Clinical trial NCT03562195
Conditions: Asthma
Keywords: Eosinophilic inflammation Mepolizumab Asthma
Sponsor: GlaxoSmithKline
Start date: 2018-08-29; Completion date: 2022-09-07
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Mepolizumab, a humanized monoclonal antibody, has been developed as an add-on treatment for subjects with severe asthma with eosinophilic inflammation. Current asthma treatment guidelines offer minimal options for the severe asthmatic subjects on intensive therapy with frequent exacerbations. There is a significant unmet medical need to provide better treatment options for this segment of the asthma population. Thus, this study is designed to evaluate the efficacy and safety of mepolizumab in Chinese severe asthmatic subjects with eosinophilic inflammation. A total number of 300 subjects will be randomized in 1:1 ratio to receive either mepolizumab or placebo along with existing standard of care therapy. The maximum study duration will be 56 weeks.

Detailed description:

Arms: arm 1: Participants received 100mg of Mepolizumab subcutaneously every 4 weeks during the total treatment period of 52 weeks in addition to their baseline Standard of Care (SOC) treatment for asthma. Participants received salbutamol as a rescue medication on need basis. arm 2: Participants received placebo matching to Mepolizumab administered subcutaneously every 4 weeks during the total treatment period of 52 weeks in addition to their baseline SOC treatment for asthma. Participants received salbutamol as a rescue medication on need basis
Interventions: intervention 1: Mepolizumab 100 milligrams intervention 2: Placebo intervention 3: Salbutamol
Intervention descriptions: intervention 1: Mepolizumab will be given as a lyophilized cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. intervention 2: Placebo will be given as 0.9 percent sodium chloride solution. intervention 3: Salbutamol MDI will be given as a rescue medication to be used on an as needed basis in this study.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 4
Study ID:  201536
Official Title of Study: A randomized, double blind, parallel group study of the 
efficacy and safety of Mepolizumab as adjunctive therapy in patients with severe 
asthma with eosinophilic inflammation
NCT number: NCT03562195
Date of Document: 18-NOV-2021


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TITLE PAGE 
Protocol Title: A randomized, double blind, parallel group study of the efficacy and 
safety of Mepolizumab as adjunctive therapy in patients with severe asthma with 
eosinophilic inflammation 
Protocol Number: 201536/04 
Compound Number: 
SB-240563 
Study Phase: III 
Approval Date: 18-NOV-2021 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited


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Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2014N197489_00 
2018-MAR-28 
Original 
2014N197489_01 
2018-NOV-30 
Amendment No. 1 
This protocol amendment is being implemented to update Medical Monitor Name and 
Contact Information, clarify inclusion criteria/exclusion criteria, randomization criteria, 
withdrawal/stopping criteria, subject and study completion, concomitant therapy, efficacy 
assessments and other minor protocol clarifications. 
2014N197489_02 
2019-MAY-17 
Amendment No. 2 
 
This protocol amendment is being implemented to update inclusion criteria 3#, switching 
FEV1 predicted value equation from NHANESIII to Quanjer, 2012, updated related 
content in pulmonary function testing section, reference and abbreviation accordingly.  
2014N197489_03 
2019-OCT-01 
Amendment No. 3 
This protocol amendment is being implemented to update Secondary Medical Monitor 
Name and Contact information, clarify eDiary objective assessment links to clinically 
significant exacerbation and update the wordings about the blinded evaluation of 
exacerbation. 
TMF-11823581 
2021-NOV-18 
Amendment No. 4 
This protocol amendment is being implemented to update Medical Monitor Name and 
Contact information, clarify type of exacerbation in some other endpoints related to 
systemic corticosteroids (SCS) usage and unscheduled healthcare resource utilization,  
added “mean days of work/school missed” as an other endpoint, updated analysis in 
synopsis, Updated the study day of V2-1 and V2-2 in Schedule of Activities table, 
updated time period for collecting SAE information, added population PK analysis as an 
optional approach for mepolizumab concentration data analysis. Due to the impact of 
pandemic and observed lower event rates under blind assessment, updated statistical 
consideration section and changed analysis methods to borrow data from MEA115588,   
and added a statistical appendix. 
 
 
.


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Medical Monitor Name and Contact Information  
Role 
Name 
email address 
Phone/Cell/ 
Pager 
Number 
Fax Number Site Address 
Primary 
Medical 
Monitor  
 
 
Building 18, 
999 Huanke 
Road, 
Pudong, 
Shanghai, 
201203, China 
Secondary 
Medical 
Monitor 
 
Building 18, 
999 Huanke 
Road, 
Pudong, 
Shanghai, 
201203, China 
SAE  
 
 
 
Building 18, 
999 Huanke 
Road, 
Pudong, 
Shanghai, 
201203, China 
 
Regulatory Agency Identifying Number(s): NA 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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SPONSOR SIGNATORY 
Protocol Title: A randomized, double blind, parallel group study of the efficacy and 
safety of Mepolizumab as adjunctive therapy in patients with severe asthma with 
eosinophilic inflammation 
Protocol Number: 201536/04 
Compound Number: 
SB-240563 
 
 
 
 
 
 
Robert Chan, MD 
Project Physician Lead, Clinical Development Group 
Director, Respiratory TAU  
 
Date 
 
 
The signed page is a separate document. 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
SPONSOR SIGNATORY ................................................................................................ 4 
1. 
PROTOCOL SUMMARY .......................................................................................... 9 
1.1. 
Synopsis ....................................................................................................... 9 
1.2. 
Schedule of Activities (SoA) ........................................................................ 14 
2. 
INTRODUCTION .................................................................................................... 19 
2.1. 
Study Rationale .......................................................................................... 19 
2.2. 
Background ................................................................................................ 19 
2.3. 
Benefit/Risk Assessment ............................................................................ 20 
2.3.1. 
Risk Assessment ......................................................................... 21 
2.3.2. 
Benefit Assessment ..................................................................... 25 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 25 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 26 
3.1. 
Pharmacokinetic Sub-Study ........................................................................ 28 
4. 
STUDY DESIGN .................................................................................................... 29 
4.1. 
Overall Design ............................................................................................ 29 
4.2. 
Treatment Arms and Duration ..................................................................... 30 
4.3. 
Type and Number of Subjects ..................................................................... 32 
4.4. 
Scientific Rationale for Study Design .......................................................... 32 
4.5. 
Justification for Dose .................................................................................. 33 
5. 
STUDY POPULATION ........................................................................................... 34 
5.1. 
Inclusion Criteria ......................................................................................... 34 
5.2. 
Exclusion Criteria ........................................................................................ 35 
5.3. 
Randomization Criteria ............................................................................... 38 
5.4. 
Pre-Screening/ Screening/Baseline/Run-in Failures ................................... 39 
5.5. 
Withdrawal/Stopping Criteria....................................................................... 39 
5.5.1. 
Liver Chemistry Stopping Criteria ................................................ 41 
5.5.1.1. 
Study Treatment Restart or Rechallenge .................... 42 
5.5.2. 
QTc Stopping Criteria .................................................................. 42 
5.6. 
Subject and Study Completion .................................................................... 43 
6. 
STUDY TREATMENT ............................................................................................ 44 
6.1. 
Investigational Product and Other Study Treatment .................................... 44 
6.2. 
Study Treatment Assignment ...................................................................... 44 
6.3. 
Blinding ....................................................................................................... 44 
6.4. 
Packaging and Labeling .............................................................................. 45 
6.5. 
Preparation/Handling/Storage/Accountability .............................................. 45 
6.6. 
Study Treatment Compliance ...................................................................... 46 
6.7. 
Treatment of Study Treatment Overdose .................................................... 46 
6.8. 
Treatment after the End of the Study .......................................................... 47 
6.9. 
Concomitant Therapy.................................................................................. 47 
6.9.1. 
Permitted Medications and Non-Drug Therapies .......................... 47 
6.9.2. 
Prohibited Medications and Non-Drug Therapies ......................... 47 


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7. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 49 
7.1. 
Screening and Critical Baseline Assessments ............................................ 49 
7.1.1. 
Pre-screening Visit (Visit 0) .......................................................... 49 
7.1.2. 
Critical procedures performed at Screen (Visit 1) ......................... 49 
7.1.3. 
Critical procedures performed at randomization (Visit 2) .............. 50 
7.2. 
Efficacy Assessments ................................................................................. 50 
7.2.1. 
Clinically Significant Exacerbations (primary endpoint) ................ 52 
7.2.2. 
eDiary Asthma Parameters and Alerts ......................................... 52 
7.2.3. 
St. George’s Respiratory Questionnaire (SGRQ) ......................... 53 
7.2.4. 
Pulmonary Function Testing including Reversibility ..................... 54 
7.2.5. 
Asthma Control Questionnaire (ACQ) .......................................... 54 
7.2.6. 
Clinician/Subject Rated Response to Therapy ............................. 55 
7.3. 
Safety Assessments ................................................................................... 55 
7.3.1. 
Physical Examinations ................................................................. 55 
7.3.2. 
Vital Signs .................................................................................... 55 
7.3.3. 
Electrocardiogram (ECG) ............................................................. 55 
7.3.4. 
Clinical Safety Laboratory Assessments ...................................... 56 
7.3.5. 
Immunogenicity............................................................................ 57 
7.4. 
Adverse Events and Serious Adverse Events ............................................. 57 
7.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 58 
7.4.2. 
Method of Detecting AEs and SAEs ............................................. 58 
7.4.3. 
Follow-up of AEs and SAEs ......................................................... 58 
7.4.4. 
Regulatory Reporting Requirements for SAEs ............................. 58 
7.4.5. 
Pregnancy ................................................................................... 59 
7.4.6. 
Cardiovascular and Death Events ................................................ 59 
7.5. 
Pharmacokinetics ....................................................................................... 59 
7.5.1. 
Blood Sample Collection .............................................................. 59 
7.5.2. 
Sample Analysis .......................................................................... 60 
7.6. 
Pharmacodynamics .................................................................................... 60 
7.7. 
Health Outcomes ........................................................................................ 60 
7.7.1. 
Health Outcome Endpoints .......................................................... 60 
7.7.1.1. 
Mean days of school/work missed .............................. 60 
7.7.2. 
Healthcare Resource Utilization ................................................... 60 
8. 
DATA MANAGEMENT ........................................................................................... 61 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 61 
9.1. 
Statistical Hypotheses................................................................................. 61 
9.2. 
Sample Size Determination ........................................................................ 62 
9.2.1. 
Sample Size Assumptions ........................................................... 62 
9.2.2. 
Sample Size Sensitivity ................................................................ 63 
9.2.3. 
Sample Size Re-estimation or Adjustment ................................... 63 
9.3. 
Data Analysis Considerations ..................................................................... 64 
9.3.1. 
Analysis Populations .................................................................... 64 
9.3.2. 
Interim Analysis ........................................................................... 64 
9.4. 
Key Elements of Analysis Plan ................................................................... 64 
9.4.1. 
Efficacy Analyses ......................................................................... 65 
9.4.1.1. 
Primary Analyses ....................................................... 67 
9.4.1.2. 
Key Secondary Analyses ............................................ 68 
9.4.1.3. 
Other Analyses ........................................................... 69 
9.4.2. 
Safety analyses ........................................................................... 69 


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9.4.2.1. 
Extent of Exposure ..................................................... 69 
9.4.2.2. 
Adverse Events .......................................................... 69 
9.4.2.3. 
Clinical Laboratory Evaluations .................................. 69 
9.4.2.4. 
Other Safety Measures ............................................... 69 
9.4.2.5. 
Immunogenicity .......................................................... 69 
9.4.3. 
Pharmacokinetic Analyses ........................................................... 70 
9.4.4. 
Pharmacodynamic Analyses ........................................................ 70 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ............................. 70 
9.4.6. 
Health Outcome Analyses ........................................................... 70 
10. STUDY GOVERNANCE CONSIDERATIONS ........................................................ 71 
10.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 71 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 71 
10.3. 
Quality Control (Study Monitoring) .............................................................. 71 
10.4. 
Quality Assurance ....................................................................................... 72 
10.5. 
Study and Site Closure ............................................................................... 72 
10.6. 
Records Retention ...................................................................................... 73 
10.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 73 
11. REFERENCES ....................................................................................................... 75 
12. APPENDICES ........................................................................................................ 78 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 78 
12.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 80 
12.3. 
Appendix 3: Adverse Events: Definition and Procedures for 
Recording, Evaluating, Follow-Up and Reporting ........................................ 84 
12.3.1. 
Definition of Adverse Events ........................................................ 84 
12.3.2. 
Definition of Serious Adverse Events ........................................... 85 
12.3.3. 
Definition of Cardiovascular Events ............................................. 86 
12.3.4. 
Recording of AEs and SAEs ........................................................ 86 
12.3.5. 
Reporting of SAEs to GSK ........................................................... 88 
12.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 90 
12.4.1. 
Definitions .................................................................................... 90 
12.4.2. 
Contraception Guidance .............................................................. 91 
12.4.3. 
Collection of Pregnancy Information: ........................................... 92 
12.5. 
Appendix 5: Cardiovascular Screening Questions ...................................... 93 
12.6. 
Appendix 6: Daily Asthma Symptom Score ................................................. 94 
12.7. 
Appendix 7: Anaphylaxis Criteria ................................................................ 95 
12.8. 
Appendix 8: New York Heart Association Functional Classification 
of Congestive Heart Failure ........................................................................ 96 
12.9. 
Appendix 9 Statistical Appendix .................................................................. 97 
12.9.1. 
Choice of posterior probability ...................................................... 97 
12.9.2. 
Overview of the proposed robust mixture prior and 
analysis strategy .......................................................................... 97 
12.9.2.1. The informative (global) prior ...................................... 98 
12.9.2.2. The vague prior .......................................................... 98 
12.9.2.3. Initial weight on informative (global) prior 
component and mixture prior ...................................... 98 


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12.9.3. 
Choice of weights ........................................................................ 98 
12.10. Appendix 10: Protocol Amendment Changes .............................................. 99 
12.10.1. Protocol Amendment 1 ................................................................ 99 
12.10.2. Protocol Amendment 2 .............................................................. 112 
12.10.3. Protocol Amendment 3 .............................................................. 115 
12.10.4. Protocol Amendment 4 .............................................................. 119 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomized, double blind, parallel group study of the efficacy and 
safety of Mepolizumab as adjunctive therapy in patients with severe asthma with 
eosinophilic inflammation 
Rationale: 
This study proposed to be conducted in China is similar in design to the global pivotal 
study MEA115588 which has established favourable benefit risk profile of mepolizumab 
in severe asthmatics with eosinophilic inflammation. While patients with severe asthma 
represent only a small percentage (5-10%) of the asthmatic population, they incur the 
greatest direct costs for the treatment of asthma. Current asthma treatment guidelines 
offer minimal options for the severe asthmatic patient on intensive therapy with frequent 
exacerbations. There is a significant unmet medical need to provide better treatment 
options for this segment of the asthma population. Previous studies in severe asthmatic 
patients with eosinophilic inflammation have demonstrated a reduction in the frequency 
of clinically significant exacerbations and a reduction in oral corticosteroids (OCS) in 
OCS-dependent subjects with mepolizumab which has also exhibited a favorable safety 
profile. This study is a Phase III study in Chinese population, to evaluate the efficacy and 
safety of mepolizumab in severe asthmatics with eosinophilic airway inflammation.  
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Efficacy 
• 
To evaluate the efficacy of mepolizumab 
100 mg subcutaneous (SC) every 
4 weeks versus placebo on the 
frequency of clinically significant 
exacerbations in adult and adolescent 
Chinese subjects with severe asthma 
with eosinophilic airway inflammation. 
Frequency of clinically significant exacerbations 
of asthma over the 52-week treatment period.  
    Clinically significant exacerbations are 
defined as: Worsening of asthma which 
requires use of systemic corticosteroids (SCS)1 
and/or hospitalizations and/or Emergency 
Department (ED) visits.  
 
1For all subjects, i.v. or oral corticosteroid for at 
least 3 days or a single IM Corticosteroid (CS ) 
dose is required. For subjects on maintenance 
systemic corticosteroids (SCS), at least double the 
existing maintenance dose for at least 3 days is 
required. 
Secondary Efficacy 
• 
To evaluate the effects of mepolizumab 
compared with placebo on a range of 
clinical markers of asthma control, 
1. Time to first clinically significant 
exacerbations 
2. Mean change in St. George’s Respiratory 
Questionnaire (SGRQ) at Week 52 


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Objectives 
Endpoints 
including exacerbations, lung function, 
and quality of life. 
3. Frequency of exacerbations requiring 
hospitalisation (including intubation and 
admittance to an ICU) or ED visits over the 
52-week treatment period 
4. Frequency of exacerbations requiring 
hospitalisation over the 52-week treatment 
period 
5. Mean change from baseline in clinic pre-
bronchodilator FEV1 at Week 52 
Safety 
• 
To evaluate the safety and tolerability of 
mepolizumab compared with placebo, in 
subjects with severe asthma with 
eosinophilic inflammation 
1. Adverse Event including systemic (i.e. 
allergic [type I hypersensitivity] and Other 
systemic) and injection site reactions 
reported throughout the 52-week treatment 
period. 
2. Haematological and clinical chemistry 
parameters. 
3. Vital signs (pulse rate and systolic and 
diastolic blood pressure). 
4. 12-lead ECG  
5. Frequency of subjects with anti-
mepolizumab antibody positive results. 
Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control. 
1. Mean change from baseline compared to 
placebo in Asthma Control Questionnaire 
(ACQ-5) score at Week 52.  
2. Percent of subjects evaluated as responders 
as measured by ACQ-5 score at Week 52. 
3. Percent of subjects evaluated as responders 
as measured by SGRQ score at Week 52. 
4. Percent of subjects recording a favourable 
treatment response as measured by the 
Subject Rated Response to Therapy at 
Week 52.   
5. Percent of subjects evaluated as having a 
favourable treatment response as measured 
by the Clinician Rated Response to Therapy 
at Week 52. 
6. Mean change from baseline in daily 
salbutamol/albuterol use 


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Objectives 
Endpoints 
7. Mean change from baseline in daily asthma 
symptom scores   
8. Mean change from baseline in awakening at 
night due to asthma symptoms requiring 
rescue medication use. 
9. Mean change from baseline in morning PEF  
10. Mean change from baseline in clinic post-
bronchodilator FEV1 at Week 52. 
11. Mean number of days with oral 
corticosteroids taken for clinically 
significant exacerbations 
12. Total prednisone (or equivalent) exposure 
for clinically significant exacerbation over 
the 52-week treatment period 
13. Frequency of all exacerbations 
14. Time to first exacerbation 
15. Time to withdrawal from study treatment 
due to asthma exacerbations 
16. Time to first exacerbation requiring 
hospitalization or ED visit 
17. Unscheduled healthcare resource 
utilization (for clinically significant 
exacerbations and other asthma related 
health care) over the 52-week treatment 
period 
18. Mean days of School/Work missed over the 
52-week treatment period  
Pharmacodynamics 
• 
To evaluate the PD of SC 
mepolizumab in Chinese subjects 
with severe asthma with eosinophilic 
airway inflammation. 
Blood eosinophil ratio to baseline 
PK Sub-Study  
• 
To evaluate the PK of SC 
mepolizumab in Chinese subjects 
with severe asthma with eosinophilic 
airway inflammation 
PK parameter estimates of mepolizumab. 
 
 


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The primary clinical question of interest is: What is the effect of adding mepolizumab to 
standard of care when compared with placebo plus standard of care on the rate of 
exacerbations over 52 weeks in Chinese participants with severe eosinophilic asthma? 
This question is to be addressed in the absence of study treatment discontinuation.   
The estimand is described by the following attributes: 
o Population: Chinese participants with severe eosinophilic asthma. 
o Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to 
placebo every 4 weeks, both treatments given on top of standard of care. Further 
details on standard of care can be found in Section 6. 
o Variable: number of clinically significant exacerbations over 52 weeks. 
o Summary measure: annulised rate of exacerbations. Comparison between the 
mepolizumab arm and placebo will be assessd with the rate ratio.  
o Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
o Rationale for estimand:  
Interest lies in the treatment effect when medication is taken as directed.  For 
participants discontinuing randomised medication, use of a hypothetical strategy 
addresses treatment effects attributable to mepolizumab in the hypothetical 
scenario where participants would not discontinue from treatment. 
Overall Design: 
This study employs a randomized, multi-centre, placebo-controlled, double-blind, 
parallel-group design. A PK sub-study will be included to meet regulatory requirements. 
Treatment Arms and Duration 
Eligible subjects will be requested to participate for a maximum of 56 weeks (Visit 1 to 
the Visit 15, inclusive) in the main study. A sub-set of subjects will participate in the PK 
sub-study for a maximum of 64 weeks (Visit 1 to Visit 15-2, inclusive). 
Following screening to assess eligibility and a run-in period for 1-4 weeks during which 
baseline data will be captured in an eDiary, subjects will be randomized in a 1:1 ratio to 
receive either mepolizumab (100 mg) SC or placebo SC added onto their existing therapy 
for asthma every 4 weeks for a total of 13 doses. The treatment period will conclude 
approximately 4 weeks after the last dose.   
For subjects who enter the PK sub-study, PK samples will be collected at the time points 
specified in the Schedule of Activities which requires 6 additional visits (to collect PK 
samples only). 


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Number of Participants: 
Approximately 429 subjects with severe asthma with eosinophilic inflammation who 
meet the protocol defined inclusion criteria will be screened to ensure the 1:1 
(mepolizumab: placebo) randomization of 300 subjects in the study (150 subjects in the 
mepolizumab treatment group and 150 subjects in the placebo treatment group). 
Subjects will be stratified based on blood eosinophil count at screening 
(300 cells/L ,<300 cells/L). A minimum of 150 subjects will be enrolled with blood 
eosinophil count 300 cells/L.  
This study will include a PK sub-study in which approximately 52 randomized subjects 
will provide PK samples, irrespective of the allocated treatment (to maintain the study 
blind). This will ensure approximately 26 subjects receiving mepolizumab will provide 
PK information. This is to meet the regulatory requirement of approximately 
20 evaluable subjects for PK analysis. 
Analysis 
The study is designed to determine the effect of Mepolizumab 100mg SC on clinically 
significant exacerbation events, compared with placebo among Chinese subjects.  
The study design mirrors the design of study MEA115588, which demonstrated benefits 
of mepolizumab compared to placebo for a global population of severe asthma patients 
with eosinophilic inflammation. This study will evaluate the effects in Chinese patients 
and, assuming that effects consistent with the global population are observed, a more 
precise evaluation of the benefit in Chinese patients will conducted by combining data 
from the local China study with MEA115588 using Bayesian dynamic borrowing (see 
Statistical Considerations in Section 9). The potential to borrow information from the 
global dataset is based on the premise that the underlying disease, its general 
management and the response to mepolizumab is similar in Chinese and non-Chinese 
patients. 
The posterior distributions of the primary endpoint, i.e. rate ratio of events between 
Mepolizumab 100mg SC vs. placebo will be derived. The hypothesis of interest for 
treatment comparison is that the rate ratio is less than 1 (alternative hypothesis testing 
boundary in study MEA115588), and the study will be considered to have shown 
evidence that supports this hypothesis if the posterior probability that the rate ratio is less 
than 1 is at least 95% (a “positive result”). Rationales to support this testing criteria can 
be found in Section 9.4.1 (Efficacy Analyses).  
The primary analyses will be performed using a generalized linear model (GLM) 
assuming the negative binomial distribution. The estimate of the rate ratio for 
mepolizumab vs. placebo as well as an estimate of the dispersion will be provided, they 
will be combined with global MEA115588 study using the robust mixture prior to obtain 
the final posterior distribution for the China rate ratio. The mean, median and 90% 
credible interval of this posterior distribution of the rate ratio will be reported, along with 
the probability that true rate ratio is less than 1. 


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The  secondary endpoints are defined in the Objective(s)/Endpoint(s) above . No 
multiplicity adjustment are planned for secondary endpoints. 
1.2. 
Schedule of Activities (SoA) 
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 Table 1, are essential and required for study conduct. This section lists 
the procedures and parameters of each planned study assessment.   
The timing of the assessments should allow the blood draw to occur at the exact nominal 
time. Patient Reported Outcomes questionnaires should be completed before any other 
assessments. 
 


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Table 1 
Schedule of Activities Table 
Procedures 
Pre-
screening
Screen/Run-
in 
Randomised Treatment (visit window is ± 7 days for V3-V15-2; 
 V2-1, V2-2, V14-1, V14-2 visit window is ± 2 days from V2 or V14 in sub-study) 
Exit Visit 
With-
drawal 
 
Visit 
V01 
V1 
V22 
V 
2-13 
V 
2-23 V3 
V4 
V5 
V6 
V7 
V8 V9 V10 V11 V12 V13 V14 
V 
14-13 
V 
14-23 V15 V 
15-13 
V 
15-23 
VEW 
 
Study Week 
 
-4 to -1 
 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
49 
50 
52 
56 
60 
 
Study Day 
 
-28~ 
-7 
1 
8 
15 
28 
56 
84 112 140 168 196 224 252 280 308 336 343 350 364 392 420 
 
Procedures 
Written Informed Consent 
(main study, PK sub-study) 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Asthma and exacerbation 
history (including triggers) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Therapy history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (including 
cardiovascular history/risk) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Assessment 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Parasitic Screening5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation criteria 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
Exacerbation review 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Spirometry (FEV1, FVC) 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Reversibility Test 
 
X 
X7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
ACQ-5 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
SGRQ 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Clinician rated response to 
therapy 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 


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Procedures 
Pre-
screening
Screen/Run-
in 
Randomised Treatment (visit window is ± 7 days for V3-V15-2; 
 V2-1, V2-2, V14-1, V14-2 visit window is ± 2 days from V2 or V14 in sub-study) 
Exit Visit 
With-
drawal 
 
Visit 
V01 
V1 
V22 
V 
2-13 
V 
2-23 V3 
V4 
V5 
V6 
V7 
V8 V9 V10 V11 V12 V13 V14 
V 
14-13 
V 
14-23 V15 V 
15-13 
V 
15-23 
VEW 
 
Study Week 
 
-4 to -1 
 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
49 
50 
52 
56 
60 
 
Study Day 
 
-28~ 
-7 
1 
8 
15 
28 
56 
84 112 140 168 196 224 252 280 308 336 343 350 364 392 420 
 
Subject rated response to 
therapy 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
             Health Outcome Assessments 
Unscheduled healthcare 
contact/resource utilization 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Safety Assessments 
Adverse Events/Serious 
Adverse Event Assessment 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Physical Examination 
 
X8 
X9 
 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
 
 
X9 
 
 
X9 
Vital Signs  
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Laboratory Assessments10 
Hematology with differential11 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Clinical Chemistry 
 
X 
 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test12 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
FSH for suspected 
menopause female 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C testing13, 14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic Sample (sub-
study only)15 
 
 
X16 
X 
X 
X16 
 
 
 
 
X16 
 
 
 
 
 
X16 
X 
X 
X 
X 
X 
X 
Immunogenicity sample17 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 


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Procedures 
Pre-
screening
Screen/Run-
in 
Randomised Treatment (visit window is ± 7 days for V3-V15-2; 
 V2-1, V2-2, V14-1, V14-2 visit window is ± 2 days from V2 or V14 in sub-study) 
Exit Visit 
With-
drawal 
 
Visit 
V01 
V1 
V22 
V 
2-13 
V 
2-23 V3 
V4 
V5 
V6 
V7 
V8 V9 V10 V11 V12 V13 V14 
V 
14-13 
V 
14-23 V15 V 
15-13 
V 
15-23 
VEW 
 
Study Week 
 
-4 to -1 
 0 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
49 
50 
52 
56 
60 
 
Study Day 
 
-28~ 
-7 
1 
8 
15 
28 
56 
84 112 140 168 196 224 252 280 308 336 343 350 364 392 420 
 
Study Supplies and Investigational Product 
Register Visit in 
RAMOS/IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administer Investigational 
Product 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Complete electronic Case 
Report Form (eCRF) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
eDiary dispense and training 
 
X18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary review 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
eDiary collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Dispense paper worksheet 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Collect/review paper 
worksheet 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Dispense Rescue Salbutamol 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Collect Used Rescue 
Salbutamol 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
1. 
The pre-screening visit (Visit 0) can occur on the same day as the screening visit (Visit 1) but must be completed prior to initiating any Visit 1 procedures. 
2. 
Visit 2 can occur 1 to 4 weeks after Visit 1. Results from Visit 1 procedures must be available for review of randomization criteria. 
3. 
Only those patients attending the PK sub-study will perform the visit. . Protocol amendment 4 updated Study Day of V2-1 (from day 7 to day 8) and V2-2 (from day 14 to 
day15) to clarify the duration of PK sample collection. On final PK Sample ID form and related PK CRF forms in InForm System, “VISIT 2 PREDOSE” refers to “VISIT2 
DAY1”, “VISIT 2 DAY7” refers “VISIT 2 DAY8”, and “VISIT 2 DAY 14” refers to “VISIT 2 DAY15” in SoA. 
4. 
Informed consent for the optional PK sub-study must be obtained before collecting a related sample. 
5. 
Parasitic screening is only required in subjects who have visited high-risk countries in the past 6 months. Sites should use local laboratories. 
6. 
Only required if results from a chest x-ray or CT-scan, taken within the past 6 months, is not available 
7. 
Reversibility test is required at screen. If subject does not reverse 12% and 200 mL in FEV1 at visit 1 (screen), the procedure may be repeated at Visit 2. 
8. 
A comprehensive physical exam should be conducted. See Section 7.3.1 for specific details of the comprehensive physical exam. 
9. 
A brief physical exam should be conducted. See Section 7.3.1 for specific details of the brief exam. 
10. During the treatment period, all lab samples (not applicable for PK samples) and procedures should be obtained pre-dose. 


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11. Differential results including eosinophil counts will be blinded from Visit 3 onwards. 
12. Urine pregnancy testing is only required for females of child bearing potential. An assessment must be made at baseline to determine child bearing potential of each female 
study participant (see Table 6). 
13. If hepatitis C positive confirmation by testing the same sample is required. See central laboratory manual for details. 
14. For subjects who are HBsAg positive at Visit 1 or HBcAb positive (documented previous positive) reflexive testing must be conducted to assess HBV DNA. 
15. Actual time for each PK sample collection needs to be recorded. 
16. PK samples must be collected pre-dose. 
17. For subjects who are ADA or NAB positive, PK sample collected with the immunogenicity sample (for subjects not in the PK sub-study) will be assessed. 
18. Thorough eDiary training should be conducted at Visit 1 and throughout the study on an as-needed basis 
 


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2. 
INTRODUCTION 
Mepolizumab, a humanised monoclonal antibody (IgG1, kappa, mAb), has been 
developed as an add-on treatment for patients with severe asthma with eosinophilic 
inflammation.  
Mepolizumab binds with high specificity and affinity to human interleukin 5 (IL-5). By 
targeting IL-5, mepolizumab prevents IL-5 from binding to the alpha chain of the IL-5 
receptor complex expressed on the eosinophil cell surface and thus inhibits IL-5 
signalling and the overexpression of peripheral blood and tissue eosinophils. Eosinophilic 
inflammation of the airways plays a central role in the pathogenesis of asthma.  
Available data do not indicate that reduction of eosinophils has any untoward effects on 
normal health [Gleich, 2013]. Thus, a therapeutic strategy targeting IL-5 with 
mepolizumab represents a focused therapeutic option which results in reduced eosinophil 
levels and important clinical benefits for patients with eosinophilic inflammation 
associated with severe asthma who are receiving optimised standard of care therapy. 
2.1. 
Study Rationale 
Previous studies in severe asthmatic patients with eosinophilic inflammation have 
demonstrated a reduction in the frequency of clinically significant exacerbations [Haldar, 
2009;  Pavord, 2012; Ortega, 2014] and a reduction in oral corticosteroids (OCS) in OCS-
dependent subjects [Nair, 2009][Bel, 2014] with mepolizumab which has also exhibited a 
favourable safety profile. Previous study details are described in the Investigator’s 
Brochure [GlaxoSmithKline Document Number CM2003/00010/13]   This study is a 
Phase III study in Chinese population, to evaluate the efficacy and safety of mepolizumab 
in severe asthmatics with eosinophilic inflammation. This study is similar in design to the 
global pivotal study MEA115588 which has established favourable benefit risk profile of 
mepolizumab in severe asthmatics with eosinophilic inflammation.  
2.2. 
Background 
While patients with severe asthma represent only a small percentage (5-10%) of the 
asthmatic population, they incur the greatest direct costs for the treatment of asthma 
[Ambrosino, 2012], [Bossley, 2012] . Asthma exacerbations are a major contributor to 
the increased healthcare costs in patients with moderate to severe asthma [Ivanova, 
2012]. They are estimated to make-up between 35-50% of medical expenditures for 
asthma [Fuhlbrigge, 2012].  Current asthma treatment guidelines offer minimal options 
for the severe asthmatic patient on intensive therapy with frequent exacerbations. As a 
result, these patients are often exposed to repeated intermittent or long-term continuous 
use of systemic corticosteroids (SCS). CS provide variable efficacy benefits for patients 
with severe asthma, some patients are completely refractory to this treatment. Regardless 
of the degree of effectiveness provided by CS, all patients are at risk of the short- and 
long-term toxicities associated with its use. Consequently, there is a significant unmet 
medical need to provide better treatment options for this segment of the asthma 
population. 
Currently available therapies are highly effective at controlling asthma symptoms and 
airway inflammation in the majority of patients. However, a proportion of asthma 


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patients remain uncontrolled despite appropriate therapy with high dose inhaled 
corticosteroids (ICS) or ICS with additional controller therapy (National Heart Lung and 
Blood Institute [NHLBI] Guidelines for the Diagnosis and Treatment of Asthma). This 
severe, uncontrolled population suffers from persistent symptoms and acute 
exacerbations of their asthma. 
Severe asthma encompasses wide ranges in both clinical symptoms and in natural history. 
This population can be defined on the basis of medication requirements, asthma 
symptoms, degree of airflow limitation, and frequency of asthma exacerbations. In terms 
of exacerbations, two or more corticosteroid-treated exacerbations have been considered 
part of the typical clinical features in this patient population [Chung, 2014b]. 
Evidence shows that patients with severe asthma are comprised of complex, overlapping 
and non-overlapping phenotypes, including an eosinophilic asthma phenotype [Chung, 
2014a] , which can be associated with increased asthma severity, atopy, late-onset 
disease, and corticosteroid insensitivity.  
Previous studies have demonstrated that mepolizumab is effective and well tolerated in 
the eosinophilic phenotype. In Nov 2015, Mepolizumab received its first approval in the 
US as an add-on maintenance treatment for patients with severe asthma aged 12 years 
and older, and with an eosinophilic phenotype [Nucala Label, 2015].  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of mepolizumab may be found in the Investigator’s 
Brochure.  The following section (Section 2.3.1) outlines the risk assessment and 
mitigation strategy for this protocol:   


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2.3.1. 
Risk Assessment 
Potential Risk of Clinical significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [mepolizumab]  
Risk of Systemic (Allergic [type I 
hypersensitivity] and Other systemic) 
Reactions, including Anaphylaxis 
Reactions reported to date across the 
mepolizumab program are summarized in the 
IB; see ‘Special Warnings and Special 
Precautions for Use’ section located in Section 
6 titled ‘Summary of Data and Guidance for the 
Investigator’. 
Acute and delayed systemic reactions, 
including hypersensitivity reactions (e.g., 
anaphylaxis, urticaria, angioedema, rash, 
bronchospasm, hypotension), have 
occurred following administration of 
mepolizumab.  These reactions generally 
occur within hours of administration, but in 
some instances had a delayed onset (i.e., 
days).   
Daily monitoring of serious adverse events 
(SAEs) by medical monitor/SAE coordinator; 
regular systematic review of adverse event 
(AE)/SAE data from ongoing studies by a GSK 
safety review team.  
Customized AE and SAE case report forms 
(CRF) are utilized for targeted collection of 
information on systemic reaction adverse 
events. 
Use of Joint National Institute of Allergy and 
Infectious Disease (NIAID)/Food Allergy and 
Anaphylaxis Network (FAAN) 2nd 
Symposium on Anaphylaxis to collect data on 
reports of anaphylaxis (see Appendix 7). 
Subjects are to be monitored in clinic for one- 
hour post-injection after the first 3 
administrations study treatment, and then 
according to standard of care for the site. 
Local injection site reactions 
The most common symptoms associated with 
subcutaneous injections included: pain, 
erythema, swelling, itching, and burning 
sensation. 
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by GSK study team and/or 
safety review team. 


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Potential Risk of Clinical significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Customised AE and SAE case report form 
(CRF) utilised for targeted collection of 
information for local injection site reaction 
adverse events. 
Risk of Immunogenicity 
Mepolizumab has low immunogenic 
potential. Overall, the immunogenicity 
results from clinical studies across 
mepolizumab program demonstrate that the 
presence of ADAs is not associated with 
any specific adverse events, anti-
mepolizumab antibodies did not discernibly 
impact the PK or PD of mepolizumab in 
the majority of subjects 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 a summary of 
immunogenicity findings in the ‘Other 
Potentially Clinically Relevant Information for 
the Investigator’ section located in Section 6 
titled ‘Summary of Data and Guidance for the 
Investigator’. 
Blood samples are collected in clinical studies 
for detection of both ADA and NAB. 
For subjects who are ADA or NAB positive, 
PK samples collected with the immunogenicity 
samples will be assessed. 
Daily monitoring of serious adverse events 
(SAEs) by medical monitor/SAE coordinator; 
regular systematic review of adverse event 
(AE)/SAE data from ongoing studies by a GSK 
safety review team. 
Potential risk for adverse cardiovascular 
(CV) effects 
No clinically relevant trends observed in ECG 
data in humans. 
Daily monitoring of SAEs by medical 
monitor/SAE Coordinator; regular systematic 


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Potential Risk of Clinical significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
In one earlier Phase III study in subjects with 
severe asthma with eosinophilic inflammation, 
a small numerical increase observed in serious 
cardiac events in the mepolizumab-treated 
group. However, an integrated safety analysis 
of phase III placebo-controlled asthma trials 
did not show an increased risk of 
cardiovascular events with mepolizumab. 
Cardiac events reported to date across the 
mepolizumab programme are summarised in 
the IB “Safety in Clinical studies” section 
under each indication studied. 
review of AE/SAE data from ongoing studies 
by a GSK safety review team. 
CV monitoring per protocol.  
As per GSK standard practice, use of 
standardized CRFs to collect additional data on 
protocol specified CV events (e.g., myocardial 
infarction, hospitalization for unstable angina 
and congestive heart failure, arterial 
thrombosis, pulmonary embolism and deep 
vein thrombosis) 
 
Potential risk for infections. 
An integrated safety analysis of the phase III 
placebo-controlled asthma trials showed similar 
reports of infections, including serious and 
opportunistic, across treatment groups.  
Infections reported to date across the 
mepolizumab development program are 
summarized in the IB; see ‘Special Precautions 
and Warnings’ (for exclusion of subjects with 
underlying parasitic infections) and 
‘Undesirable Effects’ sections located in 
Section 6 titled ‘Summary of Data and 
Guidance for the Investigator’. 
Daily monitoring of SAEs by medical monitor/ 
SAE Coordinator; regular systematic review of 
AE/SAE data from ongoing studies by a GSK 
safety review team  
 
Subjects with a known, pre-existing 
parasitic infestation within 6 months prior 
to Visit 1 are excluded 
Potential risk for malignancies - 
An integrated safety analysis of phase III 
placebo-controlled asthma trials showed similar 
Daily monitoring of SAEs by medical monitor/ 
SAE Coordinator; regular systematic review of 


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Potential Risk of Clinical significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
reports of malignancies across treatment 
groups. 
Malignancies reported to date across the 
mepolizumab development program are 
summarized in the IB section “Safety in 
Clinical Studies” under each indication. 
AE/SAE data from ongoing studies by a GSK 
safety review team  
 
Study Procedures  
Potential risk for injury with phlebotomy 
Risks with phlebotomy include bruising, 
bleeding, infection, nerve damage. 
Procedures to be performed by trained 
personnel (i.e., study nurse)  
Inclusion of a placebo arm 
The objective of the study is to compare the 
efficacy and safety of mepolizumab versus 
placebo in asthmatics subjects receiving 
standard-of-care therapy. 
Because all subjects are receiving background 
standard-of-care therapy in this study the 
Sponsor considers inclusion of a placebo arm 
to be justified. 
Blinding eosinophil counts 
This study is a double-blind study which will 
be used to support approval for the use of 
mepolizumab in the reduction of clinical 
significant exacerbations in patients with severe 
asthma with eosinophilic inflammation. 
Unblinding eosinophil counts may compromise 
the integrity of the study. 
Patients will be seen monthly by qualified 
investigators.  
Neither the site nor GSK personnel will be sent 
results from the central laboratory for: i) 
absolute eosinophil count or ii) white blood 
count differentials (% neutrophil, lymphocyte, 
monocyte, eosinophil and basophil), for each 
subject’s duration in the study for any visits 
post-randomization. However, sites will be sent 
total white blood counts throughout the study. 
 


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2.3.2. 
Benefit Assessment 
Exacerbations are a major concern to asthma patients and lead to a worsening of the 
quality of life for subjects. Mepolizumab has demonstrated significant clinical benefit in 
reducing exacerbations in severe asthma where eosinophilia is considered to play a key 
role in the pathology.  
In this study, benefit considerations for a subject may include: 
• Potential to receive active drug during study conduct that may have clinical utility. 
Interventions in at risk populations that can reduce or eliminate serious exacerbations 
will improve a patient’s quality of life and may reduce hospitalizations. 
• Contributing to the process of developing new therapies in an area of unmet need. 
• Data obtained from study 201536 will provide a robust evaluation of the efficacy and 
safety of mepolizumab in the Chinese population. Subjects participating in this study 
will be required to attend visits approximately every 4 weeks and therefore may 
benefit from the additional monitoring to their current standard asthma care. 
• Medical evaluations/assessments associated with study procedures. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Mepolizumab is approved for the treatment of severe eosinophilic asthma at a dose of 100 
mg SC every four weeks in the US, all EU Member States, Japan, as well as over 10 further 
countries. 
Mepolizumab has a well-characterised efficacy and safety profile supported by the 
clinical development programme in the treatment of severe eosinophilic asthma.  Data 
from the clinical development programme show that mepolizumab is effective in 
reducing the rate of clinically significant exacerbations, improving asthma control and 
quality of life, and reducing the requirement for daily systemic corticosteroids (SCS) in 
patients with severe eosinophilic asthma.  Overall, the safety profile showed 
mepolizumab to be well-tolerated, and comparable to placebo. Acute and delayed 
systemic reactions, including hypersensitivity reactions (e.g., anaphylaxis, urticaria, 
angioedema, rash, bronchospasm, hypotension), have occurred following administration 
of mepolizumab. In this study, systemic reaction events will be collected utilizing 
targeted case report forms, and subjects will be monitored for at least an hour following 
first 3 administrations of study intervention, and then per institutional guidelines.   
The benefit risk profile of mepolizumab for the treatment of severe eosinophilic asthma is 
positive. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 2 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy 
To evaluate the efficacy of mepolizumab 
100 mg subcutaneous (SC) every 
4 weeks versus placebo on the frequency 
of clinically significant exacerbations in 
adult and adolescent Chinese subjects 
with severe asthma with eosinophilic 
airway inflammation. 
Frequency of clinically significant exacerbations of 
asthma over the 52-week treatment period.  
    Clinically significant exacerbations are defined 
as: Worsening of asthma which requires use of 
systemic corticosteroids (SCS)1 and/or 
hospitalizations and/or Emergency Department 
(ED) visits.  
 
1For all subjects, i.v. or oral corticosteroid for at least 3 
days or a single IM CS dose is required. For subjects 
on maintenance systemic corticosteroids (SCS), at 
least double the existing maintenance dose for at least 
3 days is required. 
Secondary Efficacy 
• 
To evaluate the effects of mepolizumab 
compared with placebo on a range of 
clinical markers of asthma control, 
including exacerbations, lung function, 
and quality of life. 
1. Time to first clinically significant exacerbations 
2. Mean change in St. George’s Respiratory 
Questionnaire (SGRQ) at Week 52 
3. Frequency of exacerbations requiring 
hospitalisation (including intubation and 
admittance to an ICU) or ED visits over the 
52-week treatment period 
4. Frequency of exacerbations requiring 
hospitalisation over the 52-week treatment 
period 
5. Mean change from baseline in clinic pre-
bronchodilator FEV1 at Week 52 
Safety 
• 
To evaluate the safety and tolerability of 
mepolizumab compared with placebo, in 
subjects with severe asthma with 
eosinophilic inflammation. 
1. Adverse Event including systemic (i.e. allergic 
[type I hypersensitivity] and other systemic) 
and injection site reactions reported 
throughout the 52-week treatment period. 
2. Haematological and clinical chemistry 
parameters. 
3. Vital signs (pulse rate and systolic and 
diastolic blood pressure). 
4. 12-lead ECG  


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Objectives 
Endpoints 
5. Frequency of subjects with anti-mepolizumab 
antibody positive results. 
Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control.  
1. Mean change from baseline compared to 
placebo in Asthma Control Questionnaire 
(ACQ-5) score at Week 52.  
2. Percent of subjects evaluated as responders 
as measured by ACQ-5 score at Week 52. 
3. Percent of subjects evaluated as responders 
as measured by SGRQ score at Week 52. 
4. Percent of subjects recording a favourable 
treatment response as measured by the 
Subject Rated Response to Therapy at Week 
52.   
5. Percent of subjects evaluated as having a 
favourable treatment response as measured 
by the Clinician Rated Response to Therapy 
at Week 52. 
6. Mean change from baseline in daily 
salbutamol/albuterol use 
7. Mean change from baseline in daily asthma 
symptom scores   
8. Mean change from baseline in awakening at 
night due to asthma symptoms requiring 
rescue medication use. 
9. Mean change from baseline in morning PEF  
10. Mean change from baseline in clinic post-
bronchodilator FEV1 at Week 52. 
11. Mean number of days with oral corticosteroids 
taken for clinically significant exacerbations 
12. Total prednisone (or equivalent) exposure for 
clinically significant exacerbations over the 
52-week treatment period 
13. Frequency of all exacerbations 
14. Time to first exacerbation 
15. Time to withdrawal from study treatment due 
to asthma exacerbations 
16. Time to first exacerbation requiring 
hospitalization or ED visit 


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Objectives 
Endpoints 
17. Unscheduled healthcare resource utilization 
(for clinically significant exacerbations and 
other asthma related health care) over the 52-
week treatment period 
18. Mean days of School/Work missed over the 
52-week treatment period 
Pharmacodynamics 
• 
To evaluate the PD of SC 
mepolizumab in Chinese subjects 
with severe asthma with eosinophilic 
inflammation. 
 Blood eosinophil ratio to baseline 
3.1. 
Pharmacokinetic Sub-Study 
The endpoints outlined in Table 3 are only applicable to the pharmacokinetic (PK) sub-
study (see Section 9.4.3 or further details). 
Table 3 
Pharmacokinetic Sub-Study Objectives and Endpoints 
Objective 
Endpoints 
• To evaluate the PK of SC 
mepolizumab in Chinese subjects 
with severe asthma with eosinophilic 
inflammation. 
PK parameter estimates of mepolizumab 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study employs a multi-centre, randomized, placebo-controlled, double-blind, 
parallel-group design (Figure 1). In the main study, there will be a total of 16 clinic visits 
conducted on an outpatient basis. A pre-screening visit (V0) will be conducted to sign the 
informed consent form (ICF) and review demography, asthma history and concomitant 
medications. Once the ICF is signed the subject will be assigned a subject identifier. 
Subjects who meet the eligibility criteria at Screening (Visit 1) will complete a 1 to 
4 weeks run-in period followed by a double-blind 52-week treatment period. The run-in 
period is designed to capture baseline eDiary data. Subjects who experience an asthma 
exacerbation during the run-in should receive treatment for their exacerbation and remain 
in the run-in period until the subject has returned to their baseline asthma status for at 
least one week. Those subjects that are not able/eligible to be randomized at the end of 
the 4-week run-in period will be deemed run-in failures. Clinic visits will be at Pre-
screening (Visit 0), Screening, Randomization (Day 1, Week 0), then every 4 weeks 
during treatment period until the Exit Visit at Week 52.  The Exit Visit (Visit 15) 
represents the last day of study (i.e. 4 weeks after the last dose given at Visit 14). If a 
subject withdraws from this study, an early withdrawal visit (Visit Early Withdrawal 
[VEW]) will be performed within 4 weeks after the last dose (Section 5.5). The total 
duration of subject participation in the main study, including run-in will be 53 to 56 
weeks. Subjects will remain on their current maintenance therapy throughout the run-in 
and double-blind treatment administration periods. 
Evaluation of mepolizumab PK will be conducted in a sub-set of subjects (Section 7.5). 
At Visit 2, about 52 subjects who are randomized will be entered into the PK sub-study if 
consents for sub-study are obtained. With a ratio of 1:1 (mepolizumab: placebo), 
approximately 26 subjects are therefore expected to be allocated to the mepolizumab 
treatment group. This is to meet the regulatory requirement of approximately 
20 evaluable subjects for PK analysis. Blood samples for pharmacokinetics will be 
collected at the time points specified in the Schedule of Activities (Section 1.2).  For 
subjects who enter the PK sub-study, a total of 11 visits will be performed to collect PK 
sampling, of which 6 additional visits compare with main study at Week 1, 2 and Week 
49, 50, 56, 60 (i.e. 1, 2, 8, 12 weeks after last dose) will be conducted. Therefore, the total 
duration of subject participation, including run-in, will be 61 to 64 weeks. 


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Figure 1 
Study Schematic 
 
4.2. 
Treatment Arms and Duration 
Eligible subjects will be requested to participate for a maximum of 56 weeks (Visit 1 to 
Visit 15, inclusive) in the main study. A sub-set of subjects will participate in the PK sub-
study for a total of 64 weeks (Visit 1 to Visit 15-2, inclusive). Subjects will remain on 
their existing standard of care asthma therapy whilst completing the three phases of the 
study, as described in Table 4.  
Subjects who meet the eligibility criteria will be randomized to receive either 
mepolizumab (100 mg) or placebo at a 1:1 ratio. 
Subjects will be stratified based on blood eosinophil count at screening (300 cells/L, 
<300 cells/L). A minimum of 150 subjects will be enrolled with blood eosinophil count 
300 cells/L. 
Table 4 
Study Phases 
Phase Phase Title 
Duration 
Description 
1 
Pre-screening 
0-4 weeks 
Details about the study and procedures will 
be explained through the informed consent 
process.  
The Pre-screening Visit (Visit 0) can occur on 
the same day as the Screening Visit (Visit 1) 
but must be completed prior to initiating any 
Visit 1 procedures. 
2 
Screening / Run-in 
1 to 4 weeks 
Subjects who meet all the eligibility criteria at 
Visit 1 (Screening), will enter the run-in period 


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Phase Phase Title 
Duration 
Description 
for a minimum of 1 week and a maximum of 
4 weeks in order to continue to assess the 
subject’s eligibility for the study as well as to 
collect baseline eDiary data.  Those subjects 
that are not eligible to continue in the study at 
the end of the 4-week run-in period will be 
deemed run-in failures (see Section 5.4). 
3 
Treatment 
52 weeks 
At Visit 2 (Week 0) those subjects who 
successfully complete the run-in period as 
well as meet the pre-defined randomization 
criteria will be randomized; those subjects 
that do not meet the pre-defined 
randomization criteria will be deemed run-in 
failures (see Section 5.4). Study medication 
will be administered SC every 4 weeks for a 
total of 13 doses (Visit 2 to Visit 14, 
inclusive). The treatment period will conclude 
approximately 4 weeks after the subject was 
administered their last dose of double-blind 
study treatment. 
PK samples will be collected at Week 0, 1, 2, 
4, 24, and Week 48, 49, 50, 52, 56, 60 (or 0, 
1, 2, 4, 8, 12 weeks after last dose) in 
subjects who provided consents for PK sub-
study.  
*For information on criteria relating to study treatment withdrawal, refer to Section 5.5 


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4.3. 
Type and Number of Subjects 
Approximately 429 subjects will be screened to achieve 300 randomized at a ratio of 1:1 
(150 subjects in mepolizumab arm and 150 subjects in placebo arm). 
This study will include a PK sub-study in which approximately 52 randomized subjects 
will provide PK samples, irrespective of the allocated treatment (to maintain the study 
blind). This will ensure approximately 26 subjects receiving mepolizumab will provide 
PK information. This is to meet the regulatory requirement of approximately 
20 evaluable subjects for PK analysis. 
4.4. 
Scientific Rationale for Study Design 
This study is similar in design to the Phase III global pivotal study MEA115588, and will 
be conducted in a similar patient population, using the same definition of the primary 
endpoint. The target population will be severe asthmatics with eosinophilic phenotype 
who exacerbate despite regular use of optimized therapy in the 12 months prior to study 
start (per inclusion criteria).  Results of study MEA115588 have shown statistically and 
clinically significant improvements in reducing the frequency of protocol defined 
exacerbations in this population treated with mepolizumab. The current study will use the 
same peripheral blood eosinophil counts to identify eosinophilic subjects (i.e. either a 
peripheral blood eosinophil count of 300 cells/µL related to asthma during the past 
12 months prior the study, or a peripheral blood eosinophil count of 150 cells/µL at 
Visit 1 that was related to asthma) in combination with criteria similar to those of the 
ATS workshop on severe refractory asthma [ATS workshop, 2000] at study start.  
In study MEA115588, optimized therapy included a history of regular use of high-dose 
ICS for 12 months prior to screening, which refers to a FP dose equivalent or above 
1000 mcg/day (via a dry powder inhaler) for a monotherapy or the highest approved 
maintenance dose in the local country for an ICS/LABA combination.  The medium dose 
ICS/LABAs (Salmeterol/FP 50/250 mcg bid equivalent or above) is considered 
appropriate and as the optimized therapy in this protocol since it is more commonly used 
than the highest approved ICS/LABAs (Salmeterol/FP 50/500 mcg bid) in China as the 
maintenance therapy in severe asthmatics. (Section 5.1). In the current study, we adopted 
a 52-week treatment period because it is reasonable for collecting exacerbations as well 
as safety data.  
   
All subjects will continue on their baseline optimized asthma medications throughout the 
entire treatment duration. If for a medical reason the subject must change their baseline 
asthma medication the primary investigator should, wherever possible, discuss this with 
the study Medical Monitor prior to implementation. Allowing use of optimized therapy 
supports inclusion of a placebo group contributing to a favourable benefit: risk profile for 
participating subjects. 
The 1 to 4-week run-in period allows for the assessment of subject understanding of and 
compliance with the daily eDiary, to establish baseline diary symptoms, and to allow 
adequate time for receipt of results from assessments collected at Visit 1. 


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4.5. 
Justification for Dose 
GSK is proposing this local Phase III study to be conducted in China in patients with 
severe asthma with eosinophilic inflammation. The proposed dose and dosing regimen in 
Chinese patients is 100 mg administered subcutaneously (SC) every 4 week, the same as 
the global therapeutic dose regimen. Mepolizumab 100 mg SC (as well as the IV 
equivalent dose 75 mg) administered once every 4 weeks, have been studied extensively 
in the global Phase III studies (MEA112997, pivotal study MEA115588, and 
MEA115575).  
Mepolizumab pharmacokinetic information at the proposed clinical dose once every 
4 weeks is available in East Asian subjects (recruited in Japan and Korea) with severe 
asthma with eosinophilic inflammation from study MEA115588. Additional 
pharmacokinetic data are available following IV administration of doses from 75 mg up 
to 750 mg in East Asian subjects (recruited in Korea) with severe asthma with 
eosinophilic inflammation from study MEA112997. The population pharmacokinetic 
analysis of IV and SC mepolizumab data did not identify Race, including East Asian 
ancestry, as a covariate of mepolizumab exposure in subjects with severe asthma with 
eosinophilic inflammation. The average mepolizumab exposure (Cmax and AUC) in East 
Asian subjects with severe asthma with eosinophilic inflammation in the Japanese 
+Korean cohort is generally similar to that of the overall population and the cohort of 
White/Caucasian subjects (MEA115588). 
Over 3344 subjects have received treatment with mepolizumab in studies completed by 
Sep 2015. All trials have shown that mepolizumab is well tolerated when administered by 
IV, IM, or SC routes.  
The safety profile (study MEA115588) in severe asthma subjects from Japan and Korea 
is generally consistent with the overall population of relevant studies (MEA112997, 
pivotal study MEA115588, and MEA115575). Study MEA112997 examined 
intravenously administered mepolizumab doses of 75, 250 and 750 mg, which provided 
additional East Asian safety data over the 10-fold dose range in 24 subjects studied in 
Korea. The safety profile showed no differentiation across this 10-fold dose range. Based 
on the safety data available there was no signal of an inter-ethnic difference of concern 
for mepolizumab 100 mg SC administered once every 4 weeks for 52 weeks in subjects 
to be recruited in China in the present study. 
In the East Asian subjects as well as the overall population of the mepolizumab severe 
asthma development programme, anti-mepolizumab antibodies did not discernibly impact 
the pharmacokinetics, pharmacodynamics, or safety of mepolizumab. To date, there is no 
evidence to suggest that the immunogenicity profile of mepolizumab differs in East Asian 
subjects, relative to other subjects in the overall mepolizumab clinical programme. 
In conclusion, based on the information discussed above, we believe that mepolizumab 
100 mg SC once every 4 weeks is an appropriate dose to study in Chinese subjects with 
severe asthma with eosinophilic inflammation. 


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5. 
STUDY POPULATION 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB GlaxoSmithKline 
Document Number CM2003/00010/13 . 
Deviations from inclusion, exclusion, and randomization criteria are not allowed because 
they can potentially jeopardize the scientific integrity of the study, regulatory 
acceptability or subject safety. Therefore, adherence to the criteria as specified in the 
protocol is essential. 
5.1. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
1. Informed Consent:  Able to give written informed consent prior to participation in 
the study, which will include the ability to comply with the requirements and 
restrictions listed in the consent form.  Subjects must be able to read, comprehend, 
and write at a level sufficient to complete study related materials. 
2. Age and Weight: At least 12 years of age at Visit 0 and a minimum weight of 40 kg. 
3. FEV1: Persistent airflow obstruction as indicated by: 
• For subjects 18 years of age at visit 1, a pre-bronchodilator FEV1 <80% 
predicted normal values calculated by Quanjer reference equations [Quanjer, 
2012] 
• For subjects 12-17 years of age at visit 1: 
• A pre-bronchodilator FEV1 <90% predicted (Quanjer, 2012) recorded at 
Visit 1 OR 
• FEV1: FVC ratio <0.8 recorded at visit 1 
4. Eosinophilic information: Prior documentation of eosinophilic asthma or high 
likelihood of eosinophilic asthma as per Randomization Criteria 1. 
5. Inhaled Corticosteroid: Regular treatment with high dose inhaled corticosteroid 
(ICS) in the 12 months prior to Visit 1, of which at least 9 months accumulated 
documented is required, the 3 months prior to Visit 1 is mandatory. With or without 
maintenance oral corticosteroids(OCS)*. 
ICS dose must be 500 mcg/day fluticasone propionate (FP) or equivalent daily (for 
ICS/LABA combination preparations, Seretide 50/250 mcg bid and above or 
equivalent will meet this ICS criteria). *[Maintenance OCS is defined as a prescribed 
regimen of a minimum average daily dose of prednisone 5mg (or equivalent)]. 
6. Controller Medication:  Current treatment with one or more additional controller 
medication, besides ICS. At least one additional controller medication must have 


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been regularly used for at least 3 months prior to Visit 1. [e.g., long-acting beta-2-
agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline] 
7. Exacerbation history: Previously confirmed history of two or more exacerbations 
requiring treatment with systemic CS (intramuscular (IM), intravenous, or oral), in 
the 12 months prior to Visit 1, despite the use of high-dose ICS.  For subjects 
receiving maintenance CS, the CS treatment for the exacerbations must have been a 
two-fold increase or greater in the dose for at least 3 days is required. 
8. Gender: Male or Female  
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 4 during the intervention period 
and for at least 4 months after the last dose of study intervention. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
A WOCBP must have a negative highly sensitive pregnancy (Appendix 4)  test before 
the first dose of study intervention. 
If 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. FSH will be assessed to 
confirm child-bearing status as needed in non WOCBP. 
5.2. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Smoking history: Current smokers or former smokers with a smoking history of 10 
pack years (number of pack years = (number of cigarettes per day /20) x number of 
years smoked).  A former smoker is defined as a subject who quit smoking at least 6 
months prior to Visit 1. 
2. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically 
significant* lung condition other than asthma, in the opinion of the Investigator, is 
expected to affect the subject’s asthma status or the subject’s ability to participate in 
the study.  This includes current bacterial or viral infection of the upper or lower 
respiratory tract, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, 
or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary 
disease other than asthma) or a history of lung cancer.  


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*Clinically Significant is defined as any disease/condition that, in the opinion of the 
investigator, would put the safety of the subject at risk through participation, or 
which would affect the efficacy or safety analysis if the disease/condition 
exacerbated during the study. 
3. Abnormal Chest X-ray (or CT scan): A chest X-ray (or CT scan) that reveals 
evidence of clinically significant abnormalities not believed to be due to the presence 
of asthma. If a chest X-ray (or CT scan) is not available within 6 months prior to Visit 
1, then a chest X-ray must be conducted. 
4. Bronchial Thermoplasty and Radiotherapy: Bronchial Thermoplasty and 
Radiotherapy are excluded for 12 months prior to visit 1 and throughout the study.   
5. Malignancy: A current malignancy or previous history of cancer in remission for less 
than 12 months prior to screening (Subjects that had localized carcinoma of the skin 
which was resected for cure will not be excluded). 
6. Liver Disease: Current unstable liver or biliary disease per investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice or cirrhosis.  
NOTES:  
Stable chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, 
and chronic stable hepatitis B or C -eg, presence of hepatitis B surface antigen 
[HBsAg] or positive hepatitis C antibody test result) is acceptable if the participant 
otherwise meets entry criteria 
ALT >2 xULN 
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
7. Cardiovascular: Subjects who have known, pre-existing severe or clinically 
significant cardiovascular disease uncontrolled with standard treatment. Including but 
not limited to: 
1) known ejection fraction of <30% OR 
2) severe heart failure meeting New York Heart Association Class IV (see Appendix 
8)  classification OR 
3) hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New 
York Heart Association Class III (see Appendix 8) OR 
4) angina diagnosed less than 3 months prior to Visit 1 or at Visit 1 
8. ECG Assessment: QTc(F) >450msec or QTc(F) >480 msec for subjects with Bundle 
Branch Block at Visit 1 is exclusive.   
9. Other Concurrent Medical Conditions: Subjects who have known, pre-existing, 
clinically significant endocrine, autoimmune, metabolic, neurological, renal, 
gastrointestinal, hepatic, haematological or any other system abnormalities that are 
uncontrolled with standard treatment.  
Current malignancy except for basal and squamous skin cancer. 


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10. Eosinophilic Diseases: Subjects with other conditions that could lead to elevated 
eosinophils such as Hypereosiniophilic Syndromes, including Churg-Strauss 
Syndrome, or Eosinophilic Esophaghitis.   
11. Parasitic infection: Subjects with a known, pre-existing parasitic infestation within 6 
months prior to Visit 1 are also excluded. 
12. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or 
substance abuse within 2 years prior to Visit 1. 
Alcohol abuse is defined as: an average weekly intake of greater than 21 units or an 
average daily intake of greater than three units (males) or defined as an average 
weekly intake of greater than 14 units or an average daily intake of greater than two 
units (females).  
One unit was equivalent to a half-pint (220 mL) of beer or one (25 mL) measure of 
spirits or one glass (125 mL) of wine. 
13. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency 
virus – HIV), other than that explained by the use of corticosteroids taken as therapy 
for asthma. 
14. Xolair: Subjects who have received omalizumab [Xolair] within 130 days of Visit 1. 
15. Other Monoclonal Antibodies: Subjects who have received any monoclonal 
antibodies (other than Xolair) to treat inflammatory disease within 5 half-lives of visit 
1. 
16. Herbals: Use of herbals within 7 days prior to visit 1, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety.  
17. Investigational Medications: Subjects who have received treatment with an 
investigational drug within the past 30 days or five terminal phase half-lives of the 
drug whichever is longer, prior to visit 1 (this also includes investigational 
formulations of marketed products). 
18. Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or 
biologic. 
19. Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be 
enrolled if they plan to become pregnant during the time of study participation. 
20. Adherence: Subjects who have known evidence of lack of adherence to controller 
medications and/or ability to follow physician’s recommendations. 
21. Previous participation: Previously participated in any study with mepolizumab and 
received investigational product (including placebo).  
22. Affiliation with Investigator Site:  A subject will not be eligible for this study if 
he/she is an immediate family member of the participating investigator, sub-
investigator, study coordinator, or employee of the participating investigator. 
23. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study. 


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Re-screening of subjects will be allowed only upon approval by the medical monitor. 
5.3. 
Randomization Criteria 
Those subjects who meet the randomization criteria will be randomized into the study.   
At the end of the run-in period, study subjects must fulfil the following additional criteria 
in order to be randomized to study treatment: 
1. Eosinophilic criteria: 
1) Documented peripheral blood eosinophil count of 300cells/L that is related 
to asthma in the past 12 months prior to Visit 1  
OR 
2) A peripheral blood eosinophil count of 150cells/L at Visit 1 that is related 
to asthma.   
2. Asthma: Evidence of asthma as documented by either:  
1) Airway reversibility (FEV112% and 200 mL) demonstrated at Visit 1 or 
Visit 2 OR 
2) Airway reversibility (FEV112% and 200 mL) documented in the 12 months 
prior to visit 2 (randomization visit) OR  
3) Airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 mol 
methacholine/histamine) documented in the 12 months prior to visit 2 
(randomization visit) OR 
4) Airflow variability in clinic FEV1 20% between two clinic visits 
documented in the 12 months prior to visit 2 (randomization visit) (FEV1 
recorded during an exacerbation will not be valid) OR 
5) Airflow variability as indicated by >20% diurnal variability in peak flow 
observed on 3 or more days during the run-in 
3. eDiary Compliance: Compliance with completion of the eDiary defined as: 
1) Completion of symptom scores on 4 or more days out of the last 7 days 
immediately preceding Visit 2. 
2) Completion of information relating to rescue medication use on 4 or more 
days out of the last 7 days immediately preceding Visit 2. 
3) Completion of PEF measurements on 4 or more days out of the last 7 days 
immediately preceding Visit 2. 
4. Hepatitis B: Subjects who are Hepatitis B surface antigen (HBsAg) positive or 
HBcAb positive must not have a HBV DNA level 2000 IU/mL at Visit 1. 
5. Abnormal clinically significant finding:  Subjects have no evidence of clinically 
significant findings in their laboratory screening tests including liver chemistry at 
Visit 1. 


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6. Asthma Exacerbation: Subjects with an ongoing asthma exacerbation should 
have their randomization visit delayed until the investigator considers the subject 
has returned to their baseline asthma status at least 1 week prior to Visit 2. If the 
4-week screening period has elapsed then the subject should be considered a run-
in failure.  
An exacerbation is defined as worsening of asthma requiring the use of systemic 
corticosteroids (SCS) and/or emergency department visit, or hospitalisation.  
7. Maintenance Asthma Therapy: No changes in the dose or regimen of baseline 
ICS and/or additional controller medication (except for treatment of an 
exacerbation) during the run-in period. Herbals should not be used during the run-
in period, unless in the opinion of the Investigator and GSK Medical Monitor the 
medication will not interfere with the study procedures or compromise subject 
safety.  
5.4. 
Pre-Screening/ Screening/Baseline/Run-in Failures 
A subject will be assigned a subject number at the time the informed consent is signed. A 
subject who is assigned a subject number but does not have a Visit 1 procedure will be 
considered a pre-screen failure. 
For the purposes of this study, screening failures and run-in failures will be defined as 
follows: 
Screening failures: those subjects that complete at least one Visit 1 
(Screening) procedure but do not enter the run-in period. 
Run-in failures: those subjects that enter the run-in period but are not 
subsequently randomized. 
RAMOS-NG will be contacted to report screening and run-in failures. 
In order to ensure transparent reporting of screen/run-in failure subjects, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen/run-in failure 
information is required including demography, screen/run-in failure details, eligibility 
criteria, and any Serious Adverse Events (further details are provided in the study-
specific eCRF completion guidelines document). 
5.5. 
Withdrawal/Stopping Criteria 
Withdrawal from study treatment 
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is 
considered to be detrimental for them to continue in study treatment.  
A subject must be withdrawn from study treatment if any of the following stopping 
criteria are met: 


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• Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (Section 5.5.1) 
• QT: Meets any of the protocol-defined stopping criteria (Section 5.5.2) 
• Pregnancy: Positive pregnancy test 
Other reasons for withdrawal can include: an adverse event (including abnormal liver 
function test other than stopping criteria or abnormal laboratory results), Investigator 
unblinded study treatment, clinically significant abnormality identified on ECG reading 
other than stopping criteria, lost to follow-up, protocol violation, lack of efficacy, sponsor 
terminated study, non-compliance, or for any other reason.   
Subjects who withdraw from study treatment prematurely (for any reason) should, where 
possible, continue to be followed-up as per protocol until the completion of the Exist 
Visit assessments. If this is not possible, the Investigator must encourage the subject to 
participate in as much of the study (scheduled visits and activities, record eDiary data) as 
they are willing (or able) to. If subject cannot attend the visit on site, telephone contact is 
acceptable to collect below information: asthma exacerbation, AE/SAE, concomitant 
medication and to encourage subjects continue to record eDiary data. 
Withdrawal from the study 
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Early Withdrawal Visit and 
to return all study related materials.  In those instances where the subject specifies the 
reason for withdrawal of consent, this information will be captured in the eCRF. Patients 
will not be followed for any reason after consent has been withdrawn. 
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc). 
In the event a subject withdraws from study at, or during, a scheduled visit, and does not 
receive investigational product, an Early Withdrawal Visit is not required.  However, all 
study procedures scheduled at an Early Withdrawal Visit must be performed at this visit 
instead.     
The primary reason for withdrawal from study will be recorded in the eCRF and any data 
collected up until the point of withdrawal from study will be used in the analyses when 
appropriate.   
Pharmacokinetic Sub-Study Withdrawal 
A subject may withdraw from the PK sub-study at any time at his/her own request; a 
subject may also be withdrawn from the sub-study at any time at the discretion of the 
investigator. 


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Subjects who withdraw early from the main study must also withdraw from the sub-
study; however, subjects who withdraw early from the sub-study do not automatically 
have to withdraw from the main study. 
Details of withdrawal procedures are provided in the SRM. 
5.5.1. 
Liver Chemistry Stopping Criteria 
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal. 
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN 
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international normalized ratio; SAE = 
serious adverse event; ULN = upper limit of normal. 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2. 
5.5.1.1. 
Study Treatment Restart or Rechallenge 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed. 
5.5.2. 
QTc Stopping Criteria 
A participant who meets the bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study intervention: 
For this study, the following QTc stopping criteria will apply: 
• QTcF>500 msec or uncorrected QT>600 msec 
• Change from baseline: QTcF> 60msec 
• For patients with underlying bundle branch block, follow the discontinuation 
criteria listed below: 
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*


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Baseline QTc with Bundle Branch 
Block 
Discontinuation QTc with Bundle 
Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
530 msec 
 
5.6. 
Subject and Study Completion 
Subjects will be regarded as having completed the study if they complete all phases of the 
study (run-in, double-blind treatment administration, and Exit Visit) OR although they 
prematurely discontinue study treatment but still complete the Week 52 Visit.   
The end of the study is defined as the last subject’s last visit. 


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6. 
STUDY TREATMENT 
6.1. 
Investigational Product and Other Study Treatment 
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. 
Mepolizumab is a humanised IgG antibody (IgG1, kappa) with human heavy and light 
chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for 
individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to 
use.  The placebo in this study will be 0.9% sodium chloride solution and will be 
provided byGSK. Further information on the preparation and administration of study 
treatment can be found in Section 6.5. 
Trade label salbutamol metered dose inhalers (MDIs) will be provided. Subjects will be 
dispensed an MDI at the time of Pre-Screening to be used to primarily treat asthma 
symptoms on an as needed basis but also during the reversibility assessments (see Section 
7.2.4). The MDI should be replaced as needed and retained at the Exit Visit (or Early 
Withdrawal Visit, as applicable). 
6.2. 
Study Treatment Assignment 
At Visit 2 (Week 0) those subjects who meet the randomization eligibility criteria will be 
randomized in a 1:1 ratio (mepolizumab: placebo) to receive one of the following study 
treatments in addition to their baseline asthma treatment: 
Mepolizumab 100 mg SC into the upper arm or thigh 
Placebo 0.9% sodium chloride SC into the upper arm or thigh 
Subjects will be stratified based on blood eosinophil count at screening (300 cells/L , 
<300 cells/L). A minimum of 150 subjects will be enrolled with blood eosinophil count 
300 cells/L. 
Subjects eligible to enter the study will be assigned to treatment randomly via IWRS. In 
addition, IWRS will also be used to manage the entry of eligible subjects into the 
pharmacokinetic sub-study; subjects may not be permitted to enter the pharmacokinetic 
sub-study if the planned number of subjects in mepolizumab treatment arm has been 
reached. 
6.3. 
Blinding 
Mepolizumab and placebo will be prepared by a designated unblinded member of the 
study site staff (i.e. a qualified person who is independent of the protocol-defined study 
assessments) and will be administered by a designated blinded member of the site staff.  
Once prepared, mepolizumab and placebo will be identical in appearance. The blinding 
of all those involved in the evaluation of the study treatment (e.g. physician/nurse as well 


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as the subject) shall be maintained at all times, therefore, procedures must be in-place at 
the study site to ensure that this blinding is maintained. 
With regards to the emergency unblinding of the study treatment assigned to a specific 
subject, the following will apply: 
• 
The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator.  
• 
Investigators have direct access to the subject’s individual study treatment.  
• 
It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment.  
• 
If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study.  
• 
The date and reason for the unblinding must be fully documented in the CRF. 
• 
Subjects will be withdrawn from study treatment if the treatment code is 
unblinded by the investigator or treating physician.  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject 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 subject’s treatment assignment, may be sent to investigators in accordance 
with local regulations and/or GSK policy. 
6.4. 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
6.5. 
Preparation/Handling/Storage/Accountability 
A description of the methods and materials required for preparation of placebo or 
reconstitution of mepolizumab will be detailed in the unblinded staff manual.  
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. 
A qualified unblinded site staff member assigned to the study will be required to prepare 
the appropriate study treatment according to the study subject’s treatment assignment 
(see Section 6.2 for further details on treatment assignment): 


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• 
Mepolizumab: 1 mL of reconstituted mepolizumab (equivalent to 100 mg of 
mepolizumab) will be drawn into a 1 mL polypropylene syringe.  
• 
Placebo: 1 mL of 0.9% sodium chloride solution will be drawn into a 1 mL 
polypropylene syringe. 
A blinded staff member will administer the study treatment into the subject’s upper arm 
or thigh via SC injection. Subjects will be monitored for 1 hour after the first three 
administrations of study treatment and then according to monitoring policies for the 
center.  In the event of an acute severe reaction (e.g., anaphylaxis) following 
administration of study treatment, there are 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. 
All study treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the investigator’s unblended site staff.  In accordance with local 
regulatory requirements, the investigator’s designated unblinded site staff, or head of the 
medical institution (where applicable) must document the amount of investigational 
product dispensed and the investigator or designated blinded site staff will document the 
amount administered to study subjects. The designated unblinded site staff will document 
the amount returned by blinded staff, and the amount received from and returned to GSK, 
when applicable.  Product dispensing/accountability logs will be maintained by a 
designated unblinded member of the site staff throughout the study. Further guidance and 
information for final disposition of unused study treatment are provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study contact. 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK. 
6.6. 
Study Treatment Compliance 
Mepolizumab and placebo will be administered via SC injection to subjects at the study 
site.  Administration will be documented in the source documents and reported in the 
eCRF. 
6.7. 
Treatment of Study Treatment 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. The investigator will use clinical judgement in treating the symptoms 
of a suspected overdose. 


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6.8. 
Treatment after the End of the Study 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition. 
6.9. 
Concomitant Therapy 
6.9.1. 
Permitted Medications and Non-Drug Therapies 
All concomitant medications taken during the study will be recorded in the eCRF as well 
as the ICS usage in the past 12 months prior to Visit 1 and other additional controllers in 
the past 3 months prior to Visit 1.  The minimum requirement is that drug name and the 
dates of administration are to be recorded.  However, for ICS and OCS, the dose must be 
recorded as well as any dose changes. 
All additional asthma medications such as LABA, theophyllines or anti-leukotrienes will 
be continually used with the same dose and regimen if they have been taken regularly in 
the 3 months prior to randomization (Visit 2, Week 0).  Maintenance OCS will be 
permitted. SABAs and SAMAs are permitted as long as they are withheld for at least 6 
hours prior to clinic visit.  
If for any reasons (except asthma exacerbation) the participant must change their 
maintenance asthma treatment medications, the investigator must discuss the change with 
the Medical Monitor prior. Any changes of maintenance asthma treatment should be 
recorded in the eCRF. 
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep apnea 
is permitted, if initiated prior to the Screening Visit. This treatment must be captured in 
the eCRF. 
6.9.2. 
Prohibited Medications and Non-Drug Therapies 
The following medications are not allowed prior to screening according to the following 
schedule or during the study: 


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Table 5 
Medications not allowed prior to the screening visit and throughout 
the study 
Medication 
Washout Time 
Prior to Screening Visit 
Herbals* 
7 days 
Investigational drugs 
1 month or 5 half-lives whichever is 
longer 
Omalizumab [Xolair]  
130 days 
Other biological 
5 half-lives 
Experimental anti-inflammatory drugs (non biologicals) 
3 months 
Immunosuppressive medications such as those listed below (not all inclusive) 
• Methotrexate, troleandomycin, cyclosporin, 
azathioprine  
1 month 
• Corticosteroids intramuscular, long-acting depot if 
used to treat a condition other than asthma 
3 months 
• Regular systemic (oral or parenteral) 
corticosteroids for the treatment of conditions 
other than asthma 
3 months 
• Oral gold 
3 months 
• Chemotherapy used for conditions other than 
asthma  
12 months  
*Permitted when in the opinion of the Investigator and GSK Medical Monitor the medication will 
not interfere with the study procedures or compromise subject safety. 
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to visit one and throughout the study.  Neither CPAP nor oxygen therapy may be 
initiated after Visit 1. Oxygen therapy described as resting oxygen therapy >3L/min 
(Oxygen use 3L/min flow is not exclusionary.) 


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7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Screening and Critical Baseline Assessments 
Subjects should conduct the pre-screening visit (Visit 0) up to 28 days prior to the 
screening visit (Visit 1).  A subject number will be assigned at this time of signing 
informed consent. During the pre-screening Visit, study designated personnel should 
provide informed consent, and pharmacokinetics (PK) informed consent to potential 
study participants. Site staff will review with the subject any study related procedures that 
must be taken prior to the next visit (i.e., withholding of short-acting beta-2-agonists 
(SABAs), short-acting muscarinic antagonists (SAMAs) for 6 hours and withholding of 
asthma medication on the morning of Visit 1, etc). 
 
7.1.1. Pre-screening Visit (Visit 0) 
Subjects can complete the Pre-screening and Screening Visits on the same day. 
Informed Consent will be obtained at the pre-screen visit. Once the informed consent 
process is complete and the informed consent document has been signed, additional pre-
screening assessments can be conducted. The pre-screening assessments are defined in 
Section 1.2 and Table 1. 
• Demographic information will be captured, including year of birth, gender, ethnic 
origin, race, height, and weight. 
• Asthma history including asthma exacerbation history in previous year, asthma 
triggers, history of previous intubations. 
• Therapy history including current treatment and courses of rescue corticosteroids. 
7.1.2. 
Critical procedures performed at Screen (Visit 1) 
• Medical history including but not limited to smoking status, aspirin sensitivity. 
• Inclusion/exclusion criteria review 
• Physical exam  
• Pulmonary function tests and assessment of reversibility  
• Vital signs 
• Chest X-ray or if available review of chest X-ray/CT-scan conducted in the prior 6 
months 
• Resting 12 lead ECG 
• The cardiovascular assessment (Appendix 5) will be administered by site personnel at 
screening visit. If the subject responds ‘yes’ to any of the questions a physician must 
conduct a further evaluation to assess for previously unrecognized and undiagnosed 
angina. The results of the evaluation should be considered when determining subject 


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eligibility (see Exclusion Criteria #5).  Subject responses will be entered into the 
eCRF.  
• Laboratory tests: 
o Haematology with differential 
o Clinical Chemistry 
o Urinalysis 
o Hepatitis B Surface Antigen and hepatitis C antibody 
o Urine pregnancy test for females of child bearing potential  
o FSH will be assessed to confirm child-bearing status as needed in women of non-
child bearing potential only 
• Parasitic screening will be performed only in subjects who have visited a high risk 
country 
7.1.3. 
Critical procedures performed at randomization (Visit 2) 
• Vital signs  
• Review of randomization criteria, and data collected at screen including verification 
of eosinophilic asthma 
• Pulmonary function tests and assessment of reversibility (If reversibility was not 
achieved at Visit 1, the procedure may be repeated at this visit and this is needed to 
qualify the subject for randomization). (See Section 7.2.4) 
• Review eDiary data including PEF diurnal variability (see Section 7.2.2) 
• Asthma Control Questionnaire (ACQ-5) (see Section 7.2.5) 
• St George’s Respiratory Questionnaire (SGRQ) (see Section 7.2.3) 
• Laboratory tests: 
o Haematology with differential 
o Blood for baseline immunogenicity, PK 
o Urine pregnancy test for females of child bearing potential 
7.2. 
Efficacy Assessments 
Primary Efficacy Endpoint 
Frequency of clinically significant exacerbations of asthma as defined by: 
Worsening of asthma which requires use of systemic corticosteroids (SCS) 1and/or 
hospitalisation and/or Emergency Department (ED) visits. 
1For all subjects, i.v. or oral corticosteroid (e.g., prednisone) for at least 3 days or a 
single IM CS dose is required. For subjects on maintenance systemic corticosteroids 
(SCS)*, at least double the existing maintenance dose for at least 3 days is required.  


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*Maintenance OCS is defined as a prescribed regimen of a minimum average daily dose 
of prednisone 5 mg (or equivalent). 
In order to provide an objective assessment of the circumstances linked to the clinical 
decision that defines asthma exacerbations, the investigator must take into account 
changes on one or more of the following parameters recorded in the subject’s eDiary: 
• 
Decrease in morning peak flow 
• 
Increase in the use of rescue medication 
• 
Increase in the frequency of nocturnal awakening due to asthma symptoms requiring 
rescue medication use 
• 
Increase in overall asthma symptom score 
Secondary Efficacy Endpoints 
• Time to first clinically significant exacerbation   
• Mean change in St. George’s Respiratory Questionnaire (SGRQ) at Week 52 
• Frequency of exacerbations requiring hospitalisation (including intubation and 
admittance to an ICU) or ED visits over the 52-week treatment period 
• Frequency of exacerbations requiring hospitalisation over the 52-week treatment 
period 
• Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52   
Other Efficacy Endpoints 
1. Mean change from baseline in Asthma Control Questionnaire (ACQ-5) score at 
Week 52  
2. Percent of subjects evaluated as responders as measured by ACQ-5 score at Week 
52. 
3. Percent of subjects evaluated as responders as measured by SGRQ score at Week 52. 
4. Percent of subjects recording a favourable treatment response as measured by the 
Subject Rated Response to Therapy at Week 52 
5. Percent of subjects evaluated as having a favourable treatment response as measured 
by the Clinician Rated Response to Therapy at Week 52 
6. Mean change from baseline in daily salbutamol/albuterol use  
7. Mean change from baseline in daily asthma symptom scores  
8. Mean change from baseline in awakening at night due to asthma symptoms requiring 
rescue medication use.  
9. Mean change from baseline in morning PEF 
10. Mean change from baseline in clinic post-bronchodilator FEV1 at Week 52 


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11. Mean number of days with oral corticosteroids taken for clinically significant 
exacerbations  
12. Total prednisone (or equivalent) exposure for clinically significant exacerbations 
over the 52-week treatment period  
13. Frequency of all exacerbations 
14. Time to first exacerbation 
15. Time to withdrawal from study treatment due to asthma exacerbations  
16. Time to first exacerbation requiring hospitalisation or ED visits  
17. Unscheduled healthcare resource utilization (for clinically significant exacerbations 
and other asthma related health care) over the 52-week treatment period 
18. Mean days of School/Work missed over the 52-week treatment period 
7.2.1. 
Clinically Significant Exacerbations (primary endpoint) 
Clinically significant exacerbations recorded in the eCRF by the Investigator or designee 
will be verified using data from the eDiary to confirm that the exacerbation was 
associated with changes in peak flow, rescue medication use, nocturnal awakening due to 
asthma symptoms requiring rescue medication use or symptoms.  In the case that an 
event described as a clinically significant exacerbation is not associated with 
deterioration in at least one of these objective eDiary parameters, the investigator will be 
asked to provide an explanation to support the decision for defining the event as an 
exacerbation.  In those circumstances where the event cannot be supported by any 
objective assessment, the case will not be included as a protocol defined exacerbation but 
will be included as an investigator defined exacerbation.  This verification process will be 
overseen by GSK clinical staff to ensure consistency. 
Subjects will be asked to enter data on a daily basis into the eDiary. This data will be 
reviewed at each clinic visit by the site staff throughout the treatment period, during the 
clinic visit, to confirm an association between the exacerbation event and eDiary data.  
The period of time for which exacerbation information will be included in the primary 
endpoint analysis will be from the start of treatment until approximately 4 weeks after the 
last dose of study medication.  For consistency, exacerbations separated by less than 7 
days will be treated as a continuation of the same exacerbation. 
For safety reasons alerts will be programmed into the eDiary to encourage the subject to 
contact the investigator if their asthma worsens.  However, an alert in itself will not be 
classified as a clinically significant exacerbation. 
7.2.2. 
eDiary Asthma Parameters and Alerts 
The subject will be asked to record the following parameters daily in the eDiary from 
Visit 1 onwards: 
• 
Morning peak flow (best of three), before rescue medication usage (L/min) 


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• 
Occasions of rescue usage over the previous 24-hours 
• 
Asthma symptom score over the previous 24-hours using a 6-point scale 
(Appendix 6) 
• 
Frequency of awakening due to asthma symptoms requiring rescue medication 
use. 
(From Visit 1 to Visit 2 only, subjects will record peak flow twice a day to allow for 
calculation of PEF diurnal variability). 
For safety the following alerts, indicative of worsening asthma, will be programmed into 
the eDiary with instructions to contact the investigator if any of the alert criteria are met. 
An alert in itself will not qualify as a clinically significant exacerbation: 
• Decrease in morning PEF 30% on at least two of three successive days, 
compared with baseline (last 7 days of run-in). 
• 
An increase of 50% in rescue medication on at least two of three successive 
days, compared with the average use for the previous week. 
• 
Awakening due to asthma symptoms requiring rescue medication use for at least 
two of three successive nights. 
• 
A symptom score of 5 for at least two of three successive days. 
Subjects will also be issued a paper worksheet to record adverse events and concomitant 
medications during the study. This will be used to assist subject recall in discussions with 
the investigator, for site staff to then enter as appropriate in the eCRF. 
7.2.3. 
St. George’s Respiratory Questionnaire (SGRQ) 
The St. George’s Respiratory Questionnaire is a well-established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction [Jones, 1992].  The questionnaire will be administered at the visits specified 
in the Schedule of Activities (Section 1.2).   
The questionnaire should be completed in a quiet area, free from distraction and the 
patient should ideally be sitting at a desk or table. Explain to the subject why they are 
completing it, and how important it is for clinicians and researchers to understand how 
their illness affects them and their daily life. Ask him or her to complete the questionnaire 
as honestly as they can and stress that there are no right or wrong answers, simply the 
answer that they feel best applies to them. Explain that they must answer every question 
and that someone will be close at hand to answer any queries about how to complete the 
questionnaire. It is designed for supervised self-administration. This means that the 
subject should complete the questionnaire themselves, but someone should be available 
to give advice if required. It is designed to elicit the subject’s opinion of his/her health, 
not someone else’s opinion of it, so family, friends or members of staff should not 
influence the subject’s responses.  
Once the subject has finished, it is very important that site staff check the questionnaire to 
make sure a response has been given to every question. If they have missed an item 


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return it to the subject for completion, before they leave. To avoid biasing responses, the 
subjects should not be told the results of diagnostic tests prior to completing the 
questionnaire and should be completed before any procedures are performed on the 
subject to avoid influencing the subject’s response. 
7.2.4. 
Pulmonary Function Testing including Reversibility 
Spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Schedule of Activities (Section 1.2).  The spirometer should meet American Thoracic 
Society standards and produce a printout of all data generated, which should be stored in 
the subject’s notes. The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (2 hour) of the Visit 2 spirometry. Subjects should try to 
withhold SABAs or SAMAs for 6 hours and LABAs for 12 hours prior to clinic visit, 
if possible. Assessments to be recorded will include FEV1, FVC.  Pre-bronchodilator 
measurements will be taken at each clinic visit. In addition, at visit specified in the 
Schedule of Activities (Section 1.2) post-bronchodilator values will be recorded 
following standard reversibility testing. For subjects unable to achieve 12% reversibility 
and 200 mL change at Visit 1, reversibility can be repeated at Visit 2. Further details of 
spirometry and reversibility testing procedures are presented in the Study Reference 
Manual.  
7.2.5. 
Asthma Control Questionnaire (ACQ) 
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of a 
subject’s asthma control that can be quickly and easily completed [Juniper, 2005].  The 
questions are designed to be self-completed by the subject.  The five questions enquire 
about the frequency and/or severity of symptoms (nocturnal awakening on waking in the 
morning, activity limitation, and shortness of breath, wheeze).  The response options for 
all these questions consist of a zero (
) to six (
 
) scale. 
The subject should be given a quiet area in which to complete the questionnaire within 
the eDiary. The investigator should ask the subject to complete the questions as 
accurately as possible.  If the subject requests help or clarification with any of the 
questions, he/she will be asked to re-read the instructions and give the answer that best 
reflects how he/she felt over the previous week.  The subject should be reassured that 
there are no right or wrong answers.  The investigator should not provide the subject with 
any answer or attempt to interpret any portion of a question. 
It is recommended that the ACQ be administered at the same time during each visit.  To 
avoid biasing responses, the subjects should not be told the results of diagnostic tests 
prior to completing the questionnaire and should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response.  Adequate time 
should be allowed to complete all items on the ACQ. 
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7.2.6. 
Clinician/Subject Rated Response to Therapy 
The clinician and the subject will be asked to rate the response to therapy at the visits 
specified in the Schedule of Activities (Section 1.2). This is an overall evaluation of 
response to treatment, conducted separately by the investigator and the subject using a 
rating scale.  In this rating scale, a seven-point scale score is used with the following 
definitions: 1 = 
; 2 = 
; 3 = 
; 
4 = 
; 5 = 
; 6 = 
; and 7 = 
  
7.3. 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Section 1.2).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
7.3.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded.  
A brief physical examination will include, at a minimum，assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen). Investigators should pay special 
attention to clinical signs related to previous serious illnesses. 
7.3.2. 
Vital Signs 
As detailed in the Schedule of Activities (Section 1.2), vital signs will be measured in 
sitting position after 5 minutes rest and will include temperature, systolic and diastolic 
blood pressure and pulse rate.  
Vital signs assessments will be taken before measurement of any clinic lung function 
tests or ECGs at the specified time point. 
7.3.3. 
Electrocardiogram (ECG) 
A single twelve-lead ECG will be obtained at each timepoint specified in the Schedule of 
Activities (Section 1.2). If a routine single ECG demonstrates a prolonged QT interval, 
obtain two more ECGs over a brief period, and then use the averaged QTc values of the 
three ECGs to determine whether the patient should be discontinued from the study. 
Refer to Section 5.5 for QTc withdrawal criteria. 
ECG measurements will be made after the subject has rested in the supine position for 
5 minutes.  The ECG should be obtained after the vital signs assessments but before lung 
function testing followed by other study procedures.  Collection shortly after a meal or 
during sleep should be avoided since QT prolongation can occur at these times. 
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Paper ECG traces will be recorded at a standard paper speed of 25 mm/sec and gain of 
10 mm/mV, with a lead II rhythm strip.  
7.3.4. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments, as defined in Table 6, must be conducted in 
accordance with the Laboratory Manual, and Schedule of Activities Table.  Laboratory 
requisition forms must be completed, and samples must be clearly labelled with the 
subject number, protocol number, site/centre number, and visit date.  Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the laboratory manual. Reference ranges for all safety parameters will be provided to 
the site by the laboratory responsible for the assessments. 
All blood samples which will be taken pre-injection, will be sent to a central laboratory 
for analysis (details provided in the Laboratory Manual). Standard reference ranges will 
be used. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.   
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.   
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 6.  
Table 6 
Protocol Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
WBC count with Differential: 
RBC Count 
MCV 
Neutrophils 
Hemoglobin 
MCH 
Lymphocytes 
Hematocrit 
 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
Clinical 
Chemistry 1 
BUN 
Potassium AST (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT (SGPT) 
Total Protein 
Glucose  
Calcium 
Alkaline phosphatise 
Albumin 
Routine 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is abnormal) 


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Laboratory 
Assessments 
Parameters 
Other 
Screening 
Tests 
Hepatitis B (HBsAg) 
Hepatitis C (Hep C antibody) 
FSH (as needed in women of non-child bearing potential only) 
Urine hCG Pregnancy test (as needed for women of child bearing potential) 2 
NOTES: 
1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Appendix 2. 
2. Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or ethics committee. 
 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 4 weeks after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified. 
To maintain the treatment blind, the site will not be sent information on haematology 
differential from any visits post-randomization either from the central laboratory or from 
GSK. 
7.3.5. 
Immunogenicity 
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing on dosing days, as detailed in the Schedule of Activities (Section 1.2). A 
PK sample will be collected at the time of the immunogenicity sample collection (for 
subjects in the PK sub-study this can be the sample collected for PK assessment). For 
subjects who are ADA or NAB positive, PK samples will be assessed. 
Details for sample collection and processing may be found in the SRM. 
7.4. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3 
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. 


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7.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
Any SAEs will be collected from the start of intervention until at the time points 
specified in the Schedule of Activities Table (Section 1.2). 
• 
All AEs will be collected from the start of intervention until at the time points 
specified in the Schedule of Activities Table (Section 1.2). 
• 
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent may 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 hours, as indicated in Appendix 
3.  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 subject has been discharged from the study, 
and he/she considers the event reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
7.4.2. 
Method of Detecting AEs and SAEs 
• The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided 
in Appendix 3. 
• Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-
ended and non-leading verbal questioning of the subject is the preferred method to 
inquire about AE occurrence.   
7.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.5). Further information on follow-up procedures is 
given in Appendix 3. 
7.4.4. 
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 product 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 Board (IRB)/Independent Ethics Committee (IEC) and investigators. 
• Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions(SUSAR) according to local regulatory requirements and sponsor policy 
and are forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE(s) or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will reivew and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements. 
7.4.5. 
Pregnancy 
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 4 weeks post-last dose. 
If a pregnancy is reported then the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
7.4.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 5 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular 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. 
7.5. 
Pharmacokinetics 
7.5.1. 
Blood Sample Collection 
Blood samples for pharmacokinetic (PK) analysis of mepolizumab plasma concentration 
will be collected as per the Section 1.2, Schedule of Activities Table. Samples should be 
obtained prior to dosing on dosing days. The actual date and exact time of each blood 
sample collection will be recorded in the eCRF.   
 Details for collection and processing of samples are provided in the Study Reference 
Manual (SRM).  


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7.5.2. 
Sample Analysis 
Plasma analysis will be performed under the control of GSK PTS-DMPK/Scinovo, the 
details of which will be included in the Study Reference Manual. Concentrations of 
mepolizumab will be determined in plasma samples using the currently approved 
bioanalytical methodology.  Raw data will be archived at the bioanalytical site (detailed 
in the Study Reference Manual). 
7.6. 
Pharmacodynamics 
Blood eosinophil counts will be recorded as part of standard haematological assessments 
performed at visits specified in the Schedule of Activities Table (Section 1.2). After Visit 
2 blood eosinophil counts will be blinded to the Sponsor and site staff. 
7.7. 
Health Outcomes 
7.7.1. 
Health Outcome Endpoints 
Mean days of school/work missed 
Unscheduled healthcare resource utilization (for clinically significant exacerbations and 
other asthma related health care) 
7.7.1.1. 
Mean days of school/work missed 
The eDiary will be programmed to capture missed days of work/school.  
7.7.2. 
Healthcare Resource Utilization 
All unscheduled asthma-related health care utilization will be recorded including 
telephone contacts, specialist nurse visits, visits to a physician’s office, home visits (day 
and night time), outpatient visits, visits to urgent care, visits to the emergency 
department, and hospitalizations associated with the subject’s exacerbations will be 
recorded in the eCRF. Hospitalization data should be stratified by ward type (e.g; ICU, 
high dependency and usual care). Hospital length of stay in each type of ward will also be 
recorded.  
The resource utilization paper worksheet used by the patient to record all health care 
contacts experienced since the last visit will be presented to the investigator (or 
designated coordinator) at the visits indicated in Table 1. The investigator (or designated 
coordinator) should ask the subject if any of the health care contacts that are recorded on 
the worksheet were due to an asthma exacerbation.  The investigator can refer to his/her 
records to verify or supplement information given by the subject, if necessary.  
If any unscheduled healthcare contact is due to an asthma exacerbation, then the asthma 
Exacerbation section of the eCRF must be completed. 
Details regarding completion of the Healthcare Utilization worksheet are located in the 
SRM. 


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8. 
DATA MANAGEMENT 
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.   
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. 
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSK Drug.   
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
This is a bridging study designed to determine the effect of Mepolizumab 100mg SC on 
clinically significant exacerbation events, compared with placebo among Chinese 
subjects.  
The Chinese patient data collected in this study will be supplemented with data on the 
treatment effect for the same exacerbation endpoint from the global PhIII study 
MEA115588, using a Bayesian Dynamic Borrowing approach to analysis of the study 
(Schmidli, 2014). The potential to borrow information from the global dataset is based on 
the premise that the underlying disease, its general management and the response to 
mepolizumab is similar in Chinese and non-Chinese patients. A bridging approach is 
proposed because of the expected similarity of the treatment effect in Chinese patients 
and the global population (supported by similarities in the epidemiology, 
pathophysiology, pharmacology and clinical management of patients and consistency of 
treatment differences across key demographic factors including ethnicity), and similar 
study design specially the study population (supported by similarities in key eligibility 
criteria) between MEA115588 and this China study, hence there is low probability of the 
null effect being true. 
A frequentist hypothesis test will not be performed. Instead, the posterior distributions of 
the primary endpoint, i.e. rate ratio of events between Mepolizumab 100mg SC vs. 
placebo will be derived based on the Bayesian analysis including the global PhIII study 
MEA115588 information and the data collected on Chinese patients in this study. The 
hypothesis of interest for treatment comparison is that the rate ratio is less than 1, and the 
study will be considered to have shown evidence that supports this hypothesis if the 
posterior probability that the rate ratio is less than 1 is at least 95% (a “positive result”). 
Please see the Appendix 9 for further information on the choice of posterior probability. 


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9.2. 
Sample Size Determination 
9.2.1. 
Sample Size Assumptions 
The sample size of 300 participants (considering 256 evaluable participants and 
additional 44 subjects for drop-out) in a 1:1 ratio has been determined by the superiority 
testing of mepolizumab 100 mg SC vs. placebo, there will be 90% power to detect a 40% 
decrease in the exacerbation rate from 1.7 per annum (p.a.) on placebo to 1.02 p.a. on 
mepolizumab 100mg SC using a two sided 5% significance level. The calculation 
assumes the number of exacerbations per year follows a negative binomial distribution 
[Keene, 2007] with a dispersion parameter k=0.8. 
During the blinded evaluation, the clinically significant exacerbations which had 
occurred during the treatment period were analyzed using a generalized linear model 
assuming a negative binomial distribution and covariates of baseline maintenance OCS 
therapy (OCS vs. no OCS), EOS level at screening (>=300 cells/μL vs. <300 cells/μL), 
number of exacerbations in previous year (as an ordinal variable) and baseline disease 
severity (as % predicted FEV1). The blinded evaluation estimated, the overall event rate 
based on an assessment of blinded data was observed as 0.78 p.a., the dispersion was 2.0. 
This was lower than the expected overall event rate of the original study design 
assumptions. 
This observed reduction for overall events at blinded evaluation can be explained by a 
reduction in exacerbation events during the COVID-19 pandemic, which was not unique 
in China, it is still expected that the treatment effect of Mepolizumab compared with 
placebo will be the same in Chinese SEA population as the original study design 
assumption. Therefore, according the formula [Friede, 2010] 
𝜆̅ = (𝜆𝑇+ 𝜆𝑃)/2 
where 𝜆̅ is the observed overall events rate based on an assement of blinded data, the 𝜆𝑇 
and 𝜆𝑃 are the event rates in the treatment and placebo groups, and assuming the 
reduction in exacerbation rate with Mepolizumab will remain 40% under pandemic, the 
estimated event rates 𝜆𝑇 and 𝜆𝑃 for Mepolizumab 100mg SC and placebo are  0.975 and 
0.585 p.a. respectively. On the other hand, there exists a difference for the estimate of 
dispersion when data is blinded or unblinded, so that the blinded dispersion estimate is 
adjusted by the difference between blinded and unblinded, which is 1.6=2.0 *(0.796 / 
0.972),  where the dispersion in MEA115588 study were 0.796 (unblinded) vs. 0.972 
(blinded). 
Therefore, based on the conclusion of the blinded evaluation, assuming a 40% decrease 
in the exacerbation rate from 0.975 per annum (p.a.) on placebo to 0.585 p.a. on 
mepolizumab 100mg SC will lead to a power of 66% implying a high false negative rate 
of 34% in China study. If there is a true reduction of 40% in exacerbation rate in Chinese 
patients, based on use of Bayesian dynamic borrowing with an initial weight of 0.5 on 
global MEA115588 study result, there will be 88.6% probability to achieve a positive 
result (equivalent to the power of the study). 


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The 40% reduction in exacerbation rate has been selected as reductions of this magnitude 
or greater have been seen in previous mepolizumab studies MEA112997 and 
MEA115588. However, it should be noted that a smaller reduction in exacerbations could 
be clinically significant. Under the same assumptions, there will be 99% probability of 
showing consistent trend, which is defined as the point estimation of rate ratio between 
Mepolizumab and placebo<1 in China study, with global MEA115588. 
9.2.2. 
Sample Size Sensitivity 
The sample size in Section 9.2.1 is based on an expected reduction in this rate for 
subjects treated with mepolizumab.  If the expected reduction with mepolizumab differ 
then, at the given sample size there will be an effect on the probability of success of the 
study.  Table 7 illustrates this effect on probability of success of varying reductions in 
rates with mepolizumab, assuming the sample size remains constant at 128 subjects in 
mepolizumab arm and 128 subjects in placebo arm, excluding the additional 44 subjects 
to account for early withdrawals from study treatment.  
Table 7 
Probability of meeting the success criterion conditional on various 
assumed true treatment effects 
Reduction 
45% 
40% 
35% 
0 
Probabilities of Success 
94.6% 
88.6% 
80.0% 
11.8%* 
*The false positive rate is calculated as assumed true treatment effects is 0 between Mepolizumab and placebo. 
 
In the Table 7 , the probabilities of meeting success are conducted under various assumed 
true treatment effects when overall event rate is fixed as 0.78 based on the blinded 
evaluation and dispersion is 1.6, e.g. when reduction is 40%, then the probability of 
success is calculated by the exacerbation rates for Mepolizumab 100mg SC and placebo 
as  0.975 and 0.585 p.a. respectively. Type I error is 11.8%, which is calculated when the 
event rate for each group is 0.78, adjusted dispersion is 1.6 based on analyses of blinded 
evaluation. 
9.2.3. 
Sample Size Re-estimation or Adjustment 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after 15 
months of enrolment, or when 225 subjects have been randomized, whichever is earlier. 
If the exacerbation rates for the study are lower than planned, a sample size re-estimation 
may be conducted. Any subsequent change to the planned number of subjects 
randomized would be documented in a protocol amendment.  
Prior to protocol amendment no 4, blinded evaluations of exacerbation rate indicated data 
that deviated substantially from the original assumptions for the study. These 
assumptions were based on data prior to the COVID-19 pandemic. The planned primary 
analyses is updated inorder to maintain the planned sample size without further 
adjustment.  
 


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9.3. 
Data Analysis Considerations 
The following analysis populations will be derived as required. 
9.3.1. 
Analysis Populations 
• All Subjects Enrolled Population 
The All Subjects Enrolled (ASE) Population will comprise all subjects enrolled and for 
whom a record exists on the study database. This population will be used summarizing 
reasons for screen and run-in failures. 
• Modified Intent-to-Treat Population 
The Modified Intent-to-Treat (MITT) population will consist of all randomized subjects 
who receive at least one dose of trial medication and will be the primary population for 
all analyses of efficacy and safety data. ‘Modified’ implies that subjects who were 
randomized but did not receive study treatment were excluded. 
• Per Protocol Population 
The Per Protocol (PP) population will consist of all subjects in the Modified Intent-to-
Treat population not identified as full protocol deviators with respect to criteria that are 
considered to impact the primary efficacy analysis. The decision to exclude a subject 
from the PP Population or exclude part of their data from the PP Population analyses will 
be made prior to breaking the blind. This population will be used for a supplementary 
analysis of the primary endpoint. 
 
• PK Population 
The PK population will comprise subjects in the PK sub study who received at least one 
dose of study medication and for whom at least one pharmacokinetic sample was 
obtained, and analyzed. This will be the primary population for assessing PK. 
 
9.3.2. 
Interim Analysis 
Blinded evaluation of exacerbation rates is planned for this study. This will be done 
under blinded situation and will not treated as formal interim analysis.  
No formal interim analysis is planned. 
9.4. 
Key Elements of Analysis Plan 
The primary treatment comparison of interest in the study is mepolizumab 100mg SC vs 
placebo. This treatment comparison will be made for the primary and secondary 
endpoints. There is no adjustment for multiplicity for the secondary endpoints. 
 


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9.4.1. 
Efficacy Analyses 
Bayesian Dynamic Borrowing Design 
Bayesian dynamic borrowing (BDB) provides a clinically and statistically rigorous 
method to analyze this China bridging study. An explicit, pre-specified belief about the 
relevance of the global MEA115588 results to the Chinese population on treatment effect 
is provided as part of the prior distribution, which is a mixture with two components, one 
reflecting results from MEA115588 study and a vague component reflecting ‘no effect’.  
The prior mixture will be upated with the China data to obtain the posterior distribution, 
which will also be a mixture. The posterior weight given to the global MEA115588 study 
data is commensurate with the strength of evidence of similarity between the 
MEA115588 data and the China data. The BDB analysis ‘learns’ how much of the global 
MEA115588 study information to borrow based on the consistency between the observed 
rate ratio in the China and global studies and updates the weight on the global 
MEA115588 results accordingly. 
• The stronger the evidence of consistency, the greater the increase in the updated 
(posterior) weight on the informative component relative to the prior weight, and 
hence the greater the borrowing from the global study results. 
• Conversely, if the China study results are very different to the global study 
results, the informative component is down-weighted and final inference is based 
mostly on the observed data in the China study alone. 
• The mechanism by which the weight is updated is entirely pre-specified and 
mathematically rigorous (Schmidli, 2014) 
 
The informative prior and prior weight in BDB design 
The BDB approach will use the results from the global MEA115588 study mixed with a 
vague component worth two subjectsas an ‘informative’ but robust prior for the treatment 
comparison of interest in this China study. There are two primary analysis comparisons: 
mepolizumab 75mg IV vs placebo and mepolizumab 100mg SC vs placebo for rate of 
clinically significant exacerbations over the 32 weeks treatment period expressed as 
exacerbation rate per year in MEA115588. Since the primary outcome, rate of clinically 
significant exacerbation, showed similar treatment difference in Mepolizumab 75 mg iv 
group compared with placebo in 32-week Study MEA115588 and 52-week Study 
MEA112997, this indicates the available efficacy result of Mepolizumab 100 mg SC in 
32-week study MEA115588 could also be an informative reference data to bridge to this 
52-week China study using the same dose regimen, therefore, the results of mepolizumab 
100mg SC vs placebo in study MEA115588 are used to build the global component.  


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Table 8 
The primary analysis of clinically significant exacerbations results in 
global MEA115588 study 
Treatment 
No. 
subjects 
Rate ratio 
(95% CI) 
Normal distribution of Rate Ratio (log) 
Mean 
Standard Error 
Mepolizumab 100mg SC 
194 
0.47 
(0.35,0.64) 
-0.7474 
0.1532 
Placebo 
191 
Source: Table 13 in the CSR of MEA115588. 
The logarithmic transformation of the rate ratio will be used, which can be approximately 
Normally distributed. Therefore, in the primary analysis for the primary treatment 
comparison of mepolizumab 100mg SC and placebo for the rate of clinically significant 
exacerbations of asthma over the 52-week treatment period in this study, the global prior 
component is obtained from the sampling distribution of the log rate ratio between 
mepolizumab 100mg SC and placebo in the global study MEA115588. The mean log rate 
ratio and its associated standard error are -0.7474 and 0.1532, respectively, leading to a 
normal distribution with mean -0.7474 and standard deviation 0.1532 as the global prior 
component for the primary treatment comparison. 
A second vague distribution worth 2 subjects (one in each treatment arm) assuming no 
treatment effect in China will also be specified, to allow for the possibility that the global 
MEA115588 data do not provide relevant information about the treatment effect in 
Chinese patients. A normal distribution with mean zero and standard deviation 2.1256 
will be used as vague prior for log rate ratio in BDB design, more details can be found in 
Appendix 9 Section 12.9.2.  A weighted combination of the ‘informative’ and  ‘vague’ 
priors will be used to construct a robust mixture prior.  
In the primary analysis, a prior weight of 50% is proposed for the informative component 
of the robust mixture prior, with the remainder of the weight (50%) placed on the vague 
component to reflect a conservative starting position regarding the assumed relevance of 
the global MEA115588 results to Chinese patients. See Statistical Appendix 9 Section 
12.9.2 for more details on the robust mixture prior and Section 12.9.3 for details on the 
choice of prior weight. 
Effective Sample Size 
The updated weight itself is not directly interpretable as the fraction of the global 
MEA115588 study sample size that is borrowed. Instead, the effective sample size (ESS) 
borrowed from the global study can be quantified using the moment method implemented 
in RBesT R software package version 1.6.1, Table 9 shows the expected value of the ESS 
borrowed from the global MEA115588 study for each treatment comparison when the 
true reduction in China is assumed to be 45%, 40%, 35% and 0 as the same with Table 8. 


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Table 9 
Expected Effective Sample Size borrowed per arm from the global 
MEA115588 study for a range of possible true treatment differences 
 
The true reduction 
0 
35% 
40% 
45% 
Expected value of ESS borrowed per arm 
from the global MEA115588 study 
-42 
76 
123 
162 
 
Maximum Detectable Value for Rate Ratio 
The maximum detectable value (MDV) is the maximum rate ratio that needs to be 
observed in this China study in order to meet the pre-specified success criteria when 
combined with the global MEA115588 study results via the Bayesian dynamic borrowing 
analysis. Under the current sample size of 300 participants in total (256 evaluable 
participants and 44 subjects for drop out), assuming overall event rate is 0.78 p.a. based 
on the blinded evaluation and dispersion is 1.6, chosen weight on global component in 
the mixture prior of 0.5, and success rule that the posterior probability of the true rate 
ratio in China being less than 1 is at least 95%, the MDV for rate ratio between 
mepolizumab and placebo is 0.776.That corresponds to a minimum detectable reduction 
for mepolizumab compared with placebo of at least 22.4%. 
9.4.1.1. 
Primary Analyses 
The primary treatment effect to be estimated in this study is the frequency of clinically 
significant exacerbations of asthma over the 52-week treatment period expressed as an 
exacerbation rate p.a. Exacerbations from the start of treatment until 4 weeks after the last 
dose of study drug will be used in the analysis. Exacerbations which are separated by less 
than 7 days will be treated as a continuation of the same exacerbation. 
The numbers of clinically significant exacerbations are assumed to follow a negative 
binomial distribution. The logarithm of time on treatment will be used as an offset 
variable. The primary analysis of the rate of exacerbations will use a generalized linear 
model with a log-link function. This model will include covariates of treatment group, 
baseline maintenance OCS therapy (OCS vs. no OCS), number of exacerbations in 
previous year (as an ordinal variable), baseline disease severity (as % predicted FEV1). 
The estimate of the logarithm of the rate ratio for mepolizumab vs. placebo  and 
associated standard error will be  the data used to update the robust mixture prior to 
obtain the final posterior distribution for the China rate ratio (on the log scale). 
The mean, median and 90% credible interval of this posterior distribution of the rate ratio 
will be reported, along with the probability that true rate ratio is less than 1 (equivalent to 
the log rate ratio being less than 0). 
The following 2-component mixture prior will be used for the log rate ratio: 
𝑝(𝜃) = 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(−0.7474 , 0.1532) + 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(0 , 2.1256) 


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Sensitivity analysis will be conducted to assess the impact of different prior weights  on 
the ‘informative’ component of the robust mixture prior, and the details will be specified 
in the RAP. 
For the intercurrent event of withdrawal from study treatment, hypothetical strategy will 
be applied for primary analysis, where the logarithm of time on treatment will be used as 
an offset variable in the model.  
The detailed missing data imputation method and supportive analysis will be defined in 
full RAP. 
 
9.4.1.2. 
Key Secondary Analyses 
• Time to first clinically significant exacerbations. 
• Mean change in St. Georges Respiratory Questionnaire at Week 52  
• Frequency of clinically significant exacerbations requiring hospitalization 
(including intubation and admittance to an ICU) or ED visits over the 52-week 
treatment period 
• Frequency of clinically significant exacerbations requiring hospitalization over 
the 52-week treatment period 
• Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52 
Time to first clinically significant exacerbations will be analysed using Cox’s 
proportional hazards model with covariates of treatment group, baseline maintenance 
OCS therapy, number of exacerbations in previous year (as an ordinal variable), baseline 
disease severity (as % predicted FEV1). 
 
St. Georges Respiratory Questionnaire (SGRQ) score will be analysed using mixed 
repeated measures model adjusting for baseline maintenance OCS therapy, baseline 
SGRQ, number of exacerbations in previous year (as an ordinal variable), baseline % 
predicted FEV1, and treatment and visit, plus interaction terms for visit by baseline and 
visit by treatment group. 
The secondary endpoints of rate of exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits and rate of clinically significant 
exacerbations requiring hospitalization will be analyzed using negative binomial 
regression, as described for the primary endpoint above.  
Pre-bronchodilator FEV1 will be analyzed using mixed effects repeated measures model 
adjusting for baseline maintenance OCS therapy, baseline FEV1, number of 
exacerbations in previous year (as an ordinal variable), and treatment, and visit, plus 
interaction terms for visit by baseline and visit by treatment group. 
The point estimate as well as the estimate of the variability in above analyses will be 
provided. More details will be provided in full RAP.  
 


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9.4.1.3. 
Other Analyses 
Full details of the analyses to be performed on other efficacy endpoints will be given in 
the RAP. 
9.4.2. 
Safety analyses 
The MITT- population will be used for the analysis of safety data.  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 subjects administered investigational 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 Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary and summarized by preferred term and treatment group. 
AEs and SAEs occurring pre-treatment, during active treatment and post-treatment will 
be summarized separately. The number and percentage of subjects experiencing at least 
one AE of any type, AEs within each body system and AEs within each preferred term 
will be presented for each treatment group. Separate summaries will be provided for all 
AEs, drug-related AEs, SAEs, events of special interest (including systemic reactions and 
local injection site reactions) and for AEs leading to permanent discontinuation of study 
drug or withdrawal from the study. Additional analyses to fully describe events of special 
interest will be defined in the RAP. 
9.4.2.3. 
Clinical Laboratory Evaluations 
All laboratory parameters for Haematological and clinical chemistry will be summarized 
and tabulated. 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 
Actual values and change from baseline for other scheduled safety assessments such as 
vital signs (pulse rate, systolic and diastolic blood pressure), 12-lead ECG parameters 
(QTc and heart rate) will be summarized at each scheduled visit. Further details will be 
provided in the RAP.  
9.4.2.5. 
Immunogenicity 
Immunogenicity will be summarized using appropriate descriptive statistics. 


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9.4.3. 
Pharmacokinetic Analyses 
Blood samples will be collected to determine mepolizumab plasma concentrations at 
Visits specified in the Table 1 (Section 1.2). The mepolizumab plasma concentrations 
from this study will be analyzed using non-compartmental analysis and/or population PK 
analysis approach. When population PK analysis is considered necessary, it will be 
conducted using, for example, NONMEM 7 for determination of the population and/or 
individual systemic exposure, volume of distribution and clearance as well as characterise 
the between- and within subject variability. The effect of subjects’ characteristics such as 
body weight, age, gender, serum creatinine on mepolizumab systemic exposure will also 
be explored in order to explain the inter-subject variability in drug exposure. Population 
PK analysis may incorporate previous Caucasian PK data to explore the potential ethnic 
difference between Chinese and Caucasians in mepolizumab exposure. Pharmacokinetic 
data will be presented in graphical and/or tabular form and will be summarized 
descriptively. 
9.4.4. 
Pharmacodynamic Analyses 
Blood eosinophil ratio to baseline will be analysed using mixed model repeated measures 
adjusting for baseline, baseline maintenance OCS therapy, number of exacerbations in 
previous year (as an ordinal variable), baseline % predicted FEV1, and treatment, visit, 
visit by baseline interaction and visit by treatment group interaction. Data will be log-
transformed prior to analysis. Values of zero will be imputed as half the lowest observed 
value for that measure within the entire study database prior to the log transformation. 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
If deemed appropriate, details of any PK/PD analyses to be performed will be given in 
the RAP. 
9.4.6. 
Health Outcome Analyses 
Details of the analyses to be performed on the health outcome endpoints listed in 
Section 7.7  will be given in the RAP. 


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10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins. 
10.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following: 
• 
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
• 
Obtaining signed informed consent 
• 
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC) 
• 
GSK will provide full details of the above procedures, either verbally, in writing, 
or both. 
• 
Signed informed consent must be obtained for each subject prior to participation 
in the study 
• 
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including PK research and healthy 
economic research.   
• 
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.   
• 
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated. 
10.3. 
Quality Control (Study Monitoring) 
• 
In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.   


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• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents 
10.4. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  
In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
10.5. 
Study and Site Closure 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
GSK reserves the right to temporarily suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance. For multicenter studies, this can occur at one or more or at all sites.   
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action. 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.   


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If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation. 
10.6. 
Records Retention 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.   
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.   
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.   
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions. 
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, GSK standards/procedures, and/or institutional 
requirements.   
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator is no longer associated with the site. 
10.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
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 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 subjects, as 
appropriate. 


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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 results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 


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11. 
REFERENCES 
Ambrosino N, Paggiaro P. The management of asthma and chronic obstructive 
pulmonary disease:current status and future prospective. Expert Rev.Respir.Med. 
2012;6:117-127.  
American Heart Association. Classes of Heart Failure. Available at. 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classeso
f-Heart-Failure_UCM_306328_Article.jsp. Accessed14 August 2012. 
ATS workshop. Proceeding of the ATS workshop on refreactory asthma: current 
understaning, recommendations, and unanswered questions. Am J Respir Critt Care Med. 
2000;162:2341-2345. :  
Bel EH, Wenzel SE, Thompson PJ et al. Oral Glucocorticoid-Sparing Effect of 
Mepolizumab in Eosinophilic Asthma. N Engl J Med. 2014;371:1189-97.  
Bossley CJ, Fleming L,Gupta A, Rgegamey N, Frith J, Oates T. Pediatric severe asthma 
is characterized by eosinophilia and remodeling without TH2 cytokines. J Allergy Clin 
Immunol. 2012;129:974-982.  
Chung KF, Wenzel SE, Brozek JL et al. International ERS/ATS guidelines on definition, 
evaluation and treatment of severe asthma. EurRespir J. 2014a;43:343-373.  
Chung KF. Defining phenotypes in asthma: A step towards personalized medicine. 
Drugs. 2014b;74:719-728.  
Fuhlbrigge A, Peden D, Apter A, Boushey HA, Camargo CA Jr, Gern J et al. Asthma 
Outcomes: Exacerbations. J Allergy Clin Immunol. 2012;129:S34-48.  
GlaxoSmithKline Document Number CM2003/00010/13. Mepolizumab(SB-240563) 
Investigator's Brochure. Report Date 13-NOV-2017.  
Gleich GJ, Klion AD, Lee JJ, Weller PF. The consequence of not having eosinophils. 
Allergy. 2013;68:829-35.  
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A et al. 
Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 
2009;360:973-984. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D et al. Contraceptive 
Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc. 2011;50:table 3-2.  
ICH M3(2). Guidance for Industry.2010 Available at. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073246.pdf 


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Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA, McLaurin K. Effect of 
asthma exacerbations on health care costs among asthmatic patients with moderate and 
severe persistent asthma. J Allergy Clin Immunol. 2012;129:129-1235.  
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for 
chronic airflow limitaion-the St George's Respiratory Questionnaire. Am Rev Respir Dis. 
1992;145:1321-1327.  
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three-shortened versions of the asthma control questionnaire. Resp Med. 2005;99:553-
558.  
Keene ON, Jones M, Lane P, Anderson J. Analysis of exacerbation rates in asthma and 
chronic obstructive pulmonary disease: example from TRISTAN study. Pharm Stats. 
2007;6:89-97.  
Nair P, Pizzichini MMM, Kjarsgaard M, Inman MD, Efthimiadia A, Pizzichini E et al. 
Mpolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 
2009;360:985-993.  
Nucala Label, 2015. Availabel at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125526Orig1s000Lbl.pdf. 
Accessed on Nov 12, 2015. 
Ortega H, Liu M, Pavord I, Brusselle G, FitzGerald J, Chetta A et al. Mepolizumab 
Treatment in Patients with Severe Eosinophilic Asthma. N Engl J Med. 2014;371:1198-
207.  
Pavord I, Kom S, Howarth P, Bleecker E, Buhl R, Keene O et al. Mepolizumab for 
severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled 
trial. Lancet. 2012;380:651-59.  
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the ERS 
Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95 
year age range: the global lung function 2012 equations. Eur Respir J. 2012; 40:1324–
1343. 
Sampson HA, Munoz-Furlong A, Campbell RL 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;117:391-397.  
Zhu Haiyuan, Lakkis Hassan. Sample size calculation for comparing two negative 
binomial rates. Statist.Med. 2014;33(3):376-87.  
Friede T, Schmidli H. Blinded sample size reestimation with count data: methods and 
applications in multiple sclerosis. Statist.Med. 2010;29:1145-1156. 


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Schmidli H, Gsteiger S, Roychoudhury S, O’Hagan A, Spiegelhalter D, Neuenschwander 
B. Robust meta-analytic-predictive priors in clinical trials with historical control 
information. Biometrics. 2014;70:1023-1032. 


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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ACQ 
Asthma Control Questionnaire 
AE 
Adverse Event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATS 
American Thoracic Society 
CPAP 
Continuous Positive Airway Pressure 
CS 
Corticosteroid 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case report form 
ED 
Emergency Department 
eDiary 
Electronic diary 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GINA 
Global Initiative for Asthma 
GSK 
GlaxoSmithKline 
HBsAg 
Hepatitis B Surface Antigen 
HIV 
Human Immunodeficiency Virus 
IDMC 
Independent Data Monitoring Committee 
ICS 
Inhaled corticosteroids 
ICU 
Intensive Care Unit 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
IM 
Intramuscular 
IP 
Investigational Product 
IRB 
Institutional review board 
ITT 
Intent to Treat 
IUD 
Intrauterine Device 
IV 
Intravenous 
IWRS 
Interactive web response system 
LABA 
Long-acting beta-2-agonists 
LTRA 
Leukotriene receptor antagonist 
MedDRA 
Medicinal dictionary for regulatory activities 
mcg 
Micrograms 
MDI 
Metered Dose Inhaler 
mg 
Milligram 
N/A 
Not applicable 


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NHLBI 
National Heart Lung and Blood Institute 
OCS 
Oral corticosteroids 
p.a. 
Per annum 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic 
RAP 
Reporting and Analysis Plan 
SABA 
Short-acting beta-2-agonist 
SAE 
Serious adverse event 
SAMA 
Short-acting muscarinic antagonist 
SC 
Subcutaneous 
SCS 
Systemic corticosteroids 
SGRQ 
St. George’s Respiratory Questionnaire 
SRM 
Study reference manual 
ULN 
Upper Limit of Normal 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
RAMOS NG 
 
MedDRA 
Seretide 
 
Xolair 
 


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12.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments  
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Phase III-IV 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, if INR measured 
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 and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment 
• 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 unless allowed per protocol 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and 
Hepatitis delta antibody5. 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, within 28 days after last 
dose6 


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and GSK Medical Governance approval is 
granted  
• If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and continue participant in the 
study for any protocol specified follow up 
assessments  
 
 
 
 
 
 
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs 
• 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 perform 
liver event follow up assessments within  
24-72 hrs  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• 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 treatment 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, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 


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studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants 
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 IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody  
5. If Hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005]. 
6. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to 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 
 
Phase III-IV 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 treatment  
• 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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References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. 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, Gault E.  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.  


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12.3. 
Appendix 3: Adverse Events: Definition and Procedures for 
Recording, Evaluating, Follow-Up and Reporting  
12.3.1. 
Definition of Adverse Events 
Adverse Event 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 AE definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgement 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 treatment administration even 
though it may have been present prior to 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 overdose 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported 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 subject’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 
subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where 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. 
12.3.2. 
Definition of Serious Adverse Events 
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, etc). 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose: 
Results in death 
Is life-threatening 
NOTE: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject 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 
out-patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills 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. 


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• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious. 
• 
Examples of such events are 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 
12.3.3. 
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 
12.3.4. 
Recording of AEs and SAEs 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 


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• 
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 GSK /AE/SAE CRF page. 
• 
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 (IB) 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. 


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• 
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 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. 
 
12.3.5. 
Reporting of SAEs 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) and fax the form to GSK within 24 
hours. 
• 
The site will enter the SAE data into the electronic system as soon as it 
becomes available. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and 
verification of the relationship of each SAE to IP/study participation 
(causality) within 72 hours of SAE entry into the eCRF. 


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• 
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 SPM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor. 
• 
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 SPM. 
 


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12.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
12.4.1. 
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. 
Woman 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).  
• 
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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12.4.2. 
Contraception Guidance 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
below: 
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 
(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.) 
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 
(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 men or 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. 
Hormonal contraception may be susceptible to interaction with other medications, which may reduce the 
efficacy of the contraceptive method. 


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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 for 
this study. Male condom and female condom should not be used together (due to risk of failure with friction) 
12.4.3. 
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.  
• 
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 will be reported as an AE or 
SAE.  
• 
A spontaneous abortion 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 3. 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 
mepolizumab. 
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen.  Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required. 


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12.5. 
Appendix 5: Cardiovascular Screening Questions  
At screening each subject should be asked the following: 
Unrelated to the symptoms you experience with your asthma: 
Do you have any pain or discomfort (such as pressure) in your chest?  
If yes, does this pain/discomfort/pressure go to other areas of your body such as neck, 
jaw, throat, or down your arms (including a numbness feeling in your arm) when it 
occurs? 
When you walk at an ordinary pace on a level surface does this produce chest pain? 
If yes, respond to a and b: 
Does this chest pain or discomfort occur when you are not doing any activities such as 
resting in bed or sitting in a chair?   
Has this chest pain/discomfort been more frequent or more intense or last longer or come 
on with less exertion lately? 
When you walk uphill or hurry does this produce chest pain/discomfort? 
Do you use or have you been previously prescribed nitroglycerine to relieve the 
discomfort?   
If yes, have you needed to increase the number of pills or frequency of using the pills 
recently? 
If the subject responds “yes” to any of the above questions a study physician should 
further assess for the presence of undiagnosed or unrecognized angina when 
evaluating Exclusion Criteria 5. 
 
 


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12.6. 
Appendix 6: Daily Asthma Symptom Score 
Each morning subjects will record an asthma symptom score using the following scale: 
• 
Daily Symptom Score: 
0 =
 
1 = 
. 
2 = 
 
3 = 
 
 
4 = 
 
 
5 = 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


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12.7. 
Appendix 7: 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 hours) 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., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)  
b) Reduced 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 hours): 
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b) Respiratory compromise (e.g., dyspnea, 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 


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12.9. 
Appendix 9 Statistical Appendix 
12.9.1. 
Choice of posterior probability 
A 95% posterior probability that the true rate ratio < 1 represents a high level of 
confidence for declaring a positive treatment benefit in Chinese patients in the context of 
a bridging study where substantial evidence of treatment benefit in global (non-Chinese) 
patients already exists and is aligned with examples of Bayesian decision criteria given in 
the FDA draft guidance on Complex Innovative Designs 
[https://www.fda.gov/media/130897/download]. This represents a more rigorous 
evidentiary threshold than is typically provided by a ‘positive trend ‘design, which 
requires only that the observed rate ratio < 1. 
12.9.2. 
Overview of the proposed robust mixture prior and analysis 
strategy 
In order to formally incorporate the global MEA115588 study data in this study, the 
Bayesian analysis with a robust mixture prior distribution [Schmidli, 2014], which allows 
for “dynamic borrowing” of prior information, will be conducted. This analysis learns 
how much of the global prior information to borrow based on the consistency between 
the China data and global prior. The mixture prior was constructed by two components. 
• Component 1 is an informative prior based on the observed efficacy response 
from global study MEA115588, referred to as the “global prior” 
• Component 2 is a “vague” prior centred on a mean of zero and with variance 
scaled to represent information equivalent to one subject 
Denoting the log rate ratio for Mepolizumab 100mg SC vs. placebo as 𝜃, the prior has the 
form 
𝑝(𝜃) = 𝑤∗𝑝1(𝜃) + (1 −𝑤) ∗𝑝2(𝜃) 
where 𝑝1(𝜃) is the component containing the information from the global study prior,  
𝑝2(𝜃) is the vague component and 𝑤 is the weight. 
The prior weight 𝑤 assigned to the informative prior component represents the prior 
degree of confidence in the extrapolation strategy. At lower prior weight the mixture 
prior presents a heavier tailed distribution with more prior weight being applied to the 
non-informative vagueprior component. When the mixture prior is combined with the 
observed global data, 𝑤 is updated according to how consistent China data are with the 
global prior: the stronger the evidence of consistency, the greater the increase in the 
posterior weight 𝑤∗ relative to the prior weight 𝑤. Conversely, when there is prior-data 
conflict, 𝑤∗ will be lower than 𝑤 and will tend to zero as evidence of conflict increases, 
so that the global information is down-weighted and posterior inference is based almost 
entirely on the China data. 
 


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12.9.2.1. 
The informative (global) prior 
The global prior distribution was constructed using a normal approximation to the 
sampling distribution of the observed log rate ratio of exacerbations on mepolizumab vs. 
placebo in the subjects from global study MEA115588. The point estimation and 
standard error for the log rate ratio obtained from negative binomial regression of the 
observed exacerbation counts were used as the mean and standard deviation, respectively, 
of a normal prior distribution for the global efficacy response. Therefore, based on the 
results in global MEA115588 presented in Table 8, it provided a Normal 
(−0.7474, 0.15322) as the global prior for log rate ratio. 
12.9.2.2. 
The vague prior 
The vague prior has a mean of 0 for rate ratio on log scale (i.e. no effect in China), and 
the variance is scaled such that the information content of the prior is approximately 
equivalent to that provided by two subjects, one subject per arm. This variance was 
determined by taking the squared standard error of the log rate ratio obtained from the 
global data and multiplying it by N/2, where N is the total MEA115588 sample size. 
Therefore, the SD of the vague prior is 
𝑆𝐷= √0.15322 ∗385
2
= 2.1256 
 
12.9.2.3. 
Initial weight on informative (global) prior component and mixture prior 
An initial (prior) weight of 50% is proposed for the informative global component of the 
robust mixture prior, with the remainder of the weight (50%) placed on the vague prior to 
reflect a conservative starting position regarding the assumed relevance of the global 
MEA115588 results to Chinese. Combining the two components and their respective 
weights gives the following 2-component mixture normal: 
𝑝(𝜃) = 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(−0.7474 , 0.1532) + 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(0 , 2.1256) 
 
12.9.3. 
Choice of weights  
The scientific grounds for expecting similar benefit: risk profile in China and global 
study patients justifies a high initial weight on the informative component. However, 
based on an extensive review of the impact of the prior weight specified for the global 
MEA115588 study (prior weights explored were: 0, 0.1, 0.2, …0.9,1), a more 
conservative prior weight of 50% was felt to provide an acceptable trade-off between the 
risks of a false positive result and a false negative result, and to enable meaningful gains 
in precision due to borrowing information from the global study whilst ensuring that the 
prior does not dominate the posterior completely but allows the observed data in Chinese 
patients to contribute to the inference from the study. 


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12.10. 
Appendix 10: Protocol Amendment Changes 
12.10.1. 
Protocol Amendment 1 
This amendment applies to all sites participating in Study 201536.  
Rationale 
This protocol amendment is being implemented to update Medical Monitor Name and 
Contact Information, clarify inclusion criteria/exclusion criteria, randomization criteria, 
withdrawal/stopping criteria, subject and study completion, concomitant therapy, efficacy 
assessments and other minor protocol clarifications. 
The following revisions were made:  
• Medical Monitor Name and Contact Information updated 
• Inclusion criteria updated: controller Medication clarified 
• Withdrawal/stopping criteria updated: withdrawal from study treatment and 
withdrawal from study clarified 
• Subject and study completion clarified  
• Concomitant therapy updated: additional asthma medication treatment clarified 
• Efficacy assessments updated:  treatment duration clarified 
• Editing or typo errors revised 
• Synopsis updated based on main text update 
• References updated 
List of Specific Changes 
Section: Medical Monitor Name and Contact Information 


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Tel: 
 
 
Tower A, Ocean 
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Center no. 56, 
Mid 4th East 
Ring Rd. 
Beijing.100025 
Secondary 
Medical 
Monitor 
 
 
 
 
Tower A, Ocean 
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Center no. 56, 
Mid 4th East 
Ring Rd. 
Beijing.100025 
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No. 1 Building, 
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Tel:
 
 
Building 18, 
999 Huanke 
Road, 
Pudong, 
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201203, China 
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Medical 
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Building 18, 
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Road, 
Pudong, 
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201203, China 
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Amendment text: 
Subjects will be stratified based on blood eosinophil count at screening (300 cells/L 
and , <300 cells/L). A minimum of 150 subjects will be enrolled with blood eosinophil 
count 300 cells/L. 
 
Section: synopsis: Table 1 Schedule of Activities Table 
Original text: 
Procedures 
Pre-
screening 
Screen/Run-
in 
Randomised Treatment (visit window is ± 7 
days for V3-15 
 V2-1, V2-2, V14, V14-1, V14-2 visit window 
is ± 2 days from V2 or V14 in sub-study) 
Exit 
Visit 
With-
drawal 
 
Amendment text: 
Procedures 
Pre-
screening 
Screen/Run-
in 
Randomised Treatment (visit window is ± 7 
days for V3-15V15-2; 
 V2-1, V2-2, V14, V14-1, V14-2 visit window 
is ± 2 days from V2 or V14 in sub-study) 
Exit 
Visit 
With-
drawal 
 
 
Original text: 
Study Day 
 
-
28~
-7 
1 7 14 28 56 84 112140 168 196 224252280308 336 343 350364392480 
 
Hepatitis B and C 
testing13, 14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19. If hepatitis C positive confirmation by testing the same sample is required. See central laboratory 
manual for details. For subjects who are HBsAg positive or HBcAb positive reflexive testing must be 
conducted to assess HBV DNA. 
20. If ALT 3X ULN, reflexive testing should be conducted for HBV-DNA. 
Amendment text: 
Study Day 
 
-
28~
-7 
1 7 14 28 56 84 112140 168 196 224252280308 336 343 350364392480 
 
Hepatitis B and C 
testing13, 14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. If hepatitis C positive confirmation by testing the same sample is required. See central laboratory 
manual for details. For subjects who are HBsAg positive or HBcAb positive reflexive testing must be 
conducted to assess HBV DNA. 


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14. If ALT 3X ULN, reflexive testing should be conducted for HBV-DNA. For subjects who are HBsAg 
positive at Visit 1 or HBcAb positive (documented previous positive result) reflexive testing 
must be conducted to assess HBV DNA. 
 
 


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Section 4.2. Treatment Arms and Duration: Table 4 
Original text 
Phase Phase Title 
Duration 
Description 
3 
Treatment 
52 weeks 
At Visit 2 (Week 0) those subjects who 
successfully complete the run-in period as 
well as meet the pre-defined randomization 
criteria will be randomized; those subjects 
that do not meet the pre-defined 
randomization criteria will be deemed run-in 
failures (see Section 5.4). Study medication 
will be administered SC every 4 weeks for a 
total of 13 doses (Visit 2 to Visit 14, 
inclusive). The treatment period will conclude 
with subjects completing Exit Visit or Early 
Withdrawal Visit assessments approximately 
4 weeks after the subject was administered 
their last dose of double-blind study treatment 
(i.e. at Week 52). 
PK samples will be collected at Week 0, 1, 2, 
4, 24, and Week 48, 49, 50, 52, 56, 60 (or 0, 
1, 2, 4, 8, 12 weeks after last dose) in 
subjects who provided consents for PK sub-
study.  
 
Third: Amendment text: 
Phase Phase Title 
Duration 
Description 
3 
Treatment 
52 weeks 
At Visit 2 (Week 0) those subjects who 
successfully complete the run-in period as 
well as meet the pre-defined randomization 
criteria will be randomized; those subjects 
that do not meet the pre-defined 
randomization criteria will be deemed run-in 
failures (see Section 5.4). Study medication 
will be administered SC every 4 weeks for a 
total of 13 doses (Visit 2 to Visit 14, 
inclusive). The treatment period will conclude 
with subjects completing Exit Visit or Early 
Withdrawal Visit assessments approximately 
4 weeks after the subject was administered 


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Phase Phase Title 
Duration 
Description 
their last dose of double-blind study treatment 
(i.e. at Week 52).  
PK samples will be collected at Week 0, 1, 2, 
4, 24, and Week 48, 49, 50, 52, 56, 60 (or 0, 
1, 2, 4, 8, 12 weeks after last dose) in 
subjects who provided consents for PK sub-
study.  
 
First: section 5.1. Inclusion Criteria 
Second: Original text 
19. Controller Medication:  Current treatment with an additional controller medication, 
besides ICS, for at least 3 months. [e.g., long-acting beta-2-agonist (LABA), 
leukotriene receptor antagonist (LTRA), or theophylline] 
Third: Amendment text: 
6. Controller Medication:  Current treatment with an one or more additional 
controller medication, besides ICS. At least one additional controller medication 
must have been regularly used for at least 3 months prior to Visit 1. [e.g., long-
acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or 
theophylline]  
 
First: section 5.2. Exclusion Criteria 
Second: Original text 
3.    Chest X-ray: A chest X-ray that reveals evidence of clinically significant 
abnormalities not believed to be due to the presence of asthma. 
Third: Amendment text: 
3.    Abnormal Chest X-ray (or CT scan): A chest X-ray (or CT scan) that reveals 
evidence of clinically significant abnormalities not believed to be due to the presence of 
asthma. If a chest X-ray (or CT scan) is not available within 6 months prior to Visit 
1, then a chest X-ray must be conducted. 
 
First: section 5.3. Randomization Criteria 
Second: Original text 


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5. Abnormal clinically significant finding:  Subjects have had clinically significant 
findings in their laboratory screening tests including liver chemistry at Visit 1. 
Third: Amendment text: 
5. Abnormal clinically significant finding:  Subjects have had no evidence of 
clinically significant findings in their laboratory screening tests including liver 
chemistry at Visit 1. 
 
First: section 5.5. Withdrawal/Stopping Criteria 
Second: Original text 
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is 
considered to be detrimental for them to continue in the study. Reasons for withdrawal 
can include: an adverse event (including abnormal liver function test or abnormal 
laboratory results), Investigator unblinded study treatment, clinically significant 
abnormality identified on ECG reading, lost to follow-up, protocol violation, lack of 
efficacy, sponsor terminated study, non-compliance, pregnancy, or for any other reason.   
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Early Withdrawal Visit and 
to return all study related materials.  In those instances where the subject specifies the 
reason for withdrawal of consent, this information will be captured in the eCRF. 
Subjects who withdraw from study treatment prematurely (for any reason) should , where 
possible, continue to be followed-up as per protocol until the completion of the Exist 
Visit assessments. If this is not possible, the Investigator must encourage the subject to 
participate in as much of the study as they are willing (or able) to. Further information are 
provided in the Study Reference Manual (SRM). 
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc). 
In the event a subject withdraws at, or during, a scheduled visit, and does not receive 
investigational product, an Early Withdrawal Visit is not required.  However, all study 
procedures scheduled at an Early Withdrawal Visit must be performed at this visit 
instead.     
The primary reason for withdrawal will be recorded in the eCRF and any data collected 
up until the point of withdrawal will be used in the analyses.   
Third: Amendment text: 
Withdrawal from study treatment 


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Subjects may be withdrawn from study treatment at anytime by the Investigator if it is 
considered to be detrimental for them to continue in the study treatment.  
A subject must be withdrawn from study treatment if any of the following stopping 
criteria are met: 
• Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (section 5.5.1) 
• QT: Meets any of the protocol-defined stopping criteria (section 5.5.2) 
• Pregnancy: Positive pregnancy test 
Other rReasons for withdrawal can include: an adverse event (including abnormal liver 
function test other than stopping criteria or abnormal laboratory results), Investigator 
unblinded study treatment, clinically significant abnormality identified on ECG reading 
other than stopping criteria, lost to follow-up, protocol violation, lack of efficacy, 
sponsor terminated study, non-compliance, pregnancy, or for any other reason 
Subjects who withdraw from study treatment prematurely (for any reason) should, where 
possible, continue to be followed-up as per protocol until the completion of the Visit 
assessments. If this is not possible, the Investigator must encourage the subject to 
participate in as much of the study (scheduled visits and activities, record eDiary data) 
as they are willing (or able) to. If subject cannot attend the visit on site, telephone 
contact is acceptable to collect below information: asthma exacerbation, AE/SAE, 
concomitant medication and to encourage subjects continue to record eDiary data. 
Further information are provided in the Study Reference Manual (SRM). 
Withdrawal from the study 
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Early Withdrawal Visit and 
to return all study related materials.  In those instances where the subject specifies the 
reason for withdrawal of consent, this information will be captured in the eCRF. Patients 
will not be followed for any reason after consent has been withdrawn. 
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc). 
In the event a subject withdraws from study at, or during, a scheduled visit, and does not 
receive investigational product, an Early Withdrawal Visit is not required.  However, all 
study procedures scheduled at an Early Withdrawal Visit must be performed at this visit 
instead.     
The primary reason for withdrawal from study will be recorded in the eCRF and any data 
collected up until the point of withdrawal from study will be used in the analyses when 
appropriate.   


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First: section 5.6. Subject and Study Completion 
Second: Original text 
Subjects will be regarded as having completed the study if they complete all phases of the 
study (run-in, double-blind treatment administration, and Exit Visit).  
The end of the study is defined as the last subject’s last visit.  
Third: Amendment text: 
Subjects will be regarded as having completed the study if they complete all phases of the 
study (run-in, double-blind treatment administration, and Exit Visit) OR although they 
prematurely discontinue study treatment but still complete the Week 52 Visit. 
The end of the study is defined as the last subject’s last visit.  
 
First: section 6.9.1. Permitted Medications and Non-Drug Therapies 
Second: Original text 
All concomitant medications taken during the study will be recorded in the eCRF.  The 
minimum requirement is that drug name and the dates of administration are to be 
recorded.  However, for OCS, the dose must be recorded as well as any dose changes. 
Additional asthma medications such as theophyllines or anti-leukotrienes will be 
permitted provided they have been taken regularly in the 3 months prior to randomization 
(Visit 2, Week 0).   
…… 
Third: Amendment text: 
All concomitant medications taken during the study will be recorded in the eCRF as well 
as the ICS usage in the past 12 months prior to Visit 1 and other additional controllers 
in the past 3 months prior to Visit 1.  The minimum requirement is that drug name and 
the dates of administration are to be recorded.  However, for ICS and OCS, the dose 
must be recorded as well as any dose changes. 
All additional asthma medications such as LABA, theophyllines or anti-leukotrienes will 
be permitted provided continually used with the same dose and regimen if they have 
been taken regularly in the 3 months prior to randomization (Visit 2, Week 0).   
If for any reasons (except asthma exacerbation) the participant must change their 
maintenance asthma treatment medications, the investigator must discuss the change 


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with the Medical Monitor prior. Any changes of maintenance asthma treatment should 
be recorded in the eCRF. 
 
First: section 7.1.2. Critical procedures performed at Screen (Visit 1) 
Second: Original text 
• 
…… 
• Vital signs 
• Resting 12 lead ECG 
• 
…… 
 
Third: Amendment text: 
• 
…… 
• Vital signs 
• Chest X-ray or if available review of chest X-ray/CT-scan conducted in the prior 6 
months. 
• Resting 12 lead ECG 
• 
…… 
 
First: section 7.2 Other Efficacy Endpoints 
Second: Original text 
15. Time to withdrawal due to asthma exacerbations 
 
Third: Amendment text: 
15. Time to withdrawal from study treatment due to asthma exacerbations 
First: section 7.2.1. Clinically Significant Exacerbations (primary endpoint) 
Second: Original text 
…… 
The period of time for which exacerbation information will be included in the primary 
endpoint analysis will be from the start of treatment until the Week 52 visit 
approximately 4 weeks after the last dose of study medication.  For those subjects that 
early withdraw, the time period for primary endpoint collection will be from the start of 


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treatment until the date of withdrawal (but no greater than approximately 4 weeks post 
last dose) For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.  
…… 
Third: Amendment text: 
…… 
The period of time for which exacerbation information will be included in the primary 
endpoint analysis will be from the start of treatment until the Week 52 visit 
approximately 4 weeks after the last dose of study medication.  For those subjects that 
early withdraw, the time period for primary endpoint collection will be from the start of 
treatment until the date of withdrawal (but no greater than approximately 4 weeks post 
last dose) For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.  
…… 
First: section 7.2.3. St. George’s Respiratory Questionnaire (SGRQ) 
Second: Original text 
……The questionnaire will be administered at baseline (Visit 2) and at the Exit Visit.  
 
Third: Amendment text: 
…… The questionnaire will be administered at baseline (Visit 2) and at the Exit Visit 
visits specified in the Schedule of Activities (Section 1.2).   
 
First: section 7.2.4. Pulmonary Function Testing including Reversibility 
Second: Original text 
…… Spirometry must be performed at the same time (1 hour) of the Visit 2 spirometry. 
Subjects should try to withhold SABAs or SAMAs for 6 hours and LABAs for 12 
hours prior to clinic visit, if possible. Assessments to be recorded will include FEV1, 
FVC and PEF.  Pre-bronchodilator measurements will be taken at each clinic visit. …… 
Third: Amendment text: 
…… Spirometry must be performed at the same time (12 hour) of the Visit 2 
spirometry. Subjects should try to withhold SABAs or SAMAs for 6 hours and LABAs 
for 12 hours prior to clinic visit, if possible. Assessments to be recorded will include 
FEV1, FVC and PEF.  Pre-bronchodilator measurements will be taken at each clinic visit. 
…… 


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First: section 7.4.5. Pregnancy 
Second: Original text 
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 4 weeks post-last dose.  
Third: Amendment text: 
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 4 weeksmonths post-last dose.  
 
First: section 9.2.1. Sample Size Assumptions 
Second: Original text 
…… 
To account for the loss of patient years data from subjects who withdraw early from the 
trial, additional 44 subjects (22 in the mepolizumab treatment arm and 22 in the placebo 
treatment arm) will be randomized; …… 
Third: Amendment text: 
…… 
To account for the loss of patient years data from subjects who withdraw early from the 
trial from study treatment early, additional 44 subjects (22 in the mepolizumab treatment 
arm and 22 in the placebo treatment arm) will be randomized; …… 
 
First: section 9.2.2. Sample Size Sensitivity 
Second: Original text 
……Table 7 illustrates this effect on power of varying placebo rates and reductions in 
rates with mepolizumab, assuming the sample size remains constant at 128 subjects in 
mepolizumab arm and 128 subjects in placebo arm, excluding the additional 44 subjects 
to account for early withdrawals, and a dispersion parameter k=0.8.  
…… 
 Table 8 illustrates the estimated power which would be obtained with different 
dispersion parameter, assuming the sample size remains constant at 128 subjects in 
mepolizumab arm and 128 subjects in placebo arm, excluding the additional 44 subjects 
to account for early withdrawals, and the placebo and mepolizumab rates are 1.7 and 1.02 


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respectively. It also shows the estimated sample size which would be required for 90% 
power.  
…… 
* Early withdrawal is not taken into account. 
 
Third: Amendment text: 
……  Table 7 illustrates this effect on power of varying placebo rates and reductions in 
rates with mepolizumab, assuming the sample size remains constant at 128 subjects in 
mepolizumab arm and 128 subjects in placebo arm, excluding the additional 44 subjects 
to account for early withdrawals from study treatment, and a dispersion parameter k=0.8.  
…… 
Table 8 illustrates the estimated power which would be obtained with different dispersion 
parameter, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment, and the placebo and mepolizumab rates are 1.7 
and 1.02 respectively. It also shows the estimated sample size which would be required 
for 90% power.  
…… 
*Early withdrawal from study treatment is not taken into account 
 
12.10.2. 
Protocol Amendment 2 
This amendment applies to all sites participating in Study 201536.  
Rationale 
This protocol amendment is being implemented to update inclusion criteria 3#, switching 
FEV1 predicted value equation from NHANESIII to Quanjer2012, updeated related 
content in pulmonary function testing section, reference and abbreviation accordingly.  
The following revisions were made:  
• Inclusion criteria updated: FEV1 
• Pulmonary Function Testing including Reversibility updated: NHANES III value 
• References updated 
• Abbreviations updated  


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• Editing or typo errors revised 
List of Specific Changes: 
Section: Table 1 Schedule of Activities Table 
Original text 
Visit 
V01 V1 V22 
V 
2-
13 
V 
2-
23 
V3 V4 V5 V6 V7 V8 V9 V10V11V12V13V14
V 
14-
13 
V 
14-
23 
V15
V 
15-
13 
V 
15-
23 
 
Study Week 
 
-4 
to -
1 
 0 1 2 4 8 12 16 20 24 28 32 36 40 44 48 49 50 52 56 60 
 
Study Day 
 
-
28~
-7 
1 7 14 28 56 84 112140168196 224 252 280 308 336 343350364 392480
 
Register Visit in 
RAMOS/IWRS 
X 
X 
X 
 
 X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Complete 
electronic Case 
Report Form 
(eCRF) 
 
X 
X 
 
 X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
Amendment text: 
Visit 
V01 V1 V22
V 
2-
13
V 
2-
23 
V3V4V5 V6 V7 V8 V9 V10V11V12V13V14
V 
14-
13 
V 
14-
23 
V15
V 
15-
13 
V 
15-23  
Study Week 
 
-4 
to -
1 
 0 1 2 4 8 12 16 20 24 28 32 36 40 44 48 49 50 52 56 
60 
 
Study Day 
 
-
28~
-7 
1 7 14 28 56 84 112140168196 224 252 280 308 336 343350 364 392480420  
Register Visit in 
RAMOS/IWRS 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Complete 
electronic Case 
Report Form 
(eCRF) 
X 
X 
X X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Section 5.1. Inclusion Criteria 
Original text 
3. FEV1: Persistent airflow obstruction as indicated by: 
• For subjects 18 years of age at visit 1, a pre-bronchodilator FEV1 <80% 
predicted (NHANES III)  
• For subjects 12-17 years of age at visit 1: 


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• A pre-bronchodilator FEV1 <90% predicted (NHANES III) recorded at Visit 
1 OR 
• FEV1: FVC ratio <0.8 recorded at visit 1 
Amendment text: 
4. FEV1: Persistent airflow obstruction as indicated by: 
• For subjects 18 years of age at visit 1, a pre-bronchodilator FEV1 <80% 
predicted (NHANES III) normal values calculated by Quanjer reference 
equations [Quanjer, 2012] 
• For subjects 12-17 years of age at visit 1: 
• A pre-bronchodilator FEV1 <90% predicted (NHANES III Quanjer,2012) 
recorded at Visit 1 OR 
• FEV1: FVC ratio <0.8 recorded at visit 1 
 
Section 7.2.4. Pulmonary Function Testing including Reversibility 
Original text 
……Further details of spirometry and reversibility testing procedures are presented in the 
Study Reference Manual. For predicted FEV1 values, NHANES III values will be used 
and adjustments to these values will be mande for race [Hankinson,2010]. Asian 
equations will be used. 
Amendment text: 
……Further details of spirometry and reversibility testing procedures are presented in the 
Study Reference Manual. For predicted FEV1 values, NHANES III values will be used 
and adjustments to these values will be mande for race [Hankinson,2010]. Asian 
equations will be used. 
Section 7.4.5. Pregnancy 
Original text 
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 4 months post-last dose.  
Amendment text: 
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 4 monthsweeks post-last dose.  
Section 11. Refences 
Original text 


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Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Societh-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of 
Antherosclerosis(MESA) Lung Study. Chest. 2010;137:138-45.  
Amendment text: 
Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Societh-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of 
Antherosclerosis(MESA) Lung Study. Chest. 2010;137:138-45.  
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the 
ERS Global Lung Function Initiative. Multi-ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 
equations. Eur Respir J. 2012; 40:1324–1343. 
. 
Section 12.1 Appendix 1- Abbreviations and Trademarks 
Original text 
N/A 
Not applicable 
NHANES 
National Health and Nutrition Examination Survey 
NHLBI 
National Heart Lung and Blood Institute 
Amendment text: 
N/A 
Not applicable 
NHANES 
National Health and Nutrition Examination Survey 
NHLBI 
National Heart Lung and Blood Institute 
 
12.10.3. 
Protocol Amendment 3 
This amendment applies to all sites participating in Study 201536. 
Rationale 
This protocol amendment is being implemented to update Secondary Medical Monitor 
Name and Contact information, clarify eDiary objective assessment links to clinically 
significant exacerbation and update the wordings about the blinded evaluation of 
exacerbation.  
The following revisions were made: 
• Secondary Medical Monitor Name and Contact Information updated 
• eDiary objective assessment liks to clinically significant exacerbation clarified 


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Site Address 
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Medical 
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Building 18, 
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Road, 
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TMF-11823581 
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Amendment text: 
Primary Efficacy Endpoint 
…… 
In order to provide an objective assessment of the circumstances linked to the clinical 
decision that defines asthma exacerbations, the investigator must take into account 
changes on one or more of the following parameters recorded in the subject’s eDiary: 
• 
Decrease in morning PEF 30% on at least two of three successive days, compared 
with baseline (last 7 days of run-in). 
 
• 
Decrease in morning peak flow 
• 
An increase of 50% in rescue medication on at least two of three successive days, 
compared with the average use for the previous week. 
• 
Increase in the use of rescue medication  
• 
Awakening due to asthma symptoms requiring rescue medication use for at least two 
of three successive nights. 
• 
Increase in the frequency of nocturnal awakening due to asthma symptoms 
requiring rescue medication use 
• 
A symptom score of 5 for at least two of three successive days 
• 
Increase in overall asthma symptom score 
The real-time notification of increasing respiratory parameters from the ediary will 
triggering contact with the investigator for review via email contact or at a clinic visit. 
 
Section 9.2.3 Sample Size Re-estimation or Adjustment 
Original text: 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after one year 
of enrolment, or when 150 subjects have been randomized, whichever is earlier. A 
subsequent evaluation will be done after approximately 15 months of enrolment, or when 
225 subjects have been randomized, whichever is earlier. If the exacerbation rates for the 
study are lower than planned, a sample size re-estimation may be conducted. Any 
subsequent change to the planned number of subjects randomized would be documented 
in a protocol amendment. 
Amendment text: 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after one year 


TMF-11823581 
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119 
 
of enrolment, or when 150 subjects have been randomized, whichever is earlier. A 
subsequent evaluation will be done after approximately after15 months of enrolment, or 
when 225 subjects have been randomized, whichever is earlier. If the exacerbation rates 
for the study are lower than planned, a sample size re-estimation may be conducted. Any 
subsequent change to the planned number of subjects randomized would be documented 
in a protocol amendment. 
 
 
12.10.4. 
Protocol Amendment 4 
This amendment applies to all sites participating in Study 201536.  
Rationale 
This protocol amendment is being implemented to update Medical Monitor Name and 
Contact information, clarify type of exacerbation in some other endpoints related to 
Systemic corticosteroids (SCS) usage and unscheduled healthcare resource utilization, 
added “mean days of work/school missed” as an other endpoint, updated analysis in 
synopsis,updated the study day of V2-1 and V2-2 in Schedule of Activities table, updated 
time period for collecting SAE information, added population PK analysis as an optional 
approach for mepolizumab concentration data analysis. Due to the impact of pandemic 
and observed lower event rates under blind assessment, updated statistical consideration 
section and change analysis methods to borrow data from MEA115588.,  and added a 
statistical appendix.  
The following revisions were made: 
• Medical Monitor Name and Contact Information updated 
• Clarify type of exacerbation in some other endpoints related to SCS usage and 
unscheduled healthcare resource utilization, add an other endpoint “mean days of 
work/school missed” which is already included in Health Outcomes section 
• Updated Study Day of V2-1 (from day 7 to day 8) and V2-2 (from day 14 to 
day15) to clarify the duration of PK sample collection, and added a description in 
SoA Note 3.  
• Time period for collecting SAE Information has been updated due to the China 
local GCP update in 2020. The mentioned SAE reporting collection period will 
follow China GCP requirement.   
• Add population PK analysis as an optional approach for mepolizumab 
concentration data analysis 


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• The statistical analyses in synopsis and statistical consideration section have been 
updated due to  a high false negative rate based on the observations during the 
blinded evaluation if ignore the impact from COVID 
 


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999 Huanke 
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Pudong, 
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Role 
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email address 
Phone/Cell/ 
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Number 
Fax Number Site Address 
Primary 
Medical 
Monitor  
 
 
Building 18, 
999 Huanke 
Road, 
Pudong, 
Shanghai, 
201203, China 
Secondary 
Medical 
Monitor 
 
 
 
 
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999 Huanke 
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123 
 
Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control. 
11. Mean number of days with oral 
corticosteroids taken for exacerbations 
12. Total prednisone (or equivalent) exposure 
for exacerbation over the 52-week treatment 
period 
… 
17. Unscheduled healthcare resource 
utilization (for severe exacerbations and other 
asthma related health care) over the 52-week 
treatment period 
 
Amendment text: 
Objectives and Endpoints: 
Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control. 
11. Mean number of days with oral 
corticosteroids taken for clinically significant 
exacerbations 
12. Total prednisone (or equivalent) exposure 
for clinically significant exacerbation over the 
52-week treatment period 
… 
17. Unscheduled healthcare resource 
utilization (for clinically significant severe 
exacerbations and other asthma related health 
care) over the 52-week treatment period 
18. Mean days of School/Work missed over the 
52-week treatment period 
 
Section 1.1.  Synopsis 
Original text: 
(no wordings about estimand) 
Amendment text: 
The primary clinical question of interest is: What is the effect of adding mepolizumab to 
standard of care when compared with placebo plus standard of care on the rate of 
exacerbations over 52 weeks in Chinese participants with severe eosinophilic asthma? 
This question is to be addressed in the absence of study treatment discontinuation.   


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The estimand is described by the following attributes: 
o Population: Chinese participants with severe eosinophilic asthma. 
o Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to 
placebo every 4 weeks, both treatments given on top of standard of care. Further 
details on standard of care can be found in Section 6. 
o Variable: number of clinically significant exacerbations over 52 weeks. 
o Summary measure: : annulised rate of exacerbations. Comparison between the 
mepolizumab arm and placebo will be assessd with the rate ratio. 
o Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
o Rationale for estimand:  
Interest lies in the treatment effect when medication is taken as directed.  For 
participants discontinuing randomised medication, use of a hypothetical strategy 
addresses treatment effects attributable to mepolizumab in the hypothetical 
scenario where participants would not discontinue from treatment. 
 
Section 1.1.  Synopsis 
Original text: 
The study is designed to test the superiority of mepolizumab 100 mg SC vs. placebo.  
Significance tests will be performed at the two-sided 5% alpha level (one-sided 2.5%). 
Adjustment for multiplicity will be performed based on the hierarchical testing of the 
primary and secondary endpoints in a pre-defined order. The primary endpoint will be 
tested first and if this is significant at the two-sided 5% level, the first of the secondary 
endpoints will be tested.  Hierarchical testing will continue in a similar manner for the 
remaining secondary endpoints. 
The primary and secondary endpoints are defined in the Objective(s)/Endpoint(s) above. 
The primary analyses will be performed using a generalized linear model (GLM) 
assuming the negative binomial distribution. The primary analyses will be based on a 
two-sided hypothesis testing approach and will use data for the MITT population 
collected from the start of treatment until the Week 52 visit approximately 4 weeks after 
the last dose of study medication. 
Amendment text: 
The study is designed to test the superiority of mepolizumab 100 mg SC vs. placebo.  
Significance tests will be performed at the two-sided 5% alpha level (one-sided 2.5%). 
Adjustment for multiplicity will be performed based on the hierarchical testing of the 
primary and secondary endpoints in a pre-defined order. The primary endpoint will be 
tested first and if this is significant at the two-sided 5% level, the first of the secondary 
endpoints will be tested.  Hierarchical testing will continue in a similar manner for the 
remaining secondary endpoints. 


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The primary and secondary endpoints are defined in the Objective(s)/Endpoint(s) above. 
The primary analyses will be performed using a generalized linear model (GLM) 
assuming the negative binomial distribution. The primary analyses will be based on a 
two-sided hypothesis testing approach and will use data for the MITT population 
collected from the start of treatment until the Week 52 visit approximately 4 weeks after 
the last dose of study medication. 
The study is designed to determine the effect of Mepolizumab 100mg SC on clinically 
significant exacerbation events, compared with placebo among Chinese subjects.  
The study design mirrors the design of study MEA115588, which demonstrated benefits 
of mepolizumab compared to placebo for a global population of severe asthma patients 
with eosinophilic inflammation. This study will evaluate the effects in Chinese patients 
and, assuming that effects consistent with the global population are observed, a more 
precise evaluation of the benefit in Chinese patients will conducted by combining data 
from the local China study with MEA115588 using Bayesian dynamic borrowing (see 
Statistical Considerations in Section 9). The potential to borrow information from the 
global dataset is based on the premise that the underlying disease, its general 
management and the response to mepolizumab is similar in Chinse and non-Chinese 
patients. 
The posterior distributions of the primary endpoint, i.e. rate ratio of events between 
Mepolizumab 100mg SC vs. placebo will be derived. The hypothesis of interest for 
treatment comparison is that the rate ratio is less than 1 (alternative hypothesis testing 
boundary in study MEA115588), and the study will be considered to have shown 
evidence that supports this hypothesis if the posterior probability that the rate ratio is less 
than 1 is at least 95% (a “positive result”). Rationales to support this testing criteria can 
be found in section 9.4.1 (Efficacy Analyses).  
The primary analyses will be performed using a generalized linear model (GLM) 
assuming the negative binomial distribution. The estimate of the rate ratio for 
mepolizumab vs. placebo as well as an estimate of the dispersion will be provided, they 
will be combined with global MEA115588 study using the robust mixture prior to obtain 
the final posterior distribution for the China rate ratio. The mean, median and 90% 
credible interval of this posterior distribution of the rate ratio will be reported, along with 
the probability that true rate ratio is less than 1. 
The secondary endpoints are defined in the Objective(s)/Endpoint(s) above. No 
multiplicity adjustment are planned for secondary endpoints. 
 
Section 1.2.  Schedule of Activities (SoA) 
Original text: 
Table 10 
Schedule of Activities Table 


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Procedures 
Pre-
screenin
g 
Screen/Ru
n-in 
Randomised Treatment (visit window is ± 7 days for 
V3-V15-2; 
 V2-1, V2-2, V14-1, V14-2 visit window is ± 2 days from 
V2 or V14 in sub-study) 
Exit Visit 
With-
draw
al 
 
Visit 
V01 
V1 
V2
2 
V 
2
-
1
3 
V 
2-
23 
V
3 
V
4 
V
5 V6 V7 V8 V9 V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
V 
14-
13 
V 
14-
23 
V1
5 
V 
15-
13 
V 
15-
23 VEW 
 
Study 
Week 
 
-4 to -1 
 0 1 2 4 8 1
2 16 20 24 28 32 36 40 44 48 49 50 52 56 60 
 
Study Day 
 
-28~ 
-7 
1 7 1
4 
2
8 
5
6 
8
4 
11
2 
14
0 
16
8 
19
6 
22
4 
25
2 
28
0 
30
8 
33
6 
34
3 
35
0 
36
4 
39
2 
42
0 
 
Safety Assessments 
Adverse 
Events/Serio
us Adverse 
Event 
Assessment 
 
X 
X   X X X X X X X X X X X X 
 
 
X 
 
 
X 
 
3 
Only those patients attending the PK sub-study will perform the visit  


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Amendment text: 
Table 11 
Schedule of Activities Table 
 
Procedures 
Pre-
screeni
ng 
Screen/Ru
n-in 
Randomised Treatment (visit window is ± 7 days for V3-
V15-2; 
 V2-1, V2-2, V14-1, V14-2 visit window is ± 2 days from 
V2 or V14 in sub-study) 
Exit Visit 
With-
draw
al 
 
Visit 
V01 
V1 
V2
2 
V 
2-
13 
V 
2-23 
V
3 
V
4 
V
5 V6 V7 V8 V9 V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
V 
14
-13 
V 
14
-23 
V1
5 
V 
15
-13 
V 
15
-23 
VEW 
 
Study 
Week 
 
-4 to -1 
 0 1 2 4 8 1
2 16 20 24 28 32 36 40 44 48 49 50 52 56 60 
 
Study Day 
 
-28~ 
-7 
1 7
8 
141
5 
2
8 
5
6 
8
4 
11
2 
14
0 
16
8 
19
6 
22
4 
25
2 
28
0 
30
8 
33
6 
34
3 
35
0 
36
4 
39
2 
42
0 
 
Safety Assessments 
Adverse 
Events/Serio
us Adverse 
Event 
Assessment 
 
 
X  
 
X X X X X X X X X X X X 
 
 
X 
 
 
X 
 
3 
Only those patients attending the PK sub-study will perform the visit.  Protocol amendment 4 updated Study 
Day of V2-1 (from day 7 to day 8) and V2-2 (from day 14 to day15) to clarify the duration of PK sample collection. On 
final PK Sample ID form and related PK CRF forms in InForm System, “VISIT 2 PREDOSE” refers to “VISIT2 DAY1”, 
“VISIT 2 DAY7” refers “VISIT 2 DAY8”, and “VISIT 2 DAY 14” refers to “VISIT 2 DAY15” in SoA 
Section 3 Objectives and Endpoints 
Original text: 
Table 2  Study Objectives and Endpoints 
Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control. 
11. Mean number of days with oral 
corticosteroids taken for exacerbations 
12. Total prednisone (or equivalent) exposure 
for exacerbation over the 52-week treatment 
period 
17. Unscheduled healthcare resource 
utilization (for severe exacerbations and other 
asthma related health care) over the 52-week 
treatment period 
 
Amendment text: 
Table 2  Study Objectives and Endpoints 


TMF-11823581 
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Others   
• 
To evaluate the effects of mepolizumab 
compared with placebo on asthma 
control. 
11. Mean number of days with oral 
corticosteroids taken for clinically significant 
exacerbations 
12. Total prednisone (or equivalent) exposure 
for clinically significant exacerbation over the 
52-week treatment period 
17. Unscheduled healthcare resource 
utilization (for severe clinically significant 
exacerbations and other asthma related health 
care) over the 52-week treatment period 
18. Mean days of School/Work missed over the 
52-week treatment period 
 
Section 7.2. Efficacy Endpoints 
Original text: 
Other Efficacy Endpoints 
… 
11. Mean number of days with oral corticosteroids taken for exacerbations  
12. Total prednisone (or equivalent) exposure for exacerbations over the 52-week 
treatment period  
… 
17. Unscheduled healthcare resource utilization (for severe exacerbations and other 
asthma related health care) over the 52-week treatment period) 
Amendment text: 
Other Efficacy Endpoints 
… 
11. Mean number of days with oral corticosteroids taken for clinically significant 
exacerbations  
12. Total prednisone (or equivalent) exposure for clinically significant exacerbations over 
the 52-week treatment period  
… 
17. Unscheduled healthcare resource utilization (for severe clinically significant 
exacerbations and other asthma related health care) over the 52-week treatment 
period) 
18. Mean days of School/Work missed over the 52-week treatment period 


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Section 7.4.1. Time Period and Frequency for Collecting AE and SAE Information 
Original text: 
• 
Any SAEs will be collected from the signing of the informed consent form until at 
the time points specified in the Schedule of Activities Table. 
Amendment text: 
• 
Any SAEs will be collected from the signing of the informed consent form the 
start of intervention until at the time points specified in the Schedule of Activities 
Table (Section 1.2). 
 
Section 7.7.1. Health Outcome Endpoints 
Original text: 
• 
Mean days of school/work missed 
Unscheduled healthcare resource utilization (for severe exacerbations and other asthma 
related health care) 
 
Amendment text: 
• 
Mean days of school/work missed 
Unscheduled healthcare resource utilization (for severe clinically significant 
exacerbations and other asthma related health care) 
 
Section 9.1 Statistical Hypotheses 
Original text: 
This study is designed to test the superiority of mepolizumab 100 mg SC vs 
placebo.  Significance tests will be performed at the two-sided 5% alpha level (one-sided 
2.5%). A hierarchical testing procedure will be used to provide strong control of type I 
error for multiplicity across the primary and secondary endpoints. 
Amendment text: 
This study is designed to test the superiority of mepolizumab 100 mg SC vs 
placebo.  Significance tests will be performed at the two-sided 5% alpha level (one-sided 
2.5%). A hierarchical testing procedure will be used to provide strong control of type I 
error for multiplicity across the primary and secondary endpoints. 
This is a bridging study designed to determine the effect of Mepolizumab 100mg SC on 
clinically significant exacerbation events, compared with placebo among Chinese 
subjects.  


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The Chinese patient data collected in this study will be supplemented with data on the 
treatment effect for the same exacerbation endpoint from the global PhIII study 
MEA115588, using a Bayesian Dynamic Borrowing approach to analysis of the study 
(Schmidli, 2014). The potential to borrow information from the global dataset is based on 
the premise that the underlying disease, its general management and the response to 
mepolizumab is similar in Chinese and non-Chinese patients. A bridging approach is 
proposed because of the expected similarity of the treatment effect in Chinese patients 
and the global population (supported by similarities in the epidemiology, 
pathophysiology, pharmacology and clinical management of patients and consistency of 
treatment differences across key demographic factors including ethnicity), and similar 
study design specially the study population (supported by similarities in key eligibility 
criteria) between MEA115588 and this China study, hence there is low probability of the 
null effect being true. 
A frequentist hypothesis test will not be performed. Instead, the posterior distributions of 
the primary endpoint, i.e. rate ratio of events between Mepolizumab 100mg SC vs. 
placebo will be derived based on the Bayesian analysis including the global PhIII study 
MEA115588 information and the data collected on Chinese patients in this study. The 
hypothesis of interest for treatment comparison is that the rate ratio is less than 1, and the 
study will be considered to have shown evidence that supports this hypothesis if the 
posterior probability that the rate ratio is less than 1 is at least 95% (a “positive result”). 
Please see the Appendix 9 for further information on the choice of posterior probability. 
 
 
Section 9.2.1 Sample Size Assumptions 
Original text: 
The primary analysis is based on comparing the rate of clinically significant 
exacerbations of asthma in subjects treated with mepolizumab 100mg SC vs. Placebo. 
The null hypotheses used to test the superiority of mepolizumab 100mg SC against 
placebo will be: 
H0: i = μp  
where μi is the rate of clinically significant exacerbations on the mepolizumab 100 mg SC 
and μp is the rate of clinically significant exacerbations on the placebo arm.  
The (one-sided) alternative hypothesis is that the rate of clinically significant 
exacerbations is lower on the mepolizumab arm:  
Ha: μi < μp 
The estimated rate of clinically significant exacerbations in the placebo arm is 
1.7 exacerbations per annum (p.a.).  
With a two-sided 5% level of significance and a sample size of 256 subjects randomized 
in a 1:1 ratio (128 subjects in the mepolizumab 100 mg SC treatment group and 128 


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subjects in the placebo treatment group), it is estimated that the null hypothesis will be 
rejected if the observed reduction in clinically significant exacerbations for the 
comparison is at least 26%.  Based on a true population reduction of 40% for 100mg SC 
vs. placebo, there is a 90% chance that the observed reductions will be at least 26 % for 
the comparison and hence 90% power for demonstrating a statistically significant result 
for this assumed true population effect. 
To account for the loss of patient years data from subjects who withdraw from study 
treatment early, additional 44 subjects (22 in the mepolizumab treatment arm and 22 in 
the placebo treatment arm) will be randomized; this approximates to an additional 15% of 
patients years of data being collected.   In total 300 subjects will be randomized into the 
study with a 1:1 randomization ratio (150 subjects in the mepolizumab 100mg SC 
treatment group and 150 subjects in the placebo treatment group). 
The 40% reduction in exacerbation rate has been selected as reductions of this magnitude 
or greater have been seen in previous mepolizumab studies MEA112997 and 
MEA115588. However it should be noted that a smaller reduction in exacerbations could 
be clinically significant. The estimate of 1.7 exacerbations p.a. for placebo and the 
estimate of 0.8 for the dispersion parameter are based on the observed data from study 
MEA115588. This sample size calculation assumes the number of exacerbations per 
annum (p.a.) follow a negative binomial distribution [Keene, 2007; Zhu, 2014] .  For 
subjects who complete the study, exacerbations occurring on-treatment and within 4 
weeks of the last dose will be included in the primary analysis.   
 
 
Amendment text: 
The primary analysis is based on comparing the rate of clinically significant 
exacerbations of asthma in subjects treated with mepolizumab 100mg SC vs. Placebo. 
The null hypotheses used to test the superiority of mepolizumab 100mg SC against 
placebo will be: 
H0: i = μp  
where μi is the rate of clinically significant exacerbations on the mepolizumab 100 mg SC 
and μp is the rate of clinically significant exacerbations on the placebo arm.  
The (one-sided) alternative hypothesis is that the rate of clinically significant 
exacerbations is lower on the mepolizumab arm:  
Ha: μi < μp 
The estimated rate of clinically significant exacerbations in the placebo arm is 
1.7 exacerbations per annum (p.a.).  
With a two-sided 5% level of significance and a sample size of 256 subjects randomized 
in a 1:1 ratio (128 subjects in the mepolizumab 100 mg SC treatment group and 128 
subjects in the placebo treatment group), it is estimated that the null hypothesis will be 


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rejected if the observed reduction in clinically significant exacerbations for the 
comparison is at least 26%.  Based on a true population reduction of 40% for 100mg SC 
vs. placebo, there is a 90% chance that the observed reductions will be at least 26 % for 
the comparison and hence 90% power for demonstrating a statistically significant result 
for this assumed true population effect. 
To account for the loss of patient years data from subjects who withdraw from study 
treatment early, additional 44 subjects (22 in the mepolizumab treatment arm and 22 in 
the placebo treatment arm) will be randomized; this approximates to an additional 15% of 
patients years of data being collected.   In total 300 subjects will be randomized into the 
study with a 1:1 randomization ratio (150 subjects in the mepolizumab 100mg SC 
treatment group and 150 subjects in the placebo treatment group). 
The 40% reduction in exacerbation rate has been selected as reductions of this magnitude 
or greater have been seen in previous mepolizumab studies MEA112997 and 
MEA115588. However it should be noted that a smaller reduction in exacerbations could 
be clinically significant. The estimate of 1.7 exacerbations p.a. for placebo and the 
estimate of 0.8 for the dispersion parameter are based on the observed data from study 
MEA115588. This sample size calculation assumes the number of exacerbations per 
annum (p.a.) follow a negative binomial distribution [Keene, 2007; Zhu, 2014] .  For 
subjects who complete the study, exacerbations occurring on-treatment and within 4 
weeks of the last dose will be included in the primary analysis.   
 
The sample size of 300 participants (considering 256 evaluable participants and 
additional 44 subjects for drop-out) in a 1:1 ratio has been determined by the superiority 
testing of mepolizumab 100 mg SC vs. placebo, there will be 90% power to detect a 40% 
decrease in the exacerbation rate from 1.7 per annum (p.a.) on placebo to 1.02 p.a. on 
mepolizumab 100mg SC using a two sided 5% significance level. The calculation 
assumes the number of exacerbations per year follows a negative binomial distribution 
[Keene, 2007] with a dispersion parameter k=0.8. 
During the blinded evaluation, the clinically significant exacerbations which had 
occurred during the treatment period were analyzed using a generalized linear model 
assuming a negative binomial distribution and covariates of baseline maintenance OCS 
therapy (OCS vs. no OCS), EOS level at screening (>=300 cells/μL vs. <300 cells/μL), 
number of exacerbations in previous year (as an ordinal variable) and baseline disease 
severity (as % predicted FEV1). The blinded evaluation estimated, the overall event rate 
based on an assessment of blinded data was observed as 0.78 p.a., the dispersion was 2.0. 
This was lower than the expected overall event rate of the original study design 
assumptions. 
This observed reduction for overall events at blinded evaluation can be explained by a 
reduction in exacerbation events during the COVID-19 pandemic, which was not unique 
in China. , it is still expected that the treatment effect of Mepolizumab compared with 
placebo will be the same in Chinese SEA population as the original study design 
assumption. Therefore, according the formula [Friede, 2010] 
𝜆̅ = (𝜆𝑇+ 𝜆𝑃)/2 


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where 𝜆̅ is the observed overall events rate based on an assement of blinded data, the 𝜆𝑇 
and 𝜆𝑃 are the event rates in the treatment and placebo groups, and assuming the 
reduction in exacerbation rate with Mepolizumab will remain 40% under pandemic, the 
estimated event rates 𝜆𝑇 and 𝜆𝑃 for Mepolizumab 100mg SC and placebo are  0.975 and 
0.585 p.a. respectively. On the other hand, there exists a difference for the estimate of 
dispersion when data is blinded or unblinded, so that the blinded dispersion estimate is 
adjusted by the difference between blinded and unblinded, which is 1.6=2.0 *(0.796 / 
0.972),  where the dispersion in MEA115588 study were 0.796 (unblinded) vs. 0.972 
(blinded). 
Therefore, based on the conclusion of the blinded evaluation, assuming a 40% decrease 
in the exacerbation rate from 0.975 per annum (p.a.) on placebo to 0.585 p.a. on 
mepolizumab 100mg SC will lead to a power of 66% implying a high false negative rate 
of 34% in China study. If there is a true reduction of 40% in exacerbation rate in Chinese 
patients, based on use of Bayesian dynamic borrowing with an initial weight of 0.5 on 
global MEA115588 study result, there will be 88.6% probability to achieve a positive 
result (equivalent to the power of the study). 
The 40% reduction in exacerbation rate has been selected as reductions of this magnitude 
or greater have been seen in previous mepolizumab studies MEA112997 and 
MEA115588. However, it should be noted that a smaller reduction in exacerbations could 
be clinically significant. Under the same assumptions, there will be 99% probability of 
showing consistent trend, which is defined as the point estimation of rate ratio between 
Mepolizumab and placebo<1 in China study, with global MEA115588. 
Section 9.2.2 Sample Size Sensitivity 
Original text: 
The sample size in Section 9.2.1 is based on assumed exacerbation rates in the placebo 
group and an expected reduction in this rate for subjects treated with mepolizumab.  If the 
assumed placebo exacerbation rate or the expected reduction with mepolizumab differ 
then, at the given sample size there will be an effect on the power of the study.  Table 7 
illustrates this effect on power of varying placebo rates and reductions in rates with 
mepolizumab, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment, and a dispersion parameter k=0.8.  
Table 12 
Effect on power of varying placebo rates and reductions in rates with 
mepolizumab 
 
Placebo: Exacerbations rate p.a. 
% reduction in 
exacerbation rate p.a. 
with mepolizumab 
 
1.0 
 
1.5 
 
1.7 
 
2.4 
35% 
66% 
76% 
79% 
84% 
40% 
79% 
88% 
90% 
93% 
45% 
89% 
95% 
96% 
98% 
 


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The sample size in Section 9.2.1 is based on assumed dispersion parameter of 0.8.  If the 
actual dispersion parameter observed in the study is different, then the power to detect the 
planned difference in exacerbation rates will be affected. 
Table 8 illustrates the estimated power which would be obtained with different dispersion 
parameter, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment, and the placebo and mepolizumab rates are 1.7 
and 1.02 respectively. It also shows the estimated sample size which would be required 
for 90% power. 
Table 13 
Effect on the power of varying dispersion parameter and sample size 
required 90% power 
Dispersion 
parameter, k 
Power  
n per arm required for 90% 
power (Mepo vs placebo)* 
0.7 
91%  
120 vs. 120 
0.8 
90% 
128 vs. 128 
0.9 
88% 
136 vs. 136 
1.0 
86%  
144 vs. 144 
* Early withdrawal from study treatment is not taken into account. 
 
Amendment text: 
The sample size in Section 9.2.1 is based on assumed exacerbation rates in the placebo 
group and an expected reduction in this rate for subjects treated with mepolizumab.  If the 
assumed placebo exacerbation rate or the expected reduction with mepolizumab differ 
then, at the given sample size there will be an effect on the power of the study.  Table 7 
illustrates this effect on power of varying placebo rates and reductions in rates with 
mepolizumab, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment, and a dispersion parameter k=0.8.  
Table 14 
Effect on power of varying placebo rates and reductions in rates with 
mepolizumab 
 
Placebo: Exacerbations rate p.a. 
% reduction in 
exacerbation rate p.a. 
with mepolizumab 
 
1.0 
 
1.5 
 
1.7 
 
2.4 
35% 
66% 
76% 
79% 
84% 
40% 
79% 
88% 
90% 
93% 
45% 
89% 
95% 
96% 
98% 
 


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The sample size in Section 9.2.1 is based on assumed dispersion parameter of 0.8.  If the 
actual dispersion parameter observed in the study is different, then the power to detect the 
planned difference in exacerbation rates will be affected. 
Table 8 illustrates the estimated power which would be obtained with different dispersion 
parameter, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment, and the placebo and mepolizumab rates are 1.7 
and 1.02 respectively. It also shows the estimated sample size which would be required 
for 90% power. 
Table 15 
Effect on the power of varying dispersion parameter and sample size 
required 90% power 
Dispersion 
parameter, k 
Power  
n per arm required for 90% 
power (Mepo vs placebo)* 
0.7 
91%  
120 vs. 120 
0.8 
90% 
128 vs. 128 
0.9 
88% 
136 vs. 136 
1.0 
86%  
144 vs. 144 
* Early withdrawal from study treatment is not taken into account. 
 
The sample size in Section 9.2.1 is based on an expected reduction in this rate for 
subjects treated with mepolizumab.  If the expected reduction with mepolizumab differ 
then, at the given sample size there will be an effect on the probability of success of the 
study.  Table 7 illustrates this effect on probability of success of varying reductions in 
rates with mepolizumab, assuming the sample size remains constant at 128 subjects in 
mepolizumab arm and 128 subjects in placebo arm, excluding the additional 44 subjects 
to account for early withdrawals from study treatment.  
Table 7 Probability of meeting the success criterion conditional on various assumed 
true treatment effects 
Reduction 
45% 
40% 
35% 
0 
Probabilities of Success 
94.6% 
88.6% 
80.0% 
11.8%* 
* The false positive rate is calculated as assumed true treatment effects is 0 between 
Mepolizumab and placebo. 
In the Table 7, the probabilities of meeting success are conducted under various assumed 
trure treatment effects when overall event rate is fixed as 0.78 based on the blinded 
evaluation and dispersion is 1.6, e.g. when reduction is 40%, then the probability of 
success is calculated by the exacerbation rates for Mepolizumab 100mg SC and placebo 
as  0.975 and 0.585 p.a. respectively. Type I error is 11.8%, which is calculated when the 


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event rate for each group is 0.78, adjusted dispersion is 1.6 based on analyses of blinded 
evaluation. 
Section 9.2.3 Sample Size Re-estimation or Adjustment 
Original text: 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after 15 
months of enrolment, or when 225 subjects have been randomized, whichever is earlier. 
If the exacerbation rates for the study are lower than planned, a sample size re-estimation 
may be conducted. Any subsequent change to the planned number of subjects 
randomized would be documented in a protocol amendment.  
Amendment text: 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after 15 
months of enrolment, or when 225 subjects have been randomized, whichever is earlier. 
If the exacerbation rates for the study are lower than planned, a sample size re-estimation 
may be conducted. Any subsequent change to the planned number of subjects 
randomized would be documented in a protocol amendment.  
By the time of this protocol amendment, blinded evaluations of exacerbation rate were 
completed indicating the data deviate substantially from the assumptions made when we 
planned the trial, before the COVID-19 pandemic, thus supporting a protocol amendment 
to update the planned primary analyses without further adjustment of planned sample 
size. 
 
Section 9.4 Key Elements of Analysis Plan 
Original text: 
The primary treatment comparison of interest in this study is mepolizumab 100mg SC vs 
placebo.  This treatment comparison will be made for the primary and secondary 
endpoints. For each endpoint, different estimands may be explored depending on the 
scientific question of interest. These will be detailed in the RAP. 
Adjustment for multiplicity will be based on hierarchical testing of the primary and 
secondary endpoints in a pre-defined order.  This adjustment will provide strong control 
of the Type I error.  The primary endpoint will be tested first and if this is significant at 
the two-sided 5% level, the first secondary endpoint will be tested.  Hierarchical testing 
will continue in a similar manner for the remaining secondary endpoints in the following 
pre-defined order.  
• 
Time to first clinically significant exacerbations. 
• 
Mean change in St. George’s Respiratory Questionnaire at week 52. 


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• 
Frequency of exacerbations requiring hospitalization (including intubation 
and admittance to an ICU) or ED visits over the 52-week treatment period 
• 
Frequency of exacerbations requiring hospitalization over the 52-week 
treatment period 
• 
Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52   
The primary analyses of efficacy will be performed on the MITT population. The primary 
endpoint will also be analysed for the PP population.   
Amendment text: 
The primary treatment comparison of interest in this study is mepolizumab 100mg SC vs 
placebo.  This treatment comparison will be made for the primary and secondary 
endpoints. For each endpoint, different estimands may be explored depending on the 
scientific question of interest. These will be detailed in the RAP. 
Adjustment for multiplicity will be based on hierarchical testing of the primary and 
secondary endpoints in a pre-defined order.  This adjustment will provide strong control 
of the Type I error.  The primary endpoint will be tested first and if this is significant at 
the two-sided 5% level, the first secondary endpoint will be tested.  Hierarchical testing 
will continue in a similar manner for the remaining secondary endpoints in the following 
pre-defined order.  
• 
Time to first clinically significant exacerbations. 
• 
Mean change in St. George’s Respiratory Questionnaire at week 52. 
• 
Frequency of exacerbations requiring hospitalization (including intubation 
and admittance to an ICU) or ED visits over the 52-week treatment period 
• 
Frequency of exacerbations requiring hospitalization over the 52-week 
treatment period 
• 
Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52   
The primary analyses of efficacy will be performed on the MITT population. The primary 
endpoint will also be analysed for the PP population.   
The primary treatment comparison of interest in the study is mepolizumab 100mg SC vs 
placebo. This treatment comparison will be made for the primary and secondary 
endpoints. There is no adjustment for multiplicity for the secondary endpoints. 
 
Section 9.4.1 Efficacy Analyses 
Original text: 
(No context before section 9.4.1.1 primary analyses) 
Amendment text: 


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Bayesian Dynamic Borrowing Design 
Bayesian dynamic borrowing (BDB) provides a clinically and statistically rigorous 
method to analyze this China bridging study. An explicit, pre-specified belief about the 
relevance of the global MEA115588 results to the Chinese population on treatment effect 
is provided as part of the prior distribution, which is a mixture with two components, one 
reflecting results from MEA115588 study and a vague component reflecting ‘no effect’.  
The prior mixture will be upated with the China data to obtain the posterior distribution, 
which will also be a mixture. The posterior weight given to the global MEA115588 study 
data is commensurate with the strength of evidence of similarity between the 
MEA115588 data and the China data. The BDB analysis ‘learns’ how much of the global 
MEA115588 study information to borrow based on the consistency between the observed 
rate ratio in the China and global studies and updates the weight on the global 
MEA115588 results accordingly. 
• The stronger the evidence of consistency, the greater the increase in the updated 
(posterior) weight on the informative component relative to the prior weight, and 
hence the greater the borrowing from the global study results. 
• Conversely, if the China study results are very different to the global study 
results, the informative component is down-weighted and final inference is based 
mostly on the observed data in the China study alone. 
• The mechanism by which the weight is updated is entirely pre-specified and 
mathematically rigorous (Schmidli, 2014) 


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The informative prior and prior weight in BDB design 
The BDB approach will use the results from the global MEA115588 study mixed with a 
vague component worth two subjectsas an ‘informative’ but robust prior for the treatment 
comparison of interest in this China study. There are two primary analysis comparisons: 
mepolizumab 75mg IV vs placebo and mepolizumab 100mg SC vs placebo for rate of 
clinically significant exacerbations over the 32 weeks treatment period expressed as 
exacerbation rate per year in MEA115588. Since the primary outcome, rate of clinically 
significant exacerbation, showed similar treatment difference in Mepolizumab 75 mg iv 
group compared with placebo in 32-week Study MEA115588 and 52-week Study 
MEA112997, this indicates the available efficacy result of Mepolizumab 100 mg SC in 
32-week study MEA115588 could also be an informative reference data to bridge to this 
52-week China study using the same dose regimen, therefore, the results of mepolizumab 
100mg SC vs placebo in study MEA115588 are used to build the global component. 
Table 8 
The primary analysis of clinically significant exacerbations results in 
global MEA115588 study 
Treatment 
No. 
subjects 
Rate ratio 
(95% CI) 
Normal distribution of Rate Ratio (log) 
Mean 
Standard Error 
Mepolizumab 100mg SC 
194 
0.47 
(0.35,0.64) 
-0.7474 
0.1532 
Placebo 
191 
Source: Table 13 in the CSR of MEA115588. 
The logarithmic transformation of the rate ratio will be used, which can be approximately 
Normally distributed. Therefore, in the primary analysis for the primary treatment 
comparison of mepolizumab 100mg SC and placebo for the rate of clinically significant 
exacerbations of asthma over the 52-week treatment period in this study, the global prior 
component is obtained from the sampling distribution of the log rate ratio between 
mepolizumab 100mg SC and placebo in the global study MEA115588. The mean log rate 
ratio and its associated standard error are -0.7474 and 0.1532, respectively, leading to a 
normal distribution with mean -0.7474 and standard deviation 0.1532 as the global prior 
component for the primary treatment comparison. 
A second vague distribution worth 2 subjects (one in each treatment arm) assuming no 
treatment effect in China will also be specified, to allow for the possibility that the global 
MEA115588 data do not provide relevant information about the treatment effect in 
Chinese patients. A normal distribution with mean zero and standard deviation 2.1256 
will be used as vague prior for log rate ratio in BDB design, more details can be found in 
Appendix 9 Section 12.9.2.  A weighted combination of the ‘informative’ and  ‘vague’ 
priors will be used to construct a robust mixture prior.  
In the primary analysis, a prior weight of 50% is proposed for the informative component 
of the robust mixture prior, with the remainder of the weight (50%) placed on the vague 
component to reflect a conservative starting position regarding the assumed relevance of 
the global MEA115588 results to Chinese patients. See Statistical Appendix 9 Section 
12.9.2 for more details on the robust mixture prior and Section 12.9.3 for details on the 
choice of prior weight. 


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Effective Sample Size 
The updated weight itself is not direactly interpretable as the fraction of the global 
MEA115588 study sample size that is borrowed. Instead, the effective sample size (ESS) 
borrowd from the global study can be quantified using the moment method implemented 
in RBesT R software package version 1.6.1, Table 9 shows the expected value of the ESS 
borrowed from the global MEA115588 study for each treatment comparison when the 
true reduction in China is assumed to be 45%, 40%, 35% and 0 as the same with Table 8. 
Table 9  Expected Effective Sample Size borrowed per arm from the global MEA115588 
study for a range of possible true treatment differences 
 
The true reduction 
0 
35% 
40% 
45% 
Expected value of ESS borrowed per arm 
from the global MEA115588 study 
-42 
76 
123 
162 
 
Maximum Detectable Value for Rate Ratio 
The maximum detectable value (MDV) is the maximum rate ratio that needs to be 
observed in this China study in order to meet the pre-specified success criteria when 
combined with the global MEA115588 study results via the Bayesian dynamic borrowing 
analysis. Under the current sample size of 300 participants in total (256 evaluable 
participants and 44 subjects for drop out), assuming overall event rate is 0.78 p.a. based 
on the blinded evaluation and dispersion is 1.6, chosen weight on global component in 
the mixture prior of 0.5, and success rule that the posterior probability of the true rate 
ratio in China being less than 1 is at least 95%, the MDV for rate ratio between 
mepolizumab and placebo is 0.776. That corresponds to a minimum detectable reduction 
for mepolizumab compared with placebo of at least 22.4%. 
Section 9.4.1.1 Primary Analyses 
Original text: 
The primary treatment effect to be estimated in this study is the frequency of clinically 
significant exacerbations of asthma over the 52-week treatment period expressed as an 
exacerbation rate p.a. Exacerbation from the start of treatment until 4 weeks after the last 
dose of study drug will be used in the analysis. Exacerbations which are separated by less 
than 7 days will be treated as a continuation of the same exacerbation. 
The numbers of clinically significant exacerbations are assumed to follow a negative 
binomial distribution. The logarithm of time on treatment will be used as an offset variable. 
The primary analysis of the rate of exacerbations will use a generalised linear model with 
a log-link function. This model will include covariates of treatment group, baseline 
maintenance OCS therapy (OCS vs. no OCS), EOS level at screening (≥300 cells/μL vs.  
<300 cells/μL), number of exacerbations in previous year (as an ordinal variable), 
baseline disease severity (as % predicted FEV1). The adjusted mean rates per year, pair-
wise treatment ratios and associated p-values and confidence limits will be presented.  


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The analysis will be performed on the MITT population. A supporting analysis of the PP 
population will also be performed. 
Alternative estimands may be explored in the RAP. 
 
Amendment text: 
The primary treatment effect to be estimated in this study is the frequency of clinically 
significant exacerbations of asthma over the 52-week treatment period expressed as an 
exacerbation rate p.a. Exacerbation from the start of treatment until 4 weeks after the last 
dose of study drug will be used in the analysis. Exacerbations which are separated by less 
than 7 days will be treated as a continuation of the same exacerbation. 
The numbers of clinically significant exacerbations are assumed to follow a negative 
binomial distribution. The logarithm of time on treatment will be used as an offset variable. 
The primary analysis of the rate of exacerbations will use a generalised linear model with 
a log-link function. This model will include covariates of treatment group, baseline 
maintenance OCS therapy (OCS vs. no OCS), EOS level at screening (≥300 cells/μL vs.  
<300 cells/μL), number of exacerbations in previous year (as an ordinal variable), 
baseline disease severity (as % predicted FEV1). The adjusted mean rates per year, pair-
wise treatment ratios and associated p-values and confidence limits will be presented.  
The analysis will be performed on the MITT population. A supporting analysis of the PP 
population will also be performed. 
Alternative estimands may be explored in the RAP. 
 
The primary treatment effect to be estimated in this study is the frequency of clinically 
significant exacerbations of asthma over the 52-week treatment period expressed as an 
exacerbation rate p.a. Exacerbation from the start of treatment until 4 weeks after the last 
dose of study drug will be used in the analysis. Exacerbations which are separated by less 
than 7 days will be treated as a continuation of the same exacerbation. 
The numbers of clinically significant exacerbations are assumed to follow a negative 
binomial distribution. The logarithm of time on treatment will be used as an offset 
variable. The primary analysis of the rate of exacerbations will use a generalized linear 
model with a log-link function. This model will include covariates of treatment group, 
baseline maintenance OCS therapy (OCS vs. no OCS), number of exacerbations in 
previous year (as an ordinal variable), baseline disease severity (as % predicted FEV1). 
The estimate of the logarithm of the rate ratio for mepolizumab vs. placebo  and 
associated standard error will be  the data used to update the robust mixture prior to 
obtain the final posterior distribution for the China rate ratio (on the log scale). 
The mean, median and 90% credible interval of this posterior distribution of the rate ratio 
will be reported, along with the probability that true rate ratio is less than 1 (equivalent to 
the log rate ratio being less than 0). 
The following 2-component mixture prior will be used for the log rate ratio: 


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𝑝(𝜃) = 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(−0.7474 , 0.1532) + 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(0 2.1256) 
Sensitivity analysis will be conducted to assess the impact of different prior weights  on 
the ‘informative’ component of the robust mixture prior, and the details will be specified 
in the RAP. 
For the intercurrent event of withdrawal from study treatment, hypothetical strategy will 
be applied for primary analysis, where the logarithm of time on treatment will be used as 
an offset variable in the model.  
The detailed missing data imputation method and supportive analysis will be defined in 
full RAP. 
 
Section 9.4.1.2 Key Secondary Analyses 
Original text: 
… 
Time to first clinically significant exacerbations will be analysed using Cox’s 
proportional hazards model with covariates of treatment group, baseline maintenance 
OCS therapy, EOS level at screening, number of exacerbations in previous year (as an 
ordinal variable), baseline disease severity (as % predicted FEV1). 
 
St. Georges Respiratory Questionnaire (SGRQ) score will be analysed using mixed 
repeated measures model adjusting for baseline maintenance OCS therapy, baseline 
SGRQ, EOS level at screening, number of exacerbations in previous year (as an ordinal 
variable), baseline % predicted FEV1, and treatment and visit, plus interaction terms for 
visit by baseline and visit by treatment group. 
The secondary endpoints of rate of exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits and rate of clinically significant 
exacerbations requiring hospitalization will be analyzed using negative binomial 
regression, as described for the primary endpoint above.  
Pre-bronchodilator FEV1 will be analyzed using mixed effects repeated measures model 
adjusting for baseline maintenance OCS therapy, EOS level at screening, baseline FEV1, 
number of exacerbations in previous year (as an ordinal variable), baseline % predicted 
FEV1, and treatment, and visit, plus interaction terms for visit by baseline and visit by 
treatment group. 
 
Amendment text: 
… 
Time to first clinically significant exacerbations will be analysed using Cox’s 
proportional hazards model with covariates of treatment group, baseline maintenance 
OCS therapy, EOS level at screening, number of exacerbations in previous year (as an 
ordinal variable), baseline disease severity (as % predicted FEV1). 


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St. Georges Respiratory Questionnaire (SGRQ) score will be analysed using mixed 
repeated measures model adjusting for baseline maintenance OCS therapy, baseline 
SGRQ, EOS level at screening, number of exacerbations in previous year (as an ordinal 
variable), baseline % predicted FEV1, and treatment and visit, plus interaction terms for 
visit by baseline and visit by treatment group. 
The secondary endpoints of rate of exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits and rate of clinically significant 
exacerbations requiring hospitalization will be analyzed using negative binomial 
regression, as described for the primary endpoint above.  
Pre-bronchodilator FEV1 will be analyzed using mixed effects repeated measures model 
adjusting for baseline maintenance OCS therapy, EOS level at screening, baseline FEV1, 
number of exacerbations in previous year (as an ordinal variable), baseline % predicted 
FEV1, and treatment, and visit, plus interaction terms for visit by baseline and visit by 
treatment group. 
The point estimate as well as the estimate of the variability in above analyses will be 
provided. More details will be provided in full RAP.  
 
Section 9.4.2.4 Other Safety Measures 
Original text: 
Actual values and change from baseline for other scheduled safety assessments such as 
vital signs (pulse rate, systolic and diastolic blood pressure), 12-lead ECG parameters 
(QTcF, QTcB and heart rate) will be summarized at each scheduled visit. Further details 
will be provided in the RAP.  
Amendment text: 
Actual values and change from baseline for other scheduled safety assessments such as 
vital signs (pulse rate, systolic and diastolic blood pressure), 12-lead ECG parameters 
(QTc QTcF, QTcB and heart rate) will be summarized at each scheduled visit. Further 
details will be provided in the RAP.  
 
Section 9.4.3. Pharmacokinetic analyses 
Original text: 
• 
The mepolizumab plasma concentrations from this study will be analyzed using non-
compartmental analysis. If data permits, population PK analysis will be conducted 
using, for example, NONMEM 7 for determination of the population and/or 
individual systemic exposure, volume of distribution and clearance as well as 
characterise the between- and within subject variability. 
Amendment text: 


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• The mepolizumab plasma concentrations from this study will be analyzed using non-
compartmental analysis and/or population PK analysis approach. When population 
PK analysis is considered necessary, it will be conducted using, for example, 
NONMEM 7 for determination of the population and/or individual systemic 
exposure, volume of distribution and clearance as well as characterise the between- 
and within subject variability. 
 
Section 11. Reference 
Original text: 
… 
Zhu Haiyuan, Lakkis Hassan. Sample size calculation for comparing two negative 
binomial rates. Statist.Med. 2014;33(3):376-87.  
 
Amendment text: 
… 
Zhu Haiyuan, Lakkis Hassan. Sample size calculation for comparing two negative 
binomial rates. Statist.Med. 2014;33(3):376-87.  
Friede T, Schmidli H. Blinded sample size reestimation with count data: methods and 
applications in multiple sclerosis. Statist.Med. 2010;29:1145-1156. 
Schmidli H, Gsteiger S, Roychoudhury S, O’Hagan A, Spiegelhalter D, Neuenschwander 
B. Robust meta-analytic-predictive priors in clinical trials with historical control 
information. Biometrics. 2014;70:1023-1032. 
 
Appendix 9 
Original text: 
Appendix 9: protocol amendment changes 
… 
Amendment text: 
Appendix 9 statistical appendix 
12.9.1 Choice of posterior probability  
A 95% posterior probability that the true rate ratio < 1 represents a high level of 
confidence for declaring a positive treatment benefit in Chinese patients in the context of 


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a bridging study where substantial evidence of treatment benefit in global (non-Chinese) 
patients already exists and is aligned with examples of Bayesian decision criteria given in 
the FDA draft guidance on Complex Innovative Designs 
[https://www.fda.gov/media/130897/download]. This represents a more rigorous 
evidentiary threshold than is typically provided by a ‘positive trend ‘design, which 
requires only that the observed rate ratio < 1. 
12.9.2 overview of the proposed robust mixture prior and analysis strategy 
In order to formally incorporate the global MEA115588 study data in this study, the 
Bayesian analysis with a robust mixture prior distribution [Schmidli, 2014], which allows 
for “dynamic borrowing” of prior information, will be conducted. This analysis learns 
how much of the global prior information to borrow based on the consistency between 
the China data and global prior. The mixture prior was constructed by two components. 
• Component 1 is an informative prior based on the observed efficacy response 
from global study MEA115588, referred to as the “global prior” 
• Component 2 is a “vague” prior centred on a mean of zero and with variance 
scaled to represent information equivalent to one subject 
Denoting the log rate ratio for Mepolizumab 100mg SC vs. placebo as 𝜃, the prior has the 
form 
𝑝(𝜃) = 𝑤∗𝑝1(𝜃) + (1 −𝑤) ∗𝑝2(𝜃) 
where 𝑝1(𝜃) is the component containing the information from the global study prior,  
𝑝2(𝜃) is the vague component and 𝑤 is the weight. 
The prior weight 𝑤 assigned to the informative prior component represents the prior 
degree of confidence in the extrapolation strategy. At lower prior weight the mixture 
prior presents a heavier tailed distribution with more prior weight being applied to the 
non-informative vague prior component. When the mixture prior is combined with the 
observed global data, 𝑤 is updated according to how consistent China data are with the 
global prior: the stronger the evidence of consistency, the greater the increase in the 
posterior weight 𝑤∗ relative to the prior weight 𝑤. Conversely, when there is prior-data 
conflict, 𝑤∗ will be lower than 𝑤 and will tend to zero as evidence of conflict increases, 
so that the global information is down-weighted and posterior inference is based almost 
entirely on the China data. 
 
12.9.2.1 The informative (global) prior  
The global prior distribution was constructed using a normal approximation to the 
sampling distribution of the observed log rate ratio of exacerbations on mepolizumab vs. 
placebo in the subjects from global study MEA115588. The point estimation and 
standard error for the log rate ratio obtained from negative binomial regression of the 
observed exacerbation counts were used as the mean and standard deviation, respectively, 
of a normal prior distribution for the global efficacy response. Therefore, based on the 


TMF-11823581 
CONFIDENTIAL 
 
 
 
201536 
 
146 
 
results in global MEA115588 presented in Table 8 it provided a Normal 
(−0.7474, 0.15322) as the global prior for log rate ratio. 
 
12.9.2.2 The vague prior  
The vague prior has a mean of 0 for rate ratio on log scale (i.e. no effect in China), and 
the variance is scaled such that the information content of the prior is approximately 
equivalent to that provided by two subjects, one subject per arm. This variance was 
determined by taking the squared standard error of the log rate ratio obtained from the 
global data and multiplying it by N/2, where N is the total MEA115588 sample size. 
Therefore, the SD of the vague prior is 
𝑆𝐷= √0.15322 ∗385
2
= 2.1256 
 
12.9.2.3 Initial weight on informative (global) prior component and mixture prior 
An initial (prior) weight of 50% is proposed for the informative global component of the 
robust mixture prior, with the remainder of the weight (50%) placed on the vague prior to 
reflect a conservative starting position regarding the assumed relevance of the global 
MEA115588 results to Chinese. Combining the two components and their respective 
weights gives the following 2-component mixture normal: 
𝑝(𝜃) = 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(−0.7474 , 0.1532) + 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(0 , 2.1256) 
 
12.9.3 Choice of weights 
The scientific grounds for expecting similar benefit: risk profile in China and global 
study patients justifies a high initial weight on the informative component. However, 
based on an extensive review of the impact of the prior weight specified for the global 
MEA115588 study (prior weights explored were: 0, 0.1, 0.2, …0.9,1), a more 
conservative prior weight of 50% was felt to provide an acceptable trade-off between the 
risks of a false positive result and a false negative result, and to enable meaningful gains 
in precision due to borrowing information from the global study whilst ensuring that the 
prior does not dominate the posterior completely but allows the observed data in Chinese 
patients to contribute to the inference from the study. 
 
 


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SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  201536
Official Title of Study: A randomized, double blind, parallel group study of the 
efficacy and safety of Mepolizumab as adjunctive therapy in patients with severe 
asthma with eosinophilic inflammation
NCT number: NCT03562195
Date of Document: 24-SEP-2022


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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 5 
1.2. 
Study Design ................................................................................................ 8 
2. 
STATISTICAL HYPOTHESES ............................................................................... 10 
3. 
ANALYSIS SETS ................................................................................................... 11 
4. 
STATISTICAL ANALYSES ..................................................................................... 11 
4.1. 
General Considerations .............................................................................. 11 
4.1.1. 
General Methodology .................................................................. 11 
4.1.2. 
Baseline Definition ....................................................................... 12 
4.1.3. 
Definition of endpoint(s)/estimands .............................................. 13 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 13 
4.2.1. 
Main analytical approach ............................................................. 13 
4.2.2. 
Sensitivity analyses ..................................................................... 16 
4.2.3. 
Additional estimands .................................................................... 16 
4.2.4. 
Supplementary Analyses ............................................................. 18 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 18 
4.3.1. 
Key secondary endpoint(s) .......................................................... 18 
4.3.2. 
Main analytical approach ............................................................. 20 
4.4. 
Other Analyses ........................................................................................... 24 
4.5. 
Safety Analyses .......................................................................................... 28 
4.5.1. 
Extent of Exposure ...................................................................... 28 
4.5.2. 
Adverse Events............................................................................ 28 
4.5.3. 
Additional Safety Assessments .................................................... 31 
4.6. 
Pharmacodynamic Analyses ....................................................................... 32 
4.7. 
Pharmacokinetic Analyses .......................................................................... 33 
4.7.1. 
Pharmacokinetic Concentration ................................................... 33 
4.7.2. 
Pharmacokinetic Parameters ....................................................... 33 
4.7.3. 
Assessment of Accumulation Ratio .............................................. 35 
4.7.4. 
Population Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Analysis .............................. 35 
4.8. 
Interim Analyses ......................................................................................... 35 
4.9. 
Changes to Protocol Defined Analyses ....................................................... 35 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 36 
5.1. 
Sample Size Assumptions .......................................................................... 36 
5.2. 
Sample Size Sensitivity ............................................................................... 37 
5.3. 
Sample Size Re-estimation or Adjustment .................................................. 37 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 38 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 38 
6.1.1. 
Participant Disposition ................................................................. 38 
6.1.2. 
Demographic and Baseline Characteristics .................................. 39 
6.1.3. 
Protocol Deviations ...................................................................... 40 
6.1.4. 
Prior and Concomitant Medications ............................................. 40 
6.1.5. 
Study Intervention Compliance .................................................... 41 


 
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6.2. 
Appendix 2 Data Derivations Rule .............................................................. 41 
6.2.1. 
Planned and Actual Treatment ..................................................... 41 
6.2.2. 
Analysis Period for Exacerbations and Efficacy Endpoints ........... 42 
6.2.3. 
Study Period ................................................................................ 42 
6.2.4. 
Length of Time in Phase for Exacerbations .................................. 44 
6.2.5. 
Study Day and Reference Dates .................................................. 44 
6.2.6. 
Assessment Window ................................................................... 45 
6.2.7. 
Multiple measurements at One Analysis Time Point .................... 45 
6.2.8. 
Handling of Partial Dates ............................................................. 45 
6.2.9. 
Reversibility ................................................................................. 48 
6.2.10. 
Evaluation Process of Clinically Significant Asthma 
Exacerbations .............................................................................. 48 
6.2.11. 
eDiary Data .................................................................................. 50 
6.2.12. 
Computation of Age ..................................................................... 50 
6.2.13. 
Reasons for Exclusion from the Per Protocol Analysis ................. 51 
6.2.14. 
Daily Corticosteroid Dose Administered for an 
Exacerbation ................................................................................ 52 
6.2.15. 
Early PK Access Key Activities .................................................... 53 
6.3. 
Appendix 3 Model Checking and Diagnostic for Statistical Analyses ........... 53 
Trademarks ................................................................................................ 54 
7. 
REFERENCES ....................................................................................................... 55 
 


 
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Version history 
SAP Version 
Approval 
Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
Reporting and 
Analysis Plan (RAP) 
Critical Component 
24 Sep 2022 
Version 01 
(Date: 2018-
MAR-28) 
Not 
Applicable 
Original 
version 
 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses and output to be included in 
the Clinical Study Report (CSR) for Study 201536. Details of the planned final analyses 
are provided. 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
• To evaluate the efficacy 
of mepolizumab 100 mg 
subcutaneous (SC) every 
4 weeks versus placebo 
on the frequency of 
clinically significant 
exacerbations in adult 
and adolescent Chinese 
subjects with severe 
asthma with eosinophilic 
airway inflammation. 
• Frequency of clinically significant exacerbations of 
asthma over the 52-week treatment period.  
Clinically significant exacerbations are defined as: 
Worsening of asthma which requires use of systemic 
corticosteroids and/or hospitalizations and/or 
Emergency Department (ED) visits.  
 
For all subjects, oral corticosteroid for at least 3 days or 
a single IM Corticosteroid (CS) dose is required. For 
subjects on maintenance systemic corticosteroids, at 
least double the existing maintenance dose for at least 3 
days is required. 
Secondary 
 
• To evaluate the effects of 
mepolizumab compared 
with placebo on a range 
of clinical markers of 
asthma control, including 
exacerbations, lung 
function, and quality of 
life. 
• Time to first clinically significant exacerbations 
• Mean change in St. George’s Respiratory 
Questionnaire (SGRQ) at Week 52 
• Frequency of exacerbations requiring 
hospitalisation (including intubation and admittance 
to an ICU) or ED visits over the 52-week treatment 
period 
• Frequency of exacerbations requiring 
hospitalisation over the 52-week treatment period 
• Mean change from baseline in clinic pre-
bronchodilator FEV1 at Week 52 
Safety 
 
• To evaluate the safety 
and tolerability of 
mepolizumab compared 
with placebo, in subjects 
with severe asthma with 
• Adverse Event including systemic (i.e. allergic 
[type I hypersensitivity] and Other systemic) and 
injection site reactions reported throughout the 52-
week treatment period 
• Haematological and clinical chemistry parameters 


 
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Objectives 
Endpoints 
eosinophilic 
inflammation  
• Vital signs (pulse rate and systolic and diastolic 
blood pressure) 
• 12-lead ECG 
• Frequency of subjects with anti-mepolizumab 
antibody positive results 
Others 
 
• To evaluate the effects of 
mepolizumab compared 
with placebo on asthma 
control 
• Mean change from baseline compared to placebo in 
Asthma Control Questionnaire (ACQ-5) score at 
Week 52 
• Percent of subjects evaluated as responders as 
measured by ACQ-5 score at Week 52 
• Percent of subjects evaluated as responders as 
measured by SGRQ score at Week 52 
• Percent of subjects recording a favourable 
treatment response as measured by the Subject 
Rated Response to Therapy at Week 52 
• Percent of subjects evaluated as having a 
favourable treatment response as measured by the 
Clinician Rated Response to Therapy at Week 52 
• Mean change from baseline in daily 
salbutamol/albuterol use 
• Mean change from baseline in daily asthma 
symptom scores 
• Mean change from baseline in awakening at night 
due to asthma symptoms requiring rescue 
medication use 
• Mean change from baseline in morning PEF 
• Mean change from baseline in clinic post-
bronchodilator FEV1 at Week 52 
• Mean number of days with oral corticosteroids 
taken for clinically significant exacerbations 
• Total prednisone (or equivalent) exposure for 
clinically significant exacerbation over the 52-week 
treatment period 
• Frequency of all exacerbations 
• Time to first exacerbation 
• Time to withdrawal from study treatment due to 
asthma exacerbations 
• Time to first exacerbation requiring hospitalization 
or ED visit 


 
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Objectives 
Endpoints 
• Unscheduled healthcare resource utilization (for 
clinically significant exacerbations and other 
asthma related health care) over the 52-week 
treatment period 
• Mean days of School/Work missed over the 52-
treatment period 
Pharmacodynamics 
 
• To evaluate the PD of SC 
mepolizumab in Chinese 
subjects with severe 
asthma with eosinophilic 
airway inflammation 
• Blood eosinophil ratio to baseline 
PK Sub-Study 
 
• To evaluate the PK of SC 
mepolizumab in Chinese 
subjects with severe 
asthma with eosinophilic 
airway inflammation 
• PK parameter estimates of mepolizumab 
 
 
 
Primary estimand 
The primary clinical question of interest is: What is the effect of adding mepolizumab to 
standard of care when compared with placebo plus standard of care on the rate of 
exacerbations over 52 weeks in Chinese participants with severe eosinophilic asthma? 
This question is to be addressed in the absence of study treatment discontinuation.   
The estimand is described by the following attributes: 
o Population: Chinese participants with severe eosinophilic asthma. 
o Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to 
placebo every 4 weeks, both treatments given on top of standard of care. Further 
details on standard of care can be found in Section 6 of Protocol. 
o Variable: number of clinically significant exacerbations over 52 weeks. 
o Summary measure: annualised rate of exacerbations. Comparison between the 
mepolizumab arm and placebo will be assessed with the rate ratio. 
o Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
o Rationale for estimand:  
Interest lies in the treatment effect when medication is taken as directed.  For 
participants discontinuing randomised medication, use of a hypothetical strategy 


 
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addresses treatment effects attributable to mepolizumab in the hypothetical 
scenario where participants would not discontinue from treatment.  
Since this is a bridging study, the results from MEA115588 will be borrowed and 
compared with the data from this study. To ensure comparability between two studies, 
the Estimand framework including analysis models will be similar with MEA115588. 
1.2. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• This is a bridging study. 
• Multi-centre, randomized, placebo-controlled, double-blind, 
parallel-group design. 
• In the main study, there will be a total of 16 clinic visits conducted 
on an outpatient basis. 
• Subjects who discontinue study treatment will not be automatically 
withdrawn, but will be encouraged to stay in the study and complete 
all remaining protocol specified visits and be followed-up as per the 
protocol until the completion of the follow-up assessments. 
• The total duration of subject participation in the main study, 
including run-in will be 53 to 56 weeks.  
• Subjects will remain on their current maintenance therapy 
throughout the run-in and double-blind treatment administration 
periods. 
Study 
intervention 
• Subjects will be randomized on Day 1 to receive mepolizumab (100 
mg) SC or placebo SC added onto their existing therapy for asthma 
every 4 weeks for a total of 13 doses 
Study 
intervention 
Assignment 
• Randomization to study treatment will be stratified by blood 
eosinophil count at screening(≥300 cells/μL and <300 cells/μL). 
• Subjects will be randomized in a 1:1 ratio to receive either 
mepolizumab SC or placebo SC. 
Interim 
Analysis 
• No formal interim analysis is planned 
Pre-screen 
(Visit 0)
Screening 
(Visit 1)
Run-in
Week -4 to -1
Pre- screening
Period
0-4 weeks
R
Week
0
1
2
4
8
12
16
20
24
28
32
36
40
44
48
49
50
52
56
60
Visit
2
2-1
2-2
3
4
5
6
7
8
9
10
11
12
13
14
14-1 14-2 15
15-1 15-2
Investigational Product Administered every 4 weeks (Q4W)
SOC**+ Mepolizumab 100mg
*
SOC**+ Placebo
Exit 
Visit
*R=Randomization; ** SOC=Standard of care asthma therapy
PK sub-study only
PK Sampling


 
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201536 
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Overview of Study Design and Key Features 
• Blinded evaluation of exacerbation rates is planned for this study. 
This will be done under blinded situation and will not treated as 
formal interim analysis. 


 
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2. 
STATISTICAL HYPOTHESES  
This is a bridging study designed to determine the effect of Mepolizumab 100mg SC on 
clinically significant exacerbation events, compared with placebo among Chinese 
subjects.  
The Chinese patient data collected in this study will be supplemented with data on the 
treatment effect for the same exacerbation endpoint from the global PhIII study 
MEA115588, using a Bayesian Dynamic Borrowing approach to analysis of the study 
(Schmidli, 2014). The potential to borrow information from the global dataset is based on 
the premise that the underlying disease, its general management and the response to 
mepolizumab is similar in Chinese and non-Chinese patients. A bridging approach is 
proposed because of the expected similarity of the treatment effect in Chinese patients 
and the global population (supported by similarities in the epidemiology, 
pathophysiology, pharmacology and clinical management of patients and consistency of 
treatment differences across key demographic factors including ethnicity), and similar 
study design specially the study population (supported by similarities in key eligibility 
criteria) between MEA115588 and this China study, hence there is low probability of the 
null effect being true. 
A frequentist hypothesis test will not be performed. Instead, the posterior distributions of 
the primary endpoint, i.e. rate ratio of events between Mepolizumab 100mg SC vs. 
placebo will be derived based on the Bayesian analysis including the global PhIII study 
MEA115588 information and the data collected on Chinese patients in this study. The 
hypothesis of interest for treatment comparison is that the rate ratio is less than 1, and the 
study will be considered to have shown evidence that supports this hypothesis if the 
posterior probability that the rate ratio is less than 1 is at least 95% (a “positive result”).  
There is no adjustment for multiplicity in this study. 


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201536 
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• Continuous data will be summarized using descriptive statistics: n, mean, standard 
deviation (std), median, minimum, 25th percentile, 75th percentile and maximum.  
• Categorical data will be summarized as the number and percentage of participants 
in each category. 
• The minimum and maximum will be reported to the same number of decimal 
places as the raw data recorded in the database. The mean, median, 25th 
percentile, and 75th percentile will be reported to one more decimal place than the 
raw data recorded in the database. The SD will be reported to two more decimal 
places than the raw data recorded in the database. A maximum of four decimal 
places will be used. Percentages will be presented to one decimal place. A count 
of zero will have no corresponding percentage.  
• When the data are summarized by visit, only scheduled visits will be presented. 
 
4.1.2. 
Baseline Definition 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. 
For data collected via the eDiary device (i.e. morning peak flow, usage of rescue 
medication (i.e. salbutamol/albuterol), asthma symptom score and frequency of 
awakening due to asthma symptoms), the baseline for analyses of averaged 4-weekly data 
will be calculated using values from the run-in period as shown in Section 4.2 in 
protocol.  
Parameter 
Study Assessments can be Considered as 
Baseline 
Baseline Used in Data Display 
Screening 
Day -6 to Day 1 
(Pre-Dose) 
Day 1 (Pre-
Dose) 
[Efficacy] 
Salbutamol/albuterol 
use 
 
X 
 
Average of measurements from 
Day -6 to Day 1 pre-dose 
Asthma 
symptom scores 
 
X 
 
Average of measurements from 
Day -6 to Day 1 pre-dose 
Awakening at 
night 
 
X 
 
Average of measurements from 
Day -6 to Day 1 pre-dose 
Morning PEF 
 
X 
 
Average of measurements from 
Day -6 to Day 1 pre-dose 
[Safety] 
12-Lead ECG 
X 
 
 
Screening 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 


 
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4.1.3. 
Definition of endpoint(s)/estimands 
The primary endpoint is the frequency of clinically significant exacerbations (the same as 
protocol defined exacerbations) of asthma over the 52 weeks treatment period expressed 
as an exacerbation rate p.a. 
Exacerbation from the start of treatment until 4 weeks after the last dose of study drug 
will be used in the analysis. Exacerbations which are separated by less than 7 days will be 
treated as a continuation of the same exacerbation. 
The estimand is described by the following attributes: 
o Population: Chinese participants with severe eosinophilic asthma. 
o Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to 
placebo every 4 weeks, both treatments given on top of standard of care. Further 
details on standard of care can be found in Section 6 of Protocol. 
o Variable: number of clinically significant exacerbations over 52 weeks. 
o Summary measure: annualised rate of exacerbations. Comparison between the 
mepolizumab arm and placebo will be assessed with the rate ratio. 
o Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
o Rationale for estimand:  
Interest lies in the treatment effect when medication is taken as directed.  For 
participants discontinuing randomised medication, use of a hypothetical strategy 
addresses treatment effects attributable to mepolizumab in the hypothetical 
scenario where participants would not discontinue from treatment.  
Since this is a bridging study, the results from MEA115588 will be borrowed and 
compared with the data from this study. To ensure comparability between two studies, 
the Estimand framework including analysis models will be similar with MEA115588. 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Main analytical approach 
The primary efficacy analysis will evaluate the primary estimand in the Modified Intent-
to-Treat population, by first using a generalized linear model with a log-link function to 
get an estimate of the logarithm of the rate ratio for mepolizumab vs. placebo and 
associated standard error. These estimates will then be combined with the global 
MEA115588 study using the pre-specified robust mixture prior to obtain the posterior 
distribution for the China rate ratio (on the log scale). A 95% posterior probability that 
the true rate ratio < 1 represents a high level of confidence for declaring a positive 
treatment benefit in Chinese patients in the context of a bridging study where substantial 
evidence of treatment benefit in global (non-Chinese) patients already exists. 
 


 
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Model Specification 
• 
Generalized linear model assuming a negative binomial distribution 
• 
Terms in the model: 
o Response: number of recorded, on-treatment, clinically significant 
exacerbations experienced per subject. 
o Categorical: treatment group, baseline maintenance OCS therapy (OCS vs. no 
OCS),  
o Continuous: baseline disease severity (as % predicted FEV1), number of 
exacerbations in previous year (as an ordinal variable) 
o Offset:  logarithm of time on treatment 
Since this is a bridging study, to ensure comparability between results in MEA115588 
and this study, the analysis model including the covariates are the same with 
MEA115588. 
Model Results Presentation 
• 
Treatment group model estimated exacerbation rates, the treatment rate ratio and 
associated SE and 95% CI will be presented.  
• 
The pairwise treatment rate ratios and associated 95% CIs will also be presented 
graphically 
Bayesian Dynamic Borrowing 
A Bayesian dynamic borrowing model (Schmidli, 2014) will be used to make inference 
about the logarithmic rate ratio of exacerbations in mepolizumab 100mg SC to Placebo in 
Chinese participants. The prior distribution will be a mixture with two components: the 
first component is based on the results from the MEA115588 study; the second 
component is a vague distribution centred on 0 representing ‘no-effect’. 
An initial (prior) weight of 50% is proposed for the informative global component of the 
robust mixture prior, with the remainder of the weight (50%) placed on the vague prior to 
reflect a conservative starting position regarding the assumed relevance of the global 
MEA115588 results to Chinese. Combining the two components and their respective 
weights gives the following 2-component mixture of normals: 
𝑝(𝜃) = 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(−0.7474 , 0.1532) + 0.5 ∗𝑁𝑜𝑟𝑚𝑎𝑙(0 , 2.1256) 
The prior mixture will be updated with the data from this study to obtain the posterior 
distribution. Assuming the standard error of the estimated logarithmic rate ratio in this 
study is known, the posterior distribution will also be a mixture of normal (see details 
below). The posterior weight given to the global MEA115588 study data is 
commensurate with the strength of evidence of similarity between the MEA115588 data 
and the China data. The BDB analysis [Schmidli, 2014] ‘learns’ how much of the global 
MEA115588 study information to borrow based on the consistency between the observed 
rate ratio in the China and global studies and updates the weight on the global 
MEA115588 results accordingly. 
 
The mean, median,90% credible interval and 95% credible interval of this posterior 
distribution of the rate ratio will be reported, along with the probability that true rate ratio 


 
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Model Specification 
is less than 1 (equivalent to the log rate ratio being less than 0). The mean and SE of log 
rate ratio will be presented as well. 
 
The posterior distribution 
The robust mixture prior was constructed as weighted average of global MEA115588 and 
weak priors, which followed the structure: 
Robust mixture= 𝑤× 𝑁𝑜𝑟𝑚𝑎𝑙(𝑚𝑔𝑙𝑜𝑏𝑎𝑙, √𝑣𝑔𝑙𝑜𝑏𝑎𝑙) + (1 −𝑤) ×
𝑁𝑜𝑟𝑚𝑎𝑙(𝑚𝑣𝑎𝑔𝑢𝑒, √𝑣𝑣𝑎𝑔𝑢𝑒) 
Where 𝑚𝑔𝑙𝑜𝑏𝑎𝑙= −0.7474, 𝑣𝑔𝑙𝑜𝑏𝑎𝑙= 0.15322, 𝑚𝑣𝑎𝑔𝑢𝑒= 0, 𝑣𝑣𝑎𝑔𝑢𝑒= 2.12562 and 𝑤=
0.5. 
Assumed the observed log rate ratio from this study has the distribution with mean 
𝑚𝑐ℎ𝑖𝑛𝑎 and variance 𝑣𝑐ℎ𝑖𝑛𝑎, which were the point estimate and squared standard error of 
the log rate ratio from negative binomial regression defined previously. The sampling 
distribution for the observed data will be combined with robust mixture prior using 
standard conjugate Bayesian theory to obtain a posterior mixture distribution: 
Posterior mixture=𝑤∗× 𝑁𝑜𝑟𝑚𝑎𝑙(𝑚𝑔𝑙𝑜𝑏𝑎𝑙
∗
, √𝑣𝑔𝑙𝑜𝑏𝑎𝑙
∗
) + (1 −𝑤∗) ×
𝑁𝑜𝑟𝑚𝑎𝑙(𝑚𝑣𝑎𝑔𝑢𝑒
∗
, √𝑣𝑣𝑎𝑔𝑢𝑒
∗
) 
where: 
𝑚𝑔𝑙𝑜𝑏𝑎𝑙
∗
= 𝑣𝑔𝑙𝑜𝑏𝑎𝑙
∗
(
𝑚𝑔𝑙𝑜𝑏𝑎𝑙
𝑣𝑔𝑙𝑜𝑏𝑎𝑙+
𝑚𝑐ℎ𝑖𝑛𝑎
𝑣𝑐ℎ𝑖𝑛𝑎)  and  
1
𝑣𝑔𝑙𝑜𝑏𝑎𝑙
∗
=
1
𝑣𝑔𝑙𝑜𝑏𝑎𝑙+
1
𝑣𝑐ℎ𝑖𝑛𝑎 
𝑚𝑣𝑎𝑔𝑢𝑒
∗
= 𝑣𝑣𝑎𝑔𝑢𝑒
∗
(
𝑚𝑣𝑎𝑔𝑢𝑒
𝑣𝑣𝑎𝑔𝑢𝑒+
𝑚𝑐ℎ𝑖𝑛𝑎
𝑣𝑐ℎ𝑖𝑛𝑎)  and  
1
𝑣𝑣𝑎𝑔𝑢𝑒
∗
=
1
𝑣𝑣𝑎𝑔𝑢𝑒+
1
𝑣𝑐ℎ𝑖𝑛𝑎 
𝑤∗=
𝐶𝑔𝑙𝑜𝑏𝑎𝑙× 𝑤
𝐶𝑔𝑙𝑜𝑏𝑎𝑙× 𝑤+ 𝐶𝑣𝑎𝑔𝑢𝑒× (1 −𝑤) 
𝐶𝑔𝑙𝑜𝑏𝑎𝑙= exp {−0.5(𝑚𝑐ℎ𝑖𝑛𝑎−𝑚𝑔𝑙𝑜𝑏𝑎𝑙)
2/(𝑣𝑔𝑙𝑜𝑏𝑎𝑙+ 𝑣𝑐ℎ𝑖𝑛𝑎)}
√𝑣𝑔𝑙𝑜𝑏𝑎𝑙+ 𝑣𝑐ℎ𝑖𝑛𝑎
 
 
𝐶𝑣𝑎𝑔𝑢𝑒= exp {−0.5(𝑚𝑐ℎ𝑖𝑛𝑎−𝑚𝑣𝑎𝑔𝑢𝑒)
2/(𝑣𝑣𝑎𝑔𝑢𝑒+ 𝑣𝑐ℎ𝑖𝑛𝑎)}
√𝑣𝑣𝑎𝑔𝑢𝑒+ 𝑣𝑐ℎ𝑖𝑛𝑎
 
 
The posterior means and variances of each component are obtained from conjugate 
Bayesian updating of that individual prior component, and the posterior weight is a 
function of the prior weight and coefficients 𝐶𝑔𝑙𝑜𝑏𝑎𝑙 and 𝐶𝑣𝑎𝑔𝑢𝑒 (Schmidli, 2014) 
 
Subgroup Analyses 
Subgroup analyses of the primary endpoint will be carried out to assess consistency of the 
intervention effect across the following subgroups: 
• 
Age group: <65, 65 
• 
Sex: female vs male 


 
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Model Specification 
• 
Weight:  ≤=60 kg, >60-≤=75 kg, >75kg 
• 
Baseline predicted pre-bronchodilator FEV1: <=60%, >60%-80%, >80% 
• 
number of exacerbations in the year prior to screening (i.e., 2, 3, 4+) 
• 
Baseline use of maintenance oral corticosteroids 
• 
Baseline airway reversibility: reversible or not reversible defined in Section 6.2.9. 
• 
blood eosinophil count at screening: <150, ≥150-<300, ≥300-<500, ≥500 cells/L 
• 
Randomization stratification factor: -<300, ≥300 cells/L 
• 
If the number of participants is too small (less than [10%]) within a subgroup, then the 
subgroup categories may be redefined prior to unblinding the study. 
Missing data imputation 
• 
The primary analysis using the negative binomial model assumes that missing data is 
missing at random (MAR).  
 
4.2.2. 
Sensitivity analyses 
• Ordinarily, an analysis under a MAR assumption is implemented using direct 
likelihood, by introducing an offset into the log-linear model to allow for the 
length of the observation period. Using an underlying negative binomial model, 
missing data post study withdrawal of treatment will be imputed conditional upon 
the subjects own observed number of events prior to withdrawal of treatment 
under MAR assumption. This approach involves firstly fitting the negative 
binomial generalised linear model to the data, and sampling from the posterior 
distribution (likelihood function multiplied by a non-informative prior) of the 
estimated parameters (i.e. the betas) associated with the independent variables. 
The number of exacerbations that would have been seen based on various 
assumptions is then estimated for subjects who withdraw of treatment early. This 
number is combined with the observed exacerbations and the data is analysed as 
for the primary endpoint [Keene, 2014]. This analysis is repeated multiple times 
and the results combined using Rubin’s formulae [Barnard, 1999] as implemented 
in PROC MIANALYZE in SAS. 
• Since this is a bridging study, to keep consistent analysis model, the stratification 
variable EOS level at screening (≥300 cells/μL vs.  <300 cells/μL) will be not 
included into the primary analysis. To test the impact of stratification variable for 
the model, further sensitivity analysis will be performed adding EOS level at 
screening (≥300 cells/μL vs.  <300 cells/μL) into the primary negative binomial 
model, the missing data is assumed as missing at random (MAR). 
 
All the sensitivity analyses will not use BDB method to implement. 
 
4.2.3. 
Additional estimands  
To examine the sensitivity of the results of primary analysis to departures from the 
assumption that Intercurrent Events (IEs) did not occur, treatment policy strategy will be 
used to IEs of study treatment discontinuation not related to the COVID-19 pandemic, the 
on- and off- treatment data will be included in the analyses.  


 
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Supplemental estimand 1: 
The estimand is described by the following attributes: 
o Population: Chinese participants with severe eosinophilic asthma. 
o Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to 
placebo every 4 weeks, both treatments given on top of standard of care. Further 
details on standard of care can be found in Section 6. 
o Variable: number of clinically significant exacerbations over 52 weeks. 
o Summary measure: rate ratio of exacerbations between the mepolizumab arm and 
placebo. 
o Intercurrent events: 
o Study treatment discontinuation 
▪ Related to the COVID-19 pandemic: hypothetical strategy 
▪ Not related to the COVID-19 pandemic: treatment policy strategy 
Handling of Missing Data: 
 
Missing data will be imputed differently depending on the handling strategy for the 
specific intercurrent event. 
o Missing data due to hypothetical strategy for intercurrent event of study treatment 
discontinuation (data collected after the occurrence of the IE will be excluded 
from the analysis), assuming that missing data is missing at random (MAR).  
 
o Missing data due to study withdrawal. Study withdrawal before the completion of 
the study will create missing outcome data. This may occur concurrently or after 
the IE. The assumptions used to impute the missing part of the data for subjects 
who withdraw early from study will be as follows: 
a) Missing at Random (direct likelihood). Using the negative binomial model 
assumes that missing data is missing at random (MAR). The missing data 
will be imputed conditional upon the subjects own observed number of 
events, which are not missing, based on the negative binomial generalized 
linear model with offset variable. 
 
b) Missing at Random (multiple imputation). Using an underlying negative 
binomial model, post-withdrawal counts were imputed conditional upon 
the subject’s own observed number of events prior to withdrawal. 
 
c) Jump to Reference. Missing counts will be imputed conditional upon the 
subjects own observed number of events prior to withdrawal. The impact 
of sampling from this conditional distribution is that if their event rate 
prior to withdrawal is worse than would be expected (positive residual) on 
mepolizumab, their imputed event rate after withdrawal will be worse than 
the expected event rate on placebo. Missing data in the placebo arm are 
imputed under randomised-arm MAR. 
 
 


 
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4.2.4. 
Supplementary Analyses  
• As a supportive analysis to enable comparability of results with global 
MEA115588 study, the primary analyses may be repeated using the “Per-
protocol” analysis population (see Section 6.2.13 for the definition).  
• Impact of the Prior Weight of the robust mixture prior. 
Another supportive “tipping point” type of analysis will be conducted to assess 
the impact on the results of different prior weights given to the historical data in 
the robust mixture prior for primary endpoint.  
The prior weights of the informative global component of the prior will be varied 
from 0 to 1 in the increment of 0.05 and the primary analysis will be repeated for 
each value of the weight. When the prior weight is 0 or 1, the mixture prior will 
become a normal distribution thus the Bayesian diagram will be the standard 
conjugate analysis.  
The posterior mean, median and 90% credible interval of the posterior distribution 
will be reported for each prior weight, along with the probability that true rate 
ratio is less than 1 (equivalent to the log rate ratio being less than 0) 
 
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Key secondary endpoint(s) 
• Time to first clinically significant exacerbations. 
• Mean change in St. Georges Respiratory Questionnaire (SGRQ) at Week 52  
• Frequency of clinically significant exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits over the 52-week treatment period 
• Frequency of clinically significant exacerbations requiring hospitalization over the 
52-week treatment period 
• Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52 
 
Definition of endpoint(s)/estimands 
The principle of Estimand consideration for each key secondary endpoint is to keep a 
similar Estimand strategy for intercurrent events with study MEA115588, since it is a 
bridging study. To test the sensitivity of the results of the main estimand for key 
secondary endpoints, the supplemental estimand for these endpoints are defined in 
Section 4.3.2. 
Endpoint(s) 
• Time to first clinically significant exacerbation 
Estimand 
The estimand is described by the following attributes: 
• Population: Chinese participants with severe eosinophilic asthma  


 
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Endpoint(s) 
• Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to placebo 
every 4 weeks, both treatments given on top of standard of care.  
• Variable: Time to first clinically significant exacerbations. 
• Summary measure: Rate of first clinically significant exacerbation. Comparison between 
the mepolizumab arm and placebo will be assessed through the hazard ratio. 
• Intercurrent events: 
o Study treatment discontinuation - hypothetical strategy  
The handling strategy for the IEs of discontinuation of study intervention will be based on a 
hypothetical approach; specifically, the effects estimated will be under the hypothetical 
scenario where the IE did not occur. If a subject discontinues study treatment without any 
clinically significant exacerbations, the subject will be censored at the date of study treatment 
discontinuation which assumes censoring at random. 
Endpoint(s) 
• Mean change in St. Georges Respiratory Questionnaire (SGRQ) at Week 52  
Estimand 
The estimand is described by the following attributes: 
• Population: Chinese participants with severe eosinophilic asthma  
• Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to placebo 
every 4 weeks, both treatments given on top of standard of care.  
• Variable:  
o Mean change in St. Georges Respiratory Questionnaire (SGRQ) at Week 52. 
• Summary measure:  
o LS Mean change in St. Georges Respiratory Questionnaire (SGRQ) between the 
mepolizumab arm and placebo. 
• Intercurrent events: 
o Study treatment discontinuation- hypothetical strategy  
The handling strategy for the IEs of discontinuation of study intervention will be based on a 
hypothetical approach; specifically, the effects estimated will be under the hypothetical 
scenario where the IE did not occur. 
Endpoint(s) 
• Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52 
Estimand 
The estimand is described by the following attributes: 
• Population: Chinese participants with severe eosinophilic asthma  
• Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to placebo 
every 4 weeks, both treatments given on top of standard of care.  
• Variable:  
o Change from baseline in clinic pre-bronchodilator FEV1 at Week 52 
• Summary measure:  
o  Mean change from baseline in clinic pre-bronchodilator FEV1. Comparison 
between the mepolizumab arm and placebo will be assessed with the mean 
difference. 


 
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Endpoint(s) 
• Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
The handling strategy for the IEs of discontinuation of study intervention will be based on a 
hypothetical approach; specifically, the effects estimated will be under the hypothetical 
scenario where the IE did not occur.  
Endpoint(s) 
• Frequency of clinically significant exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits over the 52-week treatment period 
• Frequency of clinically significant exacerbations requiring hospitalization over the 52-
week treatment period 
Estimand 
The estimand is described by the following attributes: 
• Population: Chinese participants with severe eosinophilic asthma  
• Treatment condition: mepolizumab 100mg SC given every 4 weeks compared to placebo 
every 4 weeks, both treatments given on top of standard of care.  
• Variable:  
o Number of clinically significant exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits over 52 weeks. 
o Number of clinically significant exacerbations requiring hospitalization over 52 
weeks. 
• Summary measure:  
o Rate ratio of clinically significant exacerbations requiring hospitalization 
(including intubation and admittance to an ICU) or ED visits between the 
mepolizumab arm and placebo. 
o Rate ratio of clinically significant exacerbations requiring hospitalization between 
the mepolizumab arm and placebo 
• Intercurrent events: 
o Study treatment discontinuation-hypothetical strategy  
The handling strategy for the IEs will be the same with primary estimand defined in Section 
4.2.1 
 
 
4.3.2. 
Main analytical approach 
Time to first clinically significant exacerbations 
Endpoint / Variables 
• Time to first clinically significant exacerbations 
Model Specification 
• Cox’s proportional hazards model 
• Terms in the model: 


 
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Endpoint / Variables 
• Response: time to first on-treatment, clinically significant exacerbation  
• Categorical: treatment group, baseline maintenance oral corticosteroids (OCS vs 
no OCS)     
• Continuous: baseline disease severity (as % predicted FEV1),  number of 
exacerbations in the year prior to the study (as an ordinal variable (2, 3, 4+)) 
Model Checking & Diagnostics 
• The proportional hazards assumption will be examined by obtaining the Kaplan-
Meier estimates of the survival function S(t) over time separately for each 
treatment group. In addition, the ln {-ln[S(t)]} plot will be produced. 
Model Results Presentation 
• Hazard ratios and the percent reduction in risk of a first exacerbation at any time 
on-treatment during the study for the pairwise treatment comparisons with 
associated 95% CIs and p-values will be presented. 
• The probability of having an on-treatment clinically significant exacerbation at 
week 16，32 and 52and 95% CI for each treatment group will be presented. 
Sensitivity and Supportive Analyses 
• As a supportive analysis, the analysis will be repeated using the “Per-protocol” 
analysis population. 
Additional estimands 
A supplementary analysis will be performed using the “treatment policy” strategy for 
the intercurrent event of discontinuation of treatment. This analysis will include both 
on-treatment and off-treatment clinically significant exacerbation data from subjects 
who withdraw from treatment prior to W52. Exacerbations will be included provided 
the exacerbation onset date is before week 52. Participants that have not experienced a 
clinically significant exacerbation on or before the end of study date/early 
withdrawal/lost to follow up study/ date of death day are censored at the end of study 
date/early withdrawal/date of death. 
 
SGRQ at Week 52 
Endpoint / Variables 
• Mean change in St. Georges Respiratory Questionnaire at Week 52 
Details for how to score the SGRQ are outlined in the SGRQ manual (Mar, 2016). 
Model Specification 
• MMRM  
 
• 
Analysis performed using a mixed models repeated measures analysis (MMRM) 
adjusting  covariates: baseline, baseline maintenance OCS therapy (OCS vs. no 
OCS), exacerbations in the year prior to the study (as an ordinal variable), baseline 


 
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Endpoint / Variables 
% predicted FEV1,  treatment and visit, plus interaction terms for visit by baseline 
and visit by treatment group 
 
• A dataset om_dataset will be constructed to reflect the data structure of no missing 
observations, i.e. had each subject been reported with the same visits.  
 
Model Results Presentation 
• Least-square (LS) means and LS mean change from baseline values for each 
treatment group will be presented with their associated standard errors as well as 
95% CIs. The estimated treatment difference along with corresponding standard 
error, 95% CI for each Week will be presented. 
 
• 
The treatment differences (and associated 95% CIs) at week 52 will also be 
presented graphically. 
Missing data imputation 
The analysis using the MMRM model assumes that missing data is missing at random 
(MAR).  
Sensitivity and Supportive Analyses 
• To compare with MEA115588 results, a sensitivity analysis will be analysed by 
analysis of covariance (ANCOVA) with covariates of baseline, baseline 
maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the 
study (as an ordinal variable), baseline % predicted FEV1, and treatment. In this 
sensitivity analysis, the mean score for a subject at either timepoint (i.e. baseline or 
exit visit) will only be calculated if at least 75% of the questions were answered. If 
fewer than 75% of the questions were answered then the mean score for that 
subject at that timepoint will be considered missing. Only the observed data will be 
used and no imputation will be done for missing data. 
• Another sensitivity analyses of the MMRM will be performed using multiple 
imputation methods based on pattern mixture models.  
• A supportive analysis will be repeated using the “Per-protocol” analysis population 
• Another supportive analysis will be performed by domain: Symptoms domain, 
Activity domain and Impacts domain 
Additional estimands 
A supplementary analysis will be performed using the “treatment policy” strategy for 
the intercurrent event of discontinuation of treatment. This analysis will include both 
on-treatment and off-treatment value.  For missing data imputation, the missing data 
are assumed as MAR. 
 
 


 
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Clinically significant exacerbations requiring hospitalization/ ED visits and 
clinically significant exacerbations requiring hospitalization 
Endpoint(s) 
• Frequency of clinically significant exacerbations requiring hospitalization (including 
intubation and admittance to an ICU) or ED visits over the 52-week treatment period 
• Frequency of clinically significant exacerbations requiring hospitalization over the 52-
week treatment period 
Model Specification, Checking & Diagnostics, Results, Presentation 
• These endpoints will be analyzed using the same methodology as the primary analysis of 
Frequency of clinically significant exacerbations in Section 4.2.1. 
Missing data imputation 
The analysis using the negative binomial model assumes that missing data is missing at 
random (MAR). 
Sensitivity and Supportive Analyses 
• As a supportive analysis, the analysis will be repeated using the “Per-protocol” analysis 
population. 
Additional estimands 
The same additional estimand and similar methods for missing data imputation will be used as 
the primary endpoint in Section 4.2.3. 
 
Pre-bronchodilator FEV1 at Week 52 
Endpoint / Variables 
• Mean change from baseline in clinic pre-bronchodilator FEV1 at Week 52 
Model Specification 
• Mixed Models Repeated Measures (MMRM) model. 
 
• Change from baseline in pre-bronchodilator FEV1 will be analyzed using a mixed 
models repeated measures analysis (MMRM) adjusting covariates of baseline, 
baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year 
prior to the study (as an ordinal variable), treatment and visit, plus interaction terms 
for visit by baseline and visit by treatment group. A dataset om_dataset will be 
constructed to reflect the data structure of no missing observations 
 
Model Results Presentation 
• Least-square (LS) means and LS mean change from baseline values for each 
treatment group will be presented with their associated standard errors as well as 
95% CIs. The estimated treatment difference along with corresponding standard 
error, 95% CI for each Visit will be presented. 
 


 
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Endpoint / Variables 
• 
The LS mean treatment differences (and associated 95% CIs) for all visits will also 
be presented graphically. 
Missing data imputation 
The analysis using the MMRM model assumes that missing data is missing at random 
(MAR).  
Sensitivity and Supportive Analyses 
• The sensitivity analyses of the repeated measures analyses will be performed for 
the FEV1 key secondary endpoint using multiple imputation methods under MAR 
based on pattern mixture models. The method is analogous to the multiple 
imputation of exacerbation events. 
• A supportive analysis of the repeated measures pre-bronchodilator FEV1 analysis 
will be performed, excluding all values captured within 6 hours of a SABA being 
administered or 12 hours of a LABA being administered to the subject. 
• Another supportive analysis will be repeated using the “Per-protocol” analysis 
population 
 
Additional estimands 
A supplementary analysis will be performed using the “treatment policy” strategy for 
the intercurrent event of discontinuation of treatment. This analysis will include both 
on-treatment and off-treatment value. For missing data imputation, the missing data are 
assumed as MAR. 
 
4.4. 
Other Analyses 
Endpoint(s) 
• Mean change from baseline compared to placebo in Asthma Control Questionnaire 
(ACQ-5) score at Week 52 
The ACQ-5 is a 5-item questionnaire developed as a measure of patient’s asthma 
control. Response options for each question are on a 7-point scale ranging from 0 
(
) to 6 
). The questions 
are equally weighted, and the ACQ-5 score is calculated as the mean of the 5 
questions, ranging between 0 (
) to 6 (
), 
where higher scores indicate worse asthma control. 
• Mean change from baseline in clinic post-bronchodilator FEV1 at week 52 
Model Specification, Checking & Diagnostics, Results, Presentation 
• MMRM 
• These endpoints will be analyzed using a mixed models repeated measures analysis 
(MMRM) adjusting covariates: baseline, baseline maintenance OCS therapy (OCS 
vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), 
baseline % predicted FEV1, treatment and visit, plus interaction terms for visit by 
baseline and visit by treatment group. A dataset om_dataset will be constructed to 
reflect the data structure of no missing observations 
CCI
CCI
CCI
CCI


 
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Missing data imputation 
For a given visit, if the response to one of the 5 questions is missing then the ACQ-5 
score will be calculated as the mean of the available responses. If the response to more 
than one question is missing, then the ACQ-5 score will be set to missing. 
The analysis using the MMRM model assumes that missing data is missing at random 
(MAR).  
 
Endpoint(s) 
• Percent of subjects evaluated as responders as measured by ACQ-5 score at Week 
52 
ACQ-5 score responder is defined as the participant achieving a  ≥0.5-point 
improvement (decrease) from baseline in ACQ-5 score. 
• Percent of subjects evaluated as responders as measured by SGRQ score at Week 
52 
SGRQ responder is defined as ≥ 4 points improvement (decrease) from baseline in 
total score. 
Missing data imputation 
Subjects with missing values at Baseline will be excluded from analyses. Any missing 
values at post-baseline visit will be included as non-responders.  
Model Specification, Checking & Diagnostics, Results, Presentation 
• Analysis will be performed using a logistic regression model adjusting for baseline, 
treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), number of 
exacerbations in previous year (as an ordinal variable), baseline disease severity (as 
% predicted FEV1) and baseline score. 
• For the baseline covariate, if the factor of baseline covariate fails to converge, it 
will be removed from the logistic model. If the model fails to converge, e.g. due to 
the limited event number, then the endpoints will be analysed by Fisher exact test 
only. 
• The number and percentage of patients identified as responders, non-responders or 
with missing data at Week 52 will be displayed for each treatment group. The 
model estimated ratio of the odds of being a responder in the mepolizumab 
treatment group compared to placebo will be presented with 95% confidence 
intervals and the associated p-value. 
 
Endpoint(s) 
• Percent of subjects recording a favorable treatment response as measured by the 
Subject Rated Response to Therapy at Week 52. 
• Percent of subjects evaluated as having a favorable treatment response as measured 
by the Clinician Rated Response to Therapy at Week 52 
Missing data imputation 
• Subjects with missing values at Week 52 will not be imputed and will be included 
in the analysis as category of significantly worse. 


 
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Endpoint(s) 
Model Specification, Checking & Diagnostics, Results, Presentation 
• These endpoints will be analyzed using a proportional odds model (multinomial 
(ordered) logistic generalized linear model), with terms for treatment group, 
baseline maintenance OCS therapy (OCS vs. no OCS), number of exacerbations in 
previous year (as an ordinal variable), baseline disease severity (as % predicted 
FEV1). 
• The number and percentage of patients identified as each category(including 
missing data) at Week 52 will be displayed for each treatment group. The model 
estimated ratio of the odds of being a responder in the mepolizumab treatment 
group compared to placebo will be presented with 95% confidence intervals and 
the associated p-value. 
 
Endpoint(s) 
• Mean change from baseline in daily salbutamol/albuterol use 
• Mean change from baseline in daily asthma symptom scores 
• Mean change from baseline in awakening at night due to asthma symptoms 
requiring rescue medication use 
• Mean change from baseline in morning PEF 
Missing data imputation 
No imputation will be done for missing data. 
 
Model Specification, Checking & Diagnostics, Results, Presentation 
• These endpoints will be summarized by descriptive statistics: mean, SD, median, 
min and max. 
• The daily data(excluding days with missing data)will be aggregated over 4-week 
periods (weeks 1-4, 5-8, …, 48-52). Data for each 4-week period, and change from 
baseline for each 4-week periods will be summarized by treatment group. 
 
Endpoint(s) 
• Mean number of days with oral corticosteroids taken for clinically significant 
exacerbations 
• Total prednisone (or equivalent) exposure for clinically significant exacerbations 
over the 52-week treatment period 
Missing data imputation 
Only the observed data before discontinuation of study treatment will be used and no 
imputation will be done for missing data. 
 
Model Specification, Checking & Diagnostics, Results, Presentation 
• Total number of days of oral corticosteroids use for clinically significant 
exacerbations per subject will be summarised by treatment arm 


 
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Endpoint(s) 
• Total prednisone equivalent dose per clinically significant exacerbation per subject 
will be summarised by treatment arm. A summary table for OCS only and OCS 
plus other systemic routes of administration (oral, IV and IM) corticosteroids will 
be produced 
 
Endpoint(s) 
• Frequency of all exacerbations 
Missing data imputation 
The method for missing data imputation will be the same as the primary efficacy 
analysis (see Section 4.2.1 for details). 
Model Specification, Checking & Diagnostics, Results, Presentation 
• These endpoints will be analyzed using the same methodology as the primary 
analysis in Section 4.2.1 
 
Endpoint(s) 
• Time to first exacerbation 
• Time to withdrawal from study treatment due to asthma exacerbations 
• Time to first exacerbation requiring hospitalization or ED visit 
Model Specification, Checking & Diagnostics, Results, Presentation 
• These endpoints will be analyzed using the same methodology as the analysis of 
time to first clinically significant exacerbation in  Section 4.3.2. 
 
Endpoint(s) 
• Unscheduled healthcare resource utilization (for clinically significant exacerbations 
and other asthma related health care) over the 52-week treatment period 
Missing data imputation 
No imputation will be done for missing data. 
 
Model Specification, Checking & Diagnostics, Results, Presentation 
• Healthcare resource use due to a clinically significant exacerbation and other 
asthma related health care will be summarized by treatment group 
 
Endpoint(s) 
• Days of school/work missed 
Missing data imputation 
No imputation will be done for missing data. 
 


 
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Model Specification, Checking & Diagnostics, Results, Presentation 
• Number of days off school/work due to asthma symptoms for different groups will 
be summarized by mean, SD, median, minimum and maximum. 
 
4.5. 
Safety Analyses 
The MITT- population will be used for the analysis of safety data.  
AEs will be considered on-treatment for at least 4 weeks (28 days) following the last dose 
of study treatment, AEs which occur more than 28 days following the last dose of study 
treatment will be considered as post-treatment, the detailed definition can be found in 
Section 6.2.3. All primary safety analysis will use the “While on Treatment” approach, 
i.e. any safety events which occur post discontinuation of study intervention will be 
excluded. For key safety outputs, post-treatment data will be included in analysis or 
displayed separately, detailed information will be defined in the following sections. The 
listings will cover all of pre-, on- and post- treatment data. 
Generally, the missing data will not be imputed, except the AE severity and relatedness 
data. If an adverse event severity is missing, the severity is to be populated as 
‘UNKNOWN’. A worst-case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing.  
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 
 
Subject years exposure is calculated as follows: 
Subject Years Exposure = (IP Stop Date – IP Start Date + 29)/365.25 
If the IP start date is missing and there is evidence the subject received at least one dose 
of IP, the IP start date will be taken to be the date of randomisation, and if the IP end date 
is missing it will be taken to be the last on-treatment visit attended. 
Randomised subjects with no evidence of receiving at least one dose of IP will be shown 
as having zero days of exposure. 
In addition, the number of subjects administered investigational product, the number of 
treatments administered, and the number of days over which treatment was administered 
will be summarized. 
4.5.2. 
Adverse Events 
Adverse events will be summarized by system organ class and preferred term . 
AEs will be summarized for on-treatment period, unless otherwise specified. 


 
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The number and percentage of subjects experiencing at least one AE during on-treatment 
period of any type, AEs within each body system and AEs within each preferred term 
will be summarized for each treatment group. 
• Overview of all AEs 
 
The following summary tables will be produced: 
• Summary of all AEs; (on-treatment, post-treatment) 
• Summary of drug related AEs;  
• Summary of Common (≥ 3% Incidence in any Treatment Group) Adverse 
Events by Overall Frequency  
• Summary of AEs by maximum intensity  
• Summary of Severe AEs (on-treatment, post-treatment) 
• Summary of SAEs; (on-treatment, post-treatment) 
• Summary of non-SAEs  
• Summary of Common (≥ 3% Incidence in any Treatment Group) Non-Serious 
Adverse Events by Overall Frequency (on-treatment) 
• Summary of drug related SAEs (on-treatment) 
• Summary of non-fatal SAEs (on-treatment) 
• Summary of Fatal Events (on-treatment, post-treatment) 
• Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study 
• Summary of Adverse Events Leading to Interruption of Study Drug  
• Summary of AEs by ADA Assay Result Category (On-Treatment) 
• Summary of AEs by NAb (On-Treatment)  
 
The following listings will be produced: 
• Listing of Subject Numbers for Individual Adverse Events 
• Listing of all Adverse Events 
• Listing of Non-Fatal Serious Adverse Events 
• Listing of Fatal Adverse Events 
• Listing of Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study 
 
Exposure Adjusted Rate for Adverse Events 
Exposure adjusted rate for adverse events represents the frequency of events per 1000 
subject-years of exposure, which is calculated as: 
(Total number of adverse events / Total Duration of Exposure in days)/365.25*1000 
The summary of exposure adjusted for the events below will be provided: 
• All Adverse Events (on treatment) 
• Most frequent AEs reported by 3% or more subjects (on treatment) 
• Drug related AEs (on treatment) 
• Non-fatal SAEs (on treatment) 


 
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• Adverse Events Leading to Permanent Discontinuation of Study Drug or 
Withdrawal from Study (on treatment) 
 
Adverse Events of Special Interest 
Systemic reactions and local injection site reactions are adverse events of special interest 
(AESIs) which are collected using target eCRF pages within the study, and will be 
summarized separately. The summary of symptoms associated with AEs defined by the 
investigator as being systemic/local injection site reactions will be displayed. 
AESIs of potential opportunistic infections, malignancies, serious cardiac, vascular and 
thromboembolic (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 source data 
lock for this study. Further details of how relevant preferred terms are identified for the 
AESIs are given in the Program Safety Analysis Plan (PSAP). 
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. 
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. 
 
COVID-19 Assessment and COVID-19 AEs 
Listing of COVID-19 assessment and COVID-19 AEs will be provided. 
Impact of COVID-19 Pandemic on Safety Results 
The impact of the COVID-19 pandemic on the safety results will be assessed. Pandemic 
measures began in different countries at different times. The start date of pandemic in 
China was Jan. 24th. 2020, which was determined by the GSK country Issue Management 
Teams (IMT), will be used in the following summaries. 
Summaries of the incidence rates of AEs, SAEs and severe AEs, before (AE onset date < 
pandemic measure start date) and after (AE onset date >= pandemic measure start date) 
the start of the COVID-19 pandemic will be produced. 


 
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4.5.3. 
Additional Safety Assessments  
Cardiovascular events 
The following cardiovascular events on treatment will be summarised and listed: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep vein thrombosis/pulmonary embolism 
• 
Revascularization 
 
Laboratory Data 
The change from baseline values on- and post- treatment for clinical chemistry and 
haematology will be summarised. Summaries of the data outside the normal range and 
the changes from baseline relative to the normal range will also be produced, including 
‘any time post-baseline’, which will include laboratory assessments taken at scheduled, 
unscheduled and Early Withdrawal visits and will report the most extreme value(s). Data 
from subjects who have values outside the normal range will be listed.  
Urinalysis results (screening only) will be listed. 
Vital Signs 
Pre-dose systolic blood pressure, diastolic blood pressure and pulse rate including change 
from baseline for on- and post- treatment will be summarised and listed. 
ECG 
Actual and change from baseline (for post-baseline timepoints) values for QTc(F) and 
heart rate including on- and post- treatment will be summarised by treatment for 
Baseline, Week 24, Week 52 and Withdrawal visit. ECG results will also be listed. 
Abnormal findings and interpretations will be listed separately. 
Individual maximum QTc(F) values will also be summarised to show the number of 
subjects with maximum values (msec) in the following categories: 
• 
<= 450 
• 
450 < to <= 480 
• 
480 < to <= 500 
• 
> 500 
Additionally, individual maximum changes from baseline in QTc(F) values will be 
summarised to show the number of subjects with maximum changes (msec) in the 
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• 
Increase of <=30 msec 
• 
Increase of >30-<=60 msec 
• 
Increase of >60 msec 
Liver Event 
Liver event information on- and post- treatment will be summarised and all subjects who 
report a liver event will be listed. 
Immunogenicity 
For the immunogenicity assessment, two types of anti-drug antibody (ADA) assays will 
be performed:  a binding antibody assay and a neutralizing antibody assay (NAb). 
 
For the binding assay, there will be a three-tiered analysis:  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. For positive 
confirmation samples, a titre value will also be obtained to quantify the degree of binding 
in a titration assay, and the sample will be tested with the neutralizing antibody assay, 
which also reports results as positive or negative. A sample that is positive in the 
confirmation assay is considered positive for anti-SB-240563 antibodies. 
A table will be produced summarising results for the ADA assay in the mITT Population. 
The highest binding ADA assay confirmatory result obtained post-baseline for a 
participant (including both on-treatment and post-treatment data, unscheduled and early 
withdrawal visits), will be summarised with a positive result being considered higher than 
a negative one, participants with both positive and negative results will be identified in 
the positive category. Descriptive statistics for titre results will also be presented. In 
addition, the highest NAb assay result during the same period will be summarised (again 
with a positive result being considered higher than a negative one and participants with 
both positive and negative results will be identified in the positive category).  
All ADA results (i.e. screening and confirmatory assay results, titre values) will be listed. 
A listing will also be produced results for the neutralising antibody assay in the mITT 
Population, by treatment group and visit. Neutralising antibody assay results will be 
categorised as follows: 
1. Negative 
2. Positive 
 
4.6. 
Pharmacodynamic Analyses 
Blood eosinophils on treatment will be summarised by treatment group and visit.  
Ratio to baseline at W52 will be analysed using a mixed model repeated measures 
(MMRM) analysis adjusting for covariates of treatment group, baseline, baseline 


 
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maintenance oral corticosteroids (OCS vs no OCS), baseline % predicted pre-
bronchodilator FEV1, exacerbations in the year prior to the study (as an ordinal variable 
(2, 3, 4+)), visit, plus interaction terms for visit by baseline and visit by treatment group. 
Blood eosinophil counts will be log transformed (loge) prior to analysis. The log 
transformation for values of 0 GI/L will be based on a value of 0.005 GI/L. Data will be 
log-transformed prior to analysis. Visit will be fitted as a categorical variable with the 
effect of treatment group and baseline varying at each visit (i.e. visit by baseline and visit 
by treatment group interactions will also be included in the model). 
 
To assess the robustness of Blood eosinophils results from the impacts of missing dose, 
the summary of blood eosinophils without missing dose will also be provided. If the 
subject has dose missing, the data after the first missing dose will be excluded. 
 
4.7. 
Pharmacokinetic Analyses 
4.7.1. 
Pharmacokinetic Concentration 
Concentrations will be determined at a number of time points over the whole treatment 
period, ranging from the first dose to last dose when steady state was achieved (Protocol 
Table 1).  
To minimize the potential impact of missing dose on observed plasma concentrations, 
only the mepolizumab plasma concentrations for which no missing dose occurring within 
approximate 5 half-life prior to the time of the SC administration will be summarized by 
visit, i.e., the concentrations at V2-1, V2-2 and V3 without missing dose at V2; the 
concentrations at V8 without missing dose at V4-7,  the concentrations at V14 without 
missing dose at V10-V13 and the concentrations at V14-1 to V15-2 without missing dose 
at V10-V14. Standard summary statistics will be calculated (i.e. mean, standard 
deviation, median, minimum, and maximum). 
All the records of concentrations will be listed. Individual concentration-time profiles and 
median/mean profiles with all records will be plotted on both a linear and semi-log scale. 
Protocol amendment 4 updated Study Day of V2-1 (from day 7 to day 8) and V2-2 (from 
day 14 to day15) to clarify the duration of PK sample collection in Section 1.2 of 
protocol. On final PK Sample ID form and related PK CRF forms in InForm System, 
“VISIT 2 PREDOSE” refers to “VISIT2 DAY1”, “VISIT 2 DAY7” refers “VISIT 2 
DAY8”, and “VISIT 2 DAY 14” refers to “VISIT 2 DAY15” in SoA. 
Concentrations that are below the LLQ (“lower limit of quantification”) are listed as NQ 
in the raw concentration data. For NQ at pre-dose at V2, it will be imputed as 0, for post 
first dose records, NQ will be imputed as NULL. 
4.7.2. 
Pharmacokinetic Parameters  
The pharmacokinetic parameters for PK data collected following the first dose (up to Day 
28/ Visit 3) and at steady state (i.e., at Visit 14 and 15) will be calculated by standard 


 
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non-compartmental analysis according to current working practices and using Phoenix 
WinNonlin, version 6.3 or above.  
• 
Pharmacokinetic parameters described in Table 1 will be calculated, if data permits. 
Particularly some directly determined parameters, e.g., Cmax or Tmax, might not be 
reported if the data are considered insufficient to produce.  
• 
All non-compartmental parameters will be calculated based on actual sampling 
times. 
Table 1 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
AUC(0-) 
Area under the concentration-time curve during the dosing interval at steady-state, 
i.e., 4 weeks for the study 
AUC(0-t) 
Area under the concentration-time curve for the last dose, will be calculated from 
predose on Visit 14 to the time of the last quantifiable concentration (C(t)) based on 
data collected after last dose, using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid 
Cmax 
Maximum observed concentration after single dose, determined directly from the 
concentration data collected after the first dose  
Cmax_ss 
Maximum observed concentration at steady state, determined directly from the 
concentration data collected after last dose at Visit 14.   
Cavg_ss 
Averaged concentration during the dosing interval at steady state, i.e., 4 weeks for the 
study 
Tmax 
Time to reach Cmax after single dose, determined directly from the data collected 
after the first dose 
Tmax_ss 
Time to reach Cmax at steady state, determined directly from the data collected after 
last dose at Visit 14 
Ctrough 
Trough concentration prior to dose at Visit 3 
Ctrough_ss 
Trough concentration prior to dose at steady-state (Visit 14) 
t½ 
Apparent terminal half-life will be calculated as (just for data collected after last dose 
at Visit 14):  
t½ = ln(2) / lambda_z  
CL_ss/F 
Apparent Clearance at steady state, calculated as: CL_ss/F = Dose / AUC(0-) 
Vz/F 
Apparent volume of distribution based on the terminal phase observed after last dose 
at Visit 14 
z, lambda_z 
Terminal phase rate constant  
 
All derived pharmacokinetic parameters described above will be summarised and listed.  
The parameters of Cmax, Tmax and Ctrough will be summarized at Visit 2, the rest of 
parameters in table 1 will be summarized at Visit 14. For each of these parameters the 
following summary statistics will be calculated: n, mean, 95% confidence interval for the 
mean, standard deviation, median, minimum, maximum, between coefficient of variation, 
geometric mean, 95% confidence interval for the geometric mean and standard deviation 
of log-transformed data. No statistical tests will be performed. 


 
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Between subject coefficient of variation (%CVb) for log-transformed data will be 
calculated according the following methods. 
%CVb=SQRT(exp(𝑆𝐷2)-1)*100 
Where SD is the standard deviation of the log-transformed data. 
 
4.7.3. 
Assessment of Accumulation Ratio 
To assess the extent of accumulation following mepolizumab multiple doses, the 
observed accumulation ratio (Ro) for mepolizumab will be determined as ratio of 
Cmax_ss (Cmax observed after last dose) to Cmax (Cmax observed after the first dose) 
and ratio of Ctrough_ss (Ctrough before the last dose) to Ctrough (Ctrough after the first 
dose) 
Ro(Cmax) = Cmax_ss / Cmax 
Ro(Ctrough) = Ctrough_ss / Ctrough 
 
Accumulation ratios of Cmax and Ctrough will be summarised using n, mean, 95% 
confidence interval for the mean, standard deviation, median, minimum, maximum, 
between coefficient of variation, geometric mean, 95% confidence interval for the 
geometric mean and standard deviation of log-transformed data, and listed.  
This pharmacokinetic statistical analysis will only be performed if sufficient data are 
available. 
4.7.4. 
Population Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Analysis 
If deemed necessary, the pharmacokinetic and/or pharmacodynamic data collected from 
the study may be combined with data from other studies for a population 
pharmacokinetic or pharmacokinetic/pharmacodynamic analyses. In that case, an analysis 
plan will be prepared independently. All eligible pharmacokinetic or pharmacodynamic 
data collected from the study will be included into the analyses. 
4.8. 
Interim Analyses 
No formal interim analysis is planned. 
4.9. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 04 (Dated: [18-NOV-2021]). 


 
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5. 
SAMPLE SIZE DETERMINATION 
5.1. 
Sample Size Assumptions 
The sample size of 300 participants (considering 256 evaluable participants and 
additional 44 subjects for drop-out) in a 1:1 ratio has been determined by the superiority 
testing of mepolizumab 100 mg SC vs. placebo, there will be 90% power to detect a 40% 
decrease in the exacerbation rate from 1.7 per annum (p.a.) on placebo to 1.02 p.a. on 
mepolizumab 100mg SC using a two sided 5% significance level. The calculation 
assumes the number of exacerbations per year follows a negative binomial distribution 
[Keene, 2007] with a dispersion parameter k=0.8. 
During the blinded evaluation, the clinically significant exacerbations occurred during the 
treatment period were analyzed using a generalized linear model assuming a negative 
binomial distribution and covariates of baseline maintenance OCS therapy (OCS vs. no 
OCS), EOS level at screening (>=300 cells/μL vs. <300 cells/μL), number of 
exacerbations in previous year (as an ordinal variable) and baseline disease severity (as % 
predicted FEV1). The blinded evaluation concluded, the overall event rate under blinded 
was observed as 0.78 p.a., the dispersion was 2.0.  
This reduction observed for overall events at blinded evaluation can be explained by a 
reduction in exacerbation events during the COVID-19 pandemic, which was not unique 
in China. , it is still expected that the treatment effect of Mepolizumab compared with 
placebo will be the same in Chinese SEA population as the original assumption. 
Therefore, according to the formula [Friede, 2010] 
𝜆̅ = (𝜆𝑇+ 𝜆𝑃)/2 
where 𝜆̅ is the overall events rate under blinded, the 𝜆𝑇 and 𝜆𝑃 are the event rates in the 
treatment and placebo groups, and assuming the reduction will keep the same as 40% 
under pandemic, the estimated event rates 𝜆𝑇 and 𝜆𝑃 for Mepolizumab 100mg SC and 
placebo are 0.585 and 0.975 p.a. respectively. On the other hand, there exists a difference 
for the estimate of dispersion when data is blinded or unblinded, so that the dispersion is 
adjusted by the difference between blinded and unblinded, which is 1.6=2.0 *(0.796 / 
0.972), where the dispersion in MEA115588 study were 0.796 (unblinded) vs. 0.972 
(blinded). 
Therefore, based on the conclusion on blinded evaluation, assuming a 40% decrease in 
the exacerbation rate from 0.975 per annum (p.a.) on placebo to 0.585 p.a. on 
mepolizumab 100mg SC, they will lead to a power of 66% implying a high false negative 
rate of 34% in China study. If there is a true reduction of 40% in exacerbation rate in 
Chinese patients, based on use of Bayesian dynamic borrowing with an initial weight of 
0.5 on global MEA115588 study result, there will be 88.6% probability to achieve a 
positive result (equivalent to the power of the study). 
The 40% reduction in exacerbation rate has been selected as reductions of this magnitude 
or greater have been seen in previous mepolizumab studies MEA112997 and 
MEA115588. However, it should be noted that a smaller reduction in exacerbations could 


 
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be clinically significant. Under the same assumptions, there will be 99% probability of 
showing consistent trend, which is defined as the point estimation of rate ratio between 
Mepolizumab and placebo<1 in China study, with global MEA115588. 
5.2. 
Sample Size Sensitivity 
The sample size in Section 5.1 is based on an expected reduction in this rate for subjects 
treated with mepolizumab.  If the expected reduction with mepolizumab differ then, at 
the given sample size there will be an effect on the probability of success of the study.  
Table 2 illustrates this effect on probability of success of varying reductions in rates with 
mepolizumab, assuming the sample size remains constant at 128 subjects in mepolizumab 
arm and 128 subjects in placebo arm, excluding the additional 44 subjects to account for 
early withdrawals from study treatment.  
Table 2 
Probability of meeting the success criterion conditional on various 
assumed true treatment effects 
Reduction 
0.45 
0.4 
0.35 
0 
Probabilities of Success 
94.6% 
88.6% 
80.0% 
11.8%* 
*The probability of success will equal with Type I error when there is no treatment effect for 
Mepolizumab compared with placebo. 
In the Table 2, the probabilities of meeting success are conducted under various assumed 
true treatment effects when overall event rate is fixed as 0.78 based on the blinded 
evaluation and dispersion is 1.6, e.g. when reduction is 40%, then the probability of 
success is calculated by the exacerbation rates for Mepolizumab 100mg SC and placebo 
as 0.585 and 0.975 p.a. respectively. Type I error is 11.8%, which is calculated when the 
event rate for each group is 0.78, adjusted dispersion is 1.6 based on analyses of blinded 
evaluation. 
5.3. 
Sample Size Re-estimation or Adjustment 
Blinded evaluation of exacerbation rates is planned for this study. A blinded evaluation of 
exacerbation rates for the purpose of sample size re-estimation will be done after 15 
months of enrolment, or when 225 subjects have been randomized, whichever is earlier. 
If the exacerbation rates for the study are lower than planned, a sample size re-estimation 
may be conducted. Any subsequent change to the planned number of subjects 
randomized would be documented in a protocol amendment.  
By the time of this protocol amendment, blinded evaluations of exacerbation rate were 
completed indicating the data deviate substantially from the assumptions made when we 
planned the trial, before the COVID-19 pandemic, thus supporting a protocol amendment 
to update the planned primary analyses without further adjustment of planned sample 
size. 


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the MITT 
Analysis Set. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
6.1.1. 
Participant Disposition 
A summary of the number of subjects included in each population will be produced.  
The proportion of screen failures, the proportion who reported each reason for screen 
failure will be presented for the ASE population. The number of randomized subjects 
who did not receive treatment will be listed. The reason of Inclusion, Exclusion, 
Randomization Criteria is failed for screening will be summarized for ASE population. 
The deviations for these criteria will be presented as well on MITT analysis set. 
The subject’s completion status will be presented as percentage of withdrawals from the 
study as well as the reasons for withdrawal. The number and percentage of subjects who 
completed through Week 52 and who withdrew, including the primary reasons for 
withdrawal, will be displayed. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of participants who have completed the scheduled study treatment or have 
discontinued study intervention prematurely, as well as primary reasons for 
discontinuation of study intervention. 
In addition, the subjects’ study completion status and treatment status will be summarized 
by related to COVID-19 and not related to COVID-19 respectively.  
The summary of study treatment impacted by COVID-19 will be provided. 
Visits and assessments missed due to the COVID-19 pandemic, together with visits 
conducted remotely, will be listed. 
The proportion of subjects in the MITT population at each centre will be presented.  
A listing will be provided of subjects who interrupted or discontinued IP, including 
reason and date of interruption or discontinuation.  
Subjects for whom the treatment blind was broken during the study will be listed. 
A listing of planned and actual treatments will be provided for each subject by Site ID, 
and Investigator name. 


 
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6.1.2. 
Demographic and Baseline Characteristics 
Demography  
Demographic characteristics (age, sex, ethnicity, race, height, weight and body mass 
index) will be summarised and listed. For age group, it also will by categorised by group: 
12-17 years, 18-29 years, 30-49 years, 50-64 years and >= 65 years. 
Randomization stratification factor 
Randomization stratification factor blood eosinophil count at screening(≥300 cells/μL 
and <300 cells/μL) will be presented by treatment group. A shift table of differences 
between stratification factor and as Randomized (data entered into the IWRS system) will 
be produced. 
Stratification factors (randomized and actual strata) will be listed for all subjects by 
treatment group. 
Medical Conditions 
The proportion of subjects who report medical conditions in each medical condition class 
will be presented, for current and past conditions separately. Current and past medical 
conditions will be listed. 
Cardiovascular Assessment 
A summary of the baseline cardiovascular assessment will be presented. The proportion 
of subjects who report a family history of medical conditions that may indicate 
predisposition towards cardiovascular conditions will be summarised. 
Asthma History and Tobacco Use 
Asthma history including duration of asthma (including derived age of onset), OCS use 
and exacerbations in the 12 months prior to Visit 1 will be summarised and listed. 
Asthma disease characteristics and causes of exacerbations will be summarised and 
listed. 
History of tobacco use will be summarised (i.e., non-smoker, former smoker). 
Screening and Baseline Lung Function Tests 
The following Screening (Visit 1) and (Visit 2) clinic lung function results will be 
summarised. Pre and post bronchodilator FEV1 will be listed in the same listing as the 
raw FEV1 listing in Section 4.3.2. The rest of the screening lung function results detailed 
below will be listed in a separate listing. 
• 
Pre and post bronchodilator FEV1 (mL) 
• 
Pre and post-bronchodilator percent predicted FEV1 (%) 
• 
Reversibility (in mL and in %) 
• 
Pre and post bronchodilator Forced Vital Capacity FVC (mL) 
• 
Pre and post bronchodilator FEV1/FVC 


 
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6.1.3. 
Protocol Deviations 
All protocol deviations, important protocol deviations and protocol deviations which will 
lead to exclusion from PP population will be summarized. Protocol deviations will also 
be listed for the MITT population. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations (where possible without knowing the study intervention 
details) are captured and categorised in the protocol deviations dataset.  
o This dataset will be the basis for the summaries of important protocol deviations. 
Protocol deviations which result in exclusion from the analysis set will also be 
summarized.  
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
deviations leading to analysis population exclusions are captured and categorised 
in the protocol deviations ADaM dataset (note these exclusions are not captured 
in the SDTM dataset).] 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced for important protocol deviations related to COVID-19, and important 
protocol deviations not related to COVID-19 respectively. 
The date of and the reason for breaking the study blind will be listed for the MITT 
population. 
6.1.4. 
Prior and Concomitant Medications 
The proportion of subjects reporting each concomitant medication will be presented. 
Multi-ingredient medications will be presented according to their combination ATC 
classification rather than the classifications of the ingredients. Summaries will be split 
into asthma and non-asthma concomitant medications, as well as into those taken pre-
treatment, during treatment and post-treatment. Asthma medications will be grouped for 
Respiratory Medications Classes as well, which are based on pre-defined code lists 
derived from ATC classifications: 
• 
Androgens and Estrogens 
• 
Anti-IgE, Anti-IL5 
• 
Antiinfectives (antibiotics, antiseptics) 
• 
Antimycotics 
• 
Antivirals 
• 
Beta 2 Agonist 
• 
Corticosteroid 
• 
Leukotriene Receptor Antagonist 
• 
Long-acting anticholinergic 


 
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• 
Long-acting beta-2 agonist – Group 2 (Once per day) 
• 
Long-acting beta-2 agonist – Group 3 (Twice per day) 
• 
Mucolytics 
• 
Nedocromil or Cromolyn Sodium 
• 
Oxygen 
• 
PDE4 Inhibitors 
• 
Short-acting anticholinergic 
• 
Short-acting beta-2 agonist 
• 
Theophylline 
• 
Xanthine 
Classification of a medication as pre-, on- or post-treatment will be made with reference 
to the study treatment start and stop dates and the medication start date. If the medication 
start date is missing or partial then the medication will be considered on-treatment unless 
there is evidence to the contrary (e.g. the month of the start date is present and is less than 
the month of the first dose of study medication). Medications with a start date of up to 4 
weeks after the last dose of treatment will be considered on-treatment. Medications with a 
start date after this period will be considered post-treatment. 
Pre- and on-treatment respiratory medications will be summarised separately. 
A medication will be summarised in every period (pre/on-/post) in which it was taken, so 
a medication that was started in the run-in and stopped during active treatment will 
appear in both the pre-treatment and the during treatment tables. 
The listings of all asthma and non-asthma concomitant medications will be provided. 
6.1.5. 
Study Intervention Compliance 
A summary of treatment compliance is not applicable to this study; however number of 
treatments received is summarised in the Extent of Exposure Section 4.5.1. 
 
6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Planned and Actual Treatment 
For participants who received the correct treatment throughout the study, the actual 
treatment will be the same as the planned treatment. For participants who received an 
incorrect treatment, the actual treatment will be derived as follows: 
• 
If the number of doses on an incorrect treatment is less than the number of doses on the 
planned treatment then the actual treatment is assigned as planned treatment. 
• 
If the number of doses on an incorrect treatment is equal to or greater than the 
number of doses on the planned treatment then the actual treatment is assigned as 
the incorrect treatment. 


 
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6.2.2. 
Analysis Period for Exacerbations and Efficacy Endpoints 
The analysis period defines the period of time over which exacerbations and efficacy 
assessments will be included in the on and/or off-treatment phases. The start and end of 
the analysis period is defined for subjects based on their study completion status as 
follows: 
Study 
Completion 
Start Date of Analysis Period 
End Date of Analysis Period 
Completed 
First dose of investigational 
product (Day 1) 
Earlier of Date of Week 52 visit 
or Date of last dose at Week 48 
+35 days [1] 
Withdrew early 
First dose of investigational 
product (Day 1) 
Earlier of Date reported on the 
study conclusion page or Date of 
last dose at Week 48 +35 days 
[1] 
[1] Based on protocol Section 4.1, the Exit Visit (Visit 15) represents the last day of study (i.e. 4 weeks 
after the last dose given at Visit 14), allowing for the ±7 days visit window, date of last dose at week 48+35 
days is defined as the upper bound of 7 days visit window for the date of last dose at week 48+28 days.  
 
6.2.3. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study treatment period.  
Study treatment period for Exacerbation 
Treatment period 
Definition 
Pre-Treatment 
Event start date < IP start date 
On-Treatment 
Subjects who did not withdraw early 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) 
 
Subjects who withdrew early from IP: 
Event onset date is on/after IP start date & on/before the earlier of 
the IP stop date+28 days/end of analysis period. 
(IP Start Date ≤ Event Start Date ≤ 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) 


 
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Note: the IP stop date is missing or the event start date is missing then the event 
considered on-treatment  
 
Study Treatment Period for Visit Based Efficacy Assessments 
Applicable to all visit-based efficacy assessment such as FEV1, SGRQ, ACQ, 
Subject Rated Response to Therapy, Clinician Rated Response to Therapy. 
Treatment period 
Definition 
Pre-Treatment 
Visit date < IP start date 
On-Treatment 
Subjects who did not withdraw early from IP: 
Visit date is after IP start date & on/before the end of analysis 
period. 
(IP Start Date < Visit Date ≤ end of analysis period) 
 
Subjects who withdrew early from IP: 
Visit date is after IP start date & on/before earlier of the IP stop 
date +28 days/end of analysis period. 
(IP Start Date < Visit Date ≤ earlier of IP Stop Date + 28 
days/end of analysis period) 
Off-Treatment  
(IP Stop Date + 28 days < Visit Date ≤ end of analysis period) 
Post-Treatment 
Visit Date > end of analysis period 
 
Study treatment Period for Adverse Events 
Treatment period 
Definition 
Pre-Treatment 
Event start date < IP start date 
On-Treatment 
IP start date ≤ Event start date ≤ IP stop date +28 days 
Post-Treatment 
Event start date > IP stop date +28 days 
Note: the IP stop date is missing or the event start date is missing then the event 
considered on-treatment  
 
Study Treatment Period for Visit Based Safety Assessments 
Applicable to all safety assessment such as vital signs, ECG, laboratory 
assessments: 
Treatment period 
Definition 
Pre-Treatment 
Visit date < IP start date 
On-Treatment 
IP start date ≤ Visit date ≤ IP stop date +28 days 
Post-Treatment 
Visit date > IP stop date +28 days 
Study Treatment Period for Concomitant Medications 
Treatment period 
Definition 
Pre-Treatment 
Concomitant medication (CM) start date < IP start date 
On-Treatment 
IP start date ≤ CM start date ≤ IP stop date +28 days 
Post-Treatment 
CM start date > IP stop date +28 days 


 
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Note: the IP stop date is missing and CM start date is on/after IP start date then CM 
considered on-treatment  
If CM start date is missing then CM considered on-treatment  
 
6.2.4. 
Length of Time in Phase for Exacerbations 
The length of time in a phase reflects for each subject 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 subject contributes information in each phase is detailed below. 
Phase 
Length of time (Days) in Phase 
On- and Off-treatment  
(Date of End of Analysis Period – IP Start Date) +1 
On-treatment  
Subjects who did not withdraw early from IP: 
(Date of End of Analysis Period – IP Start Date) +1 
 
Subjects who withdrew early from IP: 
(IP Stop Date – IP Start Date) +28+1 
Off-treatment 
Subjects who did not withdraw early from IP: 
0 days 
 
Subjects who withdrew early from IP: 
Date of End of Analysis Period – [IP Stop Date + 28 days] 
 
Subjects who withdraw early from the study with an analysis period which ends prior to 
Day 372 will be considered to have missing data for a period of time calculated as: (Day 
372-Date of End of Analysis Period) +1. 
6.2.5. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The efficacy reference date is the date of the study intervention start date and will be used 
to calculate study day for efficacy measures and baseline characteristics, as well as 
efficacy durations.  
The study day is calculated as below: 
Assessment Date = Missing              → Study Day = Missing  
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     


 
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6.2.6. 
Assessment Window  
Clinic visits are scheduled to take place as specified in the protocol. Measurements 
outside visit windows will not be excluded from analyses on any population. For all 
clinic visits, nominal visit days and times will be used for reporting, such that if a subject 
recorded values on the Week 4 visit that were actually made on Week 3 of treatment, 
they will be presented as Week 4 values. 
If a subject withdraws at a scheduled visit, and these data were scheduled to be collected 
at that visit, the data will be summarised and analysed (as appropriate) together with data 
from subjects who did not withdraw. If a subject withdraws at a scheduled visit at which 
these data were not scheduled to be collected, or if a subject withdraws between 
scheduled visits, data will be slotted to the next visit where the data was scheduled to be 
collected according to the study flowchart. The protocol visit windows of ±7 days should 
be applied to the assignment of withdrawal visits, so that if a subject withdraws within 
the appropriate number of days from the last visit where that data was scheduled to be 
collected, they would get that data slotted to that visit and otherwise the data will be 
slotted to the next scheduled visit. The early withdrawal visit with then be re-labelled as 
the corresponding visit. 
For unscheduled visits, excluding a subject’s baseline visit (where IP is initiated) or exit 
visit, the same logic will be applied. If a subject has an unscheduled assessment within 
the appropriate number of days (±7 days) from a visit where that data was scheduled to 
be collected, this data would be slotted to that visit and otherwise the data will be slotted 
to the next scheduled visit. Liver event and log visits will be excluded from summary 
tables, but included in the ‘any time post baseline’ data. 
If there is more than one assessment associated with a particular visit interval then the 
closest assessment will be used for summary tables and analyses. Where two or more 
ECG findings slot to the same visit interval, the most ‘abnormal’ results will be used, i.e. 
according to the following hierarchy: Abnormal-Clinically Significant > Abnormal – not 
clinically significant > Normal. 
6.2.7. 
Multiple measurements at One Analysis Time Point 
When triplicate ECG assessments are taken, mean of the measurement will be calculated 
first and summary statistics will be based on the calculated mean. This will apply to both 
baseline and post baseline assessments. 
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from a central lab will be taken over the test from a local lab. If multiple assessments 
are taken from the same type of lab, the worst case will be used. 
6.2.8. 
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 


 
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Element 
Reporting Detail 
imputed for ‘slotting’ data to study phases or for specific analysis purposes as 
outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events), or elapsed time 
variables (e.g., time since diagnosis). In addition, imputed dates are not used 
for deriving the last contact date in overall survival analysis dataset. 
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start 
day 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 1st 
of month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and year 
of study intervention start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date= 1st of 
month. 
▪ 
Else set start date = study intervention 
start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 
January 1. 
Else if study intervention start date is not missing: 
o If year of start date = year of study intervention 
start date, then 
▪ 
If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date = January 1. 
▪ 
Else set start date = study 
intervention start date.       
Else set start date = January 1. 


 
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Element 
Reporting Detail 
Missing end day  A '28/29/30/31' will be used for the day (dependent on 
the month and year). 
Missing end day 
and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and 
year of study intervention start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date= 1st of 
month. 
▪ 
Else set start date = study intervention 
start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 
Else if study intervention start date is not missing: 
o If year of start date = year of study intervention 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date = January 
1. 
▪ 
Else set start date = study. intervention 
start date.       


 
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Element 
Reporting Detail 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on 
the month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
the month. 
Completely 
missing start 
date 
No imputation 
Completely 
missing end date 
The date of last visit for this participant will be used 
 
6.2.9. 
Reversibility 
Subjects’ reversibility will be assessed at Screening (Visit 1). To determine reversibility, 
the subject will follow bronchodilator procedures as per the protocol. 
Reversible is defined as an increase in FEV1 of ≥12% and ≥200mL following 
administration of albuterol/salbutamol. 
Non-reversible is defined as a post-albuterol/salbutamol increase in FEV1 of <200mL or 
a ≥200mL increase that is <12% from pre-albuterol/salbutamol FEV1. 
 
6.2.10. 
Evaluation Process of Clinically Significant Asthma 
Exacerbations 
In order to provide an objective assessment of the circumstances linked to the clinical 
decision that defines asthma exacerbations, the investigator must take into account 
changes on one or more of the following parameters recorded in the subject’s eDiary: 
 
• decrease in morning peak flow 
• increase in the use of rescue medication 
• increase in the frequency of nocturnal awakening due to asthma symptoms 
requiring rescue medication use 
• increase in overall asthma symptom score 
 
This clinical verification process is designed to validate that the exacerbations recorded 
by the investigator are associated with objective evidence, such as the eDiary parameters 
described above. 
 
The following steps will be followed for verification of asthma exacerbations: 


 
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1. Clinical Review will be performed to evaluate each exacerbation to determine the 
event meets the protocol definition. Follow up will be done with the Primary 
Investigator in the event that data needs to be queried. 
2. The medical monitor will review each exacerbation in InForm and verify the 
exacerbation against eDiary data (extracted from the PHT Portal), to confirm the 
exacerbation was associated with one of the following: 
a. Decreases in peak flow: 
i. 
as flagged by an alert in the eDiary (Decrease in morning PEF 
≥30% on at least two of three successive days, compared with 
baseline (last 7 days of run-in)) or; 
ii. 
any other decrease judged by the medical monitor to be clinically 
significant 
b.      b. Increase in rescue medication use: 
i. 
as flagged by an alert in the eDiary (An increase of ≥50% in rescue 
medication on at least two of three successive days, compared with 
the average use for the previous week) or; 
ii. 
any other increase judged by the medical monitor to be clinically 
significant (e.g. ≥4 puffs in 2 or more consecutive days) 
c. Increase in nocturnal awakenings due to asthma symptoms requiring use 
of rescue  
i. 
as flagged by an alert in the eDiary (Awakening due to asthma 
symptoms requiring successive nights) or; 
ii. 
any other increase judged by the medical monitor to be clinically 
significant 
d. Changes in Asthma Symptoms (increase in overall asthma symptom 
score): 
i. 
as flagged by an alert in the eDiary (A symptom score of 5 for at 
least two of three successive days) or; 
ii. 
any other change judged by the medical monitor to be clinically 
significant (e.g. ≥4 during 2 or more consecutive days when 
baseline is 0) 
3. The medical monitor will review data in the eDiary 10 days prior to the event start 
date and 5 days post the event start date in exceptional circumstances data from 
outside this window may be considered adequate evidence. 
4. The medical monitor will tick the relevant check-box (i.e. peak flow; rescue med 
use; nocturnal awakenings; asthma symptoms) based on whether there is objective 
evidence available (as described above) and confirm that the exacerbation is 
clinically significant. 
5. For each exacerbation for which objective evidence is not available in the eDiary 
data the medical monitor will follow up with the primary investigator to 
determine if there is alternative objective data (not in the eDiary) to support it 
being a clinically significant exacerbation. 


 
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6. A final decision will be made on whether exacerbations with no supporting 
eDiary data but possibly other objective data can be included as part of the 
primary endpoint analysis of clinically significant exacerbations. 
7. If an exacerbation with no eDiary data to support it is deemed as having another 
source of objective evidence, this will be updated in the comments section of the 
InForm adjudication page to clearly specify what evidence is supporting the 
decision. 
 
In the event that the primary investigator is unable to provide objective evidence to 
support the exacerbation, then the event will be reported as “Investigator- defined” 
exacerbation and it will only be included as part of the sensitivity analysis of the primary 
analysis. If the medical monitor deems the exacerbation to be clinically significant based 
on evidence provided by the primary investigator, it will be included as part of the 
primary endpoint analysis. 
 
6.2.11. 
eDiary Data 
The following assessments will be collected on a daily basis using an eDiary device: 
morning peak flow, usage of rescue medication (i.e. salbutamol/albutamol), asthma 
symptom score and frequency of awakening due to asthma symptoms requiring use of 
rescue medication. These data will be summarised in 4-weekly periods, as shown in the 
below table. 
Reporting Period First Day Included 
Last Day Included 
Baseline 
7 days prior to day of first dose 
Date of first dose 
Weeks 1-4  
Day after day of first dose  
28 days after day of first dose 
Weeks 5-8 
29 days after day of first dose 
56 days after day of first dose 
Weeks 9-12 
57 days after day of first dose 
84 days after day of first dose 
Weeks 13-16 
85 days after day of first dose 
112 days after day of first dose 
Weeks 17-20  
113 days after day of first dose 
140 days after day of first dose 
Weeks 21-24 
141 days after day of first dose 
168 days after day of first dose 
Weeks 25-28  
169 days after day of first dose 
196 days after day of first dose 
Weeks 29-32 
197 days after day of first dose 
224 days after day of first dose 
Weeks 33-36 
225 days after day of first dose 
252 days after day of first dose 
Weeks 37-40 
253 days after day of first dose 
280 days after day of first dose 
Weeks 41-44  
281 days after day of first dose 
308 days after day of first dose 
Weeks 45-48 
309 days after day of first dose 
336 days after day of first dose 
Weeks 49-52 
337 days after day of first dose 
Week 52 visit date (or 364 days 
after day of first dose, if earlier) 
 
6.2.12. 
Computation of Age 
Each subject’s age will be calculated based on their date of birth relative to the date of the 
screening visit. Where only a subject’s year of birth is collected, their date of birth will be 
imputed with 30th June (30 Jun YYYY). 


 
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6.2.13. 
Reasons for Exclusion from the Per Protocol Analysis 
Subjects with protocol deviations considered to potentially have an effect on efficacy will 
be removed from the Per Protocol (PP) population. Determination of the Per Protocol 
population will be done blinded to treatment before the database is frozen. The reason for 
exclusion for any subject will be documented. 
Reasons for exclusion from the PP population may be included: 
• No persistent airflow obstruction as indicated by pre-bronchodilator FEV1 <80% 
predicted (NHANES III) for subjects ≥ 18 years of age recorded at Visit 1 
(predicted pre-bronchodilator FEV1 <90% or FE1/FVC <0.8 for subjects 12 to 17 
years of age) (see Inclusion Criterion 3) 
• Absence of regular treatment with high dose ICS (ICS dose must be ≥500 
mcg/day fluticasone propionate (FP) or equivalent daily (for ICS/LABA 
combination preparations, Seretide 50/250 mcg bid and above or equivalent will 
meet this ICS criteria).) in the 12 months prior to Visit 1, of which at least 9 
months accumulated documented is required (see Inclusion Criterion 5) 
• Absence of current treatment with one or more additional controller medication, 
besides ICS, and at least one additional controller medication must have been 
regularly used for at least 3 months prior to Visit 1. (see Inclusion Criterion 6) 
• No eosinophilic airway inflammation (see Randomization Criterion 1) as defined 
by: 
o Peripheral blood eosinophil level of ≥300 cells/μL documented in the 12 
months prior to visit 1 that is related to asthma OR 
o Peripheral blood eosinophil level of ≥150 cells/μL demonstrated at Visit 
1 that is related to asthma 
• <2 asthma exacerbations in the 12 months prior to Visit 1 (see Inclusion 
Criterion7) 
• No evidence of asthma (see Randomization Criterion 2) as documented by either: 
o Airway reversibility (FEV1≥12% and 200ml) demonstrated at Visit 1 or 
Visit 2 OR 
o Airway reversibility (FEV1≥12% and 200ml) documented in the 
12months prior to visit 2 (randomization visit) OR 
o Airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 μmol 
methacholine/histamine or positive mannitol test) documented in the 12 
months prior to visit 2 (randomization visit) OR 
o Airflow variability in clinic FEV1 ≥20% between two clinic visits 
documented in the 12 months prior to visit 2 (randomization visit) ( FEV1 
recorded during an exacerbation will not be valid) OR 
o Airflow variability as indicated by >20% diurnal variability in peak flow 
observed on 3 or more days during the run-in 
• Use of omalizumab (Xolair) within 130 days of Visit 1 (see Exclusion Criteria 14) 
• Use of omalizumab (Xolair) or other prohibited medication during the study 
• Breaking of the blind at any point during the study 
• Receiving the wrong study treatment at any point during the study 
• >=2 consecutive dose missing 


 
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6.2.14. 
Daily Corticosteroid Dose Administered for an Exacerbation 
Only corticosteroids administered via oral, IV and IM routes are to be considered when 
calculating a subject’s daily prednisone/prednisolone dose associated with an 
exacerbation. All steroids administered via a sublingual route will also be considered as 
oral. 
The below corticosteroid conversion factors will be used, regardless of the route of 
administration, to scale each corticosteroid dose to a prednisone equivalent dose. These 
three routes of administration (oral, IV and IM) are to be considered equivalent as it has 
been noted that the bioavailability of methylprednisolone is considered to be roughly 
equivalent following administration as an oral, IV or IM steroid [Kenalog-40 prescribing 
information, 2011; Antal, 1983]. If there are seen to be two corticosteroid records 
associated with an exacerbation that are seen to overlap on a particular study day, these 
overlapping records will be summed in order to obtain a total prednisone/prednisolone 
equivalent dose for the day in question. 
Standardized Medication Name  
Scaling Factor 
Betamethasone  
8.33 
Betamethasone Dipropionate  
8.33 
Betamethasone Sodium Phosphate  
8.33 
Cortisone  
0.2 
Cortisone Acetate  
0.2 
Cortivazol  
17 
Deflazacort  
0.833 
Dexamethasone  
6.67 
Dexamethasone Sodium Phosphate  
6.67 
Dexamethasone Acetate 
6.67 
Fludrocortisone Acetate  
0 
Hydrocortisone  
0.25 
Hydrocortisone Sodium Succinate  
0.25 
Hydrocortisone Sodium Phosphate  
0.25 
Meprednisone  
1 
Methylprednisolone  
1.25 
Methylprednisolone Acetate  
1.25 
Methylprednisolone Sodium Succinate  
1.25 
Methylprednisone  
1.25 
Methylprednisone Acetate  
1.25 
Prednisolone  
1 
Prednisolone Acetate  
1 
Prednisolone Hemisuccinate  
1 
Prednisolone Sodium Succinate 
1 


 
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Standardized Medication Name  
Scaling Factor 
Prednisone 
1 
Prednisone Acetate  
1 
Triamcinolone  
1.25 
Triamcinolone Acetonide  
1.25 
 
6.2.15. 
Early PK Access Key Activities 
No early PK access before database freeze. 
6.3. 
Appendix 3 Model Checking and Diagnostic for Statistical 
Analyses 
Endpoints 
Exacerbation endpoints 
Analysis 
Negative Binomial Model 
Missing data is assumed missing at random. Departures from this assumption will be 
tested for the primary endpoint. 
If model fails to converge due to limited events, the covariates in the model may be 
removed. 
Endpoints 
Exacerbation endpoints 
Analysis 
Mixed Model Repeated Measures 
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. An unstructured covariance structure for the R matrix will be used by specifying 
‘type=UN’ on the REPEATED line. 
If this model fails to converge, alternative correlation structures may be considered, 
e.g. Heterogeneous AR (type=ARH(1)) or Heterogeneous CS (type=CSH) or others if 
applicable. 
 
Endpoints 
Time to first event (exacerbation) 
Analysis 
Cox proportional hazard method 
The Kaplan Meier method for computing survival function estimates will be used 
(Method = KM). 
 


 
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Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
WinNonlin 
 
 
SAS 
 
 


 
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7. 
REFERENCES 
Antal E.J., Wright III C.E., Gillespie W.R., Albert K.S. Influence of Route of 
Administration on the Pharmacokinetics of Methylprednisolone. Journal of 
Pharmacokinetics and Biopharmaceutics. 1983;11.6:561-576. 
Barnard J, Rubin D. Small Sample Degrees of Freedom with Multiple Imputations. 
Biometrika. 1999;86:948-955. 
Carpenter JR, Roger JH, Kenward MG. Analysis of Longitudinal Trials with Protocol 
Deviations: a Framework for Relevant, Accessible Assumptions, and Inference via 
Multiple Imputation. Journal of Biopharmaceutical Statistics (accepted for publication). 
2013; N/A:N/A. 
Friede T, Schmidli H. Blinded Sample Size Reestimation with Negative Binomial Counts 
in Superiority and Non-inferiority Trials. Methods Inf Med. 2010;49:618-624. 
Keene ON, Jones M, Lane P, Anderson J. Analysis of Exacerbation Rates in Asthma and 
Chronic Obstructive Pulmonary Disease: Example from TRISTAN Study. Pharm Stats. 
2007;6:89-97. 
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing Data Sensitivity Analysis for 
Recurrent Event Data Using Controlled Imputation. Pharmaceutical Statistics. 
2014;13:258-264. 
Kenalog-40 prescribing information, KENALOG®-10 INJECTION prescribing 
information. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/012041s039lbl.pdf. August 
2011. 
Schmidli H, Gsteiger S, Roychoudhury S, O’Hagan A, Spiegelhalter D, Neuenschwander 
B. Robust meta-analytic-predictive priors in clinical trials with historical control 
information. Biometrics. 2014;70:1023-1032.