Conditions: Nasal Polyps
Keywords: Chronic rhinosinusitis Eosinophilic chronic rhinosinusitis Mepolizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 169
Healthy volunteers: no

Brief summary:
This is a randomized, double blind, placebo controlled, parallel group phase III study designed to assess the clinical efficacy and safety of 100 milligrams (mg) subcutaneous (SC) mepolizumab treatment in adults with CRSwNP/ECRS for the purpose of registration in Japan and China. Approximately 160 participants will be randomized in a 1:1 ratio to receive either 100 mg SC mepolizumab or placebo SC. The study will include a 4-week run-in period followed by randomization to a 52-week treatment period, where participants will be administered 4-weekly doses of mepolizumab or placebo via a pre-filled safety syringe device (SSD) injection.

Detailed description:

Arms:
arm 1: Participants will receive one dose of 100 mg mepolizumab SC on top of SoC every 4 weeks during the 52-week treatment period. arm 2: Participants will receive one dose of placebo via SC route on top of SoC, every 4 weeks during the 52-week treatment period.

Interventions: intervention 1: Mepolizumab intervention 2: Placebo intervention 3: Standard of care
Intervention descriptions: intervention 1: Mepolizumab will be available as a clear to opalescent, colorless solution for SC injection in a single-use, safety syringe at a unit dose strength of 100 mg/milliliters (mL). intervention 2: Placebo will be available as a clear to opalescent, colorless sterile solution for SC injection in a single-use, safety syringe intervention 3: Participants will continue to receive Standard of care as they are used to before entry in the study.

Protocol document:
Prot_000.pdf: 
TMF-14790303 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
209692 
1 
 
TITLE PAGE 
Protocol Title: A randomised, double-blind, placebo controlled, parallel group Phase III 
study to assess the clinical efficacy and safety of 100 mg SC Mepolizumab in adults with 
chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis 
(ECRS) MERIT: Mepolizumab in Eosinophilic chronic RhinosinusITis study 
Protocol Number: 209692 Amendment 03 
Compound Number: 
SB240563 
Brief Title: Efficacy and safety of mepolizumab in adults with CRSwNP / ECRS 
Study Phase: Phase 3 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): Not applicable. 
Medical Monitor Name and Contact Information will be provided separately OR can 
be found in the Study Reference Manual 
Sponsor Signatory: 
Robert Chan, MD 
Project Physician Lead, Clinical Development Group Director, Respiratory TAU 
Approval Date: 21 Jul 2022 
 
Copyright 2022 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Number 
Amendment 03 
21 Jul 2022 
 
TMF-14790303 
Amendment 02 
29-JUN-2021 
TMF-13841979 
Amendment 01 
08-OCT-2020 
TMF-2114641 
Original Protocol 
14-AUG-2020 
2020N441602_00 
Amendment 03: 21 Jul 2022 
This amendment is considered substantial because it significantly impacts the scientific 
value of the study.  
Overall Rationale for the Amendment: The primary reason for this amendment is to 
change the summary measure and analysis method for the co-primary and secondary 
endpoints. This is to align with draft FDA regulatory guidance for this indication [FDA, 
2021]. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3 Objectives and 
Endpoints – 
Summary Measure 
Change in summary 
measure from difference in 
medians to difference in 
means. 
Align with draft FDA regulatory 
guidance for this indication. The 
analysis of difference in means is 
the primary comparison for both 
co-primary endpoints. 
9.2 Sample Size 
Determination 
Sample size re-calculated in 
line with change to 
summary measure for 
co-primary endpoint 
analysis. 
The sample size calculation is 
re-performed using difference of 
means to confirm that the study is 
sufficiently powered with the 
change in summary measure from 
difference of medians to 
difference of means. 
1.1 Synopsis 
3 Objectives and 
Endpoints – 
Summary Measure 
9.4.1 Primary 
Endpoint 
Participants experiencing an 
intercurrent event of surgery 
will be assigned the worst 
possible score for the 
endpoint from surgery 
onwards. 
The score assigned to a 
participant following surgery is 
changed to the worst possible 
score for the endpoint following 
consideration of the most 
appropriate approach. 
1.1 Synopsis 
Addition of intercurrent 
event of course of systemic 
It is anticipated that some 
participants may receive short 
courses of systemic CS for 
CRSwNP / ECRS as part of 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
3 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
3 Objectives and 
Endpoints – 
Summary Measure 
9.4.1 Primary 
Endpoint 
corticosteroid (CS) for 
CRSwNP / ECRS. 
standard of care during the study. 
Data collected following a course 
of systemic CS for CRSwNP / 
ECRS will be included in the 
analysis of the primary estimand 
(treatment policy). A 
supplementary estimand has been 
added whereby a course of 
systemic CS for CRSwNP / ECRS 
will be considered as a treatment 
failure, this will be incorporated 
into the endpoint (composite 
strategy) by assigning the worst 
possible score for the endpoint 
following the initiation of the 
course of systemic CS. 
1.1 Synopsis 
3 Objectives and 
Endpoints – 
Summary Measure 
9.4.1 Primary 
Endpoint 
Addition of intercurrent 
event of 2 or more 
consecutive missed doses of 
investigational product. 
There is expected to be cases 
where some participants have 
missed 2 or more consecutive 
doses of investigational product. 
Data collected during and after 
the occurrence of these missed 
doses will be included in the 
analysis of the primary estimand 
(treatment policy). 
9.4.1 Primary 
Endpoint 
Missing data for participants 
who withdraw from the 
study without having 
experienced surgery will be 
handled as missing at 
random (MAR).  
The handling of missing 
participant data following 
withdrawal from study has been 
clarified with the change in 
summary measure to a difference 
of means. Sensitivity analyses 
will be carried out to examine the 
potential impact of choices for the 
handling of participants with 
missing data. Further details of 
the multiple imputation strategies 
using an off-treatment imputation 
have been specified. 
11 References 
Removal/addition of 
references 
To align with updates to the text. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
4 
 
TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 8 
1.1. 
Synopsis ....................................................................................................... 8 
1.2. 
Schema ...................................................................................................... 19 
1.3. 
Schedule of Activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 25 
2.1. 
Study Rationale .......................................................................................... 25 
2.2. 
Background ................................................................................................ 26 
2.3. 
Benefit/Risk Assessment ............................................................................ 29 
2.3.1. 
Risk Assessment ......................................................................... 30 
2.3.2. 
Benefit Assessment ..................................................................... 35 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 35 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 36 
4. 
STUDY DESIGN .................................................................................................... 41 
4.1. 
Overall Design ............................................................................................ 41 
4.2. 
Scientific Rationale for Study Design .......................................................... 42 
4.2.1. 
Participant Input into Design ........................................................ 43 
4.3. 
Justification for Dose .................................................................................. 44 
4.4. 
End of Study Definition ............................................................................... 44 
5. 
STUDY POPULATION ........................................................................................... 45 
5.1. 
Inclusion Criteria ......................................................................................... 45 
5.2. 
Exclusion Criteria ........................................................................................ 47 
5.3. 
Randomisation Criteria ............................................................................... 50 
5.4. 
Screen/Baseline/Run-in Failures ................................................................. 52 
5.5. 
Criteria for Temporarily Delaying ................................................................ 53 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 53 
6.1. 
Study Intervention(s) Administered ............................................................. 53 
6.1.1. 
Medical Devices ........................................................................... 55 
6.2. 
Self-administration for Japanese cohort ...................................................... 55 
6.2.1. 
Training for self-administration ..................................................... 56 
6.3. 
Preparation/Handling/Storage/Accountability .............................................. 56 
6.4. 
Measures to Minimize Bias: Randomisation and Blinding ........................... 56 
6.5. 
Study Intervention Compliance ................................................................... 58 
6.6. 
Dose Modification ....................................................................................... 58 
6.7. 
Continued Access to Study Intervention after the End of the Study ............ 58 
6.8. 
Treatment of Overdose ............................................................................... 59 
6.9. 
Concomitant Therapy.................................................................................. 59 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 60 
7.1. 
Premature Discontinuation of Study Intervention ........................................ 60 
7.1.1. 
Discontinuation Criteria for Intervention ....................................... 60 
7.1.2. 
Study Specific Intervention Discontinuation Criteria ..................... 61 
7.1.3. 
Primary Reasons for Intervention Discontinuation ........................ 61 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
5 
 
7.1.4. 
IP Discontinuation Visit ................................................................ 62 
7.1.5. 
Liver Chemistry Stopping Criteria ................................................ 63 
7.1.6. 
QTc Stopping Criteria .................................................................. 65 
7.1.7. 
COVID-19 testing ......................................................................... 66 
7.1.8. 
Temporary Discontinuation .......................................................... 66 
7.1.9. 
Rechallenge ................................................................................. 66 
7.2. 
Participant Withdrawal from Study .............................................................. 66 
7.2.1. 
Primary reasons for withdrawal from the study............................. 67 
7.2.2. 
Early Withdrawal Visit .................................................................. 67 
7.3. 
Lost to Follow Up ........................................................................................ 68 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 69 
8.1. 
Critical Pre-screening, Screening and Baseline Assessments .................... 70 
8.1.1. 
Pre-screening .............................................................................. 70 
8.1.2. 
Screening .................................................................................... 70 
8.1.3. 
Critical procedures performed at Screening (Visit 1) .................... 70 
8.1.4. 
Critical procedures performed at first treatment Visit 
(Baseline Visit 2) .......................................................................... 71 
8.1.5. 
Critical procedures performed throughout treatment period ......... 72 
8.2. 
Efficacy Assessments ................................................................................. 73 
8.2.1. 
Endoscopic NP score................................................................... 73 
8.2.2. 
Computed Tomography (CT) Scan .............................................. 73 
8.2.3. 
Individual Symptoms Visual Analogue Scale (VAS) ..................... 74 
8.2.4. 
NP surgery ................................................................................... 74 
8.2.5. 
Medication ................................................................................... 74 
8.2.6. 
Health Related Quality of Life (HRQoL) assessment ................... 75 
8.2.7. 
Assessments for asthmatic participants only ................................ 75 
8.3. 
Safety Assessments ................................................................................... 76 
8.3.1. 
Physical Examinations ................................................................. 76 
8.3.2. 
Vital Signs .................................................................................... 76 
8.3.3. 
Electrocardiograms ...................................................................... 76 
8.3.4. 
Clinical Safety Laboratory Assessments ...................................... 76 
8.3.5. 
Pregnancy Testing ....................................................................... 77 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 77 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 78 
8.4.2. 
Method of Detecting AEs and SAEs ............................................. 78 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 79 
8.4.4. 
Regulatory Reporting Requirements for SAEs ............................. 79 
8.4.5. 
Pregnancy ................................................................................... 79 
8.4.6. 
Cardiovascular and Death Events ................................................ 80 
8.4.7. 
Adverse Events of Special Interest .............................................. 80 
8.4.8. 
Medical Device Incidents (Including Malfunctions) ....................... 80 
8.5. 
Pharmacokinetics ....................................................................................... 82 
8.6. 
Pharmacodynamics .................................................................................... 82 
8.7. 
Genetics ..................................................................................................... 82 
8.8. 
Biomarkers ................................................................................................. 83 
8.9. 
Immunogenicity Assessments ..................................................................... 83 
8.10. 
Health Outcomes ........................................................................................ 83 
8.10.1. 
Short Form-36 (SF-36) questionnaire .......................................... 83 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
6 
 
8.10.2. 
Work Productivity and Activity Impairment Questionnaire 
(WPAI) ......................................................................................... 84 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 84 
9.1. 
Statistical Hypotheses................................................................................. 84 
9.1.1. 
Multiple Comparisons and Multiplicity .......................................... 84 
9.2. 
Sample Size Determination ........................................................................ 86 
9.2.1. 
Sample Size Sensitivity ................................................................ 87 
9.3. 
Analysis Sets .............................................................................................. 88 
9.4. 
Statistical Analyses ..................................................................................... 89 
9.4.1. 
Primary Endpoint(s) ..................................................................... 89 
9.4.2. 
Secondary Endpoint(s) ................................................................ 92 
9.4.3. 
Safety Analysis ............................................................................ 92 
9.4.4. 
Other Analysis ............................................................................. 92 
9.5. 
Interim Analysis .......................................................................................... 92 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 93 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 93 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 93 
10.1.2. 
Financial Disclosure ..................................................................... 93 
10.1.3. 
Informed Consent Process .......................................................... 94 
10.1.4. 
Data Protection ............................................................................ 94 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 95 
10.1.6. 
Data Quality Assurance ............................................................... 95 
10.1.7. 
Source Documents ...................................................................... 96 
10.1.8. 
Study and Site Start and Closure ................................................. 96 
10.1.9. 
Publication Policy ......................................................................... 97 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 98 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 100 
10.3.1. 
Definition of AE .......................................................................... 100 
10.3.2. 
Definition of SAE ........................................................................ 101 
10.3.3. 
Definition of Cardiovascular Events ........................................... 102 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 103 
10.3.5. 
Reporting of SAE to GSK ........................................................... 105 
10.4. 
Appendix 4: Anaphylaxis Criteria .............................................................. 106 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ..................................... 107 
10.5.1. 
Definitions: ................................................................................. 107 
10.5.2. 
Contraception Guidance ............................................................ 108 
10.6. 
Appendix 6: Genetics ................................................................................ 109 
10.7. 
Appendix 7: Liver Safety: Required Actions, Monitoring and Follow-
up Assessments ....................................................................................... 110 
10.8. 
Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies ................................ 114 
10.8.1. 
Definition of Medical Device AE and ADE .................................. 114 
10.8.2. 
Definition of Medical Device SAE, SADE and USADE ............... 115 
10.8.3. 
Definition of Device Deficiency ................................................... 115 
10.8.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies ............................................................................... 116 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
7 
 
10.8.5. 
Reporting of SAEs ..................................................................... 118 
10.8.6. 
Reporting of SADEs ................................................................... 119 
10.9. 
Appendix 9: Assessment of Nasal Polyposis ............................................ 120 
10.10. Appendix 10: Lund-Mackay CT score ....................................................... 121 
10.11. Appendix 11: Abbreviations and Trademarks ............................................ 122 
10.12. Appendix 12: Medical Device or Combination Product with Device 
Deficiency/Incident Report Form ............................................................... 125 
10.13. Appendix 13: Country-specific requirements ............................................. 129 
10.14. Appendix 14: Protocol Amendment History ............................................... 130 
11. REFERENCES ..................................................................................................... 134 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
8 
 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A randomised, double-blind, placebo-controlled, parallel group Phase III 
study to assess the clinical efficacy and safety of 100 mg SC Mepolizumab in adults with 
chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis 
(ECRS) – MERIT: Mepolizumab in Eosinophilic chronic RhinosinusITis study 
Brief Title: Efficacy and safety of mepolizumab in adults with CRSwNP / ECRS 
Rationale: 
Nasal polyps (NP) is a chronic inflammatory disease of the nasal mucosa, characterised 
by soft tissue growth in the upper nasal cavity.  The presence of polyps can cause long 
term symptoms of chronic rhinosinusitis (CRS) such as prominent nasal obstruction, 
post-nasal drip, loss of smell, facial pain /pressure and nasal discharge.  These symptoms 
can greatly impact a patient’s health related Quality of Life (HRQoL).  The European 
Position Paper on Rhinosinusitis and NP [Fokkens, 2020] defines the severity of disease 
using a total severity visual analogue scale (VAS) in which a patient is asked to indicate 
on a 10 cm VAS how troublesome they consider their symptoms.  An overall VAS 
symptom score of 0-3 is defined as mild disease, >3-7 as moderate and >7-10 as severe 
[Lim, 2007].  Symptoms are invariably accompanied with findings of inflammation of the 
nasal mucosa and the presence of a polyp seen through nasal endoscopy or positive 
imaging findings, for example using computerised tomography (CT).  The aetiology of 
NP is currently unknown. 
In Japan, chronic rhinosinusitis (CRS) is recognised as a common chronic disease 
[Tokunaga, 2015]. In recent years, cases of CRS with NP (CRSwNP) associated with 
eosinophilic infiltration have increased in Japan due to westernisation of eating habits and 
environments [Tokunaga, 2015]. Patients are diagnosed with eosinophilic chronic 
rhinosinusitis (ECRS) using the JESREC (Japanese Epidemiological Survey of 
Refractory Eosinophilic Chronic Rhinosinusitis) scoring system based on the presence of 
bilateral NP, CT findings, and eosinophilia in peripheral blood. This scoring system 
provide a criterion to diagnose and classify ECRS without the use of biopsy or 
operational specimens. A patient is diagnosed as having ECRS if the JESREC score is 
11 points or higher. Additionally, patients CRS is further classified into four groups 
according to blood eosinophilia, ethmoid-dominant shadow in CT, and comorbidity 
(bronchial asthma, aspirin intolerance [AI], non-steroidal anti-inflammatory drugs 
[NSAIDs] intolerance). These four groups were significantly correlated with the rate of 
recurrence and refractory disease [Tokunaga, 2015]. 
Similarly, CRS is among the most prevalent chronic disease in China. A recent study 
found that the proportion of eosinophilic CRSwNP patients significantly increased over 
the past 11 years [Wang, 2019]. Although there are no established diagnosis criteria for 
eosinophilic CRSwNP in China so far, these patients differ significantly from 
non-eosinophilic patients in clinical characteristics and treatment outcomes: they have 
higher risk of having comorbid allergic rhinitis and asthma, are frequently associated 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
9 
 
with extensive sinus disease, and have higher polyp recurrence rate after surgery. Hence, 
precision medicine on inflammatory endotypes by verification and mapping of the 
eosinophilic disease are of great importance to optimise care pathways in Asia. 
IL-5 is the predominant cytokine in NP associated with tissue eosinophilia, promoting the 
activation and prolonged survival of eosinophils.  IL-5 is increased in NP tissue 
compared with that in healthy controls, and correlates with the degree of tissue 
eosinophilia, strongly suggesting a rationale for anti-IL-5 therapy in this condition. 
Mepolizumab (NUCALA) is a humanised monoclonal antibody (IgG1, kappa, mAb) that 
blocks human interleukin-5 (hIL-5) from binding to the IL-5 receptor complex expressed 
on the eosinophil cell surface and thus inhibits signalling.  Neutralisation of IL-5 with 
mepolizumab has been shown to reduce blood, sputum and tissue eosinophils.  This led 
GSK to develop mepolizumab as a treatment option in a number of eosinophilic diseases 
including chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic 
rhinosinusitis (ECRS). 
Mepolizumab is licensed for i) add-on maintenance treatment for severe eosinophilic 
asthma at a dose of 100 mg administered subcutaneously (SC) every 4 weeks in over 
20 countries worldwide (40 mg SC in patients 6 to 11 years in the European Union [EU], 
United States of America [US], Japan and in other markets), ii) treatment of eosinophilic 
granulomatosis with polyangiitis (EGPA) at a dose of 300 mg SC every 4 weeks in the 
US, Japan, and other markets. Mepolizumab is currently approved as a lyophilised 
powder in a vial requiring reconstitution with sterile water for injection for administration 
by a healthcare professional (Mepolizumab for Injection), and as liquid formulation in 
both a prefilled safety syringe (SSD) and prefilled autoinjector for in-clinic or at-home 
patient self-administration or administration by a caregiver (Mepolizumab Injection). 
Mepolizumab injection is currently approved in several markets such as the EU, US and 
Japan. 
As of September 2019, over 4600 participants have been exposed to at least one dose of 
mepolizumab in clinical studies across various eosinophilic-mediated indications.  In 
addition, there are currently over 900 participants receiving mepolizumab as part of three 
long term access and compassionate use programs.  All studies have shown that 
mepolizumab is well tolerated when administered by SC, intravenous (IV), or 
intramuscular (IM) routes.  The highest dose administered in these studies was 1500 mg 
IV. 
A total of 74 participants with NP have been treated with mepolizumab 750 mg IV every 
4 weeks for up to 6 months in two clinical studies (CRT110178 and MPP111782) and 
206 participants been exposed to 100 mg SC every 4 weeks for up to 12 months in a 
Phase III study (SYNAPSE, 205687). All studies provided information to suggest 
potential for efficacy and that the overall safety profile of mepolizumab in NP was 
similar to that observed in the mepolizumab clinical program in severe asthma. 
Study CRT110178 was an investigator-led, collaborative research study of randomised, 
double-blind, placebo-controlled design comparing mepolizumab versus placebo in 
participants with severe NPs that were recurrent after surgery. Participants were 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
10 
 
randomised to receive two single IV injections (28 days apart) of mepolizumab 750 mg 
IV (n=20) or placebo (n=10).  The primary endpoint was the change from baseline in 
total endoscopic NP score which was the sum of left and right nostril scores assessed by 
endoscopy at Week 8 versus baseline. An improvement was observed for mepolizumab 
patients compared to placebo at Week 8 (-1.22, 90% CI: -2.28, -0.17; one–sided 
p=0.0258). 
Study MPP111782 was a GSK Phase II study that was a two-part (Part A and Part B) 
randomised, double-blind, placebo controlled, multi-centre study to investigate the use of 
mepolizumab 750 mg IV versus placebo in reducing the need for surgery in participants 
with severe bilateral NP refractory to current SoC. All participants were in need of 
surgery at the start of the study and had at least one prior surgery. Participants were 
considered in need of surgery if they had an overall VAS symptom score of >7 and an 
endoscopic NP score of 3 in at least one nostril.  One hundred and five participants were 
randomised to receive either six 750 mg IV injections of mepolizumab (54 participants) 
or placebo (51 participants), one injection every four weeks for up to a total of 6 doses in 
Part A. Participants who no longer required surgery at the end of Part A were given the 
option to enter Part B where they were followed up for a further 6 months with no 
treatment. Limited data are available for Part B of the study as only 7 participants in the 
placebo group and 14 participants in the mepolizumab group entered before Part B was 
discontinued following a protocol amendment. 
The primary endpoint was reduction in the need for surgery at the end of Part A (4 weeks 
post last dose, Week 25). A significantly greater proportion of participants in the 
mepolizumab group compared to placebo no longer required surgery at the end of Part A 
(33% vs 10% respectively, p=0.003). The overall patient-reported VAS symptom scores 
also supported the efficacy of mepolizumab, with a treatment difference from placebo at 
Week 25 of -1.78 (95% CI: -2.88, -0.68; p=0.002, PP Population). These improvements 
were supported by changes in individual VAS symptom scores and SNOT-22, a disease 
specific measure of HRQoL. 
The above evidence supported the initiation of a single Phase III pivotal trial entitled, “A 
randomised, double-blind, parallel group Phase III study to assess the clinical efficacy 
and safety of 100 mg SC mepolizumab as an add on to maintenance treatment in adults 
with severe bilateral nasal polyps – SYNAPSE” (StudY in Nasal Polyps patients to assess 
the Safety and Efficacy of mepolizumab). 
In this study, mepolizumab was administered by the Investigator or delegate via a 
pre-filled safety syringe every 4 weeks for 52 weeks. The efficacy of mepolizumab was 
assessed using co-primary endpoints of change from baseline in endoscopic NP score at 
Week 52 and nasal obstruction VAS symptom score during the 4 weeks prior to Week 
52.  Key secondary endpoint was time to first confirmed surgery for NP by Week 52. The 
study population consisted of adult participants with recurrent severe bilateral NP. They 
had to present with a history of at least one prior surgery for NP despite treatment with 
current SoC, which included intranasal corticosteroid, and need for NP surgery. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
11 
 
The study met both co-primary endpoints, with mepolizumab demonstrating statistically 
significant improvements in both the size of polyps and in nasal obstruction, compared to 
placebo, when added to standard of care: 
• 
Difference of -0.73 (95% CI: -1.11, -0.34; p<0.001) in the median change from 
baseline total endoscopic nasal polyps score at week 52 
• 
Difference of -3.14 (95% CI: -4.09, -2.18; p<0.001) in the median change from 
baseline in mean nasal obstruction VAS score during weeks 49-52 
The key secondary endpoint of time to first confirmed nasal surgery up to week 52 was 
also statistically significant, with mepolizumab showing a 57% reduction (p=0.003) 
versus placebo in rate of undertaking a NP surgery (hazard ratio [95% CI]: 0.43 [0.25, 
0.76]).  All other secondary endpoints were statistically significant consistent with the 
findings of the co-primary and key secondary endpoints thus supporting the overall 
efficacy of mepolizumab in patients with CRSwNP. There were no new safety concerns 
identified for mepolizumab compared with placebo. 
The aim of this study is to assess the efficacy and safety of mepolizumab on top of 
standard of care (SoC) therapy in the treatment of CRSwNP / ECRS for the purpose of 
registration in Japan and China. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of 
mepolizumab 100mg SC 
compared to placebo at Week 
52 in patients with a diagnosis 
of CRSwNP / ECRS 
The primary estimands are defined as follows: 
Treatment Comparison: Mepolizumab 100 mg 
SC compared to placebo 
Population: entire trial population of patients with 
a diagnosis of CRSwNP / ECRS randomised and 
receiving treatment 
Co-primary variables:  
a) Change from baseline in total endoscopic NP 
score at Week 52 
b) Change from baseline in mean nasal 
obstruction VAS score during the 4 weeks 
prior to Week 52 
Summary measure: Difference in mean scores 
between mepolizumab and placebo 
Main Intercurrent events (ICE) anticipated: 
a) Premature discontinuation of study treatment 
unrelated to the COVID-19 pandemic – to be 
handled using a treatment policy strategy 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
12 
 
Objectives 
Endpoints 
b) Changes in background medication or start of 
a prohibited medication unrelated to the 
COVID-19 pandemic (e.g. start INCS therapy 
where absent at baseline) – to be handled using 
a treatment policy strategy 
c) Premature discontinuation of study treatment, 
change in background medication or start of 
prohibited medication related to the COVID-
19 pandemic – to be handled using a 
hypothetical strategy 
d) Surgery, which includes any procedure 
involving instruments resulting in incision and 
removal of tissue from the nasal cavity (e.g. 
polypectomy) – to be handled using a 
composite strategy by incorporating 
occurrence of the event into the definition of 
the endpoint. Specifically, participants who 
undergo surgery will be assigned the worst 
possible score for the endpoint from the day of 
surgery onwards for inclusion in the analysis. 
e) Course of systemic corticosteroids (CS) for 
CRSwNP / ECRS – to be handled using a 
treatment policy strategy 
f) Interruption to investigational product of 2 or 
more consecutive doses – to be handled using 
a treatment policy 
Secondary 
• To evaluate the impact on 
quality of life of 100mg 
mepolizumab compared to 
placebo at Week 52 in 
patients with a diagnosis of 
CRSwNP / ECRS 
• Change from baseline in SNOT-22 total score 
at Week 52 
• To evaluate the efficacy of 
100 mg mepolizumab 
compared to placebo at Week 
52 in terms of mean overall 
VAS symptom score,  mean 
composite VAS score, Lund 
Mackay CT score, mean 
individual VAS symptom 
score for loss of smell and 
impact on time to first nasal 
surgery or course of  systemic 
• Change from baseline in mean overall VAS 
symptom score during the 4 weeks prior to 
Week 52 
• Change from baseline in the mean composite 
VAS score (combining VAS scores for nasal 
obstruction, nasal discharge, mucus in the 
throat and loss of smell) during the 4 weeks 
prior to Week 52 
• Change from baseline in Lund Mackay CT 
score at Week 52 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
13 
 
Objectives 
Endpoints 
CS in patients with a 
diagnosis of CRSwNP / 
ECRS 
• Change from baseline in mean individual VAS 
symptom score for loss of smell during the 4 
weeks prior to Week 52 
• Time to first nasal surgery or course of 
systemic CS for CRSwNP / ECRS up to Week 
52   
 
Other 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
14 
 
Objectives 
Endpoints 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
15 
 
Objectives 
Endpoints 
Safety 
 
• To evaluate the safety and 
immunogenicity of 100 mg 
mepolizumab compared 
placebo in patients with a 
diagnosis of CRSwNP / 
ECRS 
• Frequency of Adverse events (AEs)/ Serious 
adverse events (SAEs) including systemic 
reactions and local injection site reactions 
reported 
• Vital signs (pulse rate, systolic and diastolic 
blood pressure) 
• Haematological and clinical chemistry 
parameters 
• 12 lead ECG derived endpoints 
• Presence of anti-mepolizumab antibodies and 
neutralising antibodies 
Pharmacokinetics and pharmacodynamics 
 
• To evaluate the 
pharmacokinetics and 
pharmacodynamics of 100 mg 
mepolizumab in a subgroup of 
participants from Japan and 
China with a diagnosis of 
CRSwNP / ECRS 
• Plasma concentration of mepolizumab  
• PK/PD (blood eosinophil count) analysis 
 
The primary estimands are the difference between mepolizumab 100 mg SC and placebo 
in a) mean change from baseline in total endoscopic NP score to Week 52 and b) mean 
change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
16 
 
Week 52 in participants with a diagnosis of CRSwNP / ECRS, regardless of IP 
discontinuation or changes in background medication/starting a prohibited medication 
unrelated to the COVID-19 pandemic, use of systemic CS for CRSwNP / ECRS or 
interruption of 2 or more consecutive doses of IP, with participants experiencing surgery 
being assigned the worst possible score from the day of surgery onwards. 
Secondary estimands for SNOT-22, VAS scores and Lund Mackay CT score will use the 
same population, summary measure and strategies for intercurrent events as for the 
primary estimands. Time to first nasal surgery or course of systemic CS for CRSwNP / 
ECRS up to Week 52 will be summarised by the hazard ratio between mepolizumab and 
placebo. The same population and strategies for intercurrent events of treatment 
discontinuation, changes in background medication/starting a prohibited medication, 
interruptions of 2 or more consecutive doses of IP and COVID-19 pandemic related 
intercurrent events will be used as for the primary estimands. For this endpoint, both 
surgery and a course of systemic CS for CRSwNP / ECRS will be considered events 
within the analysis and therefore will not be considered an intercurrent event. 
Overall Design: 
This is a randomised, double-blind, placebo controlled, parallel group Phase III study 
designed to assess the clinical efficacy and safety of 100 mg SC Mepolizumab treatment 
in adults with chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic 
rhinosinusitis (ECRS). 
The objective of the study is to evaluate the efficacy and safety of mepolizumab 100 mg, 
administered SC by the Investigator, a delegate or participant via safety syringe every 
4 weeks for 52 weeks. Efficacy of mepolizumab will be assessed using co-primary 
endpoints of change from baseline in total endoscopic NP score at Week 52 and change 
from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week 52. 
The study population will consist of adult participants (18 years of age) with CRSwNP / 
ECRS as defined by the JESREC guideline. In addition, they must have an endoscopic 
NP score of at least 5 out of a maximum score of 8, with a minimum score of 2 in each 
nasal cavity. Participants must also have a prior treatment with systemic corticosteroids 
(SCS) anytime within the past 2 years; and/or have a medical contraindication/intolerance 
to SCS; and/or had a documented history of prior surgery for NP at the screening visit. 
The study will include a 4-week run-in period followed by randomisation to a 52-week 
treatment period as a double-blind, placebo-controlled phase. Throughout the 52-week 
treatment period, participants will be on the SoC for CRSwNP / ECRS. Depending on 
local practice SoC may include intranasal corticosteroids (INCS), saline nasal douching, 
occasional short courses of systemic corticosteroids and/or antibiotics. Depending on 
local SoC/treatment, patients treated with intranasal corticosteroids (INCS) and/or 
leukotriene receptor antagonists (LTRA) are expected, if possible, to continue with these 
treatments with no interruption nor alteration to the doses throughout the study duration. 
If a patient is not on INCS or LTRA prior to screening, the patient is prohibited to start 
any INCS or LTRA during the study. 


TMF-14790303 
CONFIDENTIAL 
209692 
17 
There is a trend especially in Japan, to use orally inhaled corticosteroids exhalation 
through nose (ICS/ETN) method of administration for the management of NP for patients 
with both ECRS and concomitant asthma disease [Kobayashi, 2018]. Although longer 
term effects on ECRS disease are yet to be fully evaluated, the short-term effects of 
ICS/ETN on NP size can be significant. Therefore, participants in this study who use 
ICS/ETN method of administration for their asthma and NP disease are maintain this 
method throughout the study period. 
The treatment period will consist of thirteen, 4-weekly doses of mepolizumab or placebo, 
delivered by a pre-filled safety syringe device (SSD) injection. 
Number of Participants: 
Assuming a screen failure rate of 40%, approximately 270 participants will need to be 
screened in order to allow for approximately 160 participants to be randomised in a 1:1 
ratio to mepolizumab or placebo treatment (approximately 80 participants per arm). 
Intervention Groups and Duration: 
A liquid formulation of mepolizumab, which has currently been approved in the EU, US, 
Japan and some other markets, will be provided in a SSD. There will also be a matched 
SSD with matched placebo. For non-Japanese participants, study treatment must be 
administered by a health care professional (HCP) until week 52 (last dose at week 48). 
For Japanese participants who are willing to self-administer they can self-administer 
study treatment under observation of the HCP from Week 32 onwards. Participants who 
are successfully enrolled into the study will be randomised in a 1:1 ratio into one of two 
treatment groups, receiving a total of thirteen doses (one every four weeks) in a double-
blind manner: 
•
Group 1: 100 mg SC of mepolizumab on top of SoC
•
Group 2: Placebo SC on top of SoC
A participant is considered to have completed study treatment if he/she receives study 
treatment at Visit 14 (Week 48). A participant is considered to have completed the study 
if he/she has completed all phases of the study including the last visit (Visit 15/Week 52) 
or the last scheduled procedure shown in the SoA, whichever is earlier. 
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial 
globally, whichever is earlier. 
Initiation or changes in the dosing regimen of LTRA or allergen immunotherapy from 
screening to end of the study are not allowed. Changes in the dosing regimen of INCS 
and/or ICS/ETN from screening to end of the study are also not allowed. 
The following medications may be used by all participants: 
1. Short courses of systemic CS (for example of systemic CS for treatment of CRSwNP
/ ECRS). The use of rescue medications such as systemic CS is allowable during the
52-week treatment phase of the study (Visit 2 and onwards) but not during the run-in


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
18 
 
period; the date and time of rescue medication administration as well as the name and 
dosage regimen (dose and duration) of the rescue medication must be recorded in the 
eCRF for NP as well as for other comorbidities. 
2. Throughout the study, asthmatic participants are to be maintained on their baseline 
SoC asthma treatment. 
3. For antibiotic treatment for CRSwNP / ECRS, the type, dose and duration must also 
be recorded in the eCRF. 
The following medications are not allowed prior to screening (Visit 1) and throughout the 
study, according to the following schedule, or during the study: 
Prohibited Medication 
Time Period Prior to Screening Visit 
Investigational products (biologic or non-
biologic) 
3 months 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) 
Regular systemic corticosteroids including 
oral, intramuscular, long-acting depot 
1 month 
Methotrexate, troleandomycin, cyclosporin, 
Azathioprine 
1 month 
Oral gold 
3 months 
Chemotherapy used for conditions other than 
asthma 
12 months 
Changes in intranasal corticosteroid treatment 
1 month 
Insertion of any non-drug or drug eluting 
nasal stents such as Propel stents 
6 months 
Direct steroid injections into CRSwNP / 
ECRS 
6 months 
 
Data Monitoring/Other Committee: Not applicable 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
19 
 
1.2. 
Schema 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
20 
 
1.3. 
Schedule of Activities (SoA) 
 
Procedure 
Pre-
screening1 
Screening1  
Treatment 
 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 11 12 
13 
14 
15 
IP DISC / EW Visit 
Study Day 
(visit window 
±7 days) 
 
up to 28 ±7 
days prior to 
Day 1 
1 
29 57 85 113 141 169 197 
204 
(±1day) 225 253 281 309 
337 365 
28 ±7 days post 
last dose 
Week 
 
 
0 
4 
8 
12 16 20 24 28 
29 
32 36 40 
44 
48 
52 
 
Screening/ 
baseline 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for eosinophils 
eligibility confirmation (if required) 2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam including height 
and weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (includes substance 
usage and family history of premature 
CV disease CRSwNP/ECRS and 
asthma therapy, asthma and 
exacerbation history and concomitant 
medications) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE Review 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of HIV and Hep B, Hep C 
screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past and current medical conditions 
including cardiovascular medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of systemic CS use for NP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of NP surgery 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
21 
 
 
Procedure 
Pre-
screening1 
Screening1  
Treatment 
 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 11 12 
13 
14 
15 
IP DISC / EW Visit 
Study Day 
(visit window 
±7 days) 
 
up to 28 ±7 
days prior to 
Day 1 
1 
29 57 85 113 141 169 197 
204 
(±1day) 225 253 281 309 
337 365 
28 ±7 days post 
last dose 
Week 
 
 
0 
4 
8 
12 16 20 24 28 
29 
32 36 40 
44 
48 
52 
 
 
Parasitic screening 3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Vital signs 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of endoscopic NP 
score11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of VAS for NP symptoms 
including Overall VAS 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of Screening CT4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Laboratory assessments: 
Haematology (including blood 
eosinophils) and chemistry (including 
liver chemistries) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (WOCBP only)5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense and Train in the use of 
eDiary6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Register visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
Randomisation 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetics sample7 
 
 
X 
Efficacy 
Assessment of NP Surgery 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
Assessment of systemic CS and 
antibiotics dose and duration for NP 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
22 
 
 
Procedure 
Pre-
screening1 
Screening1  
Treatment 
 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 11 12 
13 
14 
15 
IP DISC / EW Visit 
Study Day 
(visit window 
±7 days) 
 
up to 28 ±7 
days prior to 
Day 1 
1 
29 57 85 113 141 169 197 
204 
(±1day) 225 253 281 309 
337 365 
28 ±7 days post 
last dose 
Week 
 
 
0 
4 
8 
12 16 20 24 28 
29 
32 36 40 
44 
48 
52 
 
VAS symptom score for nasal 
obstruction, nasal discharge, mucus 
in the throat, loss of smell, facial 
pain6 
 
 
 
 
Overall VAS symptom score6 
 
 
 
SNOT-228, 9, 17 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
SF-368, 9, 10 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
WPAI-GH 8, 9, 10 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
ACQ – 58, 9, 17 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
Endoscopic NP score11 
 
 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
Assessment of CT4, 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Asthma exacerbation12 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
Blood for PK13 
 
 
 
X 
 
 
 
 
 
X 
X13 
 
 
 
 
 
X 
X 
 
Blood for Immunogenicity 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Safety 
AE/SAE review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
 
Concomitant medication review 
(including INCS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
 
12-lead ECG 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Vital signs (HR and BP) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
 
Laboratory assessments: 
Haematology (including blood 
eosinophils)15 
 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
 
Laboratory assessments: chemistry 
(including liver chemistries)16 
 
 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
23 
 
 
Procedure 
Pre-
screening1 
Screening1  
Treatment 
 
Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
9a 
10 11 12 
13 
14 
15 
IP DISC / EW Visit 
Study Day 
(visit window 
±7 days) 
 
up to 28 ±7 
days prior to 
Day 1 
1 
29 57 85 113 141 169 197 
204 
(±1day) 225 253 281 309 
337 365 
28 ±7 days post 
last dose 
Week 
 
 
0 
4 
8 
12 16 20 24 28 
29 
32 36 40 
44 
48 
52 
 
 
Urinalysis 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Urine pregnancy test (WOCBP)5 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X5 
X5 
 
Dosing with study Drug/Placebo14 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
 
 
 
eDiary Compliance Check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X X 
X 
X 
X 
X 
 
eDiary Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Early withdrawal, intervention 
discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1. 
Pre-screening and screening can be performed on the same day 
2. 
A documented blood eosinophil count of >2% in the 12 months prior to Visit 0 OR through a blood sample taken between Visit 0 and Visit 1. ALL participants must meet blood 
eosinophil count of >2% by Visit 1 
3. 
Parasitic screening is only required in countries with high-risk or for participants who have visited high-risk countries in the past 6 months. Sites should use local laboratories 
4. 
A CT scan should be performed anytime during the run-in period up to a week prior randomisation.  A second CT scan should be performed at V15 or IP discontinuation/Early 
Withdrawal visit (up to 14 days prior to the nominal study visit) 
5. 
Urine Pregnancy test results to be assessed at all visits and prior to CT scan at Screening, V15 or IP discontinuation/Early Withdrawal Visit. If a urine test cannot be confirmed as 
negative (e.g., an ambiguous result), a serum pregnancy test is required.  
6. 
eDiary completion by participants will be daily every morning between Screening Visit and Visit 15 (or IP discontinuation/Early Withdrawal Visit)  
7. 
Genetics informed consent to be obtained any time prior sampling, Genetics sampling to be performed anytime while on treatment (Genetics sampling not applicable for 
participants in China) 
8. 
Performed using eDiary device  
9. 
All questionnaires will be performed before any other assessments on each particular visit, VAS scores (if not already completed at home), SNOT-22, (ACQ-5), SF-36 and WPAI. 
ACQ-5 should only be performed in Asthmatic participants.  Order of questionnaires will be detailed in the Study Reference Manual. 
10. SF-36 and WPAI will be performed at visits Baseline, week 4, week 24 and week 52 (or IP discontinuation/Early Withdrawal Visit) only 
11. For endoscopic NP scores performed at V1, 3, 4, 6, 8, 10, 12, 14, 15 (or IP discontinuation/Early Withdrawal Visit), the nasal endoscopy assessment may be performed up to 3 
days prior to the day of dosing but must not exceed the protocol defined windows of 7 days from the nominal study visit. For V2, the endoscopic NP score cannot be performed 
earlier than V2 but must be performed at V2 upon completion of all screening procedures and prior to administration of IP. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
24 
 
12. For asthmatic participants only. An asthma exacerbation is defined as worsening of asthma requiring systemic corticosteroids (i.v. or oral steroid) for at least 3 days or a single IM 
CS dose and/or emergency department visit, or hospitalisation 
13. Blood for PK will be collected at Visits 3 (pre-dose), 9 (pre-dose) and 15 (or IP discontinuation/early withdrawal). In addition, one post-dose PK collection will be at Week 29 (Visit 
9a, one week after dose at Visit 9) with a collection visit allowance of ±1 day. As for Week 29, blood sample will be collected from up to approximately first 30 Japanese and all 
Chinese participants randomised, no PK samples will be collected outside Japan and China 
14. For participants who are willing to perform self-administration within the Japanese participants cohort: self-administer from Week 32 onwards (after receiving at least two trainings 
by investigator or delegate beforehand) 
15. Laboratory assessments: Haematology (including blood eosinophils) will be taken at visits 1, 2, 3, 4, 7, 8, 10, 13, 14, 15 (or IP discontinuation/Early Withdrawal Visit) 
16. Laboratory assessments: chemistry (including liver chemistries) will be taken at visits 1, 2, 3, 4, 7, 10, 13, 15 (or IP discontinuation/Early Withdrawal Visit) 
17. ACQ-5 and SNOT-22 will be performed at baseline (visit 2), 3, 4, 5, 6, 7, 8, 11, 15, IP discontinuation/Early Withdrawal Visit 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
25 
 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
Mepolizumab (NUCALA) is a humanised monoclonal antibody (IgG1, kappa, mAb) that 
blocks human interleukin-5 (hIL-5) from binding to the IL-5 receptor complex expressed 
on the eosinophil cell surface and thus inhibits signalling.  Neutralisation of IL-5 with 
mepolizumab has been shown to reduce blood, sputum and tissue eosinophils. This led 
GSK to develop mepolizumab as a treatment option in a number of eosinophilic diseases 
including chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic 
rhinosinusitis (ECRS). 
Mepolizumab is licensed for i) add-on maintenance treatment for severe eosinophilic 
asthma at a dose of 100 mg administered subcutaneously (SC) every 4 weeks in over 20 
countries worldwide (40 mg SC in patients 6 to 11 years in the European Union [EU], 
United States of America [US], Japan and in other markets), ii) treatment of eosinophilic 
granulomatosis with polyangiitis (EGPA) at a dose of 300 mg SC every 4 weeks in the 
US, Japan, and other markets. Mepolizumab is currently approved as a lyophilised 
powder in a vial requiring reconstitution with sterile water for injection for administration 
by a healthcare professional (Mepolizumab for Injection), and as liquid formulation in 
both a prefilled safety syringe (SSD) and prefilled autoinjector for in-clinic or at-home 
patient self-administration or administration by a caregiver (Mepolizumab Injection). 
Mepolizumab Injection is currently approved in several markets such as the EU, US and 
Japan. 
As of September 2019, over 4600 participants have been exposed to at least one dose of 
mepolizumab in clinical studies across various eosinophilic-mediated indications.  In 
addition, there are currently over 900 participants receiving mepolizumab as part of three 
long term access and compassionate use programs.  All studies have shown that 
mepolizumab is well tolerated when administered by SC, intravenous (IV), or 
intramuscular (IM) routes.  The highest dose administered in these studies was 1500 mg 
IV. 
A total of 74 participants with NP have been treated with mepolizumab 750 mg IV every 
4 weeks for up to 6 months in two clinical studies (CRT110178 and MPP111782) and 
206 participants been exposed to 100 mg SC every 4 weeks for up to 12 months in a 
Phase III study (SYNAPSE, 205687).  All studies provided information to suggest 
potential for efficacy and that the overall safety profile of mepolizumab in NP was 
similar to that observed in the mepolizumab clinical program in severe asthma and there 
were no known safety concerns that would preclude developing mepolizumab in NP. 
The aim of this study is to assess the efficacy and safety of mepolizumab on top of 
standard of care (SoC) therapy in the treatment of CRSwNP/ ECRS for the purpose of 
registration in Japan and China. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
26 
 
2.2. 
Background 
Background on CRSwNP / ECRS 
Nasal polyps (NP) is a chronic inflammatory disease of the nasal mucosa, characterised 
by soft tissue growth in the upper nasal cavity.  The presence of polyps can cause long 
term symptoms of chronic rhinosinusitis (CRS) such as prominent nasal obstruction, 
post-nasal drip, loss of smell, facial pain /pressure and nasal discharge.  These symptoms 
can greatly impact a patient’s health related Quality of Life (HRQoL).  The European 
Position Paper on Rhinosinusitis and NP [Fokkens, 2020] defines the severity of disease 
using a total severity visual analogue scale (VAS) in which a patient is asked to indicate 
on a 10 cm VAS how troublesome they consider their symptoms.  An overall VAS 
symptom score of 0-3 is defined as mild disease, >3-7 as moderate and >7-10 as severe 
[Lim, 2007].  Symptoms are invariably accompanied with findings of inflammation of the 
nasal mucosa and the presence of a polyp seen through nasal endoscopy or positive 
imaging findings, for example using computerised tomography (CT).  The aetiology of 
NP is currently unknown. 
The current standard of care (SoC) for CRSwNP is treatment with INCS and, for severe 
symptoms, intermittent courses of systemic corticosteroids, when short term relief is 
required [Fokkens, 2020].  Antibiotic courses may also be required for intercurrent sinus 
infection, which often complicates severe NP.  Although many patients with NP can be 
adequately controlled with simple medical care (INCS and OCS, occasional nasal 
douching and antibiotic courses) [Alobid, 2012; Newton, 2008], progression to surgery as 
a result of severe symptoms and disruption to quality of life is common.  Surgery, when 
ultimately indicated, involves the removal of the polyp tissue and diseased mucosa, 
restoring aeration of the nasal passage and sinuses.  Over 250,000 NP surgeries are 
performed in the US annually [Bhattacharyya, 2010].  However, polyps have a strong 
tendency to recur, often requiring repeat surgery [Levine, 1990; Larsen, 1997; Rucci, 
2003; Wynn, 2004; Jankowski, 2006; Brescia, 2015] with a timescale that can vary from 
a few months to years.  Data suggests patients with NP associated with tissue 
eosinophilia constitute the majority of those who have a recurrence after surgery 
[Brescia, 2015].  Repeat (revision) surgery is associated with diminishing success and a 
higher potential for adverse effects [Bhattacharyya, 2004; Chu, 1997], hence alternative 
treatment options are needed for this patient group. 
In Japan, chronic rhinosinusitis (CRS) is recognised as a common chronic disease 
[Tokunaga, 2015]. In recent years, cases of CRS with NP (CRSwNP) associated with 
eosinophilic infiltration have increased in Japan due to westernisation of eating habits and 
environments [Tokunaga, 2015]. Patients are diagnosed as eosinophilic chronic 
rhinosinusitis (ECRS) using the JESREC (Japanese Epidemiological Survey of 
Refractory Eosinophilic Chronic Rhinosinusitis) scoring system based on the presence of 
bilateral NP, CT findings, and eosinophilia in peripheral blood. This scoring system 
provide a criterion to diagnose and classify ECRS without the use of biopsy or 
operational specimens. A patient is diagnosed as having ECRS if the JESREC score is 
11 points or higher. Additionally, patients CRS is further classified into four groups 
according to blood eosinophilia, ethmoid-dominant shadow in CT, and comorbidity 
(bronchial asthma, aspirin intolerance (AI) non-steroidal anti-inflammatory drugs 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
27 
 
[NSAIDs] intolerance). These four groups were significantly correlated with the rate of 
recurrence and refractory disease [Tokunaga, 2015].  
Similarly, CRS is among the most prevalent chronic disease in China. A recent report 
found that the proportion of eosinophilic CRSwNP patients significantly increased over 
11 years [Wang, 2019]. Although there are no established diagnosis criteria for 
eosinophilic CRSwNP in China so far, these patients differ significantly from non-
eosinophilic patients in clinical characteristics and treatment outcomes: they have higher 
risk of having comorbid allergic rhinitis and asthma, are frequently associated with 
extensive sinus disease, and have higher polyp recurrence rate after surgery. Hence, 
precision medicine on inflammatory endotypes by verification and mapping of the 
eosinophilic disease are of great importance to optimise care pathways in Asia. 
Standard of care for ECRS is systemic corticosteroids in Japan and there is a trend to use 
orally inhaled corticosteroids exhalation through nose (ICS/ETN) method of 
administration for the management of NP for patients with both ECRS and concomitant 
asthma disease [Kobayashi, 2018 ]. Although longer term effects on nasal polyp disease 
are yet to be fully evaluated, the short-term effects of ICS/ETN on NP size can be 
significant. Of note, in Japan INCS is not licensed for ECRS. 
IL-5 is the predominant cytokine in NP associated with tissue eosinophilia, promoting the 
activation and prolonged survival of eosinophils [Bachert, 1997; Bachert, 1998].  IL-5 is 
increased in NP tissue compared with that in healthy controls, and correlates with the 
degree of tissue eosinophilia, strongly suggesting a rationale for anti-IL-5 therapy in this 
condition [Bachert, 1997]. 
While the recurrence of bilateral NP despite surgery is common and known to be 
associated with the IL-5/eosinophilic pathway in adults, this is less so for children [Jones, 
1999; Fokkens, 2020]. The number of eosinophils and cells expressing messenger RNA 
for IL-4, IL-5 and IL-10 is higher in patients with CRS excluding cystic fibrosis (CF) 
versus those with CF and controls [Fokkens, 2020].  Antrochoanal polyps are also 
another form of NP more common in children that are usually unilateral and associated 
with low eosinophil tissue levels [Fokkens, 2020]. 
The role of mepolizumab in CRSwNP / ECRS 
Mepolizumab (NUCALA™) is a humanised monoclonal antibody (IgG1, kappa, mAb) 
that blocks human interleukin-5 (hIL-5) from binding to the IL-5 receptor complex 
expressed on the eosinophil cell surface and thus inhibits signalling.  Neutralisation of 
IL-5 with mepolizumab has been shown to reduce blood, sputum and tissue eosinophils. 
This led GSK to develop mepolizumab as a treatment option in a number of eosinophilic 
diseases including CRSwNP / ECRS. 
Mepolizumab is licensed for i) add-on maintenance treatment for severe eosinophilic 
asthma at a dose of 100 mg administered subcutaneously (SC) every 4 weeks in over 
20 countries worldwide (40 mg SC in patients 6 to 11 years in the European Union [EU], 
United States of America [US], Japan and in other markets), ii) treatment of eosinophilic 
granulomatosis with polyangiitis (EGPA) at a dose of 300 mg SC every 4 weeks in the 
US, Japan, and other markets. Mepolizumab is currently approved as a lyophilised 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
28 
 
powder in a vial requiring reconstitution with sterile water for injection for administration 
by a healthcare professional (Mepolizumab for Injection), and as liquid formulation in 
both a prefilled safety syringe (SSD) and prefilled autoinjector for in-clinic or at-home 
patient self-administration or administration by a caregiver (Mepolizumab Injection). 
Mepolizumab Injection is currently approved in several markets such as the EU, US and 
Japan. 
A total of 74 participants with NP have been treated with mepolizumab 750 mg IV every 
4 weeks for up to 6 months in two clinical studies (CRT110178 and MPP111782) and 
206 participants been exposed to 100 mg SC every 4 weeks for up to 12 months in a 
Phase III study (SYNAPSE, 205687). All studies provided information to suggest 
potential for efficacy and that the overall safety profile of mepolizumab in NP was 
similar to that observed in the mepolizumab clinical program in severe asthma and there 
were no known safety concerns that would preclude developing mepolizumab in NP. 
Study CRT110178 was an investigator-led, collaborative research study of randomised, 
double-blind, placebo-controlled design comparing mepolizumab versus placebo in 
participants with severe NPs that were recurrent after surgery.  Participants were 
randomised to receive two single intravenous (IV) injections (28 days apart) of 
mepolizumab 750 mg IV (n=20) or placebo (n=10).  The primary endpoint was the 
change from baseline in total endoscopic NP score which was the sum of left and right 
nostril scores assessed by endoscopy at Week 8 versus baseline.  An improvement was 
observed for mepolizumab patients compared to placebo at Week 8 (-1.22, 
90% CI: -2.28, -0.17; one–sided p=0.0258). 
Study MPP111782 was a GSK Phase II study that was a two-part (Part A and Part B) 
randomised, double-blind, placebo controlled, multi-centre study to investigate the use of 
mepolizumab 750 mg IV versus placebo in reducing the need for surgery in participants 
with severe bilateral NP refractory to current SoC.  All participants were in need of 
surgery at the start of the study and had at least one prior surgery.  Participants were 
considered in need of surgery if they had an overall VAS symptom score of >7 and an 
endoscopic NP score of 3 in at least one nostril. One hundred and five participants were 
randomised to receive either six 750 mg IV injections of mepolizumab (54 participants) 
or placebo (51 participants), one injection every four weeks for up to a total of 6 doses in 
Part A.  Participants who no longer required surgery at the end of Part A were given the 
option to enter Part B where they were followed up for a further 6 months with no 
treatment. Limited data are available for Part B of the study as only 7 participants in the 
placebo group and 14 participants in the mepolizumab group entered before Part B was 
discontinued following a protocol amendment. 
The primary endpoint was reduction in the need for surgery at the end of Part A (4 weeks 
post last dose, Week 25). A significantly greater proportion of participants in the 
mepolizumab group compared to placebo no longer required surgery at the end of Part A 
(33% vs 10% respectively, p=0.003). The overall patient-reported VAS symptom scores 
also supported the efficacy of mepolizumab, with a treatment difference from placebo at 
Week 25 of -1.78 (95% CI: -2.88, -0.68; p=0.002, PP Population).  These improvements 
were supported by changes in individual VAS symptom scores and SNOT-22, a disease 
specific measure of HRQoL. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
 
29 
 
The above evidence supported the initiation of a single Phase III pivotal trial entitled, “A 
randomised, double-blind, parallel group Phase III study to assess the clinical efficacy 
and safety of 100 mg SC mepolizumab as an add on to maintenance treatment in adults 
with severe bilateral nasal polyps – SYNAPSE” (StudY in Nasal Polyps patients to assess 
the Safety and Efficacy of mepolizumab). 
In this study, mepolizumab was administered by the Investigator or delegate via a pre-
filled safety syringe every 4 weeks for 52 weeks. The efficacy of mepolizumab was 
assessed using co-primary endpoints of change from baseline in endoscopic NP score at 
Week 52 and nasal obstruction VAS symptom score during the 4 weeks prior to Week 
52.  Key secondary endpoint was time to first confirmed surgery for NP by Week 52.  
The study population consisted of adult participants with recurrent severe bilateral NP.  
They must present with a history of at least one prior surgery for NP despite treatment 
with current SoC, which include intranasal corticosteroid, and in need for NP surgery. 
The study met both co-primary endpoints, with mepolizumab demonstrating statistically 
significant improvements in both the size of polyps and in nasal obstruction, compared to 
placebo, when added to standard of care: 
• 
Difference of -0.73 (95% CI: -1.11, -0.34; p<0.001) in the median change from 
baseline total endoscopic nasal polyps score at week 52 
• 
Difference of -3.14 (95% CI: -4.09, -2.18; p<0.001) in the median change from 
baseline in mean nasal obstruction VAS score during weeks 49-52 
The key secondary endpoint of time to first confirmed nasal surgery up to week 52 was 
also statistically significant, with mepolizumab showing a 57% reduction (p=0.003) 
versus placebo in rate of undertaking a NP surgery (hazard ratio [95% CI]: 0.43 [0.25, 
0.76]).  All other secondary endpoints were statistically significant consistent with the 
findings of the co-primary and key secondary endpoints thus supporting the overall 
efficacy of mepolizumab in patients with CRSwNP. 
Mepolizumab was well tolerated in this population with CRSwNP with no new safety 
issues identified. Taken together, the integrated evidence supports the proposition that 
mepolizumab may be effective in improving symptoms, reducing NP size and reducing 
the need for surgery in patients with CRSwNP/ ECRS and recurrent disease despite 
current optimal medical management. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of mepolizumab may be found in the 
Investigator’s Brochure (IB), summaries of findings from both clinical and non-clinical 
studies conducted with mepolizumab (SB-240563) lyophilised drug product and 
pre-filled liquid formulation can be found in the Investigator’s Brochure [GSK Document 
Number CM2003/00010/10, 2015]. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
30 
 
2.3.1. 
Risk Assessment 
The following section outlines the key risks, risk assessment and mitigation strategy for this protocol: 
Important Identified Risk 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) 
Risk of Systemic Allergic [type I hypersensitivity] 
and other systemic reactions, including Anaphylaxis 
In the placebo controlled CRSwNP study 205687, 1 
of 201 (<1%) on placebo and 2 of 206 (<1%) in the 
mepolizumab 100 mg SC group reported systemic 
reactions.  One participant in the mepolizumab 
group reported rash, the other reported erythema.  
Both were considered to represent allergic type 1 
hypersensitivity reactions by the investigator.  Both 
events resolved and both participants continued 
treatment with mepolizumab.  One participant on 
placebo reported an event of asthenia which was 
considered to represent systemic reaction - other by 
the investigator.  The event resolved with continued 
study treatment. 
In the placebo controlled severe asthma (PCSA) 
studies both acute and delayed systemic reactions 
including hypersensitivity have been reported 
following administration of mepolizumab with 
incidence rates similar between mepolizumab and 
placebo-treated participants: 
• 
54/915 participants or 6% in the 
mepolizumab [all doses combined] group  
• 
7/263 participants or 3% in the mepolizumab 
100 mg SC group 
• 
12/344 participants or 3% in the 
mepolizumab 75 mg IV group  
• 
20/412 participants or 5% in the placebo 
group. 
Regular monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by the GSK study team and/or 
safety review team.  
Customised AE and SAE case report form (CRF) 
utilised for targeted collection of information for 
systemic reaction adverse events. 
Use of Joint NIAID/FAAN 2nd Symposium on 
Anaphylaxis to collect data on reports of 
anaphylaxis (see Appendix 4: Anaphylaxis Criteria). 
Participants are monitored in clinic for at least 
1 hour following administration of IP for the first 
3 doses then per institutional guidelines.  
 
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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
31 
 
Important Identified Risk 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
The most common symptoms reported with any 
systemic reaction included headache, rash, pruritus, 
fatigue, and dizziness. While rare, serious systemic 
reactions have been reported. Events of anaphylaxis 
attributed to mepolizumab have been reported post-
marketing. 
Systemic reactions reported to date across the 
mepolizumab programme are summarised in the IB 
“Adverse Events of Special Interest” section; see 
also ‘Special Warnings and Special Precautions for 
Use’ section located in Section 6 titled ‘Summary of 
Data and Guidance for the Investigator’[GSK 
Document Number CM2003/00010/10, 2015]. 
 
Injection site reactions 
In the PCSA studies the incidence of local site 
reactions with SC administration of mepolizumab 
was higher on mepolizumab 100 mg SC group 
(21/263 or 8%) compared to mepolizumab 75mg IV 
(10/344 or 3%) or placebo (13/412 or 3%). 
Symptoms included pain, erythema, swelling, 
itching, and burning sensation.  
Local injection site reactions reported to date across 
the mepolizumab program are summarised in the IB 
“Adverse Events of Special Interest” section; see 
also Section 6 titled ‘Summary of Data and 
Guidance for the Investigator’[GSK Document 
Number CM2003/00010/10, 2015]. 
Regular monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by GSK study team and/or safety 
review team.  
Customised AE and SAE case report form (CRF) 
utilised for targeted collection of information for 
local injection site reaction adverse events. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
32 
 
Important Identified Risk 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risk of immunogenicity 
Mepolizumab has low immunogenic 
potential. Overall, the immunogenicity 
results from clinical studies across the mepolizumab 
program demonstrate that the 
presence of anti-drug antibodies (ADAs) is 
not associated with any specific adverse 
events, anti-mepolizumab antibodies did not 
discernibly impact the pharmacokinetics 
(PK) or pharmacodynamics (PD) of 
mepolizumab in the majority of participants 
and there was no evidence of a correlation 
between antibody titres and change in 
eosinophil level. 
 
Immunogenicity data reported to date across 
the mepolizumab development program are 
summarized in the IB; See Section 5.4 
‘Clinical Immunogenicity’ and in Section 6 
‘Summary of Data and guidance for the 
Investigator’ [GSK Document Number 
CM2003/00010/10, 2015]. 
Blood samples will be collected for detection of 
both ADA and neutralising antibodies (NAb). 
Study Procedures 
Potential risk for injury with phlebotomy  
Risks with phlebotomy include bruising, bleeding, 
infection, nerve damage. 
Procedures to be performed by trained personnel 
(i.e., study nurse) 
Exposure of subjects to ionising radiation from 
Cranial CT 
Two cranial CT scans are included at visits 1 and 
15, or in the event of IP discontinuation / Early 
Withdrawal. 
The total effective radiation dose from the two 
cranial CT procedures is estimated to be 4mSv. 
The average annual global background radiation 
dose is 2.4mSv and therefore the total estimated 
The minimum number of CT procedures will be 
performed to achieve study objectives (with a 52 
weeks spacing between procedures). Application of 
an increased minimum age for inclusion in the study 
was considered to further mitigate the risks. 
However, such a restriction is impracticable in this 
population and might also result in the study sample 
being skewed and unrepresentative.  Therefore, 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
33 
 
Important Identified Risk 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
dose from study procedures is less than 2-years of 
background radiation. The additional risk of 
developing a fatal malignancy as a result of this 
radiation exposure is around 1 in 5000. 
given the moderate radiation dose, a minimum age 
for inclusion of 18 years is considered justifiable. 
Exposure of foetus to ionising radiation from 
Cranial CT 
As the study procedure is a cranial CT, the abdomen 
is out of the field of view and in the event of an 
undetected pregnancy the foetal radiation dose will 
be limited to scatter and hence very small. 
Nevertheless, steps are required to avoid accidental 
exposure of pregnant subjects. 
WOCBP will be required to have a negative highly 
sensitive urine pregnancy test within the 24 hours 
before each CT scan. If a urine test cannot be 
confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the 
participant will be excluded from participation if the 
serum pregnancy result at screening is positive. 
Blinding eosinophil counts 
This study is a double-blind, placebo-controlled 
study which may be used to support approval for the 
use of mepolizumab in patients with CRSwNP / 
ECRS. Unblinded eosinophil counts after the first 
administration of IP may compromise the integrity 
of the study. 
Patients will be seen every four weeks by site staff.  
After Randomisation, neither the site staff nor 
blinded GSK personnel will be sent results from the 
central laboratory for: absolute and differential 
values for eosinophils, lymphocytes, basophils, 
neutrophils and monocytes. However, sites will be 
sent total white blood counts throughout the study. 
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 IP 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. nasal endoscopy) should be 
recorded as COVID-19 protocol deviations. 
Intercurrent events of IP discontinuation or changes 
to background therapy/use of prohibited 
medications related to the COVID-19 pandemic 
(such as quarantines, site closures or other related 
issues) will be accounted for within the analysis of 
the study. Intercurrent events related to COVID-19 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
34 
 
Important Identified Risk 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
pandemic will be handled using a hypothetical 
strategy. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
35 
 
2.3.2. 
Benefit Assessment 
In addition to asthma and NP, Mepolizumab has demonstrated clinical benefit in other 
conditions where eosinophilia is considered to play an important part in the pathology, 
e.g., HES [Rothenberg, 2008] and EGPA [Kim, 2010; Moosig, 2011]. 
Recently the Phase III study of mepolizumab in CRSwNP (SYNAPSE) finished. This 
study demonstrated the efficacy of mepolizumab 100 mg SC by showing statistically 
significant and clinically meaningful improvement in the co-primary endpoints of total 
endoscopic nasal polyp score and symptoms of nasal obstruction associated with nasal 
polyps compared with placebo when administered every 4 weeks for up to 52 weeks in 
addition to SoC therapy. 
These efficacy and safety data confirm a positive benefit: risk for mepolizumab in a 
population with CRSwNP despite SoC treatment. 
Participants in this study will be required to attend monthly visits and continue optimized 
maintenance CRSwNP / ECRS therapy and therefore may benefit both from the 
additional assurance of medicine compliance and monitoring of their current maintenance 
therapy. 
Participants may also benefit from regular monitoring of their CRSwNP / ECRS 
symptoms and potential identification of asthma exacerbations. 
Data obtained from this study will provide additional evaluation of the efficacy and 
safety of mepolizumab delivered as a pre-filled liquid formulation in a safety syringe 
both administered by an HCP or self-injection. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Current data from mepolizumab pre-clinical and clinical development indicate the ability 
of mepolizumab to inhibit IL-5 leading to consistent reduction in blood eosinophils, with 
demonstration of clinical benefit in the treatment of conditions associated with 
eosinophilic inflammation. Data from Phase II and III studies in CRSwNP have shown 
efficacy in both NP score and symptoms as well as impact on the need for surgery. In 
addition, data from the Phase III asthma programme with mepolizumab demonstrate, 
compared to placebo, a reduction in asthma exacerbations, improvements in asthma 
control and quality of life (as measured by the ACQ-5 and SGRQ, respectively), 
improvements in lung function and a reduction in OCS use in those participants on 
chronic OCS treatment.  No new safety signal was detected in the SYNAPSE on top of 
the safety data observed in asthma studies. 
The higher morbidity and mortality in severe asthma compared with CRSwNP and the 
substantial long-term safety information already collected in severe asthma, suggest that 
to date, the safety profile of mepolizumab has been favourable and the benefit/risk profile 
supports ongoing development in patients with CRSwNP / ECRS. 
Treatment will be administered by a trained health care professional at the clinic and 
participants will be closely observed for at least 1 hour following administration of IP for 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
36 
 
the first 3 doses then per institutional guidelines at all subsequent visits.  A subgroup of 
participants in Japan will be given the opportunity to self-inject at least once under the 
supervision of the health care professional during visit 10 (week 32) to 14 (week 48) 
inclusive. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy of 
mepolizumab 100 mg SC 
compared to placebo at Week 
52 in patients with a diagnosis 
of CRSwNP / ECRS 
The primary estimands are defined as follows: 
 
Treatment Comparison:  
Mepolizumab 100 mg SC compared to placebo 
 
Population: entire trial population of patients with 
a diagnosis of CRSwNP / ECRS randomised and 
receiving treatment 
 
Co-primary variables:  
a) Change from baseline in total endoscopic NP 
score at Week 52 
b) Change from baseline in mean nasal 
obstruction VAS score during the 4 weeks 
prior to Week 52 
 
Summary measure: Difference in mean scores 
between mepolizumab and placebo 
 
Main Intercurrent events (ICE) anticipated: 
a) Premature discontinuation of study treatment 
unrelated to the COVID-19 pandemic – to be 
handled using a treatment policy strategy 
b) Changes in background medication or start of 
a prohibited medication unrelated to the 
COVID-19 pandemic (e.g. start INCS therapy 
where absent at baseline) – to be handled using 
a treatment policy strategy 
c) Premature discontinuation of study treatment, 
change in background medication or start of 
prohibited medication related to the COVID-
19 pandemic – to be handled using a 
hypothetical strategy 
d) Surgery, which includes any procedure 
involving instruments resulting in incision and 
removal of tissue from the nasal cavity (e.g. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
37 
 
Objectives 
Endpoints 
polypectomy) – to be handled using a 
composite strategy by incorporating 
occurrence of the event into the definition of 
the endpoint. Specifically, participants who 
undergo surgery will be assigned the worst 
possible score for the endpoint from the day of 
surgery onwards for inclusion in the analysis. 
e) Course of systemic CS for CRSwNP / ECRS – 
to be handled using a treatment policy strategy 
f) Interruption to investigational product of 2 or 
more consecutive doses – to be handled using 
a treatment policy 
Secondary 
• To evaluate the impact on 
quality of life of 100 mg 
mepolizumab compared to 
placebo at Week 52 in 
patients with a diagnosis of 
CRSwNP / ECRS 
• Change from baseline in SNOT-22 total score 
at Week 52 
• To evaluate the efficacy of 
100 mg mepolizumab 
compared to placebo at Week 
52 in terms of mean overall 
VAS symptom score,  mean 
composite VAS score, Lund 
Mackay CT score, mean 
individual VAS symptom 
score for loss of smell and 
impact on time to first nasal 
surgery or course of systemic 
CS in patients with a 
diagnosis of CRSwNP / 
ECRS 
• Change from baseline in mean overall VAS 
symptom score during the 4 weeks prior to 
Week 52 
• Change from baseline in the mean composite 
VAS score (combining VAS scores for nasal 
obstruction, nasal discharge, mucus in the 
throat and loss of smell) during the 4 weeks 
prior to Week 52 
• Change from baseline in Lund Mackay CT 
score at Week 52 
• Change from baseline in mean individual VAS 
symptom score for loss of smell during the 4 
weeks prior to Week 52 
• Time to first nasal surgery or course of 
systemic CS for CRSwNP / ECRS up to Week 
52   
Other 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
38 
 
Objectives 
Endpoints 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
39 
 
Objectives 
Endpoints 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
40 
 
Objectives 
Endpoints 
Safety 
 
 
• To evaluate the safety and 
immunogenicity of 100 mg 
mepolizumab compared 
placebo in patients with a 
diagnosis of CRSwNP / 
ECRS 
• Frequency of Adverse events (AEs)/ Serious 
adverse events (SAEs) including systemic 
reactions and local injection site reactions 
reported 
• Vital signs (pulse rate, systolic and diastolic 
blood pressure) 
• Haematological and clinical chemistry 
parameters 
• 12 lead ECG derived endpoints 
• Presence of anti-mepolizumab antibodies and 
neutralising antibodies 
Pharmacokinetics and pharmacodynamics 
• To evaluate the 
pharmacokinetics and 
pharmacodynamics of 100 mg 
mepolizumab in a subgroup of 
participants from Japan and 
China with a diagnosis of 
CRSwNP / ECRS 
• Plasma concentration of mepolizumab  
• PK/PD (blood eosinophil count) analysis 
 
The primary estimands are the difference between mepolizumab 100 mg SC and placebo 
in a) mean change from baseline in total endoscopic NP score to Week 52 and b) mean 
change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to 
Week 52 in participants with a diagnosis of CRSwNP / ECRS, regardless of IP 
discontinuation or changes in background medication/starting a prohibited medication 
unrelated to the COVID-19 pandemic, use of systemic CS for CRSwNP / ECRS or 
interruption of 2 or more consecutive doses of IP, with participants experiencing surgery 
being assigned the worst possible score from the day of surgery onwards. 
Secondary estimands for SNOT-22, VAS scores and Lund Mackay CT score will use the 
same population, summary measure and strategies for intercurrent events as for the 
primary estimands. Time to first nasal surgery or course of systemic CS for CRSwNP / 
ECRS up to Week 52 will be summarised by the hazard ratio between mepolizumab and 
placebo. The same population and strategies for intercurrent events of treatment 
discontinuation, changes in background medication/starting a prohibited medication, 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
41 
 
interruptions of 2 or more consecutive doses of IP and COVID-19 pandemic related 
intercurrent events will be used as for the primary estimands. For this endpoint, both 
surgery and a course of systemic CS for CRSwNP / ECRS will be considered events 
within the analysis and therefore will not be considered an intercurrent event. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomised, double-blind, placebo controlled, parallel group Phase III study 
designed to assess the clinical efficacy and safety of 100 mg SC Mepolizumab treatment 
in adults with chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic 
rhinosinusitis (ECRS). 
The objective of the study is to evaluate the efficacy and safety of mepolizumab 100 mg, 
administered SC by the Investigator, a delegate or participant via safety syringe every 4 
weeks for 52 weeks. Efficacy of mepolizumab will be assessed using co-primary 
endpoints of change from baseline in total endoscopic NP score at Week 52 and change 
from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week 52. 
The secondary endpoints are described in Section 3. 
 
 
 
. 
The study population will consist of adult participants (18 years of age) with CRSwNP / 
ECRS as defined by the JESREC guideline. In addition, they must have an endoscopic 
NP score of at least 5 out of a maximum score of 8, with a minimum score of 2 in each 
nasal cavity. Participants must also have a prior treatment with systemic corticosteroids 
(SCS) anytime within the past 2 years; and/or have a medical contraindication/intolerance 
to SCS; and/or had a documented history of prior surgery for NP at the screening visit. 
For the purpose of this study, NP surgery is defined as any procedure involving 
instruments with resulting incision (cutting open) and removal of the polyp tissue from 
the nasal cavity (polypectomy).  Any procedure involving instrumentation in the nasal 
cavity resulting in dilatation of the nasal passage such as balloon sinuplasty, insertion of 
coated stents or direct injection of steroids or other medication without any removal of 
NP tissue does not fulfil this criterion.  This is because there is no significant reduction in 
overall eosinophilic load in the nasal cavity.  Consequently, it is difficult to discern 
whether any recurrence of NP disease after such procedures is driven by eosinophilia or 
not. 
Any nasal surgical procedures can influence the co-primary endpoints, therefore the 
impact of occurrence of surgery will be taken into consideration when assessing efficacy 
endpoints. Diagnostic or investigative procedures such as nasal endoscopy or dilatation of 
the air passages (e.g. balloon sinuplasty) will not be considered as surgery. 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
42 
 
The study will include a 4-week run-in period followed by randomisation to a 52-week 
treatment period as a double-blind, placebo-controlled phase. Throughout the 52-week 
treatment period, participants will be on the SoC for CRSwNP / ECRS. Depending on 
local practice SoC may include intranasal corticosteroids (INCS), saline nasal douching, 
occasional short courses of systemic CS and/or antibiotics. Depending on local SoC / 
treatment, patients treated with INCS and/ or LTRA are expected, if possible, to continue 
with these treatments with no interruption nor alteration to the doses throughout the study 
duration. If a patient is not on INCS or LTRA prior to screening, the patient is prohibited 
to start any INCS or LTRA during the study. 
There is a trend especially in Japan, to use oral ICS/ETN method of administration for the 
management of NP for patients with both ECRS and concomitant asthma disease. 
Although longer term effects on ECRS disease are yet to be fully evaluated, the short-
term effects of ICS/ETN on NP size can be significant. Therefore, participants in this 
study who use ICS/ETN method of administration for their asthma and NP disease are to 
maintain this method throughout the study period. 
The treatment period will consist of thirteen, 4-weekly doses of mepolizumab or placebo, 
delivered by a pre-filled safety syringe device (SSD) injection. 
The Schedule of Activities (SOA) is included in Section 1.3. 
4.2. 
Scientific Rationale for Study Design 
Recently the Phase III study of mepolizumab in CRSwNP (SYNAPSE) completed. This 
study demonstrated the efficacy of mepolizumab 100 mg SC by showing statistically 
significant and clinically meaningful improvement in the co-primary endpoints of total 
endoscopic nasal polyp score and symptoms of nasal obstruction associated with nasal 
polyps compared with placebo when administered every 4 weeks for up to 52 weeks in 
addition to SoC therapy. 
Consistent with the SYNPASE study this study assesses the efficacy of mepolizumab by 
measuring its ability to reduce the NP size and improve nasal obstruction (VAS score) as 
co-primary endpoints. This study will use centrally read total endoscopic NP score by 
assessing the change from baseline at Week 52. Nasal obstruction VAS score will 
additionally assess patient symptoms during the 4 weeks prior to Week 52. Secondary 
endpoints for this study are change from baseline in overall VAS symptom scores, 
SNOT-22 total score, mean composite VAS score, Lund Mackay CT score, mean 
individual VAS symptom score for loss of smell and time to first nasal surgery or course 
of systemic CS for CRSwNP / ECRS up to Week 52. 
This study will recruit patients who have CRSwNP / ECRS that are refractory to SoC 
medical treatment. In most cases these patients are at the stage of needing surgical 
intervention [Fokkens, 2020]. By deactivating and reducing the survival time of 
eosinophils in NP through IL-5 inhibition, mepolizumab can potentially reduce 
inflammation of the mucosa, and restore aeration of the nasal passage and sinuses 
through polyp volume reduction. Therefore, assessment of NP size based on endoscopic 
NP score as a measure of efficacy is objective and reasonable. 
 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
43 
 
 
 
Short courses of systemic CS are part of SoC for severe NP and are known to provide 
significant improvements in symptoms and reduction in NP size. However, this form of 
treatment strategy is limited by the short-lived beneficial effects and the significant 
systemic adverse events, which prevent prolonged and/or frequent use.  If mepolizumab 
is effective, it has the potential to reduce the overall exposure of patients to systemic 
steroid therapy, and this will be measured in the study. 
Given the importance of short courses of systemic CS and surgical events, a composite 
endpoint of time to first nasal surgery or course of systemic CS for CRSwNP / ECRS up 
to Week 52 will also be assessed as a secondary endpoint. 
The severe symptoms of NP can result in significant disruption to quality of life and 
productivity of patients. This Phase III study will utilize SNOT-22 and SF-36 
questionnaires as measures of QoL. The WPAI questionnaire is also included to assess 
the impact of treatment on absenteeism, presenteeism, productivity loss, and activity 
impairment of participants in this study. 
The target population for mepolizumab is CRSwNP / ECRS patients who are refractory 
to SoC and highly symptomatic as a consequence. Depending on local practice SoC may 
include INCS, saline nasal douching, occasional short courses of systemic CS and/or 
antibiotics before surgery is considered. 
In Japan, as INCS is not licensed for the indication of CRSwNP, participants not on 
INCS will be allowed into the study. In order to ensure balance between treatment 
groups, randomisation will be stratified by participants on INCS and not on INCS. 
Participants are treated with mepolizumab or placebo for 13 doses at 4 weeks intervals.  
Therefore, assessment of the co-primary endpoints will be conducted 52 weeks after 
initiation of therapy. 
All participants randomised to IP will have their efficacy and safety endpoints tracked for 
the duration of the study. Participants may choose to discontinue use of IP at any time but 
full accountability of IP at the end of the study is required for all participants. 
4.2.1. 
Participant Input into Design 
Ten CRSwNP / ECRS patients, five from Japan and five from China, were recruited in 
line with the Inclusion Criteria. 
Insights were gained via two, 15-minute, online qualitative surveys. 
The focus of the insights request and questions put to the patients were around: 
1. Study Rationale, Background, Benefit/Risk Assessment 
2. Study Assessments and Procedures 
3. eDiary and Informed Consent Form. 
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
44 
 
In line with the feedback received the number of time points endpoints are taken has been 
reduced and enhanced participant training will be implemented.  This includes, number of 
PK samples, Haematology draws, Nasal Endoscopies, SF-36 and WPAI questionnaires. 
4.3. 
Justification for Dose 
To date the clinical pharmacology of mepolizumab, an IgG1 mAb, is wholly consistent 
with other mAbs targeting soluble ligands: the pharmacokinetics are linear, dose-
proportional, and time-independent after both IV and SC administration.  Of note, a 
population PK meta-analysis across studies, indications and ethnic groups has not 
identified any covariates of particular clinical interest, mitigating the need for further 
investigations and dose adjustment in special populations. Mepolizumab’s potential for 
drug-drug interaction is deemed low in light of its elimination pathways and because IL-5 
does not signal via hepatocytes. 
Mepolizumab demonstrates ethnically insensitive in completed clinical trials with 
participation of patient with various indications. The population PK and PK-PD meta-
analysis across studies, and indications and ethnic groups [GSK Document Number 
2015N238436_00, 2015] did not identify any intrinsic ethnicity or disease covariates of 
clinical interest. The results of MEA115588 revealed that there was no major difference 
in plasma exposure between East Asian (Japanese and Korean) and non-East Asian 
following 100 mg SC and blood eosinophil count was suppressed throughout the 
treatment period in both East Asian (Japanese and Korean) and overall populations, with 
comparable efficacy and safety results. 
The efficacy and safety of mepolizumab 100 mg SC in patients with CRSwNP have been 
confirmed in SYNAPSE study. Population PK-PD analysis for the study demonstrated 
comparable PK profile and dose-response relationship of mepolizumab in patients with 
CRSwNP and other indications studied before. The effects of bodyweight and creatinine 
clearance, which were identified as covariates of mepolizumab clearance in historical 
studies, were also comparable with the previous population PK model. 
Given no ethnic differences in efficacy and safety of mepolizumab observed from 
completed clinical studies across various indications including asthma and CRSwNP, it 
would therefore seem reasonable to assess this dose for potential efficacy in the target 
population of majority Japanese and Chinese patients with CRSwNP / ECRS.  With 
confirmed efficacy and safety of mepolizumab in patients with NP in SYNAPSE study, 
and safety data for the range of doses of mepolizumab in participants from a host of 
diseases, the assessment of 100 mg SC to provide safety and efficacy information in 
Japanese and Chinese population is warranted. 
4.4. 
End of Study Definition 
A participant is considered to have completed study treatment if he/she receives study 
treatment at Visit 14 (Week 48). A participant is considered to have completed the study 
if he/she has completed all phases of the study including the last visit (Visit 15/Week 52) 
or the last scheduled procedure shown in the SoA, (Section 1.3) whichever is earlier. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
45 
 
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial 
globally, whichever is earlier. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment 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 at screening: 
AGE 
1. 18 years of age and older, at the time of signing the informed consent. 
 
WEIGHT 
2. Body weight greater than or equal to 40kg. 
 
GENDER 
3. Male or female participants (with appropriate contraceptive methods) to be 
eligible for entry into the study;  
NOTES: 
Contraceptive use by Women of Childbearing Potential (WOCBP) should be consistent 
with local regulations regarding the methods of contraception for those participating in 
clinical studies. 
To be eligible for entry into the study Woman of Childbearing Potential must commit 
to consistent and correct use of an acceptable method of birth control from the time of 
consent.  
• A female participant is eligible to participate if she is not pregnant or breastfeeding, 
one of the following conditions applies: 
o Is a woman of non- childbearing potential (WONCBP) as defined in 
Section 10.5: Contraception and Barrier Guidance 
OR 
o Is a WOCBP and using a contraceptive method that is highly effective (with 
a failure rate of <1% per year), preferably with low user dependency, as 
described in Section 10.5 during the study intervention period and for at 
least 105 days after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (e.g., non-


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
46 
 
compliance, recently initiated) in relationship to the first dose of study 
intervention. 
• A WOCBP must have a negative highly sensitive urine pregnancy test within 
24 hours before the first dose of study intervention. 
o If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is 
positive (see Section 8.3.5: Pregnancy Testing). 
• Additional requirements for pregnancy testing during and after study 
intervention are located in Section 8.3.5 Pregnancy Testing. 
• 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 
 
CRSwNP / ECRS DIAGNOSIS 
4. Blood eosinophils 
A documented blood eosinophil count of over 2% in the 12 months prior to Visit 0 
OR through a blood sample taken between Visit 0 and Visit 1. ALL participants 
must meet blood eosinophil count of over 2% by Visit 1. 
Participants with peripheral blood eosinophil count over 2% to 5% must also have 
comorbid bronchial asthma, aspirin intolerance, or nonsteroidal anti-inflammatory 
drug intolerance at Visit 1 assessment in order to return for Visit 2. 
5. Endoscopic bilateral NP score of at least 5 out of a maximum score of 8 (with a 
minimum score of 2 in each nasal cavity) assessed by the investigator 
6. Participants who have had at least one of the following at Visit 1: 
• previous nasal surgery for the removal of NP,  
• have used at least three consecutive days of systemic corticosteroids in the 
previous 2 years for the treatment of NP,  
• medically unsuitable or intolerant to systemic corticosteroid 
7. Participants with severe NP symptoms defined as a nasal obstruction VAS 
symptom score of >5 
8. Presence of symptoms of CRS as described by at least two different symptoms for 
at least 12 weeks prior to Visit 1, one of which should be either nasal 
blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), 
plus 
• facial pain/pressure 
and/or 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
47 
 
• 
reduction or loss of smell 
 
 
INFORMED CONSENT 
9. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
study protocol. 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
CONCURRENT CONDITIONS/MEDICAL HISTORY  
1. As a result of medical interview, physical examination, or screening investigation 
the physician responsible considers the participant unfit for the study. (e.g. 
symptomatic herpes zoster within 3 months prior to screening, evidence of 
tuberculosis (TB) active or latent) 
2. Cystic fibrosis 
3. Eosinophilic granulomatosis with polyangiitis (also known as Churg Strauss 
syndrome), Young’s, Kartagener’s or dyskinetic ciliary syndromes  
4. Antrochoanal polyps 
5. Severe nasal septal deviation preventing full assessment of nasal polyps in both 
nostrils 
6. Acute sinusitis or upper respiratory tract infection (URTI) at screening or in 
2 weeks prior to screening 
7. Ongoing rhinitis medicamentosa (rebound or chemical induced rhinitis) 
8. Participants who have had an asthma exacerbation requiring admission to hospital 
within 4 weeks of Screening. 
9. Participants who have undergone any intranasal and/or sinus surgery (for example 
polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior to 
Visit 1; nasal biopsy prior to Visit 0 for diagnostic purposes only is excepted. 
10. Participants where NP surgery is contraindicated in the opinion of the Investigator 
11. Participants with a known medical history of HIV infection. 
12. Participants with a known, pre-existing parasitic infestation within 6 months prior 
to Visit 1. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
48 
 
13. Participants who are currently receiving or have received within 3 months (or 
5 half-lives – whatever is the longest) prior to first mepolizumab dose, 
chemotherapy, radiotherapy or investigational medications/therapies. 
14. Participants with a history of sensitivity to any of the study medications, or 
components thereof or a history of drug or other allergy that, in the opinion of the 
investigator or GSK Medical Monitor, contraindicates their participation. Aspirin-
sensitive participants are acceptable. 
15. Participants with a history of allergic reaction to anti-IL-5 or other monoclonal 
antibody therapy. 
16. Participants that have taken part in previous mepolizumab clinical studies. 
17. Patients currently using INCS and inhaled corticosteroids exhalation through nose 
(ICS/ETN) for the management of their ECRS who are not willing to maintain 
using this method of administration throughout the study. 
 
 
PREGNANCY: 
24. Women who are pregnant or lactating or are planning on becoming pregnant 
during the study. 
 
OTHER DISEASES/ABNORMALITIES:  
25. Any participant who is considered unlikely to survive the duration of the study 
period or has any rapidly progressing disease or immediate life-threatening illness 
(e.g. cancer). In addition, any participant who has any other condition (e.g. 
neurological condition) that is likely to affect respiratory function should not be 
included in the study. 
 
CONCOMITANT MEDICATIONS 
18. Use of systemic corticosteroids, including oral corticosteroids (intranasal 
corticosteroid is excepted), within 4 weeks prior to screening or planned use of 
such medications during the double-blind period 
19. INCS and/or inhaled corticosteroids exhalation through nose (ICS/ETN) dose 
changes within 1 month prior to Visit 1 (if applicable). 
20. Treatments with biological or immunosuppressive treatment (other than Xolair) 
treatment within 5 terminal phase half-lives of Visit 1  
21. Omalizumab (Xolair) treatment in the 130 days prior to Visit 1 
22. Commencement or change of dose of LTRA treatment less than 30 days prior to 
Visit 1 
23. Commencement or change of dose of allergen immunotherapy within the previous 
3 months. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
49 
 
26. Other Concurrent Medical Conditions: 
• Participants who have known, pre-existing, clinically significant endocrine, 
autoimmune, cardiovascular, metabolic, neurological, renal, gastrointestinal, 
hepatic, haematological or any other system abnormalities that are uncontrolled 
with standard treatment. 
 
• Subjects with symptoms suggestive of active COVID-19 infection (i.e. fever, 
cough, etc) are excluded. 
• Subjects with known COVID-19 positive contacts within the past 14 days 
should be excluded for at least 14 days since the exposure and the subject 
remains symptom free.  
27. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency 
virus – HIV), other than that explained by the use of corticosteroids taken as 
therapy. 
 
28. A current malignancy or previous history of cancer in remission for less than 
12 months prior to screening.   
Note: Participants with successfully treated basal cell carcinoma, squamous cell 
carcinoma of the skin, or cervical carcinoma in situ, with no evidence of recurrence 
may participate in the study. 
SEVERE HEPATIC IMPAIRMENT:  
29. Unstable liver disease: Current active liver or biliary disease (with the exception 
of Gilbert’s syndrome or asymptomatic gallstones or otherwise stable chronic liver 
disease per investigator assessment).  
         Notes:  
• 
Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis. 
• 
Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 
3 months prior to first dose of study treatment) are acceptable if subject 
otherwise meets entry criteria 
ALT >2xULN  
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
Current unstable liver or biliary disease per investigator assessment defined by 
the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, persistent jaundice, or cirrhosis 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
50 
 
12-LEAD ECG:   
30. 12-lead ECG at Screening Visit 1: Participants with a QT interval, from the ECG 
conducted at Screening Visit 1, corrected with Fridericia’s formula (QTcF) 
>450msec (or QTcF >480msec in participants with bundle branch block). 
QTcF is the QT interval corrected for heart rate according to Fridericia’s formula that 
is selected for this study. It is either machine-read or manually over-read when not 
automatically machine read. This specific formula must be used to determine eligibility 
and discontinuation for an individual participant. 
Participants are excluded if an abnormal ECG finding from the 12-lead ECG conducted 
at Screening Visit 1 is considered to be clinically significant and would impact the 
participant’s participation during the study, based on the evaluation of the Investigator. 
 
DRUG OR ALCOHOL ABUSE:   
31. A known or suspected history of alcohol or drug abuse within 2 years prior to 
Screening (Visit 1) that in the opinion of the investigator would prevent the 
participant from completing the study procedures. 
 
AFFILIATION WITH INVESTIGATOR SITE:   
32. Is an investigator, sub-investigator, study coordinator, employee of a participating 
investigator or study site, or immediate family member of the aforementioned that 
is involved in this study. 
INABILITY TO READ:  
33. In the opinion of the investigator, any subject who is unable to read and/or would 
not be able to complete a questionnaire. 
 
5.3. 
Randomisation Criteria 
Those participants who meet the randomisation criteria below will be randomised into the 
study until the target of approximately 160 randomised participants is reached. 
Participants will be randomised in a 1:1 ratio into one of two treatment groups, receiving 
a total of thirteen doses (one every four weeks): 
• 
Group 1: 100 mg SC of mepolizumab on top of SoC 
• 
Group 2: Placebo SC on top of SoC 
The study will be randomised separately for each country and the randomisation will be 
stratified by background INCS use. Equal numbers of participants will be allocated to 
each treatment. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
51 
 
In rare instances and if following consultation with the Medical Monitor a participant can 
be rescreened. Rescreened participants are required to sign a new ICF. 
At the end of the run-in period, study participants must fulfil the following additional 
criteria in order to be randomised to study treatment: 
1. Confirmation of CRSwNP / ECRS with a JESREC Score ≥11* [Tokunaga, 2015] 
using values measured between Visit 1 and 2 (central laboratory blood eosinophilic 
count, CT scan, nasal endoscopy as assessed by central laboratory). 
 
2. Confirmation of at least moderate CRSwNP / ECRS for participants with peripheral 
blood eosinophil count taken in the 12 months prior to Visit 0 OR through a blood 
sample taken between Visit 0 and Visit 1 of over 2% to 5% must have documented 
co-morbid disease of bronchial asthma, aspirin intolerance, or nonsteroidal anti-
inflammatory drug intolerance. Participants with peripheral blood eosinophil count 
over 5% in the 12 months prior to Visit 0 OR through a blood sample taken between 
Visit 0 and Visit 1 do not require the presence of fore mentioned co-morbid diseases, 
and if the participant meets CT shadow: ethmoid  maxillary. 
3. Endoscopic bilateral NP score of at least 5 out of a maximum score of 8 (with a 
minimum score of 2 in each nasal cavity) taken at Visit 1 as assessed at central 
laboratory 
4. Mean nasal obstruction VAS >5 over the last 7 days preceding Visit 2 (excluding 
Visit 2) (from eDiary) 
5. eDiary compliance for VAS (at least 4 out of the last 7 days preceding Visit 2, 
(excluding Visit 2)). 
6. Not had any NP surgery or have been included into a waiting list for NP surgery 
between Visit 1 and Visit 2. 
7. Laboratory abnormality: No evidence of clinically significant abnormality in the 
haematological, biochemical or urinalysis screen at Visit 1, as judged by the 
investigator. 
8. Liver Function Tests: obtained at Visit 1: 
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.


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
52 
 
• ALT<2x ULN (upper limit of normal) 
• AST<2x ULN 
• Alk Phos ≤ 2.0x ULN 
• Bilirubin ≤ 1.5x ULN (isolated bilirubin>1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
9. Asthma Exacerbation: No asthma exacerbations during run-in period. An 
exacerbation is defined as worsening of asthma requiring the use of systemic 
corticosteroids for at least 3 days and/or emergency department visit, or 
hospitalization. 
10. Maintenance Therapy: No changes or commencement during the run-in period in the 
dose or regimen of any regular baseline medication including  
a. INCS (if relevant) 
b. Inhaled corticosteroids exhalation through nose (ICS/ETN) 
c. LTRA 
d. allergen immunotherapy 
e. course of systemic corticosteroids 
11. If the participant has an upper respiratory tract infection or cold during run-in then 
run-in should be extended so to have the Visit 2, 2 weeks post the resolution of the 
cold but no greater than a total of 6 weeks from Visit 1. Colds that are not resolved 
within the 4th week of the nominal run-in period (28 days after screening) will be 
ineligible for randomisation as they would have exceeded this 6 weeks period. 
5.4. 
Screen/Baseline/Run-in Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study (fail screening). A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials 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) related to study screening procedures. 
For the purposes of this study, screening failures will be sub-divided as follows: 
• 
Participants will be assigned a study number at the time of signing the informed 
consent (Pre-screen Visit). Participants who do not progress to the Screening Visit 
will be deemed a pre-screen failure. 
• 
Those participants that complete at least one Visit 1 (Screening) procedure but do not 
enter the run-in period will be designated as screen failures. 
• 
Those participants that enter the run-in period, but are not randomised, will be 
designated as run-in failures. 
Re screening of participants will be permitted, however, advanced approval to proceed 
with rescreening the participant must be obtained from the Medical Monitor (for contact 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
53 
 
details, see SRM). Rescreened participants should be assigned a new participant number 
for every screening/rescreening event. 
5.5. 
Criteria for Temporarily Delaying 
N/A 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
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 
Study intervention or treatment is defined as any investigational treatment(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study 
participant according to the study protocol. 
A liquid formulation of mepolizumab will be provided as pre-filled syringes in a safety 
syringe device (SSD) for this study.  The liquid formulation has a distinct advantage over 
the lyophilised product as it does not require reconstitution, and the devices (upon 
commercial registration) will simplify and facilitate administration. 
There will also be a matched safety syringe with placebo. Both active and placebo drug 
products are stored at 2-8°C condition, protected from light. 
The study consists of up to 17 visits with a maximal total treatment duration of 
approximately 52 weeks and maximum study duration of approximately 56 weeks.  
Screened participants will enter a 4 weeks run-in period, followed by up to 52 weeks 
double-blind treatment period. 
Participants who are successfully enrolled into the study will be randomised in a 1:1 ratio 
into one of two treatment groups, receiving a total of thirteen doses (one every four 
weeks): 
• 
Group 1: 100 mg SC of mepolizumab on top of SoC 
• 
Group 2: Placebo SC on top of SoC 
The end of study assessments for each individual participant will be performed at Visit 15 
(Week 52), 4 weeks following the last dose of IP. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
54 
 
 
Study Treatment 
Product name: 
Mepolizumab Injection, 100 mg/mL 
Device: 
Safety syringe  
Formulation description: 
100 mg/mL mepolizumab with sodium phosphate, citric acid, 
sucrose, Disodium EDTA, Water for Injection and polysorbate 
80  
Dosage form: 
Sterile, liquid formulation 
Unit dose 
strength(s)/Dosage level(s): 
100 mg/mL; 1.0 mL (deliverable) 
Route of Administration 
SC injection 
Dosing instructions for 
HCP: 
SC dose in thigh, abdomen or upper arm every 4 weeks 
Dosing instruction for self-
injection: 
SC dose in thigh or abdomen every 4 weeks 
Physical description: 
mepolizumab 
Clear to opalescent, colourless to pale yellow to pale brown 
sterile solution for SC injection in a single-use, safety syringe  
Physical description of 
injection device: 
Single use, disposable safety syringe device assembled with a 
pre-filled syringe containing mepolizumab solution. A plastic 
needle cover shields the needle before and after injection to 
minimise the potential for needle stick injuries. 
Manufacturer/source of 
procurement: 
Pre-filled syringe is filled with mepolizumab solution and 
assembled into a safety syringe device at GSK, Barnard 
Castle, UK. 
 
 
Study Treatment 
Product name: 
Placebo to match Mepolizumab Injection 
Device: 
Safety syringe  
Formulation description: 
sodium phosphate, citric acid, sucrose, Disodium EDTA, Water 
for injection and polysorbate 80 
Dosage form: 
Sterile, liquid formulation 
Unit dose 
strength(s)/Dosage level(s): 
1.0 mL (deliverable) 
Route of Administration 
SC injection 
Dosing instructions for 
HCP: 
SC dose in thigh, abdomen or upper arm every 4 weeks 
Dosing instruction for self-
injection: 
SC dose in thigh or abdomen every 4 weeks 
Physical description: 
placebo 
Clear to opalescent, colourless to pale yellow / pale brown 
sterile solution for SC injection in a single-use, safety syringe  
Physical description of 
injection device: 
Single use, disposable safety syringe device assembled with a 
pre-filled syringe containing placebo solution. A plastic needle 
cover shields the needle before and after injection to minimise 
the potential for needle stick injuries. 
Manufacturer/source of 
procurement: 
Pre-filled syringe is filled with placebo solution and assembled 
into a safety syringe device at GSK, Barnard Castle, UK. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
55 
 
6.1.1. 
Medical Devices 
Mepolizumab Injection, 100 mg/mL or Placebo to match Mepolizumab Injection, are 
provided for use in this study as a prefilled syringe contained within a safety syringe.  
The components that comprise the prefilled syringe, including glass barrel with pre 
staked needle and stopper are sourced from Becton Dickinson. The prefilled syringe is 
filled and assembled at GSK Barnard Castle.  The prefilled syringe is assembled with 
safety syringe device components at GSK Barnard Castle. The safety syringe components 
are also sourced from Becton Dickinson. The devices used in the study are representative 
of the devices planned to be marketed for the product. 
The instructions for use (IFU) of these injection devices are provided in the SRM. The 
instructions were developed and optimized as a result of formative human factors studies. 
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study (see 
Section 8.4.8. 
6.2. 
Self-administration for Japanese cohort 
Participants from Japanese cohorts may transition to self-administration from Week 32 
onwards. Before allowing the self-administration, the principal investigator/delegate must 
assess their knowledge/technique and document that they are competent to undertake 
self-administration. 
Following the training (see Section 6.2.1) for at least 2 visits between the Visit 5/Week 
12 and Visit 10/Week 32, the participants will self-administer study treatment by SC 
injection under medical supervision of the investigator or designee at the study site. 
Observations about the injection will be recorded by the investigator/designee using 
eCRF. The date, time of the dose, and site of administration (thigh or abdomen) of each 
dose administered in the clinic will be recorded in the source documents. 
All self-administered injections will be assessed by the investigator for success based on 
direct observation of the self-administration. 
A self-administered injection is considered successful if the following criteria are met: 
• 
Use of a correct injection site (abdomen or thigh) 
• 
Full dose administered: subject fully inserts the needle, slowly depresses the plunger 
until the stopper reaches the bottom of the syringe and activates the needle guard by 
moving the thumb up 
If the above criteria are met, the investigator will confirm the injection was successfully 
delivered. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
56 
 
6.2.1. 
Training for self-administration 
Training of study treatment, handling and administration techniques by qualified study 
site personnel will be provided to the study participants prior to self-administration. The 
training is designed to be representative of the instruction and training materials that will 
be used in the post-marketing setting. Participants will be trained by site personnel to 
self-administer the study treatment independently and will be provided with detailed 
written instructions (refer to IFU). 
6.3. 
Preparation/Handling/Storage/Accountability 
No special preparation of study treatment is required. 
Study treatment must be dispensed or administered according to procedures described 
herein.  Only participants enrolled in the study may receive study treatment.  Only 
authorised site staff may supply study treatment.  All study treatment must be stored in a 
secure area with access limited to the investigator and authorised site staff.   
• 
Mepolizumab Injection, 100 mg/mL or Placebo to match Mepolizumab injection, 
will be supplied in a single use prefilled syringe in a safety syringe devise and should 
be stored in a refrigerator at 2-8°C with protection from light. Each injection device 
will contain 100 mg mepolizumab or placebo as a single 1.0 mL injection of the 
liquid drug product.  Maintenance of a temperature log at the clinical dispensing sites 
(manual or automated) is required. 
• The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
• The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).   
• Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.  
• Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. 
• A Material Safety Data Sheet/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. 
In the case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact. 
6.4. 
Measures to Minimize Bias: Randomisation and Blinding 
Participants eligible to enter the study will be assigned to intervention randomly via 
RAMOS NG, an Interactive Web Response System (IWRS). The randomisation schedule 
will be generated using the GSK validated randomisation software RandAll NG. The 
study will be randomised separately for each country and the randomisation will be 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
57 
 
stratified by background INCS use. Equal numbers of participants will be allocated to 
each treatment. 
Participants will be assigned in a 1:1 ratio to study intervention (mepolizumab or placebo 
to match) in accordance with the randomisation schedule. Once a randomisation number 
has been assigned to a participant, it cannot be reassigned to any other participant in the 
study. 
Before the study is initiated, the web location and the log in information and directions 
for the IWRS will be provided to each site. 
Study intervention will be assigned by RAMOS NG and dispensed at the study visits 
summarized in the SoA. 
Returned or unused study treatment should not be re-dispensed to the participants. 
The site staff and central study team will be blinded to each participant’s eosinophil count 
(including white blood count differential) and to central overread nasal polyps scores 
following randomisation. 
RAMOS NG will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participants’ intervention assignment is warranted.  Participant safety must always be the 
first consideration in making such a determination.  If the investigator decides that 
unblinding is warranted, the investigator should make every effort to contact GSK prior 
to unblinding a participant’s intervention assignment unless this could delay emergency 
intervention of the participant.  If a participant’s intervention assignment is unblinded 
GSK must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and case report form, 
as applicable. 
In the case of a medical emergency or in the event of a serious medical condition, when 
knowledge of the IP is essential for the clinical management or welfare of the participant, 
an investigator or other physician managing the participant may decide to un-blind that 
participant’s treatment code. The investigator will make every effort to contact the GSK 
Medical Monitor or appropriate GSK study personnel before un-blinding to discuss 
options. If the blind is broken for any reason and the investigator is unable to contact 
GSK prior to un-blinding, the investigator must notify GSK as soon as possible following 
the un-blinding incident without revealing the participant’s study treatment assignment, 
unless the information is important to the safety of participants remaining in the study. In 
addition, the investigator will record the date and reason for revealing the blinded 
treatment assignment for that participant in the appropriate data collection tool. 
A participant may continue in the study if that participant’s treatment assignment is 
unblinded.   The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the CRF. 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
58 
 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
6.5. 
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.  The dose of study 
intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
intervention. 
When participants self-administer study intervention(s) at the study site, compliance with 
the Mepolizumab Injection, 100 mg/mL or Placebo to match Mepolizumab will be 
assessed by observation of healthcare professionals. 
Deviation(s) from the prescribed dosage regimen should be recorded. A record of the 
quantity of the Mepolizumab Injection, 100 mg/mL or Placebo to match Mepolizumab 
dispensed to and administered by each participant 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. 
• 
Participants will be monitored for 1 hour after IP administrations in the clinic 
following the first three injections. In the event of an acute severe reaction (e.g., 
anaphylaxis) following administration of study treatment, there are personnel/staff 
onsite at the treatment facility who are appropriately trained in basic life support to 
manage the participant including administration of medications (e.g., epinephrine), 
and have access to a system that can promptly transport the patient to another facility 
for additional care if appropriate. 
• 
Administration will be documented in the source documents and reported in the 
CRF. 
6.6. 
Dose Modification 
Not applicable. 
6.7. 
Continued Access to Study Intervention after the End of the 
Study 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment. 
There are no plans to provide mepolizumab to study participants following study 
completion. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
59 
 
6.8. 
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. 
6.9. 
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. 
It is permissible for subjects to be vaccinated against COVID-19 with vaccines 
authorized or approved by a regulatory authority; vaccination with an unapproved or 
unauthorized COVID-19 vaccine (i.e., a candidate vaccine) is not permissible.  
Initiation or changes in the dosing regimen of LTRA or allergen immunotherapy from 
screening to end of the study are not allowed. Changes in the dosing regimen of INCS 
and/or ICS/ETN from screening to end of the study are also not allowed. 
The following medications may be used for all participants: 
1. Short courses of systemic CS (for example systemic CS for treatment of CRSwNP / 
ECRS).  The use of rescue medications such as systemic CS is allowable during the 
52-week treatment phase of the study (Visit 2 and onwards) but not during the run-in 
period; the date and time of rescue medication administration as well as the name and 
dosage regimen (dose and duration) of the rescue medication must be recorded in the 
eCRF for CRSwNP / ECRS as well as for other comorbidities. 
2. Throughout the study, asthmatic participants are to be maintained on their baseline 
SoC asthma treatment. 
3. For antibiotic treatment for CRSwNP / ECRS, the type, dose and duration must also 
be recorded. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
60 
 
The following medications are not allowed prior to screening (Visit 1) and 
throughout the study, according to the following schedule, or during the study: 
 
Prohibited Medication 
Time Period Prior to Screening Visit 
Investigational products (biologic or non-
biologic) 
3 months 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) 
Regular systemic corticosteroids including 
oral, intramuscular, long-acting depot  
1 month 
 
Methotrexate, troleandomycin, cyclosporin, 
Azathioprine 
1 month 
 
Oral gold  
3 months 
Chemotherapy used for conditions other than 
asthma 
12 months 
 
Changes in intranasal corticosteroid treatment  1 month 
Insertion of any non-drug or drug eluting 
nasal stents such as Propel stents    
6 months 
Direct steroid injections into CRSwNP / 
ECRS 
6 months 
 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
At the point of informed consent prior to screening, participants will be requested to 
provide permission and agree to be contacted even after study withdrawal/ IP 
discontinuation to collect information relating to any surgical intervention to the NP.  
Every effort will be made to have all participants attend study visits up to Week 52 even 
if they discontinue study treatment in order to capture NP scores, symptom score, any 
subsequent surgical procedures or entry into a waiting list for NP surgery. 
7.1. 
Premature Discontinuation of Study Intervention 
7.1.1. 
Discontinuation Criteria for Intervention 
A participant may discontinue from study treatment at any time at his/her own request, or 
at the discretion of the investigator.  Participants who discontinue from study treatment 
prematurely (for any reason) should, where possible, continue to be followed-up as per 
protocol until the completion of the Week 52 Visit assessments. The participant’s NP 
surgical status will be tracked for the duration of the study. The participants are also 
allowed to have nasal surgery during the study without discontinuation from IP. 
Participants may choose to discontinue use of IP at any time but full accountability of IP 
at the end of the study is required for all participants. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
61 
 
All participants will be followed up for the study duration.  However, given that 
confirmed NP surgery can distort the anatomical architecture of the nasal cavity 
nullifying the NP score and VAS, participants who have had NP surgery prior to Week 
52 will be considered as treatment failures (taking the participant’s worst score prior to 
surgery) in the analysis of the primary endpoints.   
As a minimum the participants should agree to be contacted by telephone to enquire 
regarding any safety assessments and any NP surgery events.  
Participants will be allowed short courses of systemic CS as medically required during 
the study. 
7.1.2. 
Study Specific Intervention Discontinuation Criteria 
A participant must have IP discontinued if any of the following criteria are met: 
Pregnancy: Positive pregnancy test 
Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria. 
ECG: If a participant’s QTc interval extends beyond >500msec or uncorrected QT 
interval is >600msec or QTc is increased more than 60msec compared to baseline on two 
or more ECG tracings separated by at least 5 minutes. 
NB: Courses of systemic CS or Surgery are not a reason for Study withdrawal or IP 
discontinuation. 
7.1.3. 
Primary Reasons for Intervention Discontinuation  
The primary reason for discontinuation of IP (and sub-reason, if applicable) will be 
categorized as: 
• Adverse event  
• Lost to follow-up 
• Withdrew consent 
o participant relocated 
o frequency of visits 
o burden of procedures 
• Protocol deviation  
• Lack of efficacy 
• Study closed/terminated 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
62 
 
• Participant reached protocol-defined stopping criteria 
o Liver event 
o Pregnancy 
o QTc 
• Investigator discretion 
7.1.4. 
IP Discontinuation Visit 
Prematurely discontinuation of study treatment will be defined as any participant who is 
randomised to blinded medication and, for any reason, does not receive study treatment at 
Visit 14 (Week 48). 
A participant may discontinue from study treatment at any time at his/her own request, or 
at the discretion of the investigator.  Participants who discontinue from study treatment 
prematurely (for any reason) should, where possible, continue to be followed-up as per 
protocol until the completion of the Week 52 Visit assessments. 
Participants that discontinue from study treatment should return to the clinic 4 weeks 
after the last dose for an IP Discontinuation Visit. If possible, at the IP Discontinuation 
Visit, the following evaluations and procedures should be completed and recorded in the 
eCRF as required: 
• 
Concomitant medication assessment 
• 
Adverse event assessment 
• 
12 –lead ECG 
• 
Physical examination (recorded in source documents only) 
• 
Vital signs 
• 
Collect/review electronic diary   
• 
Urine pregnancy test - for all WOCBP  
• 
Assessment of endoscopic nasal polyp score 
• 
Assessment of surgery  
• 
Assessment of systemic CS use 
• 
Assessment of INCS use 
• 
Assessments of symptoms 
• 
Assessment of HRQoL 
• 
WPAI 
• 
PK (Japan and China only) 
• 
Lab assessments including liver chemistry and immunogenicity 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
63 
 
• 
CT scan 
• 
Assessment of asthma exacerbations 
• 
Collection of eDiary 
• 
Access the RAMOS NG to report participant’s IP discontinuation visit from the 
study 
After completion of the IP Discontinuation Visit, in cases where the participant cannot 
attend subsequent study visits in person telephone visits may be performed. 
7.1.5. 
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 treatment for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm below or 
• in the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, the investigator believes that it is in the best interest of the 
participant. 
Refer to Appendix 7 for required Liver Safety Actions, Monitoring and Follow-up 
Assessments.  


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
64 
 
Algorithm A: Liver Chemistry Stopping Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse 
event; ULN = upper limit of normal, Tbili = Total bilirubin 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
65 
 
 
Algorithm B: Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN  
 
Abbreviations: ALT = alanine transaminase; Tbili = total bilirubin; INR = international normalized ratio; 
SAE = serious adverse event; ULN = upper limit of normal, Tbili = Total bilirubin. 
7.1.6. 
QTc Stopping Criteria 
• 
QTc is the QT interval corrected for heart rate according to Fridericia's formula. 
It is either machine-read or manually over-read when not automatically machine 
read. This specific formula must be used to determine eligibility and 
discontinuation for an individual participant. 
• 
The QTc should be based on two or more ECG tracings obtained over a brief 
(e.g., 5-10 minute) recording period, with each recording separated by at least 5 
minutes. 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment: 
• 
QTc > 500msec OR Uncorrected QT > 600msec 
• 
Change from baseline of QTc > 60msec 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
66 
 
For participants with underlying bundle branch block, follow the discontinuation criteria 
listed below: 
Baseline QTc with Bundle Branch 
Block 
Discontinuation QTc with Bundle 
Branch Block 
< 450msec 
> 500msec 
450 – 480msec 
≥ 530msec 
See the SoA for data to be collected at the time of treatment discontinuation and early 
withdrawal for any further evaluations that need to be completed. 
7.1.7. 
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 52 weeks 
post randomisation date. 
• 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. 
7.1.8. 
Temporary Discontinuation 
Not applicable. 
7.1.9. 
Rechallenge 
Not applicable. 
7.1.9.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.2. 
Participant Withdrawal from Study 
• A participant may withdraw from the study at any time at his/her own request, or if 
they are lost to follow-up. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
67 
 
• 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. 
• Refer to the SoA (Section 1.3) for data to be collected at the time of study 
withdrawal and for any further evaluations that need to be completed. 
7.2.1. 
Primary reasons for withdrawal from the study 
The primary reason for study withdrawal (and sub-reason, if applicable) will be 
categorised as: 
• Adverse event  
• Lost to follow-up 
• Withdrew consent  
o participant relocated 
o frequency of visits 
o burden of procedures 
• Protocol deviation  
• Lack of efficacy  
• Study closed/terminated 
• Participant reached protocol-defined stopping criteria 
o Liver event 
o Pregnancy 
o QTc 
• Investigator discretion 
7.2.2. 
Early Withdrawal Visit 
The definition of an early participant withdrawal from the study will be any participant 
who is randomised to blinded medication and, for any reason, is withdrawn prior to 
completion of the Visit 15 (Week 52) procedures. 
A participant may voluntarily discontinue participation in the study at any time. 
Participants that withdraw from the study should return to the clinic 4 weeks after the 
previous clinic visit for an Early Withdrawal Visit. If possible, at the Early Withdrawal 
Visit, the following evaluations and procedures should be completed and recorded in the 
eCRF as required: 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
68 
 
• Concomitant medication assessment 
• Adverse event assessment 
• 12 –lead ECG 
• Physical examination (recorded in source documents only) 
• Vital signs 
• Collect/review electronic diary   
• Urine pregnancy test - for all WOCBP  
• Assessment of endoscopic nasal polyp score 
• Assessment of surgery  
• Assessment of systemic CS use 
• Assessment of INCS use 
• Assessments of symptoms 
• Assessment of HRQoL 
• WPAI 
• PK (Japan and China only) 
• Lab assessments including liver chemistry and immunogenicity 
• CT scan 
• Assessment of asthma exacerbations 
• Access the RAMOS NG to report participant’s early withdrawal from the study 
If an IP discontinuation visit has been previously performed (i.e. the participant is 
continuing within the study off-treatment and subsequently decides to withdraw), an early 
withdrawal visit is not required. 
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 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
69 
 
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.  
• Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all participants randomised, 
including those who did not get study intervention. Public sources may be searched 
for vital status information. If vital status is determined as deceased, this will be 
documented, and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
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. 
• Following randomisation laboratory results as well as central read nasal polyps 
scores that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples or during transfer to a central laboratory. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
70 
 
8.1. 
Critical Pre-screening, Screening and Baseline 
Assessments 
8.1.1. 
Pre-screening 
Participants can perform the pre-screening Visit (Visit 0) up to 2 weeks prior (unless 
specifically authorised by the medical monitor) to or on the same day as the Screening 
Visit (Visit 1).  A participant number will be assigned at the time the ICF is signed.  
During the Pre-screening Visit, study designated personnel must provide informed 
consent to study participants. 
Once the informed consent document has been signed, pre-screening assessments can be 
conducted. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity. From the pre-screening visit onwards concomitant medications, 
exacerbations and SAEs (considered as related to study participation) must be reported. 
8.1.2. 
Screening 
At the screening visit NP and asthma therapy, NP surgery history, asthma and 
exacerbation history and concomitant medications will be assessed.  Endoscopic NP 
score as well as VAS score for nasal obstruction, nasal discharge, mucus in the throat, 
loss of smell, facial pain and overall VAS symptom score will be captured. 
8.1.3. 
Critical procedures performed at Screening (Visit 1) 
Medical history including smoking status, history of sinusitis, NP history (including NP 
surgery), aspirin sensitivity, history of asthma, courses of rescue corticosteroids in the 
past 12 months, asthma exacerbation history in the previous 12 months, smoking history. 
Therapy/Concomitant medication history, including use of mepolizumab or previous 
biologics in the past 12 months. 
Cardiovascular medical history/risk factors (as detailed in the eCRF). This assessment 
must include a review of the participant responses to the cardiovascular assessment 
questions and height, weight, blood pressure, smoking history, medical conditions, and 
family history of premature cardiovascular disease. 
Physical exam  
Vital signs 
Blood for eosinophilia entry criteria 
Dispensing and training of eDiary 
Nasal obstruction VAS symptom score 
Overall VAS symptom score 
Resting 12-lead ECG  


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
71 
 
Laboratory tests. These should include: 
• Chemistry 
• Haematology with differential count 
• Hepatitis B Surface Antigen and hepatitis C antibody  
• Urinalysis 
• Urine pregnancy test- for all WOCBP 
• FSH and oestradiol will be assessed to confirm menopausal state (if applicable) 
• Parasitic screening (only in countries with a high-risk or in participants who 
have visited a high-risk country) 
• Endoscopic NP score 
• Baseline Cranial CT scan (to be performed at Screening or during run-in 
period, see SoA and SRM for details) 
• Review of Inclusion/Exclusion criteria 
• Review of exacerbations, SAEs 
Procedures conducted as part of the participant’s routine clinical management [e.g. blood 
eosinophil counts] and obtained prior to signing of informed consent may be utilised for 
screening or baseline purposes provided the procedure meets the protocol-defined criteria 
and has been performed within the timeframe defined in the SoA. 
8.1.4. 
Critical procedures performed at first treatment Visit (Baseline 
Visit 2) 
• Review eDiary compliance and retrain participant if required 
• Review randomisation criteria 
• Review the Endoscopic NP score recorded during Visit 1 (Screening) as rated 
by the central laboratory 
• Vital signs  
• Laboratory tests. This should include 
o Clinical Chemistry including liver chemistry 
o Haematology with differential 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
72 
 
o Blood for baseline immunogenicity 
o Urine pregnancy test - for all WOCBP 
8.1.5. 
Critical procedures performed throughout treatment period  
8.1.5.1. 
Daily eDiary 
All to be performed daily at home, including at study visit days. 
• Overall VAS symptom score 
• VAS for nasal obstruction, nasal discharge, mucus in the throat, loss of smell, 
facial pain  
8.1.5.2. 
(Visits 2 - 15) 
• eDiary at site 
o SNOT-22 questionnaire (selected visits only)  
o ACQ-5 (for asthmatics) (selected visits only) 
o SF-36 (selected visits only) 
o WPAI-GH (selected visits only) 
o Review eDiary and retrain if required 
• Assessment of nasal surgery (confirmed and waiting list) 
• Assessment of systemic CS dose and duration 
• Endoscopic NP score (be performed at selected visits only, refer to SoA) 
• End of study cranial CT scan (V15 or IP discontinuation/Early Withdrawal 
Visit, – performed within the visit window and up to 14 days before study 
visit) 
• Blood for PK (to be done only at visits and in countries indicated in the SoA) 
• Genetic sample (to be done one time only in any of the visits for non-Chinese 
participants) as per SoA 
• AE/SAE review 
• Concomitant medication review 
• 12-lead ECG as per SoA 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
73 
 
• Vital signs as per SoA 
• Laboratory assessments as per SoA 
• Blood for immunogenicity as per SoA 
• Urinalysis as per SoA 
• Urine pregnancy test (for all WOCBP) as per SoA 
• FSH and oestradiol will be assessed to confirm child-bearing status (following 
a positive urine test) 
8.2. 
Efficacy Assessments 
8.2.1. 
Endoscopic NP score 
Endoscopic NP score will be performed at study visits as described in the SoA. This 
score is graded based on NP size (Appendix 9) recorded as the sum of the right and left 
nostril scores with a range of 0-8; higher scores indicate worse status). 
All image recordings of endoscopies will be sent to an independent reviewer for 
centralized blinded data assessment. 
Endoscopic NP score will be performed at the site by trained heath care staff (usually 
ENT surgeon).  The images of the assessment will be sent to central labs where there will 
be central scoring of the NP. There is potential for the site score to differ from the central 
score. In such cases the output from the central labs is considered final and will be 
utilised for patient eligibility and for the analysis of the study. 
Nasal endoscopy assessment can be carried out within a 3-day window prior to dosing for 
each study visit (apart from visit 2) but must not exceed the protocol defined windows of 
7 days from the nominal study visit. 
8.2.2. 
Computed Tomography (CT) Scan 
The Lund Mackay (LMK) CT scoring system is based on localization with points given 
for degree of opacification: 0 = 
, 1 = 
, 2 = 
. 
These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, 
sphenoid, frontal sinus on each side. The osteomeatal complex (OC) is graded as 0 = 
 
 or 2 = 
. This scoring system 
has been validated in several studies. 
For patients in whom the OC is missing (because of a previous surgery) the reader should 
consider the location of the former OC and provide a scoring (as if the OC was there). 
CT scan should be performed anytime during the run-in, and at Visit 15 (Week 52) and 
IP discontinuation/Early Withdrawal Visit. 
CCI
CCI
CCI
CCI
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
74 
 
Details for CT will be available in a separate operational manual provided to the sites. CT 
scans central reading for LMK scoring will be used in the statistical analysis Appendix 
10. 
8.2.3. 
Individual Symptoms Visual Analogue Scale (VAS) 
All VAS to be used in the study will be administered using the eDiary and will be 
collected daily in the morning from screening to the end of the study period. 
Every day, the participant will be asked to indicate on a VAS the severity of 6 nasal 
polyposis symptoms (one VAS for each symptom) and symptoms overall: 
Please rate your “___________” at its worst over the previous 24 hours. 
1. nasal obstruction; 2. nasal discharge; 3. mucus in the throat; 4. loss of smell; 5. facial 
pain; 6. overall VAS symptoms score. 
The left-hand side of the scale (0) represents “
” and the right-hand side of the scale 
(100) represents “
”. Participants will be instructed on how to 
use the scale prior to using the scale.  
VAS measure a characteristic or attitude that is believed to range across a continuum of 
values and cannot easily be directly measured. The participant selects a point on the line 
that represents their current state on the continuum. In this study symptom VAS will be 
collected using an eDiary, suitably pixilated to allow the selection of all integers from 0 
to 100.  A number of publications which shows the applicability of VAS administered 
electronically and comparability to traditional paper [Hollen, 2013; Reips, 2008; Cook, 
2004; Jamison, 2002]. VAS scores will be analysed using a 0 and 10 scale reported to 1 
decimal point. 
8.2.4. 
NP surgery 
At each visit it will be recorded whether the participant is on a waiting list for NP surgery 
and whether the participant has received confirmed documented surgery. As an endpoint, 
for the purpose of this study, NP surgery is defined as any procedure involving 
instruments resulting in incision and removal of tissue from the nasal cavity 
(polypectomy). Dilatation of the air passages in the nasal cavity (e.g. balloon sinuplasty) 
will not be included in this endpoint.  Procedures occurring on the same date were 
considered as part of the same surgery event.  A clinical review will be carried out prior 
to the unblinding of treatment codes to identify all events to be considered as part of this 
endpoint. 
The study will also record whether a participant had received sinuplasty and/or was on a 
waiting list for NP surgery. 
8.2.5. 
Medication 
The number of courses of systemic steroids as well as the dose and duration of the 
courses will be recorded in the CRF.  The dose for a course of systemic CS will be 
CCI
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
75 
 
according to the participants SoC for systemic CS use for its NP condition.  The dose and 
duration of the systemic CS taken will be recorded in the eCRF. For the purpose of this 
study a course of systemic corticosteroid is considered continuous if treatment is 
separated by less than 7 days.  The methodology to convert various doses of intravenous 
and oral steroids to prednisolone-equivalent systemic CS will be provided in the SRM.   
8.2.6. 
Health Related Quality of Life (HRQoL) assessment 
Participants are to be provided with a quiet location, free from distraction to complete 
study visit questionnaires. They should be instructed to select the single response option 
for each question that most closely reflects their health over the time period indicated for 
each questionnaire. 
8.2.6.1. 
Sino-Nasal Outcome Test (SNOT-22) questionnaire 
SNOT-22 is a 22-item measure of disease specific HRQoL It will be completed by the 
participant at study visits according to the SoA (Section 1.3) on the eDiary. 
The SNOT-22 has been shown to be a reliable outcome measure for successful septal 
surgery [Buckland, 2003]. It is also recommended as a very suitable questionnaire in 
chronic rhinosinusitis (CRS) management [Morley, 2006] and its routine use is 
recommended as a tool to evaluate outcomes in nasal polyposis [Browne, 2006]. 
Participants will be asked to rate the severity of their condition on each of the 22 items 
over the previous 2 weeks using a 6-point rating scale of 0-5 including: 
 
 1 = 
; 2 = 
; 3 = 
 
; 4 = 
; 5 = 
 The total score range for 
the SNOT-22 is 0-110, where higher scores indicate greater disease impact. Psychometric 
analyses of data from the 205687 study indicate that a decrease of 28 points or greater is 
a clinically meaningful within participant change. The previously published MCID of a 
difference of >8.9 will also be reported [Hopkins, 2009]. 
8.2.7. 
Assessments for asthmatic participants only 
8.2.7.1. 
Asthma Control Questionnaire (ACQ-5) 
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
patients’ asthma control that can be quickly and easily completed [Juniper, 1999; 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 over the previous 
week (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 recall period is the 
past week.  
ACQ-5 will be assessed at clinic visits, during the study according to the SoA (Section 
1.3). Please refer to the SRM for further details. 
CCI
CCI
CCI
CCI
CCI
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
76 
 
8.3. 
Safety Assessments 
8.3.1. 
Physical Examinations 
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded at Visit 1. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital Signs 
As detailed in the SoA vital signs will be measured in semi-supine position after at least 5 
minutes rest and will include systolic and diastolic blood pressure and pulse rate. 
• 
Blood pressure and pulse measurements will preferably be assessed with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available. 
Vital signs assessments will be taken before measurement of any ECGs at the specified 
time point. 
8.3.3. 
Electrocardiograms 
A single 12-lead ECG will be obtained at each timepoint specified in the SoA using an 
ECG machine to assess heart rate and measures PR, QRS, QT, and QTc intervals (for 
further details refer to the SRM). 
If a routine single ECG after randomisation demonstrates a prolonged QT interval, obtain 
two more ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the patient should be discontinued from the study. 
ECG measurements will be made after the participant has rested in the supine position for 
5 minutes.  The ECG should be obtained after the vital signs assessments and followed by 
other study procedures as described in the SRM.  
8.3.4. 
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 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. 
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 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
77 
 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study treatment should 
be repeated until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor.  
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the 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.  
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF. 
Planned time points for all safety assessments are provided in the SoA. 
8.3.5. 
Pregnancy Testing 
 
• 
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• 
Pregnancy testing should be conducted at monthly intervals during the study 
intervention period, preferably as part of the regular onsite study visits. If a urine 
test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. 
• 
Pregnancy testing must be conducted for each WOCBP prior to the cranial CT 
scan assessment which will be performed anytime during the run-in, and at Visit 
15 (Week 52) and the IP discontinuation/Early Withdrawal Visit. 
• 
Pregnancy testing should be conducted at the end of relevant systemic exposure 
plus an additional 30 days and correspond with the time frame for female 
participant contraception in Section 5.1 Inclusion Criteria (contraception to be 
taken during the study intervention period and for at least 105 days after the last 
dose of study intervention). 
• 
Additional pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of 
pregnancy at any time during the participant’s participation in the study. 
 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
78 
 
The definitions of device-related safety events, (adverse device effects [ADEs] and 
serious adverse device effects [SADEs]), can be found in Section 10.8. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
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 study intervention or the study, 
or that caused the participant to discontinue the study (see Section 7).  
The following AEs of special interest will have customized AE and SAE pages in the 
eCRF: 
• Systemic reactions 
• Local injection site reactions 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the start of study intervention until the Exit visit/EW 
visit at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a participant consents to participate in the study. 
• All AEs will be collected from the start of intervention until the end of study 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 as Medical History/Current Medical 
Conditions not as AEs. 
• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on 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. 
8.4.2. 
Method of Detecting AEs and SAEs 
• 
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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
79 
 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 8.4), 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). 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an 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. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) 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. 
8.4.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 16 weeks after the last dose.  
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.4.4. While the investigator is not obligated to actively seek this information in 
former study participants he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
80 
 
8.4.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3. 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 within one 
week of when the death is reported. 
8.4.7. 
Adverse Events of Special Interest  
The definitions of an AE or SAE can be found in Appendix 3. 
Systemic reactions, local injection site reactions, infections, malignancies and 
cardiovascular events are considered Adverse Events of Special Interest (AESI). 
In addition, the information whether an event of systemic reaction met the diagnostic 
criteria for anaphylaxis as outlined by the Second Symposium on Anaphylaxis [Sampson, 
2006] and in Appendix 4 will be collected on the AE and SAE CRF pages. 
Systemic reactions and local injection site reactions will have targeted CRF pages. The 
remaining AESI will be identified and evaluated using MedDRA SMQs. 
The investigator and any 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 treatment or the study, 
or that caused the participant to discontinue the study treatment. 
8.4.8. 
Medical Device Incidents (Including Malfunctions) 
GSK Medical devices are being provided for use in this study as a delivery method for 
mepolizumab or matching placebo injections. In order to fulfil regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of incident or malfunction that occur 
during the study with such devices (as defined in Section 6.1.1).  
The definition of a Medical Device Incident can be found in Appendix 8. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix 3 of the protocol.  


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
81 
 
8.4.8.1. 
Time Period for Detecting Medical Device Incidents 
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the GSK 
medical devices are available for use. 
If the investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a GSK 
medical device provided for the study, the investigator will promptly notify the sponsor. 
The method of documenting Medical Device Incidents is provided in Appendix 8. 
8.4.8.2. 
Follow-up of Medical Device Incidents 
• 
All medical device incidents involving an AE, will be followed until resolution of 
the event, until the condition stabilizes, until the condition is otherwise explained, or 
until the participant is lost to follow-up (as defined in Section 7.3. The investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as 
may be indicated to elucidate as completely as practical the nature and/or causality of 
the incident. 
• 
New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator. 
8.4.8.3. 
Prompt Reporting of Medical Device Incidents to Sponsor 
• 
Medical device incidents will be reported to the sponsor within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident. 
• 
Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor.  
• 
In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
• 
The same individual will be the contact for the receipt of medical device reports and 
SAE. 
8.4.8.4. 
Safety syringe functionality assessment 
If there is an error with the medical device then refer to the Safety syringe Error / Failure 
Reporting Form in Appendix 12 returning defective Medical Devices to GSK. 
• 
Please refer to the SRM for process and contact details 
8.4.8.5. 
Regulatory Reporting Requirements for Medical Device Incidents 
• 
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfil the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
82 
 
• 
The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC. 
8.5. 
Pharmacokinetics 
Blood samples of approximately 5 mL for analysis of mepolizumab plasma concentration 
will be obtained as per the SoA. Samples obtained at Visits 3 and 9 should be drawn prior 
to dosing. One post-dose PK collection will be at Week 29 (one week after dose at Visit 
9/Week 28) with a visit allowance of 1 day. The Week 29 PK sample will be collected 
approximately from up to first 30 Japanese and all Chinese subjects randomised. The date 
and exact time of collection for each sample will be documented in the eCRF. 
A parametric modelling framework using non-linear mixed effects will be applied for 
mepolizumab population PK and population PK-PD analyses in Japanese and Chinese 
patients. The analysis will determine population PK, PK-PD parameters, e.g. Systemic 
clearance (CL), volume of distribution (V), covariate effects on systemic levels, between- 
and within-subject variability in PK parameters, as well as relationship between exposure 
of mepolizumab and reduction of blood eosinophil level if data permit. Other systemic 
exposure-clinical outcomes may be explored if deemed appropriate. 
Details for collection and processing of samples may be found in the central lab manual 
and SRM. 
• 
Genetic analyses will not be performed on these blood/plasma samples. 
Participant confidentiality will be maintained.  
• 
Intervention concentration information that would unblind the study will not be 
reported to investigative sites or blinded personnel. 
8.6. 
Pharmacodynamics 
Blood eosinophil counts will be recorded as part of the standard haematological 
assessments performed at the visits specified in the SoA.  
Following randomisation laboratory results that could unblind the study will not be 
reported to investigative sites or other blinded personnel until the study has been 
unblinded. 
8.7. 
Genetics 
Up to 6 mL blood sample for DNA isolation will be collected from CRF participants who 
have consented to participate in the genetics analysis component of the study. 
Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
83 
 
Please see Appendix 6 for information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in SRM. 
Genetics samples will not be collected from participants in China. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing, as detailed in the SoA. 
Details for sample collection and processing may be found in the central lab user manual 
and the SRM. 
8.10. 
Health Outcomes 
Additional health outcomes are evaluated in this study by means of the Short Form-36 
(SF-36) and the Work Productivity and Activity Impairment Questionnaire (WPAI) 
questionnaires. 
8.10.1. 
Short Form-36 (SF-36) questionnaire 
SF-36 will be performed by the participant at visits Baseline, week 4, week 24 and week 
52 (and IP discontinuation / Early Withdrawal Visits). 
SF-36 is one of the most widely used generic questionnaires. It consists of 36 self-
administered questions that cover eight health domains: physical functioning (PF), role 
physical (RP), bodily pain (BP), and general health (GH), vitality (VT), role emotional 
(RE), social functioning (SF), and mental health (MH) with a recall of 4 weeks. Scale 
scores range from 0 to 100 and higher scores indicate better QoL. In addition, the 
Physical Component Score (PCS) and the Mental Component Score (MCS) scores can be 
derived following the original authors’ recommendations [Ware, 1994]. 
Radenne et al. [Radenne, 1999] demonstrated a high internal validity and reliability in 
patients with NP and reported that NP impaired QoL in all SF-36 domains. [Khan, 2019]. 
also found that patients with CRSwNP had significantly lower mean SF-36 Physical 
Component Summary (PCS) and Mental Component Summary (MCS) scores than the 
general population, demonstrating that CRSwNP negatively affects HRQoL. 
Alobid, 2005 showed that a significant improvement was observed in all domains of SF-
36 after medical and surgical treatment. Both mental and physical health reached 
population levels. Combined steroid treatment and ESS had similar long-term outcomes 
on QoL. Radenne et al. [Radenne, 1999] showed that steroids and ESS improved the 
symptoms and the QoL in patients with NP especially in body pain, general health, 
vitality, social functioning, and mental health domains with no significant differences 
between both treatment regimes. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
84 
 
8.10.2. 
Work Productivity and Activity Impairment Questionnaire (WPAI) 
WPAI will be assessed by the participant at study visits described in the SoA (Section 
1.3). 
The WPAI questionnaire is an instrument to measure impairments in both paid work and 
unpaid work [Reilly, 2002]. It measures absenteeism, presenteeism as well as the 
impairments in unpaid activity because of health problem during the past seven days. It 
has been validated to quantify work impairments for numerous diseases such as asthma, 
psoriasis, irritable bowel syndrome (IBS), ankylosing spondylitis and Crohn's disease 
[Reilly, 2004; Reilly, 2010; Reilly, 2008]. In addition, the WPAI questionnaire has been 
used to compare work impairments between treatment groups in clinical studies and trials 
or between participants with different disease severity levels [Reilly, 2004; Reilly, 2010; 
Reilly, 2008; Revicki, 2007; Pearce, 2006; Chen, 2008). 
The WPAI-GH consists of six questions: 1 = 
; 2 =
 
; 3 = 
; 4 = 
; 5 = 
; 6 =
 
 [Reilly, 1993]. The recall 
period for the questions 2 to 6 is seven days. Four main outcomes can be generated from 
the WPAI: 1) percent work time missed due to health for those who were currently 
employed; 2) percent impairment while working due to health for those who were 
currently employed and actually worked in the past seven days; 3) percent overall work 
impairment due to health for those who were currently employed; 4) percent activity 
impairment due to health for all respondents [Reilly, 2002]. For those who missed work 
and did not actually work in the past seven days, the percent overall work impairment due 
to health will be equal to the percent work time missed due to health. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The study is designed to test the superiority of mepolizumab 100 mg SC vs. placebo in 
both co-primary efficacy endpoints of total endoscopic nasal polyp score at Week 52 and 
nasal obstruction VAS score during the 4 weeks prior to Week 52. Each co-primary 
endpoint will be tested at the two-sided 5% alpha level (one-sided 2.5%) and both tests 
are required to be significant to achieve the primary objective of the study. 
9.1.1. 
Multiple Comparisons and Multiplicity 
Multiplicity arising from the multiple secondary endpoints will be controlled using the 
closed testing procedure specified below for strong control of type I error. Hypotheses 
associated with the two primary (H1 and H2) and six secondary endpoints (H3 to H8) will 
be tested using a gatekeeping procedure based on the graphical approach to sequentially 
rejective multiple test procedures [Bretz, 2009]. The two primary hypotheses H1 and H2 
will each be tested first and will be allocated the level α, where α = 0.05 (two-sided). If 
these are both rejected at level α, the procedure then is as follows: the hypotheses Hi , i = 
3, ..., 8 are tested each at its local significance level αi . If a hypothesis Hi can be rejected, 
CCI
CCI
CCI
CCI
CCI
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
85 
 
its level is reallocated to one of the other hypotheses according to the pre-specified rules 
represented by Figure 1. The reallocation weights are updated in the reduced graph and 
the testing step repeated for the remaining, non-rejected hypotheses with the updated 
local significance levels. This possibly leads to further rejected null hypotheses with 
associated reallocation of the local significance levels. The procedure is repeated until no 
further hypothesis can be rejected. The reallocation of the local alpha levels is fully 
determined by the initial graph (Figure 1) and the update algorithm described by Bretz, 
2009. 
Figure 1 
Multiplicity Testing Strategy Across Primary and Secondary 
Endpoints 
 
Primary: 
H1: Total Endoscopic Nasal Polyps score at Week 52 
H2: Nasal Obstruction VAS score during the 4 weeks prior to Week 52 
Secondary: 
H3: Overall VAS score during the 4 weeks prior to Week 52 
H4: Lund Mackay CT score at Week 52 
H5: Composite VAS score during the 4 weeks prior to Week 52 
H6: SNOT-22 Total score at Week 52 
H7: Loss of smell VAS score during the 4 weeks prior to Week 52 
H8: Time to First Nasal Surgery or course of systemic CS for CRSwNP / ECRS up to Week 52 
where ε reflects an infinitesimally small value, indicating the potential for alpha to be reallocated dependent 
on the rejection of all previous tests 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
86 
 
For the initial graph above the resulting test procedure can be summarized as follows: 
• If both co-primary endpoints (H1 and H2) are rejected, the first two secondary 
endpoints (Overall VAS Symptom Score [H3] and Lund Mackay CT score [H4]) 
will each be tested at a significance level of α/2 (0.025). If either endpoint is 
rejected at the α/2 (0.025) level, the α/2 (0.025) from that given endpoint will be 
reallocated and re-used within the subsequent test of the next secondary endpoint 
according to the pre-specified rules represented by Figure 1. 
• If the Overall VAS score endpoint (H3) endpoint is rejected at the α/2 (0.025) 
level, the Composite VAS score (H5) and SNOT-22 total score (H6) will then also 
be tested. Only following rejection of both endpoints (H5 and H6) will the Loss of 
Smell VAS symptom endpoint (H7) be tested. 
• If able to reject the loss of smell VAS endpoint (H7), the α/2 level from this 
endpoint will be reallocated to the testing of the Lund Mackay CT score (H4), to 
allow a test at a full level of α, if not already rejected at the α/2 significance level. 
• Only following rejection of all other secondary endpoints (H3 to H7), will the final 
secondary endpoint of Time to First Nasal Surgery or course of systemic CS for 
CRSwNP / ECRS (H8) be tested. 
Lund Mackay CT score (H4) is an important endpoint in the clinical practice of Japan and 
China, however, has not been studied previously within the mepolizumab clinical 
development program. The above testing strategy demonstrates the importance of this 
endpoint, whilst permitting testing of other secondary endpoints if not initially rejected at 
a significance level of α/2. The Composite VAS, SNOT-22 and Loss of Smell VAS 
secondary endpoints are all correlated patient reported endpoints measuring 
improvements in symptoms; these endpoints are grouped within the above strategy for 
testing in sequence following the rejection of the of Overall VAS Score (H3) to increase 
power across these symptom endpoints. If all symptom endpoints (H3, H5, H6, H7) are 
rejected, the above strategy permits a test of the Lund Mackay CT score (H4) a full level 
of α, if not already rejected at the initial α/2 significance level. 
9.2. 
Sample Size Determination 
The sample size is based on the co-primary efficacy endpoints of total endoscopic nasal 
polyp score at Week 52 and nasal obstruction VAS score during the 4 weeks prior to 
Week 52.  
The sample size of 160 participants randomised in a 1:1 ratio to each treatment arm 
provides at least 90% power to demonstrate a statistically significant result for both 
co-primary endpoints using a mixed model repeated measures (MMRM) analysis model. 
Estimates of residual standard deviation (SD) of 1.82 for total endoscopic nasal polyp 
score at Week 52 and 3.25 for nasal obstruction VAS score during the 4 weeks prior to 
Week 52 are taken from a post-hoc MMRM analysis of observed data from study 205687 
(SYNAPSE) which assumed a  “missing at random” (MAR) assumption for missing data. 
With the above assumptions and a sample size of 160 randomized subjects (80 per arm), 
it is estimated that the null hypothesis will be rejected at the two-sided 5% level of 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
87 
 
significance for total endoscopic nasal polyp score if the observed difference between 
treatments is at least 0.57 units and for nasal obstruction VAS score if the observed 
difference between treatments is at least 1.01. 
For total endoscopic nasal polyp score, if the true difference between treatments is 1.00 
units, then the study has a probability of 93.2% of observing a difference in total 
endoscopic nasal polyp score between treatments of at least 0.57 units and therefore 
93.2% power for declaring significance on this endpoint. The estimated improvement 
observed in total endoscopic nasal polyp score for mepolizumab 100 mg SC compared to 
placebo within study 205687 (SYNAPSE) was 0.99 units (95% CI: 0.61 to 1.36). 
For nasal obstruction VAS score, if the true difference between treatments is 2.00, then 
the study has a probability of 97.2% of observing a difference in nasal obstruction VAS 
score between treatments of at least 1.01 units and therefore a 97.2% power for declaring 
significance on this endpoint. The measured improvement observed in nasal obstruction 
VAS score for mepolizumab 100 mg SC compared to placebo within study 205687 
(SYNAPSE) was 1.97 units (95% CI: 1.31 to 2.63). 
If the true population distribution of each co-primary endpoint is as described above, a 
study with sample size of 80 randomised participants randomised in 1:1 ratio to each 
treatment arm (total 160 participants) is estimated to have at least 90% power regardless 
of the degree of (positive) correlation of the endpoints. 
Assuming a screen failure rate of 40%, approximately 270 participants will need to be 
screened to achieve approximately 160 randomly assigned to study intervention for a 
total of approximately 80 participants per intervention group. All participants within the 
Intent-to-Treat analysis set (randomised participants who receive at least 1 dose of study 
treatment) will be considered evaluable within the study analysis. See Section 9.4 
regarding the strategy of handling of intercurrent events for the primary estimands. 
9.2.1. 
Sample Size Sensitivity 
Table 1 illustrates the effect of varying standard deviation and treatment effects on power 
(based on 80 subjects per arm) for of the co-primary efficacy endpoints of total 
endoscopic nasal polyp score at Week 52 and nasal obstruction VAS score during the 
4 weeks prior to Week 52. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
88 
 
Table 1 
Effect on Power with Varying Standard Deviation and Treatment 
Effect Sizes 
Total endoscopic nasal polyp score at Week 52 
Standard 
Deviation 
Treatment Difference 
0.8 
0.9 
1.0 
1.1 
1.2 
1.74 
82.4% 
90.2% 
95.1% 
97.8% 
99.1% 
1.78 
80.7% 
88.8% 
94.2% 
97.3% 
98.9% 
1.82 
78.9% 
87.5% 
93.2% 
96.7% 
98.6% 
1.86 
77.1% 
86.0% 
92.2% 
96.1% 
98.2% 
1.90 
75.4% 
84.6% 
91.1% 
95.3% 
97.8% 
Nasal obstruction VAS score during the 4 weeks prior to Week 52 
Standard 
Deviation 
Treatment Difference 
1.8 
1.9 
2.0 
2.1 
2.2 
2.95 
97.0% 
98.2% 
98.9% 
99.4% 
99.7% 
3.10 
95.4% 
97.1% 
98.2% 
98.9% 
99.4% 
3.25 
93.6% 
95.7% 
97.2% 
98.2% 
98.9% 
3.40 
91.4% 
94.0% 
95.9% 
97.3% 
98.2% 
3.55 
89.0% 
92.0% 
94.3% 
96.1% 
97.4% 
 
If required, additional participants may be randomised to mitigate against unforeseen 
events arising at a local country level or worldwide,  such changes will be reported in the 
CSR. 
9.3. 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
All Participants Enrolled  
All participants enrolled and for whom a record exists on the 
study database 
Randomised 
All randomised participants 
Intent-to-Treat 
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the 
treatment they are allocated at randomisation. 
Safety 
All randomised participants who take at least 1 dose of study 
treatment. Participants will be analysed according to the 
treatment they actually received for more than 50% of treatment 
administrations. 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s 
(LAR's), agreement to participate in a clinical study following completion of the 
informed consent process. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
89 
 
9.4. 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database release and 
unblinding and it 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 endpoints including primary and secondary endpoints. 
9.4.1. 
Primary Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Co-Primaries 
Primary Estimands 
The difference between mepolizumab 100 mg SC and placebo in a) mean 
change from baseline in total endoscopic NP score to Week 52 and b) mean 
change from baseline in mean nasal obstruction VAS score during the 4 
weeks prior to Week 52 in participants with a diagnosis of CRSwNP / ECRS, 
regardless of IP discontinuation or, changes in background medication/starting 
a prohibited medication unrelated to COVID-19, interruptions to IP of 2 or 
more consecutive doses, or use of systemic CS for CRSwNP / ECRS, with 
participants experiencing surgery being assigned the worst possible score for 
the endpoint from the day of surgery onwards. 
 
The primary treatment effect to be estimated will be the comparison of 
mepolizumab 100 mg SC to placebo. 
 
The population will be the entire trial population (patients meeting the study 
inclusion/exclusion criteria with a diagnosis of CRSwNP / ECRS) randomised 
and receiving treatment. 
 
Co-primary variables: 
• 
Change from baseline in total endoscopic nasal polyp score at Week 
52 (based on centrally read data) 
• 
Change from baseline in mean nasal obstruction VAS score during 
the 4 weeks prior to Week 52 
 
The summary measure of treatment effect for both co-primary endpoints will 
be the difference in mean scores between mepolizumab and placebo. 
The main intercurrent events (ICE) anticipated which may affect subsequent 
scores for the co-primary endpoints are: 
a) Premature discontinuation of study treatment unrelated to the 
COVID-19 pandemic – to be handled using a treatment policy 
strategy. The study will continue collecting data for participants who 
prematurely discontinue from randomised treatment. 
b) Changes in background medication or to start a prohibited medication 
(e.g. start INCS therapy where absent at baseline) unrelated to the 
COVID-19 pandemic – to be handled using a treatment policy 
strategy. These events will be captured as a protocol deviations and 
the study will continue treatment and to collect data for participants 
following this change in background medication / starting of a 
prohibited medication. Participants will not be expected to discontinue 
treatment or withdraw from the study. 
c) Premature discontinuation of study treatment, change in background 
medication or start of prohibited medication related to the COVID-19 
pandemic measures (such as quarantines, site closures or other 
related issues) – to be handled using a hypothetical strategy. Data 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
90 
 
Endpoint 
Statistical Analysis Methods 
impacted by COVID-19 related events will not be included in the 
statistical analyses and will be treated as missing data.. 
d) Surgery, which includes any procedure involving instruments resulting 
in incision and removal of tissue from the nasal cavity (e.g. 
polypectomy) – to be handled using a composite strategy by 
incorporating occurrence of the event into the definition of the 
endpoint. Specifically, participants who undergo surgery will be 
assigned the worst possible score for the endpoint from the day of 
surgery onwards for inclusion in the analysis.  
e) Course of systemic CS for CRSwNP / ECRS – to be handled using a 
treatment policy strategy. Data collected following a course of 
systemic CS for CRSwNP / ECRS will be included in the analysis 
where systemic CS will be considered as SoC treatment. 
f) 
Interruption to IP of 2 or more consecutive doses – to be handled 
using a treatment policy. These events will be recorded as protocol 
deviations and participants are expected to continue IP per-protocol 
after interruption. Data collected will be included in the analysis 
regardless of IP interruption. 
 
Any changes to the estimand strategy arising as result of unforeseen local or 
worldwide events will be documented in the Statistical Analysis Plan prior to 
unblinding of the study. 
Independent reviewers, blinded to treatment, grade the total endoscopic nasal 
polyp score from image recording of endoscopies. The total score is reported 
as the sum of the right and left nostril scores and ranges from 0 to 8, with 
higher scores indicating greater disease severity. 
Participants rate individual symptoms including nasal obstruction daily on a 
visual analogue scale (VAS) using an eDiary on a line with 101 individually 
selectable points ranging from 0 (none) to 100 (as bad as you can imagine). 
The final VAS scores for inclusion in summary and analysis tables will be 
derived from the electronically captured score by dividing each score by 10, 
and therefore will range from 0 to 10. 
Total endoscopic nasal polyp score is collected at each clinical visit, the 
primary assessment will be at week 52 (centrally read data). Nasal obstruction 
is collected daily throughout the study via eDiary. Nasal obstruction at Week 
52 will be calculated as the mean of all measurements made in the 4 weeks 
prior to the visit. The mean VAS score over the last 7 days before Visit 2 will 
be used to determine the baseline value.  
For the co-primary analyses the change from baseline value for participants 
with surgery will be based on the worst possible score for the endpoint from 
the day of surgery onwards. Missing data due to study withdrawal, intercurrent 
events due to the COVID-19 pandemic or missing data for another reason will 
be assumed to be missing at random (MAR). 
The comparison of mepolizumab with placebo will be expressed as a 
difference in mean change from baseline presented with corresponding 95% 
confidence intervals and associated p-value. The analysis will be performed 
for each co-primary endpoint using a mixed model repeated measures 
(MMRM) analysis, with covariates of treatment group, baseline score, log of 
baseline blood eosinophil count, background INCS use ,country and time 
point, plus interaction terms for time point by baseline value and time point by 
treatment group.  


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
91 
 
Endpoint 
Statistical Analysis Methods 
Sensitivity Analyses 
The following sensitivity analysis will be carried out to examine the potential 
impact of choices for the handling of participants with missing data.. 
Missing data unrelated to the COVID-19 pandemic (due to premature 
withdrawal from the study or another reason) will be imputed based on off-
treatment data.  
Missing data due intercurrent events related to the COVID-19 pandemic will 
be assumed to be missing at random and imputed based on on and off-
treatment data. 
Observed and imputed data will be combined and analysed using the same 
methods as specified for the co-primary analysis  
Supplementary Estimands  
The following additional analysis will be carried out to examine the potential 
impact of choices for the handling of data for participants starting a course of 
systemic CS for CRSwNP / ECRS. The analysis will be performed for each co-
primary endpoint where: 
• 
change from baseline for participants starting a course of systemic CS 
is based on the worst possible score for the endpoint following the 
initiation of the course of systemic CS. 
 
An additional analysis will be carried out to examine the potential impact of 
choices for the handling of data for participants undergoing surgery. The 
analysis will be performed for each co-primary endpoint where: 
• 
change from baseline for participants with surgery is based on the 
worst observed score for the participant prior to surgery. 
Further details of these analyses will be included within the SAP. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
92 
 
9.4.2. 
Secondary Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Secondary 
Estimands for the secondary variables of change from baseline in SNOT-22 
total score at Week 52, change from baseline in mean overall VAS symptom 
score, mean composite VAS score (combining VAS scores for nasal 
obstruction, nasal discharge, mucus in the throat and loss of smell) and mean 
VAS for loss of smell score at Week 52 (calculated as the mean of all 
measurements made in the 4 weeks prior to Week 52), and change from 
baseline in Lund Mackay CT score at Week 52 will use the same population, 
summary measure and strategies for intercurrent events as for the primary 
estimands. Analysis methods will be the same as for the co-primary endpoints. 
For the endpoint of time to first nasal surgery or course of systemic CS for 
CRSwNP / ECRS up to Week 52, the summary measure will be the hazard 
ratio. The anticipated intercurrent events of premature discontinuation of study 
treatment or changes in background medication/starting of a prohibited 
medication will be handled using a treatment policy strategy, such that 
available event times will be included in the analysis regardless of whether the 
event (surgery or course of systemic CS for CRSwNP / ECRS) occurred 
before or after discontinuation of randomised treatment or changes in 
background medication/starting of a prohibited medication. Data impacted by 
COVID-19 related intercurrent events will not be included in the statistical 
analyses and each subject will be censored at the time of the COVID-19 
related intercurrent event. Statistical analysis will use the Cox proportional 
hazards model with covariates of treatment group, log of baseline blood 
eosinophil count, number of previous surgeries (1, 2, >2; ordinal), background 
INCS use and country. A graph of the Kaplan-Meier estimates of the 
proportion of participants with events over time will be produced by treatment 
group. If a participant withdraws from the study before experiencing nasal 
surgery or having a course of systemic CS for CRSwNP / ECRS, the event 
time will be censored at the time of study withdrawal. 
 
9.4.3. 
Safety Analysis 
All safety analyses will be performed on the Safety Analysis Set and will be described in 
the SAP. 
9.4.4. 
Other Analysis 
All analyses of other endpoints (including self-administration of IP, PK, 
pharmacodynamic, and exploratory analyses) will be described in the SAP.  
9.5. 
Interim Analysis 
No interim analysis of data is planned for this study. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
93 
 
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, IB 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.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation 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/IEC 
▪ 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), European Medical 
Device Regulation 2017/745 for clinical device research (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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
94 
 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or their 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 their legally 
authorized representative. 
• 
Participants who are rescreened are required to sign a new ICF. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about Mepolizumab or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have Mepolizumab approved for 
medical use or approved for payment coverage.  
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 who will be required to give consent for their data to 
be used as described in the informed consent.  
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. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
95 
 
10.1.5. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
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 all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
patients received.  The investigator(s) is/are encouraged to share the summary 
results with the study subjects, as appropriate. 
• 
Under the framework of the SHARE initiative, GSK intends to make 
anonymized participant-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. Requests for access may be made through 
www.clinicalstudydatarequest.com. 
• 
GSK will provide the investigator with the randomisation codes for their site 
only after completion of the full statistical analysis. 
• 
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
 
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory, 
endoscopy, CT scan or Patient Reported Outcomes data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in study-specific CRF 
Completion Guidelines for Investigators. 
• Quality tolerance limits (QTLs) will be pre-defined in the QTL Plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• 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 including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
96 
 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
• Definition of what constitutes source data and its origin can be found in the 
Source Data Acknowledgment 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• 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.  
 
10.1.8. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
97 
 
First IC obtained by a participant, irrespective if successfully randomised to study 
intervention or screen fail is considered the first act of recruitment and will be the study 
start date. 
Study/Site Termination 
GSK or 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: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• 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 or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the subject and should assure appropriate 
participant therapy and/or follow-up 
10.1.9. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of 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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
98 
 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 2 will be performed by a central laboratory.  
• 
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration 
and/or response evaluation. If a local sample is required, it is important that the 
sample for central analysis is obtained at the same time. Additionally, if the 
local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be recorded. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Following randomisation laboratory results that could unblind the study will not be 
reported to investigative sites or other blinded personnel until the study has been 
unblinded. 
Table 2 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
 
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] 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
99 
 
Laboratory 
Assessments 
Parameters 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential) 
• Follicle-stimulating hormone and oestradiol to confirm menopausal state 
(if applicable) 
• All study-required laboratory assessments will be performed by a central 
laboratory. 
• Hepatitis B and C testing at screening visit 
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 7.1.4 and Appendix 7. All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an 
SAE. 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
100 
 
10.3. 
Appendix 3: AEs and SAEs: 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. 
 
• Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant/ LAR(s) who has 
signed the informed consent. Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care 
provider). The participants/LAR(s) will be instructed to contact the site as soon as 
possible to report medically attended event(s), as well as any events that, though 
not medically attended, are of participant/LAR’s concern. Detailed information 
about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant/LAR(s) will be collected during interview with the participants/ LAR(s) 
and by review of available medical records at the next visit. 
• Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participant in their diary.  
 
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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
101 
 
• 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 intervention- intervention 
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 
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 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. 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. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
102 
 
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. 
d. Results in persistent or significant 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. 
e. Is a congenital anomaly/birth defect 
f. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that 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. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
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 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
103 
 
• 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. 
• 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 required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
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. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
104 
 
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. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
105 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next Section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The investigator or medically qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next Section). 
• 
Contacts for SAE reporting can be found in the SRM and Investigator Site File. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM and Investigator Site File. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
106 
 
10.4. 
Appendix 4: Anaphylaxis Criteria 
Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria 
do not make a distinction based on underlying mechanism. These criteria are summarized 
as follows: 
 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue- 
uvula), and at least one of the following: 
 
a) Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia) 
 
b) Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence) 
 
2) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several 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) 
 
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
 
a) Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP 
 
b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s Baseline 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
107 
 
10.5. 
Appendix 5: Contraceptive and Barrier Guidance  
10.5.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o 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.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-oestrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of postmenopausal status before 
study enrolment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
• 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), 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. 
 
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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
108 
 
10.5.2. 
Contraception Guidance 
CONTRACEPTIVES a ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods b 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 ovulation c 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia 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. 
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.) 
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
• 
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation c 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation c 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
Effective Methods d That Are Not Considered Highly Effective Failure rate of ≥ 1% per year when used 
consistently and correctly. 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
• 
Male or female condom with or without spermicide e 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods) c 
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. 
Male condoms must be used in addition to hormonal contraception. 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. 
d. 
Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method (LAM) are not acceptable methods of contraception.  
e. 
Male condom and female condom should not be used together (due to risk of failure from friction). 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
109 
 
10.6. 
Appendix 6: Genetics 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
aetiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis 
• DNA samples will be used for research related to mepolizumab or CRSwNP / ECRS 
and related diseases. They may also be used to develop tests/assays including 
diagnostic tests) related to mepolizumab or study interventions of this drug class, and 
indication. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate). 
• Additional analyses of DNA samples may be conducted if it is hypothesized that this 
may help further understand the clinical data.  
• The samples may be analysed as part of a multi-study assessment of genetic factors 
involved in the response to mepolizumab or study interventions of this class. The 
results of genetic analyses may be reported in the clinical study report or in a separate 
study summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• The samples will be retained while research on mepolizumab (or study interventions 
of this class) or nasal polyposis continues but no longer than 15 years after the last 
subject last visit or other period as per local requirements. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
110 
 
10.7. 
Appendix 7: Liver Safety: Required Actions, Monitoring and 
Follow-up Assessments  
Liver Chemistry Stopping Criteria and Increased Monitoring Criteria are designed 
to assure participant safety and evaluate liver event aetiology. 
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 total bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions, Monitoring and Follow-up Assessments  
Actions 
Follow-Up Assessments 
• Immediately discontinue study intervention 
• Report the event to GSK within 24 hours 
• Complete the liver event form and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform follow up assessments as 
described in the Follow-up Assessment 
column 
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
MONITORING: 
If ALT 3xULN AND total bilirubin 2xULN or 
INR >1.5: 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain blood sample for pharmacokinetic 
(PK) analysis within a week of meeting 
increased liver monitoring criteria5 
• Obtain a serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma glutamyl transferase [GGT], 
glutamate dehydrogenase [GLDH], and 
serum albumin. 
• Fractionate bilirubin, if total 
bilirubin2xULN 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
111 
 
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow up 
assessments within 24 hours 
• Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• A specialist or hepatology consultation is 
recommended 
For all other stopping criteria (total bilirubin 
<2xULN and INR ≤1.5):  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, total bilirubin and 
INR) and perform liver event follow-up 
assessments within 24-72 hours  
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
RESTART/RECHALLENGE 
• Do not restart/rechallenge participant with 
study intervention since it is not allowed 
per protocol; continue participant in the 
study for any protocol specified follow-up 
assessments. 
 
• Obtain complete blood count with 
differential to assess eosinophilia.  
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on liver event form 
• Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, recreational drugs and other 
over the counter medications. 
• Record alcohol use on the liver event 
alcohol intake form  
If ALT 3xULN AND total bilirubin 2xULN 
or INR >1.5 obtain the following in addition to 
the assessments listed above: 
• 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 assay 
should be conducted (where available) to 
assess potential acetaminophen 
contribution to liver injury unless 
acetaminophen use is very unlikely in the 
preceding week. NOTE: not required in 
China 
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
to evaluate liver disease: complete Liver 
Imaging form. 
• Liver biopsy may be considered and 
discussed with local specialist if 
available, for instance: 
o In patients when serology raises the 
possibility of autoimmune hepatitis 
(AIH) 
o In patients when suspected DILI 
progresses or fails to resolve on 
withdrawal of study intervention 
o In patients with acute or chronic 
atypical presentation 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
112 
 
• If liver biopsy conducted complete liver 
biopsy form 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5 which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported to GSK as an SAE; the INR 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; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core 
Antibody (HBcAb); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, heterophile antibody or monospot testing); and Hepatitis E IgM antibody. In those with 
underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen), quantitative 
hepatitis B DNA and hepatitis delta antibody. If hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal, 2005]. 
5. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
113 
 
Liver Chemistry Increased Monitoring Criteria with Continued Study Intervention 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study 
Intervention  
Criteria 
Actions 
 
ALT 5xULN and <8xULN and total 
bilirubin <2xULN or INR≤1.5 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 total 
bilirubin <2xULN or INR≤1.5 without 
symptoms believed to be related to 
liver injury or hypersensitivity, and who 
can be monitored weekly for 4 weeks. 
 
• Notify the GSK Medical Monitor within 24 hours 
of learning of the abnormality to discuss 
participant safety.  
• Participant can continue study treatment  
• Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
total bilirubin and INR) until they resolve, stabilise 
or return to within baseline.  
• If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above. 
• If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN (total bilirubin <2xULN 
and INR≤1.5), continue to monitor liver 
chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN and INR≤1.5, monitor 
participants twice monthly until liver chemistries 
normalize or return to within baseline. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
114 
 
10.8. 
Appendix 8: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device 
Studies 
• The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and European Medical Device Regulation (MDR) 2017/745 for 
clinical device research (if applicable).  
• Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices. 
• The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study (see Section 8.4.8. for the 
list of GSK medical devices). 
10.8.1. 
Definition of Medical Device AE and ADE 
Medical Device AE and ADE Definition  
• 
An AE is any untoward medical occurrence, in a clinical study participant, users, 
or other persons, temporally associated with the use of study intervention whether 
or not considered related to the investigational medical device. 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 an investigational medical device. This definition 
includes events related to the investigational medical device or comparator and 
events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any 
event resulting from use error or from intentional misuse of the investigational 
medical device. 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
115 
 
10.8.2. 
Definition of Medical Device SAE, SADE and USADE 
A Medical Device SAE is any serious adverse event that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• A life-threatening illness or injury. The term ‘life-threatening' in the definition 
of ‘serious' refers to an event in which the participant was at risk of death at the 
time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
• A permanent impairment of a body structure or a body function. 
• Inpatient or prolonged hospitalization. Planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
• Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c. 
Led to foetal distress, foetal death or a congenital abnormality or birth defect 
SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• Any device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less 
fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the risk analysis report. 
10.8.3. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
116 
 
10.8.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies 
AE, SAE and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the AE/SAE/device deficiency form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the medical monitor. 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 the medical monitor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 
Assessment of Intensity 
• The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following 
categories:  
o Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
o Moderate: An event that causes sufficient discomfort and interferes with 
normal everyday activities. 
o Severe: An event that prevents normal everyday activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a 
category used for rating the intensity of an event; both AEs and SAEs can 
be assessed as severe. 
• 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. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
117 
 
• Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]). 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or IDFU or 
Product Information, for marketed products, in his/her assessment. 
• For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE/SAE/device deficiency 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
118 
 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator may be asked to provide GSK with a copy of any 
available post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
10.8.5. 
Reporting of SAEs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next Table) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next Section) or to the GSK medical monitor by telephone or email. 
• Contacts for SAE reporting can be found in the SRM and Investigator Site File. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in the SRM and the Investigator Site File. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
119 
 
10.8.6. 
Reporting of SADEs 
• 
SADE Reporting to GSK  
• 
NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs that must fulfil the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency. 
• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
• Contacts for SAE reporting can be found in the SRM and the Investigator Site File. 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
120 
 
10.9. 
Appendix 9: Assessment of Nasal Polyposis 
Endoscopic NP scoring: 
For consistency across sites, it is important to score NP using the following standard. 
Each nostril will be scored and the results recorded individually 
 
 
 
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.


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
121 
 
10.10. 
Appendix 10: Lund-Mackay CT score 
Change in the Lund-Mackay CT score percentage of maxillary sinus volume occupied by 
disease will be assessed in all participants. 
The Lund-Mackay CT score evaluates the patency of each sinus using a 0 to 2 scale (
 
) and has a total score range from 0 to 24 (higher scores 
indicate more opacification) (Lund, 1993; Bhattacharyya, 1999). 
 
 
 
Maximum total score: 24 
 
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.
CCI
CCI


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
122 
 
10.11. 
Appendix 11: Abbreviations and Trademarks 
ACQ-5 
Asthma Control Questionnaire 
ADA 
Antidrug Antibodies 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AI 
Aspirin intolerance 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
BEC 
Blood eosinophil counts 
BMI 
Body mass index 
BP 
Blood Pressure  
BUN 
Blood urea nitrogen 
CPK 
Serum creatine phosphokinase 
CRF 
Case Report Form 
CRS 
Chronic rhinosinusitis 
CRSwNP 
Chronic rhinosinusitis with nasal polyposis 
CS 
Corticosteroid 
CT 
Computed tomography 
CV 
Cardiovascular 
DNA  
Deoxyribonucleic acid 
ECG  
Electrocardiogram 
eCRF  
Electronic Case Report Form 
ECRS 
Eosinophilic chronic rhinosinusitis 
eDiary 
Electronic Diary 
ESS 
Endoscopic sinus surgery 
EW 
Early Withdrawal 
FDA  
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GH 
General health 
GSK  
GlaxoSmithKline 
h/hr  
Hour(s) 
HBsAg 
Presence of hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HCP 
Health care practitioner 
HIV  
Human Immunodeficiency Virus 
HPLC 
High performance liquid chromatography 
HRQoL  
Health Related Quality of Life 
HRT  
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
IBS 
Irritable bowel syndrome 
ICE 
Intercurrent event 
ICF 
Informed consent form 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
123 
 
ICH  
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
ICS/ETN 
Inhaled corticosteroids exhalation through nose 
IEC  
Independent Ethics Committee 
IL-5  
Interleukin-5 
IL-5Ra 
Interleukin-5 receptor alpha 
IM 
Intramuscular 
IMCS 
Intramuscular corticosteroid  
INCS  
Intranasal Corticosteroids 
INR 
International normalised ratio 
IP  
Investigational Product 
IRB  
Institutional Review Board 
ITT  
Intent-to-Treat 
IU  
International Unit 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV  
Intravenous 
kg  
Kilogram 
L 
Litre 
LAR 
Legally Acceptable Representative 
LDH 
lactate dehydrogenase 
MAR 
Missing at random 
MCH 
Mean Corpuscular Haemoglobin 
MCS 
Mental Component Summary 
MCV 
Mean Corpuscula Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MH 
Mental health 
mL 
Millilitre 
MMRM 
Mixed Model Repeated Measures 
msec 
Milliseconds 
NP 
Nasal Polyps 
OC 
Osteomeatal complex 
OCS 
Oral Corticosteroids 
PCS 
Physical Component Summary 
PCSA 
Placebo controlled severe asthma 
PD  
Pharmacodynamic 
PEF 
Peak expiratory flow 
PF 
Physical functioning 
PK  
Pharmacokinetic 
PP  
Per Protocol 
Q4W 
Every 4 weeks 
QTc  
Corrected QT interval 
QTcB  
QTc corrected by Bazett's formula 
QTcF  
QTc corrected by Fridericia's formula 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
124 
 
QTL 
Quality Tolerance Limit 
RAMOS NG 
Registration and Medication Ordering System Next Generation 
RBC  
Red blood cells 
RE 
Role emotional 
RP 
Role physical 
SADE 
Serious Adverse Device Effect 
SAE  
Serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneously 
SCS 
Systemic corticosteroids  
SCT 
Study conduct team 
SD  
Standard deviation 
SF 
Social functioning 
SF-36 
Short Form Health Survey 36 
SNOT  
Sino-Nasal Outcome Test 
SoA 
Schedule of activities 
SoC 
Standard of Care 
SOP  
Standard Operating Procedure 
SRM  
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
UK  
United Kingdom 
ULN  
Upper limit of normal 
URTI 
Upper respiratory tract infection 
US  
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
VAS  
Visual Analogue Scale 
VT 
Vitality 
WBC 
White Blood Count  
WOCBP 
Woman of Childbearing Potential 
WPAI 
Work Productivity and Activity Impairment 
μg  
Microgram 
μL 
Microlitre 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NUCALA 
 
ACQ-5 
 
 
SF-36 
 
 
SNOT-22 
 
 
WPAI 
 
 
Xolair 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
125 
 
10.12. 
Appendix 12: Medical Device or Combination Product with 
Device Deficiency/Incident Report Form 
INVESTIGATOR INSTRUCTIONS 
Complete the Medical Device or Combination Product with Device Deficiency/Incident 
Report Form for each person who has a deficiency/incident with medical device or 
combination product with device component defined in the protocol. Please send a copy 
of the form to GSK within 24 hours as follows. 
If the device incident is linked to an SAE please send email to both uk.gsk-rd-gcsp-ctsm-
admin@gsk.com (or fax+44(0)20 8754 7822) and gsk-rd-complaints@gsk.com. 
If the device deficiency/incident is a non-serious AE/ product complaint and not linked to 
an SAE, please send email to gsk-rd-complaints@gsk.com only. 
If a subject experienced medical device or combination product with device component 
deficiency/incident, all of the header information must be completed before sending back 
to GSK. Ensure to file original pages with the site study file. 
If an associated person (non-subject) e.g. caregiver, site staff, experienced medical 
device or combination product with device deficiency/incident, complete header 
information for the associated subject. If the person experienced the event is not related 
to a subject, enter header information where appropriate, e.g. Protocol Identifier, Centre 
Number. 
In addition, for deficiencies/incidents fulfilling the definition of an Adverse Event (AE) or 
a Serious Adverse Event (SAE), the appropriate pages of the CRF (for associated 
person)/eCRF (for subject) must be completed as described in the protocol. If there is a 
SAE, the completed CRF/eCRF pages should be sent together with this report form. If 
the subject is withdrawn due to this deficiency/incident, ensure the Study Conclusion 
page is completed. 
Note: If a copy of the SAE CRF/eCRF pages is sent with this form, this does not replace 
the procedure to report a SAE. 
 
 
Refer to the protocol for definition of Device Deficiency/Incident. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
126 
 
DEFICIENCY/INCIDENT REPORT FORM 
Who experienced the deficiency/incident? 
Subject 
Associated person 
Relationship to the subject (select one) 
Caregiver 
Clinician 
Nurse 
Other, specify _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Year of birth 
Sex 
Male 
Female 
Year 
DEVICE OR COMBINATION PRODUCT WITH DEVICE DETAILS (complete all applicable 
details) 
Manufacturer name _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Medical device or combination product with device (commercial name)_ _ _ _ _ _ _ _ _ _ _ _ _ _  
Type of device _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Model number _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Catalogue number _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Serial number(s) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Lot number(s) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Accessories/Associated device _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Software version _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Did the deficiency/incident fulfil the definition of an AE or SAE?   
Yes 
No 
If Yes, complete Non-Serious AE or SAE pages/forms as appropriate. 
STUDY TREATMENT AND CONCOMITANT MEDICATIONS 
If a subject experienced the event, enter the study treatment details on the first line (if the study 
treatment is blinded, enter "Study Treatment" on this line). List the relevant concomitant 
medications the subject received during the study period. If there are extensive concomitant 
medications, attach a copy of the Concomitant Medications pages/forms (where applicable). If an 
associated person experienced the event, list the relevant medications. 
Drug 
Name 
Dose Unit Frequency Route Date 
Started 
Taken 
Prior 
to 
Study? 
Y=Yes 
N=No 
Date 
Stopped 
Day 
Month 
Year 
Ongoing 
Medication? 
 
Y=Yes 
N=No 
Reason 
for 
Medication 
(Trade 
Name 
preferred) 
Day 
Month 
Year 
e.g., 
Zantac 
150 mg 
BID 
PO 05 AUG 08
N 
07 AUG 08
N 
Gastric ulcer 
1. 
2. 
3. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
127 
 
4. 
5. 
DETAILS OF DEFICIENCY/INCIDENT 
Onset date of deficiency/incident 
                                                                     Day         Month        Year 
Deficiency/Incident description  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Treatment given _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Outcome,  one:    
                         
Recovered/Resolved 
                         
Recovering/Resolving (leave outcome date blank) 
                         
Not recovered/Not resolved (leave outcome date blank) 
                         
Recovered/Resolved with sequelae 
                         
Fatal (complete SAE form) 
                         
Not Applicable 
Outcome date 
                                                 Day         Month        Year 
Corrective action (e.g., adjustment to device or combination product with device, return of device 
or combination product with device to manufacturer for investigation, including any device or 
combination product with device decontamination procedures necessary) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Was the subject withdrawn from the study as a result of this deficiency/incident? 
  Yes 
  No 
  Not Applicable 
Is there a reasonable possibility that the deficiency/incident was caused by the medical device or 
combination product with device component? 
  Yes 
  No 
Is device or combination product with device component available for evaluation? 
  Yes 
  No 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
128 
 
Investigator’s signature _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
(confirming that the data on these pages are accurate and complete) 
Investigator’s name (print) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
129 
 
10.13. 
Appendix 13: Country-specific requirements 
Country-specific local requirements will be added, as and when applicable. 
 
 
 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
130 
 
10.14. 
Appendix 14: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 01: 08-OCT-2020 
This amendment was considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for Amendment 01: The primary driver for the protocol amendment 
was to simply further clarify some points in the protocol that were raised as questions 
when translating into different languages. There was an attempt to clarify the study visit 
schedule, the exclusion criteria, the expected standard of care (SoC) and the concomitant 
medications permitted during the study. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of Activities 
Addition of ‘Study Day’ 
along with visit number and 
week number 
To completely clarify the visit 
windows and in what days study 
visits can occur 
Section 1.3 Schedule 
of Activities and 
Section 8.5 
Clarification to a footnote 
on collection of PK samples 
To clarify that PK samples are to be 
collected pre-dose only at Visit 3 and 
Visit 9 
Section 1.3 Schedule 
of Activities 
Addition of ACQ-5 should 
only be performed in 
Asthmatic participants. 
Order of questionnaires will 
be detailed in the Study 
Reference Manual 
To clarify that ACQ5 is only to be 
performed in Asthmatic participants 
and that the order of assessments of 
questionnaires will be detailed in the 
SRM 
Section 5.2.1 
Exclusion Criterion 5 
Replacement of wording 
regarding ‘occlusion of one 
nostril’ by referring to any 
severe nasal septal 
deviation preventing full 
assessment of nasal polyps 
in both nostrils 
To clarify the anatomy leading to 
participant being ineligible for 
randomisation and highlight the fact 
that the important thing is the 
inability to perform the assessment of 
nasal polyps 
Section 5.3 
Randomisation 
Criteria 
Deletion of corticosteroids 
as SoC criteria from 
treatment group 
descriptions 
To clarify that there is no requirement 
for corticosteroids to be part of SoC. 
Some of the participants will be on 
INCS but others will not 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
131 
 
Section 5.3 
Randomisation 
Criteria 
Addition to randomisation 
criterion number 2: 
‘Participant must meet CT 
shadow: ethmoid  
maxillary’ if not presenting 
co-morbidities 
To highlight the importance of the 
required combination of factors to 
classify eosinophilic chronic 
rhinosinusitis (ECRS) as moderate 
Section 6.2 Self-
Administration for 
Japanese Cohort 
Deletion of ‘the first dose 
of’ from wording 
explaining when the first 
self-administration can 
occur 
To clarify that the first self-
administration can only occur from 
Visit 11 onwards, after training has 
been completed at least twice 
between Visit 5 and Visit 10 
Section 8.1.4 Critical 
Procedures 
Performed at the First 
Treatment Visit 
(Baseline Visit 2) 
Deletion of laboratory test 
text: Blood for PK 
assessment (Japan and 
China only) 
To clarify that this test will be 
conducted at Visit 3 as per Section 
8.5 Pharmacokinetics 
Section 8.2.2 
Computed 
Tomography (CT) 
Scan 
Deletion of wording: 
‘whenever possible a cone 
beam CT scan should be 
utilised’ 
To avoid confusion about what to do 
if not possible and to allow flexibility 
Section 10.10 
Appendix 10 
Correction to the ‘total’ row 
of the Lund-Mackay CT 
score table 
The total score row was incorrect and 
has now been corrected 
 
Amendment 02: 29-JUN-2021 
This amendment is considered non-substantial because it neither significantly impacts the 
safety or physical/mental integrity of participants nor the scientific value of the study.  
Overall Rationale for the Amendment: The primary reason for this amendment is to 
clarify a relevant exception to exclusion criterion #9, namely that nasal biopsies for 
diagnostic purposes conducted prior to pre-screening (Visit 0) are not to be considered 
nasal surgery.  
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 – 
Synopsis (Overall 
Design) and 
Section 4.1 – 
Overall Design 
Specification that Standard 
of Care (SoC) applies to 
52-week treatment period. 
To clarify that SoC, which may 
include short courses of systemic 
corticosteroids, applies to 
52-week treatment phase and not 
to run-in period. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
132 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 – 
Synopsis (Overall 
Design) 
First occurrence of acronym 
LTRA expanded and 
acronym used where 
applicable. 
To clarify meaning of LTRA 
acronym and to apply it 
consistently throughout protocol. 
Section 1.1 – 
Synopsis 
(Intervention 
Groups and 
Duration) and 
Section 6.9 – 
Concomitant 
Therapy 
Specification of when 
rescue medications can be 
used (e.g., short courses of 
systemic corticosteroids).  
To clarify the allowance of rescue 
medications (e.g., short courses of 
systemic corticosteroids) during 
the 52-week treatment phase but 
not during the run-in period of the 
study. 
Section 1.3 – 
Schedule of 
Activities (SoA)  
Footer 11 has been 
reworded to clarify 
endoscopic NP scoring on 
V2. 
To ensure that the baseline 
endoscopy performed at V2 is 
conducted after completion of all 
screening procedures. 
Section 5.1 – 
Inclusion Criteria 
For inclusion criterion #1 
(age), the term ‘inclusive’ 
was removed. 
Term ‘inclusive’ is not applicable 
since no defined age range stated. 
Section 5.2 – 
Exclusion Criteria 
For exclusion criterion #9, 
text was added to clarify 
that nasal biopsies for 
diagnostic purposes 
conducted prior to 
pre-screening (Visit 0) are 
not to be considered nasal 
surgery.  
Relevant symptoms and signs 
resulting from a minor surgery 
(such as a nasal biopsy for 
diagnostic purposes) conducted 
prior to Visit 0 are expected to 
have resolved by randomization 
on Visit 2 (Study Day 1). 
Section 5.2 – 
Exclusion Criteria 
For exclusion criterion #18, 
‘corticosteroid nasal 
solution’ was removed. 
Corticosteroid nasal solution is 
not a systemic corticosteroid. 
Section 6.9 – 
Concomitant 
Therapy 
Inclusion of wording 
pertaining to COVID-19 
vaccines. 
To clarify the permissibility for 
subjects to be vaccinated with 
authorized or approved 
COVID-19 vaccines. 
Section 7.1.5 – 
Liver Chemistry 
Stopping Criteria 
Language regarding actions, 
monitoring, and follow-up 
assessments, and 
Algorithms A and B 
To align with current liver safety 
practices.  


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
133 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
and Appendix 7 – 
Liver Safety 
updated albeit 
discontinuation thresholds 
remain unchanged. 
Section 7.2.2- 
Early Withdrawal 
Visit 
Second last bullet 
(‘Collection of eDiary’) 
removed from list of 
procedures. 
Collection of electronic diary 
already listed (6th bullet from top). 
 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
134 
 
11. 
REFERENCES 
Alobid I, Benítez P, Bernal-Sprekelsen M, et al. Nasal polyposis and its impact on quality 
of life: comparison between the effects of medical and surgical treatments. Allergy. 2005 
Apr; 60 (4): 452-8. 
Alobid I, Mullol J.  Role of medical therapy in the management of nasal polyps.  Curr 
Allergy Asthma Rep. 2012; 12 (2): 144-153. 
Bachert C, Wagenmann M, Hauser U, et al. IL-5 is upregulated in human nasal polyp 
tissue. J Allergy Clin Immunol 1997; 99:837-842. 
Bachert C, Wagenmann M, Rudack C, et al. The role of cytokines in infectious sinusitis 
and nasal polyposis. Allergy 1998; 53: 2-13. 
Bhattacharyya N. Ambulatory sinus and nasal surgery in the United States: demographics 
and perioperative outcomes. Laryngoscope. 2010; 120 (3): 635-8. 
Bhattacharyya N. Clinical outcomes after revision endoscopic sinus surgery. Archives of 
otolaryngology--head & neck surgery. 2004; 130 (8): 975-8. 
Bhattacharyya N. Test-retest reliability of computed tomography in the assessment of 
chronic rhinosinusitis. Laryngoscope. 1999; 109: 1055-8. 
Brescia G, Marioni G, Franchella S, et al.  Can a panel of clinical, laboratory, and 
pathological variables pinpoint patients with sinonasal polyposis at higher risk of 
recurrence after surgery? Am J Otolaryngol. 2015; 36(4): 554-558. 
Bretz F, Maurer W, Brannath W, et al. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009; 28: 586-604. 
Browne JP, Hopkins C, Slack R, et al. Health-related quality of life after polypectomy 
with and without additional surgery. Laryngoscope 2006; 116: 297-302. 
Buckland JR, Thomas S, Harries PG. Can the sinonasal outcome test (SNOT-22) be used 
as a reliable outcome measure for successful septal surgery? Clin Otolaryngol. 2003; 28: 
43-7. 
Chen H, Blanc PD, Hayden ML, et al. TENOR Study Group. Assessing productivity loss 
and activity impairment in severe or difficult-to-treat asthma. Value Health. 2008; 11: 
231–239. 
Chu CT, Lebowitz RA, Jacobs JB. An analysis of sites of disease in revision endoscopic 
sinus surgery. American journal of rhinology. 1997; 11 (4): 287-91. 
Cook AJ, Roberts DA, Henderson MD, et al. Electronic pain questionnaires: a 
randomized, crossover comparison with paper questionnaires for chronic pain 
assessment. Pain. 2004 Jul; 110(1-2):310-7. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
135 
 
FDA, Draft Guidance for Industry, Chronic Rhinosinusitis with Nasal Polyps: 
Developing Drugs for Treatment. Date December 2021. https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/chronic-rhinosinusitis-nasal-polyps-
developing-drugs-treatment. Last accessed 28 June 2022 
Fokkens WJ, Lund VJ, Mullol J, et al. European Position Paper on Rhinosinusitis and 
Nasal Polyps (EPOS) 2020.  Rhinol Suppl. 2012 (23):1-298. 
GSK Document Number CM2003/00010/10, Investigator Brochure (IB) Date 03 DEC 
2015. 
GSK Document Number 2015N238436_00, A population PK and PKPD meta-analysis 
of combined intravenous and subcutaneous mepolizumab data. Date 27 MAY 2015. 
Hollen PJ, Gralla RJ, Stewart JA, et al. Can a computerized format replace a paper form 
in PRO and HRQL evaluation? Psychometric testing of the computer-assisted LCSS 
instrument (eLCSS-QL). Support Care Cancer. 2013 Jan;21(1):165-72. 
Hopkins C, Gillett S, Slack R, et al. Psychometric validity of the 22 item Sinonasal 
Outcome Test. Clin Otolaryngol. 2009; 34:447-54. 
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Adduct in 
Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 
2009; 37:1779-1784. 
Jamison RN, Gracely RH, Raymond SA, et al. Comparative study of electronic vs. paper 
VAS ratings: a randomized, crossover trial using healthy volunteers. Pain. 2002 Sep; 
99(1-2):341-7. 
Jankowski R, Pirgret D, Decroocq F, et al. Comparison of radical (nasalization) and 
functional ethmoidectomy in patients with severe nasal polyposis. A retrospective study. 
Rev Laryngol Otol Rhinol (Bord) 2006; 127:131-140. 
Jones NS. Current concepts in the management of paediatric rhinosinusitis. J Laryngol 
Otol. 1999; 113(1):1-9. 
Juniper EF, O'Byrne PM, Guyatt GH, et al. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J 1999; 14: 902–907. 
Juniper EF1, Svensson K, Mörk AC, et al. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. 2005 May; 
99(5): 553-8. 
Khan A, et al. The GALEN rhinosinusitis cohort: chronic rhinosinusitis with nasal polyps 
affects health-related quality of life. Rhinology 2019; 57: 343-351. 
Kim S, Marigowda G, Oren E, et al. Mepolizumab as a steroid sparing treatment option 
in patients with Churg-Strauss Syndrome. J Allergy Clin Immunol 2010; 125:1336-43. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
136 
 
Kobayashi Y, Yasuba H, Asako M, et al. HFA-BDP Metered-Dose Inhaler Exhaled 
Through the Nose Improves Eosinophilic Chronic Rhinosinusitis With Bronchial 
Asthma: A Blinded, Placebo-Controlled Study. Front Immunol. 2018; 9: 2192. Published 
2018 Sep 25. doi:10.3389/fimmu.2018.02192. 
Larsen K, Toss M. A long-term follow-up study of nasal polyp patients after simple 
polypectomies. Eur Arch Otorhinolaryngol 1997; 245:85-88. 
Le Gal F, Gordien E, Affolabi D, et al.  Quantification of Hepatitis Delta Virus RNA in 
Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological 
Response to Interferon Therapy in Chronically Infected Patients.  J Clin Microbiol. 
2005;43(5):2363–2369. 
Levine HL. Functional endoscopic sinus surgery: evaluation surgery and follow-up of 
250 patients. The Laryngoscope 1990; 100:79-84. 
Lim M, Lew-Gor S, Darby Y, et al. The relationship between subjective assessment 
instruments in chronic rhinosinusitis. Rhinology. 2007 Jun;45(2):144-7. 
Lund VJ, Mackay IS. Staging in rhinosinusitis. Rhinology. 1993;31(4):183-184. 
Moosig F, Gross WL, Herrmann K, et al.  Targeting interleukin-5 in refractory and 
relapsing Churg-Strauss Syndrome.  Ann Int Med 2011; 155:341-343. 
Morley AD, Sharp HR. A review of sinonasal outcome scoring systems - Which is best? 
Clinical Otolaryngology 2006; 31:103-9. 
Newton JR, Ah-See KW.  A review of nasal polyposis. Ther Clin Risk Manag. 
2008;4(2):507-512. 
Pearce DJ, Singh S, Balkrishnan R, et al. The negative impact of psoriasis on the 
workplace. J Dermatolog Treat. 2006;17:24–28. 
Philpott C, Hopkins C, Erskine S, et al. The burden of revision sinonasal surgery in the 
UK —data from the Chronic Rhinosinusitis Epidemiology Study (CRES): a 
crosssectional study. BMJ Open 2015;5:e006680. doi:10.1136/bmjopen-2014-006680. 
Radenne F, Lamblin C, Vandezande LM, et al. Quality of life in nasal polyposis. J 
Allergy Clin Immunol 1999;104: 79–84. 
Reilly Associates Health Outcomes Research, 2002. http://www.reillyassociates.net. Last 
accessed: 05 October 2020. 
Reilly MC, Bracco A, Ricci J, et al. The validity and accuracy of the Work Productivity 
and Activity Impairment questionnaire - Irritable bowel syndrome version (WPAI:IBS) 
Alimentary Pharmacology and Therapeutics. 2004; 20: 459–467. 


TMF-14790303 
CONFIDENTIAL 
 
 
209692 
137 
 
Reilly MC, Gerlier L, Brabant Y, et al. Validity, reliability, and responsiveness of the 
work productivity and activity impairment questionnaire in Crohn's disease. Clin Ther. 
2008; 30: 393–404. 
Reilly MC, Gooch KL, Wong RL, et al. Validity, reliability and responsiveness of the 
Work Productivity and Activity Impairment Questionnaire in ankylosing spondylitis. 
Rheumatology (Oxford) 2010; 49: 812–819. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics. 1993; 4: 353–365. 
Reips UD, Funke F. Interval-level measurement with visual analogue scales in Internet-
based research: VAS Generator. Behav Res Methods. 2008 Aug; 40 (3): 699-704. 
Revicki DA, Willian MK, Menter A, et al. Impact of adalimumab treatment on patient-
reported outcomes: results from a Phase III clinical trial in patients with moderate to 
severe plaque psoriasis. J Dermatolog Treat. 2007; 18: 341–350. 
Rothenberg ME, Klion AD, Roufosse FE, et al Treatment of patients with 
hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008; 358: 1215-1228. 
Rucci L, Bocciolini C, Casucci A. Nasal polyposis: microsurgical ethmoidectomy and 
interruption of autonomic innervation vs conventional surgery. ACTA Otorhinolaryngol 
Ital 2003; 23: 26-32. 
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. 
Tokunaga T, Sakashita M, Haruna T, et al. Novel scoring system and algorithm for 
classifying chronic rhinosinusitis: the JESREC Study. Allergy. 2015; 70: 995-1003. 
Wang PC, Tai CJ, Lin MS, et al. Quality of life in Taiwanese adults with chronic rhino-
sinusitis. Qual Life Res 2003; 12: 443–448. 
Wang W, Gao Y, Zhu Z, et al. Changes in the clinical and histological characteristics of 
Chinese chronic rhinosinusitis with nasal polyps over 11 years. Int Forum Allergy 
Rhinol. 2019; 9 (2): 149-157. 
Ware JE, Konsinski M, Keller SD. SF-36 physical and mental health summary scales: a 
user's manual. Boston, Massachusetts: The Health Institute New England Medical Center, 
1994. 
Wynn R, Har-El G. Recurrence rates after endoscopic sinus surgery for massive sinus 
polyposis. Laryngoscope 2004; 114: 811-813. 


Signature Page for  209692 TMF-14790303 v1.0
Signature Page for TMF-14790303 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 21-Jul-2022 09:21:00 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan Amendment 1
Study ID:  209692
Official Title of Study: A randomised, double-blind, placebo controlled, parallel 
group Phase III study to assess the clinical efficacy and safety of 100 mg SC 
Mepolizumab in adults with chronic rhinosinusitis with nasal polyps (CRSwNP) / 
eosinophilic chronic rhinosinusitis (ECRS)
Date of Document: 31-MAR-2023


CONFIDENTIAL 
 
Page 1 of 54 
 
Title Page 
Protocol Title: A randomised, double-blind, placebo controlled, parallel group Phase III 
study to assess the clinical efficacy and safety of 100 mg SC Mepolizumab in adults with 
chronic rhinosinusitis with nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis 
(ECRS) 
Study Number: 209692 
Compound Number: SB240563 
Abbreviated Title: Efficacy and safety of mepolizumab in adults with CRSwNP / ECRS 
Acronym: MERIT: Mepolizumab in Eosinophilic chronic RhinosinusITis study 
Sponsor Name:  
GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
ClinicalTrials.gov 
NCT04607005 
 
SAP Amendment Number: 1 
Copyright 2023 the GSK group of companies. All rights reserved. Unauthorised copying 
or use of this information is prohibited. 
 
 
Information Type 
: Statistical Analysis Plan (SAP) 


CONFIDENTIAL 
 
Page 2 of 54 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 6 
1.1.1. 
Objectives and Endpoints .............................................................. 6 
1.1.2. 
Estimands .................................................................................... 11 
1.2. 
Study Design .............................................................................................. 12 
2. 
STATISTICAL HYPOTHESES ............................................................................... 14 
2.1. 
Multiplicity Adjustment ................................................................................ 14 
3. 
ANALYSIS SETS ................................................................................................... 17 
4. 
STATISTICAL ANALYSES ..................................................................................... 18 
4.1. 
General Considerations .............................................................................. 18 
4.1.1. 
General Methodology .................................................................. 18 
4.1.2. 
Baseline Definition ....................................................................... 18 
4.1.3. 
Multicentre Studies ...................................................................... 18 
4.2. 
Co-primary Endpoints Analyses .................................................................. 19 
4.2.1. 
Definition of Endpoint(s) ............................................................... 19 
4.2.2. 
Main Analytical Approach ............................................................ 20 
4.2.3. 
Sensitivity Analyses ..................................................................... 21 
4.2.4. 
Supplementary Estimands ........................................................... 22 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 24 
4.3.1. 
Definition of Endpoint(s) ............................................................... 24 
4.3.2. 
Main Analytical Approach ............................................................ 25 
4.5. 
Safety Analyses .......................................................................................... 37 
4.5.1. 
Extent of Exposure ...................................................................... 37 
4.5.2. 
Adverse Events............................................................................ 38 
4.5.3. 
Additional Safety Assessments .................................................... 40 
4.6. 
Immunogenicity........................................................................................... 42 
4.7. 
Pharmacodynamic Analyses ....................................................................... 44 
4.7.1. 
Definition of Endpoint(s) ............................................................... 44 
4.7.2. 
Main Analytical Approach ............................................................ 44 
4.8. 
Population Pharmacokinetic (PopPK) Analyses .......................................... 45 
4.8.1. 
Definition of Endpoint(s) ............................................................... 45 
CCI


CONFIDENTIAL 
 
Page 3 of 54 
 
4.8.2. 
Main Analytical Approach ............................................................ 45 
4.8.3. 
Supplementary Analyses ............................................................. 46 
4.9. 
Population Pharmacokinetic/Pharmacodynamic (PopPKPD) 
Analyses ..................................................................................................... 47 
4.9.1. 
Definition of Endpoint(s) ............................................................... 47 
4.9.2. 
Main Analytical Approach ............................................................ 47 
4.10. 
Genetics Analysis ....................................................................................... 47 
4.12. 
Interim Analyses ......................................................................................... 48 
4.13. 
Changes to Protocol Defined Analyses ....................................................... 49 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 50 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 51 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 51 
6.1.1. 
List of Abbreviations .................................................................... 51 
6.1.2. 
Trademarks ................................................................................. 52 
7. 
REFERENCES ....................................................................................................... 53 
 
CCI


CONFIDENTIAL 
 
Page 4 of 54 
 
Version history 
Table 1 
SAP Version History Summary 
SAP 
Version 
Document Date 
Protocol 
Version 
(Date) on 
which SAP 
is based 
Change 
Rationale 
SAP 
03-FEB-2021 
Protocol 
Amendment 
1 
(08-OCT-
2020) 
Not Applicable 
Original version 
SAP 
Amendment 
1 
31 Mar 2023 
Protocol 
Amendment 
3 
(21-JUL-
2022) 
SAP document 
updated to 
change the 
primary 
analysis 
method to be a 
difference in 
means and 
clarify further 
intercurrent 
events 
 
 
 
 
 
 
 
 
 
 
 
Analysis of 
Time to ‘Need 
for Surgery’ 
changed to 
‘Need for 
Surgery’ at 
Week 52. 
 
Other 
administrative 
Protocol 
Amendment 3 
included a change 
in approach to 
analysis for 
primary and 
secondary 
endpoint requiring 
amendment to 
SAP.. Protocol 
Amendment 3  
included newly 
defined 
Intercurrent event 
of 2 or more 
missed consecutive 
doses and clarified 
COVID-19 related 
intercurrent events  
requiring update to 
SAP. 
 
Participants enter 
the trial with 
severe NP 
symptoms. 
 
 
 
 
 
 


CONFIDENTIAL 
 
Page 5 of 54 
 
SAP 
Version 
Document Date 
Protocol 
Version 
(Date) on 
which SAP 
is based 
Change 
Rationale 
updates have 
also been made 
within this 
Amendment, 
including: 
- Change of 
reference from 
PSAP 
 
 
 
 
 
 
- COVID-19 
SMQ has been 
removed 
 
 
 
 
 
 
- Detail of all 
Adverse Events of 
Special Interest 
(AESI) and lab 
ranges of Potential 
Clinical 
Importance (PCI) 
are now detailed in 
the OPS. 
- COVID-19 SMQ 
is not required 
within the 
reporting of the 
study. 
 


CONFIDENTIAL 
 
Page 6 of 54 
 
1. 
INTRODUCTION 
The aim of Study 209692 is to assess the efficacy and safety of mepolizumab on top of 
standard of care (SoC) therapy in the treatment of chronic rhinosinusitis with nasal 
polyps (CRSwNP) / eosinophilic chronic rhinosinusitis (ECRS) for the purpose of 
registration in Japan and China. 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report (CSR) for Study 209692. Details of the planned final analyses are provided. 
Descriptive study population analyses such as summary of demography and baseline 
characteristics and additional detail with regards to data handling conventions and the 
specification of data displays will be provided in the Output and Programming 
Specification (OPS) document. 
1.1. 
Objectives, Estimands and Endpoints 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To evaluate the efficacy 
of mepolizumab 100mg 
SC compared to placebo 
at Week 52 in patients 
with a diagnosis of 
CRSwNP / ECRS 
The primary estimands are defined as follows: 
 
Treatment Comparison:  
Mepolizumab 100 mg SC compared to placebo 
 
Population: entire trial population of patients with 
a diagnosis of CRSwNP / ECRS randomised and 
receiving study treatment 
 
Co-primary variables:  
a) Change from baseline in total endoscopic NP score 
at Week 52 
b) Change from baseline in mean nasal obstruction 
VAS score during the 4 weeks prior to Week 52 
 
Summary measure: Difference in mean scores 
between mepolizumab and placebo 
 
Main Intercurrent events (ICE) anticipated: 
a) Premature discontinuation of study treatment 
unrelated to the COVID-19 pandemic – to be 
handled using a treatment policy strategy 
b) Changes in background medication or start of a 
prohibited medication unrelated to the COVID-19 
pandemic (e.g. start INCS therapy where absent at 


CONFIDENTIAL 
 
Page 7 of 54 
 
Objectives 
Endpoints 
baseline) – to be handled using a treatment policy 
strategy 
c) Premature discontinuation of study treatment, 
change in background medication or start of 
prohibited medication related to the COVID-19 
pandemic – to be handled using a hypothetical 
strategy 
d) Surgery, which includes any procedure involving 
instruments resulting in incision and removal of 
tissue from the nasal cavity (e.g. 
polypectomy/functional endoscopic sinus surgery 
[FESS]) – to be handled using a composite strategy 
by incorporating occurrence of the event into the 
definition of the endpoint. Specifically, participants 
who undergo surgery will be assigned the worst 
possible score for the endpoint from the day after 
surgery onwards for inclusion in the analysis 
e) Course of systemic CS for CRSwNP / ECRS – to be 
handled using a treatment policy strategy 
f) Interruption to investigational product of 2 or more 
consecutive doses – to be handled using a treatment 
policy 
Secondary 
• To evaluate the impact 
on quality of life of 
100mg mepolizumab 
compared to placebo at 
Week 52 in patients with 
a diagnosis of CRSwNP 
/ ECRS 
• Change from baseline in Sino-Nasal Outcomes 
Test-22 (SNOT-22) total score at Week 52 
• To evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo at 
Week 52 in terms of 
mean overall VAS 
symptom score, mean 
composite VAS score, 
Lund Mackay CT score, 
mean individual VAS 
symptom score for loss 
of smell and impact on 
time to first nasal 
surgery or course of 
systemic CS in patients 
• Change from baseline in mean overall VAS 
symptom score during the 4 weeks prior to Week 52 
• Change from baseline in the mean composite VAS 
score (combining VAS scores for nasal obstruction, 
nasal discharge, mucus in the throat and loss of 
smell) during the 4 weeks prior to Week 52 
• Change from baseline in Lund Mackay CT score at 
Week 52 
• Change from baseline in mean individual VAS 
symptom score for loss of smell during the 4 weeks 
prior to Week 52 
• Time to first nasal surgery or course of systemic CS 
for CRSwNP / ECRS up to Week 52 


CONFIDENTIAL 
 
Page 8 of 54 
 
Objectives 
Endpoints 
with a diagnosis of 
CRSwNP / ECRS 
Other 
CCI


CONFIDENTIAL 
 
Page 9 of 54 
 
Objectives 
Endpoints 
CCI


CONFIDENTIAL 
 
Page 10 of 54 
 
Objectives 
Endpoints 
Safety 
 
 
• To evaluate the safety 
and immunogenicity of 
100mg mepolizumab 
compared placebo in 
patients with a diagnosis 
of CRSwNP / ECRS 
• Frequency of Adverse events (AEs)/ Serious 
adverse events (SAEs) including systemic reactions 
and local injection site reactions reported 
• Vital signs (pulse rate, systolic and diastolic blood 
pressure) 
• Haematological and clinical chemistry parameters 
• 12 lead ECG derived endpoints 
• Presence of anti-mepolizumab antibodies and 
neutralising antibodies 
Pharmacokinetics and pharmacodynamics 
• To evaluate the 
pharmacokinetics and 
pharmacodynamics of 
100mg mepolizumab in 
a subgroup of 
participants from Japan 
and China with a 
diagnosis of CRSwNP / 
ECRS 
• Plasma concentration of mepolizumab  
• PK/PD (blood eosinophil count) analysis 
CCI


CONFIDENTIAL 
 
Page 11 of 54 
 
1.1.2. 
Estimands 
The primary estimands are the difference between mepolizumab 100mg SC and placebo 
in a) mean change from baseline in total endoscopic NP score to Week 52 and b) mean 
change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to 
Week 52 in participants with a diagnosis of CRSwNP / ECRS, regardless of IP 
discontinuation or changes in background medication/starting a prohibited medication 
unrelated to the COVID-19 pandemic,  use of systemic CS for CRSwNP / ECRS or 
interruption of 2 or more consecutive doses of IP, with participants experiencing surgery 
being assigned the worst possible score from the day after surgery onwards. 
Secondary estimands for SNOT-22, VAS scores and Lund Mackay CT score will use the 
same population, summary measure and strategies for intercurrent events as for the 
primary estimands. Time to first nasal surgery or course of systemic CS for CRSwNP / 
ECRS up to Week 52 will be summarised by the hazard ratio between mepolizumab and 
placebo. The same population and strategies for intercurrent events of treatment 
discontinuation, changes in background medication/starting a prohibited medication, 
interruptions of 2 or more consecutive doses of IP and COVID-19 pandemic related 
intercurrent events will be used as for the primary estimands. Surgery or a course of 
systemic CS for CRSwNP / ECRS will both be considered events within the analysis of 
this endpoint and therefore neither will be considered an intercurrent event. 
Supplementary estimands for the two co-primary endpoints will use the same population 
and strategies for intercurrent events of treatment discontinuation, changes in background 
medication/starting a prohibited medication, interruptions of 2 or more consecutive doses 
of IP and COVID-19 pandemic related intercurrent events as for the primary estimand. 
Within the first supplementary estimand participants experiencing surgery or receiving a 
course of systemic CS for CRSwNP / ECRS will be assigned the worst possible score. 
Within the second supplementary estimand participants experiencing surgery will be 
assigned the participant’s own worst observed score prior to the surgery event, the 
intercurrent event of course of systemic CS for CRSwNP / ECRS will be handled using a 
treatment policy strategy as in the primary estimand. 
 


CONFIDENTIAL 
 
Page 12 of 54 
 
1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• This is a randomised, double-blind, placebo-controlled, parallel group, 
multicentre Phase III study designed to assess the clinical efficacy and safety 
of 100 mg SC Mepolizumab treatment in adults with CRSwNP / ECRS. 
• The study will include a 4-week run-in period followed by randomisation to a 
52-week treatment period as a double-blind, placebo-controlled phase. 
Throughout the entire study period (run-in + treatment period), participants will 
be on the SoC for CRSwNP / ECRS. 
• A participant is considered to have completed study treatment if he/she 
receives study treatment at Week 48 (Visit 14).  
• A participant is considered to have completed the study if he/she has 
completed all phases of the study including the last visit (Visit 15 / Week 52). 
• Initiation or changes in the background SoC dosing regimen are not permitted 
from screening to end of the study. Participants are expected, if possible, to 
continue with these treatments with no interruption nor alteration throughout 
the study duration. 
• A participant may discontinue from study treatment at any time at his/her own 
request, or at the discretion of the investigator. Participants who discontinue 
from study treatment prematurely (for any reason) should, where possible, 
continue to be followed-up as per protocol until the completion of the Week 52 
Visit assessments. 
• Participants that discontinue from study treatment should return to clinic 4 
weeks after the last dose for an Investigational Product (IP) Discontinuation 
Visit. Participants that withdraw from the study should return to clinic 4 weeks 
after the previous visit for an Early Withdrawal Visit. 
• Participants are permitted nasal surgery during the study without 
discontinuation from study treatment. The participant’s nasal polyps surgical 
status will be tracked for the duration of the study. Following discontinuation of 
study treatment, as a minimum, participants will be contacted by telephone to 
enquire regarding any safety assessments and any nasal polyps surgery 
events (received a nasal polyps surgical procedure or entry into a waiting list 
for nasal polyps surgery). 
• For the purpose of this study, nasal polyps surgery is defined as any procedure 
involving instruments with resulting incision (cutting open) and removal of the 
polyp tissue from the nasal cavity (polypectomy / functional endoscopic sinus 
surgery [FESS]). Any procedure involving instrumentation in the nasal cavity 
resulting in dilatation of the nasal passage such as balloon sinuplasty, insertion 


CONFIDENTIAL 
Page 13 of 54 
Overview of Study Design and Key Features 
of coated stents or direct injection of steroids or other medication without any 
removal of nasal polyps tissue does not fulfil this criterion. 
Study 
Treatment 
•
The treatment period will consist of thirteen doses of mepolizumab or matched
placebo, delivered by a pre-filled safety syringe device (SSD) subcutaneous
injection every 4 weeks for 52 weeks in addition to SoC therapy. The last dose
of interventional product is to be administered at Week 48 (Visit 14).
•
For non-Japanese participants, study treatment must be administered by a
healthcare professional (HCP) until week 52 (last dose at Week 48).
•
Japanese participants who are willing can self-administer study treatment
under observation of the principal investigator or delegate from Week 32
onwards. Before allowing the self-administration, the principal investigator or
delegate must assess the participant’s knowledge/technique and document
that they are competent to undertake self-administration. All self-administered
injections will be assessed for success based on direct observation.
•
No dose modifications or dose reductions are permitted within the study
protocol.
•
Participants meeting a treatment discontinuation criteria (which include
pregnancy, liver stopping criteria or ECG stopping criteria as defined in
Protocol Section 7.1.2) must have study treatment discontinued. Restart, re-
challenge or resumption of study treatment following a stopping criteria being
met is not permitted.
Study 
Treatment 
Assignment 
•
Approximately 160 participants to be randomised in a 1:1 ratio to mepolizumab
or placebo treatment in accordance with the randomisation schedule
(approximately 80 participants per arm).
•
The randomisation schedule will be generated using the GSK validated
randomisation software RandAll NG. Eligible participants will be assigned to
study treatment randomly using RAMOS NG, an Interactive Web Response
System (IWRS).
•
The study will be randomised separately for each country and the
randomisation will be stratified by background intranasal corticosteroids (INCS)
use. Equal numbers of participants will be allocated to each treatment.
Interim 
Analysis 
•
No interim analysis of data is planned for this study.


CONFIDENTIAL 
 
Page 14 of 54 
 
2. 
STATISTICAL HYPOTHESES  
The study is designed to test the superiority of mepolizumab 100mg SC vs. placebo in 
both co-primary efficacy endpoints of total endoscopic nasal polyp score at Week 52 and 
nasal obstruction VAS score during the 4 weeks prior to Week 52. Each co-primary 
endpoint will be tested at the two-sided 5% alpha level (one-sided 2.5%) and both tests 
are required to be significant to achieve the primary objective of the study. 
2.1. 
Multiplicity Adjustment 
Multiplicity arising from the multiple secondary endpoints will be controlled using the 
closed testing procedure specified below for strong control of type I error. Hypotheses 
associated with the two primary (H1 and H2) and six secondary endpoints (H3 to H8) will 
be tested using a gatekeeping procedure based on the graphical approach to sequentially 
rejective multiple test procedures [Bretz, 2009]. The two primary hypotheses H1 and H2 
will each be tested first and will be allocated the level α, where α = 0.05 (two-sided). If 
these are both rejected at level α, the procedure then is as follows: the hypotheses Hi , i = 
3, ..., 8 are tested each at its local significance level αi . If a hypothesis Hi can be rejected, 
its level is reallocated to one of the other hypotheses according to the pre-specified rules 
represented by Figure 1. The reallocation weights are updated in the reduced graph and 
the testing step repeated for the remaining, non-rejected hypotheses with the updated 
local significance levels. This possibly leads to further rejected null hypotheses with 
associated reallocation of the local significance levels. The procedure is repeated until no 
further hypothesis can be rejected. The reallocation of the local alpha levels is fully 
determined by the initial graph (Figure 1) and the update algorithm described by [Bretz, 
2009].   


CONFIDENTIAL 
 
Page 15 of 54 
 
Figure 1 
Multiplicity Testing Strategy Across Primary and Secondary 
Endpoints 
 
Primary: 
H1: Total Endoscopic Nasal Polyps score at Week 52 
H2: Nasal Obstruction VAS score during the 4 weeks prior to Week 52 
Secondary: 
H3: Overall VAS score during the 4 weeks prior to Week 52 
H4: Lund Mackay CT score at Week 52 
H5: Composite VAS score of Nasal Symptoms during the 4 weeks prior to Week 52 
H6: SNOT-22 Total score at Week 52 
H7: Loss of smell VAS score during the 4 weeks prior to Week 52 
H8: Time to First Nasal Surgery or course of systemic CS for CRSwNP / ECRS up to Week 52 
where ε reflects an infinitesimally small value, indicating the potential for alpha to be reallocated dependent 
on the rejection of all previous tests 
For the initial graph (Figure 1) the resulting test procedure can be summarized as follows: 
If both co-primary endpoints (H1 and H2) are rejected, the first two secondary endpoints 
(Overall VAS Symptom Score [H3] and Lund Mackay CT score [H4]) will each be tested 
at a significance level of α/2 (0.025). If either endpoint is rejected at the α/2 (0.025) level, 
the α/2 (0.025) from that given endpoint will be reallocated and re-used within the 
subsequent test of the next secondary endpoint according to the pre-specified rules 
represented by Figure 1. 


CONFIDENTIAL 
 
Page 16 of 54 
 
• If the Overall VAS score endpoint (H3) endpoint is rejected at the α/2 (0.025) 
level, the Composite VAS score of Nasal Symptoms (H5) and SNOT-22 total 
score (H6) will then also be tested. Only following rejection of both endpoints (H5 
and H6) will the Loss of Smell VAS symptom endpoint (H7) be tested. 
• If able to reject the loss of smell VAS endpoint (H7), the α/2 level from this 
endpoint will be reallocated to the testing of the Lund Mackay CT score (H4), to 
allow a test at a full level of α, if not already rejected at the α/2 significance level. 
• Only following rejection of all other secondary endpoints (H3 to H7), will the final 
secondary endpoint of Time to First Nasal Surgery or course of systemic CS for 
CRSwNP / ECRS (H8) be tested. 
Lund Mackay CT score (H4) is an important endpoint in the clinical practice of Japan and 
China, however, has not been studied previously within the mepolizumab clinical 
development program. The above testing strategy demonstrates the importance of this 
endpoint, whilst permitting testing of other secondary endpoints if not initially rejected at 
a significance level of α/2. The Composite VAS of Nasal Symptoms, SNOT-22 and Loss 
of Smell VAS secondary endpoints are all correlated patient reported endpoints 
measuring improvements in symptoms; these endpoints are grouped within the above 
strategy for testing in sequence following the rejection of the of Overall VAS Score (H3) 
to increase power across these symptom endpoints. If all symptom endpoints (H3, H5, H6, 
H7) are rejected, the above strategy permits a test of the Lund Mackay CT score (H4) a 
full level of α, if not already rejected at the initial α/2 significance level. 
For secondary endpoints unadjusted p-values and p-values adjusted for multiplicity, 
based on the above hierarchy, will be presented. Adjusted p-values will be calculated 
using the gMCP package within R ™. 


CONFIDENTIAL 
 
Page 17 of 54 
 
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
All Participants 
Enrolled 
• All participants enrolled and for 
whom a record exists on the study 
database 
• Study Population 
Randomised 
• All participants who were randomly 
assigned to study treatment in the 
study 
• Any participant who receives a 
treatment randomisation number will 
be considered to have been 
randomised 
• Study Population 
Intent-to-Treat 
(ITT) 
• All randomised participants who 
receive at least 1 dose of study 
treatment 
• Participants will be analysed 
according to the treatment they are 
allocated at randomisation 
• Efficacy 
Safety 
• All randomised participants who 
receive at least 1 dose of study 
treatment 
• Participants will be analysed 
according to the treatment they 
actually received for more than 50% 
of treatment administrations 
• Safety 
Pharmacokinetic 
(PK) 
• All participants in the Safety 
analysis set who have at least 1 
non-missing PK assessment (Non-
quantifiable [NQ] values will be 
considered as non-missing values). 
• Participants will be analysed 
according to the treatment they 
actually received for more than 50% 
of treatment administrations 
• PK 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s 
(LAR's), agreement to participate in a clinical study following completion of the 
informed consent process. 


CONFIDENTIAL 
 
Page 18 of 54 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
The Intent-to-Treat (ITT) analysis set will be used for all Study Population analyses and 
Efficacy analyses, and the Safety analysis set will be used for all Safety analyses. 
In the case of wrong stratification assigned at the time of randomisation, the analyses will 
be performed based on the data collected in the eCRF, not the assigned stratum at 
randomisation. 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (SD), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
4.1.2. 
Baseline Definition 
4.1.2.1. 
Visit-Based Endpoints 
For all visit-based endpoints, including the co-primary endpoint of endoscopic NP score, 
Baseline will be defined as the latest non-missing measurement collected prior to the first 
dose of study treatment. This will generally be from the Day 1 (Visit 2) assessment but 
may be from an unscheduled assessment. Where time is collected, an assessment is valid 
for use as Baseline if the date and time is prior to or the same as the date and time of first 
dose. Where time is not collected, an assessment is valid for use as Baseline if the date of 
assessment is on or before the date of first dose. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
4.1.2.2. 
eDiary Data 
Participants will report daily on the severity of individual and overall NP symptoms using 
an eDiary; this includes information for the co-primary endpoint of mean nasal 
obstruction VAS score. The baseline value for endpoints reported in the eDiary will be 
determined as the average score from the 7 days of diary data collected prior to Day 1 
(using non-missing data recorded between Day -7 and Day -1 inclusive). Participants are 
required to have at least 4 days of non-missing diary data available within the baseline 
period (7 days prior to Day 1) to meet the necessary study randomisation criteria. 
4.1.3. 
Multicentre Studies 
In this multicentre global study, the number of enrolled participants and the number 
randomised to each treatment arm will be presented by centre and country. Separate 
subgroup analyses will be performed by country (as detailed in Section 4.11.1). 
The study will be randomised separately for each country; therefore country will be 
included as a fixed effect covariate in the analysis models for all efficacy endpoints. 
Small numbers of participants in a treatment group within a country may result in model 


CONFIDENTIAL 
 
Page 19 of 54 
 
convergence issues, in these cases further combining of countries may be considered or 
exclusion of the country covariate if required. 
4.2. 
Co-primary Endpoints Analyses 
4.2.1. 
Definition of Endpoint(s) 
The co-primary endpoints for analysis are: 
• Change from baseline in total endoscopic nasal polyp score at Week 52 (based on 
centrally read data) 
• Change from baseline in mean nasal obstruction VAS score during the 4 weeks 
prior to Week 52 
4.2.1.1. 
Total Endoscopic NP Score 
Total endoscopic nasal polyp score is collected at clinical visits. Independent reviewers, 
blinded to treatment, grade the total endoscopic nasal polyp score from image recording 
of endoscopies. The total score is reported as the sum of the right and left nostril scores 
and ranges from 0 to 8, with higher scores indicating greater disease severity. 
The primary assessment will be at Week 52. Baseline will be defined as the latest non-
missing measurement collected prior to the first dose of study treatment (Section 4.1.2.1). 
4.2.1.2. 
Mean Individual VAS Symptom Scores 
Every day each participant will be asked to indicate on a visual analogue scale (VAS) the 
severity of six nasal polyposis symptoms (one VAS for each symptom and one for 
symptoms overall) at its worst over the previous 24 hours. These VAS scores will 
include: (1) 
; (2) 
; (3) 
; (4) 
 
(5) 
 and (6) 
 VAS score. 
Participants will rate symptoms daily throughout the study on a VAS using an eDiary on 
a line with 101 individually selectable points ranging from 0 
 to 100 
 
). The final VAS scores for inclusion in summary and analysis tables will be 
derived from the electronically captured score by dividing each score by 10, and therefore 
will range from 0 to 10 (reported to 1 decimal place). 
Symptoms will be calculated as the mean of all relevant VAS score measurements during 
the 4 weeks prior to Week 52. Within the 4-week period each participant must have at 
least 4 days of non-missing diary data available within each given week (7 day) period 
for a week to be evaluable and must have at least 3 weeks of evaluable data for the 4-
week period average to be derived. The mean VAS score over the last 7 days before the 
first dose of study treatment will be used to determine the baseline value of each VAS 
score (Section 4.1.2.2). 
The individual VAS symptom score of nasal obstruction will be analysed as the co-
primary endpoint in this study. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 20 of 54 
 
4.2.2. 
Main Analytical Approach 
The treatment effect to be estimated will be the comparison of mepolizumab 100 mg SC 
+ SoC to placebo + SoC. The population of interest will be the entire trial population 
(patients meeting the study inclusion/exclusion criteria with a diagnosis of CRSwNP / 
ECRS) who are randomised and receiving study treatment (ITT analysis set). 
The summary measure of treatment effect for the primary estimand of both co-primary 
endpoints will be the difference in mean scores between mepolizumab and placebo. 
The main intercurrent events (ICEs) anticipated which may affect subsequent scores for 
the co-primary endpoints are: 
a) Premature discontinuation of study treatment  unrelated to COVID-19 pandemic– 
to be handled using a treatment policy strategy. The study will continue collecting 
data for participants who prematurely discontinue from randomised treatment. 
Off-treatment data collected for these participants following treatment 
discontinuation will be included in the analysis. 
b) Changes in background medication or to start a prohibited medication (e.g. start 
INCS therapy where absent at baseline) unrelated to the COVID-19 pandemic – to 
be handled using a treatment policy strategy. These events will be captured as a 
protocol deviations and the study will continue treatment and to collect data for 
participants following this change in background medication / starting of a 
prohibited medication. Participants will not be expected to discontinue treatment 
or withdraw from the study. 
c) Premature discontinuation of study treatment or change in background 
medications or start of prohibited medication related to the COVID-19 pandemic 
(due to quarantines, site closures or other related issues) – to be handled using a 
hypothetical strategy. Data impacted by COVID-19 pandemic related events will 
not be included in the statistical analyses and will be treated as missing data. 
d) Surgery, which includes any procedure involving instruments resulting in incision 
and removal of tissue from the nasal cavity (e.g. polypectomy/FESS) – to be 
handled using a composite strategy by incorporating occurrence of the event into 
the definition of the endpoint. Specifically, participants who undergo surgery will 
be assigned the worst possible score for inclusion in the analysis of all subsequent 
visits (or 4-week periods) following surgery. Assessments taking place on the 
same day as surgery are assumed to have been carried out before the surgery. 
e) Course of systemic CS for CRSwNP / ECRS – to be handled using a treatment 
policy strategy. Data collected following a course of systemic CS for CRSwNP / 
ECRS will be included in the analysis where systemic CS will be considered as 
SoC treatment. 
f) Interruption to investigational product of 2 or more consecutive doses – to be 
handled using a treatment policy. These events will be recorded as protocol 
deviations and participants are expected to continue investigational product per-
protocol after interruption. Data collected will be included in the analysis 
regardless of IP interruption. 
This analysis will utilise the change from baseline in each of the co-primary endpoints 
where data for participants with surgery (prior to visit) are based on the worst possible 
score from the day after surgery onwards. 


CONFIDENTIAL 
 
Page 21 of 54 
 
There are two expected sources of missing data namely, participants who withdrew early 
from study and participants who experienced an intercurrent event due to COVID-19 
pandemic related restrictions. For the primary analysis, all missing data is assumed to be 
missing at random (MAR). 
Analysis will be carried out using a mixed model repeated measures analysis with 
covariates of treatment group, baseline value, log of baseline blood eosinophil count, 
background INCS use (actual strata based on information related to INCS use recorded 
on eCRF), country and time point, plus interaction terms for time point by baseline value 
and time point by treatment group. Models will be checked for issues with convergence.  
An unstructured covariance structure for the R matrix will be used by specifying 
‘type=UN’ on the REPEATED line. The Kenward and Roger method for approximating 
the denominator degrees of freedom and correcting for bias in the estimated variance-
covariance of the fixed effects will be used. The estimated means for each treatment 
group will be calculated from the model using the observed marginal distributions of the 
sample covariates (OM option in LSMEANS statement).Model-estimates of the absolute 
mean and mean change from baseline will be presented with corresponding standard 
errors for each treatment group by visit. Estimated treatment differences (Mepolizumab - 
Placebo) with corresponding 95% CIs and p-values will also be presented. 
A cumulative distribution function (CDF) plot will also be provided for the change from 
baseline in both co-primary endpoints by treatment group: (1) endoscopic nasal polyps 
score at Week 52 and (2) mean nasal obstruction VAS score during the 4 weeks prior to 
Week 52. 
When providing descriptive summaries of the co-primary endpoint data: 
1) The diary scores for each 4-week period will be calculated as the mean of the 
scores reported between timepoints (e.g. Weeks 1-4, Weeks 5-8, Weeks 9-12, 
etc.). The 4-week period average will be derived as defined within Section 
4.2.1.2. Further details of these 4-weekly periods will be defined within the OPS. 
2) Participants with the intercurrent event of nasal surgery (as discussed above) will 
be assigned the worst possible score from the day after surgery onwards. 
 
4.2.3. 
Sensitivity Analyses  
For the primary estimand missing data for any reason is considered to be missing at 
random. A sensitivity analysis will be carried out whereby missing data due to premature 
withdrawal from the study will be imputed using off-treatment data and missing data due 
to occurrence of intercurrent events related to COVID-19 will be imputed as missing at 
random. An additional strategy will be implemented for missing data from participants 
who prematurely withdrew from the study. Off-treatment imputation assumes that future 
outcomes for those who withdraw can be predicted from a combination of participant 
characteristics, the participant’s past observations and the patterns of response of 
participants who withdrew from investigational product but continued in the trial off-
treatment. Off-treatment is defined as a visit occurring over 28 days after the last dose of 
interventional product. 


CONFIDENTIAL 
 
Page 22 of 54 
 
For intercurrent events related to the COVID-19 pandemic, missing data is assumed 
MAR and will be imputed MAR. The imputation assumes that future missing outcomes 
for those who withdraw can be predicted from a combination of participant 
characteristics, the participant’s past observations and the patterns of response of 
participants who remain in the trial without any intercurrent events related to COVID-19 
(i.e. conditional on the data observed for each participant, their unavailable data are 
randomly missing). This corresponds to a standard likelihood analysis using MMRM. 
Both imputation strategies will be implemented using multiple imputation. 
Stepwise imputation methods will be implemented where imputations for a visit are 
conditioned on data from previous visits. Missing values will be imputed sequentially at 
post-baseline visits 1,…,T. At a given visit t the imputation regression model will include 
both observed and imputed outcome values from previous visits 1,…,t-1, baseline score, 
log of baseline blood eosinophil count, background INCS use, country and treatment at 
visit t. Both observed and imputed outcome values from previous visits will be used in 
the regression model. 
The treatment covariate at visit t will be equal to the randomised treatment if the 
participant was still on-treatment or a generic ‘off-treatment’ if the participant had 
already discontinued from treatment. For participants who had already discontinued from 
the study at visit t, missing values will be imputed based on the regression model and 
assuming those observations are off-treatment. 
Analysis will be performed using mixed model repeated measures as described for the 
primary analysis. For off-treatment imputation, the results will be combined across at 
least 2000 imputations using Rubin’s rules [Rubin, 1987]. 
 
4.2.4. 
Supplementary Estimands 
4.2.4.1. 
Course of Systemic Corticosteroids for CRSwNP / ECRS Handled as 
Failure 
Supplementary estimands for the two co-primary endpoints will be performed and 
analysed as detailed within Section 4.2.2, with the summary measure of treatment effect 
as the difference in mean scores between mepolizumab and placebo. 
The main intercurrent events (ICEs) anticipated and how they are to be handled are 
identical to the co-primary estimands defined within Section 4.2.2, with the exception of: 
- 
Course of systemic CS for CRSwNP / ECRS – to be handled using a composite 
strategy by incorporating occurrence of the event into the definition of the 
endpoint. Specifically, participants who receive a course of systemic CS for 
CRSwNP / ECRS will be handled as a failure and assigned the worst possible 
score for inclusion in the analysis of all subsequent visits (or 4-week periods) 
following the initiation of a course of systemic CS. Assessments taking place on 
the same day as the initiation of a course of systemic CS are assumed to have 
been carried out before the CS medication. 


CONFIDENTIAL 
 
Page 23 of 54 
 
4.2.4.2. 
Worst Observed Score Prior to Surgery 
A second supplementary estimand for the two co-primary endpoints will be performed 
and analysed as detailed within Section 4.2.2, with the summary measure of treatment 
effect as the difference in mean scores between mepolizumab and placebo. 
The main intercurrent events (ICEs) anticipated and how they are handled are identical to 
the co-primary estimands defined within Section 4.2.2, with the exception of: 
- 
Surgery, which includes any procedure involving instruments resulting in incision 
and removal of tissue from the nasal cavity (e.g. polypectomy/FESS) – to be 
handled using a composite strategy by incorporating occurrence of the event into 
the definition of the endpoint. Specifically, participants who undergo surgery will 
be assigned the participant’s worst observed score prior to the surgery event for 
inclusion in the analysis of all subsequent visits (or 4-week periods) following 
surgery. Assessments taking place on the same day as surgery are assumed to 
have been carried out before the surgery. 


CONFIDENTIAL 
 
Page 24 of 54 
 
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Definition of Endpoint(s) 
The secondary endpoints for analysis are: 
• Change from baseline in SNOT-22 total score at Week 52 
• Change from baseline in mean overall VAS symptom score during the 4 weeks 
prior to Week 52 
• Change from baseline in mean composite VAS score (combining VAS scores for 
nasal obstruction, nasal discharge, mucus in the throat and loss of smell) during 
the 4 weeks prior to Week 52 
• Change from baseline in mean VAS for loss of smell score during the 4 weeks 
prior to Week 52 
• Change from baseline in Lund Mackay CT score at Week 52 
• Time to first nasal surgery or course of systemic CS for CRSwNP / ECRS up to 
Week 52 
4.3.1.1. 
SNOT-22 Total Score 
The 22 questions of the Sino-Nasal Outcomes Test-22 (SNOT-22) questionnaire are each 
graded on a 6-point scale ranging from 0 = ‘
’ to 5 = ‘
 
’. The scores for each of the questions are summed to derive the total score for that 
participant at that visit, which ranges from 0 to 110 with higher scores representing worse 
quality of life [Hopkins, 2009]. 
The primary assessment will be at Week 52. Baseline will be defined as the latest non-
missing measurement collected prior to the first dose of study treatment (Section 4.1.2.1). 
4.3.1.2. 
Mean Individual, Overall and Composite VAS Symptom Scores 
The collection of six nasal polyposis symptoms VAS scores (one VAS for each symptom 
and for symptoms overall) are described within Section 4.2.1.2. 
Two separate composite VAS scores will be derived using the individual symptom VAS 
scores. One composite VAS score will be derived using the individual VAS scores of 
symptoms of (1) 
, (2) 
, (3) 
 and (4) 
: 
 
Composite VAS score of Nasal Symptoms =  
 
 
 
 
Sum of the four individual symptoms VAS scores / 4 
A second composite VAS score will be derived using the individual VAS scores of 
symptoms of (1) 
, (2) 
, (3) 
, (4) 
 
 and (5) 
: 
 
Composite VAS score of Nasal Symptoms and Facial Pain =  
 
 
 
 
Sum of the five individual symptoms VAS scores / 5 
The composite VAS score of Nasal Symptoms, overall VAS symptom score and 
individual VAS symptom score of loss of smell will be analysed as secondary endpoints 
in this study. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 25 of 54 
 
4.3.1.3. 
Lund Mackay CT Score 
The Lund Mackay CT scoring system is based on localization with points given for 
degree of opacification: 0 = 
, 1 = 
, 2 =
. 
These points are then applied to the maxillary, anterior ethmoid, posterior ethmoid, 
sphenoid, frontal sinus on each side. The osteomeatal complex (OC) is graded as 0 = 
 
, or 2 = 
. This scoring system 
has been validated in several studies [Bhattacharyya, 1999; Lund, 1993]. For patients in 
whom the OC is missing (because of a previous surgery) the reader should consider the 
location of the former OC and provide a scoring (as if the OC was there). 
A CT scan should be performed anytime during the run-in, and at Week 52 and IP 
discontinuation/Early Withdrawal Visit. CT scans central reading for Lund Mackay CT 
score will be used in the statistical analysis. The primary assessment will be at Week 52. 
Baseline will be defined as the latest non-missing measurement collected prior to the first 
dose of study treatment (Section 4.1.2.1). 
4.3.1.4. 
Time to First Nasal Surgery or Course of Systemic CS for CRSwNP / 
ECRS 
Nasal polyps surgery is defined as any procedure involving instruments with resulting 
incision (cutting open) and removal of the polyp tissue from the nasal cavity 
(polypectomy/FESS). Any procedure involving instrumentation in the nasal cavity 
resulting in dilatation of the nasal passage such as balloon sinuplasty, insertion of coated 
stents or direct injection of steroids or other medication without any removal of nasal 
polyps tissue does not fulfil this surgery criterion. A clinical review will be carried out 
prior to the unblinding of treatment codes to identify all events to be considered as part of 
this evaluation. 
Courses of systemic CS for CRSwNP / ECRS will be collected as a concomitant 
medication of systemic corticosteroids (taken via the following routes: oral, intravenous 
or intramuscular) with a collected reason for concomitant medication of ‘Nasal Polyps’. 
The time to first nasal surgery or course of systemic CS for CRSwNP / ECRS will be 
determined as the number of days from the date of first dose of study medication to the 
date of first event (Nasal Surgery or Course of Systemic CS for CRSwNP / ECRS, 
whichever is sooner). For participants who complete to Week 52 without experiencing 
nasal surgery or a course of systemic CS for CRSwNP / ECRS, event times will be 
censored at the time of the Week 52 visit. If a participant withdraws from the study 
before Week 52 and before experiencing nasal surgery or having a course of systemic CS 
for CRSwNP / ECRS, the event time will be censored at the time of study withdrawal. 
4.3.2. 
Main Analytical Approach 
The following secondary endpoints will be analysed as detailed for the two co-primary 
endpoints within Section 4.2.2: 
• Change from baseline in SNOT-22 total score at Week 52 
• Change from baseline in mean overall VAS symptom score during the 4 weeks 
prior to Week 52 
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 26 of 54 
 
• Change from baseline in mean composite VAS score (combining VAS scores for 
nasal obstruction, nasal discharge, mucus in the throat and loss of smell) during 
the 4 weeks prior to Week 52 
• Change from baseline in mean VAS for loss of smell score during the 4 weeks 
prior to Week 52 
• Change from baseline in Lund Mackay CT score at Week 52 (based on ANCOVA 
analysis) 
4.3.2.1. 
Time to First Nasal Surgery or Course of Systemic CS for CRSwNP / 
ECRS 
For the endpoint of time to first nasal surgery or course of systemic CS for CRSwNP / 
ECRS up to Week 52, the treatment effect to be estimated will be the comparison of 
mepolizumab 100 mg SC + SoC to placebo + SoC. The population of interest will be the 
entire trial population (patients meeting the study inclusion/exclusion criteria with a 
diagnosis of CRSwNP / ECRS) who are randomised and receiving study treatment (ITT 
analysis set) and the summary measure of treatment effect will be the hazard ratio 
(mepolizumab / placebo). The hazard ratio represents the relative probability of nasal 
surgery or course of systemic steroids for CRSwNP / ECRS at any time during the study. 
The anticipated intercurrent events of premature discontinuation of study treatment 
unrelated to the COVID-19 pandemic, changes in background medication/starting of a 
prohibited medication unrelated to the COVID-19 pandemic or interruptions of 2 or more 
consecutive doses to investigational product will be handled using a treatment policy 
strategy, such that available event times will be included in the analysis regardless of 
whether the event (surgery or course of systemic CS for CRSwNP / ECRS) occurred 
before or after discontinuation of study treatment or changes in background 
medication/starting of a prohibited medication. Data occurring after  intercurrent events 
of premature discontinuation of study treatment or changes in background 
medication/starting of a prohibited medication related to the COVID-19 pandemic will 
not be included in the statistical analyses and each participant will be censored at the time 
of the COVID-19 pandemic related intercurrent event. If a participant withdraws from the 
study before experiencing nasal surgery or having a course of systemic CS for CRSwNP / 
ECRS, the event time will be censored at the time of study withdrawal. 
Statistical analysis will use the Cox proportional hazards model with covariates of 
treatment group, log of baseline blood eosinophil count, number of previous surgeries (0, 
1, 2, >2; ordinal), background INCS use and country. A log(-log(survival)) plot by 
treatment group will be used to assess the assumption of proportional hazards. 
The number of participants with an event, the number censored due to study withdrawal , 
due to occurrence of COVID-19 related intercurrent event, and at study completion will 
be presented by treatment arm. The hazard ratio with corresponding 95% CI and p-value 
from the Cox proportional hazards model will be presented. Additionally, a summary and 
graph of the Kaplan-Meier estimates of the cumulative proportion of participants with 
nasal surgery or a course of systemic CS for CRSwNP / ECRS within each treatment arm 
over time will be produced. 


CONFIDENTIAL 
 
Page 27 of 54 
 
CCI


CONFIDENTIAL 
 
Page 28 of 54 
 
CCI


CONFIDENTIAL 
Page 29 of 54 
 
CCI


CONFIDENTIAL 
 
Page 30 of 54 
 
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.
CCI
CCI


CONFIDENTIAL 
 
Page 31 of 54 
 
 
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.
CCI


CONFIDENTIAL 
Page 32 of 54 
 
CCI


CONFIDENTIAL 
 
Page 33 of 54 
 
CCI


CONFIDENTIAL 
Page 34 of 54 
 
CCI


CONFIDENTIAL 
 
Page 35 of 54 
 
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 36 of 54 
 
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 37 of 54 
 
4.5. 
Safety Analyses 
The safety analyses will be based on the Safety analysis set, unless otherwise specified. 
4.5.1. 
Extent of Exposure 
Study treatment is administered (subcutaneously injected) approximately every 4 weeks 
and each dose viewed as providing therapeutic coverage for 4 weeks (28 days). 
Duration of exposure is calculated based on the therapeutic coverage as follows: 
• Duration (days) =  
(Last IP Administration Date – First IP Administration Date + 29) 
• Duration (months) =  
(Last IP Administration Date – First IP Administration Date + 29)*12/365.25 
• Participant-years exposure =  
(Last IP Administration Date – First IP Administration Date + 29)/365.25 
The extent of exposure to study treatment (mepolizumab/placebo) will be reported, 
including descriptive statistics of duration of exposure in addition to the number and 
percentage of participants exposed for ≥1-<3, ≥3-<6, ≥6-<9, ≥9-<12 and ≥12 months, 
based on each participant’s duration of exposure rounded to the nearest whole month. 
The number of treatments administered and total participant-years exposure will also be 
summarised. 
4.5.1.1. 
Self-administration of Study Treatment 
A subset of Japanese participants who are willing can self-administer study treatment 
under observation of the principal investigator or delegate from Week 32 onwards.  
A self-administered injection is considered successful if the following criteria are met: 
• Use of a correct injection site (abdomen or thigh) 
• Full dose administered: participant fully inserts the needle, slowly presses the 
plunger until the stopper reaches the bottom of the syringe and activates the 
needle guard by moving the thumb up 
If the above criteria are met, the investigator will confirm the injection was successfully 
delivered. 
The number and proportion of participants with at least one successful self-administered 
injection and the number and proportion of participants with all self-administered 
injections successfully delivered will be summarised. Participants with at least one 
unsuccessful self-administered injection and reasons for the unsuccessful delivery of 
study treatment will be listed. 


CONFIDENTIAL 
 
Page 38 of 54 
 
4.5.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (MedDRA dictionary), with the maximum severity of each AE determined by the 
investigator (as mild, moderate or severe). 
An overview summary of AEs, including counts and percentages of participants with any 
AE, AEs related to study treatment, AEs leading to permanent discontinuation of study 
treatment, AEs leading to withdrawal from the study, AEs leading to dose delays, SAEs, 
SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study treatment 
will be produced.  
AEs will be considered on-treatment for at least 4 weeks (28 days) following the last dose 
of study treatment. AEs which occur more than 28 days following the last dose of study 
treatment will be considered as post-treatment. The number and percentage of 
participants experiencing at least one AE during the on-treatment and post-treatment 
periods will be summarised separately. Additionally, summaries of the number and 
percentage of participants with any on-treatment AEs by maximum severity will be 
produced. If an adverse event severity is missing, the severity is to be populated as 
‘UNKNOWN’. 
The frequency and percentage of AEs will be summarized and displayed in two ways:  
1) in descending order by SOC and PT and 2) in descending order by PT only. 
Common AEs, defined as ≥3% (prior to rounding) in any treatment group, will be 
reported. The summary table will be displayed by PT only. 
A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the possible 
relationship to study treatment as “Yes”. A worst-case scenario approach will be taken to 
handle missing relatedness data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. The summary table will be displayed 
by SOC and PT. 
All SAEs during the on-treatment and post-treatment periods will be tabulated based on 
the number and percentage of participants who experienced an event within each period. 
In addition, fatal and non-fatal SAEs will be reported separately.  
Separate summaries will also be provided for study treatment-related SAEs. A study 
treatment-related SAE is defined as an SAE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst-case scenario approach will be taken to 
handle missing data, i.e. the summary table will include events with the relationship to 
study treatment as ‘Yes’ or missing. The summary tables will be displayed by SOC and 
PT. 


CONFIDENTIAL 
 
Page 39 of 54 
 
AEs leading to discontinuation of study treatment, AEs leading to withdrawal from the 
study and AEs reported on the day of dosing with study treatment will be both 
summarised. The summary tables will be displayed by SOC and PT. 
Additional summaries of on-treatment AEs by time to onset (0-<12 weeks, 12-<24 
weeks, 24-<36 weeks, 36-<48 weeks and ≥48 weeks) and on-treatment AEs in 
participants who have at least one anti-drug antibody (ADA) positive result and those 
with all negative ADA results post-baseline will be reported. 
AEs and SAE summaries will also be presented by Background INCS use subgroup 
(defined within Section 4.11.1). 
The incidence of AEs and SAEs (Fatal and Non-Fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation, COVID-19 AEs leading to study withdrawal, and 
COVID-19 AEs by maximum severity, will be obtained from the standard AE and SAE 
summaries. 
4.5.2.1. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are adverse events which are to be closely 
monitored as the development of mepolizumab progresses. 
Systemic reactions are AESIs which are collected using targeted eCRF pages and further 
categorised by the investigator as either an allergic (type I hypersensitivity) or other 
systemic reaction. These events are required to be assessed against Sampson’s diagnostic 
criteria for anaphylaxis [Sampson, 2006]. Local injection site reactions are also collected 
using targeted eCRF pages within the study. 
AESIs of potential opportunistic infections, malignancies, serious cardiac, vascular and 
thromboembolic (CVT) events and serious ischemic events will be identified from a list 
of relevant preferred terms maintained within a project level reference dataset created 
based on the latest version of the MedDRA dictionary available at the time of source data 
lock for this study. Further details of how relevant preferred terms are identified for the 
AESIs are given in the OPS. 
Separate summary tables showing the number and percent of participants with each type 
of AESI, broken down by preferred term will be created. These summaries will be 
reported as part of the standard AE/SAE tables for the AESIs of infections, serious 
infections, neoplasms, cardiac disorders and serious cardiac disorders. The relative risk 
and risk difference of each AESI between mepolizumab and placebo will be presented 
with 95% confidence intervals. 
For each AESI a profile summary table will be produced containing information on event 
characteristics including, but not be limited to, the number of participants with the AESI, 
the number of occurrences of the AESI, the number of participants with a serious event or 
a drug related event, maximum severity, outcome and action taken. 
Separate listings will be provided of participants with systemic reactions identified by the 
investigator as meeting the criteria for anaphylaxis, systemic reactions categorised as 


CONFIDENTIAL 
 
Page 40 of 54 
 
allergic (type I hypersensitivity), systemic reactions categorised as other, and all other 
AESIs. 
Summaries of AESIs will also be presented by Background INCS use subgroup (defined 
within Section 4.11.1). 
4.5.2.2. 
Impact of COVID-19 Pandemic on Adverse Event Reporting 
The number of participants with suspected, probable or confirmed for COVID-19 
infection will be reported. This display will also summarise the number of participants 
with a COVID-19 diagnosis test performed and the number of participants with positive, 
negative, or indeterminate results. 
Additionally, a listing of COVID-19 assessments and symptoms for participants with 
COVID-19 AEs will be generated. 
4.5.2.3. 
Cardiovascular Events and Deaths (All Causes) 
Cardiovascular events and deaths (all causes) will be captured on targeted CV event 
eCRF pages for the following AEs and SAEs: 
• Arrhythmias 
• Congestive heart failure 
• Cerebrovascular events/stroke and transient ischemic attack 
• Deep venous thrombosis/pulmonary embolism 
• Myocardial infarction/unstable angina 
• Peripheral arterial thromboembolism 
• Pulmonary hypertension 
• Revascularization 
• Valvulopathy 
• Death (all causes) 
A summary table will be generated of all reported cardiovascular events and deaths (all 
causes). Separate patient profiles will also be provided of participants with each of the 
above listed events. 
4.5.3. 
Additional Safety Assessments 
4.5.3.1. 
Laboratory Data 
Summaries of laboratory data including chemistry and haematology parameters, and liver 
function test data will be based on GSK Core Data Standards and unless otherwise 
specified will include on-treatment and post-treatment data. Change from baseline values 
for clinical chemistry and haematology will be summarised in separate tables using 
descriptive statistics. 
Summaries of the number and percentage of participants with worst-case changes from 
baseline with respect to both the Normal Range (NR) and Potential Clinical Importance 
(PCI) criteria (for all lab tests where a PCI ranges are defined in the OPS) will be 
generated separately. Decreases to low, changes to normal or no changes from baseline, 


CONFIDENTIAL 
 
Page 41 of 54 
 
and increases to high will be summarized for the worst-case post-baseline. If a participant 
has a decrease to low and an increase to high during the same time interval, then the 
participant is counted in both the “Decrease to Low” categories and the “Increase to 
High” categories. Participants with a missing baseline value are assumed to have been 
normal at baseline and participants with no data for a given lab test post-baseline 
(following first dose of study treatment) will be excluded from this summary. 
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced. These summaries will also be presented by Background INCS use subgroup 
(defined within Section 4.11.1). 
Liver function laboratory tests will be included with chemistry lab tests. 
Any liver stopping or liver monitoring events which occur during the study will be 
summarised. Summaries of hepatobiliary laboratory events including possible Hy’s law 
cases will also be provided in addition to what has been described above. Possible Hy’s 
law cases are defined as any elevated alanine aminotransferase (ALT)≥3×upper limit of 
normal (ULN), total bilirubin≥2×ULN and alkaline phosphatase (ALP)<2×ULN/missing. 
Total bilirubin≥2×ULN can be within 28 days following the ALT elevation and if direct 
bilirubin is available on the same day, it must be ≥35% of total bilirubin. 
ALP<2×ULN/missing means it is satisfied unless the ALP is 2xULN at the time of 
bilirubin elevation (within 28 days following the ALT elevation). The summary will be 
produced for worst-case post-baseline only. A listing will be generated of all chemistry 
and liver function tests in participants who met the protocol defined liver stopping or 
liver monitoring criteria. 
An e-DISH plot of maximum post-baseline total bilirubin versus maximum post-baseline 
ALT will be created. 
Additionally, the worst-case urinalysis results post-baseline (including both on-treatment 
and post-treatment data) relative to baseline will be reported. The percentages are based 
on the number of participants in each treatment group with data for a given test post-
baseline. Participants with a missing baseline value are to be assumed to have a negative 
baseline value. 
4.5.3.2. 
ECG 
Summaries of ECG data will be based on GSK Core Data Standards. The number of 
abnormal and clinically significant 12-lead ECG results post-baseline will be produced 
by visit, also showing the worst recorded value post-baseline (including on-treatment and 
post-treatment data). Change from baseline values for each ECG parameter will be 
summarised using descriptive statistics. 
The QTc data analysis will use the collected QTc values based on the Fridericia formula 
(QTcF). QTcF values will be rounded to the nearest integer and values will be 
categorized into the following CTCAE grade and ranges: Grade 0 
 Grade 1 
), Grade 2 
 and Grade 3 
 Summaries of 
grade increase will be provided. These summaries will display the number and 
percentage of participants with any grade increase, increase to grade 2 and increase to 
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 42 of 54 
 
grade 3 for the worst-case post-baseline only. Missing baseline grade will be assumed as 
grade 0. Participants with QTc data post-baseline (following first dose of study treatment) 
will be excluded from this summary. 
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: >30-≤60 and >60 msec. A summary of change in QTc value 
will display the number and percentage of participants with a change within each range 
for the worst-case post-baseline only. Participants with missing baseline values or with 
no QTc data post-baseline (following first dose of study treatment) will be excluded from 
this summary. 
A listing will be generated of all ECG results in participants who met the protocol 
defined QTc stopping criteria. 
4.5.3.3. 
Vital Signs 
Summaries of vital signs data [systolic blood pressure (SBP), diastolic blood pressure 
(DBP) and heart rate] will be based on GSK Core Data Standards. Change from baseline 
values for SBP, DBP and heart rate will be summarised using descriptive statistics. 
Summaries of grade increase from baseline in SBP and DBP will be provided separately. 
These summaries will display the number and percentage of participants with any grade 
increase, increase to Grade 2 and increase to Grade 3 for worst-case post-baseline only. 
The grade definition for SBP is: Grade 0 
 Grade 1 
, Grade 2 
, Grade 3 
 The grade definition for DBP is: Grade 0 
, Grade 1 
 Grade 2 
, Grade 3 
. The summaries will be produced for worst-
case post-baseline only (including both on-treatment and post-treatment data). A missing 
baseline grade will be assumed as grade 0. Participants with no SBP or DBP data post-
baseline (following first dose of study treatment) will be excluded from this summary. 
4.6. 
Immunogenicity 
An immune response to a therapeutic drug can lead to generation of anti-drug antibodies 
within the blood. For the immunogenicity assessment, two types of antibody assays will 
be performed, a binding anti-drug antibody (ADA) assay and a neutralizing antibody 
(NAb) assay. 
For the binding ADA assay, there will be three testing steps: screening, confirmation and 
titration. The screening assay produces a result of positive or negative relative to a 
screening assay cut point. Positive samples continue with the confirmation assay, which 
also produces a result of positive or negative relative to a confirmation cut point. For 
positive confirmation samples, a titre value will also be obtained to quantify the degree of 
binding in a titration assay. Participants with a positive confirmation result will be 
positive for the binding ADA assay. Participants who test positive for the binding ADA 
assay, will be tested for the NAb assay, which also reports results as positive or negative. 
Immunogenicity data will be summarised for all participants in the Safety analysis set. 
For the binding ADA assay, confirmation results at each visit will be categorised as 
negative or positive and summarised. NAb assay results will also be summarised. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 43 of 54 
 
The highest binding ADA assay confirmatory result obtained post-baseline for a 
participant (including both on-treatment and post-treatment data), will be summarised 
with a positive result being considered higher than a negative one, participants with both 
positive and negative results will be identified in the positive category. Descriptive 
statistics for titre results will also be presented. In addition, the highest NAb assay result 
during the same period will be summarised (again with a positive result being considered 
higher than a negative one and participants with both positive and negative results will be 
identified in the positive category). 
A summary of treatment emergent positive confirmatory binding ADA assay results in 
the subset of participants who did not have a positive confirmatory binding ADA assay 
result prior to the first dose of study treatment will also be presented. 
All immunogenicity results (i.e. binding ADA screening and confirmatory assay results, 
titre values and NAb results) will be listed. 


CONFIDENTIAL 
 
Page 44 of 54 
 
4.7. 
Pharmacodynamic Analyses 
The pharmacodynamic endpoints for analysis are: 
• Absolute and ratio to baseline in blood eosinophil count at Weeks 4, 8, 24 and 52 
4.7.1. 
Definition of Endpoint(s) 
Blood eosinophil counts will be measured during the course of the study over the 52 
weeks treatment period. Blood eosinophil counts will be log-transformed before analysis. 
Zero values for the baseline blood eosinophil count as well as for blood eosinophil count 
during the study will be replaced by 0.005 GI/L prior to log transformation. 
4.7.2. 
Main Analytical Approach 
The treatment effect to be estimated will be the comparison of mepolizumab 100 mg SC 
+ SoC to placebo + SoC. The population of interest will be the entire trial population 
(patients meeting the study inclusion/exclusion criteria with a diagnosis of CRSwNP / 
ECRS) who are randomised and receiving study treatment (ITT analysis set). 
The summary measure of treatment effect will be the difference in mean scores (ratio of 
the effect) between mepolizumab and placebo at Weeks 4, 8, 24 and 52. 
Only data collected while the participant was on-treatment will be used in the analysis 
(applying a ‘while on-treatment strategy’). Blood eosinophil counts taken more than 28 
days following the last dose of study treatment will not be included in the analysis. 
Missing data will be assumed to be missing at random (MAR). 
The ratio to baseline in blood eosinophil count will be analysed using mixed models 
repeated measures adjusting for covariates of treatment group, log of baseline blood 
eosinophil count, background INCS use, country and time point, plus interaction terms 
for time point by baseline and time point by treatment group. 
An unstructured covariance structure for the R matrix will be used by specifying 
‘type=UN’ on the REPEATED line. The Kenward and Roger method for approximating 
the denominator degrees of freedom and correcting for bias in the estimated variance-
covariance of the fixed effects will be used. The estimated mean for each treatment group 
will be calculated from the model using the observed marginal distributions of the sample 
covariates (OM option in LSMEANS statement). 
Model-estimates of the absolute mean and mean ratio to baseline will be back-
transformed and presented with corresponding standard errors on the log scale for each 
treatment group by visit. Estimated treatment differences (Mepolizumab/Placebo) with 
corresponding 95% CIs and p-values will also be presented. 


CONFIDENTIAL 
 
Page 45 of 54 
 
4.8. 
Population Pharmacokinetic (PopPK) Analyses 
The primary goal of this analysis is to characterize the population pharmacokinetics of 
mepolizumab administered subcutaneously in participants with CRSwNP / ECRS. The 
analysis will be based on the most recent population pharmacokinetics model established 
with historical data from various indications. The influence of demographics, baseline 
characteristics, including disease activity, and co-medication on the pharmacokinetics of 
mepolizumab in this population will also be investigated. These data will be used to 
explore potential ethnic differences between Japanese/Chinese and Caucasians in 
mepolizumab exposure. The individual participant PK parameters will be estimated and 
documented for the purposes of any subsequent exposure-response (PK/PD) analyses. 
Mepolizumab plasma concentration-time data [samples collected at Weeks 4, 28 and 52; 
at the Early Withdrawal Visit and additional visits (if applicable)] will be analysed by 
population methods using nonlinear mixed-effects modelling. The analysis will be carried 
out using appropriate software (e.g. NONMEM ™ or SAS ™). 
In support of the analysis described below, a dataset will be generated for which 
specifications will be provided in a separate document. 
4.8.1. 
Definition of Endpoint(s) 
Blood for PK will be collected at Week 4 (pre-dose), Week 28 (pre-dose) and Week 52 
(or IP discontinuation/early withdrawal). In addition, one post-dose PK will be collected 
at Week 29 (one week after dose at Week 28). As for Week 29, a blood sample will be 
collected from up to approximately the first 30 Japanese and all Chinese participants 
randomised, no PK samples will be collected outside of Japan and China at Week 29. 
Individual PK parameters and covariates will be log-transformed and standardized before 
analysis. 
Based on previous knowledge of mepolizumab 100 mg SC pharmacokinetics, 
concentrations below the limit of quantification (BLQ) of the assay are not anticipated. 
Any such results will be treated as missing. 
4.8.2. 
Main Analytical Approach 
A population PK analysis of sparse concentration data will be performed. The population 
of interest will be the entire trial population (patients meeting the study 
inclusion/exclusion criteria with a diagnosis of CRSwNP / ECRS) who are randomised 
and receiving study treatment with at least 1 non-missing PK assessment (PK analysis 
set). 
The summary measure of interest will be the log-transformed mepolizumab plasma 
concentration. For participants prematurely discontinuing study treatment, all available 
data will be included in the analysis (intercurrent event to be handled using a treatment 
policy strategy). 
Sparse blood sampling is implemented in this study for determination of mepolizumab 
plasma concentration and subsequent data analysis by population PK methods using the 


CONFIDENTIAL 
 
Page 46 of 54 
 
most recent population pharmacokinetics model (meta-analysis PK model of data across 
indications described in GSK Document Numbers: 2015N238436_00 and 
2020N427698_00). The main objectives of this population PK analysis are: 
• To evaluate mepolizumab pharmacokinetics in participants with CRSwNP / 
ECRS following the subcutaneous administration of a 100 mg dose every 4 
weeks; 
• To investigate the impact of covariates of interest in the studied CRSwNP / ECRS 
population (such as baseline characteristics, co-medication) on specific 
parameters (e.g. clearance) to identify potential sources of inter-individual 
variability in these parameters; 
• To obtain individual plasma concentration predictions for the timepoints at which 
PD is measured to allow the conduct of population PKPD analyses if deemed 
appropriate. 
Outlier data will be assessed for plausibility; however, the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report. 
Further details of the Population PK analyses will be provided in the Output and 
Programming Specification (OPS) document. 
4.8.3. 
Supplementary Analyses 
Complementing the population-PK analysis, an additional analysis of a repeated 
measures linear mixed-effects model of log-transformed concentration will be used to 
analyse the sparse PK data. All data will be analysed on an Intent-to-Treat basis using 
planned Visit, irrespective of discontinuation of study treatment (to be handled using a 
treatment policy strategy). 
The model will adjust for covariates of country, log bodyweight, log creatinine clearance, 
log serum albumin with a repeated term for Visit. An unstructured covariance structure 
for the R matrix will be used by specifying ‘type=UN’ on the REPEATED line. The 
Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. 
Selection of covariates will be based on biological plausibility, parsimony and a 
significance level of 0.05. Forwards and backwards selection criteria may be applied as 
per the population PK model. 
The estimated means for each visit will be calculated from the model using the observed 
marginal distributions of the sample covariates (OM option in LSMEANS statement). 
Model-estimates of the absolute mean and mean ratio to Week 4 (accumulation ratio) will 
be back-transformed and presented as ratios with corresponding standard errors on the 
log scale by visit. Estimated exposure ratios with corresponding 95% CIs and p-values 
will also be presented. The effects of bodyweight, creatinine clearance and serum 
albumin will be evaluated as a ratio to standard values and back transformed and 
presented as ratios with corresponding standard errors on the log scale. Estimated 
exposure ratios with corresponding 95% CIs and p-values will also be presented. 


CONFIDENTIAL 
 
Page 47 of 54 
 
4.9. 
Population Pharmacokinetic/Pharmacodynamic (PopPKPD) 
Analyses 
If deemed appropriate, a population pharmacokinetic/pharmacodynamic analysis will be 
conducted. Mepolizumab blood eosinophil count-time data will be analysed by 
population methods using nonlinear mixed-effects modelling. The analysis will be carried 
out using appropriate software (e.g. NONMEM or SAS). 
In support of the analysis described below, a specific dataset will be generated for which 
specifications will be provided in a separate document. 
4.9.1. 
Definition of Endpoint(s) 
Blood for PK are defined within Section 4.8.1. 
Blood eosinophil counts are defined within Section 4.7.1. 
4.9.2. 
Main Analytical Approach 
The population of interest will be the PK analysis set and the ITT analysis set (for blood 
eosinophils). For participants prematurely discontinuing study treatment, all available 
data will be included in the analysis (intercurrent event to be handled using a treatment 
policy strategy). 
This PopPKPD analysis will be performed by population methods using the most recent 
population PKPD model [meta-analysis PKPD model of data across indications described 
in GSK Document Numbers: 2020N427698_00, 2015N238436_00 and 2015N255079_00 
(extension of the former report)]. 
The objectives of the popPKPD analysis are: 
• To evaluate mepolizumab pharmacodynamics in participants with CRSwNP / 
ECRS following subcutaneous administration of a 100 mg dose every 4 weeks; 
• To investigate the impact of covariates of interest in the studied CRSwNP / ECRS 
population (such as baseline characteristics, co-medication) on specific 
parameters (e.g. maximum blood eosinophil reduction) in order to identify 
potential sources of inter-individual variability in these parameters. 
Outlier data will be assessed for plausibility; however, the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report. 
Further details of the popPKPD analyses will be provided in the Output and 
Programming Specification (OPS) document. 
4.10. 
Genetics Analysis 
A separate analysis plan will be produced for any analysis of genetic data. 


CONFIDENTIAL 
 
Page 48 of 54 
 
4.12. 
Interim Analyses 
No interim analysis of data is planned for this study. 
CCI
CCI
CCI


CONFIDENTIAL 
 
Page 49 of 54 
 
4.13. 
Changes to Protocol Defined Analyses 
The changes from the originally planned statistical analysis specified in the Protocol 
Amendment 3 [GlaxoSmithKline Document Number: TMF-14790303. Dated: 21-Jul-
2022] are described in Table 3. 
Table 3 
Changes to Protocol Defined Analyses  
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
Time to first ‘need for 
surgery’ (NP score ≥5 and 
overall VAS symptom 
score >7) up to Weeks 4, 8, 
24 and 52 
Need for surgery (NP 
score ≥5 and overall 
VAS symptom score 
>7) at Week 52 
It is expected that patients will 
enter the study with a ‘need for 
surgery’ due to requirement to 
meet inclusion criteria of severe 
NP symptoms.  
Lund Mackay CT score at 
Week 52 will use the same 
population, summary 
measure and strategies for 
intercurrent events as for 
the primary estimands. 
Analysis methods will be 
the same as for the co-
primary endpoints. 
Lund Mackay CT 
score at Week 52 will 
use the same 
population, summary 
measure and 
strategies for 
intercurrent events as 
for the primary 
estimands. Analysis 
methods will based 
on ANCOVA. 
Lund Mackay CT score is 
recorded once post-baseline at 
Week 52, therefore assessment 
of change from baseline via 
ANCOVA analysis is 
appropriate. 
 


CONFIDENTIAL 
 
Page 50 of 54 
 
5. 
SAMPLE SIZE DETERMINATION 
The sample size is based on the co-primary efficacy endpoints of total endoscopic nasal 
polyp score at Week 52 and nasal obstruction VAS score during the 4 weeks prior to 
Week 52.  
The sample size of 160 participants randomised in a 1:1 ratio to each treatment arm 
provides at least 90% power to demonstrate a statistically significant result for both 
co-primary endpoints using a mixed model repeated measures (MMRM) analysis model. 
Estimates of residual standard deviation (SD) of 1.82 for total endoscopic nasal polyp 
score at Week 52 and 3.25 for nasal obstruction VAS score during the 4 weeks prior to 
Week 52 are taken from a post-hoc MMRM analysis of observed data from study 205687 
(SYNAPSE) which assumed a  “missing at random” (MAR) assumption for missing data. 
With the above assumptions and a sample size of 160 randomized subjects (80 per arm), 
it is estimated that the null hypothesis will be rejected at the two-sided 5% level of 
significance for total endoscopic nasal polyp score if the observed difference between 
treatments is at least 0.57 units and for nasal obstruction VAS score if the observed 
difference between treatments is at least 1.01. 
For total endoscopic nasal polyp score, if the true difference between treatments is 1.00 
units, then the study has a probability of 93.2% of observing a difference in total 
endoscopic nasal polyp score between treatments of at least 0.57 units and therefore 
93.2% power for declaring significance on this endpoint. The estimated improvement 
observed in total endoscopic nasal polyp score for mepolizumab 100 mg SC compared to 
placebo within study 205687 (SYNAPSE) was 0.99 units (95% CI: 0.61 to 1.36). 
For nasal obstruction VAS score, if the true difference between treatments is 2.00, then 
the study has a probability of 97.2% of observing a difference in nasal obstruction VAS 
score between treatments of at least 1.01 units and therefore a 97.2% power for declaring 
significance on this endpoint. The measured improvement observed in nasal obstruction 
VAS score for mepolizumab 100 mg SC compared to placebo within study 205687 
(SYNAPSE) was 1.97 units (95% CI: 1.31 to 2.63). 
If the true population distribution of each co-primary endpoint is as described above, a 
study with sample size of 80 randomised participants randomised in 1:1 ratio to each 
treatment arm (total 160 participants) is estimated to have at least 90% power regardless 
of the degree of (positive) correlation of the endpoints. 
Assuming a screen failure rate of 40%, approximately 270 participants will need to be 
screened to achieve approximately 160 randomly assigned to study intervention for a 
total of approximately 80 participants per intervention group. All participants within the 
Intent-to-Treat analysis set (randomised participants who receive at least 1 dose of study 
treatment) will be considered evaluable within the study analysis. See Section 4.2.2 
regarding the strategy of handling of intercurrent events for the primary estimands. 


CONFIDENTIAL 
 
Page 51 of 54 
 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AERD 
Aspirin-Exacerbated Respiratory Disease 
AESI 
Adverse events of special interest 
ACQ-5 
Asthma Control Questionnaire-5 
ADA 
Anti-drug antibody 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
BLQ 
Below the limit of quantification 
CDF 
Cumulative distribution function 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease-2019 
CRSwNP 
Chronic rhinosinusitis with nasal polyps 
CS 
Corticosteroid 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CV 
Cardiovascular 
CVT 
Cardiac, vascular and thromboembolic 
DBP 
Diastolic blood pressure 
eCRF 
Electronic Case Record Form 
ECG 
Electrocardiogram 
ECRS 
Eosinophilic chronic rhinosinusitis 
ED 
Emergency department 
eDiary 
Electronic diary 
FESS 
Functional endoscopic sinus surgery 
GSK 
GlaxoSmithKline 
HCP 
Healthcare professional 
ICE 
Intercurrent event 
IMCS 
Intramuscular corticosteroid 
INCS 
Intranasal corticosteroid 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Response System 
JESREC 
Japanese Epidemiological Survey of Refractory Eosinophilic Chronic 
Rhinosinusitis 
LAR 
Legally acceptable representative 
MAR 
Missing at random 
MCID 
Minimum clinically important difference 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MMRM 
Mixed Model Repeated Measures 
NAb 
Neutralizing antibody 
NP 
Nasal polyps 
NR 
Normal range 
NSAID 
Nonsteroidal anti-inflammatory drug 
OC 
Osteomeatal complex 
OM 
Observed margins 
OPS 
Output and Programming Specification  


CONFIDENTIAL 
 
Page 52 of 54 
 
Abbreviation 
Description 
PCI 
Potential Clinical Importance  
PCS 
Physical Component Summary 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PopPK 
Population PK 
PT 
Preferred term 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
Short Form-36 
SMQ 
Standardised MedDRA Query 
SNOT-22 
Sino-Nasal Outcomes Test-22 
SOC 
System organ class 
SoC 
Standard of care 
SSD 
Safety syringe device 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
VAS 
Visual Analogue Scale 
WPAI-GH 
Work Productivity and Activity Impairment Questionnaire - General Health 
6.1.2. 
Trademarks 
Trademarks of the GSK Group of 
Companies 
 
Trademarks not owned by the GSK 
Group of Companies 
NONE 
 
NONMEM 
 
 
OPTUM 
 
 
R 
 
 
SAS 


CONFIDENTIAL 
 
Page 53 of 54 
 
7. 
REFERENCES 
Bhattacharyya N. Test-retest reliability of computed tomography in the assessment of 
chronic rhinosinusitis. Laryngoscope. 1999;109:1055-58.  
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine. 2009;28:586-604.  
GlaxoSmithKline Document Number 2015N238436_00 Study ID N/A. A population PK 
and PKPD meta-analysis of combined intravenous and subcutaneous mepolizumab data. 
Report Date 27-May-2015.  
GlaxoSmithKline Document Number 2015N255079_00 Study ID N/A. Supplementary 
outputs from a population PK and PKPD meta-analysis of combined intravenous and 
subcutaneous mepolizumab data. Report Date 04-Oct-2015.  
GlaxoSmithKline Document Number 2020N441602_00 Study ID 209692. A randomised, 
double-blind, placebo-controlled, parallel group Phase III study to assess the clinical 
efficacy and safety of 100 mg SC Mepolizumab in adults with chronic rhinosinusitis with 
nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis (ECRS) – MERIT: 
Mepolizumab in Eosinophilic chronic RhinosinusITis study. Report Date 14_Aug-2020.  
GlaxoSmithKline Document Number TMF-14790303 Study ID 209692. A randomised, 
double-blind, placebo-controlled, parallel group Phase III study to assess the clinical 
efficacy and safety of 100 mg SC Mepolizumab in adults with chronic rhinosinusitis with 
nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis (ECRS) – MERIT: 
Mepolizumab in Eosinophilic chronic RhinosinusITis study. Report Date 21-Jul-2022.  
GlaxoSmithKline Document Number TMF-2114641 Study ID 209692. A randomised, 
double-blind, placebo-controlled, parallel group Phase III study to assess the clinical 
efficacy and safety of 100 mg SC Mepolizumab in adults with chronic rhinosinusitis with 
nasal polyps (CRSwNP) / eosinophilic chronic rhinosinusitis (ECRS) – MERIT: 
Mepolizumab in Eosinophilic chronic RhinosinusITis study. Report Date 08-Oct-2020.  
GlaxoSmithKline Document Number 2020N427698_00 Study ID 205687. A randomised, 
double-blind, parallel group PhIII study to assess the clinical efficacy and safety of 100 
mg SC Mepolizumab as an add on to maintenance treatment in adults with severe 
bilateral nasal polyps - SYNAPSE (StudY in NAsal Polyps patients to assess the Safety 
and Efficacy of mepolizumab). Report Date 23-Jun-2020.  
Hopkins S, Gillet S, Slack R, Lund V J, Browne J P. Psychometric validity of the 22-item 
Sinonasal Outcome Test. Clin. Otolaryngol. 2009;34:447-454.  
Juniper E F, O'Byrne P M, Guyatt G H, Ferrie P J, King D R. Development and 
validation of a questionnaire to measure asthma control. Eur. Respir J. 1999;14:902-207.  
Juniper E F, Svensson K, Mork A C, Stahl E. Measurement properties and interpretation 
of three shortened versions of the asthma control questionnaire. Respiratory Medicine. 
2005;99:553-558.  
Lund V J, Mackay I S. Staging in rhinosinusitis. Rhinology. 1993;31(4):183-184.  
Rubin D B. Multiple Imputation for Nonresponse in Surveys. 1 ed. New York:John Wiley 
& Sons; 1987.  


CONFIDENTIAL 
 
Page 54 of 54 
 
Sampson H A, Munoz-Furlong A, Campbell R L 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. 
Journal of Allergy and Clinical Immunology. 2006;117:391-397.