
exacerbations 
for inclusion in 
the study 
Section 5.2: 
Exclusion criteria 
Criterion no.7: Added a note to clarify that 
where a single ECG demonstrates a prolonged 
QTcF interval at Screening, two more ECG 
readings should be obtained with the average of 
the triplicate QTcF measurements used to 
determine eligibility 
Criterion no.14: Deleted “(-e.g., presence of 
hepatitis B surface antigen [HbsAg] or positive 
hepatitis C antibody test result)”. 
 
 
 
Added a new exclusion criterion (no.24) related 
to COVID-19 
 
Provide clarity 
about ECG at 
Screening 
 
 
 
Deleted 
sentence 
related to 
hepatitis B and 
C 
 
Provide 
information 
related to 
COVID-19  
Exclusion. 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
Section 5.3.2: 
Randomization 
exclusion criteria 
Added a new randomization exclusion criterion 
(no.5) related to COVID-19. 
 
Provide 
information 
related to 
COVID-19  
Exclusion.  
Section 5.4: Screen 
and run-in failures 
Updated Section to clarify the information 
collected at Screening Visit 0 and Screening 
Visit 1. 
Add clarity to 
protocol. 
Section 6.1: Study 
intervention(s) 
administered 
Updated Table 1 to include the correct 
excipients of interventional product, 
mepolizumab and placebo.  
Provide correct 
information on 
interventional 
product. 
Section 6.4: Study 
intervention 
compliance 
Added text to clarify that where applicable 
study assessments and study intervention can 
be performed through home healthcare. 
Provide 
information on 
home 
healthcare. 
Section 6.5.2: 
Permitted 
medications and 
non-drug therapies 
Added BIPAP as a permitted therapy. Removed 
monoclonal antibodies to align with exclusion 
criterion no.18. 
Ensure 
consistency 
across Sections 
of the protocol. 
Section 6.5.3: 
Prohibited 
medications and 
non-drug therapies 
Clarified that morning COPD medications 
should be withheld at all visits where 
spirometry is performed. 
 
Clarified that monoclonal antibodies and 
chronic oral corticosteroids for non-COPD 
treatment are not permitted. 
Provide clarity 
on prohibited 
medications. 
Section 7.1.1: 
Liver chemistry 
stopping Criteria 
Included minor revision to align with new 
protocol template. 
Align with new 
protocol 
template 
Section 8: Study 
assessments and 
procedures 
Added text to clarify that where applicable 
study assessments can be performed through 
home healthcare. 
Provide 
information on 
home 
healthcare 
Section 8.2.3: 
Electrocardiogram 
Updated information about ECG recordings. 
Provide 
flexibility for 
ECG recording 
Section 8.3.7: 
Medical device 
deficiencies 
Updated Section to align with new protocol 
template and new regulatory requirements for 
reporting device deficiencies. 
 
Alignment 
with new 
protocol 
template. 
Section 8.7: 
Genetics 
Deleted the following sentence: In the event of 
DNA extraction failure, a replacement genetic 
blood sample may be requested from the 
Clarify that a 
replacement 
genetic sample 


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Section # and 
Name 
Description of Change 
Brief 
Rationale 
participant. Signed informed consent will be 
required to obtain a replacement sample.   
will not be 
requested. 
Section 9: 
Statistical 
Considerations 
Updated details of the primary estimand. 
Clarify 
handling of 
issues related 
to the COVID-
19 pandemic 
Section 9.4.1: 
Efficacy Analysis 
Updated details of attributes of the primary 
estimand, as well as intercurrent events and 
strategies for handling intercurrent events. 
Clarify 
handling of 
issues related 
to the COVID-
19 pandemic 
Section 10.7 
Appendix 7: Liver 
Safety 
Deleted hepatitis B surface antigen as it is no 
longer applicable. 
Included minor revision to align with new 
protocol template. 
Align with 
other sections 
of protocol 
Section 10.8 
Appendix 8: 
Device deficiency 
Updated Section to align with new protocol 
template and new regulatory requirements for 
reporting device deficiencies. 
 
Alignment 
with new 
protocol 
template 
Section 10.10: 
Appendix 10: 
COVID-19 
Measures 
Added Appendix 10: COVID-19 Measures, to 
inform about home healthcare during the 
COVID-19 pandemic.  
Added Table 4 to clarify the study assessments 
that can be performed through home healthcare. 
Provide 
information on 
home 
healthcare 
Other Protocol 
Sections 
Minor updates are made throughout the 
protocol to provide clarity and consistency. 
Provide clarity 
and 
consistency 
 


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10.12. 
Appendix 12: Abbreviations and Trademarks 
LIST OF ABBREVIATIONS 
ADA 
Anti-drug antibody 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AECOPD 
Acute exacerbations of COPD 
ALT 
Alanine aminotransferase 
ASE 
All participants enrolled population 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BP 
Blood pressure 
BIPAP 
Bilevel Positive Airway Pressure 
CAT 
COPD Assessment Test 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CEC 
Clinical endpoint committee 
COA 
Clinical Outcomes Assessment 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 
CPK 
Creatine phosphokinase 
CPAP 
Continuous positive airway pressure 
CSR 
Clinical Study Report 
CRF 
Case Report Form 
CV 
Cardiovascular 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiography 
eCRF 
Electronic case report form 
ED 
Emergency department 
eDiary 
Electronic diary 
EDTA 
Ethyl enediamine tetra acetic acid 
EGPA 
Eosinophilic Granulomatosis with Polyangitis 
EQ-5D-3L 
EuroQol questionnaire 
EQ-VAS 
EuroQol-Visual Analogue Scale 
E-RS: COPD 
Evaluating Respiratory Symptoms in COPD 
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool 
FAAN 
Food Allergy and Anaphylaxis Network 
FEV1 
Forced expiratory volume in one second 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GCSP 
GSK’s Global Clinical Safety and Pharmacovigilance 
group 
GSK 
GlaxoSmithKline 
hCG 
Human chorionic gonadotropin 
HbsAg 
Hepatitis B surface antigen 


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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HPCL 
High performance liquid chromatography 
HRQoL 
Health related quality of life 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled corticosteroid 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IP 
Interventional Product  
IM 
Intramuscular 
INR 
International normalized ratio 
IP 
Interventional Product 
IRB 
Institutional research board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
IDFU 
Instruction Direction For Use 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LABA 
Long acting beta2-agonist 
LAMA 
Long acting muscarinic antagonist 
LDH 
Lactate dehydrogenase 
LFT 
LRTI 
Liver function testing 
Lower Respiratory Tract Infection 
LTOT 
Long term oxygen therapy 
MACE 
Major Adverse Cardiovascular Event 
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MDI 
Metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Myocardial infarction 
mITT 
Modified Intent-to Treat 
mL 
Millilitre 
mMRC 
Modified Medical Research Council Grading System 
MSDS 
Materials Safety Data Sheet 
NAb 
Neutralizing Antibody 
NHANES 
National Health and Nutrition Examination Survey 
NIAID 
National Institute of Allergy and Infectious Disease 
NIMP 
Non-interventional Medicinal Product 
NYHA 
New York Heart Association 
PK 
Pharmacokinetic 
PD 
Pharmacodynamic 
PDE-4 
Phosphodiesterase-4 
PEF 
Peak expiratory flow 


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PGx 
Pharmacogenetics 
PI 
Principal Investigator 
PP 
Per protocol  
prn 
As needed 
PRO 
Patient reported outcomes 
QTcF 
QT interval corrected with Fridericia's formula 
RAP 
Reporting and analysis plan 
RBC 
Red blood cells 
SABA 
Short acting beta2-agonist 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAMA 
Short acting muscarinic antagonist 
SaO2 
Oxygen Saturation 
SC 
Subcutaneous 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SGRQ 
St. George's Respiratory Questionnaire 
SGRQ-C 
St. George's Respiratory Questionnaire for COPD  
SoA 
Schedule of Activities 
SoC 
Standard of Care 
SOC 
System Organ Class 
SS 
Safety syringe 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
ULN 
Upper limit of normal 
US 
United States  
USADE 
Unanticipated Serious Adverse Device Effect 
WOCBP 
Woman of childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
CAT 
 
EQ-5D-3L 
 
 
E-RS-COPD 
 
 
EXACT 
 
 
MedDRA 
 


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11. 
REFERENCES 
Bafadhel M, McCormick M, Saha S, McKenna S, Shelley M, Hargadon B, et al.  
Profiling of sputum inflammatory mediators in asthma and chronic obstructive 
pulmonary disease. Respiration. 2012a; 83(1):36-44. 
Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, et al.  Blood 
eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive 
pulmonary disease: randomized placebo-controlled trial. Am J Respir Crit Care Med. 
2012b; 186 (1):48-55. 
Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, et al. Acute exacerbations 
of chronic obstructive pulmonary disease: identification of biological clusters and their 
biomarkers. Am J Respir Crit Care Med. 2011; 184:662–671. 
Bafadhel M, Pavord I, Russell R. Eosinophils in COPD: just another biomarker? Lancet 
Respir Med. 2017; 5: 747–59 
Barnes P, Burney P, Silverman E, Celli B, Vestbo J, Jadwiga W, et al. Chronic 
Obstructive Obstrucrive pulmonary disease. Nature Reviews, 2015; 
doi:10.1038/nrdp.2015.76 
Benson V, Siddall J, Small M, Mullerova H. Exacerbation frequency and eosinophil 
levels for GOLD C and D COPD patients currently prescribed multiple inhaler triple 
therapy (MITT). Poster Number PA4486. ERS International Congress, September 15–19, 
2018 Paris, France. 
Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, et al.  Sputum 
eosinophilia and the short-term response to inhaled mometasone in chronic obstructive 
pulmonary disease. Thorax. 2005; 60(3):193-198. 
Celli BR, MacNee W, ATS/ERS Task Force.  Standards for the diagnosis and treatment 
of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004; 
23(6):932-946. 
Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) Patient-Reported Outcome 
(PRO) USER MANUAL (Version 8.0) Mar 2016. Available from: 
http://www.exactproinitiative.com. Accessed 11-Jul 2018 
Friede T, Schmidli H. Blinded Sample Size Reestimation with Negative Binomial Counts 
in Superiority and Non-inferiority Trials. Methods Inf Med. 2010; 49(6): 618-24 
GlaxoSmithKline document number 2017N350371_00. Mortality, exacerbations and 
healthcare resource utilisation outcomes among patients with COPD characterised by 
exacerbation history, multiple inhaler triple therapy (MITT) and raised blood eosinophils 
in the UK Clinical Practice Research Datalink (CPRD). Available at: https://www.gsk-
clinicalstudyregister.com. Accessed 16-April 2018 


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Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the 
Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. 2019 
Report.  Available from: http://goldcopd.org. Accessed 1-10-Nov-2018 
Halpin DM, Miravitlles M, Metzdorf N, Celli B. Impact and prevention of severe 
exacerbations of COPD: a review of the evidence.  International Journal of COPD 
2017:12 2891–2908 
Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Society-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of Antherosclerosis 
(MESA) Lung Study. Chest, 2010;137:138-45. 
Hankinson JL. Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Resp Crit Care Med. 1999;159:179-187.  
Hurst R, Vestbo J,Anzueto A, Locantore N, Mullerova H, Tal-Singer R. Susceptibility to 
Exacerbation in Chronic Obstructive Pulmonary Disease. NEJM. 2010 363:1128-1138 
Jones P, Harding G, Berry P, Wiklund I, Chen W-H, Leidy, N. Development and first 
validation of the COPD Assessment Test (CAT) Eur Respir J 2009 34: 648–654 
Jones P, Harding G, Wiklund I, Berry P, Tabberer M, Yu R,et al . Tests of the 
Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test 
(CAT) Following Acute Exacerbation and Pulmonary Rehabilitation. Chest 2012 142 
134-140 
Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the Tristan study. Pharmaceut. 
Statist. 2007; 6:89-87 
Leidy NK, Sexton CC, Jones PW, Notte SM, Monz BU, Nelsen L et al. Measuring 
respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary. 
Thorax 2014; 69:5 424-430 
Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S. Standardizing 
measurement of chronic obstructive pulmonary disease exacerbations. Reliability and 
validity of a patient-reported diary. Am J Respir Crit Care Med. 2011; 183:323-329  
Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V et al. Global and 
regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a 
systematic analysis for the Global Burden of Disease Study. afadhelLancet. 2012; 380: 
2095-2128 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-Specific Version of the St. George Respiratory Questionnaire. Chest. 2007 
132:456-463 


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Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005; 26:319-388. 
Müllerova H, Maskell J, Meeraus WH, Galkin D, Albers FC, Gait C.  Characterization of 
COPD patients treated with inhaled triple therapy containing inhaled corticosteroids 
[ICS], long-acting beta2-agonists [LABA], and long-acting muscarinic antagonists 
[LAMA] in the UK. Am J Respir Crit Care Med. 2017; 195: A4986. 
Pavord I, Chanez P, Criner G, Kerstjens H, Korn S, Lugogo N et al.  Mepolizumab for 
esoinophilic Chronic Obstructive Pulmunory Disease. NEJM 2017; 377:1613-1627 
Perera PN, Armstrong EP, Sherrill DL, Skrepnek GH. Acute exacerbations of COPD in 
the United States: inpatient burden and predictors of costs and mortality. COPD. 2012; 
9(2):131–141 
Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct 
Pulmon Dis 2006; 1:39–47. 
Siva R, Green H, Brightling CE, Shelley M, Hargadon B, McKenna S et al. Eosinophilic 
airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur 
Respir J 2007 29(5): 906-13. 
Toy E, Gallagher K, Stanley EL, Swensen AR, Duh MS.. The economic impact of 
exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a 
review. COPD. 2010 7(3): 214-28. 
Vedel-Krogh S, Nielsen S, Lange P, Vestbo J, Nordestgaard BG . Blood Eosinophils and 
Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General 
Population Study. Am J Respir Crit Care Med. 2016;193: 965–974 
Vogelmeier C, et al. Global Strategy for the Diagnosis, Management, and Prevention of 
Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary Am J 
Respir Crit Care Med. 2017; 195: 557–582 
World Health Organization (WHO) Report 2008 - primary Health Care (Now More Than 
Ever) https://www.who.int/respiratory/copd/burden/en/Accessed 16-April 2018 


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SAP_001.pdf: 
Statistical Analysis Plan Amendment 3
Study ID:  208657
Official Title of Study: A multi-center, randomized, double-blind, 
parallel-group, placebo-controlled study of mepolizumab 100 mg SC 
as add-on treatment in participants with COPD experiencing frequent 
exacerbations and characterized by eosinophil levels (Study 208657)
NCT ID: NCT04133909
Date of Document: 20-Aug-2024


CONFIDENTIAL 
 
 
208657 
Page 1 of 68 
Information Type: 
Statistical Analysis Plan (SAP) 
 TITLE PAGE 
Protocol Title: 
A multi-center, randomized, double-blind, parallel-group, 
placebo-controlled study of mepolizumab 100 mg SC as add-on 
treatment in participants with COPD experiencing frequent 
exacerbations and characterized by eosinophil levels (Study 
208657) 
Study Number: 
208657 
Compound 
Number: 
SB240563 
Abbreviated Title: 
Mepolizumab as Add-on Treatment IN participants with 
COPD characterized by frequent Exacerbations and Eosinophil 
Level 
Acronym: 
MATINEE 
 
Sponsor Name:  
GlaxoSmithKline Research & Development Limited 
 
Regulatory Agency Identifier Number(s):  
 
Registry 
 
ID 
Clintrials.gov 
NCT04133909 
IND 
006971 
EudraCT 
2018-001540-56 
 
 
 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited. 
 


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TABLE OF CONTENTS 
 TITLE PAGE .................................................................................................................. 1 
VERSION HISTORY ....................................................................................................... 5 
1. 
INTRODUCTION .................................................................................................... 11 
1.1. 
Objectives, Estimands and Endpoints ......................................................... 11 
1.1.1. 
Objectives and Endpoints ............................................................ 11 
1.1.2. 
Primary Estimand ........................................................................ 14 
1.2. 
Study Design .............................................................................................. 15 
2. 
STATISTICAL HYPOTHESES ............................................................................... 16 
2.1. 
Multiplicity Adjustment ................................................................................ 17 
3. 
ANALYSIS SETS ................................................................................................... 17 
4. 
STATISTICAL ANALYSES ..................................................................................... 18 
4.1. 
General Considerations .............................................................................. 18 
4.1.1. 
General Methodology .................................................................. 18 
4.1.2. 
Baseline Definition ....................................................................... 19 
4.1.3. 
Visit Windows .............................................................................. 19 
4.1.4. 
Study Completion ........................................................................ 19 
4.2. 
Primary Endpoint Analyses ......................................................................... 20 
4.2.1. 
Definition of Primary Endpoint/Estimand ...................................... 20 
4.2.2. 
Main analytical approach ............................................................. 22 
4.2.3. 
Sensitivity analyses ..................................................................... 22 
4.2.4. 
Additional estimands .................................................................... 24 
4.2.5. 
Exploratory Modelling .................................................................. 24 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 24 
4.3.1. 
Time to first moderate/severe exacerbation ................................. 24 
4.3.2. 
CAT Score Responders ............................................................... 26 
4.3.3. 
SGRQ total score Responders ..................................................... 27 
4.3.4. 
E-RS: COPD total score Responders .......................................... 28 
4.3.5. 
Annualized Rate of Exacerbations Requiring ED visit 
and/or hospitalization ................................................................... 29 
4.4. 
Other Efficacy Analyses .............................................................................. 29 
4.4.1. 
Time to first exacerbation (ED/Hospitalization, Severe) ............... 29 
4.4.2. 
Annualized Rate of Exacerbations (Severe, 
Moderate/Severe By Type of Treatment Required) ...................... 29 
4.4.3. 
Daily eDiary data (Percentage of rescue medication free 
days, Percentage of nights with no awakenings, Mean 
number of occasions of rescue medication use/day) .................... 30 
4.4.4. 
Change from baseline (Pre-bronchodilator FEV1, FVC, 
CAT Score, SGRQ Total Score, E-RS: COPD Total Score) ......... 31 
4.4.5. 
Responders (CAT, SGRQ and E-RS: COPD Responders 
at Week 24, E-RS: COPD Subscale Responders at 
Weeks 21-24 and 49-52) ............................................................. 33 
4.4.6. 
Patient and Clinician Response to Therapy ................................. 33 
4.4.7. 
Healthcare Utilization ................................................................... 34 
4.5. 
Safety Analyses .......................................................................................... 35 
4.5.1. 
Extent of Exposure ...................................................................... 35 


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4.5.2. 
Adverse Events............................................................................ 35 
4.5.3. 
Laboratory Data ........................................................................... 39 
4.5.4. 
Vital Signs .................................................................................... 39 
4.5.5. 
ECG ............................................................................................. 39 
4.5.6. 
Cardiovascular Events ................................................................. 40 
4.6. 
Immunogenicity Data .................................................................................. 40 
4.7. 
Pharmacodynamic Analyses ....................................................................... 41 
4.7.1. 
Definition of Endpoint ................................................................... 41 
4.7.2. 
Main Analytical Approach ............................................................ 42 
4.8. 
Population Pharmacokinetic (PopPK) Analyses .......................................... 42 
4.8.1. 
Definition of Endpoint(s) ............................................................... 43 
4.8.2. 
Main Analytical Approach ............................................................ 43 
4.9. 
Population Pharmacokinetic/Pharmacodynamic (PopPKPD) 
Analyses ..................................................................................................... 44 
4.9.1. 
Definition of Endpoint(s) ............................................................... 44 
4.9.2. 
Main Analytical Approach ............................................................ 44 
4.10. 
Other Analyses ........................................................................................... 45 
4.10.1. 
Subgroup Analyses ...................................................................... 45 
4.10.2. 
Subpopulation Analyses .............................................................. 47 
4.11. 
Interim Analyses ......................................................................................... 47 
4.12. 
Changes to Protocol Defined Analyses ....................................................... 47 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 49 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 51 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 51 
6.1.1. 
Participant Disposition ................................................................. 51 
6.1.2. 
Demographic and Baseline Characteristics .................................. 51 
6.1.3. 
Protocol Deviations ...................................................................... 52 
6.1.4. 
Prior and Concomitant Medications ............................................. 52 
6.1.5. 
Intercurrent Events ...................................................................... 52 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 53 
6.1.7. 
Change in Smoking Status .......................................................... 53 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 54 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 54 
6.2.2. 
Study Period ................................................................................ 54 
6.2.3. 
Treatment Phases ....................................................................... 56 
6.2.4. 
Study Day and Reference Dates .................................................. 59 
6.2.5. 
Assessment Windows .................................................................. 59 
6.2.6. 
Multiple measurements at One Visit ............................................. 61 
6.2.7. 
Handling of Partial Dates ............................................................. 61 
6.3. 
Appendix 3 Exclusions from Per-Protocol Population ................................. 63 
6.4. 
Appendix 4: Adverse Events of Special Interest .......................................... 64 
6.4.1. 
Systemic Allergic (Type I Hypersensitivity) and Other 
Systemic Reactions ..................................................................... 64 
6.4.2. 
Alterations in immune response (infections) ................................. 64 
6.4.3. 
Alterations in immune response (malignancies) ........................... 64 
6.4.4. 
Alterations in cardiovascular safety .............................................. 64 
6.4.5. 
Local Injection Site Reactions ...................................................... 65 
6.5. 
Appendix 5: Electronic Clinical Outcome Assessment (eCOA) 
Compliance ................................................................................................. 66 
6.5.1. 
Study Level compliance ............................................................... 66 


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6.5.2. 
Endpoint Level compliance .......................................................... 66 
7. 
REFERENCES ....................................................................................................... 68 


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VERSION HISTORY 
SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
SAP 
28 Jul 2022 
Amendment 
6 (06-Dec-
2021) 
Not Applicable 
Original version 
SAP 
Amendment 
1 
16 Nov 2023 
Amendment 
6 (06-Dec-
2021) 
• Definition of 
Extended 
Treatment 
Population updated 
to include all 
participants who 
receive at least one 
dose of trial 
medication.  
Population for 
selected Study 
Population and 
Safety summaries, 
not Efficacy 
summaries. 
• Definition 
amended to 
accommodate 
Extended 
Treatment 
population 
being applied to 
Study 
Population or 
Safety 
summaries. 
• Change in handling 
of intercurrent 
events of prohibited 
medication. 
• Change to 
handle all 
occurrences of 
the intercurrent 
event of 
prohibited 
medication with 
treatment policy 
regardless of 
association with 
disruptions or 
restrictions 
imposed due to 
the COVID-19 
pandemic per 
feedback from 
regulatory 
authority. 
• Addition of 
sensitivity analysis 
for primary 
endpoint regarding 
Site 239718. 
• Due to 
concerns over 
data quality at 
site, sensitivity 
analysis was 
added to 
determine 


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SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
effect of site 
results on 
primary 
endpoint. 
• Addition of 
clarification that 
time to event 
analyses are carried 
out for data up to 
week 104. 
• Provide further 
clarity for 
analysis. 
• Change in safety 
display 
presentations to 
include all data up 
to Week 104, with 
specific displays 
summarizing data 
separately for 
participants 
enrolled for 52 
weeks only and 
those in the 
Extended 
Treatment 
population. 
• Facilitate 
assessment of 
the overall 
effect of 
mepolizumab on 
safety. 
• Updated the SMQ 
to be used to 
identify adverse 
events of 
pneumonia, this 
will be Infective 
Pneumonia SMQ. 
• The Pneumonia 
SMQ is no 
longer present 
in the current 
version of 
MedDRA. 
• Amendment of 
wording in 
Immunogenicity 
section. 
• Wording 
changed to 
provide further 
clarity on the 
testing process. 
• Addition of time to 
first adjudicated 
MACE analysis 
section. 
• Additional 
analysis to 
further explore 
difference in 
MACE 
occurrence in 


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SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
the two 
treatment 
groups. 
• Addition of 
PK/PKPD analysis. 
• To document a 
PK/PKPD 
analysis may be 
conducted if 
deemed 
appropriate. 
• Addition of details 
regarding early 
release of 
unblinded PK data. 
• Early release of 
PK data to be 
carried out to 
aid in 
refinement of 
the population 
PK model. 
• Addition of 
subgroup 
(symptoms of 
chronic bronchitis) 
and removal of 
subgroups 
(screening 
eosinophil 
categories and other 
comorbidity). 
• Subgroup 
analyses of 
subjects with 
symptoms of 
chronic 
bronchitis 
determined to 
be of 
importance. 
Screening 
eosinophil 
categories were 
deemed 
unnecessary 
with screening 
eosinophil 
thresholds 
available. Other 
comorbidity was 
deemed not to 
provide a 
meaningful 
analysis. 
• Update of countries 
defining geographic 
regions. 
• Incorporating 
additional 
countries 
participating in 
MATINEE to 
their respective 


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SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
geographic 
regions. 
• Addition of 
analyses for 
Chinese, East Asia, 
South Korea and 
India 
subpopulations. 
• Documentation 
of planned 
subpopulation 
analyses. 
• Addition of outline 
of time to 
withdrawal from IP 
summary. 
• Added for 
clarity (no 
change to 
analysis). 
SAP 
Amendment 
2 
18 Jul 2024 
Amendment 
6 (06-Dec-
2021) 
• Addition of 
baseline definition 
for CAT and SGRQ 
questionnaires. 
• Added to clarify 
differences to 
other baseline 
definitions. 
• Amendment of 
wording in the 
sensitivity analysis 
for primary 
endpoint section. 
• Added clarity 
on defining the 
on and off 
treatment data 
used for 
imputation. 
• Minor amendments 
and clarifications 
added to secondary, 
pharmacodynamic 
analyses and other 
analyses. 
• Added to clarify 
time periods for 
summaries, 
populations for 
summaries and 
methodologies 
used. 
• Amendment of PK 
and PKPD analysis 
objectives to 
remove covariate 
exploration. 
• Model to be 
used is well 
established - 
covariate 
selection is not 
expected to be 
required and 
will only occur 
if original 
model is not 
deemed 
suitable.  


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SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
• Change of 
subgroup 
definitions – 
removed screening 
eosinophil 
thresholds, added 
screening 
eosinophil 
categories. Added 
<40 to age 
subgroup. 
• Analysis by 
screening blood 
eosinophil 
threshold no 
longer required, 
analysis by 
screening blood 
eosinophil 
categories 
(<500, ≥500 
cells/µL) added 
as more 
informative. 
Additional age 
subgroup level 
added for 
further 
information.  
• Subgroup analyses 
updated to include 
additional analyses 
for secondary and 
other endpoints and 
shrinkage methods 
in primary 
endpoint. 
• Additional 
analysis to 
provide further 
context behind 
main analyses. 
• Amendment of 
definitions for 
Chinese, East Asia, 
South Korea and 
India 
subpopulations 
• Definitions 
aligned to data 
categories 
collected in 
eCRF. 
• Minor amendments 
and clarifications 
added to study 
population 
analyses. 
• Added to clarify 
summaries and 
methodologies 
used. 
• Addition of text in 
demographics 
section regarding 
requirements for 
de-identified 
summaries. 
• Added in 
accordance with 
new company 
guidance. 


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SAP 
Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
• Addition of eCOA 
compliance 
appendix. 
• Added in 
accordance with 
new company 
guidance. 
SAP 
Amendment 
3 
20 Aug 2024 
Amendment 
6 (06-Dec-
2021) 
• Updates to 
formatting. 
• Applied in line 
with QC check. 
• Addition of further 
exploratory 
analyses to assess 
smoking variables. 
• Additional 
analysis to 
further explore 
the impact of 
smoking in 
COPD. 
 


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 208657. 
 
1.1. 
Objectives, Estimands and Endpoints 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To evaluate the efficacy of 
mepolizumab 100 mg 
subcutaneous (SC) 
compared to placebo, given 
every 4 weeks in liquid 
formulation by safety 
syringe (SS) to COPD 
participants at high risk of 
exacerbations despite the 
use of optimized COPD 
maintenance therapy. 
• Annualized rate of moderate/severe 
exacerbations 
Secondary 
 
• To evaluate mepolizumab 
100 mg SC compared to 
placebo given every 4 
weeks in liquid formulation 
by SS on additional efficacy 
assessments, health 
related quality of life 
(HRQoL), health care 
utilization, and symptoms 
• Time to first moderate/severe exacerbation 
• Proportion of COPD assessment test (CAT) 
responders (≥2 unit reduction in CAT score from 
baseline) at Week 52  
• Proportion of St. George's Respiratory 
Questionnaire (SGRQ) total score responders 
(measured using the St. George's Respiratory 
Questionnaire for COPD [SGRQ-C], and defined 
as ≥4 point reduction in SGRQ total score from 
Baseline) at Week 52 
• Proportion of Evaluating Respiratory Symptoms 
in COPD (E-RS: COPD) responders (≥2 unit 
reduction in total score from Baseline) at Week 
52  
• Annualized rate of exacerbations requiring 
Emergency Department (ED) visit and/or 
hospitalization 


C O N FI D E N TI A L  
 
 
2 0 8 6 5 7  
P a g e 1 2  of 6 8  
O bj e cti ve s  
E n d p oi nt s  
Ot h er  
 
•  T o f urt her i nv estig ate oth er 
e n dp oi nts  
•  C h a n ge fr o m Bas eli ne i n pr e -br o nc ho dil ator 
f orc e d ex pirat ory vol u m e i n o n e sec on d ( F E V1) 
a n d f orc e d vit al c ap acity ( F V C)  
•  C A T r es p o nd ers at W e ek 24  
•  C A T c h a ng e fr o m b aseli n e at W e ek 2 4 a n d 5 2  
•  S G R Q r es po n ders at W eek 2 4  
•  S G R Q c h an ge fr o m Bas eli ne at W eek 2 4 a n d 5 2 
•  Pr o p orti on of Ev al uati ng R es pirat ory Sy m pto ms 
i n C O P D ( E-R S: C O P D) r esp o nd ers at W e ek 2 4  
•  Pr o p orti on of E -R S: C O P D res p on d ers: su b -
sc al es of br e at hl ess n ess, co u gh a n d s p ut u m a nd 
c h est sy m pto ms at W eek 2 4 a nd 5 2 
•  C h a n ge fr o m Bas eli ne i n E-R S: C O P D T otal 
Sc or e at W e ek 2 4 a n d 5 2  
•  
 
 
C CI
C CI
C CI


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208657 
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Objectives 
Endpoints 
Safety 
 
• To evaluate the safety of 
mepolizumab in 
participants with COPD 
• Incidence of AEs/SAEs including systemic 
reactions. 
• Incidence of adjudicated SAE reports and MACE 
events (CV death, non-fatal myocardial infarction, 
and non-fatal stroke) 
• Vital signs including blood pressure (BP), body 
temperature, pulse rate  
• ECG assessments 
• Mortality (all cause including respiratory and 
cardiovascular causes of death) 
• Presence of anti-drug antibodies (ADA) to 
mepolizumab 
• Hematological and clinical chemistry parameters 
Health Outcomes 
 
• To further evaluate the 
effect of mepolizumab 100 
mg SC on health care 
utilization. 
• Healthcare utilization for COPD including 
hospitalization, ED, and physician office/clinic 
visits 
Pharmacokinetics Sub-study: 
China and US only  
 
• To evaluate the PK of 
mepolizumab 100 mg in 
liquid formulation 
administered 
subcutaneously by SS in 
Chinese participants and to 
assess potential PK ethnic 
differences between non-
Asian participants in the US 
and Chinese participants in 
China 
• Plasma mepolizumab concentrations 
 
 
 
 


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1.1.2. 
Primary Estimand 
The primary estimand is the difference between mepolizumab 100 mg SC and placebo 
(both added to optimized standard of care) in the annualized rate of moderate/severe 
exacerbations in participants with COPD experiencing frequent exacerbations and 
characterized by eosinophil levels, regardless of IP discontinuation/interruption or 
changes in background medication/starting a prohibited medication, in the absence of 
COVID-19 pandemic related intercurrent events. 
 
The primary estimand is described by the following attributes: 
 
Population: Participants with COPD experiencing frequent exacerbations and 
characterized by eosinophil levels 
 
Treatment condition: Mepolizumab 100 mg SC vs. placebo (both as add-on treatment to 
optimized standard of care) 
 
Variable: Number of moderate or severe exacerbations 
 
Intercurrent events: The anticipated intercurrent events in this trial are discontinuation of 
interventional product (IP), interruption of 2 or more consecutive doses of IP, use of 
prohibited medications and change in background medication. 
A treatment policy strategy will be used to handle the intercurrent events of 
discontinuation of IP and interruption of 2 or more consecutive doses of IP when not 
associated with disruptions or restrictions (e.g. lockdown measures, social distancing) 
imposed due to the COVID-19 pandemic. Under this strategy exacerbations and time in 
study will be included in the analysis regardless of the intercurrent event. A hypothetical 
strategy will be used to handle these intercurrent events when they are known to be 
associated with disruptions or restrictions imposed due to the COVID-19 pandemic. 
A treatment policy strategy will be used to handle the intercurrent events of change in 
background medication and use of prohibited medications. 
 
Rationale for estimand: The use of a hypothetical strategy recognizes any effect on 
exacerbations due to discontinuation or interruption of 2 or more consecutive doses of IP 
associated with disruptions or restrictions imposed due to the COVID-19 pandemic, may 
not have occurred in the hypothetical scenario of the absence of the pandemic.  
 
 
 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
a Participants must have an eosinophil count of ≥300 cells/µL at Screening Visit 0 to proceed to 
Visit 1. They are also required to have a documented historical eosinophil count of ≥150 
cells/µL in the 12 months prior to Screening Visit 0. 
b Participants with no historical eosinophil counts of ≥150 cells/µL must have an eosinophil 
count ≥150 cells/µL at Screening Visit 1. 
c R = Randomization: Randomization criteria should be assessed at Week 0 (Visit 2) prior to 
randomization. 
d For participants enrolled in the study for 52 weeks, the Exit Visit will be at Week 52, 4 weeks 
after the last dose. 
e For participants receiving study treatment beyond 52 weeks, the Exit Visit will be at Week 104 
or aligned to the date the last randomized participant is scheduled to complete their Week 52 
Exit Visit, whichever is sooner, see Protocol Section 4.4. The Exit Visit will be 4 weeks after the 
last dose.  
Design 
Features 
This is a multi-center, randomized, placebo-controlled, double-blind, 
parallel group trial evaluating mepolizumab 100 mg compared with 
placebo given every 4 weeks as a liquid formulation in a pre-filled 
safety syringe through SC injection as an add-on to optimized 
maintenance COPD therapy in participants with COPD characterized by 
eosinophil levels 
Study participants will remain in the study for at least 52 weeks and up 
to a maximum of 104 weeks. All participants will be expected to 
complete at least 52 weeks of the study. The last randomized participant 
will be scheduled to complete only 52 weeks of the study.  More 
specifically, 


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Overview of Study Design and Key Features 
o For participants enrolled for 52 weeks, their Exit Visit will occur 
at Week 52, 4 weeks after the last scheduled dose of IP. 
o For participants enrolled for (or reconsented to) an extended 
treatment duration beyond 52 weeks, their Exit Visit will be at 
Week 104 or at a scheduled visit that occurs on or before the 
date the last randomized participant is scheduled to complete 
their Week 52 Exit Visit, whichever is sooner. The Exit Visit 
will occur 4 weeks after the participants last scheduled dose of 
IP. 
Study 
interventio
n 
Interventional product will be administered as a single SC injection 
given every 4 weeks at each study visit (except for the Exit Visit), 
beginning at the Randomization Visit (Visit 2).  
 
Participants are to continue on their baseline optimized COPD 
medications throughout the study. 
Study 
interventio
n 
Assignment 
Eligible participants will be randomized 1:1 to receive mepolizumab 
100 mg or placebo in accordance with a randomization schedule 
generated using a validated randomization software, separate 
randomization schedules will be created for each country. 
Blood 
Eosinophil 
Inclusion 
Criteria 
Participants must have a blood eosinophil count of 300 cells/l at 
Screening Visit 0 and a documented historical blood eosinophil count 
of 150 cells/l in the 12 months prior to Screening Visit 0 (or at 
Screening Visit 1). 
Off-
treatment 
data 
The protocol objective is to collect data over the full study period 
whether participants continue on IP or prematurely withdraw from IP.  
Unless otherwise specified, data from participants who agree to 
continue in the study after premature withdrawal from IP will be 
included in the analysis of efficacy endpoints. 
Interim 
Analysis 
No formal interim analyses of efficacy data are planned for this study. 
See Section 5 for details regarding blinded sample size evaluation. 
 
2. 
STATISTICAL HYPOTHESES  
This study is designed to test the superiority of mepolizumab 100 mg SC vs placebo. The 
treatment comparison of interest for the primary and secondary endpoints is 
mepolizumab 100 mg SC vs placebo in the modified Intent-to-Treat (mITT) population, 
the significance test will be considered statistically significant at the two-sided 5% alpha 
level (one-sided 2.5%). 


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2.1. 
Multiplicity Adjustment 
A hierarchical testing procedure will be used to provide strong control of Type I error for 
multiplicity arising from the primary and multiple secondary endpoints.  This will be 
carried out using a step-down closed testing procedure where inference for an endpoint in 
the predefined hierarchy will be dependent on statistical significance having been 
achieved for the previous endpoints in the hierarchy.  
For example, for the primary endpoint, mepolizumab will be compared to placebo at a 
two-sided α=0.05 (one-sided α=0.025).  The next endpoint in the hierarchy (i.e. the first 
secondary endpoint) will be tested only if the test for the primary endpoint is significant 
at the one-sided 2.5% level. Testing will continue down the hierarchy for the remaining 
endpoints in an equivalent manner only if the previous endpoint in the hierarchy achieves 
statistical significance. 
The hierarchy of the primary and secondary endpoints to be tested is as follows: 
1. Annualized rate of moderate/severe exacerbations (primary endpoint) 
2. Time to first moderate/severe exacerbation 
3. Proportion CAT score responders at Week 52 
4. Proportion of SGRQ total score responders at Week 52 
5. Proportion of E-RS: COPD responders at Week 52  
6. Annualized rate of exacerbations requiring ED and/or hospitalization 
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
All Participants 
Enrolled 
Population 
All participants for whom a record exists on the study 
database. 
Reasons for 
Screen Failures 
and Run-in 
Failures 
Modified Intent-
to-Treat 
Population 
(mITT) 
All randomized participants who receive at least one 
dose of trial medication.  
Participants will be analyzed by randomized 
treatment. 
Efficacy endpoints  
mITT Population 
excluding 
past/concurrent 
Asthma (mITT2) 
All participants in the mITT population with no 
evidence of a past history or concurrent diagnosis of 
asthma.  
Participants will be analyzed by randomized 
treatment. 
Primary and 
secondary efficacy 
endpoints 


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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Safety Population 
(Safety) 
All randomized participants who receive at least one 
dose of trial medication.  
Participants will be analyzed based on actual 
treatment received for more than 50% of treatment 
administrations.  
Safety endpoints 
Per-Protocol 
Population (PP) 
All participants in the mITT population not identified as 
protocol deviators with respect to criteria that are 
considered to impact the primary efficacy endpoint. 
The decision to exclude a participant from the PP 
Population will be made prior to the unblinding of 
treatment codes.  
Supplementary 
analysis of primary 
endpoint 
Pharmacokinetic 
(PK) 
All participants enrolled in the PK sub-study who 
received at least one dose of trial medication and for 
whom at least one pharmacokinetic sample was 
obtained, analyzed and was measurable. Population 
for the PK sub-study analysis 
Data will be reported according to actual treatment 
received for more than 50% of treatment 
administrations. 
Pharmacokinetics 
endpoints 
Extended 
Treatment 
Population  
All participants who receive at least one dose of trial 
medication and who consented to participate in the 
extended treatment period beyond 52 weeks. 
Participants within this population are enrolled for up 
to 104 weeks with variable duration. 
Selected Study 
Population, 
Efficacy, Safety 
summaries 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum, and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
The efficacy analyses will be based on the mITT/mITT2 population. Where available, 
data up to Week 104 will be summarized for the mITT/mITT2 Population; where 
specified, additional displays will present information separately for participants in the 


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Extended Treatment population. Extended Treatment population study population and 
efficacy displays will be summarized based on randomized treatment. Details of 
covariates are provided in Section 4.10.1. 
4.1.2. 
Baseline Definition 
For the majority of visit-based assessments the baseline value will be the last 
measurement collected prior to the first dose of interventional product. This will be the 
pre-dose assessment taken at Visit 2, or if missing the immediately preceding value if 
available, including from an unscheduled assessment.  (Where time is collected, an 
assessment is valid for use as baseline if the date and time is prior to or the same as the 
date and time of first dose.) 
For CAT and SGRQ assessments, the baseline value is defined as the last measurement 
taken prior to, or on same date as, first dose of interventional product.  
For blood eosinophils, the screening value is defined as the value from the blood sample 
taken at Screening Visit 0, this pre-dose value is aligned with the blood eosinophil levels 
required for inclusion into the study. If missing the next available value prior to the first 
dose of interventional product will be used, however values from the blood sample taken 
at Screening Visit 1 will not be included in the determination of the screening value. The 
baseline value will be the measurement defined as the screening value. 
For entry into the study, historical blood eosinophils recorded in the 12 months prior to 
Screening Visit 0 and aligned with the study inclusion criteria are required. For 
participants who do not have a documented historical blood eosinophil count prior to 
Screening Visit 0, the value from the blood sample taken at Screening Visit 1 is used.  
For data collected every evening using the electronic diary (eDiary), the baseline value 
will be determined as the average of the 7 days of diary card data collected from the week 
prior to first dose (i.e., data collected between Day -7 and Day -1 inclusive).  
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.1.3. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. No 
assessment windows are defined for visit based assessments. Detail of premature 
withdrawal and unscheduled visit assignments is found in Section 6.2.5. 
4.1.4. 
Study Completion 
The study is designed to collect data after premature discontinuation of treatment. 
Participants are considered to have completed the study if they meet the following criteria 
regardless of premature discontinuation of interventional product.  
 


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Participants enrolled for 52 Weeks 
A participant is considered to have completed the study if they continue to participate in 
the study until the Exit Visit at Week 52. 
Participants enrolled beyond 52 Weeks (or reconsented to continue beyond 52 
Weeks) 
A participant is considered to have completed the study if they continue to participate in 
the study until the earlier of: 
The Exit Visit at Week 104  
OR 
A scheduled visit that is on or immediately before the date of the Exit Visit at Week 52 of 
the last participant to have been randomized into the study.  
By study design, the duration of study will vary for the participants enrolled beyond 52 
Weeks (or reconsented to continue beyond 52 Weeks).  
 
4.2. 
Primary Endpoint Analyses 
4.2.1. 
Definition of Primary Endpoint/Estimand 
The primary endpoint is the annualized rate of moderate or severe exacerbations 
occurring during the study period.  The study is designed to continue collecting 
exacerbation data for participants who have prematurely discontinued from IP and remain 
in the study. 
For analysis, moderate exacerbations are defined as clinically significant exacerbations 
that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe 
exacerbations are defined per protocol as clinically significant exacerbations that require 
in-patient hospitalization (i.e., ≥24 hrs.) or result in death. The study inclusion criteria 
required at least 2 moderate COPD exacerbations treated with systemic corticosteroids 
(intramuscular (IM), intravenous, or oral) with or without antibiotics or at least one 
severe exacerbation in the 12 months prior to Screening Visit 1. 
Moderate and severe exacerbations occurring from the start of interventional product (IP) 
will be included in the primary analysis regardless of whether the exacerbation occurs 
after a participant prematurely discontinues from IP.  For participants who complete the 
study (Section 4.1.4), all moderate/severe exacerbations occurring up to study completion 
will be included in the primary analysis. For participants who withdraw early from the 
study all moderate/severe exacerbations occurring up to the date of study withdrawal will 
be included in the primary analysis, these participants will be considered to have missing 
data from the date of study withdrawal up to their planned study completion date. 


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For all summaries and analyses, exacerbations occurring within 7 days of each other 
within a given participant will be handled as a continuation of the same exacerbation, 
assigned to the greatest severity. 
The primary estimand is the difference between mepolizumab 100 mg SC and placebo 
(both added to optimized standard of care) in the annualized rate of moderate/severe 
exacerbations in participants with COPD experiencing frequent exacerbations and 
characterized by eosinophil levels, regardless of IP discontinuation/interruption or 
changes in background medication/starting a prohibited medication, in the absence of 
COVID-19 pandemic related intercurrent events. 
 
The primary estimand is described by the following attributes: 
 
Population: Participants with COPD experiencing frequent exacerbations and 
characterized by eosinophil levels 
 
Treatment condition: Mepolizumab 100 mg SC vs. placebo (both as add-on treatment to 
optimized standard of care) 
 
Variable: Number of moderate or severe exacerbations 
 
Summary Measure: The summary measure of treatment effect will be the ratio of the 
frequency of exacerbations in the mepolizumab 100 mg treatment arm to the frequency in 
the placebo arm.  Exacerbation rates will be expressed as an annualized exacerbation rate. 
 
Intercurrent events: The anticipated intercurrent events for this trial are discontinuation of 
IP, interruption of 2 or more consecutive doses of IP, use of prohibited medications and 
change in background medication. 
 
A treatment policy strategy will be used to handle the intercurrent events of 
discontinuation of IP and interruption of 2 or more consecutive doses of IP when not 
associated with disruptions or restrictions (e.g. lockdown measures, social distancing) 
imposed due to the COVID-19 pandemic, under this strategy exacerbations and time in 
study will be included in the analysis regardless of the intercurrent event.  A hypothetical 
strategy will be used to handle these intercurrent events when they are known to be 
associated with disruptions or restrictions imposed due to the COVID-19 pandemic. 
Under this strategy exacerbations, and the period of time in study occurring after the 
intercurrent event, will be set to missing and handled as missing data. 
 
A treatment policy strategy will be used to handle the intercurrent events of change in 
background therapy and use of prohibited medications. 
 
Rationale for estimand: The use of a hypothetical strategy recognizes any effect on 
exacerbations due to discontinuation /interruption of 2 or more consecutive doses of IP 
associated with disruptions or restrictions imposed due to the COVID-19 pandemic, may 
not have occurred in the hypothetical scenario of the absence of the pandemic.  
 


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4.2.2. 
Main analytical approach 
Statistical Methodology Specification 
Endpoint / Variables 
Annualized rate of moderate or severe exacerbations (mITT, mITT2 and Per Protocol). 
Model Specification 
Data from previous studies show the numbers of moderate/severe exacerbations follow a 
negative 
binomial distribution. The primary analysis of the annualized rate of moderate/severe 
exacerbations will use a negative binomial model, including both on-treatment and, where 
available, off-treatment exacerbation data.  
 
The analysis model will include covariates as shown below and an offset variable of loge (length 
of time in study) which reflects the period of time in the study for which exacerbation data has 
been recorded for inclusion in the analysis model.  Missing data will be considered as missing at 
random (MAR). 
Fixed Categorical:  
Treatment group, Geographic Region, Smoking Status 
Fixed Continuous:  
Baseline disease severity (as % predicted post-bronchodilator 
FEV1), number of moderate/severe exacerbations in previous year 
(≤2, 3, ≥4 as ordinal) 
• 
Participants with missing covariate information will be excluded from the analysis. 
Model Checking & Diagnostics 
• Missing data is assumed missing at random. Departures from this assumption will be tested 
for the primary endpoint (see Section 4.2.3). 
• Models will be checked for issues with convergence. 
Model Results Presentation 
• The model estimated mean annualized rate of exacerbations will be calculated using the 
observed marginal distributions of the study population covariates by inclusion of the OM 
(obsmargins) option in the LSMEANS statement of the GENMOD procedure.  
The estimated mean annualized rate of moderate/severe exacerbations for each treatment 
group and the rate ratio for mepolizumab vs. placebo with 95% confidence intervals and 
associated p-values will be presented in a table and associated figure. 
Subgroup Analyses 
Separate exploratory subgroup analyses of the primary endpoint (mITT) will be carried out as 
detailed in Section 4.10.1. 
 
4.2.3. 
Sensitivity analyses 
Sensitivity Analyses 
Sensitivity Analysis for assumptions regarding missing data 
• Missing Data Imputation:  


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The negative binomial model assumes missing data is missing at random.  To assess the 
robustness of the primary estimand to departures from this assumption, a sensitivity analysis 
in the mITT population will be performed where missing data will be imputed.   
 
Participants who withdrew from the study early will have missing data imputed for the period 
of time between withdrawal from the study and their scheduled end of study. Missing data 
for these subjects will be imputed using observed off-treatment data collected from 
randomized participants (prior to occurrence of intercurrent events of IP discontinuation or 
interruption of 2 or more consecutive doses of IP associated with the COVID-19 pandemic) 
who continued in the study following discontinuation of randomized treatment.   
Participants who have missing data due to occurrence of intercurrent events of IP 
discontinuation or interruption of 2 or more consecutive doses of IP associated with the 
COVID-19 pandemic will have missing data imputed for the period of time between 
occurrence of the intercurrent event and their scheduled end of study. Missing data after the 
occurrence of the intercurrent event will be imputed using both on-treatment and off-
treatment data collected from randomized participants (on-treatment data prior to 
occurrence of intercurrent events associated with the COVID-19 pandemic, off treatment 
data from those not experiencing an occurrence of intercurrent events associated with the 
COVID-19 pandemic). 
 
Missing data is imputed multiple times for each subject based on a combination of their 
respective covariates and the observed data. The imputed data is combined with the 
observed exacerbations and the data is analyzed as for the primary endpoint. This analysis 
is repeated multiple times and the results combined across imputations using Rubin’s 
formulae [Rubin, 1987] as implemented in PROC MIANALYZE in SAS. 
• Tipping Point:  
A tipping point sensitivity analysis will be performed for the primary endpoint of annualized 
rate of moderate/severe exacerbations in the mITT population. This will explore the impact 
of missing data by using differing assumptions regarding the exacerbation rate in 
participants with missing data. Participants who withdrew from the study or experienced 
intercurrent events of IP discontinuation or interruption of 2 of more consecutive doses of IP 
associated with the COVID-19 pandemic will have missing data imputed for the period of 
time from study withdrawal/occurrence of event to their scheduled end of study. The missing 
data will be imputed based on a range of increases in exacerbation rates relative to the 
estimated rates obtained within each arm under the MAR assumption. The imputed 
exacerbation rates will vary independently for the mepolizumab and placebo arms and will 
include scenarios where participants with missing data in the mepolizumab arm have worse 
outcomes than participants in the placebo arm. As before, multiple imputation methods will 
be used, and results will be combined across imputations using Rubin’s method. The 
analysis results will be used to explore conditions under which there is no evidence of a 
treatment effect and clinical judgment will be applied as to the plausibility of the associated 
assumptions. 
 
• 
Site 239718: 
A sensitivity analysis will be conducted excluding the three subjects randomized at Site 
239718. This will explore the impact of patients from this site on the primary estimand. The 
analysis will otherwise be carried out as outlined within Section 4.2.2. 


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4.2.4. 
Additional estimands 
Additional Estimands 
Additional (supplementary) estimands for the primary endpoint will be presented for the mITT 
population whereby a treatment policy strategy will be used for all intercurrent events whether or 
not associated to the COVID-19 pandemic.  
 
Analysis will be as for the primary estimand and missing data due to study withdrawal will be 
handled as missing at random. In a separate analysis missing data will be imputed using 
observed off-treatment data collected from randomized participants who continued in the study 
following discontinuation of randomized treatment. 
 
These additional estimands estimate the difference between mepolizumab 100 mg SC and 
placebo (both added to optimized standard of care) in the annualized rate of moderate/severe 
exacerbations in participants with COPD experiencing frequent exacerbations and characterized 
by eosinophil levels, regardless of IP discontinuation/interruption, changes in background 
medication/starting a prohibited medication, or the impact of the COVID-19 pandemic. 
 
4.2.5. 
Exploratory Modelling 
The role of blood eosinophil counts on the effectiveness of mepolizumab with respect to 
the number of moderate/severe exacerbations will be investigated. The number of 
moderate/severe exacerbations will be predicted at each level of the screening loge blood 
eosinophil count based on a model including a screening loge blood eosinophil count 
main effect term and an interaction with treatment term. 
The best fitting form of the interaction (i.e. which maximizes the likelihood function) 
between treatment group and screening loge blood eosinophil count will also be explored. 
4.3. 
Secondary Endpoint(s) Analyses 
For all secondary endpoints the primary population of interest, the treatment condition, 
and handling of intercurrent events will be as described for the primary estimand (Section 
4.2.1).  Unless otherwise specified all analyses will include data regardless of 
discontinuation of interventional product as has been detailed for the primary endpoint. 
4.3.1. 
Time to first moderate/severe exacerbation 
4.3.1.1. 
Definition of Endpoint 
The time to first moderate/severe exacerbation will be determined as the number of days 
from the date of first dose to the date of the first moderate or severe exacerbation: 
Time to first exacerbation = date of first exacerbation – date of first dose +1 
Partial dates related to exacerbations will be queried, in the event the full start date cannot 
be determined, imputation as described in Section 6.2.7 will be applied. 


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The variable of interest is the time to first moderate/severe exacerbation.  Participants 
who complete the study without experiencing a moderate/severe exacerbation will be 
censored at their scheduled end of the study treatment period (see Section 6.2.2.1). 
Participants who withdrew early from the study or experienced an intercurrent event of IP 
discontinuation or interruption of 2 or more consecutive doses of IP associated with the 
COVID-19 pandemic before experiencing an exacerbation will be censored at the earliest 
of the date of study withdrawal and the start date of COVID-19 pandemic associated 
intercurrent event of IP discontinuation or interruption of 2 or more consecutive doses of 
IP. 
The summary measure of treatment effect will be the hazard ratio, the ratio of hazards 
corresponding to treatment with mepolizumab compared with placebo. For this endpoint 
the hazard represents the probability of moderate/severe exacerbation for a participant at 
a given point in time following first dose of interventional product, given the participant 
has not experienced the event prior to that time. Data will be presented up to week 104 
for this endpoint. 
4.3.1.2. 
Main Analytical Approach 
Statistical Methodology Specification 
Endpoint / Variables 
Time to first moderate/severe exacerbation (mITT and mITT2) 
Model Specification 
• Analysis of time to first moderate/severe exacerbation will use a Cox proportional hazards 
model with covariates as shown. Missing values will be considered as censored at random 
(non-informative censoring). 
Fixed Categorical:  
Treatment group, smoking status, geographic region 
Fixed Continuous:  
Baseline disease severity (as % predicted post-bronchodilator 
FEV1), number of moderate/severe exacerbations in previous year 
(≤2, 3, ≥4 as ordinal) 
• 
Participants with missing covariate information will be excluded from the analysis. 
Model Checking & Diagnostics 
A log(-log(survival)) plot by treatment group will be used to assess the assumption of 
proportional hazards. 
Model Results Presentation 
• The number of participants with an event, the number censored due to study withdrawal, 
due to an intercurrent event associated to the COVID-19 pandemic, and at study completion 
will be presented by treatment arm. 
• The hazard ratio with corresponding 95% CI and p-value from the Cox proportional hazards 
model will be presented. 
A summary and graph of the Kaplan-Meier estimate of the cumulative proportion of participants 
with a moderate/severe exacerbation within each treatment arm over time will be produced. 


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Subgroup Analyses 
Separate exploratory subgroup analyses will be carried out  as outlined in Section 4.10.1. 
 
4.3.2. 
CAT Score Responders 
4.3.2.1. 
Definition of Endpoint 
The COPD Assessment Test (CAT) is an 8-item questionnaire used to measure the health 
status of patients with COPD, participants rate their experience on a 6-point scale, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-
40. Higher scores indicate greater disease impact. 
The variable of interest is the proportion of CAT score responders at Week 52.  A 
participant is considered a responder if they have a 2-point or more improvement 
(reduction) in CAT Score from baseline. Participants who withdrew from study prior to 
Week 52 will be included in the analysis as a non-responder. 
Participants who experienced an intercurrent event of IP discontinuation or interruption 
of 2 or more consecutive doses of IP associated with the COVID-19 pandemic will be 
considered as having missing data from the time of the event. For these participants 
missing data will be imputed using a MAR assumption based on the observed on- and 
off-treatment scores recorded by randomized participants (prior to occurrence of any 
intercurrent events of IP discontinuation or interruption of 2 or more consecutive doses of 
IP associated with the COVID-19 pandemic), the response status of these participants 
will be determined based on the imputed value.  
Imputed data will be combined with the observed data and analyzed multiple times using 
logistic regression analysis. The results of these analyses will be combined using Rubin’s 
rule. 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder at Week 52 in the mepolizumab arm 
compared with placebo.  
4.3.2.2. 
Main Analytical Approach 
Descriptive statistics by visit will be presented for the mITT population up to Week 104, 
regardless of treatment discontinuation.  Responders will be summarized by visit up to 
Week 52 for the mITT and mITT2 populations, and by visit up to Week 104 for the 
Extended Treatment population. 
Statistical Methodology Specification 
Model Specification 
• A logistic regression model will be used to compare the proportion of responders in the 
mepolizumab arm compared to placebo for the mITT and mITT2 populations. 
• The analysis model will include the following terms: 


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Fixed Categorical:  
Treatment group, smoking status, geographic region 
Fixed Continuous:  
Baseline score 
• 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
• Models will be checked for issues with convergence. 
Model Results Presentation 
• The number and percentage of participants identified as responders, non-responders and 
the number with missing data imputed due to experiencing a COVID-19 pandemic related 
intercurrent event of IP discontinuation or interruption of 2 or more consecutive doses of IP 
prior to Week 52 will be displayed by treatment group, the non-responder group will be 
further categorized to display the number of participants withdrawn early from the study 
before Week 52 and the number with missing visit data. 
• The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression models will be displayed. 
• A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups 
will be provided by visit. 
Subgroup Analyses 
Separate exploratory subgroup analyses will be carried out as outlined in Section 4.10.1. 
4.3.3. 
SGRQ total score Responders 
4.3.3.1. 
Definition of Endpoint 
The St George’s Respiratory Questionnaire for COPD (SGRQ-C) is a 40-item 
questionnaire.  A Total score and three component scores, a Symptoms score, Activity 
score and Impacts score will be calculated based on the scoring algorithm detailed in the 
SGRQ-C Manual Version 1.3.  The total score is expressed as a percentage of overall 
impairment with 100 representing the worst possible health status and 0 the best possible 
health status. Higher scores indicate greater impairment of health.   
 
The variable of interest is the proportion of SGRQ total score responders at Week 52. A 
participant is considered a responder if they have a 4-point or more improvement 
(reduction) in SGRQ total score from baseline. Participants who withdrew from study 
prior to Week 52 will be included in the analysis as a non-responder.  
 
Participants who experienced an intercurrent event of IP discontinuation or interruption 
of 2 or more consecutive doses of IP associated with the COVID-19 pandemic will be 
considered as having missing data from the time of the event.  Missing data will be 
imputed as described in Section 4.3.2.1.  
 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder at Week 52 in the mepolizumab arm 
compared with placebo. 


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4.3.3.2. 
Main Analytical Approach  
Descriptive statistics and summaries of responders for the SGRQ total score will be 
presented as detailed in Section 4.3.2.2.   SGRQ total score responders will be analyzed 
as described in Section 4.3.2.2. Separate exploratory subgroup analyses will be carried 
out as outlined in Section 4.10.1.  
4.3.4. 
E-RS: COPD total score Responders 
4.3.4.1. 
Definition of Endpoint 
The Evaluating Respiratory Symptoms in COPD (E-RS: COPD) consists of 11 items 
from the 14 item EXACT instrument (completed each evening using an eDiary). E-RS: 
COPD is intended to capture information related to the respiratory symptoms of COPD, 
i.e., breathlessness, cough, sputum production, chest congestion, and chest tightness.  The 
E-RS: COPD has a scoring range of 0-40, higher scores indicate more severe symptoms.  
Three subscales of the E-RS: COPD are used to describe different symptoms 
(breathlessness, cough and sputum, and chest symptoms). 
 
Daily data will be slotted to baseline and 4-week periods relative to the first dose of IP as 
defined in Section 6.2.5.4. 
The variable of interest is the proportion of E-RS: COPD responders at Week 52, using 
data from the 4-week period prior to Week 52 (Weeks 49-52).  A participant is 
considered a responder if they have a 2-point or more improvement (reduction) in their 
average E-RS: COPD total score during a 4-week period compared to baseline (E-RS™: 
COPD User Manual, 2016). Participants who withdrew from study prior to the start of 
the Weeks 49-52 time-period will be included in the analysis as a non-responder.  
Participants who experienced an intercurrent event of IP discontinuation or interruption 
of 2 or more consecutive doses of IP associated with the COVID-19 pandemic prior to 
Weeks 49-52 will be considered as having missing data from the time of the intercurrent 
event.  Missing data will be imputed based on the average 4-weekly scores as described 
in Section 4.3.2.1.  
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder at Weeks 49-52 in the mepolizumab arm 
compared with placebo. 
4.3.4.2. 
Main Analytical Approach 
Descriptive statistics and summaries of responders will be presented as detailed in 
Section 4.3.2.2. with the exception of the responder summary for the Extended Treatment 
Population.  E-RS: COPD total score responders will be analyzed as described in Section 
4.3.2.2.  


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4.3.5. 
Annualized Rate of Exacerbations Requiring ED visit and/or 
hospitalization 
4.3.5.1. 
Definition of Endpoint 
Frequency of exacerbations requiring ED visit and/or hospitalization over the study 
treatment period (up to 104 weeks) represented by an annualized rate, these exacerbations 
are relatively infrequent.   Details regarding the estimand strategy for this endpoint are as 
described in Section 4.2.1. 
4.3.5.2. 
Main Analytical Approach 
The annualized rate of exacerbations requiring ED visit and/or hospitalization will be 
analyzed as described in Section 4.2.2. 
4.4. 
Other Efficacy Analyses 
The population, treatment condition and handling of intercurrent events as described for 
the primary estimand (Section 4.2.1) apply to all efficacy analyses unless otherwise 
specified. 
4.4.1. 
Time to first exacerbation (ED/Hospitalization, Severe) 
4.4.1.1. 
Definition of Endpoint 
Time to first exacerbation requiring ED and/or hospitalization and time to first severe 
exacerbation will be determined as detailed in Section 4.3.1.1. 
4.4.1.2. 
Main Analytical Approach 
The approach to analysis will be as described in Section 4.3.1.2. 
4.4.2. 
Annualized Rate of Exacerbations (Severe, Moderate/Severe By 
Type of Treatment Required) 
4.4.2.1. 
Definition of Endpoint 
Frequency of severe exacerbations and frequency of moderate/severe exacerbations by 
type of treatment required (corticosteroids alone, antibiotics alone or corticosteroids and 
antibiotics) over the study treatment period (up to 104 weeks) represented by an 
annualized rate as detailed in Section 4.2.1. 
4.4.2.2. 
Main Analytical Approach 
The approach to analysis will be as described in Section 4.2.2. 


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4.4.3. 
Daily eDiary data (Percentage of rescue medication free days, 
Percentage of nights with no awakenings, Mean number of 
occasions of rescue medication use/day) 
4.4.3.1. 
Definition of Endpoint 
Daily data collected via an eDiary will be slotted to baseline and 4-week periods relative 
to the first dose of IP as defined in Section 6.2.5.4. 
The percentage of rescue medication free days will be calculated at baseline and for each 
4-week period as: 
(100 x [No. rescue medication free days /No. days with non-missing data]). 
 
The percentage of nights with no awakenings due to COPD symptoms will be calculated 
at baseline and for each 4-week period as: 
(100 x [No. nights with no awakenings /No. days with non-missing data]). 
 
The mean number of occasions of rescue medication use per day will be calculated at 
baseline and for each 4-week period as: 
(Total occasions of rescue medication use/No. days with non-missing data). 
 
The summary measure of treatment effect for each endpoint will be the difference 
between mepolizumab and placebo in mean change from baseline at Weeks 49-52. 
4.4.3.2. 
Main Analytical Approach 
Statistical Methodology Specification 
Endpoint / Variables 
Percentage of rescue medication free days 
Percentage of nights with no awakenings due to COPD symptoms 
Mean number of occasions of rescue medication use per day 
Model Specification 
• This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including data up to Weeks 49-52 and the following terms: 
Fixed Categorical:  
Treatment group, smoking status, geographic region, Time period 
Fixed Continuous:  
Baseline value 
Repeated:  
Time period 
Interaction Terms:  
Time period by baseline, Time period by treatment group. 
• 
Participants with missing covariate information will be excluded from the analysis 
An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the 
REPEATED line. In the event that this model fails to converge, alternative correlation structures 
may be considered. 


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Model Checking & Diagnostics 
• The Kenward-Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
Model Results Presentation 
• The estimated means for each treatment group will be calculated from the model using the 
observed marginal distributions of the sample covariates (OM option in LSMEANS 
statement). 
• Model-estimates of the absolute and change from baseline values will be presented by 
treatment group. Estimated treatment differences (Mepolizumab-Placebo) with 
corresponding 95% CIs and p-values will also be presented. 
 
4.4.4. 
Change from baseline (Pre-bronchodilator FEV1, FVC, CAT Score, 
SGRQ Total Score, E-RS: COPD Total Score) 
4.4.4.1. 
Definition of Endpoint 
Change from baseline pre-bronchodilator FEV1 at Week 52 
Change from baseline pre-bronchodilator FVC at Week 52 
Change from baseline CAT score at Weeks 24 and 52 
Change from baseline SGRQ Total score at Weeks 24 and 52 
Change from baseline ERS: COPD Total score at Weeks 21-24 and Weeks 49-52 
 
For change from baseline CAT, SGRQ and E-RS: COPD: Participants who experienced 
an intercurrent event of IP discontinuation or interruption of 2 or more consecutive doses 
of IP associated with the COVID-19 pandemic will be considered as having missing data 
from the time of the event.  Missing data will be imputed as described in Section 4.3.2.1.  
 
The summary measure of treatment effect for each endpoint will be the difference 
between mepolizumab and placebo in mean change from baseline at the respective 
timepoints. 
 


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4.4.4.2. 
Main Analytical Approach 
Statistical Methodology Specification 
Endpoint / Variables 
Change from baseline pre-bronchodilator FEV1 at Week 52 
Change from baseline pre-bronchodilator FVC at Week 52 
Change from baseline CAT score at Week 24 and 52 
Change from baseline SGRQ total score at Week 24 and 52 
Change from baseline E-RS: COPD score at Weeks 21-24 and Weeks 49-52 
Model Specification 
• Endpoints will be analyzed using a mixed model repeated measures (MMRM) analysis 
including data up to Week 52/Weeks 49-52 and the following terms: 
Fixed Categorical:  
Treatment group, smoking status, geographic region, Visit/Time 
Period 
Fixed Continuous:  
Baseline value 
Repeated:  
Visit1/Time Period 
Interaction Terms:  
Visit1/Time Period by baseline, visit/time period by treatment group. 
Participants with missing covariate information will be excluded from the analysis 
1. FEV1 and FVC recorded at Baseline, Week 24 and Week 52 only. 
An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on the 
REPEATED line. In the event that this model fails to converge, alternative correlation structures 
may be considered. 
Model Checking & Diagnostics 
• The Kenward- Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
Model Results Presentation 
• The estimated means for each treatment group will be calculated from the model using the 
observed marginal distributions of the sample covariates (OM option in LSMEANS 
statement). 
• Model-estimates of the absolute and change from baseline values will be presented by 
treatment group. Estimated treatment differences (Mepolizumab-Placebo) with 
corresponding 95% CIs and p-values will also be presented. 
Subgroup Analyses 
Separate exploratory subgroup analyses for the change from baseline SGRQ total score will be 
carried out as outlined in Section 4.10.1. 
 


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4.4.5. 
Responders (CAT, SGRQ and E-RS: COPD Responders at Week 
24, E-RS: COPD Subscale Responders at Weeks 21-24 and 49-52) 
4.4.5.1. 
Definition of Endpoint 
CAT score responders at Week 24: defined as a 2-point or more improvement 
(reduction) in CAT score from baseline. 
SGRQ total score responder at Week 24: defined as a 4-point or more improvement 
(reduction) in SGRQ total score from baseline. 
E-RS: COPD responder at Weeks 21-24: defined as a 2-point or more improvement 
(reduction) in average E-RS: COPD score from baseline. 
E-RS: COPD Breathlessness Sub-Scale responder at Weeks 21-24 and Weeks 49-52: 
defined as a 1-point or more improvement (reduction) in average E-RS: COPD score 
from baseline. 
E-RS: COPD Cough and Sputum Sub-Scale responder at Weeks 21-24 and Weeks 
49-52: defined as a 0.7-point or more improvement (reduction) in average E-RS: 
COPD score from baseline. 
E-RS: COPD Chest Symptoms Sub-Scale responder at Weeks 21-24 and Weeks 49-
52: defined as a 0.7-point or more improvement (reduction) in average E-RS: COPD 
score from baseline. 
4.4.5.2. 
Main Analytical Approach 
Approach to analysis will be as described in Section 4.3.2. 
4.4.6. 
Patient and Clinician Response to Therapy 
4.4.6.1. 
Patient and clinician-rated response to therapy  
Patient-rated and clinician-rated response to therapy are assessed separately.  For each, a 
seven-point scale score is used with the following definitions: 1 = significantly improved; 
2 = moderately improved; 3 = mildly improved; 4 = no change; 5 = mildly worse; 6 = 
moderately worse; and 7 = significantly worse. 
Patient-rated and clinician-rated response to therapy will be summarized by visit up to 
Week 104. Data will be included in the summaries regardless of treatment 
discontinuation or occurrence of any other intercurrent events. 
4.4.6.2. 
Patient’s Global Rating of COPD 
The Global Rating of COPD Severity is a single global question that asks participants to 
rate their severity of COPD on a four- point scale (mild, moderate, severe, very severe).  
The Global Rating of Change in COPD question is also completed by participants with 
response options being on a 7-point Likert scale ranging from much better to much 
worse. 


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Data will be summarized up to Week 104, and regardless of treatment discontinuation or 
occurrence of any other intercurrent events.  
4.4.7. 
Healthcare Utilization 
The following data will be collected regarding unscheduled use of health care resources: 
• Number of Home Visits during Day and Night  
• Number of Emergency Room Visits 
• Inpatient days in General Ward and Intensive Care 
• Number of office/practice visits 
• Number of urgent care/outpatient visits  
Healthcare utilization associated with an exacerbation will be summarized up to Week 52 
only, and regardless of treatment discontinuation or occurrence of any other intercurrent 
events. 
4.4.7.1. 
EuroQol questionnaire (EQ-5D-3L) 
The EQ-5D-3L is a two-part self-assessment questionnaire.  The first part consists of five 
items covering five dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression).  Each dimension is measured by a three-point Likert scale (no 
problems, some problems and extreme problems). The second part is a vertical response 
scale (EQ-VAS) that has endpoints labelled “best imaginable health state” and “worst 
imaginable health state” anchored at 100 and 0, respectively.  
A participant is classified into one of 243 distinct health states (each being referred to by 
a 5-digitcode based on the responses to each dimension in the descriptive system, e.g., 
11111 or 33333). EQ-5D-3L health states are converted to a single summary index by 
applying a formula that essentially attaches weights to each of the levels in each 
dimension. The formula is based on the valuation of EQ-5D health states from general 
population samples. 
The EQ-5D-3L health state is converted to a health state value, using the value set for the 
United Kingdom as described in [Dolan, 1997]. EQ-5D-3L health state values summarize 
how good or bad health problems are on a scale anchored at 1 (full health) and 0 (state 
equivalent to dead). Health states considered worse than dead are given values <0.  
Valid non-missing responses are required to all questions for a health state value to be 
assigned, if there is a missing or ambiguous response in any dimension the health state 
value will be set to missing. 
Both parts of the EQ-5D-3L questionnaire will be summarized by visit up to Week 104. 
Data will be included in summaries regardless of treatment discontinuation or occurrence 
of any other intercurrent events. 


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4.5. 
Safety Analyses 
The safety analyses will be based on the Safety population. Data up to Week 104 will be 
summarized for the Safety Population; where specified, additional displays will present 
information separately for participants enrolled in the study for 52 weeks only and for 
those in the Extended Treatment population. Extended Treatment population safety 
displays will be summarized based on actual treatment received for more than 50% of 
administrations. Data separated by time of onset (before and after Week 52) will be 
summarized for the Safety population where specified. 
4.5.1. 
Extent of Exposure 
IP is administered approximately every 4 weeks and each dose viewed as providing 
therapeutic coverage for 4 weeks (28 days). Duration of exposure in months is calculated 
based on the therapeutic coverage as follows: 
Duration of Exposure (months) = (IP Stop Date – IP Start Date + 29) *12/365.25 
Patient years exposure is calculated as follows: 
Patient Years Exposure = (IP Stop Date – IP Start Date + 29)/365.25 
If the IP start date is missing and there is evidence the participant received at least one 
dose of IP, the IP start date will be taken to be the date of randomization. 
Randomized participants with no evidence of receiving at least one dose of IP will be 
shown as having zero months of exposure. 
Exposure will be summarized by treatment arm for all subjects in the safety population, 
for participants enrolled for 52 weeks only and for those in the Extended Treatment 
population. A listing of exposure data will also be produced. 
4.5.2. 
Adverse Events 
Summaries of adverse events (AEs), serious adverse events (SAEs) and other significant 
AEs will be based on GSK Core Data Standards. Summaries for the Safety Population 
will include AEs experienced up to Week 104. For on-treatment AEs, SAEs, common 
AEs and AESIs, separate displays will be produced for participants enrolled for 52 weeks 
only and for those in the Extended Treatment Population.  Summaries of AEs, SAEs and 
AESIs will be produced by time of onset (before and after Week 52) where specified. 
Where applicable, exposure-adjusted rates will be included in summaries. 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary), with the maximum severity of each AE determined by the 
investigator (as mild, moderate, or severe). Unless otherwise specified, summaries are 
presented in descending order of frequency by system organ class and preferred term. 
An overview summary of AEs will be generated, including counts and percentages of 
participants with any AE, AEs related to study treatment, AEs leading to permanent 


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discontinuation of study treatment, AEs leading to withdrawal from the study, SAEs, 
SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study treatment.  
Adverse events will be determined to be pre, on or post-treatment as described in Section 
6.2.3.4. The number and percentage of participants experiencing AEs during the on-
treatment and post-treatment periods will be summarized separately. Additionally, 
summaries of the number and percentage of participants with any on-treatment AEs by 
maximum severity will be produced. If an adverse event severity is missing, the severity 
will be populated as ‘UNKNOWN’.  
A separate summary will be provided for drug-related AEs. The summary will include 
events with the relationship to study intervention of ‘Yes’ or missing. On-treatment drug-
related AEs will also be reported by maximum severity.  
Summaries of SAEs, fatal and non-fatal SAEs, common AES defined as ≥3% (prior to 
rounding), AEs leading to discontinuation of study treatment, AEs leading to withdrawal 
from study, AEs reported on the day of dosing, and AEs by highest post-baseline anti-
drug antibody result will be reported separately.  
Adverse events of pneumonia will be summarized, these will be identified through 
matching of collected adverse event preferred terms with those from the Infective 
Pneumonia SMQ (narrow terms) prior to unblinding based on the latest version of the 
MedDRA dictionary available at the time of database lock for this study. 
4.5.2.1. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are adverse events which are to be closely 
monitored as the development of mepolizumab progresses. AESIs in the mepolizumab 
clinical development program are described in the mepolizumab BRMP/DRMP [GSK 
Document Number; 2020N436792]. The methods by which these events will be 
identified within this study reporting are detailed in Section 6.4. 
 
AESIs of anaphylaxis reactions, systemic reactions, and local injection site reactions are 
collected via targeted eCRF. The AESIs of potential opportunistic infections, 
malignancies, serious CVT events and serious ischemic events will be identified from a 
list of relevant preferred terms maintained within a project level reference dataset; created 
based on the latest version of the MedDRA dictionary available at the time of database 
lock for this study.  
 
Separate summary tables showing the number and percent of participants with each type 
of AESI, broken down by preferred term will be created. These summaries will be 
reported as part of the standard AE/SAE tables for the AESIs of infections, serious 
infections, neoplasms, cardiac disorders and serious cardiac disorders.  
 
The relative risk and risk difference of each AESI between mepolizumab and placebo 
will be presented with 95% confidence intervals. A forest plot displaying the relative risk 
with 95% CI will also be produced. 
 


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For each AESI a profile summary table will be produced containing information on event 
characteristics including, but not be limited to, the number of participants with the AESI, 
the number of occurrences of the AESI, the number of participants with a serious event or 
a drug related event, maximum severity, outcome and action taken. Separate listings will 
be provided of participants with systemic reactions identified by the investigator as 
meeting the criteria for anaphylaxis, systemic reactions categorized as allergic (type I 
hypersensitivity), systemic reactions categorized as other, and all other AESIs. 
 
4.5.2.2. 
Adjudication of Adverse Events and MACE 
External adjudication of all serious cases will be completed in a blinded manner by case-
based adjudication, with classification of primary cause of death for fatal cases or a 
classification of the primary event in the non-fatal cases. 
For all cases with a fatal SAE, the Clinical Endpoint Committee (CEC) members will 
indicate the primary cause of death. Additionally, the CEC members will determine if the 
death is associated with the participant’s known COPD. 
For all non-fatal SAE cases, the CEC members will be asked to categorize the primary 
SAE. If there is more than one event for a patient in the same SAE report, the primary 
event will be the adverse event of greatest medical significance. 
The categories will be as follows: 
• Cardiovascular (sudden death (for fatal events only), myocardial 
infarction/ischemic heart disease, congestive heart failure, stroke or other 
cardiovascular cause) 
o Stroke is further categorized as hemorrhagic, thromboembolic or 
indeterminate 
• Respiratory (COPD exacerbation with or without evidence of pneumonia, 
pneumonia/respiratory tract infection without COPD exacerbation, pulmonary 
embolism, other respiratory cause) 
• Cancer (lung, breast, colorectal, unknown primary, other) 
• Other 
• Unknown (inadequate information or indeterminate). 
Adjudication of all MACE (cardiovascular death, non-fatal acute MI, non-fatal acute 
stroke) will be completed by event-based adjudication in a blinded manner. MACE will 
be adjudicated based on criteria given in the CEC Charter Version3. Serious and 
nonserious events potentially representing acute MI and acute stroke will be identified for 
adjudication as events with a PT matching the list of PTs in pre-selected MedDRA 
SMQs. 
Myocardial infarctions will be classified as: 
• ST segment elevation myocardial infarction (STEMI) 
• Non-ST segment elevation myocardial infarction (NSTEMI) 
• Myocardial infarction, type (i.e., STEMI or NSTEMI) unknown 


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Strokes will be classified as intracerebral hemorrhage, subarachnoid hemorrhage, 
ischaemic (non-hemorrhagic) or undetermined. Events considered to not meet the charter 
definition of stroke but consistent with extra-axial hemorrhage will be classified as 
subdural, extradural or other.  
All fatal events will be reviewed for adjudication of MACE component cardiovascular 
death.  Cardiovascular deaths will be classified as acute MI (with sub-classifications as 
above), sudden cardiac death, heart failure, stroke (with sub-classifications as for stroke 
events above), cardiovascular procedure (with sub-classifications of PCI, CABG or 
other), cardiovascular hemorrhage (with sub-classifications of subdural, extradural, 
ruptured aortic aneurysm or other) or other cardiovascular cause (with sub-classifications 
of peripheral artery disease or other). 
4.5.2.2.1. Time to first adjudicated MACE 
Time to first adjudicated MACE will be analyzed and summarized. This will be 
determined as the number of days from the date of first dose to the date of the first 
adjudicated MACE: 
Time to first adj. MACE = date of first adj. MACE – date of first dose +1 
Partial dates related to adjudicated MACE will be queried, in the event the full start date 
cannot be determined, imputation as described in Section 6.2.7 will be applied. 
The variable of interest is the time to first adjudicated MACE. For analyses of time to 
first ‘on- and post-treatment’ MACE, participants who complete the study or withdraw 
from the study prior to completion without experiencing a MACE will be censored at 
their respective completion or study withdrawal date. For analyses of time to first ‘on-
treatment’ MACE, participants who do not experience a MACE prior to the end of their 
on-treatment period, as defined in Section 6.2.3.3 will be censored at their end of IP date 
+ 28 days. 
The analysis will be carried out using a Cox proportional hazards model with treatment 
group as the only categorical covariate. The model checking & diagnostics will follow 
the same strategy as outlined in Section 4.3.1.2. The number of participants with an 
event, the number censored due to study withdrawal and at study completion will be 
presented by treatment arm. The hazard ratio with corresponding 95% CI and p-value 
from the Cox proportional hazards model will be presented. 
4.5.2.3. 
COVID-19 Assessment and COVID-19 AEs 
The number of participants with suspected, probable, or confirmed for COVID-19 
infection will be reported. This display will also summarize the number of participants 
with a COVID-19 diagnosis test performed and the number of participants with positive, 
negative, or indeterminate results. 
The overall incidence of AEs of COVID-19 will be obtained from the standard AE 
summaries.  Additionally, a summary and a listing of COVID-19 assessments and 
symptoms for participants with COVID-19 AEs will be generated. 


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4.5.3. 
Laboratory Data 
Summaries of laboratory data including chemistry and hematology parameters, and liver 
function test data will be based on GSK Core Data Standards and unless otherwise 
specified will include on-treatment and post-treatment data.  
Summaries of the number and percentage of participants with changes from baseline with 
respect to both the Normal Range (NR) and Potential Clinical Importance (PCI) criteria 
will be generated separately. Details of PCI criteria are provided in Section 6.2.1.1.  
A listing of chemistry and hematology data will be presented for participants with 
laboratory values that meet any PCI criteria. 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. Possible Hy’s law cases are 
defined as events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN 
(>35% direct bilirubin), or ALT 3 × ULN and international normalized ratio (INR) 
>1.5. 
An e-DISH plot of maximum post baseline ALT versus maximum post baseline total 
bilirubin will be created. 
4.5.4. 
Vital Signs 
Descriptive statistics of change from baseline vital signs data [systolic blood pressure 
(SBP), diastolic blood pressure (DBP) and heart rate] will be based on GSK Core Data 
Standards.  
4.5.5. 
ECG 
Summaries of ECG data will be based on GSK Core Data Standards. Summaries will 
include ECG findings showing the number of normal/abnormal 12-lead ECG results and 
descriptive statistics by visit and for any time post-baseline.  
Individual QTc(F) values will be categorized and the number (percent) of participants 
with values in the following categories will be displayed for each visit and the highest 
post-baseline value: Grade 0 (≤450 msec), Grade 1 (>450 to ≤480 msec), Grade 2 (>480 
to ≤500 msec) and Grade 3 (>500 msec).  
Additionally, individual changes from baseline in QTc(F) values will be categorized and 
the number (percent) of participants with changes (msec) in the following categories will 
be displayed for each visit and the highest post-baseline value: <-60, ≥-60 to <-30, ≥-30 
to <0, ≥0 to ≤30, >30 to ≤60, and >60.  
A listing of ECG findings for participants with an abnormal interpretation or finding will 
be produced. 


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4.5.6. 
Cardiovascular Events 
A summary of cardiovascular (CV) events will be presented in addition to patient 
profiles. CV events include myocardial infarction/unstable angina, congestive heart 
failure, arrhythmias, valvulopathy, pulmonary hypertension, cerebrovascular 
events/stroke and transient ischemic attack, peripheral arterial thromboembolism, deep 
venous thrombosis/pulmonary embolism, and revascularization (as specified in the trial 
Protocol Section 10.4.3). 
4.6. 
Immunogenicity Data 
An immune response to a therapeutic drug can lead to generation of anti-drug antibodies 
within the blood. For the immunogenicity assessment, two types of antibody assays will 
be performed, a binding anti-drug antibody (ADA) assay and a neutralizing antibody 
(NAb) assay. 
For the binding ADA assay, there will be three testing steps: screening, confirmation, and 
titration.  The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point.  Participants 
with a positive confirmation result are considered positive for anti-mepolizumab 
antibodies.  Participants who test positive for the binding ADA assay will be tested in the 
titer assay to assess relative antibody concentrations (i.e., titer value) and will be tested 
for the NAb assay, which also reports results as positive or negative.  
Immunogenicity data will be summarized for the Safety Population up to Week 52, and 
for the Extended Treatment Population using all data. For the binding ADA assay, 
confirmation results at each visit will be categorized as negative, transient positive 
(defined as a single positive immunogenic response that does not occur at the final study 
assessment) or persistent positive (defined as a positive immunogenic response for at 
least 2 consecutive assessments or a single result at the final study assessment).  NAb 
assay results will also be summarized. 
The highest binding ADA assay confirmatory result obtained post-baseline for a 
participant (including any off-treatment data), will be summarized, participants with both 
positive and negative results being identified in the positive category.  Summary statistics 
for titre results will also be presented.  In addition, the highest NAb assay result during 
the same period will be summarized (again participants with both positive and negative 
results will be identified in the positive category). 
A summary of treatment emergent positive confirmatory binding ADA assay results in 
the subset of participants who did not have a positive confirmatory binding ADA assay 
result prior to the first dose of interventional product will also be presented. 
All immunogenicity results (i.e. binding ADA screening and confirmatory assay results, 
titre values and NAb results) will be listed. 


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4.7. 
Pharmacodynamic Analyses 
Blood eosinophils are collected as part of clinical laboratory assessments throughout the 
study.  
4.7.1. 
Definition of Endpoint 
Absolute and ratio to screening blood eosinophil counts will be summarized at each visit 
for the mITT population up to Week 104. 
The summary measure of treatment effect will be the ratio of the effect at Week 52 of 
mepolizumab compared to placebo. 
Only data collected while the participant was on-treatment will be used in the analysis 
(while on-treatment strategy). Blood eosinophil counts taken more than 28 days 
following last dose will not be included in the analysis. 


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4.7.2. 
Main Analytical Approach 
Statistical Methodology Specification 
Endpoint / Variables 
• Ratio to screening blood eosinophils (mITT) 
Model Specification 
• Blood eosinophil counts will be log transformed (loge) prior to analysis, transformations for 
values of 0 GI/L will be based on a value of 0.005 GI/L. 
• This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including the following terms: 
Fixed Categorical:  
Treatment group, smoking status, geographic region, Visit 
Fixed Continuous:  
Baseline loge blood eosinophil count,  
Repeated:  
Visit 
Interaction Terms:  
Visit by baseline, visit by treatment group. 
• 
Participants with missing covariate information will be excluded from the analysis 
• An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ 
on the REPEATED line. In the event that this model fails to converge, alternative correlation 
structures may be considered. 
Model Checking & Diagnostics 
• The Kenward-Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
Model Results Presentation 
• The estimated means for each treatment group will be calculated from the model using the 
observed marginal distributions of the sample covariates (OM option in LSMEANS 
statement). 
• Model-estimates of the absolute mean and mean ratio to baseline will be back-transformed 
and presented as ratios with corresponding standard errors on the log scale for each 
treatment group by visit.  Estimated treatment differences (Mepolizumab/Placebo) with 
corresponding 95% CIs and p-values will also be presented. 
4.8. 
Population Pharmacokinetic (PopPK) Analyses 
An optional PK Sub-study was performed for US and China participants only. The 
primary goal of this analysis is to characterize the population pharmacokinetics of 
mepolizumab administered subcutaneously in China and US participants with COPD in 
the PK sub-study. The analysis will be based on the most recent population 
pharmacokinetics model established with historical data from various indications. The 
influence of demographics, baseline characteristics, including disease activity, and co-
medication on the pharmacokinetics of mepolizumab in this population may be 
investigated. These data will be used to explore potential ethnic differences between 
China and US participants mepolizumab exposure. The individual participant PK 


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parameters will be estimated and documented for the purposes of any subsequent 
exposure response (PK/PD) analyses.  
The resultant primary and secondary PK parameters derived from the description of the 
sparse PK data by the model will be summarized as descriptive statistics by ethnicity. 
These data will serve as the basis for the comparison between ethnic groups. An 
assessment of similarity in PK will be performed by comparing summary of post-hoc 
primary PK parameters between ethnicities and whether the established model can 
describe the new data without modification.    
Mepolizumab plasma concentration-time data [samples collected at Weeks 0, 4, 24 and 
52; at the early withdrawal visit and IP discontinuation visit (if applicable)] will be 
analyzed by population methods using nonlinear mixed-effects modelling. The analysis 
will be carried out using appropriate software (e.g. NONMEM ™ or SAS ™). 
In support of the analysis described below, a dataset will be generated for which 
specifications will be provided in a separate document. 
Further to the details in the protocol regarding analysis of PK data, early release of PK 
data will be carried out to aid in refinement of the established population PK 
model.  Under this process, individual participant-level, de-identified, unblinded, and 
scrambled (i.e., random reassignment of participant identification numbers) drug 
concentration information will be analyzed prior to unblinding the study. In that case, 
independent clinical PK analysts (who have no involvement in study conduct) will have 
access to an unblinded scrambled population PK-specific dataset (e.g., drug 
concentrations, actual dosing information, demographics, and laboratory details) at one or 
more time points (e.g., prior to the final analysis) throughout the study for population PK 
model development and refinement. No AE or efficacy data will be included and no 
unblinding eosinophil or immunogenicity data will be included as part of this early 
release. 
4.8.1. 
Definition of Endpoint(s) 
Blood for PK will be collected at Week 0 (prior to first dose initiation), Week 4 (pre-
dose), Week 24 and Week 52 (or IP discontinuation/early withdrawal). Individual PK 
parameters and covariates will be log-transformed and standardized before analysis. 
Based on previous knowledge of mepolizumab 100 mg SC pharmacokinetics, 
concentrations below the limit of quantification (BLQ) of the assay are not anticipated. 
Any such results will be treated as missing. 
4.8.2. 
Main Analytical Approach 
A population PK analysis of sparse concentration data will be performed. The population 
of interest will be the PK population. 
The summary measure of interest will be the log-transformed mepolizumab plasma 
concentration. For participants prematurely discontinuing study treatment, all available 


C O N FI D E N TI A L  
 
 
2 0 8 6 5 7  
P a g e 4 4  of 6 8  
data will be i ncl u de d i n t he a nal ysis . Partici pa nts w h o e x perie n ce a n i nterc urre nt e ve nt 
wil l be ha n dle d usi n g a tr eat me nt p olic y strate g y.  
S parse bl o o d sa m pli n g is i m ple me nte d i n t his st u d y f or deter mi nati o n of m e p oliz u ma b 
plas ma c o nce ntrati o n , a n d s u bse q ue nt data a n al ysis b y p o p ulati o n P K met h o ds usi n g t he 
m ost rece nt p o p ulati o n p har mac o ki netic s m o d el ( meta-a nal ysis P K m o del of data acr oss 
i n dicati o ns descri be d i n 
 T he 
mai n o bjecti ves of t his p o p ulati o n P K a nal ysis are:  
•  T o e val uate me p oliz u m a b p har mac o ki netics i n C hi na a n d U S partici pa nts wit h C O P D 
i n t he P K s u b-st u d y f oll o wi n g t he s u bc uta ne o us a d mi nistrati o n of a 1 0 0 m g d ose 
e ver y 4 wee ks;  
•  T o o btai n i n di vi d ual plas ma c o nce ntr ati o n pre dicti o ns f o r t he ti me p oi nts at w hic h P D 
is meas ure d t o all o w t he c o n d uct of p o p ulati o n P K P D a nal yses if dee me d a p pr o priate. 
O utlier data will be assesse d f or pla usi bilit y; h o we ver, t he ai m is t o use all a vaila ble data 
w he ne ver p ossi ble. A n y decisi o n t o e xcl u de dat a w ill be f ull y d oc u me nte d a n d s pecifie d 
i n t he cli nical st u d y re p ort. 
4. 9.  
P o p ul ati o n P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c ( P o p P K P D) 
A n al y s e s  
If dee m e d a p pr o priate, a p o p ulati o n p har mac o ki netic/ p har mac o d y na mic a n al ysis will be 
c o n d ucte d. Me p oliz u ma b bl o o d e osi n o p hil c o u nt -ti me data will be a nal yze d b y 
p o p ulati o n met h o ds usi n g n o nli near mi xe d -effects m o delli n g. T he a nal ysis will be carri e d 
o ut usi n g a p pr o priate s oft ware (e. g. N O N M E M or S A S).  
I n s u p p ort of t he a n al ysis descri be d b el o w, a s pecific dataset will be g e nerate d  f or w hic h 
s pecificati o ns will be pr o vi de d i n a se parate d oc u me nt. 
4. 9. 1.  
D efi niti o n of E n d p oi nt( s)  
Bl o o d f or P K are defi ne d wit hi n Secti o n  4. 8. 1 . 
Bl o o d e osi n o p h il c o u nts are defi ne d wit hi n Secti o n  4. 7. 1 . 
4. 9. 2.  
M ai n A n al yti c al A p pr o a c h  
T he p o p ulati o n of i nterest will be t he P K a nal ysis set a n d bl o o d e osi n o p hils meas ure d i n 
eac h visit i n t he P K s u b-st u d y. F or partici p a nts pre mat urel y disc o nti n ui n g st u d y 
treat me nt, all a vaila ble d ata will be i ncl u de d i n t he a nal ysis. Partici pa nts w h o e x perie n ce 
a n i nterc urre nt e v e nt will  be ha n dle d usi n g a tr eat me nt p olic y strate g y . 
T his P o p P K P D a na l ysis will be perf or me d b y p o p ulati o n met h o ds usi n g t he m ost rece nt 
p o p ulati o n P K P D m o del
 
 
 
C CI
C CI


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The objectives of the popPKPD analysis are: 
• To evaluate mepolizumab pharmacodynamics in China and US participants with 
COPD in the PK sub-study following subcutaneous administration of a 100 mg 
dose every 4 weeks; 
Outlier data will be assessed for plausibility; however, the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report. 
4.10. 
Other Analyses 
4.10.1. 
Subgroup Analyses 
For the primary endpoint, a separate exploratory analysis within each of the below 
subgroup categories will be carried out. Unless otherwise specified no formal hypothesis 
testing in subgroups of the population will be performed, exacerbation rates/year in each 
treatment arm together with the rate ratio and associated 95% CI will be displayed. 
The following subgroups are of interest: 
Subgroup 
Categories  
Age 
<40, 40-<65, ≥65 years 
Sex 
Male, Female 
Race 
African American/African Heritage, White, Asian, Other 
Baseline Body Mass Index (kg/m2) 
Low (≤20), Medium (>20-≤30), High (>30) 
Geographic Region [1] 
Europe (Belgium, Denmark, France, Germany, Greece, Ireland, 
Italy, Netherlands, Spain, Sweden, United Kingdom), 
Eastern Europe (Hungary, Poland), 
Asia (China, Republic of Korea, Taiwan), 
South America (Argentina, Brazil, Mexico), 
North America (United States, Canada), 
Rest of World (Australia, New Zealand, Israel, India) 
Exacerbations in the previous year 
≤2, 3, ≥4 exacerbations 
Severe exacerbations in the previous 
year 
0, ≥1 exacerbation 
Screening blood eosinophil categories 
<0.5 GI/L, 0.5 GI/L  
Smoking status at Screening 
Current, Former 
Symptoms of Chronic Bronchitis 
Yes (Participants with baseline response of "most days of the 
week" or "several days of the week" to both questions regarding 
cough and sputum on SGRQ-C questionnaire), No 
Cardiovascular Disease Comorbidity 
Any past or current medical condition under Cardiac Disorders 
Modified Medical Research Council 
(mMRC) score at Screening 
<2, ≥2 
Severity of Airflow Limitation (GOLD 
Guidelines) 
Mild, Moderate, Severe, Very Severe 
Treatment Duration [2] 
Fixed Duration (‘Enrolled in study for 52 weeks’, ‘Enrolled in 
study for 52 weeks, Not agreed to extend up to 104 weeks’), 
Variable Duration (‘Enrolled in study for 52 weeks, agreed to 
extend up to 104 weeks’ or ‘Enrolled in study for up to 104 
weeks’) 


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[1] If numbers of participants within the geographic regions are too small then regions may be further 
combined for analysis.  
[2] From Treatment Duration Confirmation eCRF page. For participants who completed the study prior to 
release of Protocol Amendment 6, no information was entered into this eCRF page retrospectively, all 
such subjects were categorized as Fixed Duration. 
 
If the number of participants is too small within a subgroup category, then the subgroup 
categories may be redefined prior to unblinding the study. 
For secondary endpoints, exploratory analyses by screening blood eosinophil categories 
will be carried out for time to first moderate/severe exacerbation, CAT responders and 
SGRQ responders. Analysis by symptoms of chronic bronchitis and smoking status at 
screening will be carried out for time to first moderate/severe exacerbation, CAT 
responders, SGRQ responders and SGRQ change from baseline. Analysis by geographic 
region will be carried out for SGRQ responders and E-RS: COPD responders.  No formal 
hypothesis testing in subgroups of the population will be performed. 
Further exploratory analysis assessing the effect of smoking variables such as smoking 
duration in years and smoking intensity as measured by pack years may be carried out, 
this may include assessment of these variables as subgroups and/or as covariates of 
interest. 
4.10.1.1. 
Shrinkage Estimation Methods 
Additional to the conventional approach for the subgroup analyses specified for the 
primary endpoint, analyses using Bayesian Hierarchical Modelling will be carried out for 
all subgroups of interest, except for screening blood eosinophil categories, where the 
exchangeability assumption is not expected to hold. The rate ratios and standard errors 
from the standard subgroup analyses will be included in a Bayesian Hierarchical model to 
obtain shrinkage estimates of the subgroup-specific treatment effects. 
The subgroup-specific rate ratios, 𝜇𝑗 (𝑗=1, …, X) will be assumed to be distributed 𝜇𝑗 ∼ 
𝑁(𝜇, 𝜏2) where 𝜇 is the overall rate ratio and 𝜏2 is the between-subgroup variance. The 
following non-informative and weakly-informative priors respectively will be used in the 
model:  
• 
𝜇 ∼ 𝑁(0, 𝑆𝐷 = 100)  
• 
𝜏 ∼ half-Normal(𝑆𝐷 = 1)  
The model will be fitted using MCMC with at least 50,000 iterations, a thin of 5 and a 
burn-in of at least 1000. The posterior rate ratios with 95% Credible Interval will be 
presented by subgroup in a forest plot alongside the conventional estimates. 
A sensitivity analysis may be performed to assess the impact of the prior for 𝜏 on the 
degree of shrinkage by considering: 
• 𝜏 ∼ half-Normal(𝑆𝐷 = 0.5) 
• 
𝜏 ∼ half-Normal(𝑆𝐷 = 2) 


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4.10.2. 
Subpopulation Analyses 
The key study population, efficacy, safety analysis and some exploratory analysis will be 
repeated in the following subpopulations: 
• Chinese subpopulation – All participants of a relevant Asian heritage (Asian – 
East Asian Heritage) enrolled at sites in China Mainland and Taiwan. 
• 
East Asia subpopulation: All participants of a relevant Asian heritage (Asian – 
East Asian Heritage) enrolled at sites in China mainland, Taiwan, South Korea. 
• 
South Korea subpopulation: All participants of a relevant Asian heritage (Asian 
– East Asian Heritage and Asian – South East Asian Heritage) enrolled at sites in 
South Korea. 
• 
India subpopulation: All participants of a relevant Asian heritage (Asian – 
Central/South Asian Heritage, Asian – East Asian Heritage and Asian – South 
East Asian Heritage) enrolled at sites in India. 
Any analyses involving statistical modelling will be carried out using the same approach 
as outlined in the relevant sections of this SAP (data permitting). Geographic region will 
not be included as a covariate within any of the models. Adaptions to the statistical 
models may be made in the case of any convergence issues. 
4.11. 
Interim Analyses 
No formal interim analyses of efficacy data are planned for this study. Details regarding 
planned blinded sample size evaluations are provided in Section 5. 
 
4.12. 
Changes to Protocol Defined Analyses 
Changes to the planned statistical analysis specified in the Protocol Amendment 6 
(Dated: 06-DEC-2021) are detailed in Table 1 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
Analysis populations 
defined as All Participants 
Enrolled (ASE), Modified 
Intent-to-Treat (mITT), 
Safety, Per-Protocol (PP) 
and PK 
• 
Additional analysis 
population of mITT 
Population excluding 
past/concurrent Asthma 
(mITT2) 
• 
Additional population 
excluding participants with 
past/concurrent asthma 
required for analysis of 
primary and secondary 
endpoints to assess the 
impact of inclusion of these 
patients. 


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Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
Other endpoint of 
Annualized rate of 
moderate/ severe 
exacerbation requiring 
systemic steroids 
• 
Other endpoint of 
Annualized rate of 
moderate/ severe 
exacerbation by Type of 
Treatment Required 
(Corticosteroids alone, 
Antibiotics alone, 
Corticosteroids and 
Antibiotics)  
• 
To provide further breakdown 
of exacerbations requiring 
differing treatment courses 
and effect of mepolizumab. 
• 
For the primary estimand a 
treatment policy strategy 
will be used for the 
intercurrent events of 
discontinuation of study 
medication, use of 
medication prohibited by 
the protocol, and 
investigational product 
interruption of 2 or more 
doses, when these 
intercurrent events are not 
associated with disruptions 
or restrictions imposed due 
to the COVID-19 
pandemic. A hypothetical 
strategy will be considered 
when these intercurrent 
events have occurred as a 
result of disruptions or 
restrictions (e.g. lockdown 
measures, social 
distancing) imposed due to 
the COVID-19 pandemic. 
• For the primary estimand a 
treatment policy strategy 
will be used for the 
intercurrent events of 
discontinuation of study 
medication and 
investigational product 
interruption of 2 or more 
doses, when these 
intercurrent events are not 
associated with disruptions 
or restrictions imposed due 
to the COVID-19 pandemic. 
A hypothetical strategy will 
be considered when these 
intercurrent events have 
occurred as a result of 
disruptions or restrictions 
(e.g. lockdown measures, 
social distancing) imposed 
due to the COVID-19 
pandemic.  
• 
The change was made 
following regulatory feedback 
on the handling of the 
intercurrent event of prohibited 
medication use, a treatment 
policy strategy will be used for 
all occurrences of this 
intercurrent event.   
• 
N/A (not in protocol) 
• Individual participant-level, 
de-identified, unblinded, 
and scrambled (i.e., random 
reassignment of participant 
identification numbers) drug 
concentration information 
will be analyzed prior to 
unblinding the study. In that 
case, independent clinical 
PK analysts (who have no 
involvement in study 
conduct) will have access to 
an unblinded scrambled 
population PK-specific 
dataset (e.g., drug 
concentrations, actual 
dosing information, 
demographics, and 
• 
The change was made to aid 
population PK model 
development and refinement. 


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Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
laboratory details, but no 
AE or efficacy data) at one 
or more time points (e.g., 
prior to the final analysis) 
throughout the study  
• 
Evaluation of similarity in 
exposure will be guided by 
the confidence interval 
excluding at least a two-
fold difference. 
• An assessment of similarity 
in PK will be performed by 
comparing summary of 
post-hoc primary PK 
parameters between 
ethnicities and whether the 
established model can 
describe the new data 
without modification. 
• 
This was deemed to be a 
more meaningful analysis for 
comparing the similarity of PK 
across the US and China 
participants. 
 
5. 
SAMPLE SIZE DETERMINATION 
The primary analysis is based on comparing the annualized rate of moderate/severe 
exacerbations in participants treated with mepolizumab 100 mg SC vs. placebo. 
The null hypotheses used to test the superiority of mepolizumab 100 mg compared to 
placebo will be: 
H0: µi = µp 
where µi is the annualized exacerbation rate on the mepolizumab 100 mg SC arm and µp 
is the annualized exacerbation rate on the placebo arm. 
The (one-sided) alternative hypothesis is that the annualized exacerbation rate is lower on 
the mepolizumab arm: 
Ha: µi< µp 
The estimated annualized rate of moderate/severe exacerbations in the placebo arm was 
1.7 exacerbations (based on exacerbation data observed from studies MEA117113 and 
MEA117106 [High Stratum], which were conducted prior to the COVID-19 pandemic). 
Based on a true population reduction of 23% in the annualized rate of moderate/severe 
exacerbations following treatment with mepolizumab 100 mg SC compared to placebo, it 
was estimated that 400 participants per arm (800 participants in total) are required to 
provide 90% power to detect a statistically significant reduction at the 2-sided 5% level 
of significance. The smallest observed effect which is predicted to result in a statistically 
significant difference between mepolizumab 100 mg SC compared to placebo is 15%. 
To account for the loss of patient years’ data from participants who withdraw early from 
the trial and no longer provide any data (on- or off-treatment), the sample size includes an 
additional 44 patients to account for approximately 5.5% of patient-years data being 
missing, this being the level of missing data encountered in study MEA117113. 


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The sample size estimate is based on the number of moderate/severe exacerbations per 
year following a negative binomial distribution [Keene, 2007]. The estimate of 1.7 
moderate/severe exacerbations per year in the placebo arm and of 0.55 for the dispersion 
parameter are based on data observed from studies MEA117113 and MEA117106 (High 
Stratum).  Overall, in this study, a total of approximately 800 participants will be 
randomized with a randomization ratio of 1:1 placebo: mepolizumab 100 mg SC. 
Blinded re-evaluations of the sample size will be carried out prior to randomizing the 
800th participant to assess whether, based on the overall annualized rate of 
moderate/severe exacerbations and the level of dispersion seen within the available data, 
the initial planned sample size of 800 randomized participants would continue to provide 
90% power for this study. The sample size re-estimation will follow the method 
described in [Friede, 2010]. A negative binomial distribution will be fitted to the blinded 
exacerbations from the available data with participant follow-up time as an offset, and 
estimates obtained for the overall exacerbation rate and the dispersion (shape) parameter. 
These estimates will be used to re-calculate the sample size that would be required to 
provide 90% power. If the re-estimated sample size is less than or equal to the currently 
planned 800 randomized participants, the study will continue as planned; otherwise the 
study sample size may be increased to that indicated by the re-estimation, with a potential 
maximum increase to 1400 participants. Further blinded re-evaluations will be conducted 
to monitor whether the sample size continues to be appropriate given the emerging event 
rate. The total sample size will be between 800 as originally planned up to a potential 
maximum of 1400 participants. 
The sample size is based on an assumed exacerbation rate of 1.7 exacerbations per year in 
the placebo group and an expected reduction of 23% in this rate for participants treated 
with mepolizumab. If the true placebo exacerbation rate or the expected reduction with 
mepolizumab differ from these assumptions then, at the given sample size, there will be 
an effect on the power of the study.  Table 2 illustrates the effect on the power for the 
treatment comparison (based on 756 participants, excluding the additional 44 participants 
to account for early study withdrawals), and a dispersion parameter k=0.55. 
 
Table 2 
Effect of placebo rate and expected rate reduction with 
mepolizumab on the power of the study 
% reduction 
in annualized 
exacerbation 
rate with 
mepolizumab 
Placebo: Annualized Exacerbation Rate  
 
0.9 
 
1.1 
 
1.3 
 
1.5 
 
1.7 
 
1.9 
Study Powera 
21% 
67 
73 
78 
81 
84 
86 
22% 
72 
77 
81 
85 
87 
90 
23% 
76 
81 
85 
88 
90 
92 
a. 
Power estimate based on a 52-week follow-up for each participant 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
The study population analyses will be based on the modified Intent-to-Treat (mITT) 
Analysis Set, unless otherwise specified.  Please see Section 3 of the SAP for details of 
the analysis sets. Displays for the Extended Treatment population will be analyzed by 
randomized treatment. 
Study population summaries of participant’s disposition, treatment discontinuation, 
protocol deviations, demographic and baseline characteristics, medical conditions, prior 
and concomitant medications will be based on GSK Core Data Standards. 
6.1.1. 
Participant Disposition 
Reasons for screening and run-in failures will be summarized for the All Participants 
Enrolled analysis set. 
A summary of participant disposition with reasons for premature withdrawal from study 
will be provided along with the number of participants who consented to continue in the 
trial beyond Week 52. A summary of reasons for treatment discontinuation will be 
provided. The number of participants by region, country and center will also be provided. 
Time to withdrawal from IP will be summarized. For this, the variable of interest is the 
time to withdrawal from IP. Participants who complete the study without withdrawing 
from IP will be censored at the date of their final administered dose of IP. Participants 
who withdraw from study prior to their final scheduled dose of IP without having 
previously withdrawn from IP will be censored at their date of final administered dose of 
IP. 
An additional summary information showing the amount of time within the study period 
considered as on-treatment, off-treatment and missing will be presented. 
6.1.2. 
Demographic and Baseline Characteristics 
Demographic characteristics, race and racial combination details will be summarized, 
summaries of COPD history and baseline disease characteristics will be provided as well 
as summaries of history of tobacco use, and screening and baseline lung function 
including pre- and post-bronchodilator FEV1, FVC, ratio of FEV1/FVC and percent 
predicted FEV1 as well as reversibility.  A summary of age ranges using the EMA clinical 
trial results disclosure requirement categories based on the All Participants Enrolled 
analysis set will be provided.   
Medical conditions will be summarized following GSK Core Data Standards. 
6.1.2.1. 
De-identification of Demographic Data 
Where required for the purposes of public disclosure, de-identified versions of summaries 
of demographic data which meet the criteria for de-identification (i.e. contain categories 


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with non-zero cells of n<11 or a standard deviation of 0) will be provided.  For de-
identified versions all non-zero cells within the table will contain n≥11 and where 
applicable a standard deviation of >0)  
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
and reviewed in accordance with the Study Deviations Rules Document dated 24 August 
2022 (Version 5) or later.  Protocol deviations classified as important are detailed in the 
Study Deviations Rules Document and those requiring exclusion from the Per-Protocol 
(PP) population are provided in Section 6.3. 
• Data will be reviewed prior to unblinding and locking the database to ensure all 
important deviations are captured and categorized in the protocol deviations 
dataset. 
• Protocol deviations related to study treatment assignment will be confirmed as 
protocol deviations following unblinding for participants who received incorrect 
treatment according to the randomized treatment. 
• This dataset will be the basis for the summaries of important protocol deviations. 
Protocol deviations which result in exclusion from the per-protocol analysis set will also 
be summarized.  
Data will be reviewed prior to unblinding and locking the database to ensure all 
deviations leading to analysis population exclusions are captured and categorized in the 
protocol deviations ADaM dataset (note these exclusions are not captured in the SDTM 
dataset). 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using both the GSK Drug and WHO Drug 
dictionaries. Summaries will be based on the GSK Drug dictionary only. 
Medications identified as being taken for COPD on the CRF will be categorized into and 
summarized by respiratory medication classes (RMCs) as detailed in Section 4.5.2 of the 
supporting Output and Programming Specification (OPS) document. 
In addition, tables showing use of Long Term Oxygen Therapy (long term use defined as 
40 days or more of consecutive use) in the 12 months prior to Screening will be provided.  
6.1.5. 
Intercurrent Events 
Number and percentage of participants with intercurrent events will be summarized. 
Changes to background COPD medications will be identified programmatically and 
confirmed by blinded clinical review of concomitant medications. Instances of use of 
prohibited medications will be identified programmatically using protocol deviation 


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information under the category “Excluded medication, vaccine or device”, these will be 
confirmed by blinded clinical review. 
The following intercurrent events are categorized by association with 
disruptions/restrictions imposed due to the COVID-19 pandemic: 
• Discontinuation of interventional product will be identified using the study 
treatment discontinuation eCRF 
• IP interruptions of ≥2 consecutive missed doses are identified using the 
study treatment eCRF. 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic 
To assess the impact of the COVID-19 pandemic on study participation, the following 
study population summaries will be provided: 
• Summary of recruitment by country and site relative to COVID-19 pandemic 
measures 
• Summary of participant status and participant disposition by relationship to 
COVID-19 pandemic 
• Summary of treatment status and reasons for discontinuation of study treatment 
by relationship to COVID-19 pandemic  
• Important protocol deviations by relationship to COVID-19 pandemic 
• Summary of visits impacted by COVID-19 pandemic 
• Country level listing of Waves of COVID-19 pandemic measures 
 
6.1.7. 
Change in Smoking Status 
Smoking and eCigarette status is recorded at Baseline, Week 24, Week 52, Week 76 and 
Week 104. Smoking and eCigarette use at baseline and changes in smoking and 
eCigarette status at Week 24, Week 52, Week 76 and Week 104 will be presented. 


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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
6.2.1.1. 
Laboratory Values of Potential Clinical Concern 
Haematology 
Laboratory Parameter 
 
Units 
Age 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 
1 
12+ 
0.201  
0.599  
Hemoglobin  
G/L 
12+ 
71 
199 
Platelet Count  
GI/L 
1+ 
31  
1499  
While Blood Cell Count (WBC) 
GI/L 
12+ 
1.1 
 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Age 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
ALT 
U/L 
3-12 
 
>143  
U/L 
13+ 
 
>239  
Calcium 
mmol/L 
3+ 
1.50 
3.24 
Glucose 
mmol/L 
1+ 
2.2 
27.8 
Phosphorus, Inorg 
mmol/L 
3+ 
0.32 
 
Potassium 
mmol/L 
3+ 
2.8 
6.5 
Sodium 
mmol/L 
0+ 
120 
160 
 
6.2.2. 
Study Period 
6.2.2.1. 
Analysis Period 
The analysis period for exacerbations and efficacy endpoints is defined as the period of 
time over which exacerbations and efficacy assessments will be included in the on- 
and/or off-treatment phases (See Section 6.2.3.1).  The start and end of the analysis 
period is defined as follows:  


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Analysis Period for Exacerbations and Efficacy Endpoints 
Study 
Completion  
Start Date of Analysis 
Period 
End Date of Analysis Period [1] 
Participants enrolled for 52 weeks 
Completed  
First dose of interventional 
product (Day 1) 
Earlier of Date of Week 52 Exit Visit or Day 372 
Withdrew Early 
First dose of interventional 
product (Day 1) 
Earlier of Date reported on the study conclusion page 
[2] or Day 372 
Participants consented to participate for more than 52 weeks 
Completed  
First dose of interventional 
product (Day 1) 
Earlier of Date of Week 104 Exit visit or Day 736 or 
scheduled visit on or immediately before the date of 
Week 52 Exit Visit of the last participant to have been 
randomized into the study  
Withdrew Early 
First dose of interventional 
product (Day 1) 
Earlier of Date reported on the study conclusion page 
or Day 736  
[1] Allowing for the 7 day visit window in the protocol; Day 372/736 is defined as 371/735 days (364+7 days / 
728+7 days) after the first dose of interventional product. 
[2] eCRF completion guidelines state ‘COPD exacerbation details are collected from Screening Visit 1 through to 
last follow up (study conclusion date)’ 
 
6.2.2.2. 
Length of Time in Phase 
The length of time in a phase reflects for each participant the period of time over which 
exacerbation data has been recorded and included in the negative binomial analysis 
model. The analysis model will incorporate this information as an offset of loge (length of 
time (years) in phase). 
Length of time (years) will be calculated as Length of time (Days)/365.25. 
The length of time a participant contributes information in each phase is detailed below.  
For participants who completed the study and did not withdraw early from interventional 
product, the on-treatment period is the full analysis period; these participants have no off-
treatment data. For participants who withdrew early from interventional product the on-
treatment and off-treatment periods are as described in the table below: 


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Exacerbations – Length of Time in Phase 
Phase  
Length of time (Days) in Phase 
On- and Off-treatment 
(Date of End of Analysis Period – IP Start Date) +1 
On-treatment 
If End of Analysis Period ≤28 days after last dose: 
(Date of End of Analysis Period – IP Start Date) +1 
 
If End of Analysis Period >28 days after last dose: 
(IP Stop Date – IP Start Date) +29 
Off-treatment 
If End of Analysis Period ≤28 days after last dose: 
0 days 
If End of Analysis Period >28 days after last dose: 
Date of End of Analysis Period – [IP Stop Date + 28 days] 
Participants who withdrew early from the study with an analysis period which ends prior 
to their planned study completion date (see Section 4.1.4), will be considered to have 
missing data for the period of time from the end of the analysis period to their planned 
study completion date. 
6.2.3. 
Treatment Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of interventional product. 
6.2.3.1. 
Treatment Phases for Exacerbations 
Treatment State 
Definition 
Pre-Treatment  
Event start date < IP start date 
On-Treatment 
For participants who did not prematurely withdraw from IP: 
Event onset date is on/after IP start date & on/before the end of analysis period. 
(IP Start Date ≤ Event Start Date ≤ end of analysis period) 
 
For participants who prematurely withdrew from IP: 
Event onset date is on/after IP start date & on/before earlier of the IP stop date 
+28 
days/end of analysis period. 
(IP Start Date ≤ Event Start Date ≤ earlier of IP Stop Date + 28 days/end of 
analysis period) 
Off-Treatment 
Event onset date is after IP stop date +28 days and on/before the end of analysis 
period. 
(IP Stop Date + 28 days < Event Start Date ≤ end of analysis period) 
Post-treatment 
Event onset date is after the end of analysis period. 
(Event Start Date > end of analysis period) 
Duration of 
Exacerbation (Days) 
Event resolution date – Event onset date + 1 


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Treatment State 
Definition 
Analysis period as defined in Section 6.2.2 
If the IP stop date is missing or the event start date is partial/missing then unless there is evidence to the contrary 
the event will be considered to be On-Treatment (see Section 6.2.7) 
6.2.3.2. 
Treatment Phases for Visit Based Efficacy Assessments 
Treatment State 
Definition 
Pre-Treatment Visit 
Assessment Date  Interventional Product Start Date 
On-Treatment Visit 
For participants who did not prematurely withdraw from IP: 
Assessment date is after IP start date & on/before the end of analysis period. 
(IP Start Date < Assessment Date ≤ end of analysis period) 
 
For participants who prematurely withdrew from IP: 
Assessment date is after IP start date & on/before earlier of the IP stop date +28 
days/end of analysis period. 
(IP Start Date < Assessment Date ≤ earlier of IP Stop Date + 28 days/end of 
analysis 
period) 
Off-Treatment Visit 
IP stop date + 28 days < Assessment date ≤ end of analysis period 
Post-Treatment Visit 
Assessment date > end of analysis period 
Analysis period as defined in Section 6.2.2 
Where time of an assessment is recorded, the time of assessment and time of first dose will be considered to 
differentiate between Pre-treatment and On-treatment events. 
 
6.2.3.3. 
Treatment Phases for Visit Based Safety Assessments 
Treatment State 
Definition 
Pre-Treatment  
Assessment Date  IP Start Date 
On-Treatment 
IP Start Date < Assessment Date ≤ IP Stop Date +28 days 
Post -Treatment 
Assessment Date > IP Stop Date + 28 days 
 
6.2.3.4. 
Treatment Phases for Adverse Events 
Treatment State 
Definition 
Pre-Treatment  
Event Start Date < IP Start Date 
On-Treatment 
Event onset date is on/after IP start date & on/before IP stop date +28 days. (IP Start 
Date  Event Start Date  IP Stop Date + 28 days) 
Post-Treatment 
Event onset date is after the IP stop date + 28 days.  
(Event Start Date > IP Stop Date + 28 days) 
Onset Time 
Since 1st Dose 
(Days) 
If event onset date < IP start date = IP start date - Event onset date 
If event onset date ≥IP start date = Event onset date – IP start date +1 
Missing otherwise. 


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Treatment State 
Definition 
Duration (Days) 
Event resolution date – Event onset date + 1 
NOTES: 
If the IP stop date is missing or the event start date is partial/missing then unless there is evidence to the contrary 
the event will be considered to be On-Treatment (see Section 6.2.7). 
Where time of event is recorded, the time of event and time of first dose will be considered to differentiate between 
Pre-treatment and On-treatment events. 
 
6.2.3.5. 
Treatment Phases for Concomitant Medication Start Dates 
Treatment State 
Definition 
Started Prior to 
Screening 
Concomitant medication (CM) start date < Screening (Visit 1) Date 
Pre-Treatment 
(Started prior to 
treatment) 
Concomitant medication (CM) start date < IP start date 
On-Treatment 
(Started during 
Treatment) 
If CM start date is on/after IP start date & on/before IP stop date +28 days. 
(IP Start Date ≤ CM Start Date ≤ IP Stop Date + 28 days) 
Post-Treatment  
If CM start date is after the IP stop date + 28 days. 
(CM Start Date > IP Stop Date + 28 days) 
Onset Time 
Since 1st Dose 
(Days) 
If CM start date < IP start date = IP start date - CM start date 
If CM start date ≥ IP start date = CM start date – IP Start Date +1 
Missing otherwise. 
Duration (Days) 
CM end date – CM start date + 1 
NOTES: 
If the IP stop date is missing and CM start date is on/after IP start date then CM considered on-treatment (started 
during treatment) 
If CM start date is missing then CM considered on-treatment (started during treatment) 
 
6.2.3.6. 
Treatment Phases for Concomitant Medication Usage Dates 
Treatment State 
Definition 
Taken Prior to 
Screening 
If CM start date < Screening (Visit 1) Date 
Taken Prior to 
Treatment 
If CM start date < IP Start Date 
Taken During 
Treatment 
If CM start date ≤ IP start date and CM stop date ≥ IP start date 
If IP start date ≤ CM start Date ≤ IP Stop Date + 28 days 
Taken Post-
Treatment 
If CM start date < IP stop date+28 days and CM stop date ≥ IP stop date +28 days 
If CM start Date > IP stop date + 28 days 
NOTES: 
If the IP stop date is missing and CM start date is on/after IP start date then CM considered taken during treatment 
If CM start date is missing, then CM considered to be taken during treatment 


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6.2.4. 
Study Day and Reference Dates 
Study day is calculated as the number of days from the first dose of study medication (IP 
start date), as detailed below: 
Assessment Date = Missing 
 
Study Day = Missing  
Assessment Date < IP Start Date   
Study Day = Assessment Date – IP Start 
Date 
Assessment Date ≥ IP Start Date Study Day = Assessment Date – IP Start Date + 1 
6.2.5. 
Assessment Windows  
6.2.5.1. 
Visit Based Assessments 
No assessment windows are defined for visit based assessments.  Clinic visits as 
scheduled are subject to a ±7-day window, however assessments performed outside of 
these visit windows will still be included in analyses. Nominal visits will be used for 
reporting and analysis.   
6.2.5.2. 
Premature Withdrawals from Interventional Product or Study and 
Scheduled Exit Visits at End of Study 
Participants who withdrew prematurely from treatment or from the study and participants 
with a scheduled exit visit at end of study (i.e. where the exit visit is scheduled to occur 
on or before the date the last randomised participant is scheduled to complete their Week 
52 Exit Visit) may have data recorded under either a nominal visit at which it was 
scheduled for collection, a nominal visit at which it was not scheduled for collection, or a 
withdrawal visit. 
 
Data recorded under a visit at which it was not scheduled for collection, under a 
withdrawal visit or under a scheduled exit visit at end of study will be re-assigned to the 
next nominal visit at which collection was scheduled. This data will be summarized and 
analyzed (as appropriate) together with other data recorded as scheduled at the nominal 
visit. Data will be re-assigned according to the Schedule of Activities table, to the next 
visit where the data was scheduled for collection, unless data already exists at that visit. 
 
For example, if a participant prematurely withdraws from treatment or the study at Week 
16 (Visit 6) and completes an Early Withdrawal Visit which includes an ECG 
assessment, the ECG data collected will need to be re-assigned to a visit where ECG data 
is next scheduled for collection. In this case the ECG data will be reassigned to Week 24 
as this is the next nominal visit at which collection of ECG data is scheduled. 
 
6.2.5.3. 
Unscheduled Visits 
Data recorded at an unscheduled visit will be re-assigned to the closest available nominal 
visit at which collection of the data was scheduled unless information already exists at 
that visit. Pre-treatment unscheduled data will be re-assigned to pre-treatment nominal 


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visits. Additionally, post-baseline data will be re-assigned to post-baseline nominal visits. 
If an unscheduled visit occurs between two scheduled visits for which data has been 
reported, the data will remain in the unscheduled visit and will not be included in any by 
visit summary tables; it will however be included in relevant summaries of any time post-
baseline data and listings. 
6.2.5.4. 
Daily Data from eDiary 
Daily data collected every evening via eDiary will be summarized and analyzed in 4-
week periods, data will be slotted to a 4-week period up to Week 104. 
Analysis Window[1] 
Analysis Timepoint 
Beginning Timepoint 
Ending timepoint 
-7 
-1 (day prior to first dose) 
Baseline 
1 (day of first dose) 
28 
Weeks 1-4 
29 
56 
Weeks 5-8 
57 
84 
Weeks 9-12 
85 
112 
Weeks 13-16 
113 
140 
Weeks 17-20 
141 
168 
Weeks 21-24 
169 
196 
Weeks 25-28 
197 
224 
Weeks 29-32 
225 
252 
Weeks 33-36 
253 
280 
Weeks 37-40 
281 
308 
Weeks 41-44 
309 
336 
Weeks 45-48 
337 
364[2] 
Weeks 49-52 
365 
392 
Weeks 53-56 
393 
420 
Weeks 57-60 
421 
448 
Weeks 61-64 
449 
476 
Weeks 65-68 
477 
504 
Weeks 69-72 
505 
532 
Weeks 73-76 
533 
560 
Weeks 77-80 
561 
588 
Weeks 81-84 
589 
616 
Weeks 85-88 
617 
644 
Weeks 89-92 
645 
672 
Weeks 93-96 
673 
700 
Weeks 97-100 
701 
728 (or Week 104 visit if earlier) 
Weeks 101-104 


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Notes: 
[1] All analysis window timepoints are relative to first dose of IP. 
[2] For patients enrolled for 52 weeks the Weeks 49-52 timeslot will be defined as 337 – 364 (or Week 52 
visit if earlier) 
 
6.2.6. 
Multiple measurements at One Visit 
If there is more than one assessment reported under a nominal visit (for example data 
reported at the nominal and associated unscheduled visits), the first assessment will be 
used for summary tables and analyses. All assessments will be listed. 
For safety assessments such as ECG the most abnormal result will be reported for the 
visit based on the following hierarchy: Abnormal-Clinically Significant > Abnormal – 
not clinically significant > Normal. 
Where triplicate ECG measures are taken, the average of the triplicates will be used for 
summary statistics, and in the evaluation of the highest post-baseline measure. 
For laboratory assessments, participants with post-baseline safety data in both High and 
Low categories with respect to the Normal Range/Potential Clinical Concern will be 
counted in each of the categories for the “Any visit post-baseline” row of related 
summary tables.   
6.2.7. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in participant listing displays.   
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only. In addition, partial dates may be 
imputed for ‘slotting’ data to study phases or for specific analysis purposes as 
outlined below. 
Exacerbations 
and Adverse 
Events 
Partial dates for exacerbations and AEs recorded in the CRF will be imputed 
using the following imputations: 
Partial Start Date 
'01' will be used for a missing day and 'Jan' will be 
used for a missing month. If this results in a date prior 
to the start of study treatment then the treatment start 
date will be used. The event will then be considered to 
be ‘On-treatment’ as per Section 6.2.2. 
Partial End Date 
(for 
Exacerbations) 
'28/29/30/31' will be used for a missing day 
(dependent on the month and year) and 'Dec' will be 
used for a missing month. If this results in a date after 
the exit visit date, then the exit visit date will be used. 


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Element 
Reporting Detail 
Partial End Date 
(for Adverse 
Events) 
'28/29/30/31' will be used for a missing day 
(dependent on the month and year) and 'Dec' will be 
used for a missing month. If this results in a date after 
the study treatment stop date +28 days, then the study 
treatment stop date + 28 days will be used. 
Completely 
missing start/end 
date 
No imputation is applied. 
Concomitant 
Medications/ 
Medical 
History 
Partial dates for any concomitant medications or medical history conditions 
recorded in the CRF will be imputed using the following convention: 
 
Partial Start 
Date 
'01' will be used for the day and 'Jan' will be used for 
the month. 
Partial End Date 
'28/29/30/31' will be used for the day (dependent on the 
month and year) and 'Dec' will be used for the month. 
Completely 
missing start/end 
date 
No imputation is applied. 
 


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6.3. 
Appendix 3 Exclusions from Per-Protocol Population 
The per-protocol population includes all participants in the mITT who do not have 
protocol deviations that may significantly impact the interpretation of efficacy results.  
Specifically, a participant will be excluded from the per-protocol population if meeting 
any of the following criteria that could significantly impact the interpretation of efficacy 
results: 
Number Exclusion Description 
01 
Informed consent never signed 
02 
Did not meet at least one of the following inclusion criteria (as numbered in the 
protocol) 
1. Participant must be at least 40 years of age at Screening Visit 1 
3. COPD Diagnosis: Documented history of COPD of at least 1 year in accordance 
with the definition by the American Thoracic Society/European Respiratory Society 
7. Smoking status: Current or former cigarette smokers 
03 
Met at least one of the following exclusion criteria (as numbered in the protocol) 
1. Asthma: Participants with a past history or concurrent diagnosis of asthma 
2. Other respiratory disorders: The Investigator must judge that COPD is the primary 
diagnosis 
4. Lung resection: Participants with lung volume reduction surgery within the 12 
months prior to Screening Visit 1. 
10. Eosinophilic Disease: Participants with other conditions that could lead to 
elevated Eosinophils 
11. Parasitic Infection: Participants with a known, pre-existing parasitic infestation 
within 6 months prior to Screening Visit 1. 
15. Previous mepolizumab studies: Participants who have received interventional 
product in previous mepolizumab studies 
17. Investigational Medications: Participants who have received an investigational 
drug within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug 
04 
Did not meet the following randomization inclusion criteria (as numbered in protocol) 
1. Blood eosinophil count: Participants that do not have a historical blood eosinophil 
count that satisfies screening inclusion criterion 2 (Protocol Section 5.1) must have 
Screening Visit 1 blood eosinophil count 150 cells/L. 
05 
Use of prohibited medication during the study [1] 
06 
Occurrence of any one of the following treatment related deviations for 2 
consecutive doses or 3 doses at any time during the study: 
Received study treatment to which they were not randomized 
Study treatment not administered per protocol 
Expired study treatment administered 


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Number Exclusion Description 
Use of study treatment impacted by a temperature excursion which was not 
reported or approved, or which was disapproved for further use 
07 
Participant/investigator is unblinded 
[1] See Section 6.5.3 of protocol for prohibited medications. 
6.4. 
Appendix 4: Adverse Events of Special Interest 
6.4.1. 
Systemic Allergic (Type I Hypersensitivity) and Other Systemic 
Reactions  
Systemic reactions will be collected via a targeted eCRF and are required to be assessed 
against Sampson’s diagnostic criteria for anaphylaxis [Sampson, 2006]. 
Events reported on the eCRF as systemic reactions will be further categorized by the 
investigator as an ‘allergic (type I hypersensitivity) reaction’ or ‘systemic other’ reaction. 
Investigators are instructed to report systemic reactions with the best diagnosis/event 
term that describes the event. 
6.4.2. 
Alterations in immune response (infections) 
All infections and serious infections will be reported under the MedDRA system organ 
class of ‘Infections and Infestations’. 
Specific events of interest are Opportunistic Infections which will be identified through 
matching of collected adverse event preferred terms with those from: 
• Opportunistic infections standard MedDRA query (SMQ) (narrow terms) 
• Herpes zoster preferred term 
 
6.4.3. 
Alterations in immune response (malignancies) 
All neoplasms will be reported under the MedDRA system organ class of ‘Neoplasms, 
benign, malignant and unspecified (including cysts and polyps)’. 
Specific events of interest are Malignancies which will be identified through matching of 
collected adverse event preferred terms with those from: 
Sub-SMQs under the Malignancies SMQ 
• 
Malignant tumours sub-SMQ (narrow terms) 
• Tumours of unspecified malignancy sub-SMQ (narrow terms) 
 
6.4.4. 
Alterations in cardiovascular safety 
Cardiac disorders and serious cardiac disorders will be reported under the MedDRA 
system organ class of ‘Cardiac Disorders’. 


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Specific events of interest are Serious cardiac, vascular, and thromboembolic (CVT) 
events and Ischemic events. Serious CVT events will be identified as all serious adverse 
events classified under the MedDRA system organ classes of ‘Cardiac Disorders’ or 
‘Vascular Disorders’, and thromboembolic events will be identified through matching of 
collected adverse event preferred terms with those from: 
 
Sub-SMQs under the Embolic and thrombotic events SMQ 
• Embolic and thrombotic events, arterial sub-SMQ (narrow terms) 
• Embolic and thrombotic events, venous sub-SMQ (narrow terms) 
• Embolic and thrombotic events, vessel type unspecified and mixed arterial 
and venous sub-SMQ (narrow terms) 
Sub-SMQs under the Ischaemic Heart Disease SMQ 
• Myocardial infarction sub-SMQ (narrow terms) 
• Other Ischaemic heart disease sub-SMQ (narrow terms) 
Sub-SMQs under the Central Nervous System Vascular Disorders SMQ 
• Ischaemic central nervous system vascular conditions sub-SMQ (narrow 
terms) 
• Central nervous system vascular disorders, not specified as haemorrhagic or 
ischaemic sub-SMQ (narrow terms) 
Serious Ischemic adverse events, will be a subset of the Serious CVT events identified 
above through matching of collected adverse event preferred terms with those from: 
Sub-SMQs under the Ischaemic Heart Disease SMQ 
• Myocardial infarction sub-SMQ (narrow terms)  
• Other Ischaemic heart disease sub-SMQ (narrow terms) 
Sub-SMQs under the Central Nervous System Vascular Disorders SMQ  
• Ischaemic central nervous system vascular conditions sub-SMQ (narrow 
terms) 
• Central nervous system vascular disorders, not specified as haemorrhagic or 
ischaemic sub-SMQ (narrow terms) 
6.4.5. 
Local Injection Site Reactions 
Local injection site reactions will be collected via a targeted eCRF. 
 
 


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6.5. 
Appendix 5: Electronic Clinical Outcome Assessment 
(eCOA) Compliance 
The compliance of eCOA data will be derived at a participant level and reported across 
all participants and by treatment group.  
An eCOA will be considered complete if there is no missing data within the assessment. 
Visit-based assessments that are present at a visit due to visit slotting will be considered 
as complete assessments, however if a subject failed to complete an eCOA assessment at 
a visit that would have been slotted (e.g. at an early withdrawal visit), the visit the data 
would have been slotted to will be considered incomplete.  
6.5.1. 
Study Level compliance 
Overall eCOA compliance will be calculated based on the following patient-reported 
assessments: CAT, SGRQ, patient global rating of COPD severity, patient global rating 
of change in COPD and patient rated response to therapy which are all visit based 
assessments and daily symptom diary data. The target compliance for the study is 75%. 
On a study level, overall eCOA compliance will be calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑒𝐶𝑂𝐴𝑠 𝑎𝑐𝑟𝑜𝑠𝑠 𝑎𝑙𝑙 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠
𝑇𝑜𝑡𝑎𝑙 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑒𝐶𝑂𝐴𝑠 𝑎𝑐𝑟𝑜𝑠𝑠 𝑎𝑙𝑙 𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡𝑠 × 100 
Where expected number of complete eCOAs is calculated as: 
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑒𝐶𝑂𝐴𝑠
= ∑∑𝑑𝑎𝑡𝑎 𝑝𝑜𝑖𝑛𝑡𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑓𝑜𝑟 𝑒𝐶𝑂𝐴𝑗(𝑝𝑎𝑟𝑡𝑖𝑐𝑖𝑝𝑎𝑛𝑡 𝑖)
𝑐
𝑗=1
𝑛
𝑖=1
 
where c represents the total number of eCOAs collected and n represents the total number 
of participants.  
Overall compliance will also be categorized, with the number of subjects who are <40% 
compliant, 40-<60% compliant, 60-<80% compliant and ≥80% compliant given. 
6.5.2. 
Endpoint Level compliance 
Compliance will be derived separately at a participant level for the secondary endpoints: 
CAT, SGRQ and E-RS: COPD; and summarized for all participants as well as by 
treatment group 
Compliance for visit-based assessments (CAT and SGRQ) will be based on whether the 
participant completed the assessment for the expected number of visits. The compliance 
will be summarized for each visit time-point. The target compliance for these 
assessments is 85%. 


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Compliance for E-RS: COPD (based on daily diary data) will be based on whether the 
participant completed the expected number of daily diaries within the baseline and 4-
weekly windows used in the endpoint definition. The compliance will be categorized, 
with the number of subjects who are <40% compliant, 40-<60% compliant, 60-<80% 
compliant and ≥80% compliant given for each time window. The target compliance for 
this assessment is 80%. 
 
 


C O N FI D E N TI A L  
 
 
2 0 8 6 5 7  
P a g e 6 8  of 6 8  
7.  
R E F E R E N C E S  
D ola n  P. M o delli n g val uati o ns f or E ur o Q ol Healt h States. Me dic al C are. 1 9 9 7; 3 5: 1 0 9 5 -
1 1 0 8.  
E vi dera, I n c. Ev al u ati n g Res pir at ory Sy m pt o ms ( E -R S ™) i n C O P D ( E -R S ™: C O P D): 
User M a n u al ( Versi o n 5. 0). :; 2 0 1 6.  
Frie de T, Sc h mi dli H. Bli n de d Sa m ple Size Reesti mati o n w it h Ne gati ve Bi n o mial C o u nts 
i n S u peri orit y a n d N o n-i nferi orit y Trials. Met h o ds I nf Me d. 2 0 1 0; 4 9( 6): 6 1 8 -2 4.  
Gla x o S mit h Kli ne D oc u me nt N u m ber T M F -1 3 8 1 1 0 2 8 St u d y I D 2 0 8 6 5 7 Pr ot oc ol 
A me n d me nt 6. A m ulti -ce nter, ra n d o mize d, d o u bl e -bli n d, parallel -gr o u p, place b o -
c o ntr olle d st u d y of me p oliz u ma b 1 0 0 m g S C as a d d -o n treat me nt i n partici pa nts wit h 
C O P D e x perie nci n g fre q ue nt e xacer bati o ns a n d c haract erize d b y e osi n o p hil le vels ( St u d y 
2 0 8 6 5 7). Re p ort Date 0 6 -Dec -2 0 2 1.  
Kee ne O N, J o nes M R K, La ne P W, A n ders o n J. A nal ysis of e xacer bati o n rates i n ast h ma 
a n d c hr o nic o bst r ucti ve p ul m o nar y disease: e xa m ple fr o m t he Trista n st u d y. 
P h ar m ace utic al St atistics. 2 0 0 7; 6: 8 7 -8 9.  
R u bi n D. B, M ulti ple I m p utati o n f or N o nres p o ns e i n S ur ve ys. M ulti ple I m p ut ati o n f or 
N o nres p o nse i n S urveys. 1 e d. Ne w Y or k:J o h n Wile y & S o ns; 1 9 8 7.  
Sa m ps o n  H A, F url o n g A M, Ca m p bell R L, A d ki ns o n N F, B oc k S A, Bra n u m A, Br o w n 
S G A, Ca mra g o C A, C y d ul ka R, Galli SJ, Gi d u d u J, Gr uc halla R S, Harl or A D, He p ner 
D L, Le wis L M, Lie ber ma n P L, Metcalfe D D, O' C o n n or R, M urar o A, R u d ma n A, 
Sc h mitt C, Sc herrer D, Si m o ns F E R, T h o mas S, W o o d J P, Dec ker W W. Sec o n d 
s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort --Sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas e/ F o o d Aller g y a n d A na p h yla xis 
Net w or k s y m p osi u m. J o ur n al of Aller gy a n d Cli nic al I m m u n ol o gy. 2 0 0 6; 1 1 7: 3 9 1 -3 9 7.   
C CI