Clinical trial NCT04276233
Conditions: Asthma
Keywords: Mepolizumab Oral corticosteroids Prednisolone Prednisone Severe Eosinophilic asthma
Sponsor: GlaxoSmithKline
Start date: 2021-06-29; Completion date: 2023-10-28
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa) that blocks interleukin- 5 (IL-5) thus inhibits production and survival of eosinophils. The aim of this phase 4, open-label, single-arm study is to evaluate the safety and efficacy of Mepolizumab 100 mg SC administered every 4 weeks in Indian participants aged 18 years or above with severe eosinophilic asthma. After the first dose of mepolizumab, participants will receive 5 more doses of mepolizumab at 4 weekly intervals. Following the last dose of mepolizumab, the end of the study Visit will occur 4 weeks later. During the treatment period, OCS use and dose adjustment in participants will be as per the investigator's discretion and clinical practice.

Detailed description:

Arms: arm 1: Participants with severe eosinophilic asthma will receive Mepolizumab 100 mg subcutaneously into the upper arm or thigh every 4 weeks for a period of 24 weeks (total of 6 doses). Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.
Interventions: intervention 1: Mepolizumab intervention 2: Salbutamol
Intervention descriptions: intervention 1: Mepolizumab will be available as a lyophilized cake in sterile vials and will be reconstituted with sterile water for injection, just prior to use. intervention 2: Salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.

Protocol documents:
Prot_000.pdf: 
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The GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A Phase 4, open-label, single arm, 24-week, study to evaluate the safety 
and efficacy of mepolizumab 100 mg SC administered every 4 weeks in Indian 
participants aged ≥18 years with Severe eosinophilic asthMa (PRISM) 
Protocol Number: 209682 [Amendment 04] 
Compound Number:     SB240563 
Study Phase: Phase 4   
Short Title: Phase 4 study of mepolizumab 100 mg SC in Indian participants aged ≥18 
years with severe eosinophilic asthma  
Acronym: PRISM 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Sponsor Contact Address 
GlaxoSmithKline Pharmaceuticals Ltd., 
Dr. Annie Besant Road 
Worli, Mumbai - 400030 
Telephone: +91 22 24959595 
Medical Monitor Name and Contact Information Will be provided separately  
SPONSOR SIGNATORY 
Dr. Robert Chan 
Senior Clinical Development Director and Clinical 
Development Leader Mepolizumab, 
Clinical Sciences, GSK R&D 
Approval Date: 23 Aug 2022 
 
 
Sponsor Serious Adverse Events (SAE) Contact Information:  
Email: india.pharmacovigilance@gsk.com  
xPhone: +91-8657549542 
Regulatory Agency Identifying Number(s): [Regulatory Agency identifying 
number(s) as appropriate] 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 4 
23 Aug 2022 
TMF-14888313 
Amendment 3 
17-MAR-2021 
TMF-11899446 
Amendment 2 
05-NOV-2020 
2018N383582_01 
Amendment 1 
27-AUG-2019 
2018N383582_00 
Original Protocol 
18-JAN-2019 
2018N383582_00 
 
Amendment – 4 
Overall Rationale for the Amendment:  
Inclusion criteria no. 5 has been updated to align with the current management practice of 
SEA which does not include use of stable OCS use for prolonged periods of time and the 
changes are in line with Prescribing information of the product. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis,  
2.1 Study Rationale,  
2.3.1 Risk Assessment,  
2.3.2 Benefit 
Assessment,  
4. Study Design 
The requirement of oral 
corticosteroids (OCS) and 
associated phases (Induction 
phase, optimization phase, OCS 
reduction/Maintenance phase) 
has been removed.  
 
 
 
OCS requirement has been 
removed to align with the current 
management practice of SEA 
which does not include use of 
stable OCS use for prolonged 
periods of time and the changes 
are in line with prescribing 
information of the product.   
1.2 Schema,  
4.1 Overall Design 
The schema has been updated 
with respect to the removal of 
OCS  
Schema has been updated as OCS 
information is no longer required. 
1.3 Schedule of 
Activities (SoA) 
SoA has been updated for the 
removal of information regarding 
OCS and associated phases.  
OCS requirement has been 
removed to align with the current 
management practice of SEA 
which does not include use of 
stable OCS use for prolonged 
periods of time and the changes 
are in line with prescribing 
information of the product . 
Stringency of spirometry timings 
(i.e. must be performed at the 
same time ±1 hour of the visit 1) 
has been removed. 
To allow flexibility for the patients 
by broadening the time window 
for the spirometry within the day 
of the study visit. 
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Section # and Name 
Description of Change 
Brief Rationale 
Advisory statement for 12-Lead 
ECG has been added. 
To maintain the uniformity across 
the protocol. 
Serum IgE (total) - Serum IgE 
has been removed from week 24 
and IP discontinuation visit 
Assessment of change from 
baseline is not an objective or 
endpoint of the study 
3.0 Objectives and 
Endpoints  
 
 
Only a subset of patients (those 
completing or withdrawn from the 
study prior to protocol amendment 
4) will be assessed for this 
endpoint where a structured OCS 
tapering schedule was mandated 
within the previous study 
protocols and protocol 
amendments 
Description of estimands have 
been added for all primary, 
secondary and exploratory 
endpoints 
The rationale to add estimands is 
that estimands provide the precise 
description of what is being 
estimated for primary endpoints 
also explain about how to deal 
with intercurrent events which 
may occur during the study. 
5 Study Population 
6 Study Intervention  
8 Efficacy Assessments 
Inclusion criteria 5 has been 
updated with respect to the 
removal of requirement for 
background systemic 
corticosteroids.  
Information regarding OCS 
phases has also been removed. 
 
 
  
OCS requirement has been 
removed to align with the current 
management practice of SEA 
which does not include the use of 
a stable OCS dose for prolonged 
periods of time and the changes 
are in line with prescribing 
information of the product. 
 
Only a subset of patients (those 
completing or withdrawn from the 
study prior to protocol amendment 
4) will now be assessed for the 
 
 
 
Further additional details have 
been added regarding the efficacy 
endpoints. 
Further additional clarifying text 
has been inserted regarding the 
efficacy endpoints to be studied 
under this protocol. 
8.1.2 Number rate of 
clinically significant 
Clinically significant 
exacerbations definition with 
Additional clarifying text has been 
inserted regarding the definition of 
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Section # and Name 
Description of Change 
Brief Rationale 
exacerbations 
further clarifications added. 
a clinically significant 
exacerbation for consistent 
reporting across all patients. 
8.2.4 
Electrocardiograms 
The recommendation of triplicate 
12-lead ECG within 4 minutes 
duration has been removed.  
To reduce the burden to 
participants as a single twelve-lead 
ECG obtained at each timepoint 
specified in the Schedule of 
Activities (Section 1.3) is 
considered appropriate.  Triplicate 
ECGs are required only if routine 
single ECG demonstrates a 
prolonged QT interval to obtain 
the averaged QTc in order to 
determine whether the patient 
should be discontinued from the 
study 
9.1 Statistical 
Hypothesis 
No hypothesis testing is to be 
performed for this study. 
Sample size has been re-estimated 
based on probability of observing 
adverse events  
9.2 Sample Size 
Determination 
Sample size has been re-
estimated based on primary 
endpoint and associated 
probabilities tables added.  
The primary objective of study to 
evaluate the safety and tolerability 
of mepolizumab by descriptive 
statistics hence the sample size 
section has been updated to now 
be aligned with the primary 
objective.  
9.3 Population for 
analyses 
Enrolled Population definition 
has been updated and Per 
Protocol Population has been 
removed. 
Enrolled Population definition is 
modified for summarizing reasons 
for screen and run-in failures. 
Inclusion criteria 5 is updated 
therefore no statistical analysis 
required of the Per Protocol 
Population.  
9.4 Statistical Analyses 
9.4.1 Safety Analyses 
Further details on the reporting of 
the primary estimand have been 
inserted. 
 
 
 
. 
Further additional clarifying text 
has been inserted regarding the 
safety endpoints. 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Subgroup analysis have been 
added using baseline OCS use 
(yes, no) for separate subgroup 
reporting.  
Statistical and subgroup analysis 
has been updated for the separate 
reporting of subjects receiving 
baseline OCS use (yes, no). 
9.4.2 Efficacy Analyses 
 
. 
 
Further details on the estimation 
of secondary estimands has been 
added. Statistical analysis for 
secondary endpoints is updated 
with baseline OCS use (yes, no) 
included as a covariate within the 
analysis model. 
 
 
. 
Further additional clarifying text 
has been inserted regarding the 
efficacy endpoints. 
9.4.3 Health Outcomes 
Analyses 
 
 
.  
Further additional clarifying text 
has been inserted regarding the 
reporting of the health outcomes 
endpoints. 
10.3.5 Reporting of SAE 
to GSK 
The information for reporting 
SAE to GSK has been updated. 
To be consistent with the current 
mode of transmission of safety 
information as per agreed local 
practice. 
 
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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 9 
1.1. 
Synopsis ....................................................................................................... 9 
1.2. 
Schema ...................................................................................................... 13 
1.3. 
Schedule of Activities (SoA) ........................................................................ 14 
2. 
INTRODUCTION .................................................................................................... 20 
2.1. 
Study Rationale .......................................................................................... 20 
2.2. 
Background ................................................................................................ 20 
2.3. 
Benefit/Risk Assessment ............................................................................ 22 
2.3.1. Risk Assessment ........................................................................................ 23 
2.3.2. Benefit Assessment .................................................................................... 25 
2.3.3. Overall Benefit: Risk Conclusion ................................................................. 25 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 26 
4. 
STUDY DESIGN .................................................................................................... 29 
4.1. 
Overall Design ............................................................................................ 29 
4.1.1. Screening 30 
4.1.2. Treatment period ......................................................................................... 30 
4.1.3. IP Discontinuation Visit ............................................................................... 30 
4.2. 
Scientific Rationale for Study Design .......................................................... 31 
4.3. 
Justification for Dose .................................................................................. 31 
4.4. 
End of Study Visit ....................................................................................... 31 
5. 
STUDY POPULATION ........................................................................................... 32 
5.1. 
Inclusion Criteria ......................................................................................... 32 
5.2. 
Exclusion Criteria ........................................................................................ 34 
5.3. 
Treatment Period Criteria ............................................................................ 36 
5.4. 
Lifestyle Considerations .............................................................................. 36 
5.4.1. Caffeine, Alcohol, and Tobacco................................................................... 36 
5.5. 
Screen Failures........................................................................................... 37 
6. 
STUDY INTERVENTION ........................................................................................ 37 
6.1. 
Study Intervention(s) Administered ............................................................. 37 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 38 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 39 
6.4. 
Study Intervention Compliance ................................................................... 39 
6.5. 
Concomitant Therapy.................................................................................. 39 
6.5.1. Rescue Medicine ........................................................................................ 39 
6.5.2. Permitted Medications and Non-Drug Therapies ......................................... 40 
6.5.3. Prohibited Medications and Non-Drug Therapies ........................................ 40 
6.6. 
Dose Modification ....................................................................................... 41 
6.7. 
Intervention after the End of the Study ........................................................ 41 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 41 
7.1. 
Discontinuation of Study Intervention .......................................................... 41 
7.1.1. Liver Chemistry Stopping Criteria ................................................................ 41 
7.1.2. QTc Stopping Criteria .................................................................................. 43 


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7.1.3. Temporary Discontinuation ......................................................................... 44 
7.1.4. COVID-19 testing ........................................................................................ 44 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 44 
7.3. 
Lost to Follow Up ........................................................................................ 45 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 46 
8.1. 
Efficacy Assessments ................................................................................. 46 
8.1.1. Efficacy Endpoints....................................................................................... 46 
8.1.2. Number of clinically significant exacerbations (including 
exacerbations requiring hospitalization or ED visits) .................................... 47 
8.1.3. Pulmonary Function Testing including Reversibility using the 
Maximum Post-Bronchodilator Method ........................................................ 48 
8.1.4. eDiary 
48 
8.1.5. Asthma Control Questionnaire-5 (ACQ-5) ................................................... 49 
8.1.6. Clinician/Participant Rated Response to Therapy ....................................... 49 
8.1.7. Work Productivity and Activity Impairment Questionnaire: General 
Health (WAPI-GH)....................................................................................... 50 
8.2. 
Safety Assessments ................................................................................... 50 
8.2.1. Safety Endpoints ......................................................................................... 50 
8.2.2. Physical Examinations ................................................................................ 50 
8.2.3. Vital Signs ................................................................................................... 51 
8.2.4. Electrocardiograms ..................................................................................... 51 
8.2.5. Steroid withdrawal examination review, where applicable ........................... 51 
8.2.6. Clinical Safety Laboratory Assessments ..................................................... 52 
8.2.7. Suicidal Ideation and Behaviour Risk Monitoring ......................................... 52 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 52 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ........... 53 
8.3.2. Method of Detecting AEs and SAEs ............................................................ 53 
8.3.3. Follow-up of AEs and SAEs ........................................................................ 53 
8.3.4. Regulatory Reporting Requirements for SAEs ............................................ 54 
8.3.5. Pregnancy ................................................................................................... 54 
8.3.6. Cardiovascular and Death Events ............................................................... 54 
8.4. 
Treatment of Overdose ............................................................................... 55 
8.5. 
Pharmacokinetics ....................................................................................... 55 
8.6. 
Pharmacodynamics .................................................................................... 55 
8.7. 
Genetics ..................................................................................................... 55 
8.8. 
Biomarkers ................................................................................................. 55 
8.8.1. Immunogenicity Assessments ..................................................................... 55 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................. 56 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 56 
9.1. 
Statistical Hypotheses................................................................................. 56 
9.2. 
Sample Size Determination ........................................................................ 56 
9.3. 
Populations for Analyses ............................................................................ 57 
9.4. 
Statistical Analyses ..................................................................................... 57 
9.4.1. Safety Analyses .......................................................................................... 58 
9.4.2. Efficacy Analyses ........................................................................................ 58 
9.4.3. Health Outcomes Analyses ......................................................................... 60 
9.5. 
Interim Analyses ......................................................................................... 60 
9.5.1. Data Monitoring Committee (DMC) ............................................................. 61 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 62 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 62 
10.1.1. Regulatory and Ethical Considerations ........................................................ 62 
10.1.2. Financial Disclosure .................................................................................... 62 
10.1.3. Informed Consent Process .......................................................................... 63 
10.1.4. Data Protection ........................................................................................... 63 
10.1.5. Committees Structure ................................................................................. 63 
10.1.6. Dissemination of Clinical Study Data ........................................................... 64 
10.1.7. Data Quality Assurance .............................................................................. 64 
10.1.8. Source Documents...................................................................................... 65 
10.1.9. Study and Site Closure ............................................................................... 65 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 67 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 69 
10.3.1. Definition of AE ........................................................................................... 69 
10.3.2. Definition of SAE ......................................................................................... 70 
10.3.3. Definition of Cardiovascular Events ............................................................. 71 
10.3.4. Recording and Follow-Up of AE and SAE ................................................... 71 
10.3.5. Reporting of SAE to GSK ............................................................................ 74 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 75 
10.4.1. Definitions: .................................................................................................. 75 
10.4.2. Contraception Guidance:............................................................................. 76 
10.4.3. Collection of Pregnancy Information: ........................................................... 77 
10.5. 
Appendix 5: New York Heart Association Functional Classification 
of Congestive Heart Failure ........................................................................ 78 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 79 
10.7. 
Appendix 7: Anaphylaxis Criteria ................................................................ 82 
10.8. 
Appendix 8 : Daily Asthma Symptom Score ................................................ 83 
10.9. 
Appendix 9 - Criteria for e-Diary Alerts Indicative of a Potential 
Asthma Worsening ..................................................................................... 84 
10.10. Appendix 10: Study Procedures during COVID-19 Pandemic ..................... 85 
10.11. Appendix 11: Abbreviations and Trademarks .............................................. 90 
10.12. Appendix 12: Protocol Amendment History ................................................. 91 
11. REFERENCES ....................................................................................................... 93 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 4, open-label, single arm, 24-week, study to evaluate the safety 
and efficacy of Mepolizumab 100 mg SC administered every 4 weeks in Indian 
participants aged ≥18years with Severe eosinophilic asthma(PRISM). 
Short Title: Phase 4 study of mepolizumab 100 mg SC in Indian participants aged ≥18 
years with severe eosinophilic asthma  
Rationale: 
Indian Regulatory authorities have approved marketing of mepolizumab in India for the 
treatment of severe eosinophilic asthma based on data from multi-centre, multi-national 
studies. However, these studies did not include India as a participating country. As part of 
the approval process, the agency has asked for data to be generated in the Indian 
population. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• To evaluate the safety, and tolerability 
of mepolizumab in participants with 
severe refractory asthma with elevated 
eosinophils 
The primary estimand will be defined by the following: 
Endpoints: 
• 
Incidence of on-treatment adverse events 
(AEs), serious adverse events (SAEs) and adverse 
events of special interest (AESIs) 
Summary measure: 
• 
Counts and percentages for incidence of at 
least one AE will be summarised overall, by system 
organ class and by preferred term 
Population of interest:  
• Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• Discontinuation of treatment (for any reason) 
Strategy for intercurrent events: 
• While on-treatment strategy will be used for 
treatment discontinuation. This will estimate the 
percentage of participants experiencing an AE, 
while receiving treatment.  
AEs will be defined as on-treatment between the 
first dose up to and including 28 days following the 
last dose of mepolizumab. 
 
 
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Objectives 
Endpoints 
identical properties as for the primary estimand 
(summary measure, population of interest and key 
intercurrent events), however this supplementary 
estimand will report all AEs regardless of the 
discontinuation of study treatment. 
Endpoints: 
• 
Incidence of AEs and SAEs 
Strategy for intercurrent events: 
• Treatment policy strategy will be used for treatment 
discontinuation. This summary will therefore be 
inclusive of all on-treatment and post-treatment 
AEs. 
 
Secondary 
• 
To 
evaluate 
the 
efficacy 
of 
mepolizumab in participants with 
severe refractory asthma with elevated 
eosinophils 
The following secondary estimand is defined by the 
following: 
Endpoints: 
• 
Number of clinically significant exacerbations 
(including exacerbations requiring hospitalization 
or ED visits) 
• 
Number of exacerbations requiring hospitalization 
or ED visits 
• 
Number of exacerbations requiring hospitalization 
Summary measure: 
• 
Rate ratio comparing events/year during the 24-
week follow-up period compared to the 12 months 
prior to screening 
Population of interest:  
• 
Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• 
Discontinuation of treatment (for any reason) 
Strategy for intercurrent events: 
Treatment policy strategy will be used for treatment 
discontinuation. This will estimate the treatment effect 
over the 24 week study period regardless of treatment 
discontinuation. 
 
The remaining secondary estimands are defined by the 
following: 
Endpoints: 
• 
Change from baseline in clinic pre-bronchodilator 
FEV1 at week 24 
• 
Change from baseline in clinic post-bronchodilator 
FEV1 at week 24 
• 
Change from baseline in ACQ-5 score at week 24 


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Objectives 
Endpoints 
• 
Change from baseline in morning PEF during 
weeks 20 - 24  
Summary measure: 
• 
Mean change from baseline in clinic pre-
bronchodilator FEV1 at week 24 
• 
Mean change from baseline in clinic post-
bronchodilator FEV1 at week 24 
• 
Mean change from baseline in ACQ-5 score at 
week 24 
• 
Mean change from baseline from baseline in 
morning PEF during weeks 20 – 24 
Population of interest:  
• 
Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• 
Discontinuation of treatment (for any reason) 
Strategy for intercurrent events: 
• 
Treatment policy strategy will be used for 
treatment discontinuation. This will estimate the 
treatment effect at the end of the 24 week study 
period regardless of treatment discontinuation  
Exploratory  
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Objectives 
Endpoints 
 
Overall Design: 
This is a multi-centre, open-label, single arm 24-week study.   
During this study, all participants will remain on their existing maintenance asthma 
therapy throughout this study as per investigator’s discretion, in addition to receiving 
mepolizumab 100 mg SC. OCS use and OCS dose adjustment in participants will be as 
per the investigator’s discretion and clinical practice. 
This is an Intervention Model single group study to evaluate the safety and efficacy of 
mepolizumab in participants with severe refractory asthma with elevated eosinophils. 
Number of Participants: 
Approximately 154 participants (Assuming 35% screen failure rate) will be required to be 
screened in order for 100 participants to be enrolled onto the study treatment. 
Intervention Period and Duration: 
Participants meeting all eligibility criteria at Visit 1 (Screening visit) will enter the study. 
The screening procedures will be performed -2 weeks to -1 week (screening visit would 
be at least 7 day prior to dosing visit) before first dose of mepolizumab. At Visit 2 (Week 
0), participants will enter a 24-week treatment period, where mepolizumab 100 mg SC 
will be administered every 4 weeks. After the first dose of mepolizumab at Visit 2 (Week 
0), participants will subsequently receive a further 5 doses of mepolizumab at 4 weekly 
intervals. Following the last dose of mepolizumab at Visit 7 (Week 20), the end of study 
Visit will occur 4 weeks later (Week 24).  
Data Monitoring Committee: No  
 
 
 
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1.2. 
Schema   
V1                V2*                V3            V4          V5           V6            V7           V8 
    -2 weeks                                      Mepolizumab 100 mg, SC  
  to -1 week 
 
W0 
W4 
W8 
W12 
W16 
W20 
W24 
Screening 
visit (-2 
weeks to -1 
week) 
Treatment Period 
End of 
study 
visit 
*All screening procedures will be performed at least -2 weeks to -1 week prior to first dose of 
mepolizumab at Visit 2 (Week 0). Screening visit would be at least 7 day prior to dosing visit.  
V, visit;  W, week; SC, subcutaneous   


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1.3. 
Schedule of Activities (SoA) 
Table 1 
Time and Events Table 
Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Written 
Informed 
Consent 
x 
x 
 
 
 
 
 
 
 
 
1. Pre-screen visit can occur on the same 
day as the Visit 1 but must be 
completed prior to starting Visit 1 
(screening) procedures.  
2. Visit 2 (Week 0) must occur at least 
one week following Visit 1 (screening) 
3. Visit 2 (Week 0) will be considered 
Baseline  
Demography 
 
x 
 
 
 
 
 
 
 
x
x  
Medical History  
 
x 
 
 
 
 
 
 
 
 
 
Asthma 
and 
Exacerbation 
History 
(including triggers) 
 
x 
 
 
 
 
 
 
 
 
 
Asthma 
Therapy 
History 
 
x 
 
 
 
 
 
 
 
 
Therapy history to include a detailed 
review of prior monoclonal antibodies 
received 
for 
treatment 
of 
asthma, 
including prior investigational anti-IL5 or 
anti-IL13 preparations. 
 


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Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Oral 
Corticosteroid 
Therapy History 
 
x 
 
 
 
 
 
 
 
 
 
Smoking History 
 
x 
 
 
 
 
 
 
 
 
 
Cardiovascular 
History/risk factors 
 
x 
 
 
 
 
 
 
 
 
 
Parasitic Screening 
 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
x 
x 
 
 
 
 
 
 
 
Study inclusion/exclusion criteria should 
be reviewed at the beginning of visit 
2(Week 0). 
The review should include the results of 
any lab/safety assessments conducted at 
Visit 1 (screening). 
 
Treatment 
Period 
Criteria 
 
 
x 
 
 
 
 
 
 
 
 
Efficacy Assessments 
Exacerbation review 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Number 
of 
clinically 
significant 
exacerbations (including exacerbations 
requiring 
hospitalization, 
Emergency 
Department) visits will be evaluated 
Spirometry including 
FEV1, FVC 
 
x 
x 
 
x 
 
x 
 
x 
x 
 


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Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Maximum 
Post 
Bronchodilator 
Procedure 
 
x 
x 
 
 
 
 
 
x 
x 
Maximum Post Bronchodilator Procedure 
is required to complete reversibility 
testing.  If participant does not reverse 
12% in FEV1 at Visit 1 (screening), the 
procedure may be repeated at Visit 2 
(Week 0). 
 
OCS dose adjustment 
review 
(where 
applicable) 
 
x 
 
x 
x 
x 
x 
x 
 
 
OCS dose adjustment should be reviewed 
at scheduled in-clinic Visits 
ACQ-5 completion 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
The ACQ-5 should be completed weekly 
following Visit 1 (screening) through the 
participant’s eDiary. 
ACQ-5 review 
 
x 
x 
x 
x 
x 
Review eDiary data 
(symptoms, PEF) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
From Visit 1 (screening) to Visit 2 (Week 
0) only, participants will record peak flow 
twice a day, subsequently on morning 
only eDiary data must be reviewed on 
every Visit   
Health Outcome Assessments 
Clinician 
Rated 
Response to Therapy 
 
 
 
 
x 
 
x 
 
x 
x 
 
Participant 
Rated 
Response to Therapy 
 
 
 
 
x 
 
x 
 
x 
x 
 
WPAI-GH 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Safety Assessments 
Concomitant 
Medication 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
The concomitant procedures like 
Bronchial Thermoplasty and Radiotherapy 
are excluded for 12 months prior to Visit 1 
(screening) and throughout the study.  
Neither CPAP nor oxygen therapy may be 
initiated after Visit 1 (screening).  
Physical Examination 
 
x 
 
 
 
 
 
 
x 
x 
 
Detailed nasal exam 
(check for polyps) 
 
x 
 
 
 
 
 
 
x 
x 
 
Vital Signs  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1. Vital signs to be taken before blood 
collection for laboratory tests.  
2. Vital signs will consist of 1 pulse and 3 
blood pressure measurements (3 
consecutive blood pressure readings 
will be recorded at intervals of at least 1 
minute). The average of the 3 blood 
pressure readings will be recorded on 
the CRF. 
12 lead ECG 
 
x 
x 
 
x 
 
x 
 
x 
x 
12-lead ECG should be obtained after the 
patient has been rested in a supine 
position for at least 5 minutes.  
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Serious 
Adverse 
Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Steroid 
withdrawal 
exam review (where 
applicable) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Laboratory Assessments 
During the treatment period, all lab 
samples should be obtained pre-dose 
Haematology 
with 
differential 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Chemistry  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urinalysis 
 
x 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
S 
U 
U 
U 
U 
U 
U 
U 
U 
Pregnancy test; S = serum, U= urine 
 
HBsAg and hepatitis C 
antibody 
 
x 
 
 
 
 
 
 
 
 
Hepatitis B Antigen and Hepatitis C 
antibody (if hepatitis C antibody positive, 
a hepatitis C RIBA immunoblot assay 
should be reflexively performed on the 
serum sample to confirm the result) 
 
Serum IgE (total) 
x 
x 
x 
 
 
 
 
 
 
 
Serum IgE (Total) can be evaluated either 
at Pre-Screen visit i.e. before screening of 
patients (prior to Visit 1) or on the same 
day as ScreeningVisit 1. 


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Procedure 
Pre-
Screen 
Screenin
g 
 
Treatment Period  
(visit window is  7days) 
IP 
Discontinu
ation visit 
End of 
study 
visit 
 
Notes 
Visit 
 
1 
 
2 
3 
4 
5 
6 
7 
 
8 
 
Week 
 
-2 to -1 
0 
4 
8 
12 
16 
20 
4 
weeks 
post 
last 
dose  7 
days 
24 
or 
Early 
Withd
rawal 
 
Immunogenicity 
Assessments 
 
 
x 
 
 
 
 
 
x 
x 
Serum sample will be collected at end of 
study visit OR at IP discontinuation visit. 
Sample collection to happen at 4 weeks 
from last dose of mepolizumab or at 
patient’s 
last 
visit 
in 
case 
patient 
discontinues from the study 
Investigational Product (IP) 
Administer IP 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
Oral 
Corticosteroids 
dispensed (as needed) 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Salbutamol dispensed 
(as needed) 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Collect 
dispensed 
salbutamol as needed 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
eCRF 
Complete eCRF 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Dispense 
paper 
worksheets 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Dispense eDiary and 
PEF meter 
 
x 
 
 
 
 
 
 
 
 
 
Collect 
eDiary 
and 
PEF meter 
 
 
 
 
 
 
 
 
 
x 
 
Collect/review 
paper 
worksheets 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


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2. 
INTRODUCTION 
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa) that blocks 
interleukin-5 (IL-5) from binding to the IL-5 receptor complex expressed on the 
eosinophil cell surface and thus inhibits signalling, resulting in the reduction in 
production and survival of eosinophils. Mepolizumab is licensed for add-on maintenance 
treatment for severe eosinophilic asthma at a dose of 100 mg every 4 weeks and is 
available as a powder for solution for subcutaneous (SC) injection. 
2.1. 
Study Rationale 
This phase 4 study is a post-approval commitment for Marketing Authorization granted 
by the Drugs Controller General of India (Indian Regulatory Agency).  
In this phase 4 study, we will evaluate effect of mepolizumab as an adjunctive 
subcutaneous therapy in Indian patients 18 years and above age with severe eosinophilic 
asthma. 
2.2. 
Background 
Asthma is a common chronic inflammatory disease of the airways that affects 5 to 10% 
of adults and children (Bateman, 2004). The prevalence of asthma in India is about 2% 
with a burden of about 17 million asthmatic patients (Agarwal, 2015). The majority of 
patients with asthma can be adequately controlled by following step-wise treatment 
recommendations (GINA, 2015; NIH, 2007). However, a small minority of patients 
experience uncontrolled asthma despite following step-wise treatment recommendations 
(e.g., high dose ICS plus additional controller medications). Although patients with 
uncontrolled severe asthma represent less than 5% of the total asthma population (Barnes, 
1996), these patients experience considerable morbidity (Polosa, 2008) and are 
responsible for approximately 50% of total health care costs associated with asthma 
(Cisternas, 2003). Studies in the severe asthma population have shown that more than 
half of these patients have persistent eosinophilic (>300 cells/microL) airway 
inflammation despite corticosteroid therapy (Wenzel, 2005). 
The American Thoracic Society/European Respiratory Society (ATS/ERS) Task Force 
(Chung, 2014) for severe asthma recommends that control should first be attempted 
through the use of high-dose ICS before adding daily OCS or omalizumab (for the 
subgroup of patients with elevated IgE and who are allergic to a perennial allergen). 
Patients with severe asthma have complex treatment requirements, which in 30 to 40% of 
such patients include the regular use of oral glucocorticoids to control their asthma. Use 
of OCS on a regular basis have well-documented side effects also adherence to daily 
OCS has been documented to be as low as 50% (Robinson, 2003; Gamble, 2009). Such 
therapy can result in serious and often irreversible adverse effects. Current treatments 
with glucocorticoid-sparing properties are not recommended in patients with severe 
asthma because of their high risk–benefit ratio. Due to the undesirable safety profile of 
OCS and the limited application of omalizumab in severe asthma (Normansell, 2014), 
there are few treatment options to reduce the frequency of exacerbations and the 
dependence on systemic corticosteroids for patients with severe eosinophilic asthma. 


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Thus, there remains a high unmet need to provide better treatment options, without the 
side effects associated with systemic corticosteroids, for this small segment of the asthma 
population.  
Mepolizumab binds with high specificity and affinity to human interleukin 5 (IL-5), the 
key cytokine responsible for regulation of blood and tissue eosinophils. The 
overproduction of IL-5 has been specifically reported in patients with a variety of 
eosinophil associated disorders including asthma (Robinson, 1992; Sur, 1995). 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 
(Seminario, 1994; Rothenberg, 1998; Wardlaw, 2000; Cohn, 2004). Available data do not 
indicate that reduction of eosinophils has any untoward effects on normal health (Gleich, 
2013); patients lacking eosinophils in association with immunodeficiency or as a 
consequence of IgG-mediated eosinophil precursor destruction do not display any 
distinguishing abnormalities related to the eosinophil reduction. 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 (Haldar, 2011; Pavord, 2012).  
The drug is indicated as an add-on treatment for severe eosinophilic asthma, on the basis 
of its clinical benefit in this setting in the placebo-controlled DREAM, MENSA and 
SIRIUS trials. Based on the 52-week, phase II, DREAM study (which assessed varying 
intravenous mepolizumab dosages), intravenous mepolizumab 75 mg every 4 weeks 
(q4w) and the corresponding (recommended) subcutaneous dosage of 100 mg q4w were 
studied in the 32- and 24-week phase III MENSA and SIRIUS trials. In patients aged >12 
years with severe eosinophilic asthma in the phase III studies, adding subcutaneous 
mepolizumab 100 mg q4w to current asthma therapy significantly reduced the rate of 
clinically relevant asthma exacerbations. This mepolizumab regimen also significantly 
improved asthma control, health-related quality of life and (in one of the two studies) 
lung function and had acceptable tolerability (with headache the most common adverse 
event). In the MENSA and SIRIUS extension, COSMOS, mepolizumab provided durable 
clinical benefit over up to 84 weeks’ therapy with no new tolerability concerns. 
COLUMBA study reported long-term safety data for mepolizumab in patients with 
severe eosinophilic asthma with exposure for up to 4.5 years. There was no evidence that 
long term exposure to mepolizumab altered the safety or tolerability profile. Rates of AEs 
and SAEs reported in this study are in line with those reported in previous mepolizumab 
randomized controlled trials (Ortega, 2018). In COSMEX study it was found that the 
safety profile of mepolizumab was similar to previous shorter-term trials, with no new 
safety signals; long-term treatment provided sustained & consistent exacerbation & OCS 
reductions for up to 4.5yrs (Albers, 2018). Thus, mepolizumab is a valuable add-on 
treatment option for adults and adolescents aged 12 years or above who have severe 
eosinophilic asthma despite optimized standard therapies. Mepolizumab, based on its 
favourable safety profile, the robust data supporting its effectiveness in reducing frequent 
and severe exacerbations, improvements in quality of life, and in reducing the 
requirement for daily systemic corticosteroids with established long-term safety for 


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periods up-to 4.5 years provides a treatment option for patients who otherwise have no, or 
limited therapeutic treatment options (Deeks, 2016). 
A proof-of-concept study involving 20 patients with eosinophilic asthma showed that the 
intravenous administration of mepolizumab was effective in reducing the maintenance 
dose of prednisone while preventing exacerbations (Nair, 2009). In the Steroid Reduction 
with Mepolizumab Study (SIRIUS), the effect of mepolizumab adjunctive subcutaneous 
therapy was compared with that of placebo in reducing the use of maintenance oral 
glucocorticoids while maintaining asthma control in patients with severe eosinophilic 
asthma. In patients requiring daily oral glucocorticoid therapy to maintain asthma control, 
mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and 
improved control of asthma symptoms (Bel, 2014).  
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, Participant Information Leaflet, Prescribing Information. 


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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) 
Systemic Reactions 
(Allergic [type I 
hypersensitivity] 
and Other systemic 
reactions) 
including 
Anaphylaxis 
There have been reports of 
systemic 
reactions 
(including hypersensitivity 
reactions, 
such 
as 
anaphylaxis, bronchospasm, 
angioedema, rash, urticaria 
and 
hypotension) 
with 
mepolizumab. These are 
usually 
acute, 
occurring 
within a few hours of the 
drug being administered, 
but can also be delayed, 
occurring after several days 
Safety monitoring of participants 
will occur during SC administration 
and for one hour after the end of 
injection for the first 3 injections, 
then per institutional guidelines.  
Such monitoring will include general 
safety 
monitoring 
including 
monitoring 
for 
both 
systemic 
reactions 
(Allergic 
[type 
I 
hypersensitivity] and Other systemic 
reactions) and local site reactions. In 
the event of an acute severe reaction 
(e.g., 
anaphylaxis) 
following 
administration of study treatment, 
there must be personnel/staff onsite 
at the treatment facility who are 
appropriately trained in basic life 
support to manage the patient 
including 
administration 
of 
medications (e.g., epinephrine), and 
have access to a system that can 
promptly transport the patient to 
another facility for additional care if 
appropriate.  
Customised AE and SAE case report 
form (CRF) utilised for targeted 
collection 
of 
information 
for 
systemic reaction adverse events. 
Use of Joint National Institute of 
Allergy and Infectious Diseases 
(NIAID)/Food 
Allergy 
and 
Anaphylaxis Network (FAAN) 2nd 
Symposium 
on 
Anaphylaxis 
to 
collect 
data 
on 
reports 
of 
anaphylaxis (see Appendix 7). 
 
 


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Potential Risk of 
Clinical 
Significance 
Summary 
of 
Data/Rationale for Risk 
Mitigation Strategy 
Study Procedures 
There 
are 
few 
invasive 
procedures such as 
blood collection for 
chemistry 
assessment 
in 
which blood will 
be collected from 
peripheral 
veins. 
Also, 
ECG 
assessment will be 
conducted. 
Fainting 
associated 
with 
needle prick and contact 
dermatitis because of jelly 
applied 
before 
ECG 
assessment  
 
The participants have been informed 
about the all the study procedures 
and invasive procedure for e.g. blood 
collection during informed consent 
process. No further risk mitigation 
strategy is required. 
COVID-19 pandemic 
COVID-19 
pandemic 
The COVID-19 pandemic 
may impact the conduct of 
clinical studies. Challenges 
may arise from quarantines, 
site 
closures, 
travel 
limitations, interruptions to 
the supply chain for the 
investigational product or 
other considerations if site 
personnel 
or 
study 
participants 
become 
infected with COVID-19. 
These challenges may lead 
to difficulties in meeting 
protocol-specified 
procedures. 
Missing protocol required data/visits 
due to COVID-19 should be noted in 
participant notes and recorded as a 
COVID-19 protocol deviation. Visits 
that were conducted via the 
telephone will not be classified as 
missed visits, however missed 
assessments (e.g. spirometry) should 
be recorded as COVID-19 protocol 
deviations. 
The study CRF will capture 
information on probable, suspected 
or confirmed COVID-19 infections. 
Additionally, a further targeted CRF 
page will capture the frequency of 
missed or partially completed study 
visits or assessments due to the 
COVID-19 pandemic. 
Home healthcare visits (home visits 
and telemedicine visits) may be 
implemented for scheduled visits 
from Visit 3 onwards for participants 
unable to attend a site visit due to 
COVID-19 related restrictions. 
Intercurrent events related to the 
COVID-19 
pandemic 
(such 
as 
quarantines, site closures or other 
related issues) will be accounted for 


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Potential Risk of 
Clinical 
Significance 
Summary 
of 
Data/Rationale for Risk 
Mitigation Strategy 
within the analysis of the study. 
2.3.2. 
Benefit Assessment 
During the entire duration of the study, all the participants will receive medicines such as 
mepolizumab, OCS (as needed) and ICS plus LABA combination free of cost. Also, all 
the routine procedures, which are offered as standard of care for Asthma evaluation (for 
e.g. Spirometry assessment) and safety assessment (ECG, chemistry) will be provided 
free of cost.  
Multiple clinical studies (MENSA, SIRIUS, COSMOS) have shown that mepolizumab 
has significantly reduced clinically significant annual asthma exacerbation rate and 
improved lung function in patients with severe eosinophilic asthma. SIRIUS study 
demonstrated that in patients requiring daily oral glucocorticoid therapy to maintain 
asthma control, mepolizumab had a significant glucocorticoid-sparing effect. 
2.3.3. 
Overall Benefit: Risk Conclusion 
The benefit: risk of mepolizumab 100mg SC every 4 weeks in the approved indication of 
severe eosinophilic asthma is positive. 
 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate the safety, and 
tolerability of mepolizumab in 
participants 
with 
severe 
refractory asthma with elevated 
eosinophils 
The primary estimand will be defined by the 
following: 
Endpoints: 
• 
Incidence of on-treatment adverse events (AEs), 
serious adverse events (SAEs) and adverse events 
of special interest (AESIs) 
Summary measure: 
• 
Counts and percentages for incidence of at least 
one AE will be summarised overall, by system 
organ class and by preferred term 
Population of interest:  
• 
Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• 
Discontinuation of treatment (for any reason) 
Strategy for intercurrent events: 
• 
While on-treatment strategy will be used for 
treatment discontinuation. This will estimate the 
percentage of participants experiencing an AE, 
while receiving treatment.  
AEs will be defined as on-treatment between the 
first dose up to and including 28 days following 
the last dose of mepolizumab. 
 
A supplementary estimand will be defined using 
identical properties as for the primary estimand 
(summary measure, population of interest and key 
intercurrent events), however this supplementary 
estimand will report all AEs regardless of the 
discontinuation of study treatment. 
Endpoints: 
• 
Incidence of AEs and SAEs 
Strategy for intercurrent events: 
• 
Treatment policy strategy will be used for 
treatment discontinuation. This summary will 
therefore be inclusive of all on-treatment and 
post-treatment AEs. 
Secondary 
• 
To evaluate the efficacy of 
mepolizumab in participants 
The following secondary estimand is defined by the 
following: 


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Objectives 
Endpoints 
with severe refractory asthma 
with elevated eosinophils 
Endpoints: 
• 
Number of clinically significant exacerbations 
(including exacerbations requiring hospitalization 
or ED visits) 
• 
Number of exacerbations requiring hospitalization 
or ED visits 
• 
Number of exacerbations requiring hospitalization 
Summary measure: 
• 
Rate ratio comparing events/year during the 24-
week follow-up period compared to the 12 
months prior to screening 
Population of interest:  
• 
Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• 
Discontinuation of treatment (for any reason) 
Strategy for intercurrent events: 
• 
Treatment policy strategy will be used for 
treatment discontinuation. This will estimate the 
treatment effect over the 24 week study period 
regardless of treatment discontinuation. 
 
The remaining secondary estimands are defined by the 
following: 
Endpoints: 
• 
Change from baseline in clinic pre-bronchodilator 
FEV1 at week 24 
• 
Change from baseline in clinic post-
bronchodilator FEV1 at week 24 
• 
Change from baseline in ACQ-5 score at week 24 
• 
Change from baseline in morning PEF during 
weeks 20 - 24  
Summary measure: 
• 
Mean change from baseline in clinic pre-
bronchodilator FEV1 at week 24 
• 
Mean change from baseline in clinic post-
bronchodilator FEV1 at week 24 
• 
Mean change from baseline in ACQ-5 score at 
week 24 
• 
Mean change from baseline from baseline in 
morning PEF during weeks 20 – 24 
Population of interest:  
• 
Severe refractory asthma patients in India with 
elevated eosinophils 
Key intercurrent events: 
• 
Discontinuation of treatment (for any reason) 


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Objectives 
Endpoints 
Strategy for intercurrent events: 
• 
Treatment policy strategy will be used for 
treatment discontinuation. This will estimate the 
treatment effect at the end of the 24 week study 
period regardless of treatment discontinuation.  
Exploratory 
CCI


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a multi-centre, open-label, single arm 24-week study.  
V1                V2*                V3            V4          V5           V6            V7           V8 
    -2 weeks                                       Mepolizumab 100 mg, SC  
to -1 week 
 
W0 
W4 
W8 
W12 
W16 
W20 
W24 
Screening 
visit (-2 
weeks to -1 
week) 
Treatment Period 
End of 
study 
visit 
*All screening procedures will be performed at least -2 weeks to -1 week prior to first dose of 
mepolizumab at Visit 2 (Week 0). Screening visit would be at least 7 day prior to dosing visit. 
V, visit;  W, week; SC, subcutaneous  
The primary estimand is the incidence of AEs, SAEs and AESIs in adult Indian 
participants with severe refractory asthma with elevated eosinophils while on-treatment 
with mepolizumab 100mg SC during a 24-week study. 
 


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4.1.1. 
Screening  
Participants who meet all eligibility criteria at the Screening visit (Visit 1) will enter the 
study and asked to come to the clinic after at least 1 week for Visit 2 (Week 0).  
Participants must understand and agree to use the study drugs for the treatment of asthma, 
or asthma exacerbation, for the duration of the study. OCS use and OCS dose adjustment 
in participants will be as per the investigator’s discretion and clinical practice. 
At Visit 1, the screening visit, the screening ACQ-5 score will be captured. Participants 
who meet study eligibility criteria, are eligible to enter the Treatment period. All 
screening procedures will be performed  -2 weeks to -1 week (screening visit would be at 
least 7 day prior to dosing visit) before first dose of mepolizumab (Visit 2, Week 0).  
The ACQ-5 questionnaire has been validated in several separate studies and the minimal 
clinically important difference value of +0.5 has been established to demonstrate a 
significant clinical change in asthma status (Juniper, 1999; Korn, 2011). 
4.1.1.1. 
Exacerbation Management  
Anytime during the study when a participant experiences an exacerbation the 
exacerbation should be treated according to the investigator’s clinical practice. 
4.1.2. 
Treatment period 
At Visit 2 (Week 0), participants who meet the Treatment Period eligibility criteria will 
receive Mepolizumab 100mg SC every 4 weeks. 
Subsequently, participants will continue to receive with mepolizumab 100mg SC every 4 
weeks. During this period, participants will remain on their baseline asthma medications. 
OCS use and OCS dose adjustment in participants will be as per the investigator’s 
discretion and clinical practice.   
4.1.2.1. 
Exacerbation Management during Treatment Period 
Anytime during the study when a participant experiences an exacerbation the 
exacerbation should be treated according to the investigator’s clinical practice.   
The participant will return for each subsequent Visit, to receive their subsequent doses of 
open label study treatment, as scheduled.  
4.1.3. 
IP Discontinuation Visit 
The IP discontinuation visit will be performed 4 weeks following the last dose of 
mepolizumab with a window of ±7 days. Also, if a participant permanently stops study 
intervention, the participant is not required to withdraw from the study. Every effort 
should be made by the PI/staff to keep the subject in the study to collect important 
efficacy and safety data. In the event of discontinuation of study, the end of study visit 
activities should be performed as specified in SoA table (Section 1.3).  


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4.2. 
Scientific Rationale for Study Design 
Though safety and efficacy of mepolizumab in patients with severe eosinophilic asthma 
has been established in various clinical studies across USA and Europe, this will be the 
first clinical study to assess safety in Indian patients.  
Eosinophilic inflammation of the airways plays a central role in the pathogenesis of 
asthma (Seminario, 1994; Rothenberg, 1998; Wardlaw, 2000; Cohn, 2004). The 
overproduction of IL-5 has been specifically reported in patients with a variety of 
eosinophil associated disorders including asthma (Robinson, 1992; Sur, 1995). 
Mepolizumab binds with high specificity and affinity to human interleukin 5 (IL-5), the 
key cytokine responsible for regulation of blood and tissue eosinophils. 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.  
There is significant unmet medical need to provide better treatment options in patients 
with severe eosinophilic asthma who need systemic corticosteroids for maintenance, 
given undesirable safety profile of OCS and the limited application of omalizumab in 
severe asthma (Normansell, 2014). In patients aged ≥12 years with severe eosinophilic 
asthma in the phase III studies, adding subcutaneous mepolizumab 100 mg q4w to 
current asthma therapy significantly reduced the rate of clinically relevant asthma 
exacerbations and significantly improved asthma control and had acceptable tolerability 
(with headache the most common adverse event). Further, the SIRIUS study 
demonstrated that in patients requiring daily oral glucocorticoid therapy to maintain 
asthma control, mepolizumab had a significant glucocorticoid-sparing effect. This study 
will also evaluate the OCS sparing effect in Indian patients with severe eosinophilic 
asthma (only to be assessed in patients who completed or withdrew from the study prior 
to the adoption of protocol amendment 4). 
4.3. 
Justification for Dose 
Mepolizumab 100 mg SC every 4 weeks is as per approved dose (Prescribing 
Information) by Indian Regulatory Authorities. 
4.4. 
End of Study Visit 
A participant is considered to have completed study treatment if he/she has received a 
dose of mepolizumab at Visit 7 (Week 20) of the study.  
A participant is considered to have completed the study if he/she has completed the 24 
week treatment period of the study including the end of study visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and Treatment Period criteria, 
also known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participant must be ≥18 to 65 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Asthma: Evidence of asthma as documented by either:  
• 
Airway reversibility (FEV1≥12% and 200 ml) demonstrated at Visit 1 
(screening), or Visit 2 (Week 0) OR documented in the previous 12 months OR 
• 
Airway hyper-responsiveness (methacholine: PC20 of <8mg/mL or histamine: 
PD20 of <7.8 µmol; mannitol: decrease in FEV1 as per the labelled product 
instructions) documented in the 12 months prior to Visit 2 (Week 0) OR 
• 
Airflow variability in clinic FEV1 ≥20% between two consecutive clinic visits 
documented in the 12 months prior to Visit 2 (FEV1 recorded during an 
exacerbation should not be considered for this criteria) OR 
• 
Airflow variability as indicated by >20% diurnal variability in peak flow observed 
on 3 or more days during the optimisation period 
3. Participants with Eosinophilic asthma: prior documentation of eosinophilic asthma or 
high likelihood of eosinophilic asthma as 
FEV1: Persistent airflow obstruction as indicated by: 
For participants ≥ 18 years of age at Visit 1 (screening), or Visit 2 (Week 0), a pre-
bronchodilator FEV1 <80% predicted  
For predicted FEV1 values NHANES III values will be used and adjustments to these 
values will be made for race [Hankinson, 1999].  
4. Eosinophilic Phenotype: Airway inflammation characterized as eosinophilic in nature 
as indicated by one of the following characteristics: 
a. An elevated peripheral blood eosinophil level of ≥300 cells/µL that is related to 
asthma within the previous 12 months prior to Visit 2 (Week 0) 
OR 
b. Peripheral baseline eosinophil level ≥150 cells/µL between Visit 1 (screening) 
and Visit 2 (Week 0) that is related to asthma 


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5. Patients eligible for mepolizumab treatment as per independent clinical judgment of 
treating physician in alignment with local prescribing information. 
6. Inhaled Corticosteroids: requirement for regular treatment with high dose inhaled 
corticosteroid in the 6 months prior to Visit 1 (screening).  
For 18 years of age and older: 
• ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-actuator) or 
equivalent daily.  
7. Controller Medication:  Current treatment with an additional controller medication for 
at least 3 months OR having used and failed an additional controller medication for at 
least 3 successive months during the prior 12 months [e.g., long-acting beta2-agonist 
(LABA), leukotriene receptor antagonist (LTRA), or theophylline]. 
Sex  
8. Male or eligible female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Female Participants:  
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
o Is not a woman of childbearing potential (WOCBP)  
OR 
o Is a WOCBP and using a contraceptive method that is highly effective, with a 
failure rate of <1%, as described in Appendix 4 during the intervention period 
and for at least 16 weeks 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 (Appendix 2) pregnancy test 
(serum) within 8 weeks before the first dose of study intervention. 
• 
Additional requirements for pregnancy testing during and after study 
intervention are located in Appendix 2. 
• 
The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy 
Informed Consent 
9. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Concurrent Respiratory Disease: Presence of a clinically important lung condition 
other than asthma.  This includes but is not limited to current infection, 
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.  
2. Malignancy: A current malignancy or previous history of cancer in remission for less 
than 12 months prior screening (Participants who had localized carcinoma (i.e. basal 
or squamous cell) of the skin which was resected for cure will not be excluded).  
3. Liver Disease: Unstable liver disease (as defined by the presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices or 
persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception 
of Gilbert’s syndrome or asymptomatic gallstones). 
4. Cardiovascular: Participants who have severe or clinically significant cardiovascular 
disease uncontrolled with standard treatment. Including but not limited to: 
• 
known ejection fraction of <30% OR 
• 
severe heart failure meeting New York Heart Association Class IV (Appendix 5) 
OR 
• 
hospitalised in the 12 months prior to Visit 1 (screening) for severe heart failure 
meeting New York Heart Association Class III (Appendix 5) OR 
• 
angina diagnosed less than 3 months prior to Visit 1 (screening) or at Visit 1 
5. Other Concurrent Medical Conditions: Participants 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. 
6. Eosinophilic Diseases: Participants with other conditions that could lead to elevated 
eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss 
Syndrome, or Eosinophilic Esophaghitis.   
7. Participants with a known, pre-existing parasitic infestation within 6 months prior to 
Visit 1 (screening) are also to be excluded. 
Prior/Concomitant Therapy 
8. Omalizumab Use: Participants who have received omalizumab [Xolair] within 130 
days of Visit 1 (screening) 
9. Other Monoclonal Antibodies: Participants who have received any monoclonal 
antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 
1 (screening) 


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10. Investigational Medications: Participants 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). 
Prior/Concurrent Clinical Study Experience 
11. Participants who have previously participated in any study of mepolizumab and 
received Investigational Product (including placebo). 
 
Diagnostic assessments 
12. ECG: ECG assessment QTcF > 450msec or QTcF > 480 msec for participants with 
Bundle Branch Block. 
Participants are excluded if an abnormal ECG finding from the 12-lead ECG 
conducted at Screening (Visit 1) is considered to be clinically significant and 
would impact the participant’s participation during the study, based on the 
evaluation of the Investigator. 
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 
COVID-19 Related Exclusion 
14. Participants that have a current active COVID-19 infection, either laboratory 
confirmed or according to the investigator’s medical judgement. 
Note:  Participants who have confirmed or suspected COVID-19 infection may be re-
screened 4 weeks or more after the resolution of the COVID-19 infection and only 
after written approval from the study Medical Monitor. 
15. Participants known to be in contact with active COVID-19 positive individuals 
within the past 14 days.  
Note:  Participants may be re-screened 14 days or more following the contact, during 
which the participant should remain symptom free, and only after written approval 
from the study Medical Monitor. 
 
Other Exclusions 
16. Smoking history: Current smokers or former smokers with a smoking history of ≥10 
pack years. A former smoker is defined as a participant who quit smoking at least 6 
months prior to Visit 1 (screening) 
17. Hypersensitivity: Participants with a known allergy or intolerance to a monoclonal 
antibody or biologic. 
18. Pregnancy: Participants who are pregnant or breastfeeding. Patients should not be 
enrolled if they plan to become pregnant during the time of study participation. 


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19. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or 
substance abuse within 2 years prior to Visit 1 (screening). 
20. Adherence: Participants who have known evidence of lack of adherence to controller 
medications and/or ability to follow physician’s recommendations. 
Re-screening of participants will be allowed only upon approval by the medical monitor. 
5.3. 
Treatment Period Criteria 
Study participants must fulfil the following criteria in order to enter the Treatment Period 
(recruitment continues until approximately 100 participants enter Treatment Period): 
1. Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood 
of eosinophilic asthma as per Inclusion Criteria 3 and 4 
2. eDiary Compliance: Compliance with completion of the eDiary defined as: 
• Completion of symptom scores on 4 or more days out of the last 7 days 
immediately preceding Visit 2 (Week 0) 
• Completion of information relating to rescue medication use on 4 or more days 
out of the last 7 days immediately preceding Visit 2 (Week 0). 
• Completion of PEF measurements on 4 or more days out of the last 7 days 
immediately preceding Visit 2 (Week 0). 
3. Laboratory abnormality: No evidence of clinically significant abnormality in the 
haematological, biochemical or urinalysis screen at Visit 1 (screening), as judged by 
the investigator.  
4. Alanine transferase (ALT) < 2 x upper limit of normal (ULN) 
5. Bilirubin < 1.5 x ULN (isolated bilirubin >1.5 ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
6. No cirrhosis or current unstable liver or biliary disease per investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
oesophageal or gastric varices, or persistent jaundice. Stable non-cirrhotic chronic 
liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic 
stable hepatitis B or C e.g., presence of hepatitis B surface antigen [HBsAg] or 
positive hepatitis C antibody test result) is acceptable if the participant otherwise 
meets eligibility criteria 
5.4. 
Lifestyle Considerations 
5.4.1. 
Caffeine, Alcohol, and Tobacco 
• 
Participants who use tobacco products will be instructed that use of tobacco products 
will not be allowed from screening until after the end of study visit. 


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5.5. 
Screen Failures 
Participants will be assigned a study number at the time of signing the consent. 
Participants who do not progress to the screening visit (Visit 1) will be deemed a Pre-
screen Failure.  No data will be captured in the eCRF for these participants. 
Those participants that complete at least one additional procedure at Visit 1 (screening) 
but do not enter the Screening Period (between Visit 1 and Visit 2) will be designated as 
screen failures. Additionally, those participants that enter the Screening Period, but do 
not complete any Visit 2 procedures will be designated as run-in failures. 
A minimal set of screening information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs). 
Re-screening of participants will be allowed only upon approval by the medical monitor. 
If a patient is approved to be re-screened the patient would be required to repeat the 
screening process again from the start of the time and events table, including screening 
visit and would be assigned a new subject number.   
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Arm Name 
Single arm study 
Intervention Name 
Mepolizumab 
Type  
Biologic 
Dose Formulation 
Vial 
Unit Dose Strength(s) 
100 mg/ml 
Dosage Level(s) 
100 mg every 4 weeks 
Route of Administration 
Subcutaneous 
IMP and NIMP 
Sourcing 
 
Provided centrally by the Sponsor  


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Packaging and Labelling 
 
Study Intervention will be provided in vial. Each vial 
will be labelled as required per country requirement. 
Current Name 
Nucala 
 
6.2. 
Preparation/Handling/Storage/Accountability 
1. Mepolizumab will be provided as a lyophilised powder in sterile vials for individual 
use.  The vial will be reconstituted with Sterile Water for Injection, just prior to use.  
To administer mepolizumab 100 mg SC, reconstituted mepolizumab for injection 
will be drawn into a 1.0 ml polypropylene syringe. Study staff member will 
administer the SC dose into the participant’s upper arm, thigh or abdomen. Further 
details of dose preparation and administration can be found in the Clinical 
Investigator’s 
Brochure 
(CIB) 
[GlaxoSmithKline 
Document 
Number 
CM2003/00010/07], and the Study Reference Manual (SRM) 
2. Safety monitoring of participants will occur during SC administration and for one 
hour after the end of injection for the first 3 injections, then per institutional 
guidelines.  Such monitoring will include general safety monitoring including 
monitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-
allergic) and local site reactions. In the event of an acute severe reaction (e.g., 
anaphylaxis) following administration of study treatment, there must be 
personnel/staff onsite at the treatment facility who are appropriately trained in basic 
life support to manage the patient including administration of medications (e.g., 
epinephrine), and have access to a system that can promptly transport the patient to 
another facility for additional care if appropriate. 
3. Under normal conditions of handling and administration, study intervention 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. 
4. 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. 
5. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
6. Only participants who enter the Treatment Period may receive study intervention and 
only authorized site staff may supply or administer study intervention. All study 
interventions 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 and authorized site staff. Mepolizumab must be 
stored under the appropriate physical conditions which includes storage in a 


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refrigerator or at a temperature of 2-8C and protected from light. The contents of the 
label will be in accordance with all applicable regulatory requirements. 
7. The investigator/ designee, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
Product accountability records must be maintained throughout the course of the 
study. 
8. Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM Study Reference Manual.  
 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is single arm, open label study. Therefore, randomization and blinding are not 
applicable.  
6.4. 
Study Intervention Compliance 
• 
When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date and time of 
each dose administered in the clinic will be recorded in the source documents.   
• 
When participants self-administer asthma medications (other than mepolizumab), 
compliance with orally administered drugs for asthma (leukotriene receptor 
antagonists etc) will be assessed through querying the participant during the site 
visits and documented in the source documents and CRF. A record of the number of  
tablets dispensed to and taken by each participant for asthma management must be 
maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the CRF. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1. 
Rescue Medicine 
The study site will supply Salbutamol metered dose inhaler rescue medication that will be 
provided by the sponsor.  


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The use of rescue medications is allowable at any time during the study. The date and 
time of rescue medication administration as well as the name and dosage regimen of the 
rescue medication must be recorded. 
6.5.2. 
Permitted Medications and Non-Drug Therapies 
 
OCS use is permitted as per investigator’s discretion and changes must be recorded 
accurately in the eCRF.Additional asthma medications such as theophylline or anti-
leukotrienes will be permitted provided they have been taken regularly in the 3 months 
prior to entering the Treatment Period (Visit 2, Week 0).   
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep 
apnoea is permitted, if initiated prior to the screening visit. This treatment must be 
captured in the eCRF. 
6.5.3. 
Prohibited Medications and Non-Drug Therapies 
During this study the OCS may be used for the treatment of asthma, as needed by the 
investigator.  
Prior to screening the following medications are prohibited for the timeframe indicated in 
Table 2. These medications are also prohibited throughout the study. 
Table 2 
Medications not allowed prior to the screening visit and throughout 
the study 
Medication 
Washout 
Time 
Prior to Screening Visit 
Investigational drugs 
1 
month 
or 
5 
half-lives 
whichever is longer 
Omalizumab [Xolair]  
130 days 
Other monoclonal antibodies 
5 half-lives 
Experimental anti-inflammatory drugs (non-biologicals) 3 months 
Immunosuppressive medications such as those listed below (not all inclusive) 
Corticosteroids intramuscular, long-acting depot if used 
to treat a condition other than asthma 
3 months 
Methotrexate, troleandomycin, cyclosporin, azathioprine  1 month 
Oral gold 
3 months 
Chemotherapy used for conditions other than asthma 
12 months 
Regular systemic (oral or parenteral) corticosteroids for 
the treatment of conditions other than asthma 
3 months 
 


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Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 (screening) and throughout the study. Neither CPAP nor oxygen therapy 
may be initiated after Visit 1 (screening). 
6.6. 
Dose Modification 
Dose of mepolizumab will remain constant throughout the study. 
6.7. 
Intervention after the End of the Study 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition. GSK will not supply mepolizumab post 
study since the mepolizumab will be available commercially. At the end of the study, 
participants may be prescribed appropriate alternative asthma therapy if needed and as 
determined by the study Investigator. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Participants who permanently stop study intervention are not required to withdraw from 
the study. If for any reason a participant must permanently stop study intervention every 
effort should be made by the PI/staff to keep the subject in the study to collect important 
efficacy and safety data. 
See the SOA for data to be collected at the time of discontinuation of study intervention. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event aetiology. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm OR 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and Liver safety 
required actions and follow up assessments can be found in Appendix 6: 


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Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
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*
 
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international 
normalized ratio; SAE = serious adverse event; ULN = upper limit of normal. 


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN 
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*
 
Abbreviations: ALT = alanine transaminase; bili = bilirubin; INR = international 
normalized ratio; SAE = serious adverse event; ULN = upper limit of normal. 
7.1.1.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.2. 
QTc Stopping Criteria 
• 
QTc(f) QT correction (Fredericia) formula must be used for each individual 
participant to determine eligibility for and discontinuation from the study.  This 
formula may not be changed or substituted once the participant has been enrolled. 
The QTc should be based on the average of triplicate ECG readings obtained over a brief 
(e.g., 5-10 minute) recording period.   
• 
QTc stopping criteria are  
• QTc(F)>500 msec or uncorrected QT>600 msec 
• Change from baseline: QTc(F) > 60 msec 
• For patients with underlying bundle branch block, follow the discontinuation 
criteria listed below: 
 


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Baseline QTc (F) with Bundle 
Branch Block 
Discontinuation QTc (F) with Bundle 
Branch Block 
< 450 msec 
> 500 msec 
450 – 480 msec 
≥ 530 msec 
 
See the SoA for data to be collected at the time of intervention discontinuation and end of 
study and for any further evaluations that need to be completed. 
7.1.3. 
Temporary Discontinuation 
If a participant becomes infected with a parasitic infection whilst receiving study 
intervention and does not respond to anti-helminth treatment, temporary discontinuation 
of study intervention should be considered in consultation with GSK Medical Monitor. 
7.1.4. 
COVID-19 testing 
Participants that test positive for COVID-19 do not have to discontinue study 
intervention. Participants are encouraged to remain in the study and be followed up per 
study schedule as participants well-being allows. Effort should be made by the 
Investigator/site staff to keep the participant in the study until their nominal 24 weeks 
post initiation of investigational product. 
• COVID-19 tests during the study may be performed, as determined by the 
investigator or local guidelines. 
• All positive COVID-19 tests should be reported on the COVID-19 eCRFs and the 
AE/SAE eCRFs, as appropriate. 
• Participants that test positive for COVID-19 do not have to discontinue study 
intervention. 
• Positive tests should be reported to the appropriate local government authorities, 
per local regulations. 
 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Participants who permanently stop study intervention are not required to withdraw from 
the study. If for any reason a participant must permanently stop study intervention every 
effort should be made by the PI/staff to keep the subject in the study to collect important 
efficacy and safety data. 
 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons. This is expected to be 
uncommon. 
• At the time of discontinuing from the study, if possible, an end of study visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 


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time of study discontinuation and end of study for any further evaluations that 
need to be completed. 
• If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• Reasons for withdrawal must be captured in the eCRF and can include: an adverse 
event, lost to follow-up, protocol violation, lack of efficacy, sponsor terminated 
study, non-compliance, pregnancy, abnormal liver function test, abnormal 
laboratory results including clinically significant abnormality identified on ECG 
over-read.  
 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the 
SoA. 
• 
The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, 
will not exceed 100 mL. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
8.1. 
Efficacy Assessments 
8.1.1. 
Efficacy Endpoints 
Primary Efficacy Endpoint 
Not applicable 
Secondary Efficacy Endpoint 
• 
Number of clinically significant exacerbations 
• 
Number of exacerbations requiring hospitalization or ED visits 
• 
Number of exacerbations requiring hospitalization 
• 
Change from baseline in clinic pre-bronchodilator FEV1 at week 24 
• 
Change from baseline in clinic post-bronchodilator FEV1 at week 24 
• 
Change from baseline in ACQ-5 score at week 24  
• 
Change from baseline in morning PEF during weeks 20 – 24 
 


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8.1.2. 
Number of clinically significant exacerbations (including 
exacerbations requiring hospitalization or ED visits) 
Clinically significant exacerbations of asthma as defined by: 
 
Worsening of asthma which requires use of systemic corticosteroids1and/or 
hospitalisation and/or Emergency Department (ED) visits.  
 
1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a 
single IM CS dose is required. For subjects on maintenance systemic 
corticosteroids, at least double the existing maintenance dose for at least 3 days is 
required. 
 
Clinically significant exacerbations of asthma will be defined as the worsening of asthma 
which requires use of systemic corticosteroids. Exacerbation will be treated per the 
investigator’s clinical practice protocol with the use of oral or parenteral corticosteroids. 
 
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 worsening of asthma symptom 
score. 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.   
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For safety reasons alerts will be programmed into the eDiary to encourage the participant 
to contact the investigator if their asthma worsens (see Appendix 9). However, an alert in 
itself will not be classified as a clinically significant exacerbation. 
8.1.3. 
Pulmonary Function Testing including Reversibility using the 
Maximum Post-Bronchodilator Method 
Spirometry will be conducted, using the Spirometry equipment provided by GSK through 
a designated central laboratory at the visits specified in the Time and Events schedule.  
The spirometer should meet American Thoracic Society standards and produce a printout 
of all data generated, which should be stored in the participant’s notes.  The spirometer 
should be calibrated in accordance with the manufacturer’s instructions and a calibration 
log maintained. Participants should withhold short-acting beta-2-agonists (SABAs) for ≥6 
hours and LABAs for 12 hours prior to clinic visit. Assessments to be recorded will 
include FEV1, and FVC.     
Pre-bronchodilator measurements will be taken at baseline, week 8, 16, and 24. In 
addition, at visit specified in the Time and Events schedule, post-bronchodilator values 
will be recorded following reversibility testing, using the maximum post bronchodilator 
method. For participants unable to achieve 12% reversibility and 200mL change at Visit 
1 (screening), reversibility can be repeated at Visit 2 (Week 0). The procedures to achieve 
the maximum post-bronchodilator are those generated by the Asthma Clinical Research 
Network. Further details of spirometry and reversibility testing procedures are presented 
in the SRM.  
8.1.4. 
eDiary 
The participant will be asked to record the following parameters daily in the eDiary from 
Visit 1 (screening) onwards: 
• 
Morning peak flow (best of three), before rescue medication usage (L/min) 
• 
Number of puffs of rescue usage over the previous 24-hours 
• 
Asthma symptom score over the previous 24-hours using a 6-point scale (Appendix 
8) 
• 
Frequency of awakening due to asthma symptoms requiring rescue medication use. 
• 
Daily dose of OCS 
The participant will be asked to complete the ACQ-5 weekly in the eDiary from Visit 1 
(screening) onwards. 
From Visit 1 (screening) to Visit 2 (Week 0) only, participants will record peak flow 
twice a day to allow for calculation of PEF diurnal variability. 
Alerts indicative of worsening asthma will be programmed into the eDiary (See 
Appendix 9). Sites will view participant data regularly through a study specific web 
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eDiary data will additionally be reviewed at each clinic visit by the site staff throughout 
the treatment period. 
Note: That an alert in itself will not qualify as a clinically significant exacerbation and 
the site should follow up with the participant as appropriate. 
Participants will also be issued a paper worksheet to record adverse events and 
concomitant medications during the study. This will be used to assist participant recall in 
discussions with the investigator, for site staff to then enter as appropriate in the eCRF. 
8.1.5. 
Asthma Control Questionnaire-5 (ACQ-5) 
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
participants’ asthma control that can be quickly and easily completed in clinical practice 
(Juniper, 2005). The questions are designed to be self-completed by the participant.  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 (no 
impairment/limitation) to six (total impairment/ limitation) scale. The ACQ-5 score is a 
mean of the values recorded for the individual questions. 
Throughout the study participants should complete the ACQ-5 on a weekly basis using 
their eDiary.  
The participant should complete the questionnaire within the eDiary. The participant 
should be instructed to complete the questions as accurately as possible.  The participant 
should be reassured that there are no right or wrong answers.  If the participant 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 investigator should not provide the participant with any answer or attempt to 
interpret any portion of a question. 
If the ACQ-5 is completed through the eDiary while the participant is at a scheduled in 
clinic Visit, it is recommended that the ACQ be administered at the same time during the 
visit. To avoid biasing responses, the participants 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 participant to avoid influencing the participants’ 
response.  Adequate time should be allowed to complete all items on the ACQ. 
8.1.6. 
Clinician/Participant Rated Response to Therapy 
The clinician and the participant will be asked to rate the response to therapy at the visits 
specified in the Time and Events schedule relative to the participant’s asthma at Visit 2 
(immediately prior to the first dose of mepolizumab). This is an overall evaluation of 
response to treatment, conducted separately by the investigator and the participant using a 
rating scale.  In this rating scale, a seven-point scale score is used with the following 
definitions:  
• 1 = 
 
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• 2 = 
 
• 3 = 
 
• 4 = 
 
• 5 = 
 
• 6 = 
 
• 7 = 
.  
The clinician or participant will indicate their response on a paper questionnaire which 
will be transcribed into the eCRF by study designated site staff. 
8.1.7. 
Work Productivity and Activity Impairment Questionnaire: 
General Health (WAPI-GH) 
Asthma has a substantial effect on lost days of works, with millions of days being lost 
each year (Catley, 2011).  Furthermore, asthma results in lost productivity due to 
decreased effectiveness while working (Wilson, 2012).  The WPAI-GH is a self or 
interviewer administered tool comprised of 6 questions which address absenteeism, 
presenteeism (reduced effectiveness while working), overall work productivity loss 
(absenteeism plus presenteeism), and activity impairment.  This validated tool captures 
data from the past 7 days. WPAI-GH outcomes are scored as impairment percentages, 
with a higher percentage indicating greater impairment and less productivity (Reily 
Associates, 2018). 
Participants will initially complete the paper questionnaire, and then the study designated 
site staff will transcribe the information into the eCRF. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Safety Endpoints  
• 
Adverse Events, including both systemic (i.e., allergic/IgE-mediated and non-
allergic) and local injection site reactions reported throughout the 24-week treatment 
period.  
• 
Assessments include Physical examination, vital signs, Electrocardiogram, and 
laboratory evaluation. 
 
8.2.2. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of 
the Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems. Height and weight will also be measured and recorded. 
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• A brief physical examination will include, at a minimum, assessments of the 
abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• Detailed nasal examination for presence or absence of nasal polyps will be 
performed. 
 
8.2.3. 
Vital Signs 
• Oral/ Axillary temperature, pulse rate, respiratory rate, and blood pressure 
will be assessed. 
• Blood pressure and pulse measurements will be assessed in sitting position 
with a completely automated device. Manual techniques will be used only if 
an automated device is not available. 
• Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones). 
• Vital signs (to be taken before blood collection for laboratory tests) will 
consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood 
pressure readings will be recorded at intervals of at least 1 minute). The 
average of the 3 blood pressure readings will be recorded on the CRF. 
 
8.2.4. 
Electrocardiograms 
• Electrocardiogram measurements will be made after the participant has rested 
in the supine position for 5 minutes. The ECG should be obtained 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. 
• 
A single twelve-lead ECG will be obtained at each timepoint specified in the 
Schedule of Activities (Section 1.3). If a routine single ECG demonstrates a 
prolonged QT interval, obtain two more ECGs over a brief period (eg: 5-10 
mins), 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 (Section 7.1.2) for QTc withdrawal criteria. 
• Paper traces are required to be maintained at the site with other source 
documents. 
8.2.5. 
Steroid withdrawal examination review, where applicable 
• Assessment of steroid withdrawal (i.e. the signs and symptoms of adrenal 
insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and 
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8.2.6. 
Clinical Safety Laboratory Assessments 
• Refer to Appendix 2 for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency.  
• The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline 
or are no longer considered significantly abnormal by the investigator or 
medical monitor.  
• If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the 
sponsor notified. 
• All protocol-required laboratory assessments, as defined in Appendix 2, must 
be conducted in accordance with the laboratory manual and the SoA.  
 
8.2.7. 
Suicidal Ideation and Behaviour Risk Monitoring 
This is not applicable to this study. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
The following adverse events of special interest will have customized AE and SAE pages 
in the eCRF:  
• Systemic reactions  
• Local injection site reactions 
In addition, the investigator will be requested to assess events they consider systemic 
reactions against diagnostic criteria of anaphylaxis, and record in the CRF whether an 
event met the diagnostic criteria for anaphylaxis as outlined by the Second Symposium 
on Anaphylaxis [Sampson, 2006] and in Appendix 7 
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 
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8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the start of intervention until the end of 
study visit at the time points specified in the SoA (Section 1.3).  However, 
any SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in 
existing therapy) will be recorded from the time a participant consents to 
participate in the study.  
• All AEs will be collected from the start of intervention until the end of 
study visit at the time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but 
after obtaining informed consent will be recorded on the Medical 
History/Current Medical Conditions section of the case report form (CRF) 
not the AE section. 
• All Initial SAEs will be recorded and reported to the sponsor or designee 
immediately and under no circumstance should this exceed 24 hours of 
occurrence, as indicated in Appendix 3. The investigator will submit any 
updated SAE data /follow-up information to the sponsor within 24 hours 
of  site awareness. 
• Investigators are not obligated to actively seek AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns 
of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator 
must promptly notify the sponsor. 
 
8.3.2. 
Method of Detecting AEs and SAEs 
• The method of recording, evaluating, and assessing causality of AEs and 
SAEs and the procedures for completing and transmitting SAE reports are 
provided in Appendix 3. 
• Care will be taken not to introduce bias when detecting AE and/or SAE. 
Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study 
intervention under clinical investigation. The sponsor will comply with 
country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE 
or other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure 
and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the 
start of study intervention and until 4 months after the last dose. 
• 
If a pregnancy is reported, the investigator should inform GSK within 24 
hours of learning of the pregnancy and should follow the procedures outlined 
in Appendix 4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAE. 
 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 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 as per SAE 
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8.4. 
Treatment of Overdose 
The dose of mepolizumab considered to be an overdose has not been defined. There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. The investigator will use clinical judgment in treating the symptoms 
of a suspected overdose. 
In the event of an overdose, the investigator/ treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
mepolizumab can no longer be detected systemically (at least 90 days). 
3. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters will not be evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamics parameters will not be evaluated in this study. 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers will not be evaluated in this study. 
8.8.1. 
Immunogenicity Assessments 
Antibodies to mepolizumab will be evaluated in serum samples collected from all 
participants according to the SoA. An attempt will be made to collect the serum sample at 
the IP discontinuation visit or end of study visit from participants who discontinued study 
intervention or were withdrawn from the study. 
Serum samples will be analysed with validated analytical methods using a tiered 
approach: screening, confirmation, titration and neutralizing analysis. Positive screening 
samples will continue with the confirmation analysis. Positive confirmation samples will 
be reported as positive for ADA. Positive confirmation samples will be evaluated for a 
relative assay binding response to report a titer value and whether the antibody response 
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8.9. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
No formal hypothesis testing is considered. 
9.2. 
Sample Size Determination 
The primary objective of the study is to evaluate the safety and tolerability of 
mepolizumab over 24 weeks of treatment. The primary endpoint is incidence of AEs, 
SAEs and AESIs. Sample size is determined based on the calculation of the probability of 
observing an AE. Table 3 provides the probabilities of observing various numbers of AEs 
based on a series of theoretical risks of an event occurring in a given patient in a study of 
24 weeks duration, given a sample size of 100. For example, for a theoretical risk of an 
AE of 2/100 (true proportion value of 0.02) in this 24-week study, we would have a 
greater than 86% chance of observing at least one subject having the AE. 
Table 3 
Probabilities of observing a given number of subjects experiencing 
an adverse events or more (k) for given anticipated risks for a 
sample size of 100 patients 
Theoretical Risk of an Event* 
 
K 
0.05 
0.03 
0.02 
0.01 
0.005 
1 
0.9941 
0.9524 
0.8673 
0.6340 
0.3942 
2 
0.9629 
0.8053 
0.5967 
0.2642 
0.0898 
3 
0.8817 
0.5802 
0.3233 
0.0794 
0.0141 
4 
0.7422 
0.3528 
0.1411 
0.0184 
0.0017 
5 
0.5640 
0.1821 
0.0508 
0.0034 
0.0002 
6 
0.3840 
0.0808 
0.0155 
0.0005 
≤ 0.0001 
7 
0.2340 
0.0312 
0.0041 
≤ 0.0001 
≤ 0.0001 
8 
0.1279 
0.0106 
0.0009 
≤ 0.0001 
≤ 0.0001 
9 
0.0631 
0.0032 
0.0002 
≤ 0.0001 
≤ 0.0001 
10 
0.0282 
0.0009 
≤ 0.0001 
≤ 0.0001 
≤ 0.0001 
*Theoretical risk of an event occurring in a given patient in a study of 24 weeks duration. 
Assuming a 35% screen failure rate approximately 154 participants will be required to be 
screened in order for 100 participants to be enrolled onto the study treatment 
 


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9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
 All participants enrolled and for whom a record exists on the study 
database. This population will be used for summarizing reasons for 
screen and run-in failures. 
Safety 
All participants who take at least 1 dose of study intervention. This 
population will be used for all safety, efficacy and health outcomes 
analyses. 
 
9.4. 
Statistical Analyses 
All analyses of safety data and efficacy data will be generated for the Safety Population. 
Additionally separate subgroup analyses will also be generated by with/without baseline 
maintenance OCS use (with separate summaries in those participants receiving 
maintenance OCS at baseline and those not maintenance OCS at baseline). 
The study Statistical Analysis Plan (SAP) will be finalised prior to database lock which 
will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important primary, secondary and exploratory endpoints.  


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9.4.1. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
The study estimands are defined within Section 3 (Objectives and Endpoints). Further 
details regarding the estimation of each estimand is defined within the table below. 
Endpoint 
Statistical Analysis Methods 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by body system and preferred term. The number and 
percentage of participants experiencing at least one AE of any type, AEs within each 
body system and AEs within each preferred term will be presented. Separate summaries 
will be provided for all AEs, drug related AEs, fatal AEs, non-fatal SAEs, adverse events 
of special interest (AESIs) and AEs leading to withdrawal. Deaths and SAEs, if 
applicable, will be documented in case narrative format. Adverse events of special 
interest will include both systemic (i.e., allergic/IgE-mediated and non-allergic) and local 
injection site reactions for which further details will be collected through targeted eCRF 
pages. 
In addition, Vital Signs, 12 Lead ECG, Laboratory and Immunogenicity data will be 
summarised using a treatment policy strategy for the intercurrent event of treatment 
discontinuation, therefore reporting all data collected until study completion or 
withdrawal. 
9.4.2. 
Efficacy Analyses 
All efficacy analyses will be performed on the Safety Population. 
The study estimands are defined within Section 3 (Objectives and Endpoints). Further 
details regarding the estimation of each estimand is defined within the table below. 
 
Taking prohibited medication during the treatment period is an important protocol 
deviation (PD) and will be included in the PD summary. However, this is not considered 
as an intercurrent event for the estimands defined within this study. 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
• 
The number of clinically significant exacerbations (including 
exacerbations requiring hospitalization or ED visits) will be analysed 
using Negative Binomial regression via generalised estimating 
equations  with a covariate of time period (pre-, post-mepolizumab) 
with follow-up time within each period included as an offset within 
the model. The exacerbation rates during the pre- and post-treatment 
with mepolizumab will be presented, including rate ratio comparing 
of pre- and post-mepolizumab periods and presented with 


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Endpoint 
Statistical Analysis Methods 
corresponding 95% confidence interval.  
A treatment policy strategy will be utilised for the intercurrent event 
of treatment discontinuation.  The period of time for which 
exacerbation information will be included in the post-mepolizumab 
period will be from the start of treatment until the week 24 visit, 
regardless of treatment discontinuation. For those participants with 
premature study withdrawal, the time period will include from the 
start of treatment until the date of withdrawal. Missing data 
(following early withdrawal) will be assumed to be missing at 
random (MAR) following subject withdrawal from the study. 
Analyses will also be conducted separately using the same analysis 
model and period definitions for exacerbations requiring 
hospitalization/ED visits and also exacerbations requiring 
hospitalization.  
• 
Analysis of change from baseline in clinic pre- bronchodilator FEV1 
and post-bronchodilator FEV1 at Week 24 will be performed 
analysed as separate endpoints using a mixed models repeated 
measures (MMRM) analyses, allowing for covariates of visit, 
baseline maintenance OCS  use (yes, no) and exacerbations in the 
year prior to the study (as an ordinal variable). All data will be 
included in the endpoint analysis will be from the start of treatment 
until the week 24 visit, regardless of treatment discontinuation. Mean 
change from baseline in FEV1 will be summarised and presented with 
95% confidence interval by visit. Comparisons will be Week 24 vs. 
Baseline, and all data collected up to and including Week 24, 
including participants who have discontinued study treatment, will be 
included in the analyses. Missing data (following early withdrawal) 
will be assumed to be missing at random (MAR) following subject 
withdrawal from the study. 
• 
Analysis of change from baseline in ACQ-5 score will be performed 
using a mixed models repeated measures (MMRM) analysis, 
allowing for covariates of visit, baseline maintenance OCS  use (yes, 
no) and exacerbations in the year prior to the study (as an ordinal 
variable). All data will be included in the endpoint analysis will be 
from the start of treatment until the week 24 visit, regardless of 
treatment discontinuation. Mean change from baseline in ACQ-5 
score will be summarised and presented with 95% confidence 
interval by visit. Comparisons will be Week 24 vs. Baseline, and all 
data collected up to and including Week 24, including participants 
who have discontinued study treatment, will be included in the 
analyses. Missing data (following early withdrawal) will be assumed 
to be missing at random (MAR) following subject withdrawal from 
the study. 
• 
Analysis of change from baseline in morning PEF during Weeks 20 – 


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Endpoint 
Statistical Analysis Methods 
24 will be performed using a mixed models repeated measures 
(MMRM) analysis, allowing for covariates of visit, baseline 
maintenance OCS  use (yes, no) and exacerbations in the year prior 
to the study (as an ordinal variable). All data will be included in the 
endpoint analysis will be from the start of treatment until the week 24 
visit, regardless of treatment discontinuation. Mean change from 
baseline in PEF will be summarised and presented with 95% 
confidence interval by analysis period.  Comparisons will be Weeks 
20–24 vs. Baseline, and all data collected up to and including Weeks 
20–24, including participants who have discontinued study treatment, 
will be included in the analyses. Missing data (following early 
withdrawal) will be assumed to be missing at random (MAR) 
following subject withdrawal from the study. 
 
9.4.3. 
Health Outcomes Analyses 
All health outcome analyses will be performed on the Safety Population. 
Statistical Analysis Methods 
Clinician and Participant-Rated response to therapy and WPAI-GH composite scores at 
week 24 will be summarised using a treatment policy strategy for the intercurrent event 
of treatment discontinuation, therefore reporting all data collected until study completion 
or withdrawal. No statistical analysis will be performed. 
9.5. 
Interim Analyses 
An analysis to present cumulative data may be completed if required. 
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9.5.1. 
Data Monitoring Committee (DMC) 
Data Monitoring Committee is not used for this study. 


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


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10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study 
to the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. 
Participants or their legally authorized representative will be required to sign 
a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study centre.  
• 
The medical record must include a statement that written informed consent 
was obtained before the participant was enrolled in the study and the date the 
written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
 
10.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any 
participant records or datasets that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make 
the participant identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will 
be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be 
examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
Not applicable for this study. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. 
If this is foreseen, the investigator agrees to submit all manuscripts or 


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abstracts to the sponsor before submission. This allows the sponsor to protect 
proprietary information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study 
results. In accordance with standard editorial and ethical practice, the sponsor 
will generally support publication of multicentre studies only in their entirety 
and not as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
10.1.6. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator 
signatory will be identified for the approval of the clinical study report.  The 
investigator will be provided reasonable access to statistical tables, figures, 
and relevant reports and will have the opportunity to review the complete 
study results at a GSK site or other mutually-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study 
will be in accordance with GSK Policy. 
• 
GSK intends to make anonymized patient-level data from this trial available 
to external researchers for scientific analyses or to conduct further research 
that can help advance medical science or improve patient care. This helps 
ensure the data provided by trial participants are used to maximum effect in 
the creation of knowledge and understanding 
10.1.7. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on electronic CRF. 
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to source 
data documents.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in 
operations and quality such as Risk Management and Mitigation Strategies 
and Analytical Risk-Based Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 


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• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of 
this study must be retained by the investigator for 30 years from the issue of 
the final Clinical Study Report (CSR)/ equivalent summary unless local 
regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
10.1.8. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at 
the investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• 
Definition of what constitutes source data can be found in Data Management 
Plan. 
 
10.1.9. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 


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• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 4 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Pregnancy Testing  
• 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• 
Additional serum or urine pregnancy tests will be performed at all clinic 
visits per SoA and as determined necessary by the investigator to establish 
the absence of pregnancy at any time during the participant's participation in 
the study. 
Table 4 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC 
count 
with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ 
Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total 
and 
direct bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ 
Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
[non 
fasting- 
Random]2 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen by 


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Laboratory 
Assessments 
Parameters 
dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Screening 
Tests 
• Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) 
• Highly sensitive Serum/ urine human chorionic gonadotropin 
(hCG) pregnancy test (as needed for women of childbearing 
potential) 
• Serology- hepatitis B surface antigen [HBsAg], and hepatitis C 
virus antibody  
The results of each test must be entered into the CRF. 
Immunogenicity 
test 
• Antibodies to mepolizumab will be evaluated in serum samples 
collected from all participants 
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up 
assessments after liver stopping or monitoring event are given in Section 7.1 and 
Appendix 6. All events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × 
ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio 
(INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s 
Law), must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis). 
2. Investigator may ask for fasting and post prandial blood sugar examination at his/her 
discretion should random sample shows clinically significant value 
 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention. 
• 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 


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Events NOT Meeting the AE Definition  
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 


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Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3.3. 
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 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 


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AE and SAE Recording 
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. 
• 
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. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any significant updated / additional information in the 
SAE report section of the pdf,, scan and forward to GSK as a follow up report within 
24 hours of awareness of the additional information. 
• 
A minimum of up to 3 attempts to follow up within 3 weeks after the last visit to be 
done by the site before case closure 
• 
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 subject to conduct of post mortem, within 24 hours 
of awareness of this information. 
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. 
Alternatively, National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI- CTCAE) version 4.03 or updated will be used to evaluate AE and SAE 
 


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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. 
• 
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. 
• 
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 
• 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will try to provide GSK with a copy of any post-mortem 
findings including histopathology 
• 
New or updated information will be recorded in the originally completed CRF. 


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Follow-up of AE and SAE 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK  
• 
The primary mechanism for reporting SAE to GSK will be via email. 
• 
Site will use the Table 5 format (GSK SAE report) in order to report the event within 
24 hours of occurrence. 
• 
The site will enter the SAE data into the electronic system case report form (eCRF) 
of the CRO as soon as it becomes available and a pdf copy of completed SAE pages 
along with relevant pages of eCRF which contain same information mentioned in 
Table 5 format (GSK SAE report) will be sent to GSK for reporting the SAE. Details 
of SAE reporting with contact information will be captured in the Study Reference 
Manual (SRM). 
• 
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. 
• 
After the study is completed at a given site, the electronic case report form  
(eCRF)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 case report form  (eCRF)  has 
been taken off-line, then the site can report this information  to the medical 
monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in Title page. 
• 
The regulatory definition of Day 0 is the day when GSK or its agents first become 
aware of a valid case.  
• 
All SAEs must be submitted to CDSCO in Table 5 format (GSK SAE Report). . 
• 
PSRIs (Periodic Safety Report for Investigators) are uploaded by Global Safety in 
Veeva Clinical Operations Vault (COV). Veeva SRD (Safety Report Distribution) 
disseminates PSRIs to sites directly (SRD uses e-track contact for dissemination).  
• 
Soft / Hard copies of PSRIs will be sent to the sites by TO for EC notification. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
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. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
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10.4.2. 
Contraception Guidance:  
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of 
<1% per year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per 
year when used consistently and correctly. 
• 
Combined 
(estrogen- 
and 
progestogen-containing) 
hormonal 
contraception 
associated with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
• 
Sexual abstinence 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a. Contraceptive use by 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. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
 
 


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• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception. Male condom and female 
condom should not be used together (due to risk of failure with friction) 
10.4.3. 
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 be withdrawn 
from the study 


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10.5. 
Appendix 5: New York Heart Association Functional 
Classification of Congestive Heart Failure 
Class 
Patient Symptoms 
Class 
I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnoea (shortness of breath). 
Class 
II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnoea. 
Class 
III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnoea. 
Class 
IV 
(Severe) 
Unable to carry out any physical activity without discomfort. Symptoms 
of cardiac insufficiency at rest. If any physical activity is undertaken, 
discomfort is increased. 
Adapted from American Heart Association, 2017 


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10.6. 
Appendix 6: 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 aetiology  
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 
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 
intervention  
• Report the event to GSK within 24 
hours 
• Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2 
• Perform 
liver 
event 
follow 
up 
assessments  
• Monitor 
the 
participant 
until 
liver 
chemistries resolve, stabilize, or return to 
within baseline   i.e. Visit 3 (see 
• 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. 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• Fractionate 
bilirubin, 
if 
total 


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Liver Chemistry Stopping Criteria  
MONITORING below) 
• Do not restart/rechallenge participant 
with study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (refer to Appendix 
6)  
• If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
intervention 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 
INR) and perform liver event follow up 
assessments within 24 hrs 
• Monitor participants twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline i.e. Visit 3 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin and 
INR) and perform liver event follow up 
assessments within 24-72 hrs  
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline i.e. Visit 3 
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]).  
• Liver imaging (ultrasound, magnetic 
resonance, 
or 
computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum 
bilirubin fractionation is not immediately available, discontinue study intervention for 
that participant if ALT  3xULN and bilirubin  2xULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
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2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT 
 3xULN and INR>1.5 which may indicate severe liver injury (possible ‘Hy’s Law’), 
must be reported as an SAE (excluding studies of hepatic impairment or 
cirrhosis); the 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 immunoglobulin M (IgM) antibody; HBsAg and HBcAb; 
hepatitis C RNA; cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen 
IgM antibody (or if unavailable, heterophile antibody or monospot testing); and 
hepatitis E IgM antibody.  
5. If hepatitis delta antibody assay cannot be performed, it can be replaced with a 
polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal, 
2005]. 
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 intervention.  
Participant must return weekly for repeat 
liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until they resolve, 
stabilise or return to within baseline i.e. Visit 
3 
• 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 i.e. Visit 3. 


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10.7. 
Appendix 7: Anaphylaxis Criteria 
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the 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) 
1. 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., dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
c. 
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
2. 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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10.8. 
Appendix 8 : Daily Asthma Symptom Score 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party copyright 
laws and therefore have been excluded.


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10.9. 
Appendix 9 - Criteria for e-Diary Alerts Indicative of a 
Potential Asthma Worsening 
Criteria1 Definition 
1 
Mean AM PEF <80% of baseline stability limit 
2 
Mean asthma-related night time awakenings >50% increase over the baseline 
period (per night), >150% of the baseline mean 
3 
Rescue medication use requiring 4 or more puffs/day above the mean baseline 
value for any 2 consecutive days in the prior week, or 12 puffs or more on 
any one day in the prior week 
4 
Change in ACQ-5  +0.5 from the prior month OCS dose assessment 
5 
Symptoms of adrenal insufficiency 
1. Baseline means for AM PEF, night time awakenings, and rescue medication use are 
calculated on a per night or per day basis using participant diary information from the 
7 days prior to Visit 2 
 


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10.10. 
Appendix 10: Study Procedures during COVID-19 Pandemic 
 
Overall Rationale for this Appendix 
 
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures, including administering or using the investigational 
product or adhering to protocol-mandated visits and laboratory/diagnostic testing. 
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. These measures will remain in place until the site is able to resume normal 
working activities. 
 
Please reference Protocol Section 7.1.4 for further details regarding COVID-19 testing. 
 
• COVID-19 tests during the study may be performed, as determined by the 
investigator or local guidelines. 
• All positive COVID-19 tests should be reported on the COVID-19 eCRFs and the 
AE/SAE eCRFs, as appropriate. 
• Participants that test positive for COVID-19 do not have to discontinue study 
intervention. 
• Positive tests should be reported to the appropriate local government authorities, 
per local regulations. 
 
 
Study Procedures During COVID-19 Pandemic 
 
During the special circumstances caused by the COVID-19 pandemic, sites should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when considering the need for a participant to attend the site for a visit.  
For the duration of these special circumstances, home healthcare visits (home visits and 
telemedicine visits; see below) may be implemented for scheduled visits from Visit 3 
onwards for participants unable to attend a site visit due to COVID-19 related 
restrictions.   
  
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, however when not possible, for the duration of these special 
circumstances, the following measures may be implemented for enrolled participants:: 
 
• Clinical investigators should document in site files and in participant 
notes/Electronic Heath Records as appropriate how restrictions related to COVID-
19 led to the changes in study conduct and duration of those changes, and indicate 


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which trial participants were impacted and how those trial participants were 
impacted (as per the current local COVID-19 related regulatory guidance). 
• Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation and captured 
within the eCRF COVID-19 study impact forms. Visits that were conducted via 
the telephone will not be classified as missed visits;  however, missed assessments 
(e.g. spirometry) should be recorded as COVID-19 protocol deviations and 
captured within the eCRF COVID-19 study impact forms. 
 
Home Healthcare 
Home healthcare is defined as:  
• Visits at the participant’s home, and  
• Telemedicine visits. 
Where applicable country and local regulations and infrastructure allow, home health 
care can be performed at the discretion of the investigator and following the participant 
signing of an informed consent form specific for home healthcare.  
Home visits at the participant’s home 
These are performed at the participant’s home by qualified home healthcare personnel 
(e.g., nurse) when the participants is unable to attend a site visit due to COVID-19 
restrictions and the Investigator deems that a site visit is not necessary.   
Telemedicine visits 
These are defined as online (virtual) visits which use secure video conferences, phone 
calls, or a web portal and/or mobile application as a way of communicating with and 
monitoring the participant’s progress and safety.  Telemedicine visits are conducted by an 
investigator or designee and may be done in combination with a home visit by a qualified 
personnel/ nurse. 
The study investigator is responsible for ensuring that the identification, management, 
and reporting of exacerbations, AEs and SAEs are completed in accordance with the 
protocol and applicable regulations.  AEs are first reported by participants to the 
investigator/site staff or may be identified during interactions with the participants via 
telemedicine visits.  In addition, healthcare personnel who are visiting participants at 
home may identify AEs as well and report them to the investigator for evaluation.  
The participant should be informed of the home healthcare plan and any potential risks 
associated with home visits and telemedicine. The participant must sign an informed 
consent form specific to home healthcare. 
 
IRB/Ethics committee should be informed of the introduction of home healthcare in the 
study.  The committee should approve the home healthcare plan and the process should 
be documented in study files. 
 
 


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Study Intervention 
The home healthcare personnel will be responsible for administering the study IP (at the 
discretion of the investigator) according to procedures detailed in the protocol.   
 
 
Protocol Defined Procedures/Visits: 
 
• Study participants in the Treatment Period of the study (Visit 2 to Visit 8 should 
be contacted by sites at each scheduled study visit to collect the following:  
o SAEs 
o AEs 
o Concomitant medication 
Note: the secondary objective of the study is to evaluate the efficacy of 
mepolizumab in participants with severe refractory asthma with elevated 
eosinophils. To evaluate the efficacy, the spirometry assessments “pre- 
bronchodilator FEV1 and post-bronchodilator FEV1” will be conducted. If the 
patient cannot come to site, the spirometry assessments can be conducted at home. 
It is the collective responsibility of Sponsor, site, and CRO to ensure that 
spirometers are available to conduct the home spirometry assessments and 
adequate training of the study personnel to conduct the assessments using all 
precautions and safety measures.  
• The investigator shall contact their participants and intimate about the necessary 
precautions to ensure safety and wellbeing of the patients when encouraging them 
to visit the hospital. Investigator/designee staff need to stay in contact with the 
subject to ensure the end of study visit is completed within the prescribed window 
period (7 Days). 
• Where applicable country and local regulations (India) and infrastructure for 
home healthcare allows, home healthcare may take place at a location other than 
the clinical trial site to perform study assessments, which may include collection 
of blood and urine samples, ECG, spirometry, measurement of vital signs and 
weight, and preparation and administration of study drug (at the discretion of the 
Investigator). It is the responsibility of the investigator to inform Sponsor/CRO 
when this occurs and to document in source notes. 
• Remote visits may be performed at the participant’s home by qualified healthcare 
personnel and/or by relevant lab personnel and if the Investigator deems that a site 
visit is not necessary.  
• Home visit will be done only after patient’s consent for home visit to complete the 
study specific activities such as IP administration, spirometry and ECG 
procedures, as applicable.   
• Additional unscheduled safety assessments such as routine blood sampling may 
be performed at the discretion of the Investigator including in the participant’s 
home, if deemed necessary.  
• If visits to a site/home are not feasible, then the medical evaluation of condition 
may take place by Telemedicine visits using secure video conferences or phone 
calls as a way of communicating with and monitoring the participant’s progress. 


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Sponsor/CRO will work together with the Investigator to ensure that the Site has 
the required equipment, training and support for this model. 
Note: If the Investigator wishes to conduct a trial visit at a location that has not been 
previously assessed by GSK, it is the investigator’s responsibility to identify an adequate 
alternate location and to notify GSK of the alternate location. The investigator should 
ensure that this alternate location meets ICH GCP requirements, is well-equipped to 
perform study procedures and covered by an adequate insurance. Furthermore, the 
investigator should have sufficient oversight to ensure that the staffs at the alternate 
location are trained to perform study procedures. 
 
Study Intervention(s) 
 
• Study teams should consider a home visit for administering the Investigational 
Medicinal Product (IMP) and rescue medication (if needed) to the participant.  
The process for this procedure (Subcutaneous injection of IMP) must be agreed 
with the site who will send the site personnel to perform the activity and 
adequately document in the IMP log.  
• The Principal Investigator assumes Good Clinical Practice (GCP) responsibilities 
for IMP handling and the medical control for dispensing to patients. Site Staff 
should document the dispensing in the Dispensing/Accountability Logs adding a 
comment that this was a home visit.  
IMP includes study medication and ancillary supplies relating to IMP 
administration as needed.  
• In some cases, trial participants who no longer have access to investigational 
product or the investigational site may need additional safety monitoring. 
 
Data Management/Monitoring: 
 
• If on-site monitoring is no longer permitted, Sponsor/CRO will consider remote 
Source Data Verification/Source Document Review (SDV/SDR) where permitted 
by the clinical site/institution. Remote SDV/SDR will be proposed to study sites 
to meet a patient and/or critical quality need, e.g., to assess participant safety or to 
ensure data integrity. In case of remote SDV/SDR, Sponsor/CRO will work with 
the site to ensure subject privacy. 
 
• eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other 
data sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). 
The PI may sign/re-sign the eCRF from any computer/location by accessing the 
EDC platform using his/her unique eCRF log-in credentials. The PI may delegate 
this activity to another medically qualified and trained sub-investigator and this 
must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 
signatures. The sub-investigator must be appropriately trained on the protocol,, 
eCRF requirements (with training documented), and the DoR log updated 
accordingly. 


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• Essential Document Sign Off Process: If an investigator is unable to print and 
sign essential documents such as Protocol  /Amendment signature page then 
Email approval can be accepted by replying to the relevant email that is sent by 
Sponsor/CRO. 


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10.11. 
Appendix 11: Abbreviations and Trademarks 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline 
group 
of 
companies 
NUCALA 
 
 
None 
 


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10.12. 
Appendix 12: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 4 03-AUG-2022 
Overall Rationale for the Amendment: 
i) 
The requirement of oral corticosteroids (OCS) and associated phases (Induction 
phase, optimization phase, OCS reduction/Manitenance phase) has been removed. 
ii) Inclusion criteria (S. no. 5) have been updated from the study to align with the 
current management practice of SEA which does not include use of stable OCS use 
for prolonged periods of time and the changes are in line with Prescribing 
information of the product. 
iii) Stringency of spirometry timings (i.e. must be performed at the same time ±1 hour of 
the visit 1) has been removed. 
iv) The recommendation of triplicate 12-lead ECG within 4 minutes duration has been 
removed. 
v) The information for reporting SAE to GSK has been updated. 
Amendment -3 17-MAR-2021  
Overall Rationale for the Amendment: 
i) As per recommendation by DCGI, Immunogenicity assessments have been added at 
Induction Phase, IP discontinuation Visit/End of Study Visit. Details of 
Immunogenicity testing provided 
Amendment 2 05-NOV-2020 
Overall Rationale for the Amendment: 
i) The time point for IgE (total) are updated and testing for IgE (specific) is removed.  
ii) The immunogenicity testing is no longer applicable for this study 
iii) Changes in the spirometry assessments are made. 
iv) Rescreened patients will be assigned a new screening number.  
v) The guidance to conduct the study during COVID-19 pandemic is added.  
 


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Amendment 1 27-AUG-2019  
Overall Rationale for the Amendment: 
i) The sample size revised to 100 evaluable patients 
(ii) In the inclusion criteria, the age of the patients to be enrolled is ≥18 years 
(iii) IgE levels evaluated before screening of patients 


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Ortega H, Bradford ES, Albers FC, et al.  Long-Term Safety of Mepolizumab in Patients 
with Severe Eosinophilic Asthma: The COLUMBA Study Am J Respir Crit Care Med 
2018;197:A1367.  


TMF-14888313 
CONFIDENTIAL 
 
 
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95 
 
Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380: 651-9. 
Polosa R, Morjaria J. Immunomodulatory and biologic therapies for severe refractory 
asthma. Respir Med 2008; 102:1499-1510. 
Reily Associates. Scoring of WPAI. Available at: 
http://www.reillyassociates.net/WPAI_Scoring.html. Accessed on November 1, 2018.  
Robinson DS, Campbell DA, Durham SR, et al. Systemic assessment of difficult-to-treat 
asthma. Asthma and Allergy Research Group of the National Heart and Lung Institute. 
Eur Respir J 2003;22(3):478-83. 
Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like bronchoalveolar T-
lymphocyte population in atopic asthma. N Engl J Med 1992;326(5):298-304. 
Rothenberg, ME. Eosinophilia. N Engl J Med 1998;338(22):1592-600. 
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. 
Seminario M C and Gleich GJ. The role of eosinophils in the pathogenesis of asthma. 
Curr Opin  Immunol 1994;6(6):860-4. 
Sur S, Gleich GJ, Swanson MC, et al. Eosinophilic inflammation is associated with 
elevation of interleukin-5 in the airways of patients with spontaneous symptomatic 
asthma. J Allergy Clin Immunol 1995;96(5 Part 1):661-68.  
Wardlaw, AJ, Brightling C, Green R, et al. Eosinophils in asthma and other allergic 
diseases. Br Med Bull 2000;56(4):985-1003.  
Wenzel SE. Severe asthma in adults. Am J Respir Crit Care Med 2005; 172:149-160. 
Wilson SR, Rand CS, Cabana MD.  Asthma Outcomes: Quality of life. J Allergy Clin 
Immunol 2012; 129:S89-123. 
 


Signature Page for  209682 TMF-14888313 v1.0
Signature Page for TMF-14888313 v1.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 23-Aug-2022 07:54:08 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  209682
Official Title of Study: A Phase 4, open-label, single arm, 24-week, study to 
evaluate the safety and efficacy of mepolizumab 100 mg SC administered 
every 4 weeks in Indian participants aged ≥18 years with Severe eosinophilic 
asthMa (PRISM)
Date of Document: 21-June-2023


 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
Protocol No. 209682 
 
 
Version 2.0 
 
 
 
 
 
 
 
A Phase 4, open-label, single arm, 24-week, phase 4 study to evaluate the 
safety and efficacy of Mepolizumab 100 mg SC administered every 4 weeks in 
Indian participants aged ≥18 years with Severe eosinophilic asthma requiring 
oral corticosteroid treatment to Maintain asthma control (PRISM) 
 
 
 
 
 
 
 
Author: 
 
Version Number and Date of Protocol: Amendment 04, 13 Aug 2022  
 
 
 
PPD


 
 
 
     
 
        
      
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Statistical Analysis Plan Signature Page 
 
 
Statistical Analysis Plan for Protocol 209682. 
 
 
Upon review of this document, the undersigned approve this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
 
 
 
 
 
 
Approved By: 
 
 
 
 
 
Position: 
Manager - Statistics 
Company: 
GlaxoSmithKline Pharmaceuticals Ltd. 
 
 
 
 
 
 
 
 
Approved By: 
 
 
 
 
 
Position: 
, Statistics  
Company: 
GlaxoSmithKline Pharmaceuticals Ltd. 
 
 
 
PPD
PPD
PPD


 
 
 
     
 
        
      
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Protocol No: 209682 
Version Number: 
V2.0 
 
 
Modification History 
 
Version 
Number 
Date of the Document 
Version 
Author 
Significant Changes from  
Previous Version 
1.0 
17 Feb 2022 
 
Not Applicable – First Version 
2.0 
 8-JUN-2023 
 
As per Protocol Amendment 4  
 
 
 
PPD
PPD


 
 
 
     
 
        
      
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Protocol No: 209682 
Version Number: 
V2.0 
 
Table of Contents 
1. 
GLOSSARY OF ABBREVIATIONS 
6 
2. 
INTRODUCTION 
7 
2.1. 
Responsibilities ................................................................................................................................. 7 
2.2. 
Timing of Analyses ............................................................................................................................ 7 
3. 
STUDY OBJECTIVES 
7 
3.1. 
Primary Objective .............................................................................................................................. 7 
3.2. 
Secondary Objective ......................................................................................................................... 7 
4. 
ESTIMANDS 
8 
5. 
STUDY DESIGN 
12 
5.1. 
Brief Description .............................................................................................................................. 12 
5.2. 
Subject Selection ............................................................................................................................ 14 
5.3. 
Determination of Sample Size ........................................................................................................ 19 
5.4. 
Treatment Assignement and Masking ............................................................................................ 19 
6. 
ANALYSIS POPULATIONS 
19 
6.1. 
All Enrolled Population .................................................................................................................... 20 
6.2. 
Safety Population ............................................................................................................................ 20 
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
20 
7.1. 
General Considerations .................................................................................................................. 20 
7.2. 
Key Definitions ................................................................................................................................ 20 
8. 
INTERIM ANALYSIS 
24 
9. 
SUBJECT CHARACTERISTICS AND STUDY CONDUCT SUMMARIES 
24 
9.1. 
Subject Disposition .......................................................................................................................... 24 
9.2. 
Demographic and Baseline Characteristics .................................................................................... 25 
9.3. 
Medications ..................................................................................................................................... 26 
10. 
STATISTICAL ANALYSIS 
27 
10.1. 
Efficacy Analysis Srategy ............................................................................................................ 27 


 
 
 
     
 
        
      
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10.1.1. Secondary Efficacy Endpoints ..................................................................................................... 27 
10.2. 
Statistical Methods for Secondary Effiacacy Endpoints .................................................................. 28 
10.3. 
Statistical Methods for Health Outcome Endpoints ........................................................................ 32 
10.4. 
Statistical Methods for Exploratory Endpoints ................................................................................ 33 
10.5. 
Subgroup Analysis .......................................................................................................................... 35 
10.6. 
Multipilicty ........................................................................................................................................ 35 
10.7. 
Imputation of Missing Data ............................................................................................................. 35 
11. 
SAFETY ANALYSIS STRATEGY 
35 
11.1. 
Extent of Exposure .......................................................................................................................... 36 
11.2. 
Adverse Events ............................................................................................................................... 36 
11.3. 
Clinical Laboratory Evaluations ....................................................................................................... 39 
11.4. 
Immunogenicity ............................................................................................................................... 41 
11.5. 
Vital Signs ....................................................................................................................................... 41 
11.6. 
12-Lead Electrocardiogram ............................................................................................................. 41 
12 
PROGRAMMING CONSIDERATIONS 
43 
APPENDIX 1. MISSING DATE PROCEDURE 
45 
APPENDIX 2. CORTICOSTEROID CONVERSION FACTORS 
47 
APPENDIX 3. ASSESSMENT VISIT WINDOWS FOR EDIRARY DEVICE VARAIBLES 
49 
APPENDIX 4. CLINICALLY SIGNFICANT EXACERBATIONS 
51 
APPENDIX 5. LIST OF TABLES, FIGURES AND LISTINGS 
52 
 
 
 
 


 
 
 
     
 
        
      
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1. 
GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ACQ 
Asthma Control Questionnaire 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
ENR 
Enrolled 
EOS 
End of Study 
EOT 
End of Treatment 
FVC 
Forced Vital Capacity 
FEV 
Forced Expiratory Volume 
MCH 
Mean Corpuscular Hemoglobin 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
OCS 
Oral Corticosteroid 
PD 
Protocol Deviation 
PEF 
Peak Expiratory Flow 
PT 
Preferred Term  
PP 
Per-Protocol 
RBC 
Red Blood Count 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class 
WBC 
White Blood Count 
WHO DD 
World Health Organization Drug Dictionary 
WPAI-GH 
Work Productivity and Activity Impairment Questionnaire: General Health 


 
 
 
     
 
        
      
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2. 
INTRODUCTION 
The purpose of this document is to provide a description of the statistical methods and procedures to 
be implemented for the analysis of data from GSK 209682 study. This document is based on the 
protocol version Amendment 4, dated 23 August 2022. This Statistical Analysis Plan (SAP) has been 
developed prior to database lock for final analysis. Any changes from the planned analysis as 
described in the protocol GSK 209682 and its amendments (as applicable) are detailed here, and any 
differences described here supersede the analysis presented in the protocol. Any additional analyses 
which are conducted to supplement the planned analyses and any deviations from the planned 
analyses described in this SAP will be documented in the Clinical Study Report (CSR). 
2.1. RESPONSIBILITIES 
Tech Observer will perform the statistical analyses and will be responsible for the production and 
quality control of all tables, figures and listings. This SAP only describes the study population, efficacy 
and safety analyses for this study.  
2.2. TIMING OF ANALYSES 
The primary analysis of efficacy and safety is planned after all subjects completed the final study visit 
or withdraw early from the study. No interim analysis is planned for this study. 
3. 
STUDY OBJECTIVES 
3.1. PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate safety and tolerability of mepolizumab in subjects 
with severe refractory asthma with elevated eosinophils.  
3.2. SECONDARY OBJECTIVE 
The secondary objective of this study is to evaluate the efficacy of mepolizumab in subjects with 
severe refractory asthma with elevated eosinophils. 
 
 


 
 
 
     
 
        
      
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3.3 EXPLORATORY OBJECTIVE 
 
 
4. 
ESTIMANDS 
Primary Endpoints: 
Incidence of on-treatment adverse events (AEs), serious adverse events (SAEs) and adverse events 
of special interest (AESIs). 
The primary estimand for this endpoint is described by the following attributes: 
• 
Population: Severe refractory asthma patients in India with elevated eosinophils. 
• 
Treatment condition: Participants to receive Mepolizumab 100mg SC every 4 weeks during 24 
weeks treatment period. 
• 
Variable/endpoint: Incidence of on-treatment adverse events (AEs), serious adverse events 
(SAEs) and adverse events of special interest (AESIs). 
• 
Summary measure: Counts and percentages for incidence of at least one AE will be summarised 
overall, by system organ class and by preferred term. 
• 
Key Intercurrent events & Strategy: 
• 
Discontinuation of treatment (for any reason) - While on-treatment strategy will be used 
for treatment discontinuation. This will estimate the percentage of participants 
experiencing an AE, while receiving treatment. AEs will be defined as on-treatment 
between the first dose up to and including 28 days following the last dose of 
mepolizumab. 
Supplementary Estimand: 
This supplementary estimand will report all AEs regardless of the discontinuation of study treatment. 
• 
Population: Severe refractory asthma patients in India with elevated eosinophils. 
• 
Treatment condition: Participants to receive Mepolizumab 100mg SC every 4 weeks during 24 
weeks treatment period. 
• 
Variable/endpoint: Incidence of AEs and SAEs 
• 
Key Intercurrent events & Strategy:  
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• Treatment discontinuation (for any reason) - Treatment policy strategy will be used for treatment 
discontinuation. This summary will therefore be inclusive of all on-treatment and post-treatment 
AEs. 
Secondary Endpoints: 
• Number of clinically significant exacerbations (including exacerbations requiring hospitalization or 
ED visits) 
• Number of exacerbations requiring hospitalization or ED visits 
• Number of exacerbations requiring hospitalization 
• Change from baseline in clinic pre-bronchodilator FEV1 at week 24 
• Change from baseline in clinic post bronchodilator FEV1 at week 24 
• Change from baseline in ACQ-5 score at week 24 
• Change from baseline in morning PEF during weeks 20 – 24 
The estimand for the secondary endpoint are detailed here.  
• Number of clinically significant exacerbations (including exacerbations requiring hospitalization or 
ED visits) 
• Number of exacerbations requiring hospitalization or ED visits 
• Number of exacerbations requiring hospitalization 
The above listed secondary endpoint has estimand attributes given below.  
• 
Population: Severe refractory asthma patients in India with elevated eosinophils. 
• 
Treatment condition: Participants to receive Mepolizumab 100mg SC every 4 weeks during 
24 weeks treatment period. 
• 
Variable/endpoint: 
• 
Number of clinically significant exacerbations (including exacerbations requiring 
hospitalization or ED visits)  
• 
Number of exacerbations requiring hospitalization or ED visits   
• 
Number of exacerbations requiring hospitalization 
• 
Summary measure: Rate ratio comparing events/year during the 24-week follow-up period 
compared to the 12 months prior to screening. 
• 
Key Intercurrent events & Strategy: 


 
 
 
     
 
        
      
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• Discontinuation of treatment (for any reason) - Treatment policy strategy will be used 
for treatment discontinuation. This will estimate the treatment effect over the 24 week 
study period regardless of treatment discontinuation. 
The estimand for the remaining secondary endpoints are detailed as following. 
• 
Population: Severe refractory asthma patients in India with elevated eosinophils. 
• 
Treatment condition: Participants to receive Mepolizumab 100mg SC every 4 weeks during 
24 weeks treatment period. 
• 
Variable/endpoint: 
• Change from baseline in clinic pre-bronchodilator FEV1 at week 24 
• Change from baseline in clinic post bronchodilator FEV1 at week 24 
• Change from baseline in ACQ-5 score at week 24 
• Change from baseline in morning PEF during weeks 20 – 24 
• 
Summary measure:  
• Mean change from baseline in clinic pre-bronchodilator FEV1 at week 24  
• Mean change from baseline in clinic post-bronchodilator FEV1 at week 24  
• Mean change from baseline in ACQ-5 score at week 24  
• Mean change from baseline from baseline in morning PEF during weeks 20 – 24 
• 
Key Intercurrent events & Strategy: 
• Discontinuation of treatment (for any reason) - Treatment policy strategy will be used 
for treatment discontinuation. This will estimate the treatment effect over the 24 week 
study period regardless of treatment discontinuation 
Exploratory Endpoints: 
CCI


 
 
 
     
 
        
      
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Health Outcome Endpoints: - 
Health outcome endpoints are Clinician and Participant-Rated response to therapy and WPAI-GH 
composite scores at week 24.  
The estimand for this endpoint is described by the following attributes: 
• 
Population: Severe refractory asthma patients in India with elevated eosinophils. 
• 
Treatment condition: Participants to receive Mepolizumab 100mg SC every 4 weeks during 
24 weeks treatment period. 
• 
Variable/endpoint:  
• Clinician and Participant rated response to therapy at week 24 
• Change from baseline in each of the following WPAI-GH composite scores at week 24:  
- Percent work time missed due to general health 
- Percent impairment while working due to general health 
- Percent overall work impairment due to general health 
- Percent activity impairment due to general health 
• 
Summary measure:  
• Counts and percentages of clinician response rate to the treatment at week 24 
• Counts and percentages of participant response rate to the treatment at week 24 
CCI


 
 
 
     
 
        
      
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• Mean change from baseline in percent work time missed due to general health at week 
24 
• Mean change from baseline in precent impairment while working due to general health 
• Mean change from baseline in percent overall work impairment due to general health 
• Mean change from baseline in percent activity impairment due to general health. 
• 
Key Intercurrent events & Strategy: A treatment policy would be used if intercurrent event 
‘Discontinuation of study treatment for any reason’ occurs. That is, if a subject discontinues 
the study treatment, the data for that subject will be analyzed as collected.   
5. 
STUDY DESIGN 
5.1. BRIEF DESCRIPTION 
This is a Phase IV multi-center, open-label, single arm 24-week study to evaluate the safety and 
efficacy of mepolizumab in subjects with severe refractory asthma with elevated eosinophils.  
Assuming a 35% screen failure rate approximately 154 participants will be required to be screened in 
order for 100 participants to be enrolled onto the study treatment.  
The study schema is provided below. 
V1 
V2* 
V3 
V4 
V5 
V6 
V7 
V8 
-2 weeks to -1 week                                   Mepolizumab 100 mg, SC 
 
W0 
W4 
W8 
W12 
W16 
W20 
W24 
Screening 
visit (-2 
weeks to -1 
week) 
Treatment Period 
End of 
study 
visit 
*All screening procedures will be performed at least -2 weeks to -1 week prior to first dose of mepolizumab at Visit 2 (Week 
0). Screening visit would be at least 7 day prior to dosing visit. 
V, visit; W, week; SC, subcutaneous 
The primary estimand is the incidence of AEs, SAEs and AESIs in adult Indian participants with severe 
refractory asthma with elevated eosinophils while on-treatment with mepolizumab 100mg SC during 
a 24-week study. 


 
 
 
     
 
        
      
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5.1.1. Screening: 
Participants who meet all eligibility criteria at the Screening visit (Visit 1) will enter the study and asked 
to come to the clinic after at least 1 week for Visit 2 (Week 0). Participants must understand and agree 
to use the study drugs for the treatment of asthma, or asthma exacerbation, for the duration of the 
study. OCS use and OCS dose adjustment in participants will be as per the investigator’s discretion 
and clinical practice. At Visit 1, the screening visit, the screening ACQ-5 score will be captured. 
Participants who meet study eligibility criteria, are eligible to enter the Treatment period. All screening 
procedures will be performed -2 weeks to -1 week (screening visit would be at least 7 day prior to 
dosing visit) before first dose of mepolizumab (Visit 2, Week 0). The ACQ-5 questionnaire has been 
validated in several separate studies and the minimal clinically important difference value of +0.5 has 
been established to demonstrate a significant clinical change in asthma status. 
5.1.2. Exacerbation Management: 
Anytime during the study when a participant experiences an exacerbation the exacerbation should be 
treated according to the investigator’s clinical practice. 
5.1.3. Treatment period: 
At Visit 2 (Week 0), participants who meet the Treatment Period eligibility criteria will receive 
Mepolizumab 100mg SC every 4 weeks. Subsequently, participants will continue to receive with 
mepolizumab 100mg SC every 4 weeks. During this period, participants will remain on their baseline 
asthma medications. OCS use and OCS dose adjustment in participants will be as per the 
investigator’s discretion and clinical practice. 
5.1.4. Exacerbation Management during Treatment Period: 
Anytime during the study when a participant experiences an exacerbation the exacerbation should be 
treated according to the investigator’s clinical practice.  
The participant will return for each subsequent Visit, to receive their subsequent doses of open label 
study treatment, as scheduled. 
 


 
 
 
     
 
        
      
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5.1.4. IP Discontinuation Visit: 
The IP discontinuation visit will be performed 4 weeks following the last dose of mepolizumab with a 
window of ±7 days. Also, if a participant permanently stops study intervention, the participant is not 
required to withdraw from the study. Every effort should be made by the PI/staff to keep the subject 
in the study to collect important efficacy and safety data. In the event of discontinuation of study, the 
end of study visit activities should be performed as specified in SoA table. 
5.1.5. End of Study Visit: 
A participant is considered to have completed study treatment if he/she has received a dose of 
mepolizumab at Visit 7 (Week 20) of the study. A participant is considered to have completed the 
study if he/she has completed the 24 week treatment period of the study including the end of study 
visit. The end of the study is defined as the date of the last visit of the last participant in the study. 
5.2. SUBJECT SELECTION 
5.2.1. Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent. 
2. Evidence of asthma as documented by either: 
• Airway reversibility (FEV1≥12% and 200 ml) demonstrated at Visit 1 (screening), or Visit 2 
(Week 0) OR documented in the previous 12 months OR 
• Airway hyper-responsiveness (methacholine: PC20 of <8mg/mL or histamine: PD20 of <7.8 
μmol; mannitol: decrease in FEV1 as per the labelled product instructions) documented in the 
12 months prior to Visit 2 (Week 0) OR 
• Airflow variability in clinic FEV1 ≥20% between two consecutive clinic visits documented in the 
12 months prior to Visit 2 (FEV1 recorded during an exacerbation should not be considered 
for this criteria) OR 
• 
Airflow variability as indicated by >20% diurnal variability in peak flow observed on 3 or more 
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3. 
Participants with Eosinophilic asthma: prior documentation of eosinophilic asthma or high 
likelihood of eosinophilic asthma as 
FEV1: Persistent airflow obstruction as indicated by: 
For participants ≥ 18 years of age at Visit 1 (screening), or Visit 2 (Week 0), a prebronchodilator 
FEV1 <80% predicted 
For predicted FEV1 values NHANES III values will be used and adjustments to these values will 
be made for race [Hankinson, 1999]. 
4. 
Eosinophilic Phenotype: Airway inflammation characterized as eosinophilic in nature as indicated 
by one of the following characteristics: 
a. An elevated peripheral blood eosinophil level of ≥300 cells/μL that is related to asthma within 
the previous 12 months prior to Visit 2 (Week 0) OR 
b. Peripheral baseline eosinophil level ≥150 cells/μL between Visit 1 (screening) and Visit 2 
(Week 0) that is related to asthma. 
5. 
Patients eligible for mepolizumab treatment as per independent clinical judgment of treating 
physician in alignment with local prescribing information. 
6. 
Inhaled Corticosteroids: requirement for regular treatment with high dose inhaled corticosteroid 
in the 6 months prior to Visit 1 (screening). 
For 18 years of age and older: 
• ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-actuator) or equivalent daily. 
7.   Controller Medication: Current treatment with an additional controller medication for at least 3 
months OR having used and failed an additional controller medication for at least 3 successive 
months during the prior 12 months [e.g., long-acting beta2-agonist (LABA), leukotriene receptor 
antagonist (LTRA), or theophylline]. 
Sex 
8.    Male or eligible female 
Contraceptive use by women should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. 
Female Participants: 


 
 
 
     
 
        
      
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A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
one of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP) 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of 
<1%, as described in Appendix 4 of the protocol during the intervention period and for at least 16 
weeks 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 (Appendix 2 of the protocol) pregnancy test 
(serum) within 8 weeks before the first dose of study intervention. 
• Additional requirements for pregnancy testing during and after study intervention are located 
in Appendix 2 of the protocol. 
• The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy 
Informed Consent 
9. Capable of giving signed informed consent as described in Appendix 1 of the protocol which 
includes compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2.2. Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Concurrent Respiratory Disease: Presence of a clinically important lung condition other than 
asthma. This includes but is not limited to current infection, 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. 
2. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months 
prior screening (Participants who had localized carcinoma (i.e. basal or squamous cell) of the skin 
which was resected for cure will not be excluded). 
3. Liver Disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, 


 
 
 
     
 
        
      
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and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic 
gallstones). 
4. Cardiovascular: Participants who have severe or clinically significant cardiovascular disease 
uncontrolled with standard treatment. Including but not limited to: 
• Known ejection fraction of <30% OR 
• severe heart failure meeting New York Heart Association Class IV (Appendix 5 of the protocol) 
OR 
• 
hospitalized in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart 
Association Class III (Appendix 5 of the protocol) OR 
• 
angina diagnosed less than 3 months prior to Visit 1 (screening) or at Visit 1 
5. Other Concurrent Medical Conditions: Participants 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.  
6. Eosinophilic Diseases: Participants with other conditions that could lead to elevated eosinophils 
such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic 
Esophaghitis.  
7. Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 
(screening) are also to be excluded. 
Prior/Concomitant Therapy 
8. Omalizumab Use: Participants who have received omalizumab [Xolair] within 130 days of Visit 1 
(screening)  
9. Other Monoclonal Antibodies: Participants who have received any monoclonal antibody (other than 
Xolair) to treat inflammatory disease within 5 half-lives of Visit 1 (screening). 
10. Investigational Medications: Participants 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). 
Prior/Concurrent Clinical Study Experience 
11. Participants who have previously participated in any study of mepolizumab and received 
Investigational Product (including placebo). 
Diagnostic assessments 
12. 
ECG: ECG assessment QTcF > 450msec or QTcF > 480 msec for participants with Bundle 
Branch Block. 


 
 
 
     
 
        
      
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Participants are excluded if an abnormal ECG finding from the 12-lead ECG conducted at Screening 
(Visit 1) is considered to be clinically significant and would impact the participant’s participation 
during the study, based on the evaluation of the Investigator. 
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. 
COVID-19 Related Exclusion 
14. Participants that have a current active COVID-19 infection, either laboratory confirmed or 
according to the investigator’s medical judgement. 
Note: Participants who have confirmed or suspected COVID-19 infection may be rescreened 4 
weeks or more after the resolution of the COVID-19 infection and only after written approval from 
the study Medical Monitor.  
15. Participants known to be in contact with active COVID-19 positive individuals within the past 14 
days. 
Note: Participants may be re-screened 14 days or more following the contact, during which the 
participant should remain symptom free, and only after written approval from the study Medical 
Monitor.  
Other Exclusions 
16. Smoking history: Current smokers or former smokers with a smoking history of ≥10 pack years. A 
former smoker is defined as a participant who quit smoking at least 6 months prior to Visit 1 
(screening) 
17. Hypersensitivity: Participants with a known allergy or intolerance to a monoclonal antibody or 
biologic. 
18. Pregnancy: Participants who are pregnant or breastfeeding. Patients should not be enrolled if they 
plan to become pregnant during the time of study participation.  
19. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse 
within 2 years prior to Visit 1 (screening). 
20. Adherence: Participants who have known evidence of lack of adherence to controller medications 
and/or ability to follow physician’s recommendations. 
Re-screening of participants will be allowed only upon approval by the medical monitor. 
 


 
 
 
     
 
        
      
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5.3. DETERMINATION OF SAMPLE SIZE 
The primary objective of the study is to evaluate the safety and tolerability of mepolizumab over 24 
weeks of treatment. The primary endpoint is incidence of AEs, SAEs and AESIs. Sample size is 
determined based on the calculation of the probability of observing an AE. Table 3 provides the 
probabilities of observing various numbers of AEs based on a series of theoretical risks of an event 
occurring in a given patient in a study of 24 weeks’ duration, given a sample size of 100. For example, 
for a theoretical risk of an AE of 2/100 (true proportion value of 0.02) in this 24-week study, we would 
have a greater than 86% chance of observing at least one subject having the AE. 
Table Probabilities of observing a given number of subjects experiencing an adverse events or more 
(k) for given anticipated risks for a sample size of 100 patients. 
Theoretical Risk of an Event* 
No of AEs 
5% risk 
3% risk 
2% risk 
1% risk 
0.5% risk 
K 
0.05 
0.03 
0.02 
0.01 
0.005 
1 
0.9941 
0.9524 
0.8673 
0.6340 
0.3942 
2 
0.9629 
0.8053 
0.5967 
0.2642 
0.0898 
3 
0.8817 
0.5802 
0.3233 
0.0794 
0.0141 
4 
0.7422 
0.3528 
0.1411 
0.0184 
0.0017 
5 
0.5640 
0.1821 
0.0508 
0.0034 
0.0002 
6 
0.3840 
0.0808 
0.0155 
0.0005 
≤ 0.0001 
7 
0.2340 
0.0312 
0.0041 
≤ 0.0001 
≤ 0.0001 
8 
0.1279 
0.0106 
0.0009 
≤ 0.0001 
≤ 0.0001 
9 
0.0631 
0.0032 
0.0002 
≤ 0.0001 
≤ 0.0001 
10 
0.0282 
0.0009 
≤ 0.0001 
≤ 0.0001 
≤ 0.0001 
*Theoretical risk of an event occurring in a given patient in a study of 24 weeks’ duration. 
Assuming a 35% screen failure rate approximately 154 participants will be required to be screened in 
order for 100 participants to be enrolled onto the study treatment. 
5.4. TREATMENT ASSIGNEMENT AND MASKING 
This is an open-label study. All subjects enrolled in the induction phase will receive the study drug 
(100 mg mepolizumab SC every 4 weeks). 
6. 
ANALYSIS POPULATIONS 
For the purpose of analysis, the following population are defined: 


 
 
 
     
 
        
      
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6.1. ALL ENROLLED POPULATION  
All participants enrolled and for whom a participant number exists on the study database. This 
population will be used for summarizing reasons for screen and run-in failures.  
6.2. SAFETY POPULATION 
All participants who take at least 1 dose of study intervention. This population will be used for all 
safety, efficacy and health outcomes.  
7. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
7.1. GENERAL CONSIDERATIONS 
Continuous data will be summarized using the number of subjects (n), arithmetic mean (mean), standard 
deviation (SD), median, minimum value (min), and maximum value (max) values unless otherwise 
specified. Categorical variables will be summarized using the frequency counts (n) and percentages (%) 
for each possible value. Where log-transformed data are used, the summary statistics will include 
geometric mean and geometric standard deviation (SD). Only data from protocol scheduled visits will be 
included in the summary tables.  Data from unscheduled visits will not be included in the summary tables 
but will be included in the by-subject listings.  
7.2. KEY DEFINITIONS 
7.2.1. Study/Onset Day 
The study/onset day will be defined as the number of days since the first dose of study drug, which 
is assigned as Day 1 for analysis purposes.  Study/onset day is calculated using the formula below: 
Assessment Date Relative to First Dose of Study 
Drug 
Study Day Calculation 
Assessment/Event date < Date of first dose 
Date of assessment - Date of first dose of 
study drug 
Assessment/Event date ≥ Date of first dose 
(Date of assessment – Date of first dose 
of study drug)+1 
 
 
 


 
 
 
     
 
        
      
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7.2.2. Baseline, Change from Baseline, Relative Change from Baseline and Ratio to 
Baseline 
Baseline is defined as the value recorded at Visit 1 pre-dose assessment. For data collected via eDiary 
device, the baseline is defined as the average of 4-weekly data collected in the run-in period. 
On Visit 2, where time of assessment is collected/available, this should be used to determine if the 
assessment was performed prior to the administration of the study drug. Where time of assessment 
is not collected/available it will be assumed that all assessments on Visit 2 occurred prior to the 
administration of the study drug. 
Change from baseline, relative change from baseline and ratio to baseline are calculated as follows: 
• 
Change from baseline = (Post-baseline value – Baseline value) 
• 
Relative change from baseline (%) = (Post-baseline value – Baseline value)/(Baseline value)*100 
• 
Ratio to baseline = Post-baseline value /Baseline value 
7.2.3. Duration of Event 
Where the duration of an event is to be calculated, it will be derived as: (Event stop/end date – Event 
start date) + 1. 
7.2.4. Treatment Period 
• 
Pre-treatment period = Date of Screening to Date of first dose minus 1  
• 
On-treatment period = Date of first dose to Date of last dose plus 28 days inclusive 
• 
Post-treatment period = End of last dose plus 29 days to End of study date 
7.2.5. OCS Dose Reduction 
Percent OCS Dose Reduction during Weeks 20 - 24 = 100 * (Baseline Dose – Maintenance Dose 
during Weeks 20 - 24)/Baseline dose. 
Baseline dose is defined as the prescribed optimized prednisone/prednisolone dose following the 
OCS optimization run-in period and maintenance dose is defined as the mean average of all daily 
prednisone/prednisolone doses during the maintenance phase of Weeks 20 -24. The visit window for 
calculating OCS dose at each reporting period is described below: 
 


 
 
 
     
 
        
      
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Reporting Period 
First Day Included 
Last Day Included 
Optimised Dose 
N/A 
N/A 
Baseline – Week 4 
Day after Week 0 visit 
Day of Week 4 visit 
Week 4 – Week 8 
Day after Week 4 visit 
Day of Week 8 visit 
Week 8 – Week 12 
Day after Week 8 visit 
Day of Week 12 visit 
Week 12 – Week 16 
Day after Week 12 visit 
Day of Week 16 visit 
Week 16 – Week 20 
Day after Week 16 visit 
Day of Week 20 visit 
Maintenance Dose (Week 20 – Week 24) 
Day after Week 20 visit 
Day of Week 24 visit 
 
7.2.6. Asthma Exacerbations 
For the analysis of exacerbations, the exacerbation follow-up time is defined as: 
• 
For subjects completed the study: Date of Week 24 visit – Date of Baseline (Week 0) visit +1 
• 
For subjects with early withdrawals: Date of Withdrawal – Date of Baseline (Week 0) visit + 1  
The on-treatment assessment period for exacerbations is calculated from date of Baseline (Week 0) 
visit to date of Week 24 visit or early withdrawal (inclusive). 
7.2.7. Concomitant Medication Derivation 
Taken Before the Run-In: If medication start date < Date of Screening visit (Visit 1) (or medication 
start date is missing) 
Run-In Period Medications: 
• 
Medication start date < date of Screening visit (Visit 1) (or medication start date is missing) and 
medication stop date ≥ date of Screening visit (or medication stop date is missing), or  
• 
Date of Screening visit ≤ medication start date < Date of first dose of study drug 
On-Treatment Medications: 
• 
Medication start date < date of first dose of study drug (or medication start date is missing) and 
medication stop date ≥ date of first dose of study drug (or medication stop date is missing), or 
• 
Date of first dose of study drug ≤ medication start date ≤ date of last dose of study drug + 28 days  
• 
Date of last dose of study drug is missing and the medication start date is on or after the date of 
first dose of study drug      
• 
Medication start or stop date is missing or partial then the con-med will be considered on-treatment 
unless there is evidence to the contrary (e.g. month/year of con-med stop date is present and is 
before the month/year of study treatment start date). 


 
 
 
     
 
        
      
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Post-Treatment Medications:  
• 
Medication start date is after the date of last dose of study drug + 28 days 
• 
Medication stop date > date of last dose of study drug + 28 days or medication stop date is missing 
7.2.8. Common Calculations 
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).  
Body Mass Index (kg/m2) = Weight (kg)/Height (m)2. 
The predicted normal FEV1 and reversibility values are recoded in the CRF as per the protocol 
assessment visits. The predicted normal FEV1 is based on the NHANES III equations as described 
in the protocol and Asian equation will be used for Asian race.  
Reversible is defined as an increase in FEV1 of ≥12% and ≥200mL following administration of 
bronchodilator (albuterol/salbutamol) at any protocol assessment visit. 
Non-reversible is defined as a post-bronchodilator (post-albuterol/salbutamol) increase in FEV1 of 
<200mL or increase that is <12% from pre-bronchodilator (pre-albuterol/salbutamol) FEV1. 
A subject is considered achieved asthma control between Week 20 and Week 24 if he/she does not 
have a clinically significant exacerbation during this period between W20 and W24. The process for 
assessing clinically significant exacerbations of asthma is provided in Appendix9. Visit Windows. 
Where a subject does not prematurely withdraw from the study, or the subject withdraws prematurely 
from the study at a scheduled visit, there are no plans to derive visit windows; visits will be used in 
the analyses as reported on the CRF. 
For subjects prematurely withdrawing from the study, the EOS, unscheduled or IP discontinuation visit 
will initially be remapped to the next scheduled protocol specific assessment visit for each parameter, 
if the visit falls ±7 days of next scheduled planned visit (see below). Otherwise, the data will be 
remapped to the next planned scheduled visit. If there are more than one assessment associated with 
a particular visit interval, then the visit will be remapped to that with the closest target day. If subject 
having multiple records on same day for parameter (lab, ECG etc), then for continuous parameter 
data average value and for categorical parameter data, worst value will be presented. Please reframe 
the text accordingly. 


 
 
 
     
 
        
      
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Visit 
Target Day 
Window (Days) 
Visit 3 (Week 4) 
28 
21 to 35 
Visit 4 (Week 8) 
56 
49 to 63 
Visit 5 (Week 12) 
84 
77 to 91 
Visit 6 (Week 16) 
112 
105 to 119 
Visit 7 (Week 20) 
140 
133 to 147 
Visit 8 (Week 24) 
168 
161 to 175 
Unless otherwise stated, unscheduled visits will be included in the data listings only. If an unscheduled 
visit is present because of a visit/assessment missed due to COVID-19 factors, the unscheduled 
assessment may be used for remapping. The unscheduled visits may be used for summaries related 
to ‘any time post baseline’ assessment. 
7.2.10. MedDRA and WHO Drug Coding Versions 
Where applicable, safety data will be coded using the following coding dictionaries: 
Dictionary 
Version 
Medical Dictionary for Regulatory Activities (MedDRA) 
26.0 
World Health Organization Drug Dictionary (WHO-DD) 
March 2020 B3 
7.2.11. Software Version 
All analyses will be conducted using SAS version 9.4 or higher. 
 
8. 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
9. 
SUBJECT CHARACTERISTICS AND STUDY CONDUCT SUMMARIES 
9.1. SUBJECT DISPOSITION 
Subject disposition table will be summarized based on the safety population. The following summaries 


 
 
 
     
 
        
      
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will be included in the disposition table:  
• 
Total number of subjects enrolled in the study 
• 
Total number of subjects screen failure 
• 
Total number of subjects re-screened 
• 
Total number of subjects passed screen but not received the treatment 
• 
Total number of subjects in safety population 
• 
Number of subjects who completed the study treatment 
• 
Number of subjects who completed the study 
• 
Number and percentage of subjects who discontinued from the study 
• 
Number and percentage of subjects who pre-maturely discontinued the treatment as well as 
from the study along with reason for discontinuation.  
Percentages will be based on the number of subjects in the safety population or enrolled population. 
Number and percentages of the reasons for study discontinuation is based on the total discontinued 
subjects.  
A summary of reasons for screen failure, rescreen and the number of subjects included in the analysis 
population (Safety) will be presented based on all enrolled population. The percentages will be based 
on the number of subjects in all enrolled population.  
In addition, the following summaries will be generated based on the safety population: 
• 
Summary of inclusion, exclusion and induction phase criteria deviations 
• 
Summary of important protocol deviations 
• 
Summary of important protocol deviations related to COVID-19 pandemic 
• 
Summary of visits impacted by COVID-19 pandemic 
A by-subject listing of disposition will be provided for all enrolled population. 
9.2. DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Subjects’ demographics and baseline characteristics will be summarized for the safety population.  
Continuous variables (e.g., age and weight) will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum). Qualitative variables (e.g., sex and race) will 


 
 
 
     
 
        
      
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be summarized with counts and percentages.  
The demographic parameters will include age, gender race height, weight and body mass index. Age 
will also be presented as a categorical variable (18-29 years, 30-49 years, 50-64 years and >=65 
years). The baseline characteristics include: 
• 
Asthma history and baseline disease characteristics which includes smoking history (never, 
current and former), age at onset (years) asthama diagnosis, time since diagnosis, asthma 
duration categories (1 to <5 years, 5 to <10 years, 10 to <15 years, 15 to <20 years, 20 to <25 
years and >=25 years), experienced exacerbations in the previous 12 months, optimized OCS 
dose, duration of OCS dose prior to screening.  Baseline optimized OCS dose also presented as 
a categorical variable (<7.5 mg/day, 7.5 to <15 mg/day, 15 to <30 mg/day and >=30 mg/day). 
• 
Asthma exacerbations history which includes number of exacerbations (both descriptive and 
categorical), exacerbation types and causes of exacerbations in the previous 12 months.  
• 
Family history of cardiovascular risk factors 
• 
Past and current medical conditions 
• 
Lung function test results at screening and baseline which includes pre- and post-bronchodilator 
FEV1 (L), pre-bronchodilator percent predicted FEV1 (%), pre-bronchodilator forced vital capacity 
(FVC) (L), reversibility (in mL and in %) and pre-bronchodilator FEV1/FVC. 
By-subject listings of demographic and baseline characteristics will be provided for the safety 
populations. 
9.3. MEDICATIONS 
Medications will be coded using the latest available version of the Anatomical Therapeutic Chemical 
(ATC) classification text from the World Health Organization Drug Dictionary (WHO DD) and 
summarized separately for asthma and non-asthma medications. Asthma related medications will be 
presented by respiratory medication class and treatment period (prior treatment, on- treatment and 
post-treatment) and non-asthma related medications will be reported by ATC1 class and preferred 
name ingredients only for on-treatment period (concomitant). A by-subject listing of asthma and non-
asthma medications will be provided for the safety population.  
Medication that was started in the run-in period and stopped/continued during the on-treatment 
(concomitant) period will be included in both pre- treatment and on-treatment (concomitant) period 
summaries. 


 
 
 
     
 
        
      
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10. STATISTICAL ANALYSIS 
All analyses of safety data and efficacy data will be generated for the Safety Population. All p values 
and 2-sided confidence intervals will be considered nominal without multiplicity control. Additionally, 
separate subgroup analyses will also be generated by with/without baseline maintenance OCS use 
(with separate summaries in those participants receiving maintenance OCS at baseline and those 
not maintenance OCS at baseline). 
10.1. EFFICACY ANALYSIS SRATEGY 
10.1.1. SECONDARY EFFICACY ENDPOINTS 
There are no primary efficacy endpoints defined for this study. The efficacy analysis is defined in 
terms of secondary and other efficacy endpoints as below:   
10.1.2. Secondary Endpoints: 
• 
Number of clinically significant exacerbations.  
• 
Number of exacerbations requiring hospitalization or ED visits 
• 
Number of exacerbations requiring hospitalization 
• 
Change from baseline in clinic pre-bronchodilator FEV1 at week 24 
• 
Change from baseline in clinic post-bronchodilator FEV1 at week 24 
• 
Change from baseline in ACQ-5 score at week 24 
• 
Change from baseline in morning PEF during weeks 20 – 24.  
10.1.2. Health Outcome Endpoints: 
• 
Clinician and Subject rated response to therapy at Week 24 
• 
Mean change from baseline in WPAI-GH composite scores (percentage) at week 24: 
• 
Percent work time missed due to general health 
• 
Percent impairment while working due to general health 
• 
Percent overall work impairment due to general health 
• 
Percent activity impairment due to general health 
 


 
 
 
     
 
        
      
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10.1.3. Exploratory Endpoints: 
10.2. STATISTICAL METHODS FOR SECONDARY EFFIACACY ENDPOINTS 
10.2.1. Asthma Exacerbations: 
The number of clinically significant asthma exacerbations (including exacerbations requiring 
hospitalization or ED visits) that occur while on treatment will be analyzed using Negative Binomial 
regression using generalized linear model with a covariate of time period (pre-, post-mepolizumab as 
ordinal variable) with follow-up time within each period included as an offset within the model. The 
exacerbation rates during the pre- and post-treatment with mepolizumab will be presented, including 
comparison of pre- and post-mepolizumab exacerbation rates along with the with 95% confidence 
limits and corresponding p-value. Exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation. The following SAS code will be used: 
 
proc genmod data=modeldata plots=all; 
      class period usubjid; 
      model exbnum = period / dist = negbin link=log offset = logtime type3; 
      repeated subject = usubjid / type=UN corrw withinsubject = period; 
      lsmeans period / exp cl; 
      estimate "Period ratio" period -1 1 / exp; 
run; 
 
where exbnum = number of clinically significant asthma exacerbations 
 period = pre- and post- mepolizumab treatment periods in which the exacerbation occurred 
logtime = loge (length of time in years in pre- mepolizumab and post- mepolizumab periods)   
Length of time (years) in study will be calculated as length of time (days)/365.25.  
An unstructured covariance structure will be used in the model. If there are any convergence issue, 
then an alternative exchangeable or compound symmetric, autoregressive (AR (1)), Toeplitz 
covariance structure will be used. The variance of the mean estimate will be corrected for within-
subject correlation by using REPEATED statement for subject in the GENMOD procedure. 
The period of time for which exacerbation information will be included in the post-mepolizumab period 
will be from the start of treatment until the week 24 visit, regardless of treatment discontinuation. For 
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those participants with premature study withdrawal, the time period will include from the start of 
treatment until the date of withdrawal. Missing data (following early withdrawal) will be assumed to be 
missing at random (MAR) following subject withdrawal from the study.  
In addition, a similar analysis will be conducted for frequency of exacerbations requiring hospitalization 
or ED visits and frequency of exacerbations requiring hospitalization if there are enough subjects in 
the corresponding category.  
Treatment policy strategy will be used for intercurrent event treatment discontinuation (for any 
reason). This will estimate the treatment effect at the end of the 24 week study period regardless of 
treatment discontinuation. 
Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in 
defining the treatment effect of interest. The value for the variable of interest is used regardless of 
whether or not the intercurrent event occurs. 
Counts and percentage of subjects with any exacerbations, any clinically significant exacerbations, 
any exacerbations requiring hospitalization or ED visit and any exacerbations requiring hospitalization 
during the treatment period will be provided for the safety population. The same output will also be 
presented regardless of treatment discontinuation. In such case even if a patient not received the 
treatment but passed the screening and discontinued are also counted for the variable of interest.  
The rate of exacerbations requiring hospitalization or ER visit and rate of exacerbations requiring only 
hospitalization during the on-treatment period will be analysed using Negative Binomial regression 
model similar to the analysis for the rate of clinically significant exacerbations as described above. In 
addition, counts and percentage of subjects with the number of exacerbations (eg. 0, 1, 2, 3, 4, 5, 6, 
7, 8, 9, >=10) during the on-treatment period will be presented. 
10.2.2. Forced Expiratory Volume in 1 second (FEV1) 
Analysis of change from baseline in clinic pre-bronchodilator FEV1 at Week 8, Week 16 and Week 24 
will be performed using a mixed models repeated measures (MMRM) analysis, including visit and 
asthma exacerbations in the year prior to the study (as an ordinal variable – 0, 1, 2, 3+) and baseline 
maintenance OCS use (yes, no) (binary nominal variable) as an as covariates. Change from baseline 
in pre-bronchodilator FEV1 value along with a two-sided 95% confidence interval and p-value 
estimated from MMRM model will be presented. The following SAS code will be used: 
proc mixed data=modeldata; 
      class usubjid avisitn; 
      model chg = avisitn BASEOCSD PEXACCTN / solution ddfm=kr cl htype=3; 
      lsmeans avisitn / cl pdiff e; 


 
 
 
     
 
        
      
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      repeated avisitn / subject= usubjid type=un; 
run; 
 
Where, chg = change from baseline in clinic pre-bronchodilator FEV1 at Week 8, Week 16 and Week 
24 
Avisitn = Visit  
BASEOCSD = baseline maintenance OCS use (Yes/No) 
PEXACCTN = asthma exacerbations in the year prior to the study 
An unstructured covariance structure will be used in the model. If there are any convergence issue, 
then an alternative compound symmetric, autoregressive (AR(1)), Toeplitz covariance structure will 
be used. 
Treatment policy strategy will be used for treatment discontinuation (for any reason). This will estimate 
the treatment effect at the end of the 24 week study period regardless of treatment discontinuation. 
Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in defining 
the treatment effect of interest: the value for the variable of interest is used regardless of whether or 
not the intercurrent event occurs. 
A similar analysis will be conducted for the post-bronchodilator FEV1 value at Week 24. In addition, 
descriptive summaries for the actual and change from baseline values for pre- and post-bronchodilator 
FEV1 will be presented by scheduled visits. 
10.2.3. Asthma Control Questionnaire (ACQ-5) 
The ACQ-5 questionnaire consists of the 5 symptoms questions scored on a 7-point scale from 0 = 
 to 6 = 
. The questions are equally weighted 
and the ACQ-5 score will be the mean of the 5 questions. If a subject does not complete 1 of the 5 
questions at a visit, then the ACQ-5 score will be the mean of the responses to the remaining 4 
questions at that visit. If a subject does not complete more than 1 of the 5 questions at a visit, then 
their ACQ-5 score will be set to missing at that visit. 
Analysis of change from baseline in ACQ score at each scheduled visit will be performed using a 
mixed model repeated measures (MMRM) analysis described in section 10.2.2. including visit and 
asthma exacerbations in the year prior to the study (as an ordinal variable – 0, 1, 2, 3+) and baseline 
maintenance OCS use (yes, no) (binary nominal variable) as covariates. Change from baseline in 
ACQ scores along with two-sided 95% confidence intervals and p-values estimated from MMRM 
model will be presented by visit. 
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In addition, descriptive summaries for the actual and change from baseline values in ACQ scores will 
be presented by scheduled visits. 
Treatment policy strategy will be used for treatment discontinuation (for any reason). This will estimate 
the treatment effect at the end of the 24 week study period regardless of treatment discontinuation. 
Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in defining 
the treatment effect of interest: the value for the variable of interest is used regardless of whether or 
not the intercurrent event occurs. 
10.2.4. Peak Expiratory Flow (PEF) 
Analysis of change from baseline in morning PEF during each 4-weeks reporting period of Weeks 1-
4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20 and Weeks 21-24 will be performed using a 
mixed models repeated measures (MMRM) analysis described in section 10.2.2, including reporting 
period and asthma exacerbations in the year prior to the study (as an ordinal variable – 0, 1, 2, 3+) 
and baseline maintenance OCS use (yes, no) (binary nominal variable) as covariates. Change from 
baseline in morning PEF along with two-sided 95% confidence intervals and p-values estimated from 
MMRM model will be presented. 
All data will be included in the endpoint analysis will be from the start of treatment until the week 24 
visit, regardless of treatment discontinuation. 
Comparisons will be Weeks 20–24 vs. Baseline, and all data collected up to and including Weeks 20–
24, including participants who have discontinued study treatment, will be included in the analyses. 
Missing data (following early withdrawal) will be assumed to be missing at random (MAR) following 
subject withdrawal from the study. 
In addition, descriptive summaries for the actual and change from baseline values in morning PEF 
values will be presented by 4-weeks reporting period. 
Treatment policy strategy will be used for treatment discontinuation (for any reason). This will estimate 
the treatment effect at the end of the 24 week study period regardless of treatment discontinuation. 
Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in defining 
the treatment effect of interest: the value for the variable of interest is used regardless of whether or 
not the intercurrent event occurs. 
 
 


 
 
 
     
 
        
      
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10.3. STATISTICAL METHODS FOR HEALTH OUTCOME ENDPOINTS 
10.3.1.  Clinician and Subject Rated Response to Therapy: 
The clinician and subject rated overall evaluation of response to therapy at Week 8, Week 16 and 
Week 24 will be assessed using a 7-point scale: 1 = 
, 2 = 
, 
3 = 
, 4 = 
, 5 = 
, 6 = 
, 7 = 
. 
Counts and percentage of subjects with each response category will be summarized separately for 
clinician and subject rated overall evaluation of response to therapy by scheduled visit.  
Treatment policy strategy will be used for treatment discontinuation (for any reason). This will estimate 
the treatment effect at the end of the 24 week study period regardless of treatment discontinuation. 
Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in defining 
the treatment effect of interest: the value for the variable of interest is used regardless of whether or 
not the intercurrent event occurs. 
10.3.2.  Work Productivity and Activity Impairment Questionnaire: General Health 
(WPAI-GH) 
The WPAI-GH is a self or interviewer administered tool comprised of 6 questions which address 
absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss 
(absenteeism plus presenteeism), and activity impairment based on the data from the past 7 days. 
The WPAI-GH responses are scored as impairment percentages, with a higher percentage indicating 
greater impairment and less productivity. The following WPAI-GH composite scores will be derived: 
• 
Percent work time missed due to health: Q2/(Q2 + Q4) 
• 
Percent impairment while working due to health: Q5/10 
• 
Percent overall work impairment due to health: Q2/(Q2+Q4) +[(1-Q2/(Q2+Q4)) x (Q5/10)] 
• 
Percent activity impairment due to health: Q6/10 
The above WPAI-GH composite scores and change from baseline will be summarized by visit using 
number of subjects, mean, SD, median, minimum and maximum values. 
Treatment policy strategy will be used for treatment discontinuation (for any reason). This will estimate 
the treatment effect at the end of the 24 week study period regardless of treatment discontinuation. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


 
 
 
     
 
        
      
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Treatment policy strategy: The occurrence of the intercurrent event is considered irrelevant in defining 
the treatment effect of interest: the value for the variable of interest is used regardless of whether or 
not the intercurrent event occurs. 
10.4. STATISTICAL METHODS FOR EXPLORATORY ENDPOINTS 
CCI


 
 
 
     
 
        
      
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Nasal polyps assessment: 
Nasal polyps assessment will be performed at Screening (Visit 1) and at IP discontinuation/Week 
24 (EOS) visits. Shift from baseline to Week 24/EOS in nasal polyps categories (Present, absent, 
missing/not assessed) will be presented. 
Analysis of blood eosinophilis and Serum IgE(total): 
Analysis of ratio to baseline in blood eosinophils and Serum IgE (Total) will be performed using a 
CCI
CCI


 
 
 
     
 
        
      
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mixed model repeated measures (MMRM) analysis as described in section 10.2.3 including visit, 
baseline maintenance OCS dose and asthma exacerbations in the year prior to the study (as an 
ordinal variable – 0, 1, 2, 3+) as covariates. The analysis will be conducted using loge scale 
transformed values for blood eosinophils. The model will be used to estimate the ratio to baseline at 
each scheduled visit with 95% confidence limits and corresponding p-value. 
In addition, descriptive summaries will be presented for blood eosinophils and Serum IgE (Total) at 
each scheduled visits using number of subjects, geometric mean, geometric SD, median, minimum 
and maximum values.  
10.5. SUBGROUP ANALYSIS 
Subgroup analysis will be done according to subjects received OCS at baseline (yes, no). 
10.6. MULTIPILICTY  
There will be no hypothesis test is planned. Hence, no adjustment for the multiple comparison is 
required. 
10.7. IMPUTATION OF MISSING DATA  
Missing values will be treated as missing unless and otherwise specified. If a subject experience a 
clinically significant asthma exacerbation between Weeks 20-24, then for the purpose of assessing 
percentage of subjects achieving at least 50% reduction in OCS dose during the weeks 20-24, the 
subject will be imputed into the worst-case category of ‘no reduction in OCS Dose’. For the analysis 
of median percent OCS reduction during weeks 20-24, the subject will be imputed using the maximum 
dose of OCS observed during the 4-Weekly period across all participating subjects. 
11. SAFETY ANALYSIS STRATEGY 
All analyses described in this section will be performed on the safety population. All safety analyses 
will be reported separately of the subjects receiving baseline OCS use (yes, no).  The results will be 
descriptive in nature. Safety will be assessed based on the following assessments: 
• 
Extent of Exposure 
• 
Adverse Events 


 
 
 
     
 
        
      
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• 
Clinical Laboratory Evaluation  
• 
Immunogenicity 
• 
Vital Signs 
• 
12 Lead ECG 
• 
Steroid toxicity and withdrawal 
11.1. EXTENT OF EXPOSURE  
The total exposure to mepolizumab is calculated as the date of last dose of mepolizumab minus the 
date of first dose of mepolizumab plus 29 minus periods of interruptions (in days). Subjects who 
entered into induction phase but did not report any treatment dates will be categorized as having zero 
days of exposure. The extent of exposure will be summarized as number of injections administered 
and number of days on treatment. 
Interruption period is calculated as the date of dose of mepolizumab after interruption period minus 
the date of interruption period of mepolizumab or the date of missed dose of mepolizumab. 
11.2. ADVERSE EVENTS  
The applicable definition of an Adverse Event (AE) is in the study protocol Sections 8.3 and 10.3. All 
AEs occurring from when a subject sign informed consent to when a subject exits the study will be 
accounted for in the reporting. AEs occurring pre-treatment, on-treatment and post-treatment periods 
will be summarized for the safety population. 
A pre-treatment AE is defined as any AE with an onset date before the date of first exposure to the 
study drug. An on-treatment-AE is an event does not present prior to first exposure to the study drug 
or any pre-existing event that worsens following exposure to study drug until the last exposure to the 
study drug plus 28 days inclusive. Any AE which occurs after 28 days of last exposure to the study 
drug will be considered as post-treatment AEs. All AEs will be coded using the MedDRA central coding 
dictionary (26.0) and grouped by body system and preferred term. See Appendix 1 for imputation of 
partial dates for AEs. Imputed dates will be used to determine on-treatment status. 
The following summaries will be generated for adverse events: 
• 
AEs by treatment period (on and post-treatment), SOC and PT 
• 
Common (>=3%) non-serious on-treatment AEs by SOC and PT 


 
 
 
     
 
        
      
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• 
AE occurred on the day of dosing by SOC and PT 
• 
On-treatment drug-related AEs by SOC and PT 
• 
AEs leading to permanent discontinuation or withdrawal from study by SOC and PT 
• 
Serious AEs by treatment period (pre, on and post-treatment), SOC and PT 
• 
Non-fatal SAE by treatment period (pre, on and post-treatment), SOC and PT 
• 
Fatal SAE by treatment period (on and post-treatment), SOC and PT 
Events with missing relationship to the study drug is considered as related. In addition, a summary of 
overall AEs during the study duration will be presented which includes: 
• 
Subjects with at least one AE 
• 
Subjects with at least one drug-related AE 
• 
Subjects with AE leading to premature discontinuation 
• 
Subjects with at least one serious AE 
• 
Subjects with at least one drug-related serious AE  
• 
Subjects with at least one AE leading to death 
• 
Any on-treatment AEs 
• 
Any on-treatment SAEs 
The following listings will be generated: 
• 
Listing of all Adverse Events 
• 
Listing of Fatal Adverse Events 
• 
Listing of Non-Fatal Serious Adverse Events 
• 
Listing of Adverse Events Leading to Discontinuation of Investigational Product and/or 
Withdrawal from the Study 
11.2.1. Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are adverse events associated with the identified and 
potential risks of mepolizumab. AESIs of systemic reactions (including systemic reactions meeting 
Sampson’s criteria for anaphylaxis) and local injection site reactions are collected via targeted eCRF 
pages within the study. Events captured on the eCRF as systemic reactions will be further categorized 
by the investigator as ‘allergic (type I hypersensitivity) reactions’ or ‘systemic other reactions. AESIs 
of opportunistic Infections, malignancies, serious cardiac, vascular and thromboembolic (CVT) events 


 
 
 
     
 
        
      
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and serious ischemic events will be identified using structured MedDRA query as defined in Appendix 
xx. The following AESIs will be summarized only for the on-treatment period: 
• 
Events Reported by the Investigator as Systemic Reactions - Allergic (Type I Hypersensitivity) by 
PT  
• 
Events Reported by the Investigator as Systemic Reactions – Other Reactions by PT 
• 
Systemic Reactions Reported by the Investigator as Meeting the Criteria for Anaphylaxis by PT 
• 
Events Reported by the Investigator as Local Injection Site Reactions by PT 
• 
Potential Opportunistic Infections by PT  
• 
Malignancies by PT  
• 
Serious Cardiac, Vascular and Thromboembolic AE by PT  
• 
Serious Ischemic AEs by PT 
 A subject listing will be provided for each of the AESI categories. 
11.2.2. Cardiovascular Events 
The following cardiovascular events will be captured on targeted CV event pages of the eCRF: 
• 
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 
Counts and percentage of subjects with on-treatment cardiovascular events will be summarized. A 
subject listing will be provided. 
11.2.3. Liver Events 
A listing of all subjects with liver events will be presented with the following details: 


 
 
 
     
 
        
      
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• 
Time from the start of study treatment to the liver event and the time from the most recent 
study treatment to the liver event. 
• 
Size, final diagnosis and abnormalities of liver biopsy. 
• 
Alcohol intake and medical conditions at onset of liver event 
• 
Liver imaging abnormalities 
11.2.4. Steroid Toxicity and Withdrawal 
Steroid toxicity and withdrawal will be summarized descriptively which includes: 
• 
Prior duration of OCS use (<1 year, 1 to <5 years, 5 to <10 years, 10 to <15 years, 15 to <20 
years, 20 to <25 years, >=25 years) 
• 
Baseline optimized OCS dose both categorical (>0 - 5mg, >5 - 10mg, >10 - 15mg, >15 - 20mg, 
>20 - 25mg, >25 - 30mg, >30 - 35mg and >35mg).  
• 
Baseline medical conditions specifically summarizing the status (past, current, no medical 
condition) of the following: hypertension, endocrine disorders, eye disorders, metabolism and 
nutritional disorders, nervous system disorders, and bone fractures. 
• 
Observed and change from baseline in body weight at each visit 
• 
Observed and change from baseline in glucose levels at each visit 
11.2.5. Adverse Event Pertaining to COVID-19 
A summary of on-treatment adverse events for subjects with COVID-19 suspected, probable and 
confirmed COVID-19 diagnosis by system organ class and preferred term will be presented.  
11.3. CLINICAL LABORATORY EVALUATIONS  
Clinical laboratory evaluations include hematology, clinical chemistry, and urinalysis. A list of 
laboratory assessments to be included in the outputs are given below: 
Hematology: Hematocrit, Hemoglobin, Mean corpuscular hemoglobin (MCH), Mean corpuscular 
volume (MCV), Platelet count, Red blood cell (RBC) count, White blood cell (WBC) count, Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils and Reticulocytes. 
Clinical chemistry: ALP, ALT, AST, total bilirubin, direct bilirubin, Total Protein, Blood Urea Nitrogen, 
Creatinine, Glucose (non-fasting Random), Potassium, Sodium and Calcium.   


 
 
 
     
 
        
      
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Urinalysis: microscopy (epithelial cells, RBCs, pus cells (WBC), Dysmorphic RBC, casts, and 
crystals); and urine chemistry (specific gravity, pH, protein, glucose, bilirubin, urobilinogen, ketones 
and protein (Albumin)) 
Serology: Hepatitis B surface antigen (HBsAg) and Hepatitis C virus antibody. 
The assessment timepoints for the laboratory parameters are provided in the following table. 
Laboratory Parameters 
Assessment Time Points 
Hematology 
Screening (Visit 1), Week 0, Week 4, Week 8, Week 12, 
Week 16, Week 20, and Week 24 (EOS) 
Clinical Chemistry 
Screening (Visit 1), Week 0, Week 4, Week 8, Week 12, 
Week 16, Week 20, and Week 24 (EOS) 
Urinalysis 
Screening (Visit 1) 
Serum IgE (total) 
Pre-Screen, Screening (Visit 1) Week 0  
Serology 
Screening (Visit 1) 
Pregnancy Test 
Screening (Visit 1), Week 0, Week 4, Week 8, Week 12, 
Week 16, Week 20, and Week 24 (EOS) 
If a laboratory value which is expected to have a numeric value for summary purposes, has a character 
value with ‘<x’ or ‘>x’, the number of significant digits in the observed values will be used to determine 
how much to add or subtract in order to impute the corresponding numeric value. 
• 
Example 1: 2 Significant Digits = ‘<x‘ becomes x – 0.01 
• 
Example 2: 1 Significant Digit = ‘<x’ becomes x – 0.1 
• 
Example 3: 0 Significant Digits = ‘<x’ becomes x – 1 
Actual value and change from baseline (for quantitative measurements) will be summarized for 
hematology and clinical chemistry parameters at each scheduled visit. Shift from baseline to Week 
24/EOS visits according to normal range criteria (for quantitative measurements) will be presented for 
hematology and clinical chemistry parameters. No summaries will be provided for urinalysis and 
serology parameter results.   
A by-subject listings of all laboratory parameters will be provided which includes scheduled and 
unscheduled visits that clearly indicate the out of normal range values (where applicable) and possible 
abnormal values for the safety population.  


 
 
 
     
 
        
      
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11.4. IMMUNOGENICITY  
Immunogenicity is a measure of the immune response to a therapeutic drug (e.g. a monoclonal 
antibody) resulting in generation of anti-drug antibodies. Clinical samples are tested in a sequence of 
binding anti-drug antibody (ADA) and neutralizing antibody assays:  
• 
Screening assay- Each sample is tested for the presence of anti-drug antibodies (ADA assay) and 
initially declared positive or negative according to assay cut-off criteria. Positive samples are then 
tested in the confirmation ADA assay. Negative samples are not tested further.  
• 
Confirmation assay- Each positive sample from the screening assay is then confirmed positive in 
this assay or is declared negative. Positive samples are then tested in the neutralization (NAb) 
assay.  
• 
Titration assay- Each positive sample from the confirmation assay is assessed using serial dilution 
to provide a titre, corresponding to the highest dilution factor that still yields a positive test result.  
A table will be produced summarizing the number and percentage of confirmed positive and negative 
ADA samples in each treatment group in the Safety Population. The table will also be summarized 
the highest assay results obtained post-baseline.  
 A similar table will also be produced summarizing results for the neutralizing antibody assay in the 
Safety Population, by visit.  
All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre values, 
neutralizing antibody results will be listed. 
11.5. VITAL SIGNS  
Vital Signs parameters include blood pressure (systolic and diastolic), pulse rate, respiratory rate, 
oral/auxiliary temperature, height and weight. Vital signs assessment will be conducted at all study 
visits. Vital sign parameter values and changes from baseline will be summarized using descriptive 
statistics by visits. A by-subject listing will be provided for all vital sign parameters which includes 
scheduled and unscheduled visits.  
11.6. 12-LEAD ELECTROCARDIOGRAM  
A 12-Lead ECG will be performed at Screening, Week 0, Week 8, Week 16 and Week 24 visits. The 


 
 
 
     
 
        
      
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following ECG parameters will be assessed at each scheduled study visits: 
• 
Heart Rate (bpm) 
• 
QRS Interval (msec) 
• 
PR Interval (msec) 
• 
RR Interval (msec) 
• 
QT interval (msec) 
• 
QTc Interval (msec) 
• 
QTcF (msec) 
• 
QTcB (msec) 
• 
Overall Interpretation 
Where triplicate ECG evaluations were performed, the mean value for each subject will be used for 
the calculation of summary statistics. The data on QTc(B) was not collected in the CRF and will be 
derived using the following formula. 
𝑄𝑇𝑐(𝐵) = 
𝑄𝑇
√𝑅𝑅/1000
 
Descriptive summaries will be presented for the ECG parameter values and change from baseline by 
visit for all quantitative measurements. Overall interpretation of ECG clinical assessment will be 
summarized by counts and percentages. At each timepoint, QT, QTcF and QTcB will be categorized 
as follows, and the category based on actual value will be summarized at each visit as well as the 
category at each post-baseline visit based on change from baseline per the following criteria: 
Type of Value 
Category 1 
Category 2 
Category 3 
Actual value 
> 450 ms 
> 480 ms 
>500 ms 
Change from Baseline 
> 30 ms 
>60 ms 
 
Counts and percentages for subjects with the above categories for QT, QTcF and QTcB (>450 ms, 
>480 ms and >500 ms) parameter values and change from baseline (>30 ms increase, >60 ms 
increase and >500 ms or >60 ms increase) will be summarized at each visit. A by-subject listing of 
all ECG parameters will be provided which includes scheduled and unscheduled visits. 


 
 
 
     
 
        
      
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12 PROGRAMMING CONSIDERATIONS 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4 or higher (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and 
figure output will adhere to the following specifications.  
• 
One SAS program can create several outputs. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance. 
• 
All tables and listings will be produced in landscape orientation. Figures use the orientation 
that best facilitates interpretation of the data 
• 
All TFLs will be produced using the Courier New font, size 10. The smallest acceptable point 
size for the Regulatory Authorities is 8. 
• 
Headers and footers for figures will be in Courier New font, size 8 which is the smallest 
acceptable point size for the Regulatory Authorities. 
• 
TFLs will be in black and white (no color), unless otherwise specified. 
• 
The TLFs with subgroup analysis based on OCS dose at baseline Yes/No, the each subgroup 
category to be printed on the left side. The overall results should be presented first, followed 
by Baseline OCS=Yes, Baseline OCS=No. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and color are not used in the 
tables and listings, unless otherwise specified. Color may be used in figures containing 
multiple plotted lines as long as information is not lost when the figure is reproduced in 
monotone. 
• 
Mixed case will be used for titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 
• 
For categorical parameters, all categories will be presented in the table, even if n=0 for all 
treatment groups in a given category. For example, the frequency distribution for symptom 
severity would appear as: 
Severity Rating 
n 
Mild 
2 
Moderate 
5 
Severe 
0 
 


 
 
 
     
 
        
      
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• 
An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more subjects. 
• 
Unless otherwise specified, the estimated mean, median, Q1 and Q3 for a set of values will 
be printed out to 1 more significant digit than the original values, and standard deviations and 
standard errors will be printed out to 2 more significant digits than the original values. The 
minimum and maximum will report the same significant digits as the original values. 
• 
Confidence intervals are displayed within round brackets and separated by a comma. The 
lower limit is presented first, and the upper limit is presented second. The confidence interval 
is placed either beside or below the corresponding estimate. The estimate and the confidence 
limits are presented using the same degree of precision. 
• 
P-values will be output in the format: ‘0.xxx’, where xxx is the value rounded to 3 decimal 
places. Every p-value less than 0.001 will be presented as <0.001. If the p-value is returned 
as >0.999, then present as >0.999. 
• 
Percentage values will be printed to one decimal place. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis population for the treatment group who 
have an observation will be the denominator. Percentages after zero counts will not be 
displayed and percentages equating to 100% will be presented as 100%, without decimal 
places.  
• 
Tabular display of data for medical history, prior/concomitant medications, and all tabular 
displays of adverse event data will be presented by the body system, treatment class, or SOC 
with the highest occurrence in the active treatment group in decreasing order, assuming all 
terms are coded. Within the body system, drug class and SOC, medical history (by preferred 
term), drugs (Medication class), and adverse events (by preferred term) will be displayed in 
decreasing order. If incidence for more than 1 term is identical, they will then be sorted 
alphabetically.  
• 
Missing descriptive statistics or p-values which cannot be estimated will be reported as ‘-’ 
Missing values for numeric and character variables are displayed as blanks in data listings 
• 
The percentage of subjects will normally be calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis population 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of subjects 
exposed. Details will be described in footnotes or programming notes, as necessary.  
• 
If no relevant data are available at all for a display, then present “No data to Report”. 
 
 


 
 
 
     
 
        
      
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APPENDIX 1. 
MISSING DATE PROCEDURE 
Prior/Concomitant Medications 
For the purpose of assessing whether a medication is prior or concomitant, if a medication has a 
completely missing start date it will be considered a prior medication, and if a medication has a 
completely missing stop date it will be considered a concomitant medication. If a partial start or stop 
date occurs, the following imputation process will be implemented: 
Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for 
Stop Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of first 
study drug dose: Impute day with “01” 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: Impute 
day and month with “01JAN” 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first dose 
of study drug. 
Impute day and 
month with 
“31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: Impute 
month with “JAN” 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of medication. 
• 
No stop date will be imputed if the treatment is ongoing. 
 
Adverse Events 
For the purpose of assessing whether an AE is on on-treatment the following imputation will be used. 
If the last dose of study drug is missing and the AE start date is on or after the first dose of study drug 
then the AE will be considered as on-treatment. If the AE start date is missing or partial then the AE 
will be considered on-treatment unless there is evidence to the contrary (e.g. month/year of onset 
date is present and is earlier than the month/year of first dose of study medication). 
For assessing on-treatment or for calculation of duration of AE, if a partial start or stop date occurs, 
the following imputation process will be implemented: 


 
 
 
     
 
        
      
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Partial Missing 
Start or Stop Date 
Imputation for Start Date 
Imputation for Stop 
Date 
Day missing, month 
and year present 
• 
Month and/or year different to month and year of 
first study drug dose: Impute day with “01”. 
• 
Month and/or year same as month and year of first 
study drug dose: Impute day with same day as first 
dose of study drug. 
Impute day with last 
day of the month 
Day and month 
missing, year 
present 
• 
Year different to year of first study drug dose: 
Impute day and month with “01JAN”. 
• 
Year same as year of first study drug dose: Impute 
month and day with same month and day as first 
dose of study drug.  
Impute day and 
month with “31DEC” 
Month missing, day 
and year present 
• 
Year different to year of first study drug dose: 
Impute month with “JAN”. 
• 
Year same as year of first study drug dose: Impute 
month with same month as first dose of study drug. 
Impute with “DEC” 
Caveats 
• 
If any imputed start date leads to a start date that is after the stop date, then 
the start date will be imputed with the date of the stop of AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
     
 
        
      
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APPENDIX 2. 
CORTICOSTEROID CONVERSION FACTORS 
All corticosteroids administered via oral, IV and IM routes are to be considered when calculating a 
subject’s daily prednisone/prednisolone dose regardless of reason for administration. All steroids 
administered via a sublingual route will also be considered as oral. 
The following 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.  If there are seen to be two corticosteroid records 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 
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 


 
 
 
     
 
        
      
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Standardized Medication Name 
Scaling Factor 
Prednisolone Sodium Succinate 
1 
Prednisone 
1 
Prednisone Acetate 
1 
Triamcinolone 
1.25 
Triamcinolone Acetonide 
1.25 
 
 
 
 
 


 
 
 
     
 
        
      
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V2.0 
 
APPENDIX 3. 
ASSESSMENT VISIT WINDOWS FOR EDIRARY DEVICE VARAIBLES 
The following assessments will be collected daily using an eDiary device: 
• 
Morning peak flow 
• 
Number of occasions of usage of rescue medication (i.e. salbutamol) 
• 
Asthma symptom score 
• 
Frequency of awakening due to asthma symptoms requiring use of rescue medication 
• 
ACQ scores 
To derive 4-weekly average values, the following assessment visit window will be used: 
 
Reporting 
Period 
First Day Included 
Last Day Included 
Baseline  
7 days prior to Visit 2 
Day 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 
Week 24 visit date (or 168 days 
after day of first dose if earlier) 
 
The average 4-weekly values will be derived based on the non-missing values in the corresponding 
period 4-weekly period. At least 7 days of eDiary parameter data is required in the corresponding 4-
weekly period to get the reliable estimate. 
The ACQ scores, which are collected weekly using the eDiary device will be summarized in a weekly 
period using the following assessments: 
 
Reporting Period 
First Day 
Included 
Last Day 
Included 
Multiple ACQ scores in period  
Optimisation Phase 
All days prior to study day -4 
 Not to be summarised 
Baseline 
Study day -7 
Study day 1 
Take score closest to day 1 
Week 1 
Study day 2 
Study day 12 
Take score closest to day 8 
Week 2 
Study day 13 
Study day 19 
Take score closest to day 15 
Week 3 
Study day 20 
Study day 26 
Take score closest to day 22 
Week 4 
Study day 27 
Study day 33 
Take score closest to day 29 
Week 5 
Study day 34 
Study day 40 
Take score closest to day 36 
Week 6 
Study day 41 
Study day 47 
Take score closest to day 43 
Week 7 
Study day 48 
Study day 54 
Take score closest to day 50 


 
 
 
     
 
        
      
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Statistical Analysis Plan,  
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Protocol No: 209682 
Version Number: 
V2.0 
 
Reporting Period 
First Day 
Included 
Last Day 
Included 
Multiple ACQ scores in period  
Week 8 
Study day 55 
Study day 61 
Take score closest to day 57 
Week 9 
Study day 62 
Study day 68 
Take score closest to day 64 
Week 10 
Study day 69 
Study day 75 
Take score closest to day 71 
Week 11 
Study day 76 
Study day 82 
Take score closest to day 78 
Week 12 
Study day 83 
Study day 89 
Take score closest to day 85 
Week 13 
Study day 90 
Study day 96 
Take score closest to day 92 
Week 14 
Study day 97 
Study day 103 
Take score closest to day 99 
Week 15 
Study day 104 
Study day 110 
Take score closest to day 106 
Week 16 
Study day 111 
Study day 117 
Take score closest to day 113 
Week 17 
Study day 118 
Study day 124 
Take score closest to day 120 
Week 18 
Study day 125 
Study day 131 
Take score closest to day 127 
Week 19 
Study day 132 
Study day 138 
Take score closest to day 134 
Week 20 
Study day 139 
Study day 145 
Take score closest to day 141 
Week 21 
Study day 146 
Study day 152 
Take score closest to day 148 
Week 22 
Study day 153 
Study day 159 
Take score closest to day 155 
Week 23 
Study day 160 
Study day 166 
Take score closest to day 162 
Week 24 
Study day 167 onwards 
 Take score closest to day 169 
 
 
 
 
 
 
 
 
 
 


 
 
 
     
 
        
      
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Statistical Analysis Plan,  
The GlaxoSmithKline group of companies 
 
 
 
 
Protocol No: 209682 
Version Number: 
V2.0 
 
APPENDIX 4. 
CLINICALLY SIGNFICANT EXACERBATIONS 
Clinically significant exacerbations of asthma is defined as the worsening of asthma, which requires 
use of systemic corticosteroids. Exacerbations will be treated per the investigator’s clinical practice 
protocol with the use of oral or parenteral corticosteroids.  
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 worsening of asthma symptom score. 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. 
For safety reasons alerts will be programmed into the eDiary to encourage the participant to contact 
the investigator if their asthma worsens. However, an alert in itself will not be classified as a clinically 
significant exacerbation. 
 
 
 


 
 
 
     
 
        
      
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Statistical Analysis Plan,  
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Protocol No: 209682 
Version Number: 
V2.0 
 
APPENDIX 5. 
LIST OF TABLES, FIGURES AND LISTINGS 
 
List of Tables 
 
Table 
Number 
Table Title 
14.1.1.1 
Summary of Subject Disposition (Enrolled Population) 
14.1.1.2 
Summary of Reasons for Discontinuation (Safety Population) 
14.1.1.3 
Summary of Reasons for Screen or Run-in Failure (All Enrolled Population) 
14.1.1.4 
Summary of Inclusion, Exclusion and Induction Phase Criteria Deviations (Safety Population) 
14.1.1.5 
Summary of Important Protocol Deviations (Safety Population) 
14.1.1.6 
Summary of Important Protocol Deviations Leading to Exclusion to Treatment (Safety Population) 
14.1.1.7 
Summary of Important Protocol Deviations Related to COVID-19 Pandemic (Safety Population) 
14.1.1.8 
Summary of Visits Impacted by COVID-19 Pandemic (Safety Population) 
14.1.2.1 
Summary of Demographic Characteristics (Safety Population) 
14.1.2.2 
Summary of Asthma History and Baseline Disease Characteristics (Safety Population) 
14.1.2.3 
Summary of Asthma Exacerbation History (Safety Population) 
14.1.2.4 
Summary of Family History of Cardiovascular Risk Factors (Safety Population) 
14.1.2.5 
Summary of Medical Conditions (Safety Population) 
14.1.2.6 
Summary of Asthma Medications Taken by Treatment Period and Respiratory Medication Class 
(Safety Population) 
14.1.2.7 
Summary of Non-Asthma Concomitant Medications Taken During Treatment (Safety Population) 
14.1.2.8 
Summary of Screening, Run-in and Baseline Lung Function Results (Safety Population) 
14.1.3 
Summary of Treatment Exposure and Number of Study Drug Administration (Safety Population) 
14.2.1.1 
Analysis of Subject Achieved at least 50% Reduction in OCS Dose During Weeks 20-24 
Relative to Baseline, while Maintaining Asthma Control (Safety Population) 
14.2.1.2 
Summary of OCS Dose Categories During Weeks 20-24 (5 mg Cut-off) (Safety Population) 
14.2.1.3 
Summary of OCS Dose Category During Each Reporting Period (Safety Population) 
14.2.1.4 
Summary of Percent Change from Baseline OCS Dose Categories Relative to Baseline by 
Reporting Period (Safety Population) 
14.2.1.5 
Summary of OCS Dose (mg/day) and Change from Baseline During Each Reporting Period 
(Safety Population) 
14.2.1.6. 
Summary of Median Percent OCS Dose (mg/day) Reduction During Weeks 20-24 While 
Maintaining Asthma Control (Safety Population) 
14.2.2.1 
Overview of Exacerbations (Safety Population) 
14.2.2.2 
Summary of Frequency of Clinically Significant Exacerbations (Safety Population) 
14.2.2.3 
Analysis of Rate of Clinically Significant Exacerbations (Safety Population) 
14.2.2.4 
Summary of Frequency of Exacerbations Requiring Hospitalization or Emergency 
Department Visits (Safety Population) 
14.2.2.5 
Analysis of Rate of Exacerbations Requiring Hospitalization or Emergency 
Department Visits (Safety Population) 
14.2.2.6 
Summary of Frequency of Exacerbations Requiring Hospitalization (Safety Population) 
14.2.2.7 
Analysis of Rate of Exacerbations Requiring Hospitalization (Safety Population) 
14.2.3.1 
Analysis of Change from Baseline in Clinic Pre-Bronchodilator FEV1 by Visit (Safety Population) 
14.2.3.2 
Analysis of Change from Baseline in Clinic Post-Bronchodilator FEV1 by Visit (Safety Population) 
14.2.3.3 
Summary of Pre-Bronchodilator FEV1 (Safety Population) 
14.2.3.4 
Summary of Post-Bronchodilator FEV1 (Safety Population) 
14.2.4.1 
Analysis of Change from Baseline in Asthma Control Questionnaire (ACQ-5) Scores(Safety 
Population) 
14.2.4.2 
Summary of Asthma Control Questionnaire (ACQ-5) Scores (Safety Population) 
14.2.5.1 
Analysis of Change from Baseline in Morning Peak Expiratory Flow (L/min) by 4-Week (Safety 
Population) 
14.2.5.2 
Summary of Morning Peak Expiratory Flow (L/min) by 4-Week Reporting Period (Safety 
Population) 
14.2.6.1 
Summary of Clinician Rated Overall Evaluation of Response to Therapy (Safety Population) 


 
 
 
     
 
        
      
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Statistical Analysis Plan,  
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Protocol No: 209682 
Version Number: 
V2.0 
 
14.2.6.2 
Summary of Subject Rated Overall Evaluation of Response to Therapy (Safety Population) 
14.2.7 
Summary of Work Productivity and Activity Impairment Score Composite Scores (WPAI:GH) 
(Safety Population) 
14.2.8.1 
Analysis of Change from Baseline in Salbutamol Use (occasions/day) by 4-Week Period (Safety 
Population) 
14.2.8.2 
Summary of Daily Salbutamol Use (occasions/day) by 4-Week Period (Safety Population) 
14.2.8.3 
Analysis of change from baseline Daily Asthma Symptom Scores by 4-Week Period (Safety 
Population) 
14.2.8.4 
Summary of Daily Asthma Symptom Scores by 4-Week Period (Safety Population) 
14.2.8.5 
Analysis of Change From Baseline Awakening at Night Due to Asthma Symptoms Requiring 
Rescue Medication Use by 4-Week Period (Safety Population) 
14.2.8.6 
Summary of Awakening at Night Due to Asthma Symptoms Requiring Rescue Medication Use by 
4-Week Period (Safety Population) 
14.2.8.7 
Summary of Nasal Polyps Shifts from Baseline to Week 24/EOS (Safety Population) 
14.2.8.8 
Analysis of Ratio to Baseline in Blood Eosinophils (Unit) at Week 24 (Safety Population) 
14.2.8.9 
Summary of Blood Eosinophils (Unit) (Safety Population) 
14.2.8.10 
Analysis of Ratio to Baseline in Serum IgE (Total) Level (Unit) at Week 24 (Safety Population) 
14.2.8.11 
Summary of Total IgE Level (Unit) (Safety Population) 
14.3.1.1 
Overview of All Adverse Events (Safety Population) 
14.3.1.2 
Summary of Adverse Events by Treatment Period (On and Post-Treatment), System Organ Class 
And Preferred Term (Safety Population) 
14.3.1.3 
Summary of Common (>=3%) Non-serious Adverse Events by Treatment Period (On and 
Post-Treatment), System Organ Class and Preferred Term (Safety Population) 
14.3.1.4 
Summary of Adverse Events Occurred on the Day of Dosing by System Organ Class and 
Preferred Term (Safety Population) 
14.3.1.5 
Summary of On-treatment Drug-Related Adverse Events by System Organ Class and Preferred 
Term (Safety Population) 
14.3.1.6 
Summary of On-treatment Adverse Events Leading to Premature Discontinuation of Study by 
System Organ Class and Preferred Term (Safety Population) 
14.3.2.1 
Summary of Serious Adverse Events by Treatment Period (Pre, On and Post-Treatment), System 
Organ Class and Preferred Term (Safety Population) 
14.3.2.2 
Summary of Non-Fatal Serious Adverse Events by Treatment Period (Pre, On and 
Post-Treatment), System Organ Class and Preferred Term (Safety Population) 
14.3.2.3 
Summary of All Fatal Adverse Events by Treatment Period (On and Post-treatment), System 
Organ Class and Preferred Term (Safety Population) 
14.3.2.4 
Summary of On-Treatment Serious Adverse Events and Adverse Events of Special Interest by 
System Organ Class and Preferred Term (Safety Population) 
14.3.3.1 
Summary of On-treatment Adverse Events of Special Interest: Events Reported by the 
Investigator as Systemic Reactions - Allergic (Type I Hypersensitivity) (Safety Population) 
14.3.3.2 
Summary of On-Treatment Adverse Events of Special Interest: Events Reported by the 
Investigator as Systemic Reactions – Other Reactions (Safety Population) 
14.3.3.3 
Summary of On-Treatment Adverse Events of Special Interest: Systemic Reactions Reported by 
the Investigator as Meeting the Criteria for Anaphylaxis (Safety Population) 
14.3.3.4 
Summary of On-Treatment Adverse Events of Special Interest: Events Reported by the 
Investigator as Local Injection Site Reactions (Safety Population) 
14.3.3.5 
Summary of On-Treatment Adverse Events of Special Interest: Potential Opportunistic 
Infections (Safety Population) 
14.3.3.6 
Summary of On-Treatment Adverse Events of Special Interest: Malignancies (Safety Population) 
14.3.3.7 
Summary of On-Treatment Adverse Events of Special Interest: Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Safety Population) 
14.3.3.8 
Summary of On-Treatment Adverse Events of Special Interest: Serious Ischemic Adverse Events 
(Safety Population) 
14.3.3.9 
Summary of On-Treatment COVID-19 Assessments for Subjects with Suspected, Probable or 
Confirmed COVID-19 Case Diagnosis by System Organ Class and Preferred Term (Safety 
Population) 
14.3.3.10 
Summary of On-Treatment All Cardiovascular Events Reported by the Investigator (Safety 
Population) 
14.3.4.1 
Summary of Hematology Parameters (Safety Population) 


 
 
 
     
 
        
      
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Protocol No: 209682 
Version Number: 
V2.0 
 
14.3.4.2 
Summary of Clinical Chemistry Parameters (Safety Population) 
14.3.4.3 
Summary of Shifts from Baseline to Week 24/EOS in Hematology Parameters (Safety Population) 
14.3.4.4 
Summary of Shifts from Baseline to Week 24/EOS in chemistry Parameters (Safety Population) 
14.3.5.1 
Summary of Binding Anti-Drug Antibody (ADA) Assay: Highest Confirmatory Result (Safety 
Population) 
14.3.5.2 
Summary of Neutralizing Antibody Assay: Highest Result (Safety Population) 
14.3.5.3 
Summary of Binding Anti-Drug Antibody (ADA) Assay: Highest Treatment Emergent Confirmatory 
Result (Safety Population) 
14.3.6 
Summary of Vital Signs Parameter Results (Safety Population) 
14.3.7.1 
Summary of ECG Parameter Results (Safety Population) 
14.3.7.2 
Summary of ECG Findings (Safety Population) 
14.3.7.3 
Summary of Abnormal Values for ECG Parameters According to Range Criteria (Safety 
Population) 
14.3.8.1 
Summary of Steroid Toxicity and Withdrawal (Safety Population) 
14.3.8.2 
Summary of Steroid Toxicity and Withdrawal: Serum Glucose and Body Weight (Safety 
Population) 
 
List of Figures 
 
Figure 
Number 
Figure Title 
14.4.1.1 
Time to Discontinuation of Study Treatment (Safety Population) 
14.4.1.2 
Histogram of OCS Doses Received by 4-Weeks Reporting Period (Safety Population) 
14.4.1.3 
Change from Baseline in Pre-Bronchodilator FEV1(mL) values (Safety Population) 
14.4.1.4 
Change from Baseline Asthma Control Questionnaire (ACQ-5) Scores by 4-Weeks Reporting 
Period (Safety Population) 
14.4.1.5 
Change from Baseline in Morning PEF by 4-Weeks Reporting Period (Safety Population) 
 
 
List of Listings 
 
Listing 
Number 
Listing Title 
16.2.1.1 
Listing of Patient Disposition (All Enrolled Population) 
16.2.1.2 
Listing of Subjects with Inclusion, Exclusion and Induction Phase Criteria Deviations (Safety 
Population) 
16.2.2.1 
Listing of Important Protocol Deviations (Safety Population) 
16.2.2.2 
Listing of Non-Important Protocol Deviations Related to COVID-19 Pandemic (Safety Population) 
16.2.2.3 
Listing of Visits Impacted by COVID-19 Pandemic (Safety Population) 
16.2.4 
Listing of Demographic Characteristics (Safety Population) 
16.2.5.1 
Listing of Study Drug Exposure (Safety Population) 
16.2.5.2 
Listing of Asthma and Exacerbation History (Safety Population)  
16.2.5.3 
Listing of Concomitant Medication (Safety Population) 
16.2.6.1 
Listing of Oral Corticosteroid Therapy by Treatment Period (Safety Population) 
16.2.6.2 
Listing of Exacerbations (Safety Population) 
16.2.7.1 
Listing of All Adverse Events (Safety Population) 
16.2.7.2 
Listing of Non-Fatal Serious Adverse Events (Safety Population) 
16.2.7.3 
Listing of Adverse Events of Special Interest 
16.2.7.4 
Listing of COVID-19 Assessments and Symptom Assessments for Subjects with COVID-19 
Adverse Events (Safety Population) 
16.2.8.1 
Listing of All Laboratory Data for Subjects with any Value Outside of the Normal Range (Safety 
Population) 
16.2.8.2 
Listing of Urinalysis Data (Safety Population) 
16.2.8.3 
Listing of Serology Data (Safety Population) 
16.2.8.4 
Listing of Subjects Who Became Pregnant During the Study (Safety Population) 
16.2.8.5 
Listing of Immunogenicity Results (Safety Population) 


 
 
 
     
 
        
      
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Statistical Analysis Plan,  
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Protocol No: 209682 
Version Number: 
V2.0 
 
16.2.9 
Listing of Electrocardiogram Findings for Abnormal Interpretations (Safety Population) 
16.2.3.1 
Listing of Reasons for Considering as a Serious Adverse Event (Safety Population) 
16.2.3.2 
Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug or Withdrawal 
from the Study (Safety Population) 
16.4.1 
Listing of Pre-post Bronchodilator (Safety Population) 
 
 
 
 
 
 
 
 


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Date of signature: 20-Jun-2023 06:31:50 GMT+0000
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