Clinical trial NCT03085797
Conditions: Nasal Polyps
Keywords: SB240563 Nasal Polyps Mepolizumab Phase 3 Parallel group Efficacy
Sponsor: GlaxoSmithKline
Start date: 2017-05-25; Completion date: 2019-12-11
Enrollment: 414 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Nasal polyps (NP) has long been known as chronic inflammatory disease of the nasal mucosa. This disease is characterized by the presence of polyps in the upper nasal cavity, originating from within the ostiomeatal complex. The presence of polyps can cause long-term symptoms such as prominent nasal obstruction, post-nasal drip, loss of smell, and discharge.

Mepolizumab (SB240563) is an Immunoglobulin G 1 \[IgG1\], kappa humanized monoclonal antibody (mAB) that blocks human interleukin-5 (hIL-5) from binding to the interleukin-5 (IL-5) receptor complex expressed on the eosinophil cell surface and thus inhibits signaling. Neutralization of IL-5 with mepolizumab has been shown to reduce blood, sputum and tissue eosinophils and hence is assumed to be a treatment option in a number of eosinophilic diseases including NP.

The aim of this randomized, double-blind, parallel group, phase 3 (PhIII) study is to assess the clinical efficacy and safety of 100 milligram (mg) subcutaneous (SC) mepolizumab as an add on to maintenance treatment in adults with severe bilateral NP. The study will include a 4-week run in period followed by randomization to a 52-week treatment period. Participants will receive mepolizumab 100 mg or placebo SC by the investigator or delegate via a pre-filled safety syringe every 4 weeks for 52 weeks. Throughout the entire study period (run in + treatment period + follow up), participants will receive a standard of care (SoC) for NP which consists of daily mometasone furorate (MF) nasal spray, and if required, saline nasal douching, occasional short courses of high dose oral corticosteroids (OCS) and/or antibiotics. The treatment period will consist of thirteen, 4-weekly doses of mepolizumab or placebo. In addition, up to the first 200 randomized participants will be followed up every other month for up to a further 6 months after the Visit 15 (7 months post last dose) in order to assess maintenance of response and to validate a physiological model derived from the previous Phase 2 study. Approximately 400 participants will be randomized (200 participants per treatment arm) in to the study. Total duration of the study will be 76 weeks for first 200 randomized participants and 52 weeks for remainder of participants who are not participating in the 6 months no treatment follow up.

Detailed description:

Arms: arm 1: Participants will receive total thirteen doses of 100 mg SC of mepolizumab in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate. arm 2: Participants will receive total thirteen doses of SC matching placebo in thigh, abdomen or upper arm every 4 weeks for 52 weeks on top of SoC which includes daily nasal spray of mometasone furoate.
Interventions: intervention 1: Mepolizumab intervention 2: Placebo intervention 3: Mometasone furoate
Intervention descriptions: intervention 1: Mepolizumab injection 100 mg/millilitre (mL) is a clear to opalescent, colorless to pale yellow to pale brown sterile solution for SC injection in a single-use, safety syringe. intervention 2: Placebo is a clear to opalescent, colorless sterile solution for SC injection in a single-use, safety syringe. intervention 3: All participants will receive mometasone furoate usually 400 micrograms (mcg), 2 actuations (50 mcg/actuation) in each nostril twice daily. Intolerant participants will use 200g (2 actuations \[50 g/actuation\] in each nostril once daily).

Protocol documents:
Prot_000.pdf: 
2016N294302_04
CONFIDENTIAL
GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: 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)
Protocol Number: 205687 /04
Short Title: Effect of Mepolizumab in severe bilateral nasal polyps 
Compound Number:
SB240563
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information will be provided separately in the 
SPM 
Regulatory Agency Identifying Number(s):

BBIND 006971 

EU EudraCT  2016-004255-70
Approval Date: 13-FEB-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
2016N294302_04
13-FEB-2020
2016N294302_03
20-Feb-2018
2016N294302_02
14-July-2017
2016N294302_01
15-May-2017
Original Protocol (2016N294302_00)
08-Dec-2016
Amendment 01 15-May-2017
Overall Rationale for the Amendment: The purpose of this amendment is to support 
country-specific requirements and amendments for South Korea.
Section # 
and Name
Description of Change
Brief Rationale
Appendix 10
Include IP label, provide 
additional clarification about 
the inclusion criteria age as per 
local regulations, provide 
details of OCS supplied for 
South Korea
Country specific requirement for South 
Korea
Amendment 02 14-JUL-2017
Overall Rationale for the Amendment: The main purpose of this amendment is to 
reflect comments from investigators to clarify points in the protocol that might be 
confusing or inconsistent.  In addition it also reflects the removal of CT scans and exit 
interviews as well as simplifying some of the endpoints such as reduction of endoscopic 
NP endpoints. 
 
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Section # and Name
Description of Change
Brief Rationale
Title
Added the following to the title 
‘SYNAPSE  (StudY in NAsal 
Polyps patients to assess the Safety 
and Efficacy of mepolizumab)’
For clarification
Throughout the protocol 
The word ‘subject’ was changed to 
‘participant’
For consistency
Overall design at synopsis and 
Section 5.1
Deleted the following: For Japanese and 
Korean participants CT scans will be 
included as “other” endpoints as CT scans 
are part of the diagnostic algorithm in Japan 
and provide important information for the 
East Asian population.
Deleted because CT 
scans are no longer 
required
Section 2 SOA
The following amendments or additions 
were carried out for clarification:

Treatment day was changed to study 
day 

First day of dosing is Day 1 and visit 
days are changed to reflect this

Concurrent medication review (including 
INCS) row added at Pre screen

Added asthma exacerbation as an 
example in medical history

Row added: Dispense “Medical 
Problems and Medication Taken 
Worksheet” every visit from V1-V17 

Row added: Collect “Medical Problems 
and Medication Taken Worksheet” from 
V2-V18 and EW visit

NP endoscopy assessment removed 
from visits 9, 11 and 13

CT scans assessments were removed

Exit interview was removed

Nasal secretion for biomarkers 
collection removed

Updated Medication history wording to 
include INCS

Clarified that Genetic sample is the 
same as PGX

The following was removed from 
footnote 1 ‘Baseline value is calculated 
For clarification
 
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Section # and Name
Description of Change
Brief Rationale
as the average score in the last 7 days 
before Visit 2. The value at all other 
treatment phase visits is calculated as 
the average score in the previous 28 
days.’

Added to clarify that UPSIT test will be 
performed only in selected countries 

A new row was added for SAE review 
from V1 while AEs are only reviewed 
and collected from V2

Foot note 4 for PK was changed to 
reflect that PK at visits 5 and 8 will no 
longer be performed

Foot note on exit interviews was 
removed.  Foot note numbers were 
changes to reflect this

Foot note added to clarify that 
dispensing of MF is not required if study 
visit 15, 18 or EW is the last study visit

Foot note added to clarify that PGx 
informed consent can be taken at any 
time prior PGx sampling

Foot note added to allow a window of 3 
days pre dosing to perform the 
endoscopies but must not exceed the 
protocol defined windows of 7 days 
from the nominal study visit

Foot note added to clarify that nasal 
endoscopy score assessment will be 
performed at visits 2, 3, 4, 5, 6, 7, 8, 10, 
12, 14, 15, 16, 17, 18 and EW
To reduce participant 
burden
To improve flexibility
To reduce participant 
burden
Section 4. Objectives and 
Endpoints
Added to clarify ‘worsening of asthma 
requiring systemic corticosteroids (i.v. or oral 
steroid) for at least 3 days or a single IM CS 
dose and/or ED visit and/or hospitalisation 
for asthma,  
Removed the following: 
•Change from baseline in Lund-Mackay 
computed tomography (CT) scan 
opacification score of the sinuses at Week 
52 (Japan and Korea only)
For clarification
 
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Section # and Name
Description of Change
Brief Rationale
Section 6.1 Inclusion Criteria 3 
and Section 9.3.7 Pregnancy 
and Section 12.5 Contraceptive 
Guidance and Collection of 
Pregnancy Information
Changed 105 Days and 16 weeks to 4 
months after the last drug administration as 
the time frame the WOCBP must commit to 
the contraception guidance 
For consistency 
Section 6.1 Inclusion Criteria 5
The word ‘historical’ was added to CT scan 
for clarification
For clarification
Section 6.1 Inclusion Criteria 6
Reworded the inclusion criteria to the 
following:
Presence of two different symptoms for at 
least 12 weeks prior to screening of either:
nasal blockage/obstruction/congestion 
or 
nasal discharge (anterior/posterior nasal 
drip) 
and at least one of the following:
nasal discharge (anterior/posterior nasal 
drip)
facial pain/pressure
reduction or loss of smell 
For clarification
Section 6.1 Inclusion Criteria 9
Added ‘including intranasal liquid steroid 
wash/ douching’
For clarification
Section 6.1 Exclusion Criteria 13
Changed ‘prior to first mepolizumab dose‘ to 
‘prior to screening visit’
Deleted chemotherapy 
For clarification
Section 6.2 Exclusion Criteria 16
Change ‘while at screening’ to ‘Not willing to 
be removed from a waiting list for NP 
surgery (if on one) or have pre-planned 
surgery date cancelled if randomized   A 
waiting list is a list of patients waiting for a 
non-emergency or elective surgical 
procedure.’
For flexibility  
Section 6.2 Exclusion Criteria 18
Deleted ‘or corticosteroid nasal solution 
(intranasal corticosteroid is excepted), 
For clarification
Section 6.2 Exclusion Criteria 22
Added ‘change of dose’ to the leukotriene 
antagonist treatment
For clarification
Section 6.2 Exclusion Criteria 23
Added ‘commencement or change of dose’
added to allergen immunotherapy
For clarification
Section 6.2 Exclusion Criteria 28
Deleted
Duplication of exclusion 
criteria 12
 
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Section # and Name
Description of Change
Brief Rationale
Section 6.2 Exclusion Criteria 31
Added ‘selected by the site’
For clarification
Section 6.3 randomisation criteria 
11
Added the following:

‘Agree to be removed from the waiting 
list for NP surgery or have pre-planned 
surgery date cancelled’

‘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 hospitalization ‘

No changes in allergen immunotherapy 
allowed
Deleted the following:
Have been included into a waiting list for NP 
surgery
For clarification
Section 7.1 treatments 
administered Study treatment 
Table for placebo
Changed mepolizumab for placebo and 
changed the description of placebo from 
‘colourless’ to ‘colourless to pale yellow / 
pale brown ‘
Correction of 
transcription error
Section 7.6 Concomitant therapy
Added ‘Initiation or changes in the doses of 
leukotriene receptor antagonist or allergen 
immunotherapy from screening to end of the 
study are not allowed.’
Added ‘or methy-prednisolone for Korea 
only)
For clarification
Section 7.6 Concomitant therapy; 
medication table
Clarified that ‘Initiation or changes in the 
dosing regimen of leukotriene receptor 
antagonist or immunotherapy from screening 
to end of the study are not allowed.’ 
On the table ‘Prohibited’ was added to 
medication
‘washout’ was replaced by ‘time period’
‘intranasal liquid steroid wash/douching 
(intranasal corticosteroid spray excepted)’ 
was deleted 
For clarification
Section 8.12
Early 
Withdrawal Visit
‘as soon as possible’ was changed to ‘28 
days after the last dose’
For consistency 
Section 9.1.1 Pre screening
Changed ‘2 weeks’ to 2 weeks prior (unless 
specifically authorised by the medical 
monitor)
For clarification
 
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Section # and Name
Description of Change
Brief Rationale
Removed “including informed consent for 
the optional pharmacogenetics part of the 
study, as applicable)”
Section 9.1.5 Critical procedures 
performed throughout treatment 
period (Visits 2 - 15) and Section 
9.2.7. Olfaction testing: University 
of Pennsylvania Smell 
Identification Test (UPSIT)
Clarified that UPSIT test will be performed 
only in selected countries 
For clarification and 
flexibility
Section  9.1.5.Critical procedures 
performed throughout  treatment 
period (Visits 2 - 15)
Clarified that 12-lead ECG only to be 
performed at V2 and V15
Clarified Lab assessments are Haematology 
at all visits and biochemistry (including liver 
chemistries) at visits 2 and 15 only.
Clarified that nasal endoscopy assessment 
will be performed at visits 2, 3, 4, 5, 6, 7, 8, 
10, 12, 14 and 15
Removed CT scans
Removed Nasal secretions for biomarkers
Removed exit interview
For clarification
Section 9.2.1 endoscopy NP 
score
Added nasal endoscopy assessments 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.
Allow flexibility in 
assessments
Section 9.2.3. Computed 
tomography (CT) scan
Removed this section as CT scans no longer 
performed
For clarification
Section 9.3.8.3. Prompt 
Reporting of Medical Device 
Incidents to Sponsor
Deleted ‘The same individual will be the 
contact for the receipt of medical device 
reports and SAE.’
Duplication
Section.9.4.3. electrocardiograms
Clarified that the order of assessments is in 
the SPM
Clarification
 
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Section # and Name
Description of Change
Brief Rationale
Section 9.4.4. Clinical Safety 
Laboratory Assessments
Added that the lab assessments are defined 
in Appendix 2
Clarification
Section 9.5 Pharmacokinetics
Removed collection of samples at visits 5 
and 8
Reduce burden of 
assessments
Section 9.7 Genetics
Adjusted the blood volume to up to 6 ml
Allow flexibility
Section 9.8 Exploratory 
Biomarkers
Removed nasal secretions
Reduce burden of 
assessments
Section 9.11. exit interviews
Removed
Not required
Section 10.3 Statistical Analysis
Removed reference to analysis of exit 
interviews
To reflect removal of 
exit interviews from 
protocol
Section 12.2. Appendix 2: Clinical 
Laboratory Tests; Table 1
Removed % Reticulocytes
Added Hepatitis B and C testing
Rectify that 
Reticulocytes will not 
be specifically 
measured
Clarify that Hep B and 
C testing will be 
performed
Section 12.3. Appendix 3: Study 
Governance Considerations
Added ‘the Directive 2001/20/EC’
This Directive might still 
be active at study start
Section 12.4. Appendix 4: 
Adverse Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
The following was deleted:
‘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. Also, "lack of 
efficacy" or "failure of expected 
pharmacological action" constitutes an AE or 
SAE.’
It was part of the 
hidden text/ protocol 
template instructions 
and should have been 
deleted as it contradicts
the bullet just before
Section .12.5. Appendix 5: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information
Deleted the following
“Male participants with partners who become 
pregnant

Investigator will attempt to collect 
pregnancy information on any male 
participant’s female partner of a male 
study participant who becomes 
pregnant while participating in this 
study. This applies only to participants 
who receive study treatment.

After obtaining the necessary signed 
informed consent from the pregnant 
For consistency with 
the main body of the 
protocol
 
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Section # and Name
Description of Change
Brief Rationale
female partner directly, the investigator 
will record pregnancy information on 
the appropriate form and submit it to 
GSK within 24 hours of learning of the 
partner’s pregnancy. 

Partner will also be followed to 
determine the outcome of the 
pregnancy. Information on the status of 
the mother and child will be forwarded 
to GSK

Generally, follow-up will be no longer 
than 6 to 8 weeks following the 
estimated delivery date. Any 
termination of the pregnancy will be 
reported regardless of fetal status 
(presence or absence of anomalies) or 
indication for procedure.”
Changed the following ’24 hrs ‘to ‘2 weeks’ 
for the time when the pregnancy needs to be 
reported
Section 12.12. Appendix 12: 
Assessment of nasal polyposis
Changed the diagram of Nasal polyps score
For clarification
Section 12.12 Appendix 13: CT 
scans
Removed this section
For clarification as no 
longer performed
References
Removed Lund 1993 and Bhattacharyya 
1999
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Amendment 03 20-Feb-2018
Overall Rationale for the Amendment: The purpose of this amendment is to clarify 
that screen failures can also be re screened (not just run in failures) and that the ECG 
machine does not need to be automated. 
Section # and Name
Description of Change
Brief Rationale
6.5 Screen/ Baseline/Run-
in Failures
Change from:
Individuals who do not meet the 
criteria for participation in this study 
(screen failure) may not be re-
screened. Re screening of 
participants that failed run-in will be 
permitted, however, advanced 
approval to proceed with re screen 
the participant must be obtained 
from the Medical Monitor (for 
contact details, see SPM).
Change to:
Re screening of participants will be 
permitted, however, advanced 
approval to proceed with re 
screening the participant must be 
obtained from the Medical Monitor 
(for contact details, see SPM).
To clarify that re 
screening is allowed not 
only for run-in failures 
but also screen failures
9.4.3 Electrocardiograms
Change from:
A single 12-lead ECG will be 
obtained at each timepoint specified 
in the SoA using an ECG machine 
that automatically calculates the 
heart rate and measures PR, QRS, 
QT, and QTc intervals.  
Change to:
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 SPM).
To clarify that ECG 
machines with no 
automatic facility to 
calculate heart rate and 
measures PR, QRS, QT, 
and QTc intervals can 
be used.  
 
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Amendment 04 13-FEB-2020
Overall Rationale for the Amendment:
In order to reflect regulatory authority feedback, the following changes were made 1) 
updated analysis methodology for the co-primary endpoints, 2) clarification of the 
definition of surgery to include more invasive procedures for the secondary endpoint, 3) 
assess the proportion of patients requiring systemic steroids for nasal polyps instead of 
the total burden of systemic steroids. This amendment also includes two additional 
secondary endpoints of composite nasal symptoms score and loss of smell symptom score 
that were previously included as ‘other’ endpoints.
Section # and Name
Description of Change
Brief Rationale
Synopsis, Section 4: objectives 
and endpoints
Moved the following endpoints from ‘other’ to 
secondary endpoints:

Proportion of participants requiring 
systemic steroids for nasal polyps up 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 mean 
individual VAS symptom score for loss 
of smell during the 4 weeks prior to 
Week 52.
Moved the following endpoint from 
secondary to ‘other’: 

Number of milligrams (mgs) per year of 
prednisolone-equivalent OCS dose up 
to Week 52.
To reflect the 
movement of “other
endpoints” to 
secondary endpoints 
following regulatory 
authority feedback
Clarify endpoints
Synopsis, Section 5.1: Overall 
design
Change from:
Other secondary endpoints are overall 
exposure to systemic steroids, expressed as 
mgs/year of prednisolone-equivalent oral 
corticosteroids (OCS), change from baseline 
in overall VAS symptom score, QoL (SNOT-
22) at Week 52, with other time points being 
captured as “other” endpoints.
Change to:
secondary endpoints are the proportion of 
participants requiring systemic steroids for 
To clarify endpoints 
following regulatory 
authority feedback
 
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Section # and Name
Description of Change
Brief Rationale
nasal polyps, change from baseline in 
overall VAS symptom score, composite VAS 
score (combining VAS scores for nasal 
obstruction, nasal discharge, mucus in the 
throat and loss of smell) and loss of smell 
VAS score, QoL (SNOT-22) at Week 52, 
with other time points being captured as 
“other” endpoints.
‘Other’ endpoints
Section 4: objectives and 
endpoints
Change from:

Change from baseline in mean 
individual VAS symptom scores for 
nasal discharge, mucus in the throat, 
loss of smell and facial pain during the 4 
weeks prior to Week 52.
Change to:

Change from baseline in mean 
individual VAS symptom scores for 
nasal discharge, mucus in the throat 
and facial pain during the 4 weeks prior 
to Week 52
Change from:

Percentage of participants classified at 
Week 52 as responders according to a 
9 point or greater decrease from 
baseline in SNOT-22 total score.
Change to

Percentage of participants classified at 
Week 52 as responders according to a 
8.9 point or greater decrease from 
baseline in SNOT-22 total score.
The following was added:

Change from baseline in SNOT-22 
domain scores at Week 52.
To reflect changes in
‘other’ endpoints 
following regulatory 
authority feedback and 
to correct a 
typographical error
Section 5.1: Overall design
Change from:
As stated above, actual surgery is an 
important secondary efficacy endpoint.  
Given any surgical procedure can influence 
the co-primary endpoint, after randomization 
NP surgery is defined as any procedure 
involving instruments resulting in incision 
and removal of tissue (eg polypectomy) or 
dilatation of the air passages (eg balloon 
sinuplasty) in the nasal cavity.  
To refine the definition
of surgery following 
regulatory authority 
feedback
 
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Section # and Name
Description of Change
Brief Rationale
Change to:
Any nasal surgical procedures can influence 
the co-primary endpoints, as can dilatation 
of the air passages (eg balloon sinuplasty) in 
the nasal cavity, therefore the impact of 
occurrence of either surgery or sinuplasty 
will be taken into consideration when 
assessing efficacy endpoints.  As stated 
above, actual surgery is an important 
secondary efficacy endpoint. Evaluation of 
this key secondary endpoint will be based 
only on invasive procedures involving 
instruments resulting in incision and removal 
of tissue (eg polypectomy).  
Definition of surgery
Section 9.2.3.: NP surgery
Change from:
At each visit it will be recorded whether the 
participant is on a waiting list for NP surgery 
and whether the participant has received 
actual 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 (polypectomy) or dilatation of the 
air passages (e.g. balloon sinuplasty) in the 
nasal cavity
Change to:
At each visit it will be recorded whether the 
participant is on a waiting list for NP surgery 
and whether the participant has received 
actual documented surgery and/or 
sinuplasty. 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 (polypectomy) 
in the nasal cavity
To refine the definition 
of surgery following 
regulatory authority 
feedback
Section 10.2: Population 
Analyses
Changed from:
All participants who sign the ICF
Change to:
All participants enrolled and for whom a 
record exists on the study database
To clarify the definition 
of the All Participants 
Enrolled population
Section 10.3: statistical analyses
Changed from:
4. Number of mgs per year of prednisolone-
equivalent dose
To reflect the change in 
secondary endpoints
following regulatory 
authority feedback
 
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Section # and Name
Description of Change
Brief Rationale
Changed to:
4. Proportion of participants requiring 
systemic steroids for nasal polyps 
5. Change from baseline in the mean 
composite VAS score (nasal obstruction, 
nasal discharge, mucus in the throat and 
loss of smell) 
6. Change from baseline in mean individual 
VAS symptom score for loss of smell
Section 10.3.1: efficacy analyses
Change from:
Total endoscopic nasal polyp score is 
collected at each clinical visit, the primary 
assessment will be at week 52. 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 (excluding the day of the visit). The 
mean VAS score over the last 7 days before 
Visit 2 will be used to determine the baseline 
value. 
Each primary endpoint will be analysed 
using a categorical approach. The change 
from baseline in each endpoint at Week 52 
will categorised by various levels of 
improvement (e.g. 1 point decrease, 2 point 
decrease, 3 point decrease, 4 point or 
greater decrease), no change or worsening 
in score, and a least favourable category of 
actual surgery by Week 52. Participants who 
withdraw prematurely from the study will be 
included in the lowest efficacy category 
(actual surgery). 
Each co-primary endpoint will be analysed 
using an ordinal logistic regression model 
(proportional odds model) with covariates of 
treatment group, baseline score and region. 
The comparison of mepolizumab with 
placebo will be expressed as an odds ratio 
and presented with corresponding 95% 
confidence interval and p-value.
NP score and symptom scores have usually 
been analysed using models based on a 
normal distribution assumption for the 
response.  Such models do not 
To reflect the change in 
analysis following 
regulatory authority 
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Section # and Name
Description of Change
Brief Rationale
acknowledge the bounded response for the 
scales and there is no ideal approach to 
inclusion of surgery as a worst response. 
For the proportional odds model, it is 
unnecessary to assign scores to the 
response categories, and if the model holds 
for a particular set of response categories, it 
holds with the same effects when the 
response scale is collapsed in any way 
(McCullagh, 1980). In comparisons of two 
treatments with no adjustment for 
covariates, this approach becomes 
equivalent to the Wilcoxon test.
Change to:
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 (excluding the day of 
the visit). The mean VAS score over the last 
7 days before Visit 2 will be used to 
determine the baseline value. 
Participants who undergo surgery/sinuplasty 
prior to Week 52 will be assigned their worst 
observed value prior to surgery/sinuplasty.  
Participants who withdraw from the study 
without having experienced 
surgery/sinuplasty will be assigned their 
worst observed score prior to study 
withdrawal.
The comparison of mepolizumab with 
placebo will be expressed as a difference in 
median change from baseline presented 
with corresponding 95% confidence 
intervals, the p-value for the difference 
between treatment groups will be based on 
the non-parametric Wilcoxon rank-sum test.
The difference in median change between 
placebo and mepolizumab with associated 
95% confidence intervals will be assessed 
by quantile regression using a bootstrap 
approach (Mehrotra DV 2017; Keene ON
2018), with covariates of treatment group, 
baseline score, baseline blood eosinophil 
count and region.
 
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Section # and Name
Description of Change
Brief Rationale
Change from:
Change from baseline in mean overall VAS 
symptom score at Week 52 (calculated as 
the mean of all measurements made in the 4 
weeks prior to the visit (excluding the day of 
the visit)), change from baseline in SNOT-22 
total score at Week 52 and number of mgs 
per year of prednisolone-equivalent OCS 
steroid dose will be analysed using a 
categorical approach as for the primary 
endpoint
Change to:
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 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 SNOT-22 total score at Week 52 
will be analysed in a similar manner to the 
co-primary endpoints.  The proportion of 
participants requiring systemic steroids for 
nasal polyps will be analysed using a logistic 
regression model
References
Added:
Mehrotra DV, Liu F, Permutt T. Missing data 
in clinical trials: control-based mean 
imputation and sensitivity analysis.  
Pharmaceutical Statistics 2017; 16: 378-392.
Keene O.N. Strategies for composite 
estimands in confirmatory clinical trials: 
Examples from trials in nasal polyps and 
steroid reduction. Pharmaceutical Statistics. 
2018;18:78-84
To support changes 
following regulatory 
authority feedback
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
SYNOPSIS.............................................................................................................22
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................27
3.
INTRODUCTION....................................................................................................33
3.1.
Study Rationale ..........................................................................................33
3.2.
Benefit/Risk Assessment ............................................................................36
3.2.1.
Risk Assessment .........................................................................37
3.2.2.
Benefit Assessment.....................................................................40
3.2.3.
Overall Benefit: Risk Conclusion..................................................41
4.
OBJECTIVES AND ENDPOINTS...........................................................................41
5.
STUDY DESIGN ....................................................................................................44
5.1.
Overall Design ............................................................................................44
5.2.
Number of Participants ...............................................................................46
5.3.
Participant and Study Completion...............................................................46
5.4.
Scientific Rationale for Study Design ..........................................................46
5.5.
Dose Justification........................................................................................48
6.
STUDY POPULATION...........................................................................................50
6.1.
Inclusion Criteria.........................................................................................50
6.2.
Exclusion Criteria........................................................................................52
6.3.
Randomisation Criteria ...............................................................................55
6.4.
Participant and Study Completion...............................................................56
6.5.
Screen/Baseline/Run-in Failures.................................................................56
7.
TREATMENTS.......................................................................................................57
7.1.
Treatments Administered............................................................................58
7.1.1.
Medical Devices...........................................................................59
7.2.
Method of Treatment Assignment ...............................................................59
7.3.
Blinding.......................................................................................................59
7.4.
Preparation/Handling/Storage/Accountability..............................................60
7.5.
Treatment Compliance................................................................................61
7.6.
Concomitant Therapy..................................................................................61
7.7.
Treatment after the End of the Study ..........................................................62
8.
STUDY WITHDRAWAL AND IP DISCONTINUATION CRITERIA..........................63
8.1.
Withdrawal from Study................................................................................63
8.1.1.
Primary reasons for withdrawal from the study.............................64
8.1.2.
Early Withdrawal Visit ..................................................................64
8.2.
Premature Discontinuation of Study Treatment (investigational 
product - IP)................................................................................................65
8.2.1.
Discontinuation Criteria for IP ......................................................65
8.2.2.
Study Specific IP Discontinuation Criteria ....................................65
8.2.3.
Primary reasons for IP discontinuation.........................................65
8.2.3.1.
Liver Chemistry Stopping Criteria ...............................66
 
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8.2.3.2.
QTc Stopping Criteria.................................................68
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................68
9.1.
Critical pre-Screening, Screening and Baseline Assessments ....................69
9.1.1.
Pre screening ..............................................................................69
9.1.2.
Screening ....................................................................................69
9.1.3.
Critical procedures performed at Screening (Visit 1)....................69
9.1.4.
Critical procedures performed at first treatment Visit 
(Baseline Visit 2)..........................................................................70
9.1.5.
Critical procedures performed throughout treatment period 
(Visits 2 - 15) ...............................................................................71
9.1.6.
Critical procedures performed throughout follow up period 
(Visits 16 - 18) .............................................................................72
9.2.
Efficacy Assessments.................................................................................72
9.2.1.
Endoscopic NP score...................................................................72
9.2.2.
Individual Symptoms Visual Analogue Scale (VAS).....................73
9.2.3.
NP surgery...................................................................................73
9.2.4.
Medication ...................................................................................73
9.2.5.
Peak Nasal Inspiratory Flow (PnIF)..............................................74
9.2.6.
Olfaction testing: University of Pennsylvania Smell 
Identification Test (UPSIT)...........................................................74
9.2.7.
Health Related Quality of Life (HR QoL) assessments.................74
9.2.7.1.
Sino-Nasal Outcome Test (SNOT-22) 
questionnaire..............................................................74
9.2.8.
Assessments for asthmatic participants only................................75
9.2.8.1.
Asthma Control Questionnaire (ACQ-5)......................75
9.3.
Adverse Events...........................................................................................75
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................75
9.3.2.
Method of Detecting AEs and SAEs.............................................76
9.3.3.
Follow-up of AEs and SAEs.........................................................76
9.3.4.
Regulatory Reporting Requirements for SAEs .............................76
9.3.5.
Cardiovascular and Death Events................................................77
9.3.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................77
9.3.7.
Pregnancy ...................................................................................77
9.3.8.
Medical Device Incidents (Including Malfunctions).......................78
9.3.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................78
9.3.8.2.
Follow-up of Medical Device Incidents........................78
9.3.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................78
9.3.8.4.
Safety syringe functionality assessment .....................79
9.3.8.5.
Returning defective Medical Devices to GSK..............79
9.3.8.6.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................79
9.3.9.
Treatment of Overdose................................................................79
9.4.
Safety Assessments ...................................................................................79
9.4.1.
Physical Examinations.................................................................79
9.4.2.
Vital Signs....................................................................................79
9.4.3.
Electrocardiograms......................................................................80
9.4.4.
Clinical Safety Laboratory Assessments ......................................80
 
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9.5.
Pharmacokinetics .......................................................................................80
9.6.
Pharmacodynamics ....................................................................................81
9.7.
Genetics .....................................................................................................81
9.8.
Exploratory Biomarkers...............................................................................81
9.9.
Immunogenicity Assessments.....................................................................81
9.10.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................81
9.10.1.
Short Form-36 (SF-36) questionnaire ..........................................81
9.10.2.
Work Productivity and Activity Impairment Questionnaire 
(WPAI).........................................................................................82
10. STATISTICAL CONSIDERATIONS........................................................................83
10.1.
Sample Size Determination ........................................................................83
10.2.
Populations for Analyses ............................................................................83
10.3.
Statistical Analyses.....................................................................................84
10.3.1.
Efficacy Analyses.........................................................................84
10.3.2.
Safety Analyses...........................................................................86
10.3.3.
Other Analyses ............................................................................86
10.3.4.
Interim Analyses ..........................................................................86
11. REFERENCES.......................................................................................................87
12. APPENDICES........................................................................................................92
12.1.
Appendix 1: Abbreviations and Trademarks................................................92
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................97
12.3.
Appendix 3: Study Governance Considerations..........................................99
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................103
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................109
12.6.
Appendix 6: Genetics................................................................................112
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................113
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................117
12.9.
Appendix 9: SYRINGE ERROR / FAILURE REPORTING FORM.............119
12.10. Appendix 10: Country-specific requirements.............................................122
12.11. Appendix 11: Anaphylaxis Criteria ............................................................123
12.12. Appendix 12: Assessment of nasal polyposis ...........................................124
12.13. Appendix 13 - Inspection of the Safety Syringe Form.................................125
12.14. Appendix 14: Protocol Amendment History...............................................126
 
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1.
SYNOPSIS
Protocol Title: 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)
Short Title: Effect of Mepolizumab in severe bilateral nasal polyps
Rationale:
Mepolizumab is a humanized 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 signaling.  Neutralization of IL-5 with 
mepolizumab has been shown to reduce blood, sputum and tissue eosinophils and this has 
led GSK to develop mepolizumab as a treatment option in a number of eosinophilic 
diseases including nasal polyps (NP). 
NUCALA (mepolizumab) is currently approved in countries such as the United States 
(US), Europe, Japan, Canada, Australia, South Korea, Switzerland and Taiwan as an add-
on maintenance treatment (100 mg subcutaneously [SC] once every 4 weeks [Q4W]) for 
patients with severe asthma, and with an eosinophilic phenotype.  NUCALA is currently 
provided as a lyophilized powder in a vial requiring reconstitution with sterile water for 
injection, however development of a liquid formulation is also underway.  
As of September 2016, approximately 3744 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 300 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 750 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 Phase II clinical studies (CRT110178 and 
MPP111782).    Both 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 of mepolizumab versus placebo in participants 
with severe primary NPs (Grade 3 or 4) or NPs that were recurrent after surgery (Grade 1 
to 4).  Participants were randomized to receive two single IV injections (28 days apart) 
of mepolizumab 750 mg IV (n=20) or placebo (n=10).  The study was double blind up to 
48 weeks.  The primary endpoint was the change from baseline in total endoscopic NP 
score (sum of left and right nostril scores) assessed by endoscopy at Week 8. There was a 
statistically significant difference between mepolizumab 750 mg IV compared to placebo 
at Week 8 (-1.22, 90% CI: -2.28, -0.17; one –sided p=0.0258). 
 
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In the responder analysis (last observation carried forward - LOCF), mepolizumab 
produced a significant reduction in NP score in 60% of participants versus 10% of 
participants who received placebo.  These effects were confirmed by changes on 
computed tomography (CT) scans.  There were also significant improvements in 
symptoms such as loss of smell, postnasal drip, and obstruction at Week 8 with 
mepolizumab, but not in rhinorrhoea.  
Study MPP111782 was originally designed as a two-part (Part A and Part B) randomized, 
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 standard of care (SoC).  All participants 
were in need of surgery at the start of the study and had at least one prior surgery.  One 
hundred and five participants were randomized to receive either six 750 mg IV injections 
of mepolizumab (54 participants) or placebo (51 participants), every 4 weeks.  
Participants who no longer required surgery at the end of Part A had 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.
The primary endpoint was reduction in the need for surgery at the end of Part A (4 weeks 
post last dose, Week 25), defined as both an improvement in overall visual analogue scale 
(VAS) symptom score and reduction in the endoscopic NP score. A significantly greater 
proportion of participants in the mepolizumab group no longer required surgery at the 
end of Part A (p=0.003).  A difference in mean change from baseline in total endoscopic 
NP score was observed between placebo and mepolizumab as early as Week 5, with a 
clear difference by Week 9.  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).  Statistically 
significant differences in favour of mepolizumab compared to placebo were also 
observed in Week 25 for individual VAS symptom scores and Sino-Nasal Outcome Test
(SNOT)-22 questionnaire.  
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 recurrent disease despite current optimal medical management.  
 
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Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the efficacy of 100mg 
mepolizumab compared to placebo

Change from baseline in total endoscopic NP 
score at Week 52.

Change from baseline in mean nasal obstruction 
VAS score during the 4 weeks prior to Week 52.
Secondary

To evaluate the impact on actual 
nasal surgery of 100mg mepolizumab 
compared to placebo

Time to first nasal surgery up to Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Change from baseline in mean overall VAS 
symptom score during the 4 weeks prior to 
Week 52.

To evaluate the impact on quality of 
life of 100mg mepolizumab 
compared to placebo

Change from baseline in SNOT-22 total score at 
Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Proportion of participants requiring systemic 
steroids for nasal polyps up to Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

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.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Change from baseline in mean individual VAS 
symptom score for loss of smell during the 4 
weeks prior to Week 52.
Overall Design:
This is a randomized, 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 NP.
The objective is to evaluate the safety and efficacy of mepolizumab 100 mg, administered 
SC by the Investigator or delegate via a pre-filled safety syringe every 4 weeks for 52 
weeks.  Efficacy of mepolizumab will be assessed using co-primary endpoints of change 
from baseline in endoscopic NP score (0-8) at Week 52 and nasal obstruction VAS 
symptom score during the 4 weeks prior to Week 52. Measurement of the co-primary 
endpoints will also be assessed throughout the study.
 
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The key secondary endpoint is time to first actual surgery for NP by Week 52. Other 
secondary endpoints are the proportion of participants requiring systemic steroids for 
nasal polyps, change from baseline in overall VAS symptom score, composite VAS score 
(combining VAS scores for nasal obstruction, nasal discharge, mucus in the throat and 
loss of smell) and loss of smell VAS score, QoL (SNOT-22) at Week 52, with other time 
points being captured as “other” endpoints. 
The study population will consist of adult participants (18 years of age) with recurrent 
severe bilateral NP (defined as an average nasal obstruction VAS symptom score of >5 
and 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 history of at least one prior 
surgery for NP, have recurrent NP despite treatment with current SoC and in need for NP 
surgery. The need for current NP surgery is defined when the participant has an overall 
VAS symptom score greater than 7 in addition to a NP score 3 in at least one nostril.
Study Schematic
The study will include a 4 week run in period followed by randomisation to a 52-week 
treatment period.  Throughout the entire study period (run in + treatment period + follow 
up), participants will be on the SoC for NP which consists of daily mometasone furorate 
nasal spray (MF), and if required, saline nasal douching, occasional short courses of high 
dose OCS and/or antibiotics. At the start of run in and throughout the study, participants 
will be placed on MF at the maximum prescribed dose (if not already) according to local 
label, if available, or in line with local SoC. The maximum dose is 2 actuations (50 
micrograms (μg)/actuation) in each nostril twice daily which equals a total daily dose of 
400 μg.  For participants intolerant to this dose, the lower dose of 200g can be used (2 
actuations (50 g /actuation) in each nostril once daily. The treatment period will consist 
of thirteen, 4-weekly doses of mepolizumab or placebo, delivered by SC injection.  In 
addition, up to the first 200 randomized participants will be followed up every other 
month for up to a further 6 months after the Visit 15 (7 months post last dose) in order to 
assess maintenance of response and to validate a physiological model derived from the 
previous PhII study.  
 
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Number of Participants:
Assuming a screen fail rate of 30%, approximately 570 participants will need to be 
screened in order to allow for approximately 400 participants randomized (200 
participants per arm).
Treatment Groups and Duration:
The currently marketed drug product, Nucala (mepolizumab), is supplied as a 100 mg 
single-dose vial containing a sterile, preservative-free, lyophilized powder for 
reconstitution and SC injection.  
A liquid formulation of mepolizumab is under development which will be provided as 
pre-filled syringes in a safety syringe device for this study.  The liquid formulation in a 
safety syringe device must be administered by a health care professional in this study. 
There will also be a matched safety syringe with placebo. 
Participants who are successfully enrolled into the study will be randomized 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 which includes intranasal MF
• Group 2: Placebo SC on top of SoC which includes intranasal MF 
A participant is considered to have completed study treatment if he/she attends study 
Visit 15 (Week 52). 
For up to the first 200 randomized participants, the final study visit will be Week 76 
(Visit 18).  For the remainder of participants who are not participating in the 6 months no 
treatment follow up, the final study visit will be Week 52 (Visit 15).
The end of the whole 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.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Pre 
scree9
Screening 8
Treatment 
Phase
No treatment Follow6
Visit
0
1
2
3 -14
15
16-17
18
EW Visit
Study day
(Visit 
window 7 
days)
(28 days prior 
to Day 1)
1
29, 57, 85, 113, 141, 169, 
197, 225, 253, 281, 309, 
337
365
421, 477
533
28 days 
post last 
visit
Week
0
4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48
52
60, 68
76
Screening/ 
baseline
Informed consent15
X
Concurrent medication review (including 
INCS)
X
X
Inclusion and exclusion criteria
X
Demography
X
Full physical exam including height and 
weight
X
Medical history (including past and present 
medical conditions, substance usage 
family history of premature CV disease)
and asthma exacerbation
X
History of HIV and Hep B and Hep C 
screen
X
Parasitic screening10
X
Medication History including INCS and
OCS use for NP
X
History of NP surgery 
X
Screening 12-lead ECG
X
 
 
 
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Procedure
Pre 
scree9
Screening 8
Treatment 
Phase
No treatment Follow6
Visit
0
1
2
3 -14
15
16-17
18
EW Visit
Study day
(Visit 
window 7 
days)
(28 days prior 
to Day 1)
1
29, 57, 85, 113, 141, 169, 
197, 225, 253, 281, 309, 
337
365
421, 477
533
28 days 
post last 
visit
Week
0
4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48
52
60, 68
76
Screening Vital signs
X
Dispense “Medical Problems and 
Medication Taken Worksheet”
X
X
Collect “Medical Problems and Medication 
Taken Worksheet”
X
SAE review
X
Assessment of endoscopic NP score
X
Overall  VAS symptom score and VAS for 
nasal obstruction to be captured on eDiary 
after training
X
Screening Laboratory assessments 
(include liver chemistries) 
X
Screening Urinalysis
X
Urine pregnancy test (WOCBP only)
X
Dispense MF and eDiary 
X
Register visit 
X
X
X
X
X
X
X
X
Review randomisation criteria
X
 
 
 
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Procedure
Pre 
scree9
Screening 8
Treatment 
Phase
No treatment Follow6
Visit
0
1
2
3 -14
15
16-17
18
EW Visit
Study day
(Visit 
window 7 
days)
(28 days prior 
to Day 1)
1
29, 57, 85, 113, 141, 169, 
197, 225, 253, 281, 309, 
337
365
421, 477
533
28 days 
post last 
visit
Week
0
4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48
52
60, 68
76
Randomisation (if applicable)
X
Genetic sample (PGX)
X
Efficacy11
Assessment of Surgery (actual and waiting 
list)
X
X
X
X
X
X
Assessment of OCS dose and duration
X
X
X
X
X
X
Overall VAS symptom score 1
X
X
X
X
X
X
VAS symptom score for nasal obstruction, 
nasal discharge, mucus in the throat, loss 
of smell and facial pain 1
X
X
X
X
X
X
SNOT-22 5
X
X
X
X
X
X
SF-36 5, 7
X
X7
X
X
X
X
PnIF 2
X
X
X
UPSIT 13
X
X
X
 
 
 
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Procedure
Pre 
scree9
Screening 8
Treatment 
Phase
No treatment Follow6
Visit
0
1
2
3 -14
15
16-17
18
EW Visit
Study day
(Visit 
window 7 
days)
(28 days prior 
to Day 1)
1
29, 57, 85, 113, 141, 169, 
197, 225, 253, 281, 309, 
337
365
421, 477
533
28 days 
post last 
visit
Week
0
4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48
52
60, 68
76
Endoscopic NP score 16, 17
X
X16, 17
X
X
X
X
WPAI-SHP 5
X
X
X
X
X
X
ACQ – 5,3, 5
X
X
X
X
Asthma exacerbation
X
X
X
X
Blood for PK4
X
X
X
X9
X
Blood for biomarkers 
X
X
Safety
AE/SAE review
X
X
X
X
X
X
Dispense “Medical Problems and 
Medication Taken Worksheet”
X
X
X
X
X
Collect “Medical Problems and Medication 
Taken Worksheet”
X
X
X
X
X
X
X
Concurrent medication review (including 
INCS)
X
X
X
X
X
X
12-lead ECG
X
X
X
Vital signs (HR and BP)
X
X
X
X
Laboratory assessment: Haematology
X
X
X
X
X
X
All other Laboratory assessments 
(including liver chemistries) 
X
X
X
Blood for immunogenicity
X
X
X9
X
Urinalysis
X
X
X
Urine pregnancy test (WOCBP)
X
X
X
X
Medication/ 
supplies
Dispense and train on eDiary for run in 
and remainder of the study
X
 
 
 
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Procedure
Pre 
scree9
Screening 8
Treatment 
Phase
No treatment Follow6
Visit
0
1
2
3 -14
15
16-17
18
EW Visit
Study day
(Visit 
window 7 
days)
(28 days prior 
to Day 1)
1
29, 57, 85, 113, 141, 169, 
197, 225, 253, 281, 309, 
337
365
421, 477
533
28 days 
post last 
visit
Week
0
4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48
52
60, 68
76
Review and re train on eDiary (if required)
X
X
X
X
X
X
eDiary completion 12
X
X
X
X
X
X
Review compliance and dispense MF
X
X
X14
X
X14
X14
Dosing with study drug (active/ placebo)
X
X
Collect eDiary for the first 200 randomized
participants
X
X
Collect eDiary for remainder of the 
participants
X
X
1.
Performed daily on the electronic Diary. 
2.
Performed monthly at study visits 
3.
For asthmatic participants only
4.
Blood for PK will be collected at pre dose Visit 2 (baseline) and then pre dose at Visits 3, 15 and 17 
5.
Performed at site during study visits
6.
For approximate up to the first 200 randomized participants 
7.
SF36 at visits 3, 5, 7, 9, 11, 13, 15, 16, 17 and 18 only
8.
Pre-screening and screening can be performed on the same day
9.
At Visit 17 only
10. 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
11. All questionnaires will be performed before any other assessments on each particular visit, VAS scores, SNOT-22, SF-36 and WPAI
 
 
 
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12. eDiary completion by participants will be daily every morning between screening visit and Visit 18 (or EW if appropriate) for the first 200 randomized
participants or between screening and Visit 15 (or EW if appropriate) for the remainder of the participants.
13. UPSIT performed at Visits 2, 3, 5, 7, 9, 11, 13, 15 NB: UPSIT test will be performed only in selected countries
14. Dispensing of MF is not required if study 15, 18 or EW is the last study visit
15. PGx informed consent can be performed anytime prior sampling
16. The 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.  
17. Endoscopy NP score assessment will be performed at visits 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 15, 16, 17, 18 and EW

Abbreviations: ACQ, - Asthma Control Questionnaire; ECG – Electrocardiogram; EW- Early Withdrawal ; MF- mometasone furorate; NP- nasal polyps ; 
OCS- Oral Corticosteroids; PD- Pharmacodynamic ; PK- Pharmacokinetic ; PnIF- Peak Nasal Inspiratory Flow; SNOT- Sino-Nasal Outcome Test; SF-36 -
Short Form Health Survey 36; UPSIT -  University of Pennsylvania Smell Identification Test; VAS- Visual Analogue Scale; WOCBP -women of child 
bearing potential ;  WPAI-  Work Productivity and Activity Impairment

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study team member 
and then archived in the sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the ICF.
 
 
 
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3.
INTRODUCTION
3.1.
Study Rationale
Background on Nasal Polyposis
Nasal polyps (NP) is a chronic inflammatory disease of the nasal mucosa, characterized 
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 HR QoL.  The European Position Paper on Rhinosinusitis 
and NP [EPOS, 2012] defines the severity of disease using a total severity visual analog 
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 
computerized tomography (CT).  The etiology of NP is currently unknown.
Current standard of care for patients with NP is treatment with intranasal corticosteroids 
(INCS) followed by short courses of oral corticosteroids (OCS) in severe cases when 
short term relief is required [EPOS, 2012].  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, Philpott, 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.
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; EPOS, 2012]. 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 [EPOS, 2012].  Antrochoanal polyps are also another form of 
 
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NP more common in children that are usually unilateral and associated with low 
eosinophil tissue levels [EPOS, 2012].
The role of mepolizumab in NP
Mepolizumab is a humanized 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 signaling.  Neutralization of IL-5 with 
mepolizumab has been shown to reduce blood, sputum and tissue eosinophils and this has 
led GSK to develop mepolizumab as a treatment option in a number of eosinophilic 
diseases including NP. 
NUCALA (mepolizumab) is currently approved in countries such as the United States 
(US), Europe, Japan, Canada, Australia, South Korea, Switzerland and Taiwan as an add-
on maintenance treatment (100 mg subcutaneously [SC] once every 4 weeks [Q4W]) for 
patients with severe asthma, and with an eosinophilic phenotype.  NUCALA is currently 
provided as a lyophilized powder in a vial requiring reconstitution with sterile water for 
injection, however development of a liquid formulation is also underway.  
As of September 2016, approximately 3744 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 300 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, IV, or intramuscular (IM) 
routes.  The highest dose administered in these studies was 750 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 Phase II clinical studies (CRT110178 and 
MPP111782).    Both studies provided information to suggest some 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 randomized, 
double-blind, placebo-controlled design of mepolizumab versus placebo in participants 
with severe primary NPs (Grade 3 or 4) or NPs that were recurrent after surgery (Grade 1 
to 4).  Participants were randomized to receive two single intravenous (IV) injections (28 
days apart) of mepolizumab 750 mg IV (n=20) or placebo (n=10).  The study was double 
blind up to 48 weeks.  The primary endpoint was the difference in total endoscopic NP 
score which was the sum of left and right nostril scores assessed by endoscopy at Week 8 
versus baseline.  Given the grading of each nostril ranged from 0 (no polyp) to 4 (large 
polyp causing complete obstruction of the inferior meatus), a total score of up to 8 was 
possible.  A statistically significant difference from placebo was observed for the 
treatment comparison of mepolizumab 750 mg IV versus placebo at Week 8 (-1.22, 
90% CI: -2.28, -0.17; one –sided p=0.0258). These effects were confirmed by changes on 
CT scans.  There were also significant improvements in symptoms such as loss of smell, 
postnasal drip, and obstruction at Week 8 with mepolizumab, but not in rhinorrhoea.  A 
significant decrease in blood eosinophil counts (BEC) in the mepolizumab group 
compared with the placebo group was also observed. 
 
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Study MPP111782 was originally designed as a two-part (Part A and Part B) randomized, 
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 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 
randomized 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 
chance to enter Part B where they were followed up for a further 6 months with no 
treatment.  
The primary endpoint was a reduction in the need for surgery at the end of Part A 
(4 weeks post last dose, Week 25).  This was taken as a combination of reduced severity 
of the NP condition as defined by an improvement in overall VAS symptom score (a 
score of 7 or below) with at least a reduction in endoscopic NP score to less than 3 or if 
the overall VAS symptom score is still greater than 7 then an endoscopic NP score to 1 or 
less for the nostril which has the highest score at baseline. Investigators agreed that these 
thresholds would clearly indicate that a participant had dropped below the threshold at 
which surgery would normally be indicated.  By these criteria, a significantly greater 
proportion of participants in the mepolizumab group no longer required surgery at the 
end of Part A (p=0.003).  A difference in the mean change from baseline in total 
endoscopic NP score between mepolizumab and placebo at Week 25 of -1.21 was 
demonstrated (95% CI: -1.92 to -0.50; p=0.001; ITT Population, LOCF). 
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).  
For individual VAS symptom scores including rhinorrhoea, mucus in the throat, nasal 
obstruction and loss of smell, the treatment differences were statistically significant in 
favor of mepolizumab compared with placebo at Week 25 (p0.002), and treatment 
differences could be observed as early as Week 9.  
Participants in the mepolizumab group had a greater clinical and statistical improvement 
in the SNOT-22 questionnaire, a measure of HR QoL associated with CRS and NP, at 
Week 25, compared with participants who received placebo.  
There were 14 participants in the mepolizumab group and 7 participants in the placebo 
group that entered Part B before this part of the study was discontinued.  Data from these 
participants suggest the beneficial effects of mepolizumab treatment on NP score and 
symptoms may persist after cessation of treatment.
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 recurrent disease despite current optimal medical management.  
 
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3.2.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB-240563) lyophilised drug product can be found in the Investigator’s 
Brochure [GSK Document Number CM2003/00010/10].  
 
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3.2.1.
Risk Assessment
The following section outlines the key risks, risk assessment and mitigation strategy for this protocol based on mepolizumab lyophilised 
formulation.  The safety profile of the mepolizumab liquid formulation is anticipated to be similar to the lyophilised formulation.  
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) 
Risk of Systemic Reactions including allergic 
reactions
Biopharmaceutical products - may elicit systemic 
(e.g. hypersensitivity) reactions.
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. 
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 summarized in the IB 
“Adverse Events of Special Interest” section; see also 
Daily 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 11: 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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
‘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].
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 summarized 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].
Daily monitoring of serious adverse events (SAEs) 
by medical monitor; regular systematic review of 
adverse event (AE)/SAE data from ongoing studies 
by GSK study team and/or safety review team. 
Customised AE and SAE case report form (CRF) 
utilised for targeted collection of information for 
local injection site reaction adverse events.
Potential risk of immunogenicity
Biopharmaceutical products may elicit anti-drug 
antibody (ADA) and neutralising antibody (NAB), 
which have the potential to modulate 
pharmacokinetic (PK), pharmacodynamic (PD) or 
produce adverse reactions. 
Mepolizumab has low immunogenic potential. Both 
incidence and titer data from completed studies 
demonstrate a low risk for loss of efficacy associated 
with AEs and/or altered PK/PD. Immunogenicity 
data reported to date across the mepolizumab 
development program are summarized in the IB; See 
Section 5.4‘Clinical Immunogenicity’ and a 
summary of immunogenicity findings in Section 6
‘Other Potentially Clinically Relevant Information 
for the Investigator’[ GSK Document 
Number CM2003/00010/10].
Blood samples will be collected for detection of both 
ADA and Nab.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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)
 
 
 
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As of September 2016, approximately 3744 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 300 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, IV, or intramuscular (IM) 
routes.  The highest dose administered in these studies was 750 mg IV.
Mepolizumab is currently approved for severe asthma with an eosinophilic phenotype at 
a dose of 100 mg SC every 4 weeks.  In this population, over 1200 participants with 
severe asthma that have received at least one dose of mepolizumab, of which 
approximately 1000 have received mepolizumab at 100 mg SC, either as part of a 
randomized placebo-controlled study or in open-label extensions studies.  The total 
treatment exposure for the approximate 1000 participants who received mepolizumab 100 
mg SC was equivalent to over 1000 participant years.  In addition, over 914 participants 
have been treated with mepolizumab 100 mg SC up to 12 months and over 340 
participants for approximately 3.5 years.  
In studies of patients with severe asthma, 177 participants had concomitant diagnosis of 
NP and received mepolizumab with 143 participants receiving mepolizumab for ≥1 year.  
Given patients with severe asthma in general have higher morbidity and mortality than 
those with severe NP, the substantial long-term safety information already collected in 
severe asthma could be considered relevant and informative for patients with NP.
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 Phase II clinical studies (CRT110178 and 
MPP111782).    Both studies provided information to suggest 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.  Of note, the dose of 750 mg IV every 4 weeks used in 
the two Phase II studies was significantly higher than the 100 mg SC every 4 weeks that 
is proposed for the two Phase III studies. 
3.2.2.
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].
In the proposed study, benefit considerations for a participant may include:

Potential to receive active drug during study conduct that may have clinical utility

Contributing to the process of developing new therapies in an area of unmet need

Medical evaluations/assessments associated with study procedures
 
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3.2.3.
Overall Benefit: Risk Conclusion
Current data from mepolizumab preclinical 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 studies in NP 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. 
The higher morbidity and mortality in severe asthma compared with NP 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 bilateral severe NP. 
The change in drug product presentation from a lyophilised drug product to a liquid drug 
product in a safety syringe is not anticipated to alter the overall benefit: risk.  Treatment 
will be administered by a trained health care professional at the clinic and participants 
will be closely observed for at least 1 hr following administration of IP for the first 3 
doses then per institutional guidelines.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the efficacy of 100 
mg mepolizumab compared to 
placebo

Change from baseline in total endoscopic NP score 
at Week 52

Change from baseline in mean nasal obstruction 
VAS score during the 4 weeks prior to Week 52.
Secondary

To evaluate the impact on actual 
nasal surgery of 100mg 
mepolizumab compared to 
placebo

Time to first nasal surgery up to Week 52.

To further evaluate the efficacy 
of 100mg mepolizumab compared 
to placebo

Change from baseline in mean overall VAS.
symptom score during the 4 weeks prior to Week 
52.

To evaluate the impact on quality 
of life of 100mg mepolizumab 
compared to placebo

Change from baseline in SNOT-22 total score at 
Week 52.

To further evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo

Proportion of participants requiring systemic 
steroids for nasal polyps up to Week 52.
 
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Objectives
Endpoints

To further evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo

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.

To further evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo

Change from baseline in mean individual VAS 
symptom score for loss of smell during the 4 weeks 
prior to Week 52.
Objectives
Endpoints
“Other”

To further evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo

Percentage of participants classified as responders 
according to a 1 point or greater decrease from 
baseline in NP Score at Week 52.

Change from baseline in mean individual VAS 
symptom scores for nasal discharge, mucus in the 
throat and facial pain 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, loss of smell 
and facial pain) during the 4 weeks prior to Week 
52.

Change from baseline in UPSIT at Week 52.

Change from baseline in PnIF at Week 52.

To evaluate the impact on quality 
of life of 100mg mepolizumab 
compared to placebo

Percentage of participants classified at Week 52 as 
responders according to a 8.9 point or greater 
decrease from baseline in SNOT-22 total score.

Change from baseline in SNOT-22 domain scores at 
Week 52.

To further evaluate the impact on 
requirement for nasal surgery of 
100mg mepolizumab compared 
to placebo

Rate of nasal surgery up to Week 52.

Time to first inclusion on waiting list for NP surgery 
up to Week 52.

Percentage of participants who are included on 
waiting list for NP surgery.  

Percentage of participants classified as ‘need for 
surgery’ responders according to NP score and 
overall VAS symptom score.

To evaluate exploratory 
biomarker of nasal polyposis and 
response to 100mg mepolizumab 
compared to placebo

Evaluate exploratory blood biomarkers (including 
blood eosinophils) on response to mepolizumab.
 
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Objectives
Endpoints

To evaluate the impact on health 
outcomes of 100mg 
mepolizumab compared to 
placebo

Change from baseline in SF-36 Mental Component 
Summary (MCS), Physical Component Summary 
(PCS) and 8 summary scores at Week 52.

Change from baseline in WPAI Questionnaire at 
Week 52. 

To further evaluate the efficacy 
of 100mg mepolizumab 
compared to placebo on systemic 
steroid use such as OCS and 
antibiotic use as part of SoC

Number of Courses of systemic steroid therapy up 
to Week 52.

Number of mgs per year of prednisolone-
equivalent OCS dose up to Week 52.

Number of days on systemic steroid therapy up to 
Week 52.

Time to first course of OCS up to Week 52.

Number of courses of antibiotic up to Week 52.

To further evaluate the efficacy 
of 100mg mepolizumab 
compared placebo in the sub-
group of participants with 
Asthma
In addition to endoscopic NP score, VAS symptoms 
score, medication and surgery, the following asthma 
related endpoints will be assessed:

Change from baseline in Asthma Control 
Questionnaire (ACQ - 5) score at Week 52.

Number of clinically significant asthma 
exacerbations 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 ED visit and/or hospitalisation for 
asthma up to Week 52.

To assess the maintenance of 
response after cessation of 
mepolizumab treatment 
compared to placebo
For all participants who enter post treatment follow-up 
period, the following will be assessed at Week 76:

Change from baseline in total endoscopic NP score.

Change from baseline in mean nasal obstruction 
VAS score.

Change from baseline in mean individual VAS 
symptom score for nasal discharge, mucus in 
throat, loss of smell, facial pain and overall VAS 
symptom score during the 4 weeks prior to Week 
76.

Number of mgs per year of prednisolone-equivalent 
OCS dose.

Change from baseline in SNOT-22 total score.

Change from baseline in SF-36 Mental Component 
Summary (MCS), Physical Component Summary 
(PCS) and 8 summary scores.

Change from baseline in WPAI Questionnaire.

Time to first nasal surgery including off treatment 
period from randomization to Week 76.

Time to first inclusion on waiting list for NP surgery 
up to Week 76.
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a randomized, 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 NP.  
The objective is to evaluate the safety and efficacy of mepolizumab 100 mg, administered 
SC by the Investigator or delegate via a pre-filled safety syringe every 4 weeks of a 
52week treatment period.  Efficacy of mepolizumab will be assessed using a co-primary 
endpoints of change from baseline in endoscopic NP score (0-8) and nasal obstruction 
VAS symptom score during the 4 weeks prior to Week 52. Measurement of the co-
primary endpoints will also be assessed at all other time points through the study.
The key secondary endpoint is time to first actual surgery for NP by Week 52. Other 
secondary endpoints are the proportion of participants requiring systemic steroids for 
nasal polyps, change from baseline in overall VAS symptom score, composite VAS score 
(combining VAS scores for nasal obstruction, nasal discharge, mucus in the throat and 
loss of smell) and loss of smell VAS score, QoL (SNOT-22) at Week 52, with other time 
points being captured as “other” endpoints. 
For those participants who have a concomitant diagnosis of asthma, the level of asthma 
control as assessed by Asthma Control Questionnaire (ACQ-5) and the number of 
clinically significant asthma exacerbation will also be measured as “other” endpoint. 
The population will consist of adult participants (18 years of age) with recurrent severe 
bilateral NP (defined as an average obstruction VAS symptom score of >5 and 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).  They must also have a history of at least one prior surgery for NP 
Objectives
Endpoints
Safety

To evaluate the safety and 
tolerability of 100mg 
mepolizumab compared to 
placebo

Frequency of Adverse events (AEs)/ Serious adverse 
events (SAEs) including systemic and injection site 
reactions reported throughout the treatment 
period.

Vital signs (pulse rate, systolic and diastolic blood 
pressure) throughout the treatment period.

Hematological and clinical chemistry parameters 
throughout the treatment period.

12 lead ECG derived endpoints.

Presence of anti-mepolizumab antibodies.
Pharmacokinetics

To evaluate the 
pharmacokinetics of 100mg 
mepolizumab

PK concentrations and Population PK parameters

PK/PD (blood eosinophil count) analysis
 
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and recurrent NP despite treatment with current standard of care.  Participants must be in 
current need for NP surgery as defined by an overall VAS symptom score greater than 7 
in addition to a NP score 3 in at least one nostril.
For the purpose of inclusion into 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 actually driven by 
eosinophilia or not.
Any nasal surgical procedures can influence the co-primary endpoints, as can dilatation 
of the air passages (eg balloon sinuplasty) in the nasal cavity, therefore the impact of 
occurrence of either surgery or sinuplasty will be taken into consideration when assessing 
efficacy endpoints.  As stated above, actual surgery is an important secondary efficacy 
endpoint. Evaluation of this key secondary endpoint will be based only on invasive 
procedures involving instruments resulting in incision and removal of tissue (eg 
polypectomy).  Diagnostic or investigative procedures such as nasal endoscopy would not 
be considered as surgery. 
To ensure that this study can detect a difference in surgical outcome between the two 
treatment arms, participants, whom in the opinion of the investigator are contraindicated 
for NP surgery, will be excluded.
Figure 1
Study Schematic
The study will include a 4-week run in period followed by randomization to a 52-week 
treatment period.  Throughout the entire study period (run in + treatment period + follow 
up), participants will be on the SoC for NP which consists of daily MF, saline nasal 
douching as required and, if required, occasional short courses of high dose OCS and/or 
antibiotics.  Patients who have NP surgery during the study are allowed to continue on 
study treatment till completion of the 52-week treatment period.  This is to reflect the real 
 
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life circumstances in which mepolizumab is intended to be used as a concomitant therapy 
on top of SoC. During the run-in period, participants will complete baseline safety 
evaluations, measures of NP status and be educated in the completion of participant
eDiary.  At the start of run in and throughout the study, participants will be placed on MF 
at the maximum prescribed dose (if not already) according to local label, if available, or 
in line with local SoC.  The treatment period will consist of thirteen, 4-weekly doses of 
mepolizumab or placebo, delivered by SC injection on top of SoC. The previous phase II 
study suggests persistence of beneficial effects after cessation of mepolizumab treatment.  
A physiological model linking mepolizumab binding to IL-5, IL-5 to blood eosinophil 
count, and blood eosinophil count to endoscopic NP score was used to describe the wash-
out phase of the previous Phase II studies.  This model was then used to predict the 
current proposed dose of 100 mg SC of mepolizumab.  To validate this physiological 
model, the first 200 randomized participants will be followed up every other month for 
up to a further 6 months after the Week 52 visit (7 months post last dose).  This number 
of participants is also thought to be sufficient to inform on the maintenance of response 
after cessation of treatment.  
5.2.
Number of Participants
This study will investigate NP participants most likely to benefit from mepolizumab 
treatment.  GSK believes that a patient population with severe NP (as defined by an 
obstruction VAS assessment of symptoms >5 with recurrent bilateral NP, despite current 
SoC) is most likely to be associated with nasal tissue eosinophilia and therefore has the 
potential to benefit from treatment with anti-IL5 monoclonal antibody treatment.
Assuming a screen fail rate of 30%, approximately 570 participants will need to be 
screened in order to allow for 400 participants randomized (200 participants per arm).
5.3.
Participant and Study Completion
Final treatment visit: For all participants this will be Week 52 (Visit 15), 4 weeks after 
the last expected injection at Visit 14.
Final study visit: for up to the first 200 randomized participants this will be Week 76 
(Visit 18) and for the remainder will be Week 52 (Visit 15).
The end of the whole 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.
5.4.
Scientific Rationale for Study Design
GSK propose to assess the efficacy of mepolizumab by objectively measuring its ability 
to reduce the NP size and the effects of this reduction in improving the typical symptoms 
associated with NP.  This study will use centrally read total endoscopic NP score by 
assessing the change from baseline at Week 52 as well as the patient assessed nasal 
obstruction VAS symptom score as the co primary outcome measures.  In addition, the 
key secondary endpoint of actual surgery will be assessed at 52 weeks as surgery is also 
of great importance to patients and physicians. 
 
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This study will recruit patients who have severe NP that are refractory to SoC medical 
treatment.  In most cases these patients are at the stage of needing surgical intervention 
[EPOS, 2012]. 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 when supported with data from a symptomatic endpoint such
as nasal obstruction VAS score.
The proposal is to have the co primaries of endoscopic score and nasal obstruction VAS 
score so as to capture both objective assessment of obstruction and symptoms.  
Other NP symptoms consisting of nasal discharge, mucus in the throat, loss of smell, 
facial pain and overall VAS symptom score will be assessed throughout the duration of 
this Phase III study, including follow up. 
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.
Participants are treated with mepolizumab for 13 doses at 28 day intervals.  Therefore,
assessment of the primary endpoint will be conducted 52 weeks after initiation of 
therapy.  
Two Phase II studies conducted with mepolizumab in severe NP suggest that although 
treatment with up to 6, 4-weekly doses, are sufficient to demonstrate efficacy of 
mepolizumab compared to placebo, the maximal effect may not have been achieved.  
Extending the exploration to thirteen 4 weekly doses will therefore increase the 
knowledge on the time to potential maximal effect.  
In Study CRT110178 significant clinical improvement in NP score was observed after 
two doses of mepolizumab.  The second study, MPP111782, also demonstrated a 
reduction in the need for surgery, as assessed by a pre-defined composite endpoint based 
on endoscopic NP score and overall VAS symptom score after 6 doses.  A reduction in 
the number of participants undergoing surgery was also observed.  Surgery is an 
important endpoint for patients and physicians as well as payors as it shows a direct cost 
burden.  Given there is a potential for delay between the decision to have surgery and the 
actual surgical event, this study will also measure time to admission to a waiting list for 
NP surgery, a potential surrogate for actual surgery.
Short courses of OCS 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 
 
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effective, it has the potential to reduce the overall exposure of patients to systemic steroid 
therapy, and this will be measured in the study.   
The target population for mepolizumab in NP is patients who are refractory to current 
SoC and highly symptomatic as a consequence.  Mepolizumab is intended to be 
administered chronically on a background of INCS, and other medical therapy usually 
given as short courses as required (OCS, occasional nasal douching, antibiotic courses) 
before surgery is considered.  There is currently no other chronic treatment that can be 
added to INCS that can be considered appropriate for an active control in this population. 
As such, placebo added to SoC will be utilized as the appropriate control.
Mometasone furoate (MF) is the only INCS currently approved for the treatment for NP 
both in Europe and US and will be part of the SoC in this study. All participants will be 
provided and are required to take MF at the maximum prescribable dose according to 
local label, if available, or as per local SoC.  This is usually 400 micrograms (μg) which 
equals 2 actuations (50 μg/actuation) in each nostril twice daily. For participants that are 
intolerant to this dose, the lower dose of 200g can be used (2 actuations (50 g 
/actuation) in each nostril once daily).
All participants randomized to IP will have their co-primary endpoint and NP surgical 
status 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.  To provide information on the durability and maintenance of mepolizumab 
effect after cessation of treatment, up to the first 200 participants randomized will be 
followed for a further 6 months without treatment with IP. 
5.5.
Dose Justification
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 and indications 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.  Based on these clinical pharmacology findings and the results of 
study MPP111782, the clinical pharmacology of mepolizumab administered to 
participants with NP is considered similar to those with severe asthma.
The proposed dose of 100 mg SC in NP in this study is supported by data from several 
studies:

Clinical efficacy of mepolizumab in participants with NP has only been investigated 
at a supra-pharmacological dose of 750 mg IV Q4W to date, although participants 
were followed for six months of washout.

Two studies in participants with severe asthma MEA112997 and MEA114092 
provided evidence of a dose response to suppression of blood eosinophil count.
 
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
In study MEA112997, the lowest dose of 75 mg IV (equivalent to the proposed 
100 mg SC dose) gave 78% inhibition.

Higher doses of 250 mg IV and 750 mg IV provided only modest increases in 
suppression (86% and 88%, respectively) indicating that the lowest dose provides 
approximately 90% of maximal pharmacological response attributable to drug.

A subsequent clinical pharmacology study MEA114092 confirmed equivalence of 
the SC route of administration and identified the half-maximal pharmacological dose 
of 11 mg SC, consistent with study MEA112997.

The approved severe asthma dosing regimen of 100 mg SC dose Q4W provides 55% 
overlap with 750 mg IV data when given 4-weekly.
Since initiation of the NP Phase II program, a meta-analysis of mepolizumab blood 
eosinophil exposure and dose response across all indications has been conducted to 
investigate the role disease plays in mepolizumab response.  When examined, the 
distribution of baseline eosinophil count (BEC) in participants enrolled in the Phase II NP 
studies was broadly similar to that seen in the severe asthma program after adjustment for 
inhaled and oral corticosteroid usage, and hence the exposure and dose responses for 
other diseases are predictive of NP.  This finding was confirmed using BEC data from the 
Phase II NP study MPP111782.  These data were predicted independently using a 
physiological exposure-response model of mepolizumab binding to IL-5, coupled to IL-5 
action on BEC.  After validation, the model was used to simulate alternative dosing 
regimens of interest in patients with NP, and then estimate the degree of pharmacological 
overlap 100 mg and 300 mg SC doses have with the tested 750 mg IV Q4W regimen for 
a range of dosing frequencies.  Results show considerable overlap between monthly 
doses of 100 mg and 300 mg SC and the tested 750 mg IV Q4W. 
In addition, the Phase II studies assessing mepolizumab safety and efficacy in NP 
CRT110178 and MPP111782 both followed participants for periods beyond treatment 
with mepolizumab 750 mg IV.  During the six-month period following mepolizumab 
treatment, there was evidence of sustained treatment effect.  The BEC suppression 
continues to correlate with a reduced clinical score until NP participants show evidence 
of blood eosinophil return to baseline after approximately three months (three 
mepolizumab half-lives).  Although numbers are small in both studies, these consistent 
observations provide a qualitative guide to the degree of blood eosinophil suppression 
necessary for sustained chronic dosing.  Simulations of blood eosinophil count for the 
two studies suggest that 100 mg Q4W will provide consistent blood eosinophil 
suppression to levels that were seen during the period of washout where efficacy was 
sustained.
Given the considerable human safety data in severe asthma, it would therefore seem 
reasonable to assess this dose for potential efficacy in the target population of patients 
with NP.  Considering the observed IV similarity of clinical pharmacology between 
patients with severe asthma and NP, overlapping pharmacological response predicted 
from a model validated in participants with NP, and experiential 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 this study is warranted.
 
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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. 18 years of age and older inclusive, at the time of signing the informed consent.
WEIGHT
2. Body weight greater or equal to 40kg.
Gender
3. Male or female participants (with appropriate contraceptive methods) to be eligible 
for entry into the study; 
i.
To be eligible for entry into the study Woman of Childbearing Potential 
(WOCBP; see Appendix 5 for definition) must commit to consistent and correct use 
of an acceptable method of birth control from the time of consent, for the duration of 
the trial, and for 4 months after last study drug administration. See Appendix 5 for a 
listing of acceptable methods of birth control.
Previous polyps surgery
4. Participants who have had at least one previous surgery in the previous 10 years for 
the removal of NP. NP Surgery is defined as any procedure involving instruments 
with resulting incision (cutting open) and removal of polyp tissue from the nasal 
cavity (polypectomy).  For the purpose of inclusion into this study 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 is not accepted.
 
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Current polyps diagnosis medication and need for surgery
5. Participants with bilateral NP as diagnosed by endoscopy or historical CT scan
6. Presence of at least two different symptoms for at least 12 weeks prior to screening:

nasal blockage/obstruction/congestion 
or 

nasal discharge (anterior/posterior nasal drip) 
and at least one of the following:

nasal discharge (anterior/posterior nasal drip)

facial pain/pressure

reduction or loss of smell
7. Participants with severe NP symptoms defined as an obstruction VAS symptom score 
of >5  
8. Severity consistent with a need for surgery as described by:
a) Participants with an overall VAS symptom score >7
b) Participants with an 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) 
9. Treatment with INCS (including intranasal liquid steroid wash/douching) for at least 
8 weeks prior to screening
INFORMED CONSENT
10. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
 
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6.2.
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.
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.
Nasal septal deviation occluding one nostril
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 V1
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.
13. Participants who are currently receiving, or have received within 3 months (or 5 half 
lives – whatever is the longest) prior to screening visit, 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. Not willing to be removed from a waiting list for NP surgery (if on one) or have pre-
planned surgery date cancelled if randomized  A waiting list is a list of patients 
waiting for a non-emergency or elective surgical procedure.
17. Participants that have taken part in previous mepolizumab, reslizumab, dupilumab or 
benralizumab studies 
 
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Pregnancy:
24. Women who are pregnant or lactating or are planning on becoming pregnant during 
the study.
Smoking History:
25. Participants who currently smoke (including e-cigarettes) or have smoked in the last 
6 months
Other Diseases/Abnormalities:
26. 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.
27. 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.
28. Immunocompromised, other than that explained by the use of corticosteroids taken as 
therapy
29. 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.
CONCOMITANT MEDICATIONS
18. Use of systemic corticosteroids (including oral corticosteroids) within 4 weeks prior 
to screening or planned use of such medications during the double-blind period
19. INCS dose changes within 1 month prior to screening.
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 leukotriene antagonist treatment less than 30 
days prior to Visit 1
23. Commencement or change of dose of allergen immunotherapy within the previous 3 
months.
 
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Severe Hepatic Impairment: 
30. 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 participant
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
12-Lead ECG:  
31. QTc >450 msec or QTc > 480 msec in participants with bundle branch block at visit 1
NOTES: 
The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF). It is either machine-read or manually over-read 
The specific formula used to determine eligibility and discontinuation for an individual 
participant should be selected by the site prior to initiation of the study and the same 
method should be utilized throughout the study for the individual. 
Drug or Alcohol Abuse:  
32. 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:  
33. Is an investigator, sub-investigator, study coordinator, employee of a participating 
investigator or study site, or immediate family member of the afore mentioned that is 
involved in this study.
 
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Inability to Read: 
34. In the opinion of the investigator, any participant who is unable to read and/or would 
not be able to complete a questionnaire.
6.3.
Randomisation Criteria
Those participants who meet the randomization criteria below will be randomized into 
the study until the target of approximately 400 randomized participants is reached.
At the end of the run-in period, study participants must fulfil the following additional 
criteria in order to be randomized to study treatment:
1. Endoscopic NP score of at least 3 in one nostril and 2 in the other as per over read 
from central lab taken at Visit 1
2. Mean overall VAS >7 over the last 7 days preceding Visit 2 (excluding Visit 
2)(from eDiary)
3. Mean nasal obstruction VAS score >5 over the last 7 days preceding Visit 2 
(excluding Visit 2) (from eDiary)
4. Not had any NP surgery or have been included into a waiting list for NP surgery 
between Visit 1 and Visit 2
5. eDiary compliance for VAS (4 out of the last 7 days preceding Visit 2).  
6. Laboratory abnormality: No evidence of clinically significant abnormality in the 
haematological, biochemical or urinalysis screen at Visit 1, as judged by the 
investigator.
7. Liver Function Tests: obtained at Visit 1:
a.
ALT<2x ULN (upper limit of normal)
b. AST<2x ULN
c.
Alk Phos ≤ 2.0x ULN
d. Bilirubin ≤ 1.5x ULN (isolated bilirubin>1.5x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%)
8. Asthma Exacerbation: No asthma exacerbations during run-in period. 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 hospitalization.
9. Maintenance Therapy: No changes or commencement during the run-in period in 
the dose or regimen of any regular baseline medication including 
a.
INCS 
b. a course of systemic corticosteroids, such as OCS 
c.
leukotriene receptor antagonists 
d. allergen immunotherapy 
 
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10. If the participant has a cold during run in then run in should be extended so to 
have the baseline visit, 2 weeks post the resolution of the cold but no greater than 
a total of 6 weeks from screening. Colds that are not resolved within the 4th week 
of the nominal run-in period (28 days after screening) will be ineligible for 
randomization as they would have exceeded this 6 week period
11. Agree to be removed from a waiting list for NP surgery, if on one, or have pre-
planned NP surgery date cancelled
6.4.
Participant and Study Completion
For determination of participant disposition, participants will be considered to have 
completed the study upon completion of Visit 15 (Week 52).  
The end of the study is defined as the last participant’s last visit. 
6.5.
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).
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 randomized, will be 
designated as run-in failures.
Re screening of participants will be permitted, however, advanced approval to proceed 
with re screening the participant must be obtained from the Medical Monitor (for contact 
details, see SPM).
 
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7.
TREATMENTS
Study 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.
The currently marketed drug product, Nucala (mepolizumab), is supplied as a 100 mg 
single-dose vial containing a sterile, preservative-free, lyophilized powder for 
reconstitution and subcutaneous injection.  
A liquid formulation of mepolizumab is under development which will be provided as 
pre-filled syringes in a safety syringe device for this study.  The liquid formulation has a 
distinct advantage over the lyophilized product as it does not require reconstitution, and 
the devices (upon commercial registration) will simplify and facilitate administration.  
The liquid formulation in a safety syringe device must be administered by a health care 
professional in this study.
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 treatment consists of up to 18 visits with a maximal total treatment duration of 
the study of approximately 52 weeks and maximum study duration of approximately 82 
weeks.  Screened participants will enter a 4 week run in period, followed by up to 52 
week treatment period.  Up to the first 200 randomized participants will be further 
followed up for a drug free period of up to 28 weeks with no injections.
Participants who are successfully enrolled into the study will be randomized 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 which includes intranasal 
mometasone furorate (MF)

Group 2: Placebo SC on top of SoC which includes intranasal MF 
All participants will be provided and are required to take MF at the maximum 
prescribable dose according to local label, if available, or as per local SoC.  This is 
usually 400 micrograms (μg), 2 actuations (50 μg/actuation) in each nostril twice daily.  
For participants that are intolerant to this dose, the lower dose of 200g can be used (2 
actuations (50 g /actuation) in each nostril once daily).
Study treatment completion is taken as Visit 15 which is Week 52 of the study for each 
individual participant.
 
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7.1.
Treatments Administered
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:
SC dose in thigh, abdomen or upper arm 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:
SC dose in thigh, abdomen or upper arm 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.
 
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7.1.1.
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 SPM. 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 9.3).
7.2.
Method of Treatment Assignment
Participants eligible to enter the study will be assigned to treatment randomly via an
interactive response technology (IRT) system. The randomization schedule will be 
generated using the GSK validated randomization software RandAll NG. The study will 
be randomized separately for each country. Participants will be assigned to study 
treatment in accordance with the randomisation schedule. Once a randomization number 
has been assigned to a participant, it cannot be reassigned to any other participant in the 
study.
Study treatment will be dispensed at the study visits summarized in SoA  
Returned study treatment should not be re-dispensed to the participants.
7.3.
Blinding
The site staff and central study team will be blinded to each participant’s eosinophil count 
(including white blood count differential).
RAMOS NG will be programmed with blind-breaking instructions. The blind may be 
broken if, in the opinion of the investigator, it is in the participant’s best interest for the 
investigator to know the study treatment assignment.  GSK must be notified before the 
blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the participant’s condition (eg, antidote is available). In this 
case, 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 CRF, as 
applicable.
 
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In the case of a medical emergency or in the event of a serious medical condition, 
when knowledge of the investigational product 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 
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.
7.4.
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 SPM. 
 
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
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.
7.5.
Treatment Compliance

Participants will receive study treatment 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 treatment 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 treatment.  

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.
7.6.
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.
The study site will supply INCS (MF) and oral OCS (prednisolone, prednisone or methy-
prednisolone for Korea only) as part of SoC medication that will be provided by the 
sponsor detailed in the SPM. 
Initiation or changes in the dosing regimen of leukotriene receptor antagonist or allergen 
immunotherapy from screening to end of the study are not allowed. Changes in the 
dosing regimen of INCS from screening to end of the study are not allowed.
The following medications may be used for all participants:
 
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1. Short courses of high doses of OCS (dose and duration as per SoC for NP).  The dose 
and duration will be recorded in the eCRF.
2. Throughout the study, asthmatic participants are to be maintained on their baseline 
SoC asthma treatment.
3. Although the use of rescue medications such as OCS is allowable at any time during 
the study, the date and time of rescue medication administration as well as the name 
and dosage regimen of the rescue medication must be recorded.
4. For antibiotic treatment for NP, the type, dose and duration must also be recorded. 
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 
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 NP 
6 months
7.7.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.
There are no plans to provide mepolizumab following study completion.
 
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8.
STUDY WITHDRAWAL AND IP DISCONTINUATION 
CRITERIA
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 even if they 
discontinue study treatment  in order to capture NP size scores, symptom score, any 
subsequent entry into a surgical waiting list for NP surgery and actual surgical 
procedures.  
The following actions must be taken in relation to a participant who fails to attend the 
clinic for a required study visit:

The site must attempt to contact the participant and re-schedule the missed visit as 
soon as possible. 

The site must 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. 

In cases where the participant is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the participant (where 
possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts should 
be documented in the participant’s medical record. 

Should the participant continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”.
8.1.
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.

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 for data to be collected at the time of study withdrawal and follow-
up and for any further evaluations that need to be completed.
 
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8.1.1.
Primary reasons for withdrawal from the study
The primary reason for study withdrawal (and sub-reason, if applicable) will be 
categorized as:

Withdrew consent
o
participant relocated
o
frequency of visits
o
burden of procedures
o
other (specify)

Study closed/terminated

Lost to follow-up
8.1.2.
Early Withdrawal Visit
The definition of an early participant withdrawal from the study will be any participant 
who is randomized to blinded medication and, for any reason, is withdrawn prior to 
completion of the Visit 15 procedures.
A participant may voluntarily discontinue participation in the study at any time.    
Participants that withdraw from the study should return to the clinic return to the clinic 28 
days after the last dose 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:

Concomitant medication assessment

Adverse event assessment

12 –lead ECG

Physical examination (recorded in source documents only)

Collect/review electronic diary  

Urine pregnancy test for females of childbearing potential 

Assessment of endoscopic nasal polyp score

Assessment of surgery 

Assessment of OCS use

Assessment of INCS use

Assessments of symptoms

Assessment of QoL

WPAI

PK
 
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
Lab assessments including liver chemistry and immunogenicity
Access the RAMOS NG to report participant’s early withdrawal from the study
8.2.
Premature Discontinuation of Study Treatment 
(investigational product - IP)
8.2.1.
Discontinuation Criteria for IP
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 follow-up Visit assessments. The participant’s NP 
surgical status will be 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.
All participants will be followed up for the study duration.  However, given that actual
NP surgery can distort the anatomical architecture of the nasal cavity nullifying the NP 
size score and VAS, participants who have had NP surgery prior to Week 52 will be 
considered as treatment failures in the analysis of the primary endpoints.  
Unlike the Phase II study, participants in the Phase III program will be allowed short 
courses of systemic OCS to control their NP symptoms during the study and as a 
consequence will help to minimize the overall withdrawal rates.  
8.2.2.
Study Specific IP 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 > 600 msec 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 OCS or Surgery are not a reason for Study withdrawal or IP 
discontinuation. 
8.2.3.
Primary reasons for IP 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
 
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o
participant relocated
o
frequency of visits
o
burden of procedures
o
other (specify)

Protocol deviation 

Lack of efficacy 

Study closed/terminated

Participant reached protocol-defined stopping criteria
o
Liver event
o
Pregnancy
o
QTc

Investigator discretion
8.2.3.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant. 
 
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Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7
Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7
 
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8.2.3.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
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
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
9.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the SoA Table, are essential and required for study conduct.

This section lists the procedures and parameters of each planned study assessment.  
The exact timing of each assessment is listed in the SoA.
 
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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

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 (eg, 
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.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Critical pre-Screening, Screening and Baseline 
Assessments
9.1.1.
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.
9.1.2.
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.
9.1.3.
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, 
omalizumab or previous biologics in the past 12 months. 
 
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
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 

Dispensing and training of eDiary

Nasal obstruction VAS symptom score

Overall VAS symptom score

Resting 12-lead ECG 

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 will be assessed to confirm child-bearing status (if applicable)
Parasitic screening (only in countries with a high-risk or in participants who have 
visited a high-risk country)

Endoscopic NP score

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.
9.1.4.
Critical procedures performed at first treatment Visit (Baseline 
Visit 2)

Review eDiary and re train if required

Review randomisation criteria

Review the Endoscopic NP score recorded during V1 as rated by the core lab

Vital signs 

Blood for biomarker

Laboratory tests. This should include

Clinical Chemistry
 
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
Haematology with differential

Blood for baseline immunogenicity

Blood for PK assessment

Urine pregnancy test for WOCBP
9.1.5.
Critical procedures performed throughout treatment period 
(Visits 2 - 15)

SNOT-22 questionnaire

SF-36 (Visits 2, 3, 5, 7, 9, 11, 13, 15 only)

WPAI

ACQ-5 (for asthmatics)

Review eDiary and re train if required

Overall VAS symptom score

VAS for nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial 
pain (daily in eDiary)

Assessment of Surgery (actual and waiting list)

Assessment of OCS dose and duration

Endoscopic NP score (be performed at visits 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 and 15)

PnIF 

UPSIT (Visits 2, 3, 5, 7, 9, 11, 13, 15 only). UPSIT test will be performed only in 
selected countries

Blood for PK (to be done only in visits indicated in the SoA)

Genetic sample (to be done one time only in any of the visits)

Blood for biomarker (Visit 15)

AE/SAE review

Concurrent medication review

12-lead ECG (Visits 2 and 15 only)

Vital signs

Laboratory assessments (Haematology at all visits and biochemistry, (including liver 
chemistries) at visits 2 and 15 only.

Blood for immunogenicity

Urinalysis

Urine pregnancy test (for WOCBP)
 
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9.1.6.
Critical procedures performed throughout follow up period (Visits 
16 - 18)

Review eDiary and re train if required

Overall VAS symptom score

VAS for nasal obstruction, nasal discharge, mucus in the throat, loss of smell, facial 
pain (Daily on eDiary)

SNOT-22 questionnaire

SF-36 (at Visits 16, 17 and 18)

Assessment of Surgery (actual and waiting list)

Assessment of OCS dose and duration

Endoscopic NP score

WPAI

Blood for PK (at Visit 17 only)

AE/SAE review

Concurrent medication review

Blood for immunogenicity
9.2.
Efficacy Assessments
9.2.1.
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 12 (recorded as the sum of the right and left 
nostril scores with a range of 0-8; higher scores indicate worse status).  
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. The output from the central labs is considered final for the 
purpose of this 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.
 
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9.2.2.
Individual Symptoms Visual Analogue Scale (VAS)
All scales to be used in the study will be on 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 5 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.
 
Participants will be instructed on how to 
use the scale prior to using the scale. 
VAS is an instrument that measures a characteristic or attitude that is believed to range 
across a continuum of values and cannot easily be directly measured.
 In this study patient reported symptom VAS will be 
collected using an eDiary.  Given that there is no direct relationship between pixel size 
and mm, on electronic systems the key is that the line must (just like the paper version), 
have 101 individually selectable points.  There are a number of publications which shows 
the applicability of VAS electronically and its comparability to traditional paper [Hollen, 
2013, Reips, 2008, Cook, 2004, Jamison, 2002]. In summary, the length of the VAS 
doesn’t matter, and participant’s responses are not altered by implementing the VAS 
electronically. For the purpose of this protocol a VAS score of 7 in the overall symptom 
score and 5 in NP obstruction symptoms score are equivalent to 70 units and 50 units in 
the electronic VAS as measured using the eDiary.  
9.2.3.
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 actual documented surgery and/or sinuplasty. 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 (polypectomy) in the 
nasal cavity.
9.2.4.
Medication
The number of courses of systemic steroids and OCS as well as the dose and duration of 
the courses will be recorded in the CRF.  The dose for a course of OCS will be according 
to the participants SoC for OCS use for its NP condition.  The dose and duration of the 
OCS taken will be recorded in the eCRF. For the purpose of this study a course of 
 
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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 OCS will be provided in the SPM.  
9.2.5.
Peak Nasal Inspiratory Flow (PnIF)
A PnIF Meter will be used to derive forced inspiratory peak flow through the nose during 
the study according to the SoA (Section 2). Please refer to the Study Procedures Manual 
for further details.
PnIF will be measured using an IN-CHECK flow meter. After blowing their nose, 
participants inspired forcefully from the residual volume to total lung capacity with their 
mouth closed. All measurements were made in the sitting position and a good seal around 
the face mask was ensured. The highest value of three consecutive (maximal) readings 
was recorded.
9.2.6.
Olfaction testing: University of Pennsylvania Smell Identification 
Test (UPSIT)
UPSIT will be used at the time points indicated in the SoA (Section 2) to assess each 
participant’s sense of smell. 
UPSIT test will be performed only in selected countries.
UPSIT is a test that is commercially available for smell identification to test the function 
of an individual's olfactory system. It is the gold standard of smell identification tests for 
its reliability and practicality (Doty, 1989). 
This test is a measurement of the individual's ability to detect odours at a suprathreshold 
level. The test is usually administered in a waiting room and takes only a few minutes. 
The test consists of 4 different 10 page booklets, with a total of 40 questions (Doty, 
2007). On each page, there is a different "scratch and sniff" strip which are embedded 
with a microencapsulated odorant. There is also a four choice multiple choice question on 
each page. The scents are released using a pencil. After each scent is released, the patient 
smells the level and detects the odour from the four choices. There is an answer column 
on the back of the test booklet, and the test is scored out of 40 items. The score is 
compared to scores in a normative database from 4000 normal individuals, this tells the 
level of absolute smell function. The score also indicates how the patient does in 
accordance to their age group and gender. Please refer to the SPM for further details.
9.2.7.
Health Related Quality of Life (HR QoL) assessments
9.2.7.1.
Sino-Nasal Outcome Test (SNOT-22) questionnaire
SNOT-22 will be completed by the participant monthly at study visits according to the 
SoA (Section 2) under the supervision of the health care professional. The SNOT-22 will 
be completed electronically at study visits.  Patients are to be provided with a quiet 
location, free from distraction and instructed that to select the single response option fro 
each question that most closely reflects their health.
 
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Participants will be asked to rate the severity of their condition on each of the 22 items 
over the previous 2 weeks using a
 
 [Hopkins, 2009].
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].
9.2.8.
Assessments for asthmatic participants only
9.2.8.1.
Asthma Control Questionnaire (ACQ-5)
ACQ-5 will be assessed at clinic visits under the supervision of the health care 
professional, during the study according to the SoA (Section 2). 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 
 
scale. Please refer to the SPM for further details.
9.3.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The following adverse events of special interest will have a customized AE and SAE 
pages in the eCRF:

Local injection site reactions

Systemic reactions
In addition, the information whether an event met the diagnostic criteria for anaphylaxis 
as outlined by the Second Symposium on Anaphylaxis [Sampson, 2006] and in Appendix 
11 will be collected on the AE and SAE CRF pages.
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 (see Section 8). 
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the end of the study at 
the time points specified in the SoA (Section 2).
 
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
All AEs will be collected from the start of treatment until [the end of the study at the 
time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Appendix 4. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. 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 treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.3.2.
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. 
9.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non serious AEs of special 
interest will be followed until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up. Further information on follow-up procedures is given in 
Appendix 4.
9.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment 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 treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, summary or listing of SAE) from the sponsor will 
 
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review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.3.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 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.
9.3.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in participants with Nasal 
Polyposis and can be serious/life threatening:

Nasal polyp surgery including sinuplasty
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of a SAE).  These events will be recorded 
on the DRE page in the participant’s CRF within 2 months.  These DREs will be 
monitored by a SCT on a routine basis.   
NOTE: However, if either of the following conditions apply, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event was 
related to treatment with the investigational product
9.3.7.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 4 months post last dose.

If a pregnancy is reported, the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
 
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9.3.8.
Medical Device Incidents (Including Malfunctions)
GSK Medical devices are being provided for use in this study. 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 7.1.1). 
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 4 of the protocol. 
9.3.8.1.
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.
9.3.8.2.
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 5.5). 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.
9.3.8.3.
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 
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9.3.8.4.
Safety syringe functionality assessment
During administration of the safety syringe the HCP will be asked to inspect the medical 
device and complete the inspection questions in Appendix 13.
If there is an error with the medical device then refer to the Safety syringe Error / Failure 
Reporting Form in Appendix 9.
9.3.8.5.
Returning defective Medical Devices to GSK
All defective devices will be returned to GSK

Please refer to the SPM for all details
9.3.8.6.
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.

The investigator, or responsible person according to local requirements (eg, the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.9.
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.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
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.
9.4.2.
Vital Signs

As detailed in the SoA vital signs will be measured in semi-supine position after 5 
minutes rest and will include systolic and diastolic blood pressure and pulse rate.

Vital signs assessments will be taken before measurement of any ECGs at the 
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9.4.3.
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 SPM).

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 SPM. 
9.4.4.
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 investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 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 etiology 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 (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.
9.5.
Pharmacokinetics

Blood samples for analysis of mepolizumab plasma concentration will be 
obtained as per the SoA.  Samples obtained at Visits 2, 3, and 15 should be drawn 
prior to dosing.  Participants going into no treatment follow up will have 
additional sample at Visit 17. The date and exact time of collection for each 
sample will be documented in the eCRF.
 
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
Details for collection and processing of samples may be found in the SPM.
9.6.
Pharmacodynamics
Blood eosinophil counts will be recorded as part of the standard haematological 
assessments performed at the visits specified in the SoA. From Visit 2 onwards, blood 
eosinophil counts will not be communicated to investigators, in order to maintain the 
blind.
9.7.
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.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in SPM.
9.8.
Exploratory Biomarkers
Blood samples will be collected during this study and may be used for the purposes of 
measuring novel biomarkers to identify factors that may influence severe NP, and/or 
medically related conditions, as well as the biological and clinical responses to 
mepolizumab. If relevant, this approach will be extended to include the identification of 
biomarkers associated with adverse events. Samples will be collected at the time points 
indicated in SoA.
9.9.
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 SPM.
9.10.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
evaluated in this study by means of the Short Form-36 (SF-36) and the Work Productivity 
and Activity Impairment Questionnaire (WPAI) questionnaires.
9.10.1.
Short Form-36 (SF-36) questionnaire
SF-36 will be performed monthly by the participant at study visits (Section 2) under the 
supervision of the health care professional.
 
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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 
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] reported the unique study that has investigated the impact 
of NP demonstrating that NP impair QoL in all SF-36 domains. Using the SF-36 and 
compared with a healthy population, other studies has also demonstrated that chronic 
rhinosinusitis has a considerable impact on all SF-36 domains except for physical 
functioning [Gliklich, 1997; Winstead, 1998; Durr, 1999; Wang, 2003].
Participants with NP had lower scores in all SF-36 domains except for physical 
functioning and general health than participants with chronic obstructive pulmonary 
disease [Alonso, 1998], coronary artery disease [Failde, 2000], and asthma [Espinosa, 
2002].
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.
9.10.2.
Work Productivity and Activity Impairment Questionnaire (WPAI)
WPAI will be assessed by the participant at study visits described in the SoA (Section 2)
under the supervision of the health care professional.
The WPAI questionnaire is an instrument to measure impairments in both paid work and 
unpaid work [Reilly, 1993; Reilly Associates]. 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 Associates; 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: 
[Reilly, 1993; Reilly 
Associates]. 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 
 
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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, 1993; Reilly 
Associates]. 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.
10.
STATISTICAL CONSIDERATIONS
The study is designed to test the superiority of mepolizumab 100mg SC vs. placebo. 
Significance tests will be performed at the two-sided 5% alpha level (one-sided 2.5%).
10.1.
Sample Size Determination
The sample size is based on the co-primary efficacy endpoints of total endoscopic nasal 
polyp score and nasal obstruction VAS score at Week 52 and the key secondary endpoint 
of time to actual surgery. A trial of 200 participants per treatment group is estimated to 
have over 90% power to observe statistical significance at the two sided 5% level for 
both co-primary endpoints and for the key secondary endpoint of time to actual surgery.  
The calculation for the co-primary endpoints is based on analysis of study MPP111782.  
This analysis showed 27% of placebo participants with a one-point improvement in NP 
score compared to 52% of mepolizumab participants.  For nasal blockage, 39% of 
placebo participants showed a one-point improvement in NP score compared to 70% of 
mepolizumab participants.  
For surgery, 90% power to observe statistical significance at the two sided 5% level is 
based on a true reduction in the proportion of participants receiving surgery from 40% on 
placebo to 25% on mepolizumab. In the six month study MPP111782, 20% of 
participants on placebo and 9% of participants on mepolizumab received surgery; a 
greater proportion of participants receiving surgery is expected in this twelve month 
study.
The smallest observed effect predicted to result in a statistically significant difference 
between treatment groups is a reduction in the proportion of participants receiving 
surgery from 40% on placebo to 30% on mepolizumab.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Participants Enrolled 
All participants enrolled and for whom a record exists on the study 
database
Randomized
All randomized participants
 
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Intent-to-Treat
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they are allocated at randomisation.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received for more than 50% of treatment 
administrations.
10.3.
Statistical Analyses
To strongly control the type I error rate for the primary and secondary outcomes, 
adjustment for multiplicity will be performed based on a hierarchical testing of endpoints 
in a pre-defined order. The co-primary endpoints will be tested first and if these 
comparisons are both significant at the two-sided 5% level, the first of the secondary 
endpoints will be tested. Testing will continue in a similar manner for the remaining 
secondary endpoints dependent on statistical significance having been achieved for the 
previous endpoint in the hierarchy.
The secondary endpoints will be tested in the following pre-defined order:
1. Time to first nasal surgery 
2. Change from baseline in overall VAS symptom score 
3. Change from baseline in SNOT-22 total score 
4. Proportion of participants requiring systemic steroids for nasal polyps 
5. Change from baseline in the mean composite VAS score (nasal obstruction, nasal 
discharge, mucus in the throat and loss of smell) 
6. Change from baseline in mean individual VAS symptom score for loss of smell
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Co-Primaries
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 
(excluding the day of the visit). The mean VAS score over the last 7 days before 
Visit 2 will be used to determine the baseline value. 
Participants who undergo surgery/sinuplasty prior to Week 52 will be assigned 
their worst observed value prior to surgery/sinuplasty.  Participants who withdraw 
from study without having experienced surgery/sinuplasty will be assigned their 
 
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Endpoint
Statistical Analysis Methods
worst observed score prior to study withdrawal.
The comparison of mepolizumab with placebo will be expressed as a difference in 
median change from baseline presented with corresponding 95% confidence 
intervals, the p-value for the difference between treatment groups will be based 
on the non-parametric Wilcoxon rank-sum test.  The difference in median change 
between placebo and mepolizumab with associated 95% confidence intervals will 
be assessed by quantile regression using a bootstrap approach (Mehrotra DV
2017; Keene O.N 2018), with covariates of treatment group, baseline score, 
baseline blood eosinophil count and region.
Secondary
Time to actual NP surgery will be compared between treatment groups using a 
Cox’s proportional hazards model with covariates of treatment group, baseline NP 
score, baseline nasal obstruction score and region. Graphs of the Kaplan-Meir 
estimates of the proportion of participants with events over time will be produced 
by treatment group.
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 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 SNOT-22 total score at Week 52 will be 
analysed in a similar manner to the co-primary endpoints.  The proportion of 
participants requiring systemic steroids for nasal polyps will be analysed using a 
logistic regression model.
“other”
Will be described in the reporting and analysis plan
 
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10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population and will be described in 
the reporting and analysis plan.
10.3.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses 
will be presented separately from the main clinical study report (CSR). 
10.3.4.
Interim Analyses
No interim analysis of data is planned for this study.
 
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11.
REFERENCES
Alobid I, Benítez P, Bernal-Sprekelsen M, Roca J, Alonso J, Picado C, Mullol J. Nasal 
polyposis and its impact on quality of life: comparison between the effects of medical and 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ-5
Asthma Control Questionnaire
AE 
Adverse Event
ALT 
Alanine aminotransferase (SGPT)
AST 
Aspartate aminotransferase (SGOT)
BEC
blood eosinophil counts
BMI 
Body mass index
BP
bodily pain
CRF 
Case Report Form
CRS
chronic rhinosinusitis
CT
Computed tomography
CV
Cardiovascular
DNA 
Deoxyribonucleic acid
DRE
disease related events
ECG 
Electrocardiogram
eCRF 
Electronic Case Report Form
EW
Early Withdrawal
eDiary
Electronic Diary
ESS
Endoscopic sinus surgery
FDA 
Food and Drug Administration
GCP 
Good Clinical Practice
GCSP 
Global Clinical Safety and 
Pharmacovigilance
 
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GH
general health
GSK 
GlaxoSmithKline
HBsAg
presence of hepatitis B surface antigen
HCP
Health care practitioner
HIV 
Human Immunodeficiency Virus
h/hr 
Hour(s)
HR QoL 
Health Related Quality of Life
HRT 
Hormone Replacement Therapy
IBS
irritable bowel syndrome
ICH 
International Conference on Harmonization 
of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
ICF
Informed consent form
IEC 
Independent Ethics Committee
IL-5 
Interleukin-5
IL-5Ra
Interleukin-5 receptor alpha
IM
intramuscular
INCS 
Intranasal Corticosteroids
INR
International normalised ratio
IP 
Investigational Product
IRB 
Institutional Review Board
ITT 
Intent-to-Treat
IU 
International Unit
IV 
Intravenous
kg 
Kilogram
L
Litre
 
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LOCF 
Last observation carried forward
μg 
Microgram
μL 
Microlitre
MCS
Mental Component Summary
MedDRA 
Medical Dictionary for Regulatory 
Activities
MH
mental health
MF
Mometasone furoate
mg 
Milligrams
mL 
Millilitre
msec 
Milliseconds
NP
Nasal Polyps
OCS
Oral Corticosteroids
PCS
Physical Component Summary
PCSA
placebo controlled severe asthma
PD 
Pharmacodynamic
PF
physical functioning
PGx 
Pharmacogenetics
PK 
Pharmacokinetic
PnIF 
Peak Nasal Inspiratory Flow
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
RAMOS 
Registration and Medication Ordering 
 
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System
RAP 
Reporting and Analysis Plan
RBC 
Red blood cells
RE
role emotional
RP
role physical
SAE 
Serious adverse event(s)
SC
Subcutaneously
SCT
Study conduct team
SD 
Standard deviation
SF
social functioning
SF-36
Short Form Health Survey 36
SGRQ
St George questionnaire
SNOT 
Sino-Nasal Outcome Test
SoA
Schedule of activities
SoC
Standard of Care
SOP 
Standard Operating Procedure
SPM 
Study Procedures Manual
SUSAR
suspected unexpected serious adverse 
reactions
ULN 
Upper limit of normal
UPSIT
University of Pennsylvania Smell 
Identification Test
UK 
United Kingdom
US 
United States
URTI
Upper respiratory tract infection
VAS 
Visual Analogue Scale
 
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VT
Vitality
WOCBP
Woman of Childbearing Potential
WPAI
Work Productivity and Activity Impairment
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NUCALA
Acq-5
In-check
Mometasone Furorate (Mf)
Sf-36
Snot-22
Upsit
Wpai
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 1 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment 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 treatment decision or response 
evaluation, the results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
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 
[nonfasting]
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick

Microscopic examination (if blood or protein is abnormal)
 
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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only and if urine positive)

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2

All study-required laboratory assessments will be performed by a 
central laboratory.

Hepatitis B and C testing
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 8.1 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 (excluding 
studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.
 
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12.3.
Appendix 3: Study Governance Considerations
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 International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, the Directive 
2001/20/EC  or European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
 
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guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
 
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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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 (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion 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. 
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.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
 
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The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment 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 fulfill the definition of an AE 
or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
 
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
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, 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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
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 detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
 
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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 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 treatment 
 
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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.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.  New or updated information will be recorded in 
the originally completed CRF.

The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information.
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) and fax the form to GSK within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
 
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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) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in SPM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SPM.
 
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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the foetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study participant is not required.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly from the
time of consent, for the duration of the trial, and for 4 months after the last mepolizumab
administration  as described in Table 2. 
 
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Table 2
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device

Intrauterine hormone-releasing system 

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
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 drug. 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.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 4 months corresponding to time needed to eliminate study treatment plus 30 days 
for study treatments with genotoxic potential  after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 

Additional pregnancy testing should be performed as per SoA 
 
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
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 10 mIU/mL will be performed and assayed in 
the central laboratory 
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 2
weeks of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating 

will discontinue study treatment or be withdrawn from the study
 
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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; 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 Nasal polyposis 
and related diseases. They may also be used to develop tests/assays including 
diagnostic tests) related to mepulizumab (or study treatments of this drug class), and 
nasal polyposis. 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)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

DNA samples will be analyzed for investigate the relationship between genetic 
variants, Response to medicine, including mepolizumab or any concomitant 
medicines; NP susceptibility, severity, and progression and related conditions . 
Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to mepolizumab or study treatments 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 treatments of 
this class) or nasal polyosis continues but no longer than 15 years or other period as 
per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and Hepatitis 
delta antibody5.

Obtain blood sample for pharmacokinetic 
(PK) analysis, within 28 days after last 
dose6
 
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Liver Chemistry Stopping Criteria 
granted 

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). NOTE: not required in 
China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
 
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studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If Hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment 

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 
 
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12.8.
Appendix 8: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study. 
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
 
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Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

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 an incident. 
This includes any amendment to the device design to prevent recurrence.
 
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12.9.
Appendix 9: SYRINGE ERROR / FAILURE REPORTING 
FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of safety syringe failure/user error at 
site and submit to GSK
via email to
Primary Investigator:
Protocol #:
205687
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
participant #:
E-mail (print clearly):
Site Address:
Date Dispensed:
Date Returned:
Has the safety syringe been used by the HCP?       ___ No             ___ Yes
(Considered a biohazard.)  
Was there an AE or SAE associated with this failure/error?  ___ No   ___Yes 
If yes, please enter the eDC AE sequence number:____________________
Please provide description of user error:
Which of the following user errors apply? Tick all that apply:
__   Did not check expiration date
__   Incorrect preparation or incorrect choice of injection site 
__   Did not check product solution
 
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__   Needle shield not removed from safety syringe
__   Syringe pulled away before end of injection (i.e., before the plunger is pushed all the way 
down)
__   Did not check inspection window for white plunger
__   Other (please specify below).
Description of other user error:
Reason for Safety Syringe failure. Tick all that apply:
__  Safety Syringe leaking
__   Components broken / cracked
__   Cannot remove needle cap 
__ Inspection window not clear
__   Bent needle
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot push the plunger rod down (i.e., required force is too high)
__   Other (please specify below)
Description of other syringe failure:
Packaging failure. Tick all that apply:
__   Device damaged
 
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__   Packaging damaged or can’t read label
__   Security seal was broken
__   Syringe missing from kit
__   Other (please specify below)
Description of other packaging failure:
Error/failure outcome (check one):
   Participant received no dose
   Participant received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement syringe 
provided
    Dose omitted
    Participant withdrawn
Replacement Syringe Dispensed Date:
Instructions for further processing: Please fax or email completed Form to The GSK
Pen Failure Processing Team at
or email address.  Please contact
your study monitor with any questions or for troubleshooting.  Maintain the Form and in
the participants’ records. You may be contacted further concerning the malfunctioned
safety syringe.
 
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12.10.
Appendix 10: Country-specific requirements
South Korea Investigational Product Labels
In this study participant identification number and visit number will not be included in 
the IP label. However, it will be tracked at site pharmacy when the IP is dispensed to 
each participant.
Korea Participants: In regards to Inclusion criteria 1, only adult participants as per local 
laws at the time of signing the informed consent will be eligible for inclusion in this 
study.
The OCS supplied for Korea participants will be prednisolone, prednisone or methyl-
prednisolone.
 
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12.11.
Appendix 11: Anaphylaxis Criteria
Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria 
do not make a distinction based on underlying mechanism. These criteria are summarized 
as follows:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
b) Reduce d blood pressure or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c) Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence)
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced blood pressure 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 blood pressure
b) Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% 
decrease from that person’s baseline
 
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12.12.
Appendix 12: 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
 
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12.13.
Appendix 13 - Inspection of the Safety Syringe Form
Injection Assessment – Safety Syringe
Was the full dose successfully
administered?
Yes, injection successful
No, injection not successful (please complete the questions below1)
No, injection not attempted
Were there any observations with respect to the user tasks that indicate that the 
full dose has not been administered? Check all that apply.
-
Incorrect injection site selected, record location below
-
Needle not fully inserted into site
-
Plunger not slowly pushed down
-
Plunger not pushed all the way down until the stopper reaches
the bottom of the syringe
-
Thumb not moved up, plunger not risen and needle guard
not activated
-
Evidence of liquid leaking from injection site (i.e. potentially
indicating a premature lift or a wet injection)
-
Other (please specify below)
Were there any observations with respect to the device that indicate that the full
dose has not been dispensed? Check all that apply.
-
Syringe leaking
-
Components broken / cracked
-
Cannot push the plunger rod down (i.e., required force is too high)
-
Other (please specify below)
Footnote 1 refers to the Safety Syringe Error / Failure Reporting Form Section 12.9. Failure in either of 
these two events requires the appropriate form to be completed. HCP should review the user tasks in
completing the injection, the device and the packaging and complete form in Section 12.9 to 
capture any issues.
 
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12.14.
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).
 
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SAP_001.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
205687 
1 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for Study 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) 
Compound Number 
: SB240563 
Effective Date 
: 20-FEB-2020 
Description: 

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report for Study 205687 (Protocol 2016N294302_04)

This version of the RAP includes amendments to the originally approved RAP.
RAP Author: 
Author 
Date 
 
14-Feb-2020
Statistics Director (Biostatistics) 
 
14-Feb-2020
Senior Director (Clinical Pharmacology) 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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CONFIDENTIAL 
The GlaxoSmithKline group of companies 
205687 
2 
RAP Team Review Confirmations 
(Method: E-mail): 
Reviewer 
Date 
 
17-Feb-2020
Study Physician Lead (Clinical Development, Respiratory) 
 
17-Feb-2020
Project Physician Lead (Clinical Development, Respiratory) 
 
17-Feb-2020
Clinical Investigation Lead (Clinical Development, Respiratory) 
 
14-Feb-2020
Director (SERM Safety & Medical Governance Pharma) 
 
17-Feb-2020
Programmer (Biostatistics) 
 
17-Feb-2020
Senior Director (Clinical Pharmacology) 
 
17-Feb-2020
Director (Patient Reported Outcomes) 
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature): 
Approver 
Date 
 
20-Feb-2020
Senior Statistics Director (Biostatistics) 
 
20-Feb-2020
Programming Director (Biostatistics) 
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TABLE OF CONTENTS 
PAGE 
1.
INTRODUCTION ...................................................................................................... 8
1.1. 
RAP Amendments ........................................................................................ 8 
2.
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Study Objective(s) and Endpoint(s)............................................................... 9 
2.2. 
Study Design .............................................................................................. 12 
2.3. 
Statistical Hypotheses................................................................................. 13 
2.4. 
Changes to the Protocol Defined Statistical Analysis Plan .......................... 13 
3.
PLANNED ANALYSES .......................................................................................... 14 
3.1. 
Interim Analyses ......................................................................................... 14 
3.2. 
Final Analyses ............................................................................................ 14 
4.
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 15 
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS ..................................................................................................... 15 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 15 
5.2. 
Baseline Definitions .................................................................................... 16 
5.2.1. 
Visit-based endpoints .................................................................. 16 
5.2.2. 
eDiary Data .................................................................................. 16 
5.3. 
Multicentre Studies ..................................................................................... 16 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 17 
5.4.1. 
Covariates and Other Strata ........................................................ 17 
5.4.2. 
Examination of Subgroups ........................................................... 17 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 18 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 19 
6.
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
7.
EFFICACY ANALYSES .......................................................................................... 20 
7.1. 
Primary Efficacy Analyses .......................................................................... 20 
7.1.1. 
Endpoint / Variables ..................................................................... 20 
7.1.2. 
Summary Measure ...................................................................... 21 
7.1.3. 
Population of Interest ................................................................... 21 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 21 
7.1.5. 
Statistical Analyses / Methods ..................................................... 21 
7.1.5.1. 
Statistical Methodology Specification .......................... 21 
7.2. 
Secondary Efficacy Analyses ...................................................................... 23 
7.2.1. 
Time to first nasal surgery ............................................................ 23 
7.2.1.1. 
Summary Measure ..................................................... 23 
7.2.1.2. 
Population of Interest .................................................. 23 
7.2.1.3. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 23 
7.2.1.4. 
Statistical Analyses / Methods .................................... 23 
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7.2.2. 
Change from Baseline in Mean Overall VAS Symptom 
Score During the 4 weeks Prior to Week 52, Mean 
Composite VAS Score and Mean Loss of Smell VAS 
Score ........................................................................................... 24 
7.2.2.1. 
Details regarding the summary measure, 
population of interest and the strategy for 
intercurrent events are provided in Section 
7.1.2 to Section 7.1.4.Statistical Analyses / 
Methods ..................................................................... 24 
7.2.3. 
Change from Baseline in Sino-Nasal Outcomes TEST 22 
(SNOT-22) Total Score at Week 52 ............................................. 25 
7.2.3.1. 
Statistical Analyses / Methods .................................... 25 
7.2.4. 
Proportion of subjects requiring systemic steroids for nasal 
polyps up to Week 52 .................................................................. 26 
7.2.4.1. 
Summary Measure ..................................................... 26 
7.2.4.2. 
Population of Interest .................................................. 26 
7.2.4.3. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 26 
7.2.4.4. 
Statistical Analyses / Methods .................................... 27 
7.3. 
Other Efficacy Analyses .............................................................................. 27 
7.3.1. 
Total Endoscopic Nasal Polyps Score Responders ..................... 27 
7.3.1.1. 
Summary Measure ..................................................... 28 
7.3.1.2. 
Population of Interest .................................................. 28 
7.3.1.3. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 28 
7.3.1.4. 
Statistical Analyses / Methods .................................... 28 
7.3.2. 
Change from Baseline in Mean Individual and Composite 
VAS Symptom Scores ................................................................. 29 
7.3.2.1. 
Statistical Analyses / Methods .................................... 29 
7.3.3. 
SNOT-22 Responders ................................................................. 30 
7.3.3.1. 
Summary Measure ..................................................... 30 
7.3.3.2. 
Population of Interest .................................................. 30 
7.3.3.3. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 30 
7.3.3.4. 
Statistical Analyses / Methods .................................... 30 
7.3.4. 
SNOT-22 Domain Scores ............................................................ 31 
7.3.5. 
Need for Surgery ......................................................................... 31 
7.3.5.1. 
Summary Measure ..................................................... 31 
7.3.5.2. 
Population of Interest .................................................. 31 
7.3.5.3. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 31 
7.3.5.4. 
Statistical Analyses / Methods .................................... 31 
7.3.6. 
Rate of Nasal Surgery.................................................................. 32 
7.3.7. 
Time to First Inclusion on Waiting List for NP Surgery ................. 32 
7.3.8. 
Waiting List for NP surgery .......................................................... 32 
7.3.9. 
Change from baseline in UPSIT (University of 
Pennsylvania Smell Identification Test) ........................................ 33 
7.3.9.1. 
Statistical Analyses / Methods .................................... 33 
7.3.10. 
Change from baseline in PnIF (Peak Nasal Inspiratory 
Flow) ............................................................................................ 33 
7.3.11. 
Health Outcomes ......................................................................... 34 
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7.3.11.1. SF-36 Mental Component Summary (MCS), 
Physical Component Summary (PCS) and 8 
summary scores ......................................................... 34 
7.3.11.2. Work Productivity and Activity Impairment 
Questionnaire (WPAI) ................................................. 34 
7.3.12. 
Systemic Steroid Use................................................................... 34 
7.3.12.1. Number of mgs per year of prednisolone-
equivalent OCS dose for nasal polyps up to 
Week 52 ..................................................................... 34 
7.3.12.2. Days on Therapy ........................................................ 34 
7.3.12.3. Time to First Course of Systemic Steroids .................. 34 
7.3.13. 
Number of Courses of Antibiotics ................................................. 34 
7.3.14. 
Time to first nasal surgery or course of systemic steroids ............ 35 
7.3.14.1. Summary Measure ..................................................... 35 
7.3.14.2. Population of Interest .................................................. 35 
7.3.14.3. Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................ 35 
7.3.14.4. Statistical Analyses / Methods .................................... 36 
7.4. 
Participants with Asthma ............................................................................. 36 
7.5. 
Maintenance of response ............................................................................ 37 
8.
SAFETY ANALYSES ............................................................................................. 37 
8.1. 
Adverse Events Analyses ........................................................................... 37 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 37 
8.3. 
Clinical Laboratory Analyses ....................................................................... 38 
8.4. 
Other Safety Analyses ................................................................................ 38 
8.4.1. 
ECG and Vital Signs .................................................................... 38 
8.4.2. 
Immunogenicity Data ................................................................... 39 
9.
PHARMACODYNAMIC ANALYSES....................................................................... 40 
9.1. 
Pharmacodynamic Analyses ....................................................................... 40 
9.1.1. 
Endpoint / Variables ..................................................................... 40 
9.1.2. 
Summary Measure ...................................................................... 40 
9.1.3. 
Population of Interest ................................................................... 40 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 40 
9.1.5. 
Statistical Analyses / Methods ..................................................... 40 
9.1.5.1. 
Statistical Methodology Specification .......................... 40 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 41 
10.1. 
Primary Pharmacokinetic Analyses ............................................................. 41 
10.2. 
Population Pharmacokinetic Methodology .................................................. 42 
10.3. 
Exploratory Pharmacokinetic Analyses ....................................................... 42 
10.3.1. 
Summary Measure ...................................................................... 42 
10.3.2. 
Population of Interest ................................................................... 42 
10.3.3. 
Statistical Analyses / Methods ..................................................... 43 
11. POPULATION PHARMACOKINETIC/ PHARMACODYNAMIC (POPPKPD)
ANALYSES ............................................................................................................ 44 
11.1. 
Population Pharmacokinetic/Pharmacodynamic Methodology .................... 44 
12. EXPLORATORY EXPOSURE-EFFICACY RESPONSE ANALYSIS ...................... 45 
12.1. 
Population of Interest .................................................................................. 45 
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12.2. 
Endpoints.................................................................................................... 45 
12.3. 
Methodology ............................................................................................... 45 
12.3.1. 
Statistical analysis using exposure quartiles ................................ 45 
12.3.1.1. Statistical Methodology Specification .......................... 45 
13. REFERENCES ....................................................................................................... 47
14. APPENDICES ........................................................................................................ 48
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 48 
14.1.1. 
Exclusions from Per Protocol Population ..................................... 48 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 51 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 51 
14.3. 
Appendix 3: Assessment Windows ............................................................. 57 
14.3.1. 
Visit Based Assessments ............................................................. 57 
14.3.2. 
Unscheduled Visits ...................................................................... 57 
14.3.3. 
Data from eDiary .......................................................................... 57 
14.3.4. 
Premature Withdrawals from Interventional Product or 
Study ........................................................................................... 58 
14.4. 
Appendix 4: Study Phases .......................................................................... 59 
14.4.1. 
Study Phases .............................................................................. 59 
14.4.1.1. Phases for Efficacy Assessments ............................... 59 
14.4.1.2. Phases for Safety Assessments ................................. 59 
14.4.1.3. Phases for Adverse Events ........................................ 59 
14.4.1.4. Phases for Concomitant Medication Start 
Dates .......................................................................... 60 
14.4.1.5. Phases for Concomitant Medication Usage 
Dates .......................................................................... 61 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 62 
14.5.1. 
Reporting Process ....................................................................... 62 
14.5.2. 
Reporting Standards .................................................................... 62 
14.5.3. 
Reporting Standards for Pharmacokinetic Data ........................... 63 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 64 
14.6.1. 
General ........................................................................................ 64 
14.6.2. 
Analysis Population ..................................................................... 64 
14.6.3. 
Study Population .......................................................................... 64 
14.6.4. 
Change from Baseline ................................................................. 67 
14.6.5. 
Efficacy ........................................................................................ 67 
14.6.6. 
Safety .......................................................................................... 72 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 75 
14.7.1. 
Premature Withdrawals ................................................................ 75 
14.7.2. 
Handling of Missing Data ............................................................. 75 
14.7.2.1. Handling of Missing Dates .......................................... 76 
14.7.2.2. Handling of Partial Dates ............................................ 76 
14.7.2.3. Missing Data for Statistical Analysis ........................... 77 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 78 
14.8.1. 
Laboratory Values of Potential Clinical Concern .......................... 78 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 79 
14.9.1. 
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................ 79 
14.9.2. 
Population Pharmacokinetic (PopPK) Methodology ..................... 79 
14.9.2.1. Base Model ................................................................ 79 
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14.9.2.2. Investigation of Covariates ......................................... 80 
14.9.2.3. Covariate Model Selection Procedures ....................... 80 
14.9.2.4. Model Evaluation ........................................................ 81 
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 82 
14.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 82 
14.10.2. Pharmacokinetic / Pharmacodynamic Methodology ..................... 82 
14.10.3. Base Model .................................................................................. 82 
14.10.4. Investigation of Covariates ........................................................... 82 
14.11. Appendix 11: Abbreviations & Trade Marks ................................................ 84 
14.11.1. Abbreviations ............................................................................... 84 
14.11.2. Trademarks ................................................................................. 85 
14.12. Appendix 12: List of Data Displays.............................................................. 86 
14.12.1. Data Display Numbering .............................................................. 86 
14.12.2. Mock Example Shell Referencing ................................................ 86 
14.12.3. Deliverables ................................................................................. 86 
14.12.4. Study Population Tables .............................................................. 87 
14.12.5. Study Population Figures ............................................................. 89 
14.12.6. Efficacy Tables ............................................................................ 90 
14.12.7. Efficacy Figures ........................................................................... 99 
14.12.8. Safety Tables ............................................................................. 102 
14.12.9. Safety Figures ........................................................................... 110 
14.12.10. Pharmacokinetic Population (PopPK) Tables ............................. 110 
14.12.11. Pharmacokinetic Population (PopPK) Figures ........................... 111 
14.12.12. Pharmacokinetic/Pharmacodynamic Population 
(PopPK/PD) Tables ................................................................... 112 
14.12.13. Pharmacokinetic/Pharmacodynamic Population 
(PopPKPD) Figures ................................................................... 112 
14.12.14. Exposure-Efficacy Figures ......................................................... 113 
14.12.15. ICH and Other Listings ............................................................... 114 
14.13. Appendix 13: Example Mock Shells for Data Displays .............................. 121 
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8 
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Study 205687 (Protocol 2016N294302_04): 
Revision Chronology for Protocol: 
Original Protocol 
(2016N294302_00) 
08-Dec-2016
Original 
2016N294302_01 
15-May-2017
To support country-specific requirements and amendments for 
South Korea. 
2016N294302_02 
14-July-2017
To clarify wording, document removal of CT scans and exit 
interviews, simplifying some of the endpoints 
2016N294302_03 
20-Feb-2018
To clarify that screen failures can be re-screened, and that the 
ECG machine does not need to be automated 
2016N294302_04 
13-Feb-2020
To reflect the feedback received from regulatory authorities 
regarding 1) analysis methodology for the co-primary endpoints, 
2) clarify the definition of surgery to more invasive procedures,
3) assess courses of steroids used rather than total burden.
This amendment also reflects two additional secondary
endpoints.
1.1. 
RAP Amendments 
Revision chronology: 
RAP Section 
Amendment Details 
Reporting and Analysis Plan _Final: Effective Date 05-SEP-2019 
Reporting and Analysis Plan Amendment 1: Effective Date 20-FEB-2020 
Section 2.1,Section 
5.4,Section 7,Section 
14.6.5 

To reflect the changes in protocol amendment 4
Section 12 

Updated measures of exposure for the exploratory exposure-efficacy
response analysis
Section 14.8.1 

Updated definition for ALT values of potential clinical concern
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1. 
Study Objective(s) and Endpoint(s)
Objectives 
Endpoints 
Primary Objectives 
Co-Primary Endpoints 

To evaluate the efficacy of 100mg
mepolizumab compared to placebo

Change from baseline in total endoscopic NP 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.
Secondary Objectives 
Secondary Endpoints 

To evaluate the impact on actual
nasal surgery of 100mg mepolizumab
compared to placebo

Time to first nasal surgery up to Week 52.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo

Change from baseline in mean overall VAS symptom
score during the 4 weeks prior to Week 52.

To evaluate the impact on quality of
life of 100mg mepolizumab compared
to placebo

Change from baseline in SNOT-22 total score at Week 52.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo

Proportion of participants requiring systemic steroids for
nasal polyps up to Week 52.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo

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.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo

Change from baseline in mean individual VAS symptom
score for loss of smell during the 4 weeks prior to Week
52.
Other Objectives 
Other Endpoints 

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo

Percentage of participants classified as responders
according to a 1 point or greater decrease from baseline in
NP Score at Week 52 (based on centrally ready data).

Change from baseline in mean individual VAS symptom
scores for nasal discharge, mucus in the throat, and facial
pain 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, loss of smell and facial
pain) during the 4 weeks prior to Week 52.

Change from baseline in UPSIT at Week 52.

Change from baseline in PnIF at Week 52.

To evaluate the impact on quality of
life of 100mg mepolizumab compared
to placebo

Percentage of participants classified at Week 52 as
responders according to an 8.9 point or greater decrease
from baseline in SNOT-22 total score.

Change from baseline in SNOT-22 domain scores at
Week 52.

To further evaluate the impact on

Rate of nasal surgery up to Week 52.
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Objectives 
Endpoints 
requirement for nasal surgery of 
100mg mepolizumab compared to 
placebo 

Time to first inclusion on waiting list for NP surgery up to
Week 52.

Percentage of participants who are included on waiting list
for NP surgery.

Percentage of participants classified as ‘need for surgery’
responders according to NP score (based on centrally
ready data) and overall VAS symptom score.

To evaluate exploratory biomarkers of
nasal polyposis and response to
100mg mepolizumab compared to
placebo

Evaluate exploratory blood biomarkers (including blood
eosinophils) on response to mepolizumab.

To evaluate the impact on health
outcomes of 100mg mepolizumab
compared to placebo

Change from baseline in SF-36 Mental Component
Summary (MCS), Physical Component Summary (PCS)
and 8 summary scores at Week 52.

Change from baseline in WPAI Questionnaire at Week 52.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo on systemic steroid use such
as OCS and antibiotic use as part of
SoC

Number of Courses of systemic steroid therapy up to
Week 52.

Number of mgs per year of prednisolone-equivalent OCS
dose up to Week 52.

Number of days on systemic steroid therapy up to Week
52.

Time to first course of OCS up to Week 52.

Number of courses of antibiotics up to Week 52.

To further evaluate the efficacy of
100mg mepolizumab compared to
placebo in the subgroup of
participants with Asthma
In addition to endoscopic NP score, VAS symptoms score, 
medication and surgery, the following asthma related endpoints 
will be assessed: 

Change from baseline in Asthma Control Questionnaire
(ACQ-5) score at Week 52.

Number of clinically significant asthma exacerbations
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 ED visit and/or hospitalisation
for asthma up to Week 52.

To assess the maintenance of
response after cessation of
mepolizumab treatment compared to
placebo
For all participants who enter post treatment follow-up period, 
the following will be assessed at Week 76: 

Change from baseline in total endoscopic NP score
(centrally read data).

Change from baseline in mean nasal obstruction VAS
score.

Change from baseline in mean individual VAS symptom
score for nasal discharge, mucus in throat, loss of smell,
facial pain and overall VAS symptom score during the 4
weeks prior to Week 76.

Number of mgs per year of prednisolone-equivalent OCS
dose.

Change from baseline in SNOT-22 total score.

Change from baseline in SF-36 Mental Component
Summary (MCS), Physical Component Summary (PCS)
and 8 summary scores.

Change from baseline in WPAI Questionnaire.
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Objectives 
Endpoints 
 
Time to first nasal surgery including off treatment period 
from randomization to Week 76. 
 
Time to first inclusion on waiting list for NP surgery up to 
Week 76. 
Safety Objectives 
Safety Endpoints 
 
To evaluate the safety and tolerability 
of 100mg mepolizumab compared to 
placebo 
 
Frequency of adverse events (AEs)/ serious adverse 
events (SAEs) including systemic and injection site 
reactions reported throughout the treatment period. 
 
Vital signs (pulse rate, systolic and diastolic blood 
pressure) throughout the treatment period. 
 
Hematological and clinical chemistry parameters 
throughout the treatment period. 
 
12 lead ECG derived endpoints. 
 
Presence of anti-mepolizumab antibodies. 
Pharmacokinetics Objectives 
Pharmacokinetics Endpoints 
 
To evaluate the pharmacokinetics 
(PK) of 100mg mepolizumab 
 
PK concentrations and Population PK parameters 
 
PK/PD (blood eosinophil count) analysis 
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2.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design Features 
 
Multi-centre, randomised, placebo-controlled, double-blind, parallel-
group design. 
 
The study will include a 4-week run in period followed by a 52-week 
randomised treatment period with visits every 4 weeks. 
 
Patients prematurely discontinued from study treatment continue, 
where possible, being followed up per the protocol schedule 
 
Patients who have surgery for nasal polyps during the study are 
allowed to continue on study treatment until completion of the 52-week 
treatment period 
 
Following Week 52, there is a planned study drug free, 6-month, follow-
up period for the first 200 randomised participants, to investigate 
maintenance of response to study treatment.  
Main participant entry 
criteria 
 
Participants aged ≥18 years with severe bilateral nasal polyps and at 
least one surgery in the previous 10 years for the removal of nasal 
polyps (see Section 6 of protocol). 
Dosing 
 
The study treatment period will consist of thirteen, 4-weekly doses with 
the last dose of interventional product to be administered at Week 48 
(Visit 14). 
 
Interventional product is given in addition to standard of care (SoC): 
daily mometasone furoate nasal spray (MF), saline nasal douching as 
required and, if required, occasional short courses of high dose oral 
corticosteroids (OCS) and/or antibiotics. 
Schedule of Activities 
 
See Appendix 2: Schedule of Activities 
Treatment Assignment 
 
400 participants (planned) will be randomised in a 1:1 ratio to receive 
mepolizumab or matching placebo (i.e. 200 per treatment group) 
delivered subcutaneously via a pre-filled safety syringe in addition to 
SoC. 
 
Randomisation schedule generated using GSK validated randomisation 
software RandAll NG, stratified by country. 
 
Treatment assigned randomly via an interactive voice response system 
(IVRS). 
Interim Analysis 
 No interim analysis of data is planned for this study. 
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2.3. 
Statistical Hypotheses 
The study is designed to test the superiority of mepolizumab 100mg SC vs. placebo in 
addition to standard of care. Significance tests will be guided by a two-sided 5% alpha 
level (one-sided 2.5%). 
2.4. 
Changes to the Protocol Defined Statistical Analysis Plan 
Minor changes/deviations from the planned statistical analysis specified in Protocol 
Amendment 4 (Dated: 13 Feb 2020) are outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
Co-primary endpoint defined as 
Change from baseline in total 
endoscopic nasal polyps (NP) 
score at Week 52. 
Co-primary endpoint defined as 
Change from baseline in total 
endoscopic NP score at Week 52 
(based on centrally read data). 
To clarify the total endoscopic 
NP score used in the analysis of 
the co-primary endpoint is based 
on data from the blinded 
independent review of 
endoscopy data (as per Protocol 
Section 9.2.1). 
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3. 
PLANNED ANALYSES 
Planned dry run(s) will be performed on a subset of blinded data, with the aim of 
ensuring the required displays detailed in Appendix 12: List of Data Displays are 
correctly created and formatted. 
3.1. 
Interim Analyses 
No interim analysis of data is planned for this study. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants have completed the study as defined in the protocol  
2. All required database cleaning activities have been completed and database freeze 
(DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met, and the 
randomisation codes have been released. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Enrolled 
 
All participants enrolled and for whom a record exists 
on the study database. 
Reasons for screen 
and run-in failures 
Randomized 
 
All randomized participants 
Study population 
Intent-To-Treat 
(ITT) 
 
All randomized participants who take at least 1 dose of 
study treatment. 
 
Data will be analysed according to randomised 
treatment arm. 
Subject disposition 
Efficacy endpoints 
Safety 
 
All randomized participants who take at least 1 dose of 
study treatment. 
 
Data will be analysed according to actual treatment 
received for more than 50% of treatment 
administrations (see Section 14.6.2). 
Safety endpoints 
Per-Protocol 
(PP) [1] 
 
All participants in the ITT population who have not been 
identified as protocol deviators with respect to criteria 
that are considered to impact the primary efficacy 
analysis. 
 
Protocol deviations that would exclude participants from 
the PP population are defined in Appendix 1: Protocol 
Deviation Management and Definitions for Per-Protocol 
Population 
Supplementary 
analyses of co-primary 
endpoints 
Pharmacokinetic 
(PK) [1] 
All participants in the ITT population for whom at least 
one PK sample was obtained, analysed and 
measurable. 
Pharmacokinetic 
endpoints 
Follow-up after 
 
Participants in the ITT population who participate in the 
Efficacy/safety 
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Population 
Definition / Criteria 
Analyses Evaluated 
Week 52 (FU) [1] 
‘No treatment follow-up’ period after Visit 15. 
 
Data will be summarised according to randomised 
treatment arm. 
endpoints 
Refer to Appendix 12: List of Data Displays which details the population used for each display. 
[1] Analysis population not defined in protocol, added for clarification of analysis requirements. 
4.1. 
Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP) dated 10 January 
2018 (Version 1.01).  Protocol deviations classified as important are detailed in the 
PDMP and those requiring exclusion from the Per-Protocol (PP) population are detailed 
in Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population. 
 
A final blinded review of all deviations will take place at the database release stage to 
ensure all important deviations are identified as well as those leading to exclusion of the 
participant from the PP population. 
 
Important protocol deviations and deviations which result in exclusion from the PP 
population will be summarised and listed.  A separate listing of all inclusion/ exclusion 
criteria deviations based on data as recorded on the eligibility page of the eCRF will also 
be provided. 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF[1]  
1 
Placebo 
Placebo 
1 
2 
Mepolizumab 100mg SC 
Mepolizumab 100mg SC 
2 
[1] TLF=Tables, Listings, Figures (as specified in Appendix 12: List of Data Displays) 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
Mepolizumab 100mg SC vs Placebo 
 
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5.2. 
Baseline Definitions 
5.2.1. 
Visit-based endpoints 
The co-primary endpoint of endoscopic NP score (based on centrally read data) is 
assessed at Screening (Visit 1) and Day 1 (Visit 2), the Screening value is used to 
confirm if a participant has met the criteria for randomisation.  Baseline will be defined 
as the Day 1 value, if missing the immediately preceding centrally read value prior to 
Day 1 will be used. 
For all other visit-based endpoints, Baseline will be defined as the latest non-missing 
measurement collected prior to the first dose of interventional product.  This will 
generally be from the Day 1 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. 
5.2.2. 
eDiary Data 
Participants 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). 
5.3. 
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, country and region. 
Region will be included as a fixed effect covariate in the analysis models for efficacy 
endpoints (as detailed in Section 5.4).  Countries have been grouped into the following 
regions with consideration for standard of care medical practice, number of participants 
enrolled and regulatory considerations. 
Region 
Countries 
Europe (EU) 
Germany, Netherlands, Romania, Sweden, UK 
United States (US) 
United States 
Rest of World (RoW) 
South Korea, Argentina, Australia, Canada, Russia 
NOTE: Small numbers of participants in a treatment group within a region may result in model convergence issues, in 
these cases further combining of regions may be considered or if required exclusion of the region covariate. 
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5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
Covariates to be included in the statistical analysis models of the co-primary efficacy 
endpoints: 
 Randomised treatment group  
 Region 
 Baseline score 
 Baseline loge blood eosinophil count 
Covariates to be included in the statistical analysis model of time to first nasal surgery: 
 Randomised treatment group  
 Region 
 Baseline total NP endoscopic score (based on centrally read data) 
 Baseline nasal obstruction VAS 
 Baseline loge blood eosinophil count 
 Number of previous surgeries (1, 2, >2; as an ordinal variable) 
Covariates to be included in the statistical analysis model of proportion of subjects with 
at least one course of systemic steroids for nasal polyps up to Week 52:  
 Randomised treatment group 
 Region 
 Baseline total NP score (based on centrally read data) 
 Baseline nasal obstruction VAS 
 Baseline loge blood eosinophil count 
 Number of OCS courses for NP in the previous 12 months (0, 1, >1, as an ordinal 
variable) 
Section 7 provides full details of the analysis methods for each of the efficacy endpoints. 
5.4.2. 
Examination of Subgroups 
This section details the subgroups of interest within this study.  For each co-primary 
endpoint, a separate exploratory analysis within each of the subgroup categories will be 
carried out.  Subgroup analyses for all other endpoints are detailed in the statistical 
methods/analysis sections.  Unless otherwise stated no formal hypothesis testing in 
subgroups of the population will be performed. 
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If, following unblinding, the analysis model within a subgroup category fails to converge 
due to small numbers of participants, the model will be rerun with consideration of 
further refining regions or if required exclusion of the region covariate.  Failing this, 
subgroup categories may be further refined when possible, otherwise only a descriptive 
summary of the data will be presented.  Footnotes will clearly identify the covariates 
included in the analysis model. 
There is a biological rationale for potentially observing greater efficacy with increasing 
levels of baseline blood eosinophils.  Except for baseline blood eosinophils, differential 
treatment effects are not expected for any of the other subgroups listed above and 
therefore any differences in efficacy of mepolizumab compared to placebo observed in 
subgroup categories will be viewed as exploratory. 
5.5. 
Multiple Comparisons and Multiplicity 
The treatment comparison of mepolizumab 100mg SC vs. placebo is of interest for the 
co-primary and secondary endpoints.  Multiplicity arising from the multiple secondary 
endpoints will be controlled through testing of the secondary endpoints using a closed 
testing procedure according to the following pre-defined hierarchy: 
1. Time to first nasal surgery  
2. Change from baseline in overall VAS symptom score  
3. Change from baseline in SNOT-22 total score  
4.  Proportion of subjects requiring systemic steroids for nasal polyps 
5. Change from baseline in the mean composite VAS score (nasal obstruction, nasal 
discharge, mucus in the throat and loss of smell)  
6. Change from baseline in mean individual VAS symptom score for loss of smell 
Subgroup 
Categories  
Participants with Asthma 
Concurrent asthma, No concurrent asthma 
Aspirin Exacerbated Respiratory 
Disease (AERDS) 
Current AERDS, No Current AERDS 
Number of previous surgeries 
1, 2, >2 
Baseline Blood Eosinophil 
Categories (GI/L) 
≤0.3 GI/L; >0.3 to ≤0.5 GI/L; >0.5 to ≤0.7 GI/L; >0.7 GI/L 
Region 
Europe, United States, Rest of World 
Age 
18-<40, 40-<65, ≥65 years 
Gender 
Male, Female 
Race 
African American/African Heritage, White, Asian, Other 
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For strong control of type I error, statistical significance for the first secondary endpoint 
in the pre-defined hierarchy will be dependent on statistical significance having been 
achieved for the two co-primary endpoints.  Statistical significance for the subsequent 
secondary endpoints will be dependent on statistical significance having been achieved 
for the previous endpoints in the hierarchy. 
For secondary endpoints, unadjusted p-values and p-values adjusted for multiplicity 
based on the above hierarchy, will be presented. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
6.
STUDY POPULATION ANALYSES
6.1. 
Overview of Planned Study Population Analyses 
All displays will be based on the ITT population, unless otherwise specified. 
Study population displays including summaries of subject disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications 
and treatment exposure will be based on GSK Core Data Standards.  Additional summary 
information showing the amount of time within the 52-week treatment period considered 
as on-treatment, off-treatment and missing will be presented. 
A summary of subject disposition and duration of time spent in the no-treatment follow-
up will be provided for the subset of participants who participated in the 6-month no-
treatment follow-up. 
Details of the planned displays are presented in Appendix 12: List of Data Displays. 
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7. 
EFFICACY ANALYSES 
Data reported up to Week 52 will be included in the analyses described in Section 7.1 to 
Section 7.4.  Details of all planned displays are provided in Appendix 12: List of Data 
Displays and will be based on GSK data standards and statistical principles. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
The primary treatment effect to be estimated (estimand) will be the comparison of 
mepolizumab 100mg SC to placebo for the co-primary endpoints of: 
 Change from baseline in total endoscopic NP 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 
 
Independent reviewers blinded to treatment, grade the total endoscopic NP 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, the scale range is 0 (none) to 100 (as bad as you 
can imagine), with higher scores indicating greater disease severity, for analysis derived 
scores ranging from 0 to 10 are used (see Section 14.6.5). 
 
Surgery/sinuplasty represents an intercurrent event as any nasal surgical procedure or 
dilatation of the air passages in the nasal cavity can affect subsequent scores for the co-
primary endpoints.  For analysis of the co-primary endpoints the intercurrent event of 
surgery/sinuplasty includes any procedure involving instruments resulting in incision and 
removal of tissue (e.g. polypectomy) or dilatation of the air passages (e.g. balloon 
sinuplasty) in the nasal cavity. 
 
A composite strategy will be used for the intercurrent event of surgery/sinuplasty and a 
treatment policy strategy will be used for the intercurrent event of discontinuation of 
study medication.    The study is designed to continue collecting data for participants who 
have prematurely discontinued from randomised treatment, off-treatment data collected 
for these participants will be included in the primary analysis. 
 
Subjects who undergo surgery/sinuplasty prior to Week 52 will be assigned their worst 
observed NP score prior to the surgery/sinuplasty for the change from baseline value at 
Week 52 in total endoscopic NP score.  Subjects who withdraw from study before Week 
52 without having experienced surgery/sinuplasty will be assigned their worst observed 
NP score prior to study withdrawal. 
 
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Similarly, for the mean nasal obstruction VAS, subjects who undergo surgery/sinuplasty 
will be assigned their worst observed 4-week mean prior to surgery for change from 
baseline during the 4-weeks prior to Week 52.   Subjects who withdraw from the study 
before Week 52 without having experienced surgery/sinuplasty will be assigned their 
worst observed 4-week mean prior to study withdrawal. 
 
Sensitivity analyses to examine the impact of handling missing data as described above 
are detailed in Section 7.1.5. 
7.1.2. 
Summary Measure 
The summary measure of treatment effect will be the difference between mepolizumab 
and placebo in the variable medians. 
7.1.3. 
Population of Interest  
The primary population of interest for analysis of the co-primary endpoints is defined by 
the study inclusion/exclusion and randomisation criteria and is therefore the ITT 
population. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The anticipated intercurrent events occurring prior to Week 52 for the co-primary 
endpoints are: Surgery/sinuplasty, which includes any procedure involving instruments 
resulting in incision and removal of tissue (e.g. polypectomy) or dilatation of the air 
passages (e.g. balloon sinuplasty) in the nasal cavity and premature discontinuation of 
interventional product. 
 
For each co-primary endpoint, the anticipated intercurrent event of  surgery/sinuplasty 
will be handled using a composite strategy such that the occurrence of the event is 
incorporated into the definition of the endpoint.  In participants who do not experience 
surgery/sinuplasty, the anticipated intercurrent event of premature discontinuation of 
interventional product will be handled using a treatment policy strategy, such that in these 
participants all data reported at week 52 for total endoscopic NP score (or during the 4-
week period prior to Week 52 for nasal obstruction VAS) will be included in the analysis, 
regardless of discontinuation from treatment. 
7.1.5. 
Statistical Analyses / Methods 
7.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
 Change from baseline in in total endoscopic NP score (based on centrally read data) at Week 
52 
 Change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week 
52 
Model Specification 
 For each co-primary endpoint, the p-value for the difference in median change from baseline 
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between treatments will be based on the non-parametric Wilcoxon rank-sum test. 
 The difference in median change from baseline with 95% confidence intervals will be estimated 
by quantile regression using a bootstrap approach ([Keene, 2018], [Mehrotra, 2017]).  The 
analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 Median change from baseline within each treatment group. 
 Estimated difference between treatments in median change from baseline with 95% confidence 
interval (CI). 
 p-value comparing treatments groups from the Wilcoxon rank-sum test. 
 A cumulative distribution function (CDF) plot will be provided for the change from baseline in 
endoscopic NP score at Week 52 by treatment group. 
Subgroup Analyses 
 Section 5.4.2 identifies the subgroups of interest for the co-primary endpoints. 
Sensitivity and Supportive Analyses 
For sensitivity and supplementary analyses, the same methodology as for the primary efficacy 
analysis will be used. 
 
Sensitivity analyses 
 For the primary analysis the change from baseline value for participants with 
surgery/sinuplasty or missing data at Week 52 (due to premature withdrawal from the study or 
another reason) will be based on the worst observed score prior to surgery/sinuplasty or study 
withdrawal respectively.  The following sensitivity analyses will be carried out to examine the 
potential impact of choices for the handling of subjects with missing data and for the handling 
of data for subjects undergoing surgery/sinuplasty.  Sensitivity analysis will be performed for 
each co-primary endpoint where: 
o a) change from baseline for subjects with missing data is based on the worst possible 
score across all subjects and change from baseline for subjects with 
surgery/sinuplasty is based on the worst observed score prior to surgery/sinuplasty. 
o b) change from baseline for subjects with surgery/sinuplasty or with missing data is 
based on the worst possible score across all subjects. 
 
Supplementary analyses 
 A supplementary analysis of each co-primary endpoint will be performed on the Per-Protocol 
(PP) population (see Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population). 
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7.2. 
Secondary Efficacy Analyses 
For each secondary endpoint the primary treatment effect to be estimated (estimand) will 
be the comparison of mepolizumab 100mg SC to placebo. 
7.2.1. 
Time to first nasal surgery 
Evaluation of the key secondary endpoint of nasal surgery will be based on invasive 
procedures involving instruments resulting in incision and removal of tissue 
(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 will be 
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 
evaluation. 
The time to first nasal surgery will be determined as the number of days from the date of 
first dose of study medication to the date of first nasal surgery (see Section 14.6.5). If a 
participant withdraws from the study before Week 52 and before experiencing nasal 
surgery, the nasal surgery event time will be censored at the time of study withdrawal. 
7.2.1.1. 
Summary Measure 
The summary measure of treatment effect will be the hazard ratio, the ratio of hazards 
corresponding to treatment with mepolizumab compared with placebo.  For this endpoint 
the hazard represents the probability of nasal surgery for a participant at a given point in 
time following first dose of interventional product, given the participant has not 
experienced the event prior to that time. 
7.2.1.2. 
Population of Interest 
The primary population of interest is the ITT population. 
7.2.1.3. 
Strategy for Intercurrent (Post-Randomization) Events 
A treatment policy strategy will be used for the intercurrent event of premature 
discontinuation of interventional product, such that available nasal surgery times will be 
included in the analysis regardless of whether the surgery occurred before or after 
discontinuation of interventional product. 
7.2.1.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Time to first nasal surgery  
Model Specification 
 Cox proportional hazards model with covariates as follows: 
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline total nasal polyps endoscopic score (centrally read data), 
Baseline nasal obstruction VAS, Loge baseline blood eosinophil 
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count, Number of previous surgeries (1, 2, >2; ordinal) 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 A log(-log(survival)) plot by treatment group will be used to assess the assumption of 
proportional hazards. 
Model Results Presentation 
 The number of participants with an event, the number censored due to study withdrawal and at 
study completion will be presented by treatment arm. 
 The hazard ratio with corresponding 95% CI and p-value from the Cox proportional hazards 
model will be presented. 
 A summary and graph of the Kaplan-Meier estimate of the cumulative proportion of participants 
with nasal surgery within each treatment arm over time will be produced. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 Sensitivity analyses will be performed to assess the censoring-at-random assumption of the 
cox proportional hazards model where participants who withdraw from the study before 
experiencing surgery have their event times censored at the time of study withdrawal. 
 Sensitivity analysis will be carried out where missing event times for participants randomised to 
mepolizumab who withdraw from the study before experiencing surgery will be imputed using a 
censoring-not-at-random method as described in [Jackson, 2014].  A step-change in event rate 
equivalent to a loss of benefit from mepolizumab will be imputed for these participants after 
their censoring time.  This means a reduction in relative event rate equivalent to 1/(estimated 
treatment effect). Missing event times for placebo will imputed under a censoring-at-random 
assumption.  
 
7.2.2. 
Change from Baseline in Mean Overall VAS Symptom Score 
During the 4 weeks Prior to Week 52, Mean Composite VAS Score 
and Mean Loss of Smell VAS Score 
Change from baseline during the 4-weeks prior to Week 52 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 loss of 
smell score will be analysed as detailed for the co-primary endpoint of change from 
baseline in mean nasal obstruction VAS score.  
 
7.2.2.1. 
Details regarding the summary measure, population of interest and the 
strategy for intercurrent events are provided in Section 7.1.2 to Section 
7.1.4.Statistical Analyses / Methods 
Endpoint / Variables 
 Change from baseline in mean overall VAS symptom score during the 4 weeks prior to Week 
52 
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 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 loss of smell VAS symptom score during the 4 weeks prior to 
Week 52 
Model Specification 
 For each endpoint the p-value for the difference in median change from baseline between 
treatments will be based on the non-parametric Wilcoxon rank-sum test. 
 The difference in median change from baseline with 95% confidence intervals will be estimated 
by quantile regression using a bootstrap approach. 
 The analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 Median change from baseline within each treatment group. 
 Estimated difference between treatments in median change from baseline with 95% confidence 
interval (CI). 
  p-value comparing treatment groups from the Wilcoxon rank-sum test. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for these endpoints 
 
7.2.3. 
Change from Baseline in Sino-Nasal Outcomes TEST 22 (SNOT-
22) Total Score at Week 52 
The 22 questions of the SNOT-22 are each graded on a 
 
 
 
Details regarding the summary measure, population of interest and the strategy for 
intercurrent events are provided in Section 7.1.2 to Section 7.1.4. 
 
7.2.3.1. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Change from baseline in SNOT-22 total score at Week 52 
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Model Specification 
 The p-value for the difference in median change from baseline between treatments will be 
based on the non-parametric Wilcoxon rank-sum test. 
 The difference in median change from baseline with 95% confidence intervals will be estimated 
by quantile regression using a bootstrap approach. 
 The analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 Median change from baseline within each treatment group. 
 Estimated difference between treatments in median change from baseline with 95% confidence 
interval (CI). 
 p-value comparing treatment groups from the Wilcoxon rank-sum test. 
  
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.2.4. 
Proportion of subjects requiring systemic steroids for nasal 
polyps up to Week 52 
7.2.4.1. 
Summary Measure 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant requiring at least one course of systemic steroids up to 
Week 52 in the mepolizumab arm compared with placebo. 
7.2.4.2. 
Population of Interest 
The population of interest is the ITT population. 
7.2.4.3. 
Strategy for Intercurrent (Post-Randomization) Events 
Data will be included regardless of the occurrence of events such as surgery or treatment 
discontinuation. 
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7.2.4.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 The proportion of subjects requiring at least one course of systemic steroids for nasal polyps 
up to Week 52 
Model Specification 
 A logistic regression model will be used to compare the proportion of participants requiring a 
course of systemic steroids up to week 52 in the mepolizumab arm compared to placebo. 
 The odds ratio comparing treatment groups will be estimated using the observed marginal 
distribution of the sample covariates. 
 The analysis model will include the following terms: 
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Number of OCS courses for NP in last 12 months (0, 1, >1; ordinal), 
baseline total endoscopic NP score (based on centrally read data), 
baseline nasal obstruction VAS score, Loge baseline blood 
eosinophil 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence 
Model Results Presentation 
 The number and percentage of participants identified as requiring at least one course of 
systemic steroids for nasal polyps will be displayed by treatment group, as will the number of 
courses of therapy required. 
 The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression model will be displayed. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.3. 
Other Efficacy Analyses 
7.3.1. 
Total Endoscopic Nasal Polyps Score Responders 
A responder is defined as a participant achieving a ≥1-point improvement (decrease) 
from baseline in total endoscopic NP score (based on centrally read data) at Week 52.  
Participants with missing data at Baseline or Week 52 (due to early study withdrawal or 
any other reason) will be included in the analysis as a non-responder. 
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7.3.1.1. 
Summary Measure 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder in the mepolizumab arm compared with 
placebo. 
7.3.1.2. 
Population of Interest 
The population of interest is the ITT population. 
7.3.1.3. 
Strategy for Intercurrent (Post-Randomization) Events 
See Section 7.1.4. for details. 
7.3.1.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Total endoscopic nasal polyps score responders  
Participants with a ≥ 1-point improvement from baseline in total endoscopic NP at Week 52 
(based on centrally read data) will be included in the analysis as a responder. 
The following participants will be included in the analysis as a non-responder: 
o Participants who had actual surgery prior to Week 52 
o Participants who withdrew early from the study or who had missing data at 
Baseline or Week 52 
Model Specification 
 A logistic regression model will be used to compare the proportion of responders in the 
mepolizumab arm compared to placebo. 
 The odds ratio comparing treatment groups will be estimated using the observed marginal 
distribution of the sample covariates. 
 The analysis model will include the following terms: 
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 The number and percentage of participants identified as responders and non-responders for 
analysis will be displayed by treatment group, the non-responder group will be further 
categorized to display the number of participants with actual surgery, the number withdrawn 
early from the study and the number with missing baseline data. 
 The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression model will be displayed. 
 A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups will 
be provided by visit. 
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Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.3.2. 
Change from Baseline in Mean Individual and Composite VAS 
Symptom Scores 
Participants rate individual symptoms daily on a visual analogue scale using an eDiary, 
the scale range for each symptom is
 
Change from baseline during the 4-
weeks prior to Week 52 in mean individual VAS symptom scores for nasal discharge, 
mucus in throat and facial pain and the mean composite VAS score (combining nasal 
obstruction, nasal discharge, mucus in the throat, loss of smell and facial pain), will be 
analysed as detailed for the co-primary endpoint of change from baseline in mean nasal 
obstruction VAS score during the 4 weeks prior to Week 52. 
Details regarding the summary measure, population of interest and the strategy for 
intercurrent events are provided in Section 7.1.2 to Section 7.1.4. 
7.3.2.1. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Change from baseline in individual VAS symptom scores of nasal discharge, mucus in throat 
and facial pain during the 4 weeks prior to Week 52 
 Change from baseline in mean composite VAS score (combining nasal obstruction, nasal 
discharge, mucus in the throat, loss of smell and facial pain) during the 4 weeks prior to Week 
52 
Model Specification 
 For each endpoint the p-value for the difference in median change from baseline between 
treatments will be based on the non-parametric Wilcoxon rank-sum test. 
 The difference in median change from baseline with 95% confidence intervals will be estimated 
by quantile regression using a bootstrap approach. 
 The analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 Median change from baseline within each treatment group. 
 Estimated difference between treatments in median change from baseline with 95% confidence 
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interval (CI). 
 p-value comparing treatment groups from the Wilcoxon rank-sum test. 
  
Subgroup Analyses 
 No subgroup analyses are planned for these endpoints. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for these endpoints. 
 
7.3.3. 
SNOT-22 Responders  
A responder is defined as a participant achieving a ≥8.9-point improvement (decrease) 
from baseline in SNOT-22 total score at Week 52.  Participants with missing data at 
Baseline or Week 52 (due to early study withdrawal or any other reason) will be included 
in the analysis as a non-responder. 
7.3.3.1. 
Summary Measure 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder in the mepolizumab arm compared with 
placebo. 
7.3.3.2. 
Population of Interest 
The population of interest is the ITT population. 
7.3.3.3. 
Strategy for Intercurrent (Post-Randomization) Events 
See Section 7.1.4. for details. 
7.3.3.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Participants with a ≥ 8.9-point improvement from baseline in SNOT-22 score at Week 52 will 
be included in the analysis as a responder. 
 The following participants will be included in the analysis as a non-responder: 
o Participants who had actual surgery prior to Week 52 
o Participants who withdrew early from the study or who had missing data at Baseline or 
Week 52 
Model Specification 
 See Section 7.3.1.4   
Model Checking & Diagnostics 
 See Section 7.3.1.4 
Model Results Presentation 
 See Section 7.3.1.4 
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Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.3.4. 
SNOT-22 Domain Scores 
There are six proposed domain scores for the SNOT-22 (nasal, non-nasal symptoms, 
ear/facial symptoms, sleep, fatigue, emotional consequences).  For each domain the 
actual and change from baseline score will be summarised by visit.  These summaries 
will be based on datasets where the intercurrent events of actual surgery and treatment 
discontinuation have been handled as detailed in Section 7.1.4. 
 
7.3.5. 
Need for Surgery 
Participants enter the trial with severity of nasal polyps consistent with the need for 
surgery (inclusion criteria 8 of study protocol).  Participants are identified as no longer 
having a need for surgery based on improvements in the total nasal polyps endoscopy 
score (centrally read) and overall VAS score at Week 52 (further details in Section 
14.6.5).  Participants with missing data at Week 52 (due to early study withdrawal or any 
other reason) will be identified as still having a need for surgery at Week 52. 
7.3.5.1. 
Summary Measure 
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant no longer having a need for surgery at Week 52 in the 
mepolizumab arm compared with placebo. 
7.3.5.2. 
Population of Interest 
The population of interest is the ITT population. 
7.3.5.3. 
Strategy for Intercurrent (Post-Randomization) Events 
See Section 7.1.4. for details. 
7.3.5.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Need for surgery at week 52 will be assessed for each participant as detailed in Section 14.6.5. 
 The following participants will be included in the analysis as still having a need for surgery: 
o Participants who had surgery prior to Week 52 
o Participants who withdrew early from the study or who had missing data at Baseline or 
Week 52 
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Model Specification 
 A logistic regression model will be used to compare the proportion of participants who no 
longer have a need for surgery in the mepolizumab arm compared to placebo. 
 The odds ratio comparing treatment groups will be estimated using the observed marginal 
distribution of the sample covariates. 
 The analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline total nasal polyps endoscopic score (centrally read data), 
Baseline overall VAS score, Loge baseline blood eosinophil count 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checking for issues with convergence. 
Model Results Presentation 
 The number and percentage of participants identified as no longer having a need/still having a 
need for surgery will be displayed by treatment group, the still having a need for surgery group 
will be further categorized to display the number participants with actual surgery, the number 
withdrawn early from the study and the number with missing Baseline data. 
 The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression model will be displayed. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.3.6. 
Rate of Nasal Surgery 
A summary of the number and percentage of participants who have undergone surgery 
will be presented, the rate of surgery will also be presented for each treatment arm. 
7.3.7. 
Time to First Inclusion on Waiting List for NP Surgery 
A summary and graph of the Kaplan-Meier estimates of the cumulative proportion of 
participants having been placed on a waiting list for nasal polyps surgery/sinuplasty over 
time will be provided. 
7.3.8. 
Waiting List for NP surgery 
A summary of the number and percentage of participants placed on a waiting list for 
nasal polyp surgery at each visit and over the whole study will be presented. 
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7.3.9. 
Change from baseline in UPSIT (University of Pennsylvania Smell 
Identification Test) 
UPSIT is designed to test the function of an individual’s olfactory system.  The test is 
scored out of 40 with a lower score indicating a worse outcome.  The test will be 
performed only by participants at sites in the UK, US and Canada.  Details regarding the 
summary measure, population of interest and the strategy for intercurrent events are 
provided in Section 7.1.2 to Section 7.1.4.  
7.3.9.1. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Change from baseline in UPSIT at Week 52 
Model Specification 
 The p-value for the difference in median change from baseline between treatments will be 
based on the non-parametric Wilcoxon rank-sum test. 
 The difference in median change from baseline with 95% confidence intervals will be estimated 
by quantile regression using a bootstrap approach. 
 The analysis model will include the following terms:  
Fixed Categorical:  
Treatment group, Country 
Fixed Continuous:  
Baseline score, Loge baseline blood eosinophil count 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 Median change from baseline within each treatment group. 
 Estimated difference between treatments in median change from baseline with 95% confidence 
interval (CI) and p-value comparing treatments from the Wilcoxon rank-sum test. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.3.10. 
Change from baseline in PnIF (Peak Nasal Inspiratory Flow) 
A PnIF meter will be used to derive forced inspiratory peak flow through the nose.  A 
summary of PnIF data and change from baseline at each visit will be presented.  These 
summaries will be based on a dataset where the intercurrent events of surgery/sinuplasty 
and treatment discontinuation have been handled as detailed in Section 7.1.4. 
 
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7.3.11. 
Health Outcomes 
7.3.11.1. 
SF-36 Mental Component Summary (MCS), Physical Component 
Summary (PCS) and 8 summary scores 
Certified scoring of the SF-36 survey will be performed using OPTUM™ software. 
The eight domain scores (bodily pain, general health, mental health, physical functioning, 
role emotional, role physical, social functioning and vitality) as well as the physical and 
mental component summary scores are provided by the software. 
Domain and component summary scores will be summarised by visit, including change 
from baseline.  These summaries will be based on a dataset where the intercurrent events 
of surgery/sinuplasty and treatment discontinuation have been handled as detailed in 
Section 7.1.4. 
 
7.3.11.2. 
Work Productivity and Activity Impairment Questionnaire (WPAI) 
The WPAI questionnaire is an instrument to measure impairment in paid and unpaid 
work.  Summary information from the WPAI at each visit will include information on 
employment status, hours missed from work due to health problems and due to other 
reasons, hours actually worked, and how much health problems affected productivity and 
activity. 
 
7.3.12. 
Systemic Steroid Use 
7.3.12.1. 
Number of mgs per year of prednisolone-equivalent OCS dose for 
nasal polyps up to Week 52 
The total number of milligrams (mgs) of prednisolone-equivalent OCS per year for nasal 
polyps will be summarised for each treatment arm based on the use reported for each 
subject up to Week 52, data will be included in the summary regardless of the occurrence 
of events such as surgery or treatment discontinuation. 
7.3.12.2. 
Days on Therapy 
The mean number of days and percentage of days on systemic steroids for nasal polyps 
will be presented for each treatment arm.  Data will be included in the summary 
regardless of the occurrence of events such as surgery or treatment discontinuation. 
7.3.12.3. 
Time to First Course of Systemic Steroids 
A summary and graph of the Kaplan-Meier estimates of the cumulative proportion of 
participants with a first course of systemic steroids for nasal polyps over time will be 
provided. 
7.3.13. 
Number of Courses of Antibiotics 
A summary of the number of courses of antibiotics will be presented for each treatment 
arm.  Courses of antibiotics which are separated by less than 7 days will be considered a 
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continuation of the same course.  Data will be included in the summary regardless of the 
occurrence of events such as surgery or treatment discontinuation. 
7.3.14. 
Time to first nasal surgery or course of systemic steroids 
The time to first nasal surgery or course of systemic steroids for nasal polyps will be 
determined as the number of days from the date of first dose of study medication to the 
date of first nasal surgery or course of systemic steroids for nasal polyps (see Section 
14.6.5). If a participant withdraws from the study before experiencing nasal surgery or 
having a course of systemic steroids for nasal polyps, the event time will be censored at 
the time of study withdrawal. 
7.3.14.1. 
Summary Measure 
The summary measure of treatment effect will be the hazard ratio, the ratio of hazards 
corresponding to treatment with mepolizumab compared with placebo.  For this endpoint 
the hazard represents the probability of nasal surgery or course of systemic steroids for 
nasal polyps for a participant at a given point in time following first dose of 
interventional product, given the participant has not experienced either event prior to that 
time. 
7.3.14.2. 
Population of Interest 
The primary population of interest is the ITT population. 
7.3.14.3. 
Strategy for Intercurrent (Post-Randomisation) Events 
A treatment policy strategy will be used for the intercurrent event of premature 
discontinuation of interventional product, such that available event times will be included 
in the analysis regardless of whether the event occurred prior to discontinuation of 
randomised treatment. 
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7.3.14.4. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Time to first nasal surgery or course of systemic steroids for nasal polyps 
Model Specification 
 Cox proportional hazards model with covariates as follows: 
Fixed Categorical:  
Treatment group, Region 
Fixed Continuous:  
Baseline total nasal polyps endoscopic score (centrally read data), 
Baseline nasal obstruction VAS, Loge baseline blood eosinophil 
count, Number of previous surgeries (1, 2, >2; ordinal) 
 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 A log(-log(survival)) plot by treatment group will be used to assess the assumption of 
proportional hazards. 
Model Results Presentation 
 The number of participants with an event, the number censored due to study withdrawal and at 
study completion will be presented by treatment arm. 
 The hazard ratio with corresponding 95% CI and p-value from the Cox proportional hazards 
model will be presented. 
 A summary and graph of the Kaplan-Meier estimate of the cumulative proportion of participants 
with nasal surgery within each treatment arm over time will be produced. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint. 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint. 
 
7.4. 
Participants with Asthma 
A subgroup analysis by concurrent asthma will be carried out for each of the following 
endpoints:  
 Total endoscopic nasal polyps score (Centrally Read) 
 Nasal obstruction VAS score 
 Proportion of subjects requiring systemic steroids for nasal polyps up to Week 52 
 
In addition, for participants with asthma the Asthma Control Questionnaire (ACQ-5) 
score and number of clinically significant asthma exacerbations will be summarised.  
These summaries will be based on a dataset where the intercurrent events of 
surgery/sinuplasty and treatment discontinuation have been handled as detailed in Section 
7.1.4. 
 
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7.5. 
Maintenance of response 
The following endpoints will be summarised for the subset of participants who entered 
the no-treatment 6-month follow up period after Week 52.  All data reported by these 
participants for the duration of their time in the study will be included in these 
summaries, this will include data reported prior to entering the follow-up period (whether 
or not the subject had prematurely discontinued from interventional product during that 
time) and data reported after entering the follow-up period.  
 Change from baseline in total endoscopic NP score (centrally read) 
 Change from baseline in mean nasal obstruction VAS score  
 Change from baseline in mean individual VAS symptom score for nasal 
discharge, mucus in throat, loss of smell and facial 
 Change from baseline in mean overall VAS symptom score 
 Proportion of subjects requiring systemic steroids for nasal polyps 
 Number of mgs per year of prednisolone-equivalent OCS dose 
 Change from baseline in SNOT-22 total score 
 Time to first nasal surgery 
 Time to first inclusion on waiting list for NP surgery 
 
8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population.  Unless otherwise specified 
data reported as part of the no-treatment follow-up will not be included in summaries of 
on-treatment data or post-treatment data.  Data reported during the no-treatment follow-
up will be summarised separately. 
Summaries of adverse events (AEs), serious adverse events (SAEs) and other significant 
AEs will be based on GSK Core Data Standards. The details of the planned displays are 
provided in Appendix 12: List of Data Displays. 
8.1. 
Adverse Events Analyses 
8.2. 
Adverse Events of Special Interest Analyses 
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 via targeted eCRF 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.  Local injection site reactions are also collected via targeted 
eCRF 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 
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of relevant preferred terms maintained within a project level reference dataset created 
based on the MedDRA dictionary available at the time of source data lock for this study. 
Further details of how relevant preferred terms are identified for the AESIs are given in 
the Program Safety Analysis Plan (PSAP). 
Separate summary tables showing the number and percent of participants with each type 
of AESI, broken down by preferred term will be created.  These summaries will be 
reported as part of the standard AE/SAE tables for the AESIs of infections, serious 
infections, neoplasms, cardiac disorders and serious cardiac disorders.  The relative risk 
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, summaries by maximum severity and separately by outcome.  
 
Separate listings will be provided of participants with systemic reactions identified by the 
investigator as meeting the criteria for anaphylaxis, systemic reactions categorised as 
allergic (type I hypersensitivity), systemic reactions categorised as other, and all other 
AESIs. 
 
8.3. 
Clinical Laboratory Analyses 
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. 
A scatter plot of maximum post-baseline ALT vs maximum post-baseline total bilirubin 
will be produced. In addition, if any liver stopping or liver monitoring events occur 
during the study, summaries of liver monitoring/stopping event reporting and 
hepatobiliary laboratory abnormalities will be produced. 
The details of the planned displays are in Appendix 12: List of Data Displays. 
8.4. 
Other Safety Analyses 
8.4.1. 
ECG and Vital Signs 
Summaries of ECG and vital signs data will be based on GSK Core Data Standards. The 
details of the planned displays are presented in Appendix 12: List of Data Displays. 
For ECG data, summaries of the maximum post-baseline and change from baseline 
values for QTc(F), QTc(B) and heart rate will be provided. 
Individual maximum and maximum change from baseline QTc(F) and QTc(B) values 
will be categorised as detailed in Section 14.6.6.  The number (percent) of participants in 
each of the categories will be displayed. 
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The number of abnormal and clinically significant ECG results post baseline will be 
produced showing the worst recorded value post baseline. 
8.4.2. 
Immunogenicity Data 
An immune response to a therapeutic drug can lead to generation of anti-drug antibodies 
within the blood. For the immunogenicity assessment, two types of antibody assays will 
be performed, a binding anti-drug antibody (ADA) assay and a neutralizing antibody 
(NAb) assay. 
For the binding ADA assay, there will be three testing steps: screening, confirmation and 
titration.  The screening assay produces a result of positive or negative relative to a 
screening cut point.  Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point.  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 subjects in the safety population 
(excluding data reported during the follow-up period after Week 52), as well as for the 
subjects entering the follow-up period after Week 52 (using all data). 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. 
The highest binding ADA assay confirmatory result obtained for a participant (including 
any off-treatment data), will be summarised with a positive result being considered 
higher than a negative one, participants with both positive and negative results being 
identified in the positive category.  Summary statistics for titre results will also be 
presented.  In addition, the highest NAb assay result during the same period will be 
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 interventional product will also be presented. 
All immunogenicity results (i.e. binding ADA screening and confirmatory assay results, 
titre values, NAb results and observed mepolizumab concentration) will be listed. 
 
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9. 
PHARMACODYNAMIC ANALYSES 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
9.1. 
Pharmacodynamic Analyses 
The treatment effect to be estimated (estimand) will be the comparison of mepolizumab 
100mg SC to placebo for change from baseline blood eosinophils at Week 52. 
9.1.1. 
Endpoint / Variables 
Absolute and ratio to baseline blood eosinophil counts will be summarised at each visit. 
9.1.2. 
Summary Measure 
The summary measure of treatment effect will be the ratio of the effect at Week 52 of 
mepolizumab compared to placebo. 
9.1.3. 
Population of Interest 
The population of interest is the Intent to Treat population. 
9.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Only data collected while the participant was on-treatment will be used in the analysis 
(‘while on-treatment strategy).  Blood eosinophil counts taken more than 28 days 
following last dose will not be included in the analysis.   
Missing data will be assumed to be missing at random. 
9.1.5. 
Statistical Analyses / Methods 
9.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
 Ratio to baseline blood eosinophils 
Model Specification 
 Blood eosinophil counts will be log transformed (loge) prior to analysis, transformations for 
values of 0 GI/L will be based on a value of 0.005 GI/L (see Section 14.6.6). 
 This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including the following terms: 
Fixed Categorical:  
Treatment group, Region, Visit 
Fixed Continuous:  
Baseline loge blood eosinophil count,  
Repeated:  
Visit 
Interaction Terms:  
Visit by baseline, visit by treatment group. 
 
Participants with missing covariate information will be excluded from the analysis 
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 An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line 
Model Checking & Diagnostics 
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. 
Model Results Presentation 
 The estimated means for each treatment group will be calculated from the model using the 
observed marginal distributions of the sample covariates (OM option in LSMEANS statement). 
 Model-estimates of the absolute mean and mean ratio to baseline will be back-transformed 
and presented as ratios with corresponding standard errors on the log scale for each treatment 
group by visit.  Estimated treatment differences (Mepolizumab/Placebo) with corresponding 
95% CIs and p-values will also be presented. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint 
 
10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
The primary goal of this analysis is to characterize the population pharmacokinetics of 
mepolizumab administered subcutaneously in participants with severe nasal polyps.  The 
influence of subject demographics, baseline characteristics, including disease activity, 
and co-medication on the pharmacokinetics of mepolizumab in this population will be 
investigated.  The individual subject PK parameters will be estimated and documented 
for the purposes of any subsequent exposure-response (PK/PD) analyses. 
In support of the analysis described below, a dataset will be generated for which 
specifications will be provided in a separate document. 
The details of the planned displays are provided in Appendix 12: List of Data Displays 
and will be based on GSK Data Standards and statistical principles.  Refer to Data 
Display Standards & Handling Conventions (Section 14.5.3 Reporting Standards for 
Pharmacokinetic Data). 
10.1. 
Primary Pharmacokinetic Analyses 
A population PK analysis of sparse concentration data will be performed on the PK 
population. 
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis. 
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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. 
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. 
10.2. 
Population Pharmacokinetic Methodology 
Sparse blood sampling is implemented in this study for determination of mepolizumab 
plasma concentration and subsequent data analysis by population PK methods using the 
most recent population pharmacokinetics model (meta-analysis PK model of data across 
indications described in GlaxoSmithKline Document Number 2015N238436_00).  Since 
mepolizumab PK following intravenous administration in NP subjects has already been 
established, the main objectives of this population PK analysis are: 
 To evaluate mepolizumab pharmacokinetics in subjects with NP following the 
subcutaneous administration of a 100 mg dose every 4 weeks. 
 To investigate the impact of covariates of interest in the studied NP 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. 
 
Further details are provided in Appendix 9: Population Pharmacokinetic (PopPK) 
Analyses. 
 
10.3. 
Exploratory Pharmacokinetic Analyses 
Complementing the population-PK analysis, a repeated measures linear mixed-effects 
model of loge-transformed concentration will be used to analyse the sparse (Weeks 4, 52 
and 68) data.  All data will be analysed on an ITT basis using planned Visit, irrespective 
of withdrawal.  The model will adjust for Region and Visit number and consider the 
covariates listed above.  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. 
10.3.1. 
Summary Measure 
Log-transformed mepolizumab plasma concentration. 
10.3.2. 
Population of Interest 
The population of interest is the PK population. 
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10.3.3. 
Statistical Analyses / Methods 
Endpoint / Variables 
 Plasma concentration 
Model Specification 
 Plasma concentration will be log transformed (loge) prior to analysis, values BQL will be set to 
missing. 
 This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including the following terms: 
Fixed Categorical:  
Region, Visit 
Fixed Continuous:  
loge bodyweight, loge creatinine clearance, loge serum albumin 
Repeated:  
Visit 
Interaction Terms:  
None 
 
Participants with missing covariate information will be excluded from the analysis 
 An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line 
Model Checking & Diagnostics 
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. 
Model Results Presentation 
 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. 
 Effects of bodyweight, creatinine clearance and serum albumin will be evaluated as 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. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint 
 
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11. 
POPULATION PHARMACOKINETIC/ 
PHARMACODYNAMIC (POPPKPD) ANALYSES 
In support of the analysis described below, a specific dataset will be generated for which 
specifications will be provided in a separate document. 
The details of the planned displays are presented in Appendix 12: List of Data Displays. 
11.1. 
Population Pharmacokinetic/Pharmacodynamic 
Methodology 
If deemed appropriate, a population pharmacokinetic/pharmacodynamic analysis will be 
conducted on the PK population and the ITT population (for blood eosinophils). 
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the 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 prior to log transformation (consistent with 
approaches used in other analyses). 
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. 
Blood eosinophil counts were measured during the course of the study over the 52 weeks 
treatment period and will be analysed by population methods using the most recent 
population PKPD model (meta-analysis PKPD model of data across indications described 
in GlaxoSmithKline Document Number 2015N238436_00). 
The objectives of the population PKPD analysis are: 
 To evaluate mepolizumab pharmacodynamics in subjects with NP following 
subcutaneous administration of a 100 mg dose every 4 weeks; 
 To investigate the impact of covariates of interest in the studied NP 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. 
Further details are provided in Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses. 
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12.
EXPLORATORY EXPOSURE-EFFICACY RESPONSE
ANALYSIS
If deemed appropriate an exposure-efficacy response analysis for the change from 
baseline in total endoscopic NP score and change from baseline in mean nasal obstruction 
VAS score during the 52-week study treatment period and subsequent 6-month follow-up 
period will be conducted. 
12.1. 
Population of Interest 
The exploratory exposure-efficacy response analysis will be performed on the ITT 
population. 
12.2. 
Endpoints 
Two measures of exposure will be considered for this analysis: 
i)
Dose/bodyweight (Week 52 endpoints only)
ii) Cav = Average concentration defined as 100 mg / (post-hoc apparent individual
clearance x 28d) 
Summary exposures (i) and (ii) will be categorised by quartiles for categorical analysis. 
12.3. 
Methodology 
12.3.1. 
Statistical analysis using exposure quartiles 
12.3.1.1. 
Statistical Methodology Specification 
Endpoint / Variables 

Change from baseline in total endoscopic NP score (based on centrally read data) at Week 52,
categorized for analysis as in Section 7.1.5.1.

Change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week
52, categorized for analysis as in Section 7.1.5.1.
Model Specification 

Each co-primary endpoint will be analyzed using ordinal logistic regression to compare the
odds between treatment exposure quartiles to placebo of being in a more favorable endpoint
category.

Odds ratios will be estimated from the ordinal logistic regression model using the observed
marginal distribution of the sample covariates.

The analysis model will include the following terms:
Fixed Categorical: 
Region 
Fixed Continuous: 
Treatment (placebo and exposure quartiles), Baseline score, Loge 
baseline blood eosinophil count 
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 
Participants with missing covariate information will be excluded from the analysis 
Model Checking & Diagnostics 
 Models will be checked for issues with convergence. 
Model Results Presentation 
 A forest plot of the estimated odds ratio and 95% CI for the comparison of quartiles will be 
provided. 
Subgroup Analyses 
 No subgroup analyses are planned for this endpoint 
Sensitivity and Supportive Analyses 
 No sensitivity/supportive analyses are planned for this endpoint 
 
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13. 
REFERENCES 
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 N/A Study ID Health Outcomes Study. Evaluation 
of the measurement properties of visual analog scales and the SNOT-22 in nasal polyps. 
Report Date Jan-2018.  
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.  
Jackson D, White, I.R., Seaman, S., Evans, H., Baisley, K., Carpenter, J. Relaxing the 
independent censoring assumption in the Cox proportional hazards model using multiple 
imputation. Statistics in Medicine. 2014;33:4681-4694.  
Keene O.N. Strategies for composite estimands in confirmatory clinical trials: Examples 
from trials in nasal polyps and steroid reduction. Pharmaceutical Statistics. 2018;18:78-
84.  
Mehrotra D.V., Permutt T. Missing data in clinical trials: control-based mean imputation 
and sensitivity analysis. Pharmaceutical Statistics. 2017;16:378-392.  
Relevant CDISC documentation available on www.cdisk.org 
 
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14.
APPENDICES
14.1. 
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
14.1.1. 
Exclusions from Per Protocol Population 
Participants with protocol deviations considered to potentially effect efficacy will be 
excluded from the Per Protocol (PP) population.  Determination of exclusion of a 
participant from the Per Protocol population will be made, where possible, before the 
database is frozen. 
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population: 
Number 
Exclusion Description 
01 
Informed consent never signed 
02 
Does not meet at least one of the following inclusion criteria (as numbered in the protocol): 
1. 18 years of age and older inclusive, at the time of signing the informed consent.
4. Participants who have had at least one previous surgery in the previous 10 years for the
removal of NP.
5. Participants with bilateral NP as diagnosed by endoscopy or historical CT scan.
6. Presence of at least two different symptoms for at least 12 weeks prior to screening:
nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) and
at least one of the following: nasal discharge (anterior/posterior nasal drip); facial
pain/pressure; reduction or loss of smell.
7. Participants with severe NP symptoms defined as an obstruction VAS symptom score of
>5.
8. Severity consistent with a need for surgery as described by:
a) Participants with an overall VAS symptom score >7
b) Participants with an 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)
9. Treatment with INCS (including intranasal liquid steroid wash/douching) for at least 8
weeks prior to screening.
10. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
03 
Meets any of the following exclusion criteria (as numbered in the protocol) 
1. As a result of medical interview, physical examination, or screening investigation the
physician responsible considers the participant unfit for the study.
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. Nasal septal deviation occluding one nostril.
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.
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Number 
Exclusion Description 
9. Participants who have undergone any intranasal and/or sinus surgery (for example 
polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior V1. 
12. Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 
1. 
13. Participants who are currently receiving or have received within 3 months (or 5 half-lives 
– whatever is the longest) prior to screening visit, 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 another monoclonal antibody 
therapy. 
17. Participants that have taken part in previous mepolizumab, reslizumab, dupilumab or 
benralizumab studies. 
18. Use of systemic corticosteroids (including oral corticosteroids) within 4 weeks prior to 
screening or planned use of such medications during the double-blind period. 
19. INCS dose changes within 1 month prior to screening. 
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 leukotriene antagonist treatment less than 30 
days prior to Visit 1. 
23. Commencement or change of dose of allergen immunotherapy within the previous 3 
months. 
28. Immunocompromised, other than that explained by the use of corticosteroids taken as 
therapy. 
04 
Does not meet any of the following randomisation criteria (as numbered in the protocol): 
1. Endoscopic NP score of at least 3 in one nostril and 2 in the other as per over read from 
central lab taken at Visit 1. 
2. Mean overall VAS >7 over the last 7 days preceding Visit 2 (excluding Visit 2) (from 
eDiary). 
3. Mean nasal obstruction VAS score >5 over the last 7 days preceding Visit 2 (excluding 
Visit 2) (from eDiary). 
4. Not had any NP surgery or have been included into a waiting list for NP surgery between 
Visit 1 and Visit 2. 
5. eDiary compliance for VAS (4 out of the last 7 days preceding Visit 2). 
8. Asthma Exacerbation: No asthma exacerbations during run-in period. An exacerbation is 
defined as worsening of asthma requiring the use of systemic corticosteroids (i.v. or oral 
steroid) for at least 3 days or a single IM CS dose and/or emergency department visit, or 
hospitalization. 
9. Maintenance Therapy: No changes or commencement during the run-in period in the 
dose or regimen of any regular baseline medication including a) INCS, b) course of systemic 
corticosteroids, such as OCS, c) leukotriene receptor antagonists, d) allergen 
immunotherapy. 
10. If the participant has a cold during run in then run in should be extended so to have the 
baseline visit, 2 weeks post the resolution of the cold but no greater than a total of 6 weeks 
from screening.  Colds that are not resolved within the 4th week of the nominal run-in period 
(28 days after screening) will be ineligible for randomization as they would have exceed this 
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Number 
Exclusion Description 
6 week period. 
05 
Use of any prohibited medication during the study [1] 
06 
Received the wrong study treatment at any point during the study 
07 
Two or more of the following deviations related to wrong study 
treatment/administration/dose: 
• 
Study treatment not administered per protocol 
• 
Study treatment administered while contraindication 
• 
Expired study treatment administered 
• 
Use of study treatment impacted by a temperature excursion which was not 
reported or approved, or which was disapproved for further use 
• 
Study treatment not available at site for administration 
• 
Missed dose 
• 
Other deviations related to wrong study treatment/administration/dose 
08 
Patient/Investigator unblinded 
NOTES: 
[1] See Section 7.6 of protocol for a list of prohibited medications 
 
 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
 
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14.3. 
Appendix 3: Assessment Windows 
14.3.1. 
Visit Based Assessments 
No assessment windows are defined for visit based assessments. Clinic visits are 
scheduled to take place as specified in Appendix 2: Schedule of Activities and are subject 
to a  7-day window, however assessments performed outside of these visit windows will 
still be included in any analyses. Nominal visits will be used for reporting and analysis. 
14.3.2. 
Unscheduled Visits 
Data recorded at an unscheduled visit will be re-assigned to the closest nominal visit at 
which collection of the data was scheduled, unless information already exists at that visit. 
If an unscheduled visit occurs between two scheduled visits for which data has been 
reported, the data will remain in the unscheduled visit and will not be included in any by 
visit summary tables; it will however be included in relevant summaries of any time post-
baseline data and listings. 
14.3.3. 
Data from eDiary 
The overall severity of nasal polyposis and of individual symptoms of nasal polyposis 
will be collected daily on a visual analogue scale using an eDiary.  For the purposes of 
analysis, data from the eDiary will be slotted as shown in Table 2. 
Table 2 
Definition of Baseline and Week 52 Periods for eDiary Data 
Analysis Window 
Analysis Timepoint 
Beginning Timepoint 
Ending Timepoint 
Baseline 
Date of First Dose - 7 
Date of First Dose -1 
Weeks 1-4 
Later of:  
Date of Visit 3 (Week 4) – 28 
Date of First Dose + 1 
Date of Visit 3 (Week 4) - 1 
Weeks 5-8 
Later of:  
Date of Visit 4 (Week 8) – 28 
Date of Visit 3 (Week 4)  
Date of Visit 4 (Week 8) - 1 
Weeks 9-12 
Later of:  
Date of Visit 5 (Week 12) – 28 
Date of Visit 4 (Week 8) 
Date of Visit 5 (Week 12) -1 
Weeks 13-16 
Later of:  
Date of Visit 6 (Week 16) – 28 
Date of Visit 5 (Week 12) 
Date of Visit 6 (Week 16) -1 
Weeks 17-20 
Later of:  
Date of Visit 7 (Week 20) – 28 
Date of Visit 6 (Week 16) 
Date of Visit 7 (Week 20) - 1 
Weeks 21-24 
Later of:  
Date of Visit 8 (Week 24) – 28 
Date of Visit 7 (Week 20) 
Date of Visit 8 (Week 24) - 1 
Weeks 25-28 
Later of: 
Date of Visit 9 (Week 28) - 1 
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Analysis Window 
Analysis Timepoint 
Beginning Timepoint 
Ending Timepoint 
Date of Visit 9 (Week 28) – 28 
Date of Visit 8 (Week 24) 
Weeks 29-32 
Later of:  
Date of Visit 10 (Week 32) – 28 
Date of Visit 9 (Week 28) 
Date of Visit 10 (Week 32) - 1 
Weeks 33-36 
Later of:  
Date of Visit 11 (Week 36) – 28 
Date of Visit 10 (Week 32) 
Date of Visit 11 (Week 36) - 1 
Weeks 37-40 
Later of:  
Date of Visit 12 (Week 40) – 28 
Date of Visit 11 (Week 36) 
Date of Visit 12 (Week 40) - 1 
Weeks 41-44 
Later of:  
Date of Visit 13 (Week 44) – 28 
Date of Visit 12 (Week 40) 
Date of Visit 13 (Week 44) - 1 
Weeks 45-48 
Later of:  
Date of Visit 14 (Week 48) – 28 
Date of Visit 13 (Week 44) 
Date of Visit 14 (Week 48) - 1 
Weeks 49-52 
(Primary timepoint for 
analysis) 
Later of:  
Date of Visit 15 (Week 52) – 28 
Date of Visit 14 (Week 48) 
Date of Visit 15 (Week 52) - 1 
Weeks 53-56 
Later of:  
Date of Visit 16 (Week 60) – 56 
Date of Visit 15 (Week 52) 
Date of Visit 16 (Week 60) - 29 
Weeks 57-60 
Date of Visit 16 (Week 60) - 28 
Date of Visit 16 (Week 60) - 1 
Weeks 61-64 
Later of:  
Date of Visit 17 (Week 68) – 56 
Date of Visit 16 (Week 60) 
Date of Visit 17 (Week 68) - 29 
Weeks 65-68 
Date of Visit 17 (Week 68) - 28 
Date of Visit 17 (Week 68) - 1 
Weeks 69-72 
Later of:  
Date of Visit 18 (Week 76) – 56 
Date of Visit 17 (Week 68) 
Date of Visit 18 (Week 76) - 29 
Weeks 73-76 
Date of Visit 18 (Week 76) - 28 
Date of Visit 18 (Week 76) - 1 
NOTES: 
 
Data collected on Day 1 (Date of first dose) will not be used in analysis/summaries 
 
Analysis periods will be up to a maximum of 28 days 
 
Where a missing visit date prevents the start or end of a period from being determined, an imputed date (Date of 
First Dose + Week of Visit with missing date x 7) will be used. 
14.3.4. 
Premature Withdrawals from Interventional Product or Study 
Any data reported at the early withdrawal visit will be re-assigned to the closest available 
scheduled visit, unless information already exists at that visit.  Data reported at the early 
withdrawal visit which has been re-assigned to a scheduled visit will be included in 
analyses, summary tables and figures by scheduled visit.  Data reported at the early 
withdrawal visit will be included in the assessment of maximum or worst-case post-
baseline summaries for any relevant endpoints, and all data will be included in listings. 
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14.4. 
Appendix 4: Study Phases 
14.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of interventional product. 
14.4.1.1. 
Phases for Efficacy Assessments 
Study Phase 
Definition 
Pre-Treatment  
Assessment Date  Interventional Product Start Date 
On-Treatment 
Participants who did not withdraw early from Interventional Product: 
Interventional Product Start Date < Assessment Date ≤ Earlier of Interventional 
Product Stop Date +28 days / Week 52 Visit Date 
 
Participants who withdrew early from Interventional Product: 
Interventional Product Start Date < Assessment Date ≤ Earlier of Interventional 
Product Stop Date +28 days/Date of Phase Conclusion 
Off-Treatment 
Participants who did not withdraw early from Interventional Product: 
Interventional Product Stop Date +28 days < Assessment Date  Week 52 Visit Date 
 
Participants who withdrew early from Interventional Product: 
Interventional Product Stop Date + 28 days < Assessment Date  Date of Phase 
Conclusion 
Off-Treatment 
(Follow-up after 
Week 52) 
Participants who enter the follow-up period after Week 52: 
Week 52 Visit Date < Assessment Date  
 
14.4.1.2. 
Phases for Safety Assessments 
Study Phase 
Definition 
Pre-Treatment  
Assessment Date  Interventional Product Start Date 
On-Treatment 
Interventional Product Start Date < Assessment Date ≤ Interventional Product Stop 
Date +28 days 
Post -Treatment 
Participants who do not enter the follow-up period after Week 52: 
Interventional Product Stop Date + 28 days < Assessment Date 
 
Participants who enter the follow-up period after Week 52: 
Interventional Product Stop Date + 28 days < Assessment Date ≤Week 52 Visit Date 
Post -Treatment 
(Follow-up after 
Week 52) 
Participants who enter the follow-up period after Week 52: 
Week 52 Visit Date < Assessment Date 
 
14.4.1.3. 
Phases for Adverse Events 
Study Phase 
Definition 
Pre-Treatment  
Event Start Date < Interventional Product Start Date 
On-Treatment 
Interventional Product Start Date  Event Start Date  Interventional Product Stop 
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Study Phase 
Definition 
Date + 28 days 
Post -Treatment 
Participants who do not enter the follow-up period after Week 52: 
Event Start Date > Interventional Product Stop Date + 28 days 
 
Participants who enter the follow-up period after Week 52: 
Interventional Product Stop Date + 28 days < Event Date ≤Week 52 Visit Date 
Post -Treatment 
(Follow-up after 
Week 52) 
Participants who enter the follow-up period after Week 52: 
Week 52 Visit Date < Event Date 
NOTES: An event will be considered On-treatment if the event start date is missing and/or the interventional product 
stop date is missing 
Where time of event is recorded, the time of event and time of first dose will be considered to differentiate between 
Pre-treatment and On-treatment events. 
 
14.4.1.4. 
Phases for Concomitant Medication Start Dates 
Study Phase 
Definition 
Pre-Treatment 
(Started prior to 
treatment) 
Concomitant medication (CM) start date < IP start date 
On-Treatment 
(Started during 
Treatment) 
If CM start date is on/after IP start date & on/before IP stop date +28 days. 
(IP Start Date ≤ CM Start Date ≤ IP Stop Date + 28 days) 
Post-Treatment 
(Started post-
treatment) 
If CM start date is after the IP stop date + 28 days. 
(CM Start Date > IP Stop Date + 28 days) 
Follow-Up After 
Week 52 (started 
during the Follow-
up period after 
Week 52) 
Participants who enter the follow-up period after Week 52: 
If CM start date is after the Week 52 Visit date. 
NOTES: If the IP stop date is missing and/or the CM start date is missing then the CM is considered to have started 
on-treatment 
 
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14.4.1.5. 
Phases for Concomitant Medication Usage Dates 
Study Phase 
Definition 
Taken Prior to 
Treatment 
If CM start date < IP Start Date 
Taken During 
Treatment 
If CM start date < IP start date and CM stop date ≥ IP start date 
If IP start date < CM start Date ≤ IP Stop Date + 28 days 
Taken Post-
Treatment 
If CM start date ≤ IP stop date+28 days and CM stop date > IP stop date +28 days 
If CM start Date > IP stop date + 28 days 
NOTES: If the IP stop date is missing and CM start date is on/after IP start date then CM considered taken during 
treatment 
If CM start date is missing, then CM considered to be taken during treatment 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
HARP Compound 
Analysis Datasets  
 
Analysis datasets will be created according to CDISC standards [SDTM IG Version 3.2 & ADaM IG 
Version 1.1]. 
 
Analysis datasets will include variables to clearly indicate whether each observation was observed 
while the patient was on randomized treatment, observed after the patient discontinued randomized 
treatment, or was imputed or is missing. 
Generation of RTF Files 
 
RTF files will be generated for the final reporting effort. 
14.5.2. 
Reporting Standards 
General 
 
All data displays (Tables, Figures & Listings) will use the term “Subject” rather than “Participant” which 
reflects CDISC and GSK Data Display Standards terminology. 
 
Templates and standards within the current GSK Integrated Data Standards Library (IDSL) will be used 
for reporting unless otherwise stated. 
IDSL standards located at https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx (under supporting 
documentation/component/statistical displays) will be applied:  
 
4.03 to 4.24: General Principles 
 
5.01 to 5.08: Principles Related to Data Listings 
 
6.01 to 6.11: Principles Related to Summary Tables 
 
7.01 to 7.13: Principles Related to Graphics  
Formats 
 
GSK IDSL Statistical Principles for the precision to which data and summary statistics are to be 
presented will in general be adopted, these may be adjusted to a clinically interpretable number of 
decimal places (d.p.). 
 
For Blood Eosinophil Counts displayed as GI/L the following will be applied: 
Geometric Mean, Median, Min and Max (2 d.p.); SD Logs (3 d.p.) 
Planned and Actual Time 
 
Reporting for tables, figures and formal statistical analyses: 
 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
 
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
 
Reporting for data listings:  
 
Planned and actual time relative to study drug dosing will be shown in listings. 
 
Unscheduled or unplanned readings will be presented within the subject’s listings. 
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Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables and/or figures, however they will be included 
in listings. 
 
Data from unscheduled visits may be included in summary tables/figures when the unscheduled visit 
has been reassigned (Section 14.3.2).  
 
Data from unscheduled visits will be included in any-time post-baseline summaries 
Early Withdrawal from Interventional Product or from Study 
 Data recorded at the early withdrawal visit will be re-assigned to the next scheduled visit, 
unless information already exists at that visit.  Early withdrawal data re-assigned to a 
scheduled visit will be included in analyses, summary tables and figures by scheduled visit. 
Early withdrawal visit data that is not re-assigned to a scheduled visit will not be included in 
analyses, summary tables or figures by scheduled visit. 
 Data recorded at early withdrawal visits will be included in the assessment of maximum or 
worst-case post-baseline for relevant endpoints. 
 
Data from all early withdrawal visits will be included in listings. 
 
Descriptive Summary Statistics 
Continuous Data 
n, mean, standard deviation or standard error, median, minimum, maximum  
Categorical Data 
N, n, frequency, % 
Graphical Displays 
 
Refer to IDSL Statistical Principals for Graphics  
14.5.3. 
Reporting Standards for Pharmacokinetic Data 
 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: BLQ concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics only. 
NONMEM/Pop PK 
File 
Pop-PK file (CSV and SAS format) for the POP-PK and POP-PKPD analyses 
performed by the Clinical Pharmacology Modelling and Simulation function will be 
created according to the POP-PKPD Dataset Specification document.  
Pharmacokinetic Parameter Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
 
Unless otherwise specified, if there are multiple measurements reported under the same nominal visit, 
the value of the first assessment will be used in any derivation of summary statistics, all individual 
measurements will be presented in any data listings. 
 
Participants with post-baseline safety data in both High and Low categories with respect to the Normal 
Range/Potential Clinical Concern will be counted in each of the categories for the “Any visit post-
baseline” row of any related summary tables. 
Study Day 
 
Calculated as the number of days from the first dose of study medication (IP start date). 
 
If Visit Date = Missing              → Study Day = Missing  
 
If Visit Date < First Dose Date → Study Day = Visit Date – IP Start Date 
 
If Visit Date ≥ First Dose Date → Study Day = Visit Date – (IP Start Date) + 1     
 
14.6.2. 
Analysis Population 
Actual Treatment for Safety Population 
 
Analysis of safety data will be by actual treatment arm. 
 
For participants identified as having any discrepancies between the treatment group they were 
randomised to and the treatment received, the actual treatment arm will be derived based on the 
treatment received for more than 50% of all treatment administrations.  For all other participants, actual 
treatment arm will be the same as the randomised treatment arm. 
 
14.6.3. 
Study Population 
Demographics 
Age 
 Year of birth is collected as ‘YYYY’ and will be presented as collected in listings 
 Date of birth will be imputed as ‘30th June YYY’ 
 
Age is calculated according to GSK standard IDSL algorithms and is based on the imputed 
date of birth relative to the date of Visit 1 (Screening). 
BMI 
 
BMI will be calculated as Weight (kg) / [Height (m)]2 
 
Exposure 
Extent of Exposure (Therapeutic Coverage) 
 
IP is administered 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: 
o Duration of Exposure (days) = (IP Stop Date – IP Start Date + 29) 
o Duration of Exposure (months) = (IP Stop Date – IP Start Date + 29) * 12/365.25 
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Exposure 
Extent of Exposure (Therapeutic Coverage) 
 
Subject Years Exposure is calculated as follows;  
o Subject Years Exposure = (IP Stop Date – IP Start Date + 29)/365.25 
 
If the IP start date is missing and there is evidence the participant received at least one dose of IP, the 
IP start date will be taken to be the date of randomisation, if the IP end date is missing it will be taken to 
be the last on-treatment visit attended. 
 
Randomised participants with no evidence of receiving at least one dose of IP will be considered as 
having zero days of exposure. 
 
Exposure for treatment period and no-treatment follow-up 
Number of years on and off-treatment or missing 
 
All participants are expected to participate in the study for at least 52 weeks (±7 days) 
 
The number of years on-treatment will be calculated as follows:  
o (IP Stop Date – IP Start Date + 29)/365.25 
 
The number of years off-treatment will be calculated as follows:  
o Date of Phase Conclusion – (IP stop date +28)/365.25 
 
The number of years missing will be calculated as follows for subjects who withdrew from study:  
o 1 – (number of years on-treatment) – (number of years off-treatment) 
Duration of time in no-treatment follow-up 
 
This will be calculated in months for subjects who enter no-treatment follow-up after Week 52 as 
follows: 
o (Date of study end – Date of Week 52) * 12/365.25 
 
Concomitant Medications (CM) 
Time since first dose (days)  
 
The time since first dose will be calculated as follows:  
If CM start date < IP start date = CM start date - IP start date 
If CM start date ≥ IP start date = CM start date – IP Start Date +1 
Missing otherwise. 
 
 
The duration in days will be calculated as follows:  
CM end date – CM start date + 1 
NOTES: Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates 
Subgroups 
Participants With Asthma 
 
Concurrent asthma: Subjects with a response of ‘Current’ for the medical condition of ‘Asthma’. 
 
No concurrent asthma: Subjects with a response of ‘Past’, ‘Not Assessed’ or ‘No Medical Condition’ for 
the medical condition of ‘Asthma’.  Subjects with a missing response will also be included in this 
category. 
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Subgroups 
Aspirin Exacerbated Respiratory Disease (AERDS)  
 
Current AERDS: Subjects with a response of ‘Current’ for the medical condition of ‘Drug Allergy’. 
 
No Current AERDS: Subjects with a response of ‘Past’, ’Not Assessed’ or ‘No Medical Condition’ for the 
medical condition of ‘Drug Allergy’.  Subjects with a missing response will also be included in this 
category. 
Number of previous surgeries 
 
Participants will be categorised as follows based on data collected on the eCRF regarding number of 
previous surgeries: 1, 2, >2 
Baseline Blood Eosinophil Categories 
 
Categories for baseline blood eosinophils will be: 
o ≤0.3 GI/L; >0.3 to ≤0.5 GI/L; >0.5 to ≤0.7 GI/L; >0.7 GI/L 
 
Blood eosinophils are reported in GI/L, each category is rounded to 1 d.p. which is equivalent to 
rounding blood eosinophils to the nearest 100 cells/µL. 
Region 
 
Europe: Participants from sites in Germany, Netherlands, Romania, Sweden, UK 
 
United States: Participants from sites in US 
 
Rest of World: Participants from sites in South Korea, Argentina, Australia, Canada, Russia 
Age Categories 
 
Participants will be categorised as follows based on the derived age: 
 
18-<40 years, 40 - < 65 years, ≥65 years. 
Race Categories 
 
Subjects will be categorised by Race based on the Geographic Ancestry reported on the eCRF: 
 
Race Category 
Geographic Ancestry reported on the eCRF 
African American/African Heritage 
African American/African Heritage 
White 
White – Arabic/North African Heritage 
White – White/Caucasian/European Heritage 
Asian 
Asian – Central/South Asian Heritage 
Asian – East Asian Heritage 
Asian – Japanese Heritage 
Asian – South East Asian Heritage 
Other 
American Indian or Alaskan Native 
Native Hawaiian or Other Pacific Islander 
Multiple Race 
 
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14.6.4. 
Change from Baseline 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
% Change from Baseline 
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline] 
Ratio to Baseline [1] 
= Post-Dose Visit Value / Baseline 
NOTES: Refer to Section 5.2 for definition of Baseline. Unless otherwise stated, if Baseline or the Post-Dose value is 
missing the result will be set to missing. 
[1] For loge transformed data Ratio to Baseline is the back transformed change from baseline value  
 
14.6.5. 
Efficacy 
Assigning the worst score for subjects with surgery or missing data 
Relevant efficacy endpoints 
 
Subjects who undergo surgery/sinuplasty will have their worst observed score (or worst observed 4-
week mean) assigned for all subsequent visits (or 4-week periods) following surgery/sinuplasty.  The 
assigned value will be the worst observed value from baseline up to before the surgery/sinuplasty.  
Assessments taking place on the same day as surgery/sinuplasty are assumed to have been carried 
out before the surgery/sinuplasty. 
 
Subjects who have not experienced surgery/sinuplasty and have missing values due to study 
withdrawal, will have their worst observed score (or worst observed 4-week mean) assigned for all 
missing visits (or 4-week periods) following study withdrawal.  The assigned value will be the worst 
observed value from baseline up until study withdrawal. 
 
Subjects with missing data for other reasons will have their worst observed score (or worst observed 4-
week mean) prior to the missing visit (or missing 4-week period) assigned. 
 
Total Endoscopic Nasal Score 
Responder 
 
A responder will be defined as a participant with a ≥1-point improvement from baseline in total 
endoscopic nasal score (centrally read). 
 
Participants with no improvement/worsening or with missing data will be considered a non-responder 
for analysis. 
 
 
VAS scores (individual and composite) 
Individual VAS Scores 
 
VAS scores are captured electronically using an eDiary, participants indicate their response on a line 
. 
 
The final VAS scores for inclusion in summary and analysis tables will be derived from the electronically 
captured score by 
. 
Change from baseline categories 
 
The baseline scores will be calculated as the mean of the scores reported between the 7 days prior to 
the first dose. 
 
The scores for each 4-week period will be calculated as the mean of the scores reported between 
timepoints detailed in Section 14.3.3. 
Composite VAS scores 
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VAS scores (individual and composite) 
 
Two separate composite VAS scores will be derived using the final VAS scores: 
 
Composite of nasal obstruction, nasal discharge, mucus in the throat and loss of smell 
o 
 
 
Composite of nasal obstruction, nasal discharge, mucus in the throat, loss of smell and facial pain 
o 
 
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Nasal Surgery (reported on the disease related events page of the eCRF) 
Time to first nasal surgery 
 
Calculated as (Date of first nasal surgery – Date of first dose of study treatment) + 1 
 
 
Analysis excluding data from the follow-up period after Week 52:  
For participants who withdraw from the study before Week 52 and before experiencing surgery, event 
times will be censored at the time of study withdrawal  
For participants who complete to Week 52 without experiencing surgery, event times will be censored 
at the time of the Week 52 visit. 
 
 
Analysis including data from the follow-up period after Week 52:  
For participants who withdraw from the follow-up period before completion and before experiencing 
surgery, event times will be censored at the time of study withdrawal. 
For participants who complete the follow-up period without experiencing surgery, event times will be 
censored at time of completion of follow-up. 
Need for surgery 
 
Need for surgery at Week 52 is based on the overall VAS symptoms score and the endoscopic NP 
score (centrally read).  Participants will be classified as having a need for surgery if they meet the 
following: 
o Overall VAS symptoms score >7 (Weeks 49-52) and total endoscopic NP score ≥5 (Week 52, 
centrally read) 
 
Participants who have undergone nasal polyps surgery at any time prior to the week 52 visit, or who 
have a missing endoscopic NP score (centrally read) at Week 52, or missing overall VAS symptom 
score (Weeks 49-52) will be identified for analysis as still having a need for surgery. 
Rate of surgery 
 
The crude rate of surgery will be presented for each treatment arm, this will be calculated as:  
 
 
*365.25 
 
Systemic steroid use 
Conversion of glucocorticoid dose to mgs of prednisolone equivalent OCS use 
 
The total number of mgs of prednisolone equivalent OCS use per year will be calculated as follows and 
will be based on systemic steroids taken via the following routes: Oral, Intravenous, Intramuscular:  
*365.25 
 
The following table from the study reference manual will be used for conversion of intravenous and oral 
steroid use into prednisolone equivalent OCS use in mgs: 
 
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Systemic steroid use 
Glucocorticoid 
Approximate equivalent dose (mg) 
Short-Acting 
Cortisone 
25 
Hydrocortisone 
20 
Intermediate-Acting 
Methylprednisolone 
4 
Prednisolone 
5 
Prednisone 
5 
Triamcinolone 
4 
Long- Acting 
Betamethasone 
0.6-0.75 
Dexamethasone 
0.75 
 
Participants who withdraw early from the study will have yearly use estimated based on use during the 
study. 
Courses of Therapy 
 
A course of systemic steroid therapy is defined by the start and stop date of therapy. 
 
If the start date of a course of systemic steroid therapy occurs <7 days from the stop date of the 
previous course, it will be considered a continuation of the same course. 
Days on Therapy 
 
The duration of a course of systemic steroids will be calculated as the number of days between the start 
and stop date of the course: stop date – start date +1 
 
 
For each participant the total number of days on systemic steroids will be calculated as the sum of the 
duration of each of their courses of therapy. 
 
 
For each participant the percentage of days on systemic steroids will be calculated as follows: 
 
*100 
 
 
Nasal Surgery or Course of Systemic Steroids 
Time to first nasal surgery or course of systemic steroids 
 
Calculated as (Date of first nasal surgery/course of systemic steroids – Date of first dose of study 
treatment) + 1 
 
Analysis excluding data reported in the follow-up period after Week 52:  
For participants who withdraw from the study before Week 52 and before experiencing either event, 
event times will be censored at the time of study withdrawal 
For participants who complete to Week 52 without experiencing either event, event times will be 
censored at the time of the Week 52 visit 
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Antibiotic Use 
Courses of Therapy 
 
A course of antibiotics is defined by the start and stop date of therapy. 
 
If the start date of a course of antibiotics occurs <7 days from the stop date of the previous course, it 
will be considered a continuation of the same course. 
 
SNOT-22 
SNOT-22 Total Score 
 Each question of the SNOT-22 is graded on a 
 
  The scores for each of the questions will be summed to derive 
 [Hopkins, 2009]. 
 
 If a participant does not complete any questions at a visit the total score for that visit will be 
missing. 
 If a participant has some (but no more than 50%) missing responses to questions at a visit, 
then the missing responses will be imputed with the unrounded mean of the non-missing 
responses at that visit. The SNOT-22 total score for that visit will then be rounded to the 
nearest integer. 
SNOT-22 Responder 
 A responder is defined as having a ≥8.9-point improvement (decrease) from baseline in SNOT-
22 total score. 
SNOT-22 Domain Scores 
 
The six SNOT-22 domain scores are shown below; the domain scores are derived from the 
sum of the individual item-scores shown [Health Outcomes Study, 2018]: 
 
Domain 
Items/Questions 
Nasal 
Non-nasal 
symptoms 
Ear/facial 
symptoms 
Sleep 
Fatigue 
Emotional 
consequences 
 
UPSIT 
UPSIT total score 
 
The total score is calculated as the number of times the correct smell is identified out of a possible 4 
choices, for 40 different smells. 
 
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Work Productivity and Activity Impairment Questionnaire (WPAI) 
 
 
The following summary variables will be derived from the 6 WPAI questions: 
 
Summary variable 
Derivation 
 
ACQ-5 
ACQ-5 Score 
 
ACQ-5 is a 5-item questionnaire developed as a measure of patient’s asthma control.  Response 
options for each question are on 
 
 
 
The questions are equally weighted, and the ACQ-5 score is calculated as the mean of the 5 questions, 
 
 
For a given visit, if the response to one of the 5 questions is missing then the ACQ-5 score will be 
calculated as the mean of the available responses.  If the response to more than one question is 
missing, then the ACQ-5 score will be set to missing. 
 
Asthma exacerbations 
Clinically significant asthma exacerbation 
 
A clinically significant asthma exacerbation is defined as a worsening of asthma requiring systemic 
steroids (i.v. or oral) for at least 3 days or a single intra-muscular corticosteroid dose, and/or an ED visit 
and/or hospitalisation. 
 
14.6.6. 
Safety 
Adverse Events 
Drug Related AE’s 
 
AEs where the response to “Is there a reasonable possibility that the AE may have been caused by the 
Study Treatment?” is “Yes” or it is missing 
AE’s Leading to Permanent Discontinuation of Study Treatment or Withdrawal from Study 
 
AE’s leading to permanent discontinuation of study treatment are defined as AEs where the response to 
“Most Clinically Significant Action Taken with Study Treatment(s) as a Result of the AE” is “Study 
Treatment(s) Withdrawn”. 
 
AEs leading to withdrawal from study are defined as AEs where the response to “Did the subject 
withdraw from study as a result of this AE?” is “Yes”. 
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AE’s on Day of Dosing 
 
These are defined as AEs with an onset date on the same day as dosing with interventional product 
and an onset time on or after the time of dosing with interventional product on the given day.  
AE Time Since First Dose 
 
If AE onset time is missing, calculate in days as follows: 
o If AE start date < Date of first dose of Interventional Product, then  
Time since first dose = AE start date - Date of first dose of Interventional Product  
o If AE start date ≥ Date of first dose of Interventional Product, then  
Time since first dose = AE start date – Date of first dose of Interventional Product +1 
o If AE start date or date of first dose of Interventional Product is missing time since first dose is 
missing. 
 
 
If AE onset time is present, calculate as above but in days, hours, minutes using AE start date/time and 
date/time of first dose of interventional product 
AE Duration in Days 
 
If AE onset time is missing calculate in days: AE end date - AE start date + 1  
 
If AE onset time is present calculate in days, hours, minutes as above but using AE end date/time and 
AE start date/time. 
 
If AE start/end date is missing duration is missing. 
AE’s of Special Interest 
 
Section 8.2 provides a full list of AEs of special interest for this compound. 
 
AESIs of anaphylaxis reactions, systemic reactions, and local injection site reactions are collected via 
targeted eCRF. 
 
The AESIs of potential opportunistic infections, malignancies, serious CVT events and serious ischemic 
events will be identified from a list of relevant preferred terms maintained within a project level 
reference dataset; created based on the latest version of the MedDRA dictionary available at the time of 
database freeze for this study (See Program Safety Analysis Plan for additional details). 
 
ECG 
Multiple Assessments 
 
Where multiple assessments are performed at a given time point, the mean value over the replicate 
assessments will be used for summary statistics; the highest value amongst the individual replicate 
assessments will be used in the evaluation of the highest post-baseline value. 
QTc values 
 
A single 12-lead ECG machine will be used to assess heart rate and measure PR, QRS, QT and QTc 
intervals 
 
QTc(F) will be derived from QT (uncorrected) and RR interval as: 
 
 
QTc(B) will be derived from QT (uncorrected) and RR interval as: 
 
 
If present the reported QTc value will be included in any summaries, else the derived QTc value will be 
included. 
Categorised QTc values 
Individual maximum QTc(F) and QTc(B) values and maximum change from baseline QTc(F) and QTc(B) will 
be categorised as follows:  
 
Lower 
Upper 
QTc Interval (msec) 
 
≤ 450 
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> 450 
≤ 480 
> 480 
≤ 500 
> 500 
 
QTc Change from 
Baseline (msec) 
 
≤ 30 
> 30 
≤ 60 
> 60 
 
 
Laboratory Parameters 
Character Values 
 
If a laboratory value which is expected to have a numeric value for summary purposes has a non-
detectable level reported in the database, where the numeric value is missing, but instead  a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, a numeric value will be imputed; the number of significant digits in the observed value will be 
used to determine how much to add or subtract to impute the corresponding numeric value:  
o Example 1: 2 Significant Digits = ‘< x ‘imputed as x – 0.01 
o Example 2: 1 Significant Digit   = ‘> x’ imputed as x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ imputed as x –1 
 
Laboratory values with missing values due to being below the limit of quantification (BLQ) for that 
parameter will have a value imputed as half the lower limit of quantification for that measure (i.e. the 
lowest observed value for that measure within the entire study database). 
 
 Values of potential clinical concern and those outside the ≥2, ≥3 etc. limit of normal will be identified as 
detailed in Section 14.8.  
Blood Eosinophils 
 
Blood eosinophil counts will be log transformed (loge) prior to analysis.  The log transformation for 
values of 0GI/L will be based on a value of 0.005GI/L. 
Biomarkers 
 
No analyses of additional biomarker will be carried out as part of this RAP.  
 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
 
The protocol objective is to collect data over the full study treatment period (up to Week 
52) for all participants, whether they continue on interventional product (IP) and 
complete Week 52 on-treatment, or whether they withdraw prematurely from IP.   
o For the participants who withdraw prematurely from IP before Week 52 and 
agree to the continued collection of data off-treatment, data will be collected 
for up to 52 weeks after randomization (or up to 76 weeks if the participant 
enters the Follow-up period after Week 52) either through clinic visits or via 
phone contact, in accordance with the participants existing visit schedule. 
o Where available, off-treatment data will be included in the analysis of the co- 
primary endpoints and, unless otherwise indicated, in the analysis of other 
efficacy endpoints.   
 
 
A participant will be considered to have completed study treatment if he/she continues 
to take study treatment until Visit 14 (Week 48) and completes Visit 15 (week 52).  
 
As specified in the protocol participants will be considered to have completed the study 
upon completion of Visit 15 (Week 52) regardless of whether they continue to take IP. 
 
 
A participant eligible for the no-treatment follow-up will be considered to have 
completed follow-up if they continue to participate in the study until Visit 18 (Week 76) 
 
 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
 
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits. 
Pre-
Screen/Scre
en and Run-
in Failures 
 
Participants are assigned a subject number at the time of signing informed consent. 
 
Pre-Screen Failure: A participant who is assigned a subject number but did not 
continue through to Visit 1.  
 
Screening Failure: Participant performs a Visit 1 procedure, but does not enter the run-
in period 
 
Run-in Failure: Participant enters the run-in period, may perform a Visit 2 procedure, 
but is not subsequently randomised.  
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated using a “blank” in data listings. Where all data for 
a specific visit are missing the visit will be excluded from the listing.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed. 
 
Values reported as ‘BLQ’ are not considered as missing data and are handled as detailed in 
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Element 
Reporting Detail 
Section 14.6.6, these values will be displayed in the listings and included in any 
summary/analysis outputs. 
Outliers 
 
All data will be included in the summaries and analyses of each endpoint.  The 
exclusion of participants or participant data from any supplementary analyses will be 
documented within footnotes and where required the clinical study report. 
Covariate 
information 
 
Participants with missing information for a covariate included in the analysis model will 
be excluded from the analysis. 
14.7.2.1. 
Handling of Missing Dates 
Element 
Reporting Detail 
General 
Start or end dates which are completely missing (i.e. no day, month or year is specified) will 
remain missing, with no imputation applied.  
Derivations requiring this information such as time to onset and duration will be set to 
missing. 
 
14.7.2.2. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in subject listings. 
Adverse 
Events 
 
The eCRF allows for the possibility of partial dates to be recorded for AE start and end 
dates. 
 
For partial dates the following imputations will be applied: 
o Partial Start Date: '01' will be used for a missing day and ‘Jan’ will be used for 
a missing month.  If this results in a date prior to the start of study treatment, 
then the treatment start date will be used. The event will then be considered 
‘On-treatment’ as per Section 14.4.1.3. 
o Partial Stop Date: '28/29/30/31' will be used for a missing day (dependent on 
the month and year) and 'Dec' will be used for a missing month.  If this results 
in a date after the study stop date, then the study stop date will be used. 
 
The above imputations will be applied when calculating the time to onset and duration 
of the event. 
Concomitant 
Medications 
 
For concomitant medications partial dates will be imputed as follows: 
o Partial start date: '01' will be used for a missing day and 'Jan' will be used for a 
missing month 
o Partial stop date: '28/29/30/31' will be used for a missing day (dependent on the 
month and year) and 'Dec' will be used for a missing month. 
 
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14.7.2.3. 
Missing Data for Statistical Analysis 
Element 
Reporting Detail 
General 
 
The study is designed to collect data for the 52 weeks following randomisation for all 
participants, including for participants who prematurely withdraw from interventional 
product.  The following scenarios may arise. 
1) Participant completes interventional product and study 
2) Participant prematurely withdrawn from interventional product and agrees to 
continued data collection off-treatment for 52 weeks following randomisation 
3) Participant prematurely withdrawn from interventional product and initially 
agrees to continued off-treatment data collection, but subsequently withdraws from 
the study prior to 52 weeks following randomisation 
4) Participant prematurely withdrawn from interventional product and does not 
agree to continued off-treatment data collection 
 
 
For participants under any scenario missing data may arise intermittently due to 
nonattendance at scheduled visits.  For participants under scenarios 3 and 4 missing 
data will arise due to premature withdrawal from the study. 
 
 
Unless otherwise specified on-treatment data and where available off-treatment data 
will be included in the analysis of efficacy endpoints. 
 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
14.8.1. 
Laboratory Values of Potential Clinical Concern 
Haematology 
Laboratory Parameter 
 
Units 
Age 
Category 
(years) 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit 
Ratio of 1 
12+ 
0.201 
0.599 
Haemoglobin 
G/L 
12+ 
71 
199 
Platelet Count  
GI/L 
1+ 
31 
1499 
While Blood Cell Count (WBC) 
GI/L 
12+ 
1.1 
 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Age 
Category 
(years) 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
ALT 
U/L 
3-12 
 
>143 
U/L 
13+ 
 
>239 
Calcium 
mmol/L 
3+ 
1.50 
3.24 
Creatinine Phosphokinase 
IU/L 
12+ 
 
>5 x ULN 
Glucose 
mmol/L 
1+ 
2.2 
27.8 
Phosphorus, Inorg 
mmol/L 
3+ 
0.32 
 
Potassium 
mmol/L 
3+ 
2.8 
6.5 
Sodium 
mmol/L 
0+ 
120 
160 
 
Possible Hy’s Law Cases 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT, Bilirubin 
 
 
ALT ≥ 3xULN and Bilirubin ≥ 2xULN 
(>35% direct) 
ALT, INR 
 
 
ALT ≥ 3xULN and INR > 1.5 
NOTES: ULN=Upper Limit of Normal 
 
 
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14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
14.9.1. 
Population Pharmacokinetic (PopPK) Dataset Specification 
Specifications for the generation of the dataset will be provided in a separate document. 
14.9.2. 
Population Pharmacokinetic (PopPK) Methodology 
Mepolizumab plasma concentration-time data (samples collected at Weeks 4, 52 and 68; 
at the Early Withdrawal Visit and the additional follow-up 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). 
14.9.2.1. 
Base Model 
In consideration of the sparse sampling (3 samples post-start of treatment over 68 weeks: 
Week 4, 52 and 68) and the wealth of mepolizumab PK knowledge, the most recent 
population PK model will be applied directly to the dataset without estimation (e.g. 
maxevals=0 in NONMEM) and predictions generated, against which the model will be 
validated prospectively using appropriate goodness of fit tests.  For example, the 
Anderson-Darling and Cramér–von Mises tests are accepted methods of comparing 
Empirical Distribution Functions for model and data (i.e. PK concentrations) to evaluate 
whether independent observations (i.e. observed PK concentrations from the study) are 
adequately described by a model (i.e. most recent population PK model). 
The following will be obtained: 
 A description of the key models tested during the model development will be 
provided and tabulated; 
 Population mepolizumab plasma PK parameter estimates with 95% CI from the final 
model will be tabulated.  Goodness of fit plots for the final model will be presented; 
 Individual post-hoc PK parameter estimates (such as area under the plasma 
concentration-time curve over the dosing interval [AUC (0-)], CAV [AUC (0-)/]) 
will be summarised descriptively and listed; 
 Individual post-hoc predicted plasma concentrations will be summarised descriptively 
and listed; 
 Accumulation ratio estimate will be assessed at Week 52. 
The most recent model consists of a two-compartment pharmacokinetic model with first-
order absorption and elimination. Bodyweight is incorporated into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volumes, respectively.  Albumin and creatinine clearance are also included as 
covariates of mepolizumab clearance on physiological grounds, however their effects are 
small and not of clinical relevance.  Details of the model can be found in report 
GlaxoSmithKline Document Number 2015N238436_00. 
 
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14.9.2.2. 
Investigation of Covariates 
The impact of the following prospectively selected covariates on mepolizumab exposure 
(e.g. clearance) will be evaluated using the procedures described in Section 14.9.2.3. 
Category 
Covariates 
Demographics 
Weight (included in the structural model), age, race, 
gender, country 
Baseline clinical status 
Creatinine clearance, albumin (both already included in the 
current model), serum creatinine, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, bilirubin, 
total protein 
Baseline disease status 
Total endoscopic NP score (centrally read), mean nasal 
obstruction VAS, number of previous surgeries, blood 
eosinophils and baseline OCS dose 
Concomitant medications 
If data permits[1], e.g.  leukotriene receptor antagonists, 
proton pump inhibitors, statins, antihistamines, pain relief 
(e.g. paracetamol, NSAIDs) and antihypertensive drugs 
Others 
Presence/absence of anti-drug antibodies and previous 
biologics use (monoclonal antibodies). 
[1] Attempt to investigate those classes of drug will be made providing data permits. 
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PK parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.4 (or higher).  Individual PK parameters and covariates 
will be log-transformed and standardized before analysis.  For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses.  Co-linearity between covariates will be carefully 
considered. 
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the procedures described in Section 14.9.2.3.  If deemed 
appropriate box plots of systemic clearance versus covariates of interest (e.g. 
immunogenicity status) will be provided. 
 
14.9.2.3. 
Covariate Model Selection Procedures 
The covariate model building will follow a step-wise process consisting of a forward and 
backward selection procedure.  The likelihood ratio test will be used to evaluate the 
significance of incorporating or removing covariates into the population model based on 
alpha levels set a priori.  For forward and backward selections, a significance level of 
0.05 and 0.01 for first order conditional estimation with interaction (FOCE-I) will be 
used, respectively, in line with criteria used in previous analyses. 
 Step-wise forward addition procedure 
Each covariate will be included individually in the ‘base model’ to identify covariates 
resulting in a decrease in the objective function value (OFV) of > 3.84, χ2 < 0.05 for 1 
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degree of freedom (df) using FOCE-I.  The retained covariates will then be added to the 
base model one by one, starting with the most significant ones until all covariates have 
been tested.  Note, if a covariate exponent estimate is numerically small, the covariate 
will not be retained; irrespective of objective function.  This will also be supported by 
examination of the goodness of fit. This will constitute the full model. 
 Backward elimination procedure 
From the full model, the significance of each covariate will be tested individually by 
removing covariates one by one until all non-significant covariates have been excluded.  
A covariate will be retained if upon removal, the OFV increase by more than 6.64 points 
(χ2< 0.01 for 1 df) using FOCE-I.  Note, a covariate may be retained in the model despite 
being found non-statistically significant, if there is a strong rationale for its inclusion.  
This will constitute the final model. 
Note: centering of continuous covariates may be considered, as appropriate.  The mean or 
median value of the subjects included in the analysis may be used for example. 
The impact of the presence of anti-mepolizumab antibodies may not be formally tested as 
a covariate in the model, considering the low incidence observed in the mepolizumab 
programme to date.  Instead a graphical approach will be used, if deemed appropriate. 
14.9.2.4. 
Model Evaluation 
The uncertainty in the parameter estimates will be assessed (e.g. from the standard error 
estimates provided by NONMEM or from the 95% CI estimates provided by other 
appropriate analysis conducted using other software).  Furthermore, the model 
performance will be investigated using a set of goodness of fit plots as well as Visual 
Predictive Check (VPC) method.  Other evaluation methods may be used (e.g. 
bootstrapping) if deemed appropriate. 
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14.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
14.10.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
Specifications for the generation of the dataset will be provided in a separate document. 
14.10.2. 
Pharmacokinetic / Pharmacodynamic Methodology 
Mepolizumab blood eosinophil count-time data (samples collected every 4 weeks from 
Baseline to Week 52, and at Weeks 60, 68 and 76) 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). 
14.10.3. 
Base Model 
The most recent population PKPD model will be applied directly to the dataset without 
estimation (e.g. maxevals=0 in NONMEM) and predictions generated against which the 
model will be validated prospectively using appropriate goodness of fit tests as described 
in Section 14.9.2.1 (using the observed data from the study). 
The following will be obtained: 
 A description of the key models tested during the model development will be 
provided and tabulated. 
 The population PD parameter estimates with 95% CI from the final model will be 
tabulated.  Goodness of fit plots for the final model will be presented. 
The most recent population PKPD model consists of an indirect response model 
parameterised in term of baseline blood eosinophil count (KRO), rate of elimination of 
eosinophils in the blood (Kout), concentration resulting in 50% of maximum drug effect 
(IC50) and maximum effect (Imax).  Observed baseline blood eosinophil count is included 
as covariates of both predicted baseline and mepolizumab inhibitory response; and 
disease for predicted baseline blood eosinophil count.  Details of the model can be found 
in GlaxoSmithKline Document Number 2015N238436_00 and GlaxoSmithKline 
Document Number 2015N255079_00 (extension of the former report). 
14.10.4. 
Investigation of Covariates 
The impact of the following prospectively selected plausible covariates on relevant 
parameters (i.e., baseline blood eosinophil count and maximum effect) will be evaluated. 
Category 
Covariates 
Demographics 
Age, race, gender 
Baseline disease status 
Total endoscopic NP score (centrally read), mean nasal 
obstruction VAS, number of previous surgeries, blood 
eosinophils and baseline OCS dose 
Others 
If data permits[1], e.g.  leukotriene receptor antagonists, 
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proton pump inhibitors, statins, antihistamines, pain relief 
(e.g. paracetamol, NSAIDs) and antihypertensive drugs 
[1] Attempt to investigate those covariates will be made providing data permits. 
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PD parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.4 (or higher).  Individual PD parameters and covariates 
will be log-transformed and standardized before analysis.  For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses.  Co-linearity between covariates will be carefully 
considered. 
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the same procedures as described in Section 14.9.2.3 for 
the population PK model. 
 
Model evaluation will be as described in Section 14.9.2.4 for the population PK model. 
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14.11. 
Appendix 11: Abbreviations & Trade Marks 
14.11.1. 
Abbreviations 
Abbreviation 
Description 
ACQ 
Asthma Control Questionnaire 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
A&R 
Analysis and Reporting  
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
DBF 
Database Freeze 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
ECG 
Electrocardiogram 
ED 
Emergency Department 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IP 
Interventional Product 
ITT 
Intent-To-Treat 
MMRM 
Mixed Model Repeated Measures 
NP 
Nasal Polyps 
OCS 
Oral Corticosteroid 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PnIF 
Peak Nasal Inspiratory Flow 
PP 
Per Protocol 
PopPK 
Population PK 
PopPKPD 
Pharmacokinetic / Pharmacodynamic 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
SAC 
Statistical Analysis Complete 
SC 
Subcutaneous 
SDSP 
Study Data Standardization Plan 
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Abbreviation 
Description 
SDTM 
Study Data Tabulation Model 
SF-36 
Short Form-36 
SNOT-22 
Sino-Nasal Outcome Test -22 
SoC 
Standard of Care 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
UPSIT 
University of Pennsylvania Smell Identification Test 
VAS 
Visual Analogue Scale 
WPAI 
Work Productivity and Impairment 
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
 
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14.12. 
Appendix 12: List of Data Displays 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.22 
1.1 
Efficacy 
2.1 to 2.69 
2.1 to 2.25 
Safety 
3.1 to 3.68 
3.1 to 3.3 
Population Pharmacokinetic (PopPK) 
4.1 to 4.7 
4.1 to 4.9 
Pharmacokinetic / Pharmacodynamic 
(PopPKPD) 
5.1 to 5.4 
5.1 to 5.8 
Exposure-Efficacy 
 
6.1 to 6.4 
Section 
Listings 
ICH and Other Listings 
1 to 52 
 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Population Pharmacokinetic (PopPK) 
POPPK_Fn 
POPPK_Tn 
POPPK_Ln 
Pharmacokinetic / Pharmacodynamic 
(PopPKPD) 
POPPKPD_Fn 
POPPKPD_Tn 
POPPKPD_Ln 
Efficacy Exposure 
EE_Fn 
EE_Tn 
EE_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL/Shell’ or ‘Programming Notes’ column with an associated 
reference.’ 
 
14.12.3. 
Deliverables 
 
Delivery Priority [1] 
Description 
SAC [1] 
Headline Results 
SAC [2] 
Final Statistical Analysis Complete 
NOTES:  
[1] Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
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14.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
ITT 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
SAC [1] 
1.2. 
ITT 
SHELL 
Summary of Time On- and Off-Treatment by Withdrawal 
Scenario 
Withdrawal scenarios are detailed in 
Section 14.7.2.3.  Add footnote to 
indicate exclusion of data from the 
follow-up period after Week 52 
SAC [2] 
1.3. 
ITT 
ES1 
Summary of Subject Disposition (Week 52) 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.4. 
FU 
ES1 
Summary of Subject Disposition (Follow-Up Period after Week 
52) 
 
SAC [2] 
1.5. 
FU 
SHELL 
Summary of Duration of Time in Follow-Up Period after Week 52 
 
SAC [2] 
1.6. 
ENROLLED 
ES6 
Summary of Screening and Run-In Status and Reasons for 
Screen and Run-In Failures 
Journal Requirements 
SAC [2] 
1.7. 
ENROLLED 
NS1/SHELL 
Summary of Number of Subjects by Region, Country and Centre 
EudraCT/Clinical Operations 
Add in column for region, add a total for 
each region and a total for each 
country. 
SAC [2] 
Protocol Deviation 
1.8. 
ITT 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC [2] 
Population Analysed 
1.9. 
ENROLLED 
SP1 
Summary of Study Populations  
IDSL 
SAC [1] 
1.10. 
Randomised 
SP2A 
Summary of Exclusions from the Intent-to-Treat and Safety 
Populations 
IDSL 
SAC [2] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Demographic and Baseline Characteristics 
1.11. 
ITT 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.12. 
ENROLLED 
DM11 
Summary of Age Ranges 
EudraCT 
SAC [2] 
1.13. 
ITT 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC [2] 
1.14. 
ITT 
Shell 
Summary of Nasal Polyps Disease History and Characteristics 
Include Disease Duration 
(years/months); Number of previous 
surgeries; Number of Courses of OCS 
for NP in previous 12 months. Baseline 
Nasal Polyps endoscopy score 
(centrally read and investigator read); 
Baseline SNOT-22. 
SAC [1] 
1.15. 
ITT 
Shell 
Summary of Previous Exacerbation History 
To include separate summary of 
information for Asthma and COPD 
Exacerbation History 
SAC [2] 
Medical Conditions 
1.16. 
ITT 
MH4 
Summary of Past Medical Conditions 
ICH E3  
SAC [2] 
1.17. 
ITT 
MH4 
Summary of Current Medical Conditions 
ICH E3  
SAC [2] 
Prior and Concomitant Medications 
1.18. 
ITT 
CM1 
Summary of Medications Started Prior to Treatment 
ICH E3; ATC classification to be 
displayed for combination medications 
(not for individual ingredients) 
SAC [2] 
1.19. 
ITT 
CM1 
Summary of Concomitant Medications Started During Treatment 
ICH E3; ATC classification to be 
displayed for combination medications 
(not for individual ingredients). 
Footnote: Includes medications started 
after first dose and before last dose + 
28 days. 
SAC [2] 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.20. 
ITT 
CM1 
Summary of Systemic Corticosteroids Started During Treatment 
Footnote: Includes medications started 
after first dose and before last dose + 
28 days. 
SAC [2] 
Exposure 
1.21. 
ITT 
SHELL 
Summary of Exposure (Therapeutic Coverage) to Interventional 
Product 
ICH E3 
Range of Exposure (months): 1-<3, 3-
<6, 6-<9, 9-<12, >=12Also add subject 
years exposure 
SAC [2] 
1.22. 
ITT 
SHELL 
Summary of Number of Treatments Administered 
 
SAC [2] 
 
14.12.5. 
Study Population Figures 
Study Population Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1.  
ITT 
SHELL 
Subject Withdrawal from Interventional Product 
Footnote: Kaplan-Meier estimates of 
time to withdrawal from IP. Subjects 
are represented from Day 1 to Day of 
withdrawal from IP 
SAC [2] 
 
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14.12.6. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Co-Primary Endpoints 
2.1.  
ITT 
SHELL 
Summary of Total Endoscopic Nasal Polyps Score (Centrally 
Read) 
Footnote: Includes data reported up to 
Week 52 
Include actual scores and change from 
baseline 
Based on the primary analysis dataset 
SAC [1] 
2.2.  
ITT 
SHELL 
Analysis of Median Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 
 
SAC [1] 
2.3.  
ITT 
SHELL 
Sensitivity Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52: 
Assigned Worst Possible Score Across All Subjects for Missing 
and Worst Observed Score for Surgery/Sinuplasty 
 
SAC [2] 
2.4.  
ITT 
SHELL 
Sensitivity Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52: 
Assigned Worst Possible Score Across All Subjects for Missing 
and Surgery/Sinuplasty 
 
SAC [2] 
2.5.  
PP 
SHELL 
Supplementary Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52: 
Per-Protocol Population 
 
SAC [2] 
2.6.  
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Participants with Asthma 
 
SAC [2] 
2.7.  
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Aspirin Exacerbated Respiratory Disease (AERDS) 
 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.8.  
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Number of Previous Surgeries 
 
SAC [2] 
2.9.  
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Baseline Blood Eosinophil Categories 
 
SAC [2] 
2.10. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Region 
 
SAC [2] 
2.11. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Age 
 
SAC [2] 
2.12. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Gender 
 
SAC [2] 
2.13. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52 by 
Race 
 
SAC [2] 
2.14. 
ITT 
SHELL 
Summary of Individual VAS Symptom Scores 
Footnote: Includes data reported up to 
Week 52 
Subheaders: Nasal Obstruction, Nasal 
Discharge, Mucus in Throat, Loss of 
Smell, Facial Pain 
SAC [2] 
2.15. 
ITT 
SHELL 
Analysis of Median Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) 
 
SAC [1] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.16. 
ITT 
SHELL 
Sensitivity Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52):- Assigned Worst 
Possible Mean Across All Subjects for Missing and Worst 
Observed Mean for Surgery/Sinuplasty 
 
SAC [2] 
2.17. 
ITT 
SHELL 
Sensitivity Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52): Assigned Worst Possible Mean 
Across All Subjects for Missing and Surgery/Sinuplasty 
 
SAC [2] 
2.18. 
PP 
SHELL 
Supplementary Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52): Per-Protocol Population 
 
SAC [2] 
2.19. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Subjects with Asthma 
 
SAC [2] 
2.20. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Aspirin Exacerbated 
Respiratory Disease (AERDS) 
 
SAC [2] 
2.21. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Number of Previous 
Surgeries 
 
SAC [2] 
2.22. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Baseline Blood 
Eosinophil Categories 
 
SAC [2] 
2.23. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Region 
 
SAC [2] 
2.24. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Age 
 
SAC [2] 
2.25. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Gender 
 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.26. 
ITT 
SHELL 
Subgroup Analysis of Median Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52) by Race 
 
SAC [2] 
Secondary Endpoints 
2.27. 
ITT 
SHELL 
Analysis of Time to First Nasal Surgery 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.28. 
ITT 
SHELL 
Sensitivity Analysis of Time to First Nasal Surgery: Tipping Point 
Analysis 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.29. 
ITT 
SHELL 
Summary of Overall VAS Score 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.30. 
ITT 
SHELL 
Analysis of Median Change from Baseline Overall VAS Score 
(Weeks 49-52) 
 
SAC [1] 
2.31. 
ITT 
SHELL 
Summary of SNOT-22 Total Score 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.32. 
ITT 
SHELL 
Analysis of Median Change from Baseline SNOT-22 at Week 52 
 
SAC [1] 
2.33. 
ITT 
SHELL 
Summary and Analysis of Proportion of Subjects Requiring 
Systemic Steroids for Nasal Polyps up to Week 52 
Footnote: Courses of systemic steroids 
separated by <7 days are considered a 
continuation of the same course 
Include n (%) with 0 vs ≥1 and 0, 1, 2, 
etc courses and total number of 
courses 
SAC [1] 
2.34. 
ITT 
SHELL 
Subgroup Analysis of Proportion of Subjects Requiring Systemic 
Steroids for Nasal Polyps up to Week 52 by Participants with 
Asthma 
Footnote: Courses of systemic steroids 
separated by <7 days are considered a 
continuation of the same course 
Include n (%) with 0 vs ≥1 and 0, 1, 2, 
etc courses and total number of 
courses 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.35. 
ITT 
SHELL 
Summary of Composite VAS Scores 
Footnote: Includes data reported up to 
Week 52 
Subheaders: Composite - Nasal 
Symptoms [1] and Composite - Nasal 
Symptoms and Facial Pain [2] 
Footnote: [1] Composite - Nasal 
Symptoms includes nasal obstruction, 
nasal discharge, mucus in the throat 
and loss of smell 
[2] Composite - Nasal Symptoms and 
Facial Pain includes nasal obstruction, 
nasal discharge, mucus in the throat 
and loss of smell and facial pain 
SAC [1] 
2.36. 
ITT 
SHELL 
Analysis of Median Change from Baseline Composite VAS 
Score - Nasal Symptoms (Weeks 49-52) 
 
SAC [1] 
2.37. 
ITT 
SHELL 
Analysis of Median Change from Baseline Loss of Smell VAS 
Score (Weeks 49-52) 
 
SAC [1] 
2.38. 
ITT 
SHELL 
Summary of P-values for Treatment Comparisons Adjusted for 
Multiplicity According to Hierarchy of Endpoints 
 
SAC [1] 
Other Endpoints 
2.39. 
ITT 
SHELL 
Summary of Total Endoscopic Nasal Polyps Score (Investigator 
Read) 
Footnote: Includes data reported up to 
Week 52 
 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data  
SAC [2] 
2.40. 
ITT 
SHELL 
Summary and Analysis of Total Endoscopic Nasal Polyps Score 
(Centrally Read) Responders 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.41. 
ITT 
SHELL 
Analysis of Median Change from Baseline VAS Scores: Nasal 
Discharge, Mucus in Throat, Facial Pain (Weeks 49-52) 
 
SAC [2] 
2.42. 
ITT 
SHELL 
Analysis of Median Change from Baseline Composite VAS 
Score - Nasal Symptoms and Facial Pain (Weeks 49-52) 
 
SAC [2] 
2.43. 
ITT 
SHELL 
Summary and Analysis of SNOT-22 Responders at Week 52 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.44. 
ITT 
SHELL 
Summary of SNOT-22 Domain Scores 
Footnote: Includes data reported up to 
Week 52 
Subheaders: Nasal, Non-nasal 
symptoms, Ear/facial symptoms, Sleep, 
Fatigue, Emotional consequences  
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
2.45. 
ITT 
SHELL 
Summary and Analysis of Need for Surgery to Week 52 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.46. 
ITT 
SHELL 
Summary of Frequency and Rate of Nasal Surgery 
Include n (%) with 0, 1, 2, etc surgeries 
and crude rate 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.47. 
ITT 
SHELL 
Time to First Inclusion on Waiting List for Nasal Polyps Surgery 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.48. 
ITT 
SHELL 
Summary of Subjects Placed on Waiting List for Surgery to 
Week 52 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.49. 
ITT 
SHELL 
Summary of University of Pennsylvania Smell Identification Test 
(UPSIT) 
Footnote: Includes data reported up to 
Week 52 
Footnote: performed in UK, US and 
Canada only 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.50. 
ITT 
SHELL 
Analysis of Median Change from Baseline University of 
Pennsylvania Smell Identification Test (UPSIT) 
Footnote: performed in UK, US and 
Canada only 
SAC [2] 
2.51. 
ITT 
SHELL 
Summary of Peak Nasal Inspiratory Flow (PNIF) 
Include actual and change from 
baseline 
Footnote: Includes data reported up to 
Week 52 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
2.52. 
ITT 
SHELL 
Summary of Total Prednisolone-equivalent OCS Use for Nasal 
Polyps (mgs per year) 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.53. 
ITT 
SHELL 
Summary of Days on Systemic Steroids for Nasal Polyps 
Footnote: Includes data reported up to 
Week 52 
Include days on therapy and 
percentage of days on therapy 
SAC [2] 
2.54. 
ITT 
SHELL 
Time to First Course of Systemic Steroids for Nasal Polyps 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.55. 
ITT 
SHELL 
Analysis of Time to First Nasal Surgery or Course of Systemic 
Steroids for Nasal Polyps 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.56. 
ITT 
SHELL 
Summary of Number of Courses of Antibiotics 
Footnote: Includes data reported up to 
Week 52 
Footnote: Courses of antibiotics 
separated by <7 days are considered a 
continuation of the same course 
Include n (%) with 0 vs ≥1 and 0, 1, 2, 
courses and total number of courses 
SAC [2] 
2.57. 
ITT 
SHELL 
Summary of On-Treatment Blood Eosinophils (GI/L) 
Include absolute and ratio to baseline 
values 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.58. 
ITT 
SHELL 
Analysis of On-Treatment Blood Eosinophils (GI/L) Ratio 
Compared to Baseline Mixed Model Repeated Measures 
 
SAC [2] 
Other Endpoints – Health Economics/Medical Resource Utilisation 
2.59. 
ITT 
SHELL 
Summary of SF-36 Domain Scores and Component Summary 
Scores 
Include 8 domain scores bodily pain, 
general health, mental health, physical 
functioning, role emotional, role 
physical, social functioning and vitality 
and Mental and Physical Component 
Summary scores. 
Include actual and change from 
baseline 
 
Footnote: Includes data reported up to 
Week 52 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
2.60. 
ITT 
SHELL 
Summary of Work Productivity and Activity Impairment 
Questionnaire (WPAI) 
Footnote: Includes data reported up to 
Week 52 
Include only summary variables 
SAC [2] 
Other Endpoints – Participants with Asthma 
2.61. 
ITT 
SHELL 
Summary of ACQ-5 in Participants with Asthma 
Include actual and change from 
baseline 
Footnote: Includes data reported up to 
Week 52 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.62. 
ITT 
SHELL 
Summary of Frequency of Clinically Significant Asthma 
Exacerbations in Participants with Asthma 
Provide n (%) with 0 vs ≥1 and 0, 1, 2 
etc exacerbations and total number of 
exacerbations 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
Other Endpoints – Maintenance of Response Following Cessation of Interventional Product (Follow-Up Period After Week 52) 
2.63. 
FU 
SHELL 
Summary of Total Endoscopic Nasal Polyps Score (Centrally 
Read) for Subjects in the Follow-Up Period After Week 52 
Include actual and change from 
baseline 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
2.64. 
FU 
SHELL 
Summary of Individual VAS Symptom Scores for Subjects in the 
Follow-Up Period After Week 52 
Include actual and change from 
baseline 
Include nasal obstruction, nasal 
discharge, mucus in throat, loss of 
smell, facial pain, overall VAS score 
Programming Note: summaries from 
dataset with assigned values for 
subjects with surgery/missing data 
SAC [2] 
2.65. 
FU 
SHELL 
Summary of SNOT-22 for Subjects in the Follow-Up Period After 
Week 52 
Include actual and change from 
baseline 
Programming Note: summaries from 
dataset with assigned values for 
subjects with 
surgery/sinuplasty/missing data 
SAC [2] 
2.66. 
FU 
SHELL 
Time to First Nasal Surgery for Subjects in the Follow-Up Period 
After Week 52 
 
SAC [2] 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.67. 
FU 
SHELL 
Summary of Number of Courses of Systemic Steroids for 
Subjects in the Follow-Up Period After Week 52 
Footnote: Courses of systemic steroids 
separated by less than 7 days are 
considered a continuation of the same 
course 
SAC [2] 
2.68. 
FU 
SHELL 
Summary of Total Prednisolone-equivalent OCS Use for Nasal 
Polyps (mgs per year) 
 
SAC [2] 
2.69. 
FU 
SHELL 
Summary of Blood Eosinophils (GI/L) for Subjects in the Follow-
up Period After Week 52 
 
SAC [2] 
 
14.12.7. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Co-Primary Endpoints 
2.1.  
ITT 
SHELL 
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) at Week 52 
Show percentages in each category 
Programming Note: dataset with 
assigned values for subjects with 
surgery/missing data 
SAC [1] 
2.2.  
ITT 
SHELL 
Figure of Median Change from Baseline Total Endoscopic Nasal 
Polyps Score (Centrally Read) by Visit 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.3.  
ITT 
SHELL 
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) at Week 52: Cumulative Distribution 
Function 
Programming Note: dataset with 
assigned values for subjects with 
surgery/missing data 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.4.  
ITT 
SHELL 
Figure of Median Change from Baseline Total Endoscopic Nasal 
Polyps Score (Centrally Read) at Week 52: Primary and 
Sensitivity Analyses 
Include primary and sensitivity analyses 
SAC [2] 
2.5.  
ITT 
SHELL 
Figure of Change from Baseline Nasal Obstruction VAS Score 
(Week 49-52) 
Show percentages in each category 
Programming Note: dataset with 
assigned values for subjects with 
surgery/missing data 
SAC [1] 
2.6.  
ITT 
SHELL 
Figure of Median Change from Baseline Nasal Obstruction VAS 
Score in each 4-Weekly Period 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.7.  
ITT 
SHELL 
Figure of Median Change from Baseline Nasal Obstruction VAS 
Score (Week 49-52): Primary and Sensitivity Analyses 
Include primary and sensitivity analyses 
SAC [2] 
Secondary Endpoints 
2.8.  
ITT 
SHELL 
Kaplan-Meier Time to First Nasal Surgery 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.9.  
ITT 
SHELL 
Sensitivity Time to First Nasal Surgery: Tipping Point 
Heat Map 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.10. 
ITT 
SHELL 
Sensitivity Time to First Nasal Surgery: Tipping Point – MAR 
Assumption for Placebo 
2-dimensional 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.11. 
ITT 
SHELL 
Figure of Median Change from Baseline Overall VAS Score in 
Each 4-Weekly Period 
Median and 95%CIFootnote: Includes 
data reported up to Week 52 
SAC [1] 
2.12. 
ITT 
SHELL 
Figure of Median Change from Baseline SNOT-22 by Visit 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.13. 
ITT 
SHELL 
Figure of Median Change from Baseline Composite VAS Score - 
Nasal Symptoms in each 4-Weekly Period 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
2.14. 
ITT 
SHELL 
Figure of Median Change from Baseline Loss of Smell VAS 
Score in each 4-Weekly Period 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
Other Endpoints 
2.15. 
ITT 
SHELL 
Figure of Total Endoscopic Nasal Polyps Score (Centrally Read) 
Responders by Visit 
OR and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.16. 
ITT 
SHELL 
Figure of University of Pennsylvania Smell Identification Test 
(UPSIT) Change from Baseline by Visit 
Median and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.17. 
ITT 
SHELL 
Figure of SNOT-22 Responders by Visit 
OR and 95%CI 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.18. 
ITT 
SHELL 
Kaplan-Meier Time to First Inclusion on Waiting List for Nasal 
Polyps Surgery 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.19. 
ITT 
SHELL 
Kaplan-Meier Time to First Course of Systemic Steroids 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.20. 
ITT 
SHELL 
Kaplan-Meier Time to First Nasal Surgery or Course of Systemic 
Steroids 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
2.21. 
ITT 
SHELL 
Figure of On-Treatment Blood Eosinophils Absolute Values 
No reference line. 
Include screening/baseline geometric 
mean values without 95% CI. 
Week 4 onwards adjusted estimates 
from MMRM model with 95% CI. 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.22. 
ITT 
SHELL 
Figure of On-Treatment Blood Eosinophils Ratio to Baseline 
Reference line at 1 
SAC [2] 
Other Endpoints – Maintenance of Response Following Cessation of Interventional Product (Follow-Up Period After Week 52) 
2.23. 
FU 
SHELL 
Kaplan-Meier Time to First Nasal Surgery for Subjects in the 
Follow-Up Period After Week 52 
 
SAC [2] 
2.24. 
FU 
SHELL 
Kaplan-Meier Time to First Inclusion on Waiting List for Nasal 
Polyps Surgery for Subjects in the Follow-Up Period After Week 
52 
 
SAC [2] 
2.25. 
FU 
SHELL 
Figure of Blood Eosinophils for Subjects in the Follow-Up Period 
After Week 52 
 
SAC [2] 
 
14.12.8. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
Safety 
AE13/SHELL 
Adverse Event Overview 
 
SAC [1] 
3.2.  
Safety 
AE1 
Summary of On-Treatment Adverse Events by System Organ 
Class and Preferred Term 
ICH E3 
SAC [1] 
3.3.  
Safety 
AE1 
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term 
Footnote: Includes data reported up to 
Week 52 
SAC [1] 
3.4.  
FU 
AE1 
Summary of Adverse Events Reported During the Follow-Up 
Period After Week 52 by System Organ Class and Preferred 
Term 
 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.5.  
Safety 
AE3 
Summary of Common (>=3% in Any Treatment Group) On-
Treatment Adverse Events by Overall Frequency 
ICH E3 
≥3% (prior to rounding to nearest 
percent) 
SAC [2] 
3.6.  
Safety 
AE5a 
Summary of On-Treatment Adverse Events by System Organ 
Class and Maximum Severity 
Add a Total column across all severities 
SAC [2] 
3.7.  
Safety 
AE1 
Summary of Drug-Related On-Treatment Adverse Events by 
System Organ Class and Preferred Term 
ICH E3 
SAC [2] 
3.8.  
Safety 
AE5a 
Summary of Drug Related On-Treatment Adverse Events by 
System Organ Class and Maximum Severity 
Add a Total column across all 
severities 
SAC [2] 
3.9.  
Safety 
AE15 
Summary of Common (>=3% In Any Treatment Group) Non-
Serious On-Treatment Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT≥3% (prior to 
rounding to nearest percent) 
SAC [2] 
3.10. 
Safety 
AE1 
Summary of On-Treatment Adverse Events by Highest Post-
Baseline Anti-Drug Antibody Result 
Add in row with n in each ADA result 
category. 
Footnote: Highest Post-Baseline Anti-
Drug Antibody result excluding data 
from no-treatment follow-up period. 
SAC [2] 
3.11. 
Safety 
AE1 
Summary of Post-Treatment Adverse Events by Highest Post-
Baseline Anti-Drug Antibody Result 
Add in row with n in each ADA result 
category. 
Footnote: Highest Post-Baseline Anti-
Drug Antibody result excluding data 
from no-treatment follow-up period. 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.12. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ Class 
IDSL; Footnote: Includes data reported 
up to Week 52 
SAC [2] 
3.13. 
Safety 
AE1 
Summary of Adverse Events Leading to Withdrawal from Study 
by System Organ Class 
IDSL; Footnote: Includes data reported 
up to Week 52 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.14. 
Safety 
AE1 
Summary of Adverse Events Reported on Day of Dosing by 
System Organ Class 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
Serious and Other Significant Adverse Events 
3.15. 
Safety 
AE3 
Summary of Fatal Serious Adverse Events 
 
SAC [1] 
3.16. 
Safety 
AE3 
Summary of Fatal Drug-Related Serious Adverse Events 
 
SAC [2] 
3.17. 
Safety 
AE1 
Summary of Non-Fatal Serious Adverse Events by System 
Organ Class 
Include on-treatment and post-
treatment 
SAC [2] 
3.18. 
Safety 
AE1 
Summary of Non-Fatal Serious On-Treatment Adverse Events 
by System Organ Class 
 
SAC [1] 
3.19. 
Safety 
AE1 
Summary of Non-Fatal Serious Post-Treatment Adverse Events 
by System Organ Class 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.20. 
Safety 
AE1 
Summary of Serious Adverse Events by System Organ Class 
Include on-treatment and post-
treatment 
SAC [1] 
3.21. 
Safety 
AE1 
Summary of Serious On-Treatment Adverse Events by System 
Organ Class 
 
SAC [2] 
3.22. 
Safety 
AE1 
Summary of Serious Post-Treatment Adverse Events by System 
Organ Class 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.23. 
FU 
AE1 
Summary of Serious Adverse Events Reported During the 
Follow-Up Period After Week 52 by System Organ Class 
 
SAC [2] 
3.24. 
Safety 
AE1 
Summary of Serious Drug-Related On-Treatment Adverse 
Events by System Organ Class 
 
SAC [2] 
3.25. 
Safety 
AE1 
Summary of Pre-Treatment Serious Adverse Events by System 
Organ Class 
 
SAC [2] 
3.26. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
FDAAA, EudraCT 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.27. 
Safety 
SHELL 
Summary of Deaths 
Includes all deaths separating those 
reported in no-treatment follow-up 
SAC [2] 
Adverse Events of Special Interest 
3.28. 
Safety 
SHELL 
Summary of On-Treatment Serious AEs and AEs of Special 
Interest: Incidence, Relative Risk and Risk Difference (Placebo 
vs 100mg SC) 
 
SAC [2] 
3.29. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Systemic Reactions Reported by the Investigator as Meeting the 
Criteria for Anaphylaxis 
 
SAC [2] 
3.30. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Systemic Reactions – 
Allergic (Type I Hypersensitivity) and Other Reactions 
 
SAC [2] 
3.31. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Systemic Reactions – 
Allergic (Type I Hypersensitivity) 
 
SAC [2] 
3.32. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Systemic Reactions –
Other Reactions 
 
SAC [2] 
3.33. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Local Injection Site 
Reactions 
 
SAC [2] 
3.34. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Serious Cardiac, Vascular and Thromboembolic Events 
 
SAC [2] 
3.35. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Serious Ischemic Events 
 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.36. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Malignancies 
 
SAC [2] 
3.37. 
Safety 
AE1 
Summary of On-Treatment Adverse Events of Special Interest: 
Potential Opportunistic Infections 
 
SAC [2] 
3.38. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Systemic Reactions Reported by the Investigator as 
Meeting the Criteria for Anaphylaxis 
 
SAC [2] 
3.39. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Systemic 
Reactions – Allergic (Type I Hypersensitivity) and Other 
Reactions 
 
SAC [2] 
3.40. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Systemic 
Reactions – Allergic (Type I Hypersensitivity) 
 
SAC [2] 
3.41. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Systemic 
Reactions –Other Reactions 
 
SAC [2] 
3.42. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Local Injection 
Site Reactions 
 
SAC [2] 
3.43. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Serious Cardiac, Vascular and Thromboembolic Events 
 
SAC [2] 
3.44. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Serious Ischemic Events 
 
SAC [2] 
3.45. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Malignancies 
 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.46. 
Safety 
SHELL 
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Potential Opportunistic Infections 
 
SAC [2] 
Laboratory: Chemistry  
3.47. 
Safety 
LB1 
Summary of On-Treatment Chemistry Changes from Baseline  
ICH E3 
Includes Baseline values 
SAC [2] 
3.48. 
Safety 
LB3 
Summary of On-Treatment Chemistry Shifts from Baseline 
Relative to Normal Range 
ICH E3 
Include Any Time Post Baseline 
Add footnotes: 
Note: Any Time Post Baseline – 
Includes scheduled and any 
unscheduled assessments 
Subjects may be counted in more than 
one category. 
SAC [2] 
3.49. 
Safety 
LB3 
Summary of On-Treatment Chemistry Shifts from Baseline 
Relative to PCI Criteria 
ICH E3 
Include Any Time Post Baseline 
Add footnotes: 
Note: Any Time Post Baseline – 
Includes scheduled and any 
unscheduled assessments 
Subjects may be counted in more than 
one category. 
SAC [2] 
Laboratory: Hematology 
3.50. 
Safety 
LB1 
Summary of On-Treatment Haematology Changes from 
Baseline  
ICH E3 
Includes Baseline values 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.51. 
Safety 
LB3 
Summary of On-Treatment Haematology Shifts from Baseline 
Relative to Normal Range 
ICH E3 
Include Any Time Post Baseline 
Add footnotes: 
Note: Any Time Post Baseline – 
Includes scheduled and any 
unscheduled assessments 
Subjects may be counted in more than 
one category. 
SAC [2] 
3.52. 
Safety 
LB3 
Summary of On-Treatment Haematology Shifts from Baseline 
Relative to PCI Criteria 
ICH E3 
Include Any Time Post Baseline 
Add footnotes: 
Note: Any Time Post Baseline – 
Includes scheduled and any 
unscheduled assessments 
Subjects may be counted in more than 
one category. 
SAC [2] 
Laboratory: Urinalysis 
3.53. 
Safety 
UR1 
Summary of Worst Case On-Treatment Urinalysis Results Post-
Baseline Relative to Baseline  
ICH E3 
SAC [2] 
Laboratory: Hepatobiliary (Liver) 
3.54. 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC [2] 
3.55. 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
SAC [2] 
ECG 
3.56. 
Safety 
EG1 
Summary of ECG Findings  
IDSL 
SAC [2] 
3.57. 
Safety 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC [2] 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.58. 
Safety 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
IDSL 
SAC [2] 
3.59. 
Safety 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
IDSL 
SAC [2] 
Vital Signs 
3.60. 
Safety 
VS1 
Summary Vital Signs 
 
SAC [2] 
3.61. 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC [2] 
Immunogenicity 
3.62. 
Safety 
SHELL 
Summary of Binding Anti Drug Antibody Assay: Highest 
Confirmatory Result 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.63. 
Safety 
SHELL 
Summary of Binding Anti Drug Antibody Assay: Highest 
Treatment Emergent Confirmatory Result 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.64. 
Safety 
SHELL 
Summary of Neutralising Antibody Assay: Highest Result 
Footnote: Includes data reported up to 
Week 52 
SAC [2] 
3.65. 
FU 
SHELL 
Summary of Binding Anti Drug Antibody Assay: Highest 
Confirmatory Result for Subjects in the Follow-up Period After 
Week 52 
Footnote: Includes all available data 
SAC [2] 
3.66. 
FU 
SHELL 
Summary of Binding Anti Drug Antibody Assay: Highest 
Treatment Emergent Confirmatory Results for Subjects in the 
Follow-up Period After Week 52 
Footnote: Includes all available data 
SAC [2] 
3.67. 
FU 
SHELL 
Summary of Neutralising Antibody Assay: Highest Result for 
Subjects in the Follow-up Period After Week 52 
Footnote: Includes all available data 
SAC [2] 
3.68. 
Safety 
SHELL 
Summary of On-Treatment Blood Eosinophils (GI/L) by Anti 
Drug Antibody Status 
 
SAC [2] 
 
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14.12.9. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  
Safety 
AE10 
Common (>=3% In Any Treatment Group) On-Treatment 
Adverse Events and Relative Risk  
IDSL 
SAC [2] 
3.2.  
Safety 
SHELL 
On-treatment Serious Adverse Events and Adverse Events of 
Special Interest (Placebo vs Mepolizumab 100mg SC) 
Provide relative risk with 95% CI 
SAC [2] 
Laboratory 
3.3.  
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
IDSL 
SAC [2] 
 
14.12.10. Pharmacokinetic Population (PopPK) Tables 
Pharmacokinetic Population (POPPK): Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.1.  
PK 
PK01 
Summary of Plasma Mepolizumab Concentration-Time Data 
(Observed and Predicted) 
 
SAC [2] 
4.2.  
PK 
PK06 
Summary Statistics of Individual Model Predicted Plasma 
Mepolizumab Pharmacokinetic Parameters (Non-transformed 
and Log-transformed) 
 
SAC [2] 
4.3.  
PK 
- 
Description and Evaluation of Key PK Models Tested 
Provided by CPMS 
SAC [2] 
4.4.  
PK 
- 
Population PK Parameter Estimates with 95% CI of Final PK 
Model 
Provided by CPMS 
SAC [2] 
4.5.  
PK 
- 
Demographics Summary 
Provided by CPMS 
SAC [2] 
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Pharmacokinetic Population (POPPK): Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.6.  
PK 
- 
Samples Summary 
Provided by CPMS 
SAC [2] 
4.7.  
PK 
- 
Accumulation Ratio Estimate at Week 52 
Provided by CPMS 
SAC [2] 
 
14.12.11. Pharmacokinetic Population (PopPK) Figures 
Pharmacokinetic Population (POPPK): Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.1.  
PK 
- 
Plasma Mepolizumab Concentration-Time Profiles (by 
Treatment) 
Provided by CPMS 
SAC [2] 
4.2.  
PK 
- 
Model Goodness of Fit Plots 
Provided by CPMS 
SAC [2] 
4.3.  
PK 
- 
Continuous Covariate Correlation Plot 
Provided by CPMS 
SAC [2] 
4.4.  
PK 
- 
Categorical Covariate Correlation Plot 
Provided by CPMS 
SAC [2] 
4.5.  
PK 
- 
Automated Covariate Selection 
Provided by CPMS 
SAC [2] 
4.6.  
PK 
- 
Visual Predictive Check 
Provided by CPMS 
SAC [2] 
4.7.  
PK 
- 
Observed Plasma Mepolizumab Concentration-Time Profiles by 
Anti-Drug Antibody Status 
Provided by CPMS 
SAC [2] 
4.8.  
PK 
- 
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Subject) 
Provided by CPMS 
SAC [2] 
4.9.  
PK 
- 
Box Plot of Systemic Clearance versus Covariates of Interest 
Provided by CPMS 
SAC [2] 
 
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14.12.12. Pharmacokinetic/Pharmacodynamic Population (PopPK/PD) Tables 
Pharmacokinetic/Pharmacodynamic Population (POPPK/PD): Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.1.  
PK and PD 
- 
Description and Evaluation of Key PKPD Models Tested 
Provided by CPMS 
SAC [2] 
5.2.  
PK and PD 
- 
Population PD Parameter Estimates with 95% CI of Final PKPD 
Model 
Provided by CPMS 
SAC [2] 
5.3.  
PK and PD 
- 
Demographics Summary 
Provided by CPMS 
SAC [2] 
5.4.  
PK and PD 
- 
Samples Summary 
Provided by CPMS 
SAC [2] 
 
14.12.13. Pharmacokinetic/Pharmacodynamic Population (PopPKPD) Figures 
Pharmacokinetic/Pharmacodynamic Population (POPPK/PD): Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.1.  
PK and PD 
- 
Blood Eosinophil Count-Time Profiles 
Provided by CPMS 
SAC [2] 
5.2.  
PK and PD 
- 
Model Goodness of Fit Plots 
Provided by CPMS 
SAC [2] 
5.3.  
PK and PD 
- 
Continuous Covariate Correlation Plot 
Provided by CPMS 
SAC [2] 
5.4.  
PK and PD 
- 
Categorical Covariate Correlation Plot 
Provided by CPMS 
SAC [2] 
5.5.  
PK and PD 
- 
Automated Covariate Selection 
Provided by CPMS 
SAC [2] 
5.6.  
PK and PD 
- 
Visual Predictive Check 
Provided by CPMS 
SAC [2] 
5.7.  
PK and PD 
- 
Observed Blood Eosinophil Count -Time Profiles by Anti-Drug 
Antibody Status 
Provided by CPMS 
SAC [2] 
5.8.  
PK and PD 
- 
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Subject) 
Provided by CPMS 
SAC [2] 
 
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14.12.14. Exposure-Efficacy Figures 
Exposure-Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.1.  
ITT 
- 
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic Nasal Polyps Score (Centrally 
Read) at Week 52 vs Dose/Body Weight 
Provided by CPMS 
Post-SAC [2] 
6.2.  
ITT 
 
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic Nasal Polyps Score (Centrally 
Read) at Week 52 vs Cav 
Provided by CPMS 
Post-SAC [2] 
6.3.  
ITT 
- 
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52) vs 
Dose/Body Weight 
Provided by CPMS 
Post-SAC [2] 
6.4.  
ITT 
- 
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52) vs 
Cav 
Provided by CPMS 
Post-SAC [2] 
 
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14.12.15. ICH and Other Listings 
ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
ENROLLED 
ES7 
Listing of Reasons for Screen and Run-In Failures 
Journal Guidelines 
SAC [2] 
2.  
ITT 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC [2] 
3.  
ITT 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
Include and identify withdrawals from 
no-treatment follow-up 
SAC [2] 
4.  
ENROLLED 
ES9 
Listing of Subjects Who Were Rescreened 
 
SAC [2] 
5.  
ITT 
BL1 
Listing of Subjects for Whom the Treatment Blind was Broken 
ICH E3 
SAC [2] 
6.  
ITT 
TA1 
Listing of Planned and Actual Treatments 
IDSL 
SAC [2] 
Protocol Deviations 
7.  
ITT 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
SAC [2] 
8.  
ITT 
IE3 
Listing of Subjects with Inclusion/Exclusion/Randomisation 
Criteria Deviations 
ICH E3 
SAC [2] 
Populations Analysed 
9.  
Randomised 
SP3 
Listing of Subjects Excluded from Any Population 
ICH E3 
SAC [2] 
Demographic and Baseline Characteristics 
10.  
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC [2] 
11.  
ITT 
DM9 
Listing of Race 
ICH E3 
SAC [2] 
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ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
12.  
ITT 
SHELL 
Listing of Nasal Polyps Disease History and Baseline 
Characteristics 
Include Disease Duration 
(years/months); Number of previous 
surgeries; Number of Courses of OCS 
for NP in previous 12 months; History 
of Sinusitis; Baseline Nasal Polyps 
endoscopy score (centrally read and 
investigator read); Nasal Obstruction 
VAS, Overall VAS, Baseline SNOT-22; 
Baseline SF-36. Include tobacco 
history. 
SAC [2] 
Prior and Concomitant Medications 
13.  
ITT 
CM3 
Listing of Concomitant Medications 
IDSL 
Include column to identify entries 
coming from the systemic corticosteroid 
eCRF page 
SAC [2] 
Efficacy 
14.  
ITT 
SHELL 
Listing of Surgical Events 
Programming Note: Include indication 
of surgeries included in evaluation of 
key secondary endpoint  
SAC [2] 
Exposure 
15.  
Randomised 
SHELL/EX3 
Listing of Exposure Data 
ICH E3 
SAC [2] 
Adverse Events 
16.  
Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
add Phase (pre/on/post-trt) 
SAC [2] 
17.  
Safety 
AE8 
Listing of All Adverse Events on Day of Dosing 
 
SAC [2] 
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ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
18.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
Split on-treatment, post-treatment, 
reported during follow-up period after 
Week 52 
SAC [2] 
19.  
Safety 
AE8 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment or Withdrawal from Study 
ICH E3 
add Phase (pre/on/post-trt) 
SAC [2] 
20.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
SAC [2] 
Serious and Other Significant Adverse Events 
21.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC [2] 
22.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC [2] 
23.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC [2] 
24.  
Safety 
DTH3 
Listing of Deaths 
 
SAC [2] 
25.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
All Cause Deaths 
 
SAC [2] 
26.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Arrhythmias 
 
SAC [2] 
27.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure 
 
SAC [2] 
28.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke 
 
SAC [2] 
29.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Deep venous Thrombosis/Pulmonary Embolism 
 
SAC [2] 
30.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Myocardial Infarction/Unstable Angina 
 
SAC [2] 
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ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
31.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism 
 
SAC [2] 
32.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension 
 
SAC [2] 
33.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Revascularisation 
 
SAC [2] 
34.  
Safety 
IDSL 
Patient Profiles of Investigator Reported Cardiovascular Events: 
Valvulopathy 
 
SAC [2] 
Adverse Events of Special Interest 
35.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Meeting the Criteria for 
Anaphylaxis 
add Phase(on/post-trt) 
add number of doses taken prior to the 
event and symptoms related to the 
event 
SAC [2] 
36.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Systemic Reactions – 
Allergic (Type I Hypersensitivity) 
add Phase(on/post-trt) 
add number of doses taken prior to the 
event and symptoms related to the 
event 
SAC [2] 
37.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Systemic Reactions –
Other Reactions 
add Phase(on/post-trt) 
add number of doses taken prior to the 
event and symptoms related to the 
event 
SAC [2] 
38.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Events Reported by the Investigator as Local Injection Site 
Reactions 
add Phase(on/post-trt) 
add number of doses taken prior to the 
event and symptoms related to the 
event 
SAC [2] 
39.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Serious Cardiac, Vascular and Thromboembolic Events 
add Phase(on/post-trt) 
SAC [2] 
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118 
 
ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
40.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Serious Ischemic Events 
add Phase(on/post-trt) 
SAC [2] 
41.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Malignancies 
add Phase(on/post-trt) 
SAC [2] 
42.  
Safety 
AE8 
Listing of On-Treatment Adverse Events of Special Interest: 
Potential Opportunistic Infections 
add Phase(on/post-trt) 
SAC [2] 
Hepatobiliary (Liver) 
43.  
Safety 
MH2 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
IDSL 
SAC [2] 
44.  
Safety 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline 
 
SAC [2] 
45.  
Safety 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
SAC [2] 
46.  
Safety 
SU2 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
IDSL 
SAC [2] 
All Laboratory 
47.  
Safety 
LB5 
Listing of Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC [2] 
48.  
Safety 
LB5 
Listing of Haematology Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC [2] 
49.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC [2] 
50.  
Safety 
UR2A/UR2B 
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
SAC [2] 
ECG 
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ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
51.  
Safety 
EG3 / EG4 
Listing of All ECG Values for Subjects with Protocol Defined 
QTc Stopping Criteria 
IDSL 
SAC [2] 
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ICH and Other Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Immunogenicity 
52.  
Safety 
IMM2 
Listing of Immunogenicity Data 
Include column titled: Screening 
Binding Assay, Confirmation Antibody 
Assay, Confirmation Assay Titre, 
Neutralizing Antibody Assay 
SAC [2] 
 
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14.13. 
Appendix 13: Example Mock Shells for Data Displays 
Shells are available upon request. 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
205687
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 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)
Compound Number 
:
SB240563
Effective Date 
:
05-SEP-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report for Study 205687 (Protocol 2016N294302_03).
RAP Author:
Author
Date
16-AUG-2019
Statistics Director (Biostatistics)
16-AUG-2019
Senior Director (Clinical Pharmacology)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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The GlaxoSmithKline group of companies
205687
2
RAP Team Review Confirmations
(Method: E-mail):
Reviewer
Date
20-AUG-2019
Study Physician Lead (Clinical Development, Respiratory)
21-AUG-2019
Project Physician Lead (Clinical Development, Respiratory)
21-AUG-2019
Clinical Investigation Lead (Clinical Development, Respiratory)
21-AUG-2019
Director (SERM Safety & Medical Governance Pharma)
21-AUG-2019
Programming Manager (Biostatistics)
21-AUG-2019
Senior Director (Clinical Pharmacology)
Clinical Statistics & Clinical Programming Line Approvals
(Method: Pharma TMF eSignature):
Approver
Date
05-SEP-2019
Senior Statistics Director (Biostatistics)
 (on behalf of 
)
01-SEP-2019
Programming Director (Biostatistics)
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205687
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.
Study Design ..............................................................................................11
2.3.
Statistical Hypotheses.................................................................................12
2.4.
Changes to the Protocol Defined Statistical Analysis Plan..........................12
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Interim Analyses .........................................................................................13
3.2.
Final Analyses ............................................................................................13
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................15
5.2.1.
Visit-based endpoints ..................................................................15
5.2.2.
eDiary Data..................................................................................15
5.3.
Multicentre Studies .....................................................................................15
5.4.
Examination of Covariates, Other Strata and Subgroups............................16
5.4.1.
Covariates and Other Strata ........................................................16
5.4.2.
Examination of Subgroups...........................................................16
5.4.2.1.
Baseline Blood Eosinophils as a Predictive 
Biomarker...................................................................17
5.5.
Multiple Comparisons and Multiplicity .........................................................17
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................18
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
7.
EFFICACY ANALYSES..........................................................................................19
7.1.
Primary Efficacy Analyses ..........................................................................19
7.1.1.
Endpoint / Variables.....................................................................19
7.1.2.
Summary Measure ......................................................................20
7.1.3.
Population of Interest...................................................................20
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................20
7.1.5.
Statistical Analyses / Methods .....................................................20
7.1.5.1.
Statistical Methodology Specification..........................21
7.2.
Secondary Efficacy Analyses......................................................................23
7.2.1.
Time to first nasal surgery............................................................23
7.2.1.1.
Summary Measure .....................................................23
7.2.1.2.
Population of Interest..................................................23
7.2.1.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................23
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7.2.1.4.
Statistical Analyses / Methods ....................................23
7.2.2.
Change from Baseline in Mean Overall VAS Symptom 
Score During the 4 weeks Prior to Week 52.................................24
7.2.2.1.
Summary Measure .....................................................24
7.2.2.2.
Population of Interest..................................................24
7.2.2.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................24
7.2.2.4.
Statistical Analyses / Methods ....................................25
7.2.3.
Change from Baseline in Sino-Nasal Outcomes TEST 22 
(SNOT-22) Total Score at Week 52 .............................................26
7.2.3.1.
Summary Measure .....................................................26
7.2.3.2.
Population of Interest..................................................26
7.2.3.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................26
7.2.3.4.
Statistical Analyses / Methods ....................................26
7.2.4.
Number of mgs per year of prednisolone-equivalent OCS 
dose up to Week 52.....................................................................27
7.2.4.1.
Summary Measure .....................................................27
7.2.4.2.
Population of Interest..................................................27
7.2.4.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................27
7.2.4.4.
Statistical Analyses / Methods ....................................28
7.3.
Other Efficacy Analyses..............................................................................29
7.3.1.
Total Endoscopic Nasal Polyps Score Responders .....................29
7.3.1.1.
Summary Measure .....................................................29
7.3.1.2.
Population of Interest..................................................29
7.3.1.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................29
7.3.1.4.
Statistical Analyses / Methods ....................................29
7.3.2.
Change from baseline in individual and composite VAS 
symptom scores...........................................................................30
7.3.2.1.
Summary Measure .....................................................30
7.3.2.2.
Population of Interest..................................................31
7.3.2.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................31
7.3.2.4.
Statistical Analyses / Methods ....................................31
7.3.3.
SNOT-22 Responders .................................................................32
7.3.3.1.
Summary Measure .....................................................32
7.3.3.2.
Population of Interest..................................................32
7.3.3.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................32
7.3.3.4.
Statistical Analyses / Methods ....................................32
7.3.4.
Need for Surgery .........................................................................33
7.3.4.1.
Summary Measure .....................................................33
7.3.4.2.
Population of Interest..................................................33
7.3.4.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................33
7.3.4.4.
Statistical Analyses / Methods ....................................33
7.3.5.
Rate of Nasal Surgery..................................................................34
7.3.6.
Time to First Inclusion on Waiting List for NP Surgery .................34
7.3.7.
Waiting List for NP surgery ..........................................................34
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7.3.8.
Change from baseline in UPSIT (University of 
Pennsylvania Smell Identification Test)........................................34
7.3.8.1.
Summary Measure .....................................................35
7.3.8.2.
Population of Interest..................................................35
7.3.8.3.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................35
7.3.8.4.
Statistical Analyses / Methods ....................................35
7.3.9.
Change from baseline in PnIF (Peak Nasal Inspiratory 
Flow)............................................................................................36
7.3.10.
Health Outcomes.........................................................................36
7.3.10.1.
SF-36 Mental Component Summary (MCS), 
Physical Component Summary (PCS) and 8 
summary scores.........................................................36
7.3.10.2.
Work Productivity and Activity Impairment 
Questionnaire (WPAI).................................................36
7.3.11.
Systemic Steroid Use...................................................................36
7.3.11.1.
Number of Courses of Therapy...................................36
7.3.11.2.
Days on Therapy........................................................37
7.3.11.3.
Time to First Course of Systemic Steroids..................37
7.3.12.
Antibiotic Use...............................................................................37
7.3.12.1.
Number of Courses of Therapy...................................37
7.3.13.
Time to first nasal surgery or course of systemic steroids............37
7.3.13.1.
Summary Measure .....................................................37
7.3.13.2.
Population of Interest..................................................37
7.3.13.3.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................37
7.3.13.4.
Statistical Analyses / Methods ....................................38
7.4.
Participants with Asthma.............................................................................38
7.5.
Maintenance of response............................................................................39
8.
SAFETY ANALYSES .............................................................................................39
8.1.
Adverse Events Analyses ...........................................................................39
8.2.
Adverse Events of Special Interest Analyses..............................................39
8.3.
Clinical Laboratory Analyses.......................................................................40
8.4.
Other Safety Analyses ................................................................................40
8.4.1.
ECG and Vital Signs....................................................................40
8.4.2.
Immunogenicity Data ...................................................................41
9.
PHARMACODYNAMIC ANALYSES.......................................................................42
9.1.
Pharmacodynamic Analyses.......................................................................42
9.1.1.
Endpoint / Variables.....................................................................42
9.1.2.
Summary Measure ......................................................................42
9.1.3.
Population of Interest...................................................................42
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................42
9.1.5.
Statistical Analyses / Methods .....................................................42
9.1.5.1.
Statistical Methodology Specification..........................42
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................43
10.1.
Primary Pharmacokinetic Analyses.............................................................43
10.2.
Population Pharmacokinetic Methodology ..................................................44
10.3.
Exploratory Pharmacokinetic Analyses .......................................................44
10.3.1.
Summary Measure ......................................................................44
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10.3.2.
Population of Interest...................................................................44
10.3.3.
Statistical Analyses / Methods .....................................................45
11. POPULATION PHARMACOKINETIC/ PHARMACODYNAMIC (POPPKPD)
ANALYSES ............................................................................................................46
11.1.
Population Pharmacokinetic/Pharmacodynamic Methodology ....................46
12. EXPLORATORY EXPOSURE-EFFICACY RESPONSE ANALYSIS ......................47
12.1.
Population of Interest..................................................................................47
12.2.
Endpoints....................................................................................................47
12.3.
Methodology...............................................................................................47
12.3.1.
Statistical analysis using exposure quartiles ................................47
12.3.1.1.
Statistical Methodology Specification..........................47
13. REFERENCES.......................................................................................................49
14. APPENDICES........................................................................................................50
14.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................50
14.1.1.
Exclusions from Per Protocol Population .....................................50
14.2.
Appendix 2: Schedule of Activities ..............................................................53
14.2.1.
Protocol Defined Schedule of Events...........................................53
14.3.
Appendix 3: Assessment Windows .............................................................59
14.3.1.
Visit Based Assessments.............................................................59
14.3.2.
Unscheduled Visits ......................................................................59
14.3.3.
Data from eDiary..........................................................................59
14.3.4.
Premature Withdrawals from Interventional Product or 
Study ...........................................................................................60
14.4.
Appendix 4: Study Phases..........................................................................61
14.4.1.
Study Phases ..............................................................................61
14.4.1.1.
Phases for Efficacy Assessments...............................61
14.4.1.2.
Phases for Safety Assessments .................................61
14.4.1.3.
Phases for Adverse Events ........................................62
14.4.1.4.
Phases for Concomitant Medication Start 
Dates..........................................................................62
14.4.1.5.
Phases for Concomitant Medication Usage 
Dates..........................................................................63
14.5.
Appendix 5: Data Display Standards & Handling Conventions....................64
14.5.1.
Reporting Process .......................................................................64
14.5.2.
Reporting Standards....................................................................64
14.5.3.
Reporting Standards for Pharmacokinetic Data ...........................65
14.6.
Appendix 6: Derived and Transformed Data ...............................................66
14.6.1.
General........................................................................................66
14.6.2.
Analysis Population .....................................................................66
14.6.3.
Study Population..........................................................................66
14.6.4.
Change from Baseline .................................................................69
14.6.5.
Efficacy........................................................................................69
14.6.6.
Safety ..........................................................................................73
14.7.
Appendix 7: Reporting Standards for Missing Data.....................................76
14.7.1.
Premature Withdrawals................................................................76
14.7.2.
Handling of Missing Data.............................................................76
14.7.2.1.
Handling of Missing Dates..........................................77
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14.7.2.2.
Handling of Partial Dates............................................77
14.7.2.3.
Missing Data for Statistical Analysis ...........................78
14.8.
Appendix 8: Values of Potential Clinical Importance ...................................79
14.8.1.
Laboratory Values of Potential Clinical Concern ..........................79
14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................80
14.9.1.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................80
14.9.2.
Population Pharmacokinetic (PopPK) Methodology.....................80
14.9.2.1.
Base Model ................................................................80
14.9.2.2.
Investigation of Covariates .........................................81
14.9.2.3.
Covariate Model Selection Procedures.......................81
14.9.2.4.
Model Evaluation........................................................82
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses ....................83
14.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................83
14.10.2. Pharmacokinetic / Pharmacodynamic Methodology.....................83
14.10.3. Base Model..................................................................................83
14.10.4. Investigation of Covariates...........................................................83
14.11. Appendix 11: Abbreviations & Trade Marks ................................................85
14.11.1. Abbreviations...............................................................................85
14.11.2. Trademarks .................................................................................86
14.12. Appendix 12: List of Data Displays..............................................................87
14.12.1. Data Display Numbering..............................................................87
14.12.2. Mock Example Shell Referencing ................................................87
14.12.3. Deliverables.................................................................................87
14.12.4. Study Population Tables..............................................................88
14.12.5. Study Population Figures.............................................................90
14.12.6. Efficacy Tables ............................................................................91
14.12.7. Efficacy Figures .........................................................................100
14.12.8. Safety Tables.............................................................................104
14.12.9. Safety Figures ...........................................................................112
14.12.10.Pharmacokinetic Population (PopPK) Tables.............................112
14.12.11.Pharmacokinetic Population (PopPK) Figures ...........................113
14.12.12.Pharmacokinetic/Pharmacodynamic Population 
(PopPK/PD) Tables ...................................................................114
14.12.13.Pharmacokinetic/Pharmacodynamic Population 
(PopPKPD) Figures ...................................................................115
14.12.14.Exposure-Efficacy Figures .........................................................115
14.12.15.ICH and Other Listings...............................................................117
14.13. Appendix 13: Example Mock Shells for Data Displays ..............................123
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205687
8
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Study 205687 (Protocol 2016N294302_03):
Revision Chronology for Protocol:
Original Protocol 
(2016N294302_00)
08-Dec-2016
Original
2016N294302_01
15-May-2017
To support country-specific requirements and amendments for 
South Korea.
2016N294302_02
14-July-2017
To clarify wording, document removal of CT scans and exit 
interviews, simplifying some of the endpoints
2016N294302_03
20-Feb-2018
To clarify that screen failures can be re-screened, and that the 
ECG machine does not need to be automated
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Co-Primary Endpoints

To evaluate the efficacy of 100mg 
mepolizumab compared to placebo

Change from baseline in total endoscopic NP 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.
Secondary Objectives
Secondary Endpoints

To evaluate the impact on actual
nasal surgery of 100mg mepolizumab 
compared to placebo

Time to first nasal surgery up to Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Change from baseline in mean overall VAS symptom 
score during the 4 weeks prior to Week 52.

To evaluate the impact on quality of 
life of 100mg mepolizumab compared 
to placebo

Change from baseline in SNOT-22 total score at Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Number of mgs per year of prednisolone-equivalent OCS 
dose up to Week 52.
Other Objectives
Other Endpoints

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo

Percentage of participants classified as responders
according to a 1 point or greater decrease from baseline in 
NP Score at Week 52 (based on centrally ready data).

Change from baseline in mean individual VAS symptom 
scores for nasal discharge, mucus in the throat, loss of 
smell and facial pain during the 4 weeks prior to Week 52.

Change from baseline in the mean composite VAS score 
 
 
 
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9
Objectives
Endpoints
(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 the mean composite VAS score 
(combining VAS scores for nasal obstruction, nasal 
discharge, mucus in the throat, loss of smell and facial 
pain) during the 4 weeks prior to Week 52.

Change from baseline in UPSIT at Week 52.

Change from baseline in PnIF at Week 52.

To evaluate the impact on quality of 
life of 100mg mepolizumab compared 
to placebo

Percentage of participants classified at Week 52 as
responders according to a 9 point or greater decrease 
from baseline in SNOT-22 total score.

To further evaluate the impact on
requirement for nasal surgery of
100mg mepolizumab compared to 
placebo

Rate of nasal surgery up to Week 52.

Time to first inclusion on waiting list for NP surgery up to 
Week 52.

Percentage of participants who are included on waiting list 
for NP surgery.

Percentage of participants classified as ‘need for surgery’ 
responders according to NP score (based on centrally 
ready data) and overall VAS symptom score.

To evaluate exploratory biomarkers of 
nasal polyposis and response to 
100mg mepolizumab compared to 
placebo

Evaluate exploratory blood biomarkers (including blood 
eosinophils) on response to mepolizumab.

To evaluate the impact on health
outcomes of 100mg mepolizumab 
compared to placebo

Change from baseline in SF-36 Mental Component
Summary (MCS), Physical Component Summary (PCS) 
and 8 summary scores at Week 52.

Change from baseline in WPAI Questionnaire at Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo on systemic steroid use such 
as OCS and antibiotic use as part of 
SoC

Number of Courses of systemic steroid therapy up to 
Week 52.

Number of days on systemic steroid therapy up to Week 
52.

Time to first course of OCS up to Week 52.

Number of courses of antibiotics up to Week 52.

To further evaluate the efficacy of 
100mg mepolizumab compared to 
placebo in the subgroup of 
participants with Asthma
In addition to endoscopic NP score, VAS symptoms score, 
medication and surgery, the following asthma related endpoints 
will be assessed:

Change from baseline in Asthma Control Questionnaire 
(ACQ-5) score at Week 52.

Number of clinically significant asthma exacerbations 
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 ED visit and/or hospitalisation 
for asthma up to Week.

To assess the maintenance of
response after cessation of
For all participants who enter post treatment follow-up period, 
the following will be assessed at Week 76:
 
 
 
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Objectives
Endpoints
mepolizumab treatment compared to 
placebo

Change from baseline in total endoscopic NP score
(centrally read data).

Change from baseline in mean nasal obstruction VAS 
score.

Change from baseline in mean individual VAS symptom 
score for nasal discharge, mucus in throat, loss of smell, 
facial pain and overall VAS symptom score during the 4 
weeks prior to Week 76.

Number of mgs per year of prednisolone-equivalent OCS 
dose.

Change from baseline in SNOT-22 total score.

Change from baseline in SF-36 Mental Component
Summary (MCS), Physical Component Summary (PCS) 
and 8 summary scores.

Change from baseline in WPAI Questionnaire.

Time to first nasal surgery including off treatment period 
from randomization to Week 76.

Time to first inclusion on waiting list for NP surgery up to 
Week 76.
Safety Objectives
Safety Endpoints

To evaluate the safety and tolerability 
of 100mg mepolizumab compared to
placebo

Frequency of adverse events (AEs)/ serious adverse
events (SAEs) including systemic and injection site
reactions reported throughout the treatment period.

Vital signs (pulse rate, systolic and diastolic blood
pressure) throughout the treatment period.

Hematological and clinical chemistry parameters
throughout the treatment period.

12 lead ECG derived endpoints.

Presence of anti-mepolizumab antibodies.
Pharmacokinetics Objectives
Pharmacokinetics Endpoints

To evaluate the pharmacokinetics 
(PK) of 100mg mepolizumab

PK concentrations and Population PK parameters

PK/PD (blood eosinophil count) analysis
 
 
 
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2.2.
Study Design
Overview of Study Design and Key Features
Design Features

Multi-centre, randomised, placebo-controlled, double-blind, parallel-
group design.

The study will include a 4-week run in period followed by a 52-week 
randomised treatment period with visits every 4 weeks.

Patients prematurely discontinued from study treatment continue, 
where possible, being followed up per the protocol schedule

Patients who have surgery for nasal polyps during the study are 
allowed to continue on study treatment until completion of the 52-week 
treatment period

Following Week 52, there is a planned study drug free, 6-month, follow-
up period for the first 200 randomised participants, to investigate 
maintenance of response to study treatment.
Main participant entry 
criteria

Participants aged ≥18 years with severe bilateral nasal polyps and at 
least one surgery in the previous 10 years for the removal of nasal 
polyps (see Section 6 of protocol).
Dosing

The study treatment period will consist of thirteen, 4-weekly doses with 
the last dose of interventional product to be administered at Week 48
(Visit 14).

Interventional product is given in addition to standard of care (SoC): 
daily mometasone furoate nasal spray (MF), saline nasal douching as 
required and, if required, occasional short courses of high dose oral 
corticosteroids (OCS) and/or antibiotics.
Schedule of Activities

See Appendix 2: Schedule of Activities
Treatment Assignment

400 participants (planned) will be randomised in a 1:1 ratio to receive 
mepolizumab or matching placebo (i.e. 200 per treatment group) 
delivered subcutaneously via a pre-filled safety syringe in addition to 
SoC.

Randomisation schedule generated using GSK validated randomisation 
software RandAll NG, stratified by country.

Treatment assigned randomly via an interactive voice response system 
(IVRS).
Interim Analysis

No interim analysis of data is planned for this study.
 
 
 
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2.3.
Statistical Hypotheses
The study is designed to test the superiority of mepolizumab 100mg SC vs. placebo in
addition to standard of care. Significance tests will be guided by a two-sided 5% alpha 
level (one-sided 2.5%).
2.4.
Changes to the Protocol Defined Statistical Analysis Plan
Minor changes/deviations from the originally planned statistical analysis specified in 
Protocol Amendment 3 (Dated: 20 FEB 2018) are outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Each co-primary endpoint will be 
analysed using an ordinal logistic 
regression model (proportional 
odds model) with covariates of 
treatment group, baseline score 
and region.
Each co-primary endpoint will be 
analysed using an ordinal logistic 
regression model (proportional 
odds model) with covariates of 
treatment group, baseline score, 
loge baseline blood eosinophil 
count and region.
Including a covariate for baseline 
blood eosinophils to provide an 
estimate of treatment effect 
adjusted for differing levels of 
baseline blood eosinophils. 
‘All Participants Enrolled’ analysis 
population defined as all 
participants who sign the ICF.
‘All Participants Enrolled’ analysis 
population defined as all 
participants enrolled and for whom 
a record exists on the study 
database.
Clarifying population definition 
used to report on reasons for 
screen failure and run-in failure.
Co-primary endpoint defined as 
Change from baseline in total 
endoscopic nasal polyps (NP) 
score at Week 52.
Co-primary endpoint defined as 
Change from baseline in total 
endoscopic NP score at Week 52 
(based on centrally read data).
To clarify the total endoscopic 
NP score used in the analysis of 
the co-primary endpoint is based 
on data from the blinded 
independent review of 
endoscopy data (as per Protocol 
Section 9.2.1).
 
 
 
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3.
PLANNED ANALYSES
Planned dry run(s) will be performed on a subset of blinded data, with the aim of 
ensuring the required displays detailed in Appendix 12: List of Data Displays are 
correctly created and formatted.
3.1.
Interim Analyses
No interim analysis of data is planned for this study
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol
2.
All required database cleaning activities have been completed and database freeze
(DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met, and the 
randomisation codes have been released.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Enrolled

All participants who sign the Informed Consent Form
and who have a record on the database
Reasons for screen 
and run-in failures
Randomized

All randomized participants
Study population
Intent-To-Treat 
(ITT)

All randomized participants who take at least 1 dose of 
study treatment.

Data will be analysed according to randomised 
treatment arm.
Subject disposition
Efficacy endpoints
Safety

All randomized participants who take at least 1 dose of 
study treatment.

Data will be analysed according to actual treatment 
received for more than 50% of treatment 
administrations (see Section 14.6.2).
Safety endpoints
Per-Protocol 
(PP) [1]

All participants in the ITT population who have not been 
identified as protocol deviators with respect to criteria 
that are considered to impact the primary efficacy 
analysis.

Protocol deviations that would exclude participants from 
the PP population are defined in Appendix 1: Protocol 
Deviation Management and Definitions for Per-Protocol 
Population
Supplementary 
analyses of co-primary 
endpoints
Pharmacokinetic 
(PK) [1]
All participants in the ITT population for whom at least 
one PK sample was obtained, analysed and 
measurable.
Pharmacokinetic 
endpoints
Follow-up after 

Participants in the ITT population who participate in the 
Efficacy/safety
 
 
 
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Population
Definition / Criteria
Analyses Evaluated
Week 52 (FU) [1]
‘No treatment follow-up’ period after Visit 15.

Data will be summarised according to randomised 
treatment arm.
endpoints
Refer to Appendix 12: List of Data Displays which details the population used for each display.
[1] Analysis population not defined in protocol, added for clarification of analysis requirements.
4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP) dated 10 January 
2018 (Version 1.01).  Protocol deviations classified as important are detailed in the 
PDMP and those requiring exclusion from the Per-Protocol (PP) population are detailed 
in Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population.
A final blinded review of all deviations will take place at the database release stage to 
ensure all important deviations are identified as well as those leading to exclusion of the 
participant from the PP population.
Important protocol deviations and deviations which result in exclusion from the PP 
population will be summarised and listed.  A separate listing of all inclusion/ exclusion 
criteria deviations based on data as recorded on the eligibility page of the eCRF will also 
be provided.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF[1]
1
Placebo
Placebo
1
2
Mepolizumab 100mg SC
Mepolizumab 100mg SC
2
[1] TLF=Tables, Listings, Figures (as specified in Appendix 12: List of Data Displays)
Treatment comparisons will be displayed as follows using the descriptors as specified:
Mepolizumab 100mg SC vs Placebo
 
 
 
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5.2.
Baseline Definitions
5.2.1.
Visit-based endpoints
The co-primary endpoint of endoscopic NP score (based on centrally read data) is 
assessed at Screening (Visit 1) and Day 1 (Visit 2), the Screening value is used to 
confirm if a participant has met the criteria for randomisation.  Baseline will be defined 
as the Day 1 value, if missing the immediately preceding centrally read value prior to 
Day 1 will be used.
For all other visit-based endpoints, Baseline will be defined as the latest non-missing 
measurement collected prior to the first dose of interventional product.  This will 
generally be from the Day 1 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.
5.2.2.
eDiary Data
Participants 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).
5.3.
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, country and region.
Region will be included as a fixed effect covariate in the analysis models for efficacy 
endpoints (as detailed in Section 5.4). Countries have been grouped into the following 
regions with consideration for standard of care medical practice, number of participants 
enrolled and regulatory considerations.
Region
Countries
Europe (EU)
Germany, Netherlands, Romania, Sweden, UK
United States (US)
United States
Rest of World (RoW)
South Korea, Argentina, Australia, Canada, Russia
NOTE: Small numbers of participants in a treatment group within a region may result in model convergence issues, in 
these cases further combining of regions may be considered or if required exclusion of the region covariate.
 
 
 
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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Covariates to be included in the statistical analysis models of the co-primary efficacy 
endpoints:

Randomised treatment group 

Region

Baseline score

Baseline loge blood eosinophil count
Covariates to be included in the statistical analysis model of time to first nasal surgery:

Randomised treatment group 

Region

Baseline total NP endoscopic score (based on centrally read data)

Baseline nasal obstruction VAS

Baseline loge blood eosinophil count

Number of previous surgeries (1, 2, >2; as an ordinal variable)
Covariates to be included in the statistical analysis model of Number of mgs per year of 
prednisolone-equivalent OCS: 

Randomised treatment group

Region

Baseline total NP score (based on centrally read data)

Baseline nasal obstruction VAS

Baseline loge blood eosinophil count

Number of OCS courses for NP in the previous 12 months (0, 1, >1, as an ordinal 
variable)
Section 7 provides full details of the analysis methods for each of the efficacy endpoints.
5.4.2.
Examination of Subgroups
This section details the subgroups of interest within this study.  For each co-primary 
endpoint, a separate exploratory analysis within each of the subgroup categories will be 
carried out.  Subgroup analyses for all other endpoints are detailed in the statistical 
methods/analyses sections.  Unless otherwise stated no formal hypothesis testing in 
subgroups of the population will be performed.
 
 
 
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If, following unblinding, the analysis model within a subgroup category fails to converge 
due to small numbers of participants, the model will be rerun with consideration of 
further refining regions or if required exclusion of the region covariate.  Failing this,
subgroup categories may be further refined when possible, otherwise only a descriptive 
summary of the data will be presented.  Footnotes will clearly identify the covariates 
included in the analysis model.
Except for baseline blood eosinophils, differential treatment effects are not expected for 
any of the other subgroups listed above and therefore any differences in efficacy of
mepolizumab compared to placebo observed in subgroup categories will be viewed as 
exploratory.
5.4.2.1.
Baseline Blood Eosinophils as a Predictive Biomarker
There is a biological rationale for potentially observing greater efficacy with increasing 
levels of baseline blood eosinophils.  The role of baseline blood eosinophil counts on the 
effectiveness of mepolizumab with respect to the co-primary endpoints will be further 
assessed using a statistical model including terms for baseline blood eosinophil count 
(loge) as a continuous variable (as defined in Section 5.2) and its interaction with 
treatment. The analysis will also be adjusted for region and baseline score, as described 
in Section 5.4.1. Fractional polynomial transformations of baseline blood eosinophil 
count may also be explored to find the best fitting model for the relationship.
5.5.
Multiple Comparisons and Multiplicity
The treatment comparison of mepolizumab 100mg SC vs. placebo is of interest for the 
co-primary and secondary endpoints.  Multiplicity arising from the multiple secondary 
endpoints will be controlled through testing of the secondary endpoints using a closed 
testing procedure according to the following pre-defined hierarchy:
1. Time to first nasal surgery 
2. Change from baseline in overall VAS symptom score 
Subgroup
Categories 
Participants with Asthma
Concurrent asthma, No concurrent asthma
Aspirin Exacerbated Respiratory 
Disease (AERDS)
Current AERDS, No Current AERDS
Number of previous surgeries
1, 2, >2
Baseline Blood Eosinophil
Categories (GI/L)
≤0.3 GI/L; >0.3 to ≤0.5 GI/L; >0.5 to ≤0.7 GI/L; >0.7 GI/L
Region
Europe, United States, Rest of World
Age
18-<40, 40-<65, ≥65 years
Gender
Male, Female
Race
African American/African Heritage, White, Asian, Other
 
 
 
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3. Change from baseline in SNOT-22 total score 
4. Number of mgs per year of prednisolone-equivalent dose
For strong control of type I error, statistical significance for the first secondary endpoint 
in the pre-defined hierarchy will be dependent on statistical significance having been 
achieved for the two co-primary endpoints.  Statistical significance for the subsequent 
secondary endpoints will be dependent on statistical significance having been achieved 
for the previous endpoints in the hierarchy.
For secondary endpoints, unadjusted p-values and p-values adjusted for multiplicity 
based on the above hierarchy, will be presented.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
14.3
Appendix 3: Assessment Windows
14.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
14.5
Appendix 5: Data Display Standards & Handling Conventions
14.6
Appendix 6: Derived and Transformed Data
14.7
Appendix 7: Reporting Standards for Missing Data
14.8
Appendix 8: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
All displays will be based on the ITT population, unless otherwise specified.
Study population displays including summaries of subject disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications
and treatment exposure will be based on GSK Core Data Standards.  Additional summary 
information showing the amount of time within the 52-week treatment period considered 
as on-treatment, off-treatment and missing will be presented.
A summary of subject disposition and duration of time spent in the no-treatment follow-
up will be provided for the subset of participants who participated in the 6-month no-
treatment follow-up.
Details of the planned displays are presented in Appendix 12: List of Data Displays.
 
 
 
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7.
EFFICACY ANALYSES
Data reported as part of the follow-up period after Week 52 will be excluded from the 
analyses described in Section 7.1 to Section 7.4.  Details of all planned displays are 
provided in Appendix 12: List of Data Displays and will be based on GSK data standards 
and statistical principles.
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary treatment effect to be estimated (estimand) will be the comparison of 
mepolizumab 100mg SC to placebo for the co-primary endpoints of:

Change from baseline in total endoscopic NP 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
Independent reviewers blinded to treatment, grade the total endoscopic NP score from 
image recording of endoscopies, the total score is reported as the sum of the right and left 
nostril scores and ranged from 0 to 8, with higher scores indicating greater disease
severity.
Participants rate individual symptoms including nasal obstruction daily on a visual 
analogue scale using an eDiary, the scale range is 0 (none) to 100 (as bad as you can 
imagine), with higher scores indicating greater disease severity, for analysis derived 
scores ranging from 0 to 10 are used (see Section 14.6.5).
A composite strategy will be used for the intercurrent event of actual surgery and a 
treatment policy strategy for the intercurrent event of discontinuation of study 
medication.  The study is designed to continue collecting data for participants who have 
prematurely discontinued from randomised treatment, off-treatment data collected for 
these participants will be included in the primary analysis.
For each co-primary endpoint, change from baseline will be categorised for analysis into 
varying levels of improvement, no change or worsening, and a least favourable category 
of actual surgery (Section 7.1.5.1).
Participants with missing data at Baseline will be included in the ‘no change/worsening’ 
category for analysis.  For analysis of total endoscopic NP score, participants with 
missing visit information (due to early study withdrawal or any other reason) will, in the 
absence of actual surgery, be included in the ‘no change/worsening’ category for 
analysis.  For analysis of nasal obstruction VAS, participants with missing data for a 4-
week period will, in the absence of surgery, be included in the ‘no change/worsening’ 
category for that 4-week period.  Sensitivity analyses to examine the impact of handling 
missing data as described above are detailed in Section 7.1.5.
 
 
 
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Each co-primary endpoint will be analysed as an ordinal categorical variable [Keene, 
2018].  NP score and VAS symptom scores have usually been analysed using models
which assume the response is normally distributed.  Such models do not acknowledge the 
bounded response for the scales and there is no ideal approach for inclusion of actual 
surgery as a worst response. For the proportional odds model, it is not necessary to 
assign scores to the response categories, and if the model holds for a particular set of 
response categories, it holds with the same effects when the response scale is collapsed in 
any way [McCullagh, 1980]. In the comparison of two treatments with no adjustment for
covariates, this approach becomes equivalent to the Wilcoxon test.
7.1.2.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant achieving a greater improvement by category for 
mepolizumab compared with placebo.
7.1.3.
Population of Interest 
The primary population of interest for analysis of the co-primary endpoints is defined by 
the study inclusion/exclusion and randomisation criteria and is therefore the ITT 
population.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
The anticipated intercurrent events occurring prior to the week 52 analysis time point for 
the co-primary endpoints are: Actual surgery for nasal polyps and premature 
discontinuation of interventional product.
For each co-primary endpoint, the anticipated intercurrent event of actual surgery will be 
handled using a composite strategy such that the occurrence of the event is incorporated 
into the definition of the endpoint.  In participants who do not experience actual surgery, 
the anticipated intercurrent event of premature discontinuation of interventional product 
will be handled using a treatment policy strategy, such that in these participants all data 
reported at week 52 for total endoscopic NP score (or during the 4-week period prior to 
Week 52 for nasal obstruction VAS) will be included in the analysis, regardless of 
discontinuation from treatment.
7.1.5.
Statistical Analyses / Methods
Each co-primary endpoint will be analysed using an ordinal logistic regression model 
(proportional odds model) with covariates as detailed. The treatment effect of 
mepolizumab compared with placebo will be expressed as an odds ratio with 
corresponding 95% confidence interval and p-value.
 
 
 
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7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables
Change from baseline in total endoscopic NP score (based on centrally read data) at Week 52 and 
other defined visits, will be categorized for analysis as follows: 
1.
≥ 5-point improvement
2.
4-point improvement
3.
3-point improvement
4.
2-point improvement
5.
1-point improvement
6.
No change/worsening
7.
Nasal surgery prior to visit

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data at a visit will be included in the ‘no 
change/worsening’ category for the respective visit.

If a participant had actual surgery prior to a visit, they will be included in the ‘Nasal surgery 
prior to visit’ category regardless of whether a score for the respective visit was obtained.
Change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week 52,
and other defined 4-week periods, will be categorized for analysis as follows: 
1.
> 5-point improvement
2.
>4 to 5-point improvement
3.
>3 to 4-point improvement
4.
>2 to 3-point improvement
5.
>1 to 2-point improvement
6.
>0 to 1-point improvement
7.
No change/worsening
8.
Nasal surgery prior to visit

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data for the 4-week period will be 
included in the ‘no change/worsening’ category for the respective period.

If a participant had actual surgery prior to or during a 4-week period, they will be included in the 
‘Nasal surgery prior to visit’ category regardless of whether data for the respective period was 
obtained.
Model Specification

Each co-primary endpoint will be analyzed using ordinal logistic regression to compare the 
odds between treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
 
 
 
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Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each analysis category will be displayed by 
treatment group, as will the estimated odds ratio, 95% confidence interval (CI) and p-value 
comparing treatments from the ordinal logistic regression model.

A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups at 
each visit will be provided.

A cumulative distribution function (CDF) plot will be provided for the change from baseline in 
endoscopic NP score at Week 52 by treatment group. Participants having had nasal surgery 
prior to Week 52 will be included as having the worst outcome for the study.
Subgroup Analyses

Section 5.4.2 identifies the subgroups of interest for the co-primary endpoints.
Sensitivity and Supportive Analyses
For sensitivity and supplementary analyses an ordinal logistic regression model (proportional odds 
model) with covariates as for the primary efficacy analysis will be used.
Sensitivity analyses

In the primary analysis participants with missing data at baseline or Week 52 (due to 
premature withdrawal from the study or another reason) will be included in the ‘no change or 
worsening’ category for analysis.  Sensitivity analyses will be carried out to examine the 
potential impact of choices for the handling of missing data.  Sensitivity analysis will be 
performed where the participants with missing data are included in the:
o
a) least favourable category of actual surgery for each co-primary endpoint
o
b) 1-point improvement category for total endoscopic NP score and the 0 to 1-point 
improvement category for mean nasal obstruction VAS.
Supplementary analyses

A supplementary analysis will be performed for each co-primary endpoint where the 
anticipated intercurrent event of premature discontinuation of interventional product will be 
handled using a composite strategy, such that the event is incorporated into the definition of 
the endpoint.  For this supplementary analysis, all participants in the population of interest will 
be included in this sensitivity analysis, the co-primary endpoints will be analysed as follows: 
o
The least favourable treatment response category will incorporate the intercurrent 
events of actual surgery and premature discontinuation of interventional product, this 
will be labelled as ‘Nasal surgery prior to visit or premature discontinuation of 
interventional product’

A supplementary analysis of each co-primary endpoint will be performed on the Per-Protocol 
(PP) population (see Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population)
 
 
 
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7.2.
Secondary Efficacy Analyses
For each secondary endpoint the primary treatment effect to be estimated (estimand) will 
be the comparison of mepolizumab 100mg SC to placebo.
7.2.1.
Time to first nasal surgery
The time to first nasal surgery will be determined as the number of days from the date of 
first dose of study medication to the date of first nasal surgery (see Section 14.6.5). If a 
participant withdraws from the study before Week 52 and before experiencing nasal 
surgery, the nasal surgery event time will be censored at the time of study withdrawal.
7.2.1.1.
Summary Measure
The summary measure of treatment effect will be the hazard ratio, the ratio of hazards 
corresponding to treatment with mepolizumab compared with placebo.  For this endpoint 
the hazard represents the probability of nasal surgery for a participant at a given point in 
time following first dose of interventional product, given the participant has not 
experienced the event prior to that time.
7.2.1.2.
Population of Interest
The primary population of interest is the ITT population.
7.2.1.3.
Strategy for Intercurrent (Post-Randomization) Events
A treatment policy strategy will be used for the intercurrent event of premature 
discontinuation of interventional product, such that available nasal surgery times will be 
included in the analysis regardless of whether the surgery occurred before or after 
discontinuation of interventional product.
7.2.1.4.
Statistical Analyses / Methods
Endpoint / Variables
Time to first nasal surgery 
Model Specification

Cox proportional hazards model with covariates as follows:
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline total nasal polyps endoscopic score (centrally read data), 
Baseline nasal obstruction VAS, Loge baseline blood eosinophil 
count, Number of previous surgeries (1, 2, >2; ordinal)

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

A log(-log(survival)) plot by treatment group will be used to assess the assumption of 
proportional hazards.
 
 
 
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Model Results Presentation

The number of participants with an event, the number censored due to study withdrawal and at 
study completion will be presented by treatment arm.

The hazard ratio with corresponding 95% CI and p-value from the Cox proportional hazards 
model will be presented.

A summary and graph of the Kaplan-Meier estimate of the cumulative proportion of participants 
with nasal surgery within each treatment arm over time will be produced.
Subgroup Analyses

No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

Sensitivity analyses will be performed to assess the censoring-at-random assumption of the 
cox proportional hazards model where participants who withdraw from the study before 
experiencing surgery have their event times censored at the time of study withdrawal.

Sensitivity analysis will be carried out where missing event times for participants randomised to 
mepolizumab who withdraw from the study before experiencing surgery will be imputed using a 
censoring-not-at-random method as described in [Jackson, 2014].  A step-change in event rate 
equivalent to a loss of benefit from mepolizumab will be imputed for these participants after 
their censoring time.  This means a reduction in relative event rate equivalent to 1/(estimated 
treatment effect). Missing event times for placebo will imputed under a censoring-at-random 
assumption.
7.2.2.
Change from Baseline in Mean Overall VAS Symptom Score 
During the 4 weeks Prior to Week 52
Change from baseline in mean overall VAS symptom score will be categorised for 
analysis into varying levels of improvement, no change or worsening, and a least 
favourable category of actual surgery.  Participants with missing data at Baseline or at 
Week 52 (due to study withdrawal or any other reason) will be included in the ‘no 
change/worsening’ category for analysis.
7.2.2.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds for a participant achieving a greater improvement by category with
mepolizumab compared with placebo.
7.2.2.2.
Population of Interest
The primary population of interest is the ITT population.
7.2.2.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
 
 
 
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7.2.2.4.
Statistical Analyses / Methods
Endpoint / Variables
Change from baseline in mean overall VAS symptom score during the 4 weeks prior to Week 52, 
and other defined 4-week periods, will be categorized for analysis as follows:
1.
> 5-point improvement
2.
>4 to 5-point improvement
3.
>3 to 4-point improvement
4.
>2 to 3-point improvement
5.
>1 to 2-point improvement
6.
>0 to 1-point improvement
7.
No change/worsening
8.
Nasal surgery prior to visit

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data for the 4-week period will be 
included in the ‘no change/worsening’ category for the respective period

If a participant had actual surgery prior to or during a 4-week period, they will be included in the 
‘Nasal surgery prior to visit’ category regardless of whether data for the respective period was 
obtained.
Model Specification

This endpoint will be analyzed using ordinal logistic regression to compare the odds between 
treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each ‘change from baseline’ category will be 
displayed by treatment group, as will the estimated odds ratio, 95% CI and p-value comparing 
treatments from the ordinal logistic regression model.

A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups at 
each visit will be provided.
Subgroup Analyses

No subgroup analyses are planned for this endpoint
Sensitivity and Supportive Analyses

No sensitivity analyses are planned for this endpoint
 
 
 
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7.2.3.
Change from Baseline in Sino-Nasal Outcomes TEST 22 (SNOT-
22) Total Score at Week 52
The 22 questions of the SNOT-22 are each graded on 
 
 The scores for each of the questions 
are summed to derive the total score which ranges 
.
Change from baseline at Week 52 will be categorised for analysis into varying levels of 
improvement, no change or worsening and a least favourable category of actual surgery.  
Participants with missing data at Week 52 (due to early study withdrawal or any other 
reason) will be included for analysis in the ‘no change/worsening’ category.
7.2.3.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds for a participant achieving a greater improvement by category for 
mepolizumab compared with placebo.
7.2.3.2.
Population of Interest
The primary population of interest is the ITT population.
7.2.3.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.2.3.4.
Statistical Analyses / Methods
Endpoint / Variables
Change from baseline in SNOT-22 total score at Week 52, and other defined visits, will be 
categorized as follows:
1.
>45-point improvement
2.
>36 to 45-point improvement
3.
>27 to 36-point improvement
4.
>18 to 27-point improvement
5.
>9 to 18-point improvement
6.
>0 to 9-point improvement
7.
No change/worsening
8.
Nasal surgery prior to visit 

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data at a visit will be included in the ‘no 
change/worsening’ category for the respective visit

If a participant had actual surgery prior to a visit, they will be included in the ‘Nasal surgery 
prior to visit’ category regardless of whether a score for the respective visit was obtained.
 
 
 
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Model Specification

This endpoint will be analyzed using ordinal logistic regression to compare the odds between 
treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each ‘change from baseline’ category will be 
displayed by treatment group, as will the estimated odds ratio, 95% CI and p-value comparing 
treatments from the ordinal logistic regression model.

A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups at 
each visit will be provided.
Subgroup Analyses

No subgroup analyses are planned for this endpoint
Sensitivity and Supportive Analyses

No sensitivity analyses are planned for this endpoint
7.2.4.
Number of mgs per year of prednisolone-equivalent OCS dose up 
to Week 52
The total number of milligrams (mgs) of prednisolone-equivalent OCS use per year will 
be categorised and analysed as an ordinal categorical variable representing a composite of
varying levels of prednisolone-equivalent OCS use in mgs per year up to Week 52.
7.2.4.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds for a participant achieving a greater improvement by category for 
mepolizumab compared with placebo.
7.2.4.2.
Population of Interest
The primary population of interest is the ITT population.
7.2.4.3.
Strategy for Intercurrent (Post-Randomization) Events
The anticipated intercurrent events for this endpoint are actual surgery and premature 
discontinuation of interventional product, these will be handled using a treatment policy 
 
 
 
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strategy such that all data will be included in the analysis, regardless of the occurrence of 
either intercurrent event.
7.2.4.4.
Statistical Analyses / Methods
Endpoint / Variables
The total number of mgs of prednisolone-equivalent OCS use per year (see Section 14.6.5) will be 
categorized for analysis as follows: 
1.
0mg
2.
>0 to 100mg
3.
>100 to 200mg
4.
>200 to 400mg
5.
>400mg
6.
Nasal Surgery

If a participant had actual surgery, they will be included in the ‘Nasal surgery’ category 
regardless of the total use of prednisolone equivalent OCS.
Model Specification

This endpoint will be analyzed using ordinal logistic regression to compare the odds between 
treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Number of OCS courses for NP in last 12 months (0, 1, >1; ordinal), 
baseline total endoscopic NP score (based on centrally read data), 
baseline nasal obstruction VAS score, Loge baseline blood 
eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each category will be displayed by treatment group, 
with the estimated odds ratio, 95% CI and p-value comparing treatments from the ordinal 
logistic regression model.

A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups 
will be provided.
Subgroup Analyses

Analysis will be carried out of the following subgroups: Participants with asthma.  See Section 
5.4.2 for further details.
Sensitivity and Supportive Analyses
 
 
 
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
No sensitivity analyses are planned for this endpoint
7.3.
Other Efficacy Analyses
7.3.1.
Total Endoscopic Nasal Polyps Score Responders
A responder is defined as a participant achieving a ≥1-point improvement (decrease)
from baseline in total endoscopic NP score (based on centrally read data) at Week 52.  
Participants with missing data at Baseline or Week 52 (due to early study withdrawal or 
any other reason) will be included in the analysis as a non-responder.
7.3.1.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder in the mepolizumab arm compared with 
placebo.
7.3.1.2.
Population of Interest
The population of interest is the ITT population.
7.3.1.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.3.1.4.
Statistical Analyses / Methods
Endpoint / Variables
Participants with a ≥1-point improvement from baseline in total endoscopic NP at Week 52 (based 
on centrally read data) will be included in the analysis as a responder.

The following participants will be included in the analysis as a non-responder:
o
Participants who had actual surgery prior to Week 52
o
Participants who withdrew early from the study or who had missing data at Baseline or 
Week 52
Model Specification

A logistic regression model will be used to compare the proportion of responders in the 
mepolizumab arm compared to placebo.

The odds ratio comparing treatment groups will be estimated using the observed marginal 
distribution of the sample covariates.

The analysis model will include the following terms:
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics
 
 
 
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
Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of participants identified as responders and non-responders for 
analysis will be displayed by treatment group, the non-responder group will be further 
categorized to display the number of participants with actual surgery, the number withdrawn 
early from the study and the number with missing baseline data.

The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression model will be displayed.

A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups will 
be provided by visit.
Subgroup Analyses

No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for this endpoint.
7.3.2.
Change from baseline in individual and composite VAS symptom 
scores
Participants rate individual symptoms daily on a visual analogue scale using an eDiary, 
the scale range for each symptom is
 
The following endpoints will be analysed in the same manner and using the same change 
from baseline categories as the co-primary endpoint of change from baseline in mean 
nasal obstruction VAS score during the 4 weeks prior to Week 52:

Change from baseline in mean individual VAS symptom scores during the 4 weeks 
prior to Week 52 for: 
o
nasal discharge
o
mucus in the throat
o
loss of smell
o
facial pain

Change from baseline in the mean composite VAS score during the 4 weeks prior to 
Week 52 for: 
o
Composite of nasal obstruction, nasal discharge, mucus in the throat and loss 
of smell
o
Composite of nasal obstruction, nasal discharge, mucus in the throat, loss of 
smell and facial pain
7.3.2.1.
Summary Measure
See Section 7.1.2. for details.
 
 
 
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7.3.2.2.
Population of Interest
See Section 7.1.3. for details.
7.3.2.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.3.2.4.
Statistical Analyses / Methods
Endpoint / Variables
Change from baseline during the 4 weeks prior to Week 52, and other defined 4-week periods, will 
be categorized for analysis as follows: 
1.
> 5-point improvement
2.
>4 to 5-point improvement
3.
>3 to 4-point improvement
4.
>2 to 3-point improvement
5.
>1 to 2-point improvement
6.
>0 to 1-point improvement
7.
No change/worsening
8.
Nasal surgery prior to visit

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data for the 4-week period will be 
included in the ‘no change/worsening’ category for the respective period.

If a participant had actual surgery prior to or during a 4-week period, they will be included in the 
‘Nasal surgery prior to visit’ category regardless of whether data for the respective period was 
obtained.
Model Specification

For each endpoint an ordinal logistic regression model will be used to compare the odds 
between treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each analysis category will be displayed by 
treatment group, as will the estimated odds ratio, 95% confidence interval (CI) and p-value 
comparing treatments from the ordinal logistic regression model.
 
 
 
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
A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups at 
each visit will be provided.
Subgroup Analyses

No subgroup analyses are planned for these endpoints.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for these endpoints.
7.3.3.
SNOT-22 Responders
A responder is defined as a participant achieving a ≥9-point improvement (decrease)
from baseline in SNOT-22 total score at Week 52.  Participants with missing data at 
Baseline or Week 52 (due to early study withdrawal or any other reason) will be included
in the analysis as a non-responder.
7.3.3.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant being a responder in the mepolizumab arm compared with 
placebo.
7.3.3.2.
Population of Interest
The population of interest is the ITT population.
7.3.3.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.3.3.4.
Statistical Analyses / Methods
Endpoint / Variables
Participants with a ≥9-point improvement from baseline in SNOT-22 score at Week 52 will be 
included in the analysis as a responder.

The following participants will be included in the analysis as a non-responder:
o
Participants who had actual surgery prior to Week 52
o
Participants who withdrew early from the study or who had missing data at Baseline or 
Week 52
Model Specification

See Section 7.3.1.4  
Model Checking & Diagnostics

See Section 7.3.1.4
Model Results Presentation

See Section 7.3.1.4
Subgroup Analyses
 
 
 
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
No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for this endpoint.
7.3.4.
Need for Surgery
Participants enter the trial with severity of nasal polyps consistent with the need for 
surgery (inclusion criteria 8 of study protocol).  Participants are identified as no longer 
having a need for surgery based on improvements in the total nasal polyps endoscopy 
score (centrally read) and overall VAS score at Week 52 (further details in Section 
14.6.5).  Participants with missing data at Week 52 (due to early study withdrawal or any 
other reason) will be identified as still having a need for surgery at Week 52.
7.3.4.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant no longer having a need for surgery at Week 52 in the 
mepolizumab arm compared with placebo.
7.3.4.2.
Population of Interest
The population of interest is the ITT population.
7.3.4.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.3.4.4.
Statistical Analyses / Methods
Endpoint / Variables
Need for surgery at week 52 will be assessed for each participant as detailed in Section 14.6.5.

The following participants will be included in the analysis as still having a need for surgery:
o
Participants who had actual surgery prior to Week 52
o
Participants who withdrew early from the study or who had missing data at Baseline or 
Week 52
Model Specification

A logistic regression model will be used to compare the proportion of participants who no 
longer have a need for surgery in the mepolizumab arm compared to placebo.

The odds ratio comparing treatment groups will be estimated using the observed marginal 
distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline total nasal polyps endoscopic score (centrally read data), 
Loge baseline blood eosinophil count
 
 
 
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
Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checking for issues with convergence.
Model Results Presentation

The number and percentage of participants identified as no longer having a need/still having a 
need for surgery will be displayed by treatment group, the still having a need for surgery group 
will be further categorized to display the number participants with actual surgery, the number 
withdrawn early from the study and the number with missing Baseline data.

The estimated odds ratio, 95% CI and p-value comparing treatments from the logistic 
regression model will be displayed.
Subgroup Analyses

No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for this endpoint.
7.3.5.
Rate of Nasal Surgery
A summary of the number and percentage of participants who have undergone surgery 
will be presented, the rate of surgery will also be presented for each treatment arm.
7.3.6.
Time to First Inclusion on Waiting List for NP Surgery
A summary and graph of the Kaplan-Meier estimates of the cumulative proportion of 
participants having been placed on a waiting list for nasal polyps surgery over time will 
be provided.
7.3.7.
Waiting List for NP surgery
A summary of the number and percentage of participants placed on a waiting list for 
nasal polyp surgery at each visit and over the whole study will be presented.
7.3.8.
Change from baseline in UPSIT (University of Pennsylvania Smell 
Identification Test)
UPSIT is designed to test the function of an individual’s olfactory system.  The test is 
scored out of 40 with a lower score indicating a worse outcome.  The test will be 
performed only by participants at sites in the UK, US and Canada.  Change from baseline 
in UPSIT total score will be categorised for analysis into varying levels of improvement, 
no change or worsening, and a least favourable category of actual surgery.  Participants 
with missing data at Baseline or at Week 52 (due to study withdrawal or any other 
reason) will, in the absence of surgery, be included in the ‘no change or worsening 
category’ for analysis.
 
 
 
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7.3.8.1.
Summary Measure
The summary measure of treatment effect will be the odds ratio which represents the 
relative odds of a participant achieving a greater improvement by category for 
mepolizumab compared with placebo.
7.3.8.2.
Population of Interest
The population of interest is the ITT population.
7.3.8.3.
Strategy for Intercurrent (Post-Randomization) Events
See Section 7.1.4. for details.
7.3.8.4.
Statistical Analyses / Methods
Endpoint / Variables
Change from baseline in UPSIT at Week 52 and other defined visits, will be categorized for 
analysis as follows: 
1.
> 20-point improvement
2.
>10 to 20-point improvement
3.
>0 to 10-point improvement
4.
No change/worsening
5.
Nasal surgery prior to visit

For analysis, participants with missing data at Baseline will be included in the ‘no 
change/worsening’ category, participants with missing data at a visit will be included in the ‘no 
change/worsening’ category for the respective visit

If a participant had actual surgery prior to a visit, they will be included in the ‘Nasal surgery 
prior to visit’ category regardless of whether a score for the respective visit was obtained.
Model Specification

Change from baseline in UPSIT will be analyzed using ordinal logistic regression to compare 
the odds between treatment groups of being in a more favorable endpoint category.

The odds ratio comparing treatment groups will be estimated from the ordinal logistic 
regression model using the observed marginal distribution of the sample covariates.

The analysis model will include the following terms: 
Fixed Categorical: 
Treatment group, Country
Fixed Continuous: 
Baseline score, Loge baseline blood eosinophil count
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each analysis category will be displayed by 
treatment group, as will the estimated odds ratio, 95% CI and p-value comparing treatments 
from the ordinal logistic regression model.
 
 
 
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
A forest plot of the estimated odds ratio and 95% CI for the comparison of treatment groups at 
each visit will be provided.
Subgroup Analyses

No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for this endpoint.
7.3.9.
Change from baseline in PnIF (Peak Nasal Inspiratory Flow)
A PnIF meter will be used to derive forced inspiratory peak flow through the nose.  A 
summary of PnIF data and change from baseline at each visit will be presented.
7.3.10.
Health Outcomes
7.3.10.1.
SF-36 Mental Component Summary (MCS), Physical Component 
Summary (PCS) and 8 summary scores
Certified scoring of the SF-36 survey will be performed using OPTUM™software.
The eight domain scores (bodily pain, general health, mental health, physical functioning, 
role emotional, role physical, social functioning and vitality) as well as the physical and 
mental component summary scores are provided by the software.
Domain and component summary scores will be summarised by visit, including change 
from baseline.  Data will be included in these summaries regardless of the occurrence of 
events such as actual surgery or treatment discontinuation.
7.3.10.2.
Work Productivity and Activity Impairment Questionnaire (WPAI)
The WPAI questionnaire is an instrument to measure impairment in paid and unpaid 
work.  Summary information from the WPAI at each visit will include information on 
employment status, hours missed from work due to health problems and due to other 
reasons, hours actually worked, and how much health problems affected productivity and 
activity. Data will be included in these summaries regardless of the occurrence of events 
such as actual surgery or treatment discontinuation.
7.3.11.
Systemic Steroid Use
7.3.11.1.
Number of Courses of Therapy
A summary of the number of courses of systemic steroids will be presented for each 
treatment arm.  Courses of systemic steroids which are separated by less than 7 days will 
be considered a continuation of the same course.  Data will be included in the summary 
regardless of the occurrence of events such as surgery or treatment discontinuation.
 
 
 
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7.3.11.2.
Days on Therapy
The mean number of days and percentage of days on systemic steroids will be presented 
for each treatment arm.  Data will be included in the summary regardless of the 
occurrence of events such as surgery or treatment discontinuation.
7.3.11.3.
Time to First Course of Systemic Steroids
A summary and graph of the Kaplan-Meier estimates of the cumulative proportion of 
participants with a first course of systemic steroids over time will be provided.
7.3.12.
Antibiotic Use
7.3.12.1.
Number of Courses of Therapy
A summary of the number of courses of antibiotics will be presented for each treatment 
arm.  Courses of antibiotics which are separated by less than 7 days will be considered a 
continuation of the same course.  Data will be included in the summary regardless of the 
occurrence of events such as surgery or treatment discontinuation.
7.3.13.
Time to first nasal surgery or course of systemic steroids
The time to first nasal surgery or course of systemic steroids will be determined as the 
number of days from the date of first dose of study medication to the date of first nasal 
surgery or course of systemic steroids (see Section 14.6.5). If a participant withdraws 
from the study before experiencing nasal surgery or course of systemic steroids, the event 
time will be censored at the time of study withdrawal.
7.3.13.1.
Summary Measure
The summary measure of treatment effect will be the hazard ratio, the ratio of hazards 
corresponding to treatment with mepolizumab compared with placebo.  For this endpoint 
the hazard represents the probability of nasal surgery or course of systemic steroids for a 
participant at a given point in time following first dose of interventional product, given 
the participant has not experienced either event prior to that time.
7.3.13.2.
Population of Interest
The primary population of interest is the ITT population.
7.3.13.3.
Strategy for Intercurrent (Post-Randomisation) Events
A treatment policy strategy will be used for the intercurrent event of premature 
discontinuation of interventional product, such that available event times will be included 
in the analysis regardless of whether the event occurred prior to discontinuation of 
randomised treatment.
 
 
 
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7.3.13.4.
Statistical Analyses / Methods
Endpoint / Variables
Time to first nasal surgery or course of systemic steroids
Model Specification

Cox proportional hazards model with covariates as follows:
Fixed Categorical: 
Treatment group, Region
Fixed Continuous: 
Baseline total nasal polyps endoscopic score (centrally read data), 
Baseline nasal obstruction VAS, Loge baseline blood eosinophil 
count, Number of previous surgeries (1, 2, >2; ordinal)

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

A log(-log(survival)) plot by treatment group will be used to assess the assumption of 
proportional hazards.
Model Results Presentation

The number of participants with an event, the number censored due to study withdrawal and at 
study completion will be presented by treatment arm.

The hazard ratio with corresponding 95% CI and p-value from the Cox proportional hazards 
model will be presented.

A summary and graph of the Kaplan-Meier estimate of the cumulative proportion of participants 
with nasal surgery within each treatment arm over time will be produced.
Subgroup Analyses

No subgroup analyses are planned for this endpoint.
Sensitivity and Supportive Analyses

No sensitivity/supportive analyses are planned for this endpoint.
7.4.
Participants with Asthma
A subgroup analysis by concurrent asthma will be carried out for each of the following 
endpoints: 

Total endoscopic nasal polyps score (Centrally Read)

Nasal obstruction VAS score

Total Prednisolone-equivalent OCS Use (mgs per year)
In addition, for participants with asthma the Asthma Control Questionnaire (ACQ-5) 
score and number of clinically significant asthma exacerbations will be summarised.
 
 
 
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7.5.
Maintenance of response
The following endpoints will be summarised for the subset of participants who entered 
the no-treatment 6-month follow up period after Week 52.  All data reported by these 
participants for the duration of their time in the study will be included in these 
summaries, this will include data reported prior to entering the follow-up period (whether 
or not the subject had prematurely discontinued from interventional product during that 
time) and data reported after entering the follow-up period.

Change from baseline in total endoscopic NP score (centrally read)

Change from baseline in mean nasal obstruction VAS score 

Change from baseline in mean individual VAS symptom score for nasal 
discharge, mucus in throat, loss of smell and facial

Change from baseline in mean overall VAS symptom score

Number of mgs per year of prednisolone-equivalent OCS dose

Change from baseline in SNOT-22 total score

Time to first nasal surgery

Time to first inclusion on waiting list for NP surgery
8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population.  Unless otherwise specified 
data reported as part of the no-treatment follow-up will not be included in summaries of 
on-treatment data or post-treatment data.  Data reported during the no-treatment follow-
up will be summarised separately.
Summaries of adverse events (AEs), serious adverse events (SAEs) and other significant 
AEs will be based on GSK Core Data Standards. The details of the planned displays are 
provided in Appendix 12: List of Data Displays.
8.1.
Adverse Events Analyses
8.2.
Adverse Events of Special Interest Analyses
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 via targeted eCRF 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.  Local injection site reactions are also collected via targeted 
eCRF 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 
 
 
 
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based on the MedDRA dictionary available at the time of source data lock for this study. 
Further details of how relevant preferred terms are identified for the AESIs are given in 
the Program Safety Analysis Plan (PSAP).
Separate summary tables showing the number and percent of participants with each type 
of AESI, broken down by preferred term will be created.  These summaries will be 
reported as part of the standard AE/SAE tables for the AESIs of infections, serious 
infections, neoplasms, cardiac disorders and serious cardiac disorders.  The relative risk 
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, summaries by maximum severity and separately by outcome. 
Separate listings will be provided of participants with systemic reactions identified by the 
investigator as meeting the criteria for anaphylaxis, systemic reactions categorised as 
allergic (type I hypersensitivity), systemic reactions categorised as other, and all other 
AESIs.
8.3.
Clinical Laboratory Analyses
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.
A scatter plot of maximum post-baseline ALT vs maximum post-baseline total bilirubin 
will be produced. In addition, if any liver stopping or liver monitoring events occur 
during the study, summaries of liver monitoring/stopping event reporting and 
hepatobiliary laboratory abnormalities will be produced.
The details of the planned displays are in Appendix 12: List of Data Displays.
8.4.
Other Safety Analyses
8.4.1.
ECG and Vital Signs
Summaries of ECG and vital signs data will be based on GSK Core Data Standards. The 
details of the planned displays are presented in Appendix 12: List of Data Displays.
For ECG data, summaries of the maximum post-baseline and change from baseline 
values for QTc(F), QTc(B) and heart rate will be provided.
Individual maximum and maximum change from baseline QTc(F) and QTc(B) values 
will be categorised as detailed in Section 14.6.6.  The number (percent) of participants in 
each of the categories will be displayed.
 
 
 
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The number of abnormal and clinically significant ECG results post baseline will be 
produced showing the worst recorded value post baseline.
8.4.2.
Immunogenicity Data
An immune response to a therapeutic drug can lead to generation of anti-drug antibodies 
within the blood. For the immunogenicity assessment, two types of antibody assays will 
be performed, a binding anti-drug antibody (ADA) assay and a neutralizing antibody 
(NAb) assay.
For the binding ADA assay, there will be three testing steps: screening, confirmation and 
titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point. 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 subjects in the safety population 
(excluding data reported during the follow-up period after Week 52), as well as for the 
subjects entering the follow-up period after Week 52 (using all data). 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.
The highest binding ADA assay confirmatory result obtained for a participant (including 
any off-treatment data), will be summarised with a positive result being considered 
higher than a negative one, participants with both positive and negative results being 
identified in the positive category.  Summary statistics for titre results will also be 
presented. In addition, the highest NAb assay result during the same period will be 
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 interventional product will also be presented.
All immunogenicity results (i.e. binding ADA screening and confirmatory assay results, 
titre values, NAb results and observed mepolizumab concentration) will be listed.
 
 
 
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9.
PHARMACODYNAMIC ANALYSES
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
9.1.
Pharmacodynamic Analyses
The treatment effect to be estimated (estimand) will be the comparison of mepolizumab 
100mg SC to placebo for change from baseline blood eosinophils at Week 52.
9.1.1.
Endpoint / Variables
Absolute and ratio to baseline blood eosinophil counts will be summarised at each visit.
9.1.2.
Summary Measure
The summary measure of treatment effect will be the ratio of the effect at Week 52 of 
mepolizumab compared to placebo.
9.1.3.
Population of Interest
The population of interest is the Intent to Treat population.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Only data collected while the participant was on-treatment will be used in the analysis
(‘while on-treatment strategy).  Blood eosinophil counts taken more than 28 days 
following last dose will not be included in the analysis.  
Missing data will be assumed to be missing at random.
9.1.5.
Statistical Analyses / Methods
9.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Ratio to baseline blood eosinophils
Model Specification

Blood eosinophil counts will be log transformed (loge) prior to analysis, transformations for 
values of 0 GI/L will be based on a value of 0.005 GI/L (see Section 14.6.6).

This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including the following terms:
Fixed Categorical: 
Treatment group, Region, Visit
Fixed Continuous: 
Baseline loge blood eosinophil count, 
Repeated: 
Visit
Interaction Terms: 
Visit by baseline, visit by treatment group.

Participants with missing covariate information will be excluded from the analysis
 
 
 
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
An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line
Model Checking & Diagnostics
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.
Model Results Presentation

The estimated means for each treatment group will be calculated from the model using the 
observed marginal distributions of the sample covariates (OM option in LSMEANS statement).

Model-estimates of the absolute mean and mean ratio to baseline will be back-transformed 
and presented as ratios with corresponding standard errors on the log scale for each treatment 
group by visit.  Estimated treatment differences (Mepolizumab/Placebo) with corresponding 
95% CIs and p-values will also be presented.
Subgroup Analyses

No subgroup analyses are planned for this endpoint
Sensitivity and Supportive Analyses

No sensitivity analyses are planned for this endpoint
10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
The primary goal of this analysis is to characterize the population pharmacokinetics of 
mepolizumab administered subcutaneously in participants with severe nasal polyps.  The 
influence of subject demographics, baseline characteristics, including disease activity, 
and co-medication on the pharmacokinetics of mepolizumab in this population will be 
investigated.  The individual subject PK parameters will be estimated and documented 
for the purposes of any subsequent exposure-response (PK/PD) analyses.
In support of the analysis described below, a dataset will be generated for which 
specifications will be provided in a separate document.
The details of the planned displays are provided in Appendix 12: List of Data Displays
and will be based on GSK Data Standards and statistical principles.  Refer to Data 
Display Standards & Handling Conventions (Section 14.5.3 Reporting Standards for 
Pharmacokinetic Data).
10.1.
Primary Pharmacokinetic Analyses
A population PK analysis of sparse concentration data will be performed on the PK 
population.
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis.
 
 
 
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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.
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.
10.2.
Population Pharmacokinetic Methodology
Sparse blood sampling is implemented in this study for determination of mepolizumab 
plasma concentration and subsequent data analysis by population PK methods using the 
most recent population pharmacokinetics model (meta-analysis PK model of data across 
indications described in GlaxoSmithKline Document Number 2015N238436_00). Since 
mepolizumab PK following intravenous administration in NP subjects has already been
established, the main objectives of this population PK analysis are:

To evaluate mepolizumab pharmacokinetics in subjects with NP following the 
subcutaneous administration of a 100 mg dose every 4 weeks.

To investigate the impact of covariates of interest in the studied NP 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.
Further details are provided in Appendix 9: Population Pharmacokinetic (PopPK) 
Analyses.
10.3.
Exploratory Pharmacokinetic Analyses
Complementing the population-PK analysis, a repeated measures linear mixed-effects 
model of loge-transformed concentration will be used to analyse the sparse (Weeks 4, 52 
and 68) data. All data will be analysed on an ITT basis using planned Visit, irrespective 
of withdrawal. The model will adjust for Region and Visit number and consider the 
covariates listed above. 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.
10.3.1.
Summary Measure
Log-transformed mepolizumab plasma concentration.
10.3.2.
Population of Interest
The population of interest is the PK population.
 
 
 
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10.3.3.
Statistical Analyses / Methods
Endpoint / Variables

Plasma concentration
Model Specification

Plasma concentration will be log transformed (loge) prior to analysis, values BQL will be set to 
missing.

This endpoint will be analyzed using a mixed model repeated measures (MMRM) analysis 
including the following terms:
Fixed Categorical: 
Region, Visit
Fixed Continuous: 
loge bodyweight, loge creatinine clearance, loge serum albumin
Repeated: 
Visit
Interaction Terms: 
None

Participants with missing covariate information will be excluded from the analysis

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line
Model Checking & Diagnostics
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.
Model Results Presentation

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.

Effects of bodyweight, creatinine clearance and serum albumin will be evaluated as 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.
Subgroup Analyses

No subgroup analyses are planned for this endpoint
Sensitivity and Supportive Analyses

No sensitivity analyses are planned for this endpoint
 
 
 
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11.
POPULATION PHARMACOKINETIC/
PHARMACODYNAMIC (POPPKPD) ANALYSES
In support of the analysis described below, a specific dataset will be generated for which 
specifications will be provided in a separate document.
The details of the planned displays are presented in Appendix 12: List of Data Displays.
11.1.
Population Pharmacokinetic/Pharmacodynamic 
Methodology
If deemed appropriate, a population pharmacokinetic/pharmacodynamic analysis will be 
conducted on the PK population and the ITT population (for blood eosinophils).
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the 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 prior to log transformation (consistent with 
approaches used in other analyses).
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.
Blood eosinophil counts were measured during the course of the study over the 52 weeks 
treatment period and will be analysed by population methods using the most recent 
population PKPD model (meta-analysis PKPD model of data across indications described 
in GlaxoSmithKline Document Number 2015N238436_00).
The objectives of the population PKPD analysis are:

To evaluate mepolizumab pharmacodynamics in subjects with NP following 
subcutaneous administration of a 100 mg dose every 4 weeks;

To investigate the impact of covariates of interest in the studied NP 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.
Further details are provided in Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses.
 
 
 
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12.
EXPLORATORY EXPOSURE-EFFICACY RESPONSE 
ANALYSIS
If deemed appropriate an exposure-efficacy response analysis for the change from 
baseline in total endoscopic NP score and change from baseline in mean nasal obstruction 
VAS score during the 52-week study treatment period and subsequent washout period to 
Week 60 will be conducted.
12.1.
Population of Interest
The exploratory exposure-efficacy response analysis will be performed on the ITT 
population.
12.2.
Endpoints
Three measures of exposure will be considered for this analysis:
i)
Dose/bodyweight (Week 52 endpoints only)
ii) C52 = week 52 mepolizumab trough concentration (Week 52 endpoints only)
iii) Predicted individual concentration during the treatment and washout phase (all 
observations)
Summary exposures (i) and (ii) will be categorised by quartiles for categorical analysis.
12.3.
Methodology
12.3.1.
Statistical analysis using exposure quartiles
12.3.1.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in total endoscopic NP score (based on centrally read data) at Week 52 
and other defined visits, categorized for analysis as in Section 7.1.5.1.

Change from baseline in mean nasal obstruction VAS score during the 4 weeks prior to Week 
52, and other defined 4-week periods, categorized for analysis as in Section 7.1.5.1.
Model Specification

Each co-primary endpoint will be analyzed using ordinal logistic regression to compare the 
odds between treatment exposure quartiles to placebo of being in a more favorable endpoint 
category.

Odds ratios will be estimated from the ordinal logistic regression model using the observed 
marginal distribution of the sample covariates.

The analysis model will include the following terms:
Fixed Categorical: 
Region
 
 
 
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Fixed Continuous: 
Treatment (placebo and exposure quartiles), Baseline score, Loge
baseline blood eosinophil count

Participants with missing covariate information will be excluded from the analysis
Model Checking & Diagnostics

Models will be checked for issues with convergence.
Model Results Presentation

The number and percentage of patients in each quartile will be displayed, as will the estimated 
odds ratio and 95% CI comparing quartiles from the ordinal logistic regression model.

A forest plot of the estimated odds ratio and 95% CI for the comparison of quartiles will be 
provided.
Subgroup Analyses

No subgroup analyses are planned for this endpoint
Sensitivity and Supportive Analyses

No subgroup analyses are planned for this endpoint
 
 
 
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13.
REFERENCES
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
Jackson D., White, I.R., Seaman, S., Evans, H., Baisley, K., Carpenter, J. Relaxing the 
independent censoring assumption in the Cox proportional hazards model using multiple 
imputation. Statistics in Medicine. 2014;33:4681-4694. 
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. 
Keene O.N. Strategies for composite estimands in confirmatory clinical trials: Examples 
from trials in nasal polyps and steroid reduction. Pharmaceutical Statistics. 2018;18:78-
84. 
McCullagh P. Regression models for ordinal data. Journal of the Royal Statistical 
Society, Series B. 1980;43:109-142. Relevant CDISC documentation available on 
www.cdisk.org
 
 
 
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14.
APPENDICES
14.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
14.1.1.
Exclusions from Per Protocol Population
Participants with protocol deviations considered to potentially effect efficacy will be 
excluded from the Per Protocol (PP) population.  Determination of exclusion of a 
participant from the Per Protocol population will be made, where possible, before the 
database is frozen.
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Informed consent never signed
02
Does not meet at least one of the following inclusion criteria (as numbered in the protocol):
1. 18 years of age and older inclusive, at the time of signing the informed consent.
4. Participants who have had at least one previous surgery in the previous 10 years for the 
removal of NP.
5. Participants with bilateral NP as diagnosed by endoscopy or historical CT scan.
6. Presence of at least two different symptoms for at least 12 weeks prior to screening: 
nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip) and 
at least one of the following: nasal discharge (anterior/posterior nasal drip); facial 
pain/pressure; reduction or loss of smell.
7. Participants with severe NP symptoms defined as an obstruction VAS symptom score of 
>5.
8. Severity consistent with a need for surgery as described by:
a) Participants with an overall VAS symptom score >7
b) Participants with an 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)
9. Treatment with INCS (including intranasal liquid steroid wash/douching) for at least 8 
weeks prior to screening.
10. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
03
Meets any of the following exclusion criteria (as numbered in the protocol)
1. As a result of medical interview, physical examination, or screening investigation the 
physician responsible considers the participant unfit for the study.
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. Nasal septal deviation occluding one nostril.
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.
 
 
 
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Number
Exclusion Description
9. Participants who have undergone any intranasal and/or sinus surgery (for example 
polypectomy, balloon dilatation or nasal stent insertion) within 6 months prior V1.
12. Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 
1.
13. Participants who are currently receiving or have received within 3 months (or 5 half-lives 
– whatever is the longest) prior to screening visit, 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 another monoclonal antibody 
therapy.
17. Participants that have taken part in previous mepolizumab, reslizumab, dupilumab or 
benralizumab studies.
18. Use of systemic corticosteroids (including oral corticosteroids) within 4 weeks prior to 
screening or planned use of such medications during the double-blind period.
19. INCS dose changes within 1 month prior to screening.
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 leukotriene antagonist treatment less than 30 
days prior to Visit 1.
23. Commencement or change of dose of allergen immunotherapy within the previous 3 
months.
28. Immunocompromised, other than that explained by the use of corticosteroids taken as 
therapy.
04
Does not meet any of the following randomisation criteria (as numbered in the protocol):
1. Endoscopic NP score of at least 3 in one nostril and 2 in the other as per over read from 
central lab taken at Visit 1.
2. Mean overall VAS >7 over the last 7 days preceding Visit 2 (excluding Visit 2) (from 
eDiary).
3. Mean nasal obstruction VAS score >5 over the last 7 days preceding Visit 2 (excluding 
Visit 2) (from eDiary).
4. Not had any NP surgery or have been included into a waiting list for NP surgery between 
Visit 1 and Visit 2.
5. eDiary compliance for VAS (4 out of the last 7 days preceding Visit 2).
8. Asthma Exacerbation: No asthma exacerbations during run-in period. An exacerbation is 
defined as worsening of asthma requiring the use of systemic corticosteroids (i.v. or oral 
steroid) for at least 3 days or a single IM CS dose and/or emergency department visit, or 
hospitalization.
9. Maintenance Therapy: No changes or commencement during the run-in period in the 
dose or regimen of any regular baseline medication including a) INCS, b) course of systemic 
corticosteroids, such as OCS, c) leukotriene receptor antagonists, d) allergen 
immunotherapy.
10. If the participant has a cold during run in then run in should be extended so to have the 
baseline visit, 2 weeks post the resolution of the cold but no greater than a total of 6 weeks 
from screening. Colds that are not resolved within the 4th week of the nominal run-in period 
(28 days after screening) will be ineligible for randomization as they would have exceed this 
 
 
 
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Number
Exclusion Description
6 week period.
05
Use of any prohibited medication during the study [1]
06
Received the wrong study treatment at any point during the study
07
Two or more of the following deviations related to wrong study 
treatment/administration/dose:
•
Study treatment not administered per protocol
•
Study treatment administered while contraindication
•
Expired study treatment administered
•
Use of study treatment impacted by a temperature excursion which was not 
reported or approved, or which was disapproved for further use
•
Study treatment not available at site for administration
•
Missed dose
•
Other deviations related to wrong study treatment/administration/dose
08
Patient/Investigator unblinded
NOTES:
[1] See Section 7.6 of protocol for a list of prohibited medications
 
 
 
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14.2.
Appendix 2: Schedule of Activities
14.2.1.
Protocol Defined Schedule of Events
 
 
 
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14.3.
Appendix 3: Assessment Windows
14.3.1.
Visit Based Assessments
No assessment windows are defined for visit based assessments. Clinic visits are 
scheduled to take place as specified in Appendix 2: Schedule of Activities and are subject 
to a 7-day window, however assessments performed outside of these visit windows will 
still be included in any analyses. Nominal visits will be used for reporting and analysis.
14.3.2.
Unscheduled Visits
Data recorded at an unscheduled visit will be re-assigned to the closest nominal visit at 
which collection of the data was scheduled, unless information already exists at that visit. 
If an unscheduled visit occurs between two scheduled visits for which data has been 
reported, the data will remain in the unscheduled visit and will not be included in any by 
visit summary tables; it will however be included in relevant summaries of any time post-
baseline data and listings.
14.3.3.
Data from eDiary
The overall severity of nasal polyposis and of individual symptoms of nasal polyposis 
will be collected daily on a visual analogue scale using an eDiary.  For the purposes of 
analysis, data from the eDiary will be slotted as shown in Table 2.
Table 2
Definition of Baseline and Week 52 Periods for eDiary Data
Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Baseline
Date of First Dose - 7
Date of First Dose -1
Weeks 1-4
Later of: 
Date of Visit 3 (Week 4) – 28
Date of First Dose + 1
Date of Visit 3 (Week 4) - 1
Weeks 5-8
Later of: 
Date of Visit 4 (Week 8) – 28
Date of Visit 3 (Week 4) 
Date of Visit 4 (Week 8) - 1
Weeks 9-12
Later of: 
Date of Visit 5 (Week 12) – 28
Date of Visit 4 (Week 8)
Date of Visit 5 (Week 12) -1
Weeks 13-16
Later of: 
Date of Visit 6 (Week 16) – 28
Date of Visit 5 (Week 12)
Date of Visit 6 (Week 16) -1
Weeks 17-20
Later of: 
Date of Visit 7 (Week 20) – 28
Date of Visit 6 (Week 16)
Date of Visit 7 (Week 20) - 1
Weeks 21-24
Later of: 
Date of Visit 8 (Week 24) – 28
Date of Visit 7 (Week 20)
Date of Visit 8 (Week 24) - 1
Weeks 25-28
Later of: 
Date of Visit 9 (Week 28) - 1
 
 
 
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Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Date of Visit 9 (Week 28) – 28
Date of Visit 8 (Week 24)
Weeks 29-32
Later of: 
Date of Visit 10 (Week 32) – 28
Date of Visit 9 (Week 28)
Date of Visit 10 (Week 32) - 1
Weeks 33-36
Later of: 
Date of Visit 11 (Week 36) – 28
Date of Visit 10 (Week 32)
Date of Visit 11 (Week 36) - 1
Weeks 37-40
Later of: 
Date of Visit 12 (Week 40) – 28
Date of Visit 11 (Week 36)
Date of Visit 12 (Week 40) - 1
Weeks 41-44
Later of: 
Date of Visit 13 (Week 44) – 28
Date of Visit 12 (Week 40)
Date of Visit 13 (Week 44) - 1
Weeks 45-48
Later of: 
Date of Visit 14 (Week 48) – 28
Date of Visit 13 (Week 44)
Date of Visit 14 (Week 48) - 1
Weeks 49-52
(Primary timepoint for 
analysis)
Later of: 
Date of Visit 15 (Week 52) – 28
Date of Visit 14 (Week 48)
Date of Visit 15 (Week 52) - 1
Weeks 53-56
Later of: 
Date of Visit 16 (Week 60) – 56
Date of Visit 15 (Week 52)
Date of Visit 16 (Week 60) - 29
Weeks 57-60
Date of Visit 16 (Week 60) - 28
Date of Visit 16 (Week 60) - 1
Weeks 61-64
Later of: 
Date of Visit 17 (Week 68) – 56
Date of Visit 16 (Week 60)
Date of Visit 17 (Week 68) - 29
Weeks 65-68
Date of Visit 17 (Week 68) - 28
Date of Visit 17 (Week 68) - 1
Weeks 69-72
Later of: 
Date of Visit 18 (Week 76) – 56
Date of Visit 17 (Week 68)
Date of Visit 18 (Week 76) - 29
Weeks 73-76
Date of Visit 18 (Week 76) - 28
Date of Visit 18 (Week 76) - 1
NOTES:

Data collected on Day 1 (Date of first dose) will not be used in analysis/summaries

Analysis periods will be up to a maximum of 28 days

Where a missing visit date prevents the start or end of a period from being determined, an imputed date (Date of 
First Dose + Week of Visit with missing date x 7) will be used.
14.3.4.
Premature Withdrawals from Interventional Product or Study
Any data reported at the early withdrawal visit will be re-assigned to the closest available 
scheduled visit, unless information already exists at that visit.  Data reported at the early 
withdrawal visit which has been re-assigned to a scheduled visit will be included in 
analyses, summary tables and figures by scheduled visit.  Data reported at the early 
 
 
 
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withdrawal visit will be included in the assessment of maximum or worst-case post-
baseline summaries for any relevant endpoints, and all data will be included in listings.
14.4.
Appendix 4: Study Phases
14.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of interventional product.
14.4.1.1.
Phases for Efficacy Assessments
Study Phase
Definition
Pre-Treatment 
Assessment Date Interventional Product Start Date
On-Treatment
Participants who did not withdraw early from Interventional Product:
Interventional Product Start Date < Assessment Date ≤ Earlier of Week 52 Visit 
Date/Day 372[1]
Participants who withdrew early from Interventional Product:
Interventional Product Start Date < Assessment Date ≤ Earlier of Interventional 
Product Stop Date +28 days/Date of Phase Conclusion
Off-Treatment
Participants who did not withdraw early from Interventional Product:
Day 372 < Assessment Date Week 52 Visit Date
Participants who withdrew early from Interventional Product:
Interventional Product Stop Date + 28 days < Assessment Date Date of Phase 
Conclusion
Off-Treatment
(Follow-up after 
Week 52)
Participants who enter the follow-up period after Week 52:
Week 52 Visit Date < Assessment Date 
[1] Allowing for the ±7-day window in the protocol; Day 372 is defined as 371 days (364+7 days) after the first dose of 
interventional product
14.4.1.2.
Phases for Safety Assessments
Study Phase
Definition
Pre-Treatment 
Assessment Date Interventional Product Start Date
On-Treatment
Interventional Product Start Date < Assessment Date ≤ Interventional Product Stop 
Date +28 days
Post -Treatment
Participants who do not enter the follow-up period after Week 52:
Interventional Product Stop Date + 28 days < Assessment Date
Participants who enter the follow-up period after Week 52:
Interventional Product Stop Date + 28 days < Assessment Date ≤Week 52 Visit Date
Post -Treatment
(Follow-up after 
Week 52)
Participants who enter the follow-up period after Week 52:
Week 52 Visit Date < Assessment Date
 
 
 
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14.4.1.3.
Phases for Adverse Events
Study Phase
Definition
Pre-Treatment 
Event Start Date < Interventional Product Start Date
On-Treatment
Interventional Product Start Date Event Start Date Interventional Product Stop 
Date + 28 days
Post -Treatment
Participants who do not enter the follow-up period after Week 52:
Event Start Date > Interventional Product Stop Date + 28 days
Participants who enter the follow-up period after Week 52:
Interventional Product Stop Date + 28 days < Event Date ≤Week 52 Visit Date
Post -Treatment
(Follow-up after 
Week 52)
Participants who enter the follow-up period after Week 52:
Week 52 Visit Date < Event Date
NOTES: An event will be considered On-treatment if the event start date is missing and/or the interventional product
stop date is missing
Where time of event is recorded, the time of event and time of first dose will be considered to differentiate between 
Pre-treatment and On-treatment events.
14.4.1.4.
Phases for Concomitant Medication Start Dates
Study Phase
Definition
Pre-Treatment 
(Started prior to 
treatment)
Concomitant medication (CM) start date < IP start date
On-Treatment
(Started during
Treatment)
If CM start date is on/after IP start date & on/before IP stop date +28 days.
(IP Start Date ≤ CM Start Date ≤ IP Stop Date + 28 days)
Post-Treatment
(Started post-
treatment)
If CM start date is after the IP stop date + 28 days.
(CM Start Date > IP Stop Date + 28 days)
Follow-Up After 
Week 52 (started 
during the Follow-
up period after 
Week 52)
Participants who enter the follow-up period after Week 52:
If CM start date is after the Week 52 Visit date.
NOTES: If the IP stop date is missing and/or the CM start date is missing then the CM is considered to have started 
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14.4.1.5.
Phases for Concomitant Medication Usage Dates
Study Phase
Definition
Taken Prior to 
Treatment
If CM start date < IP Start Date
Taken During 
Treatment
If CM start date < IP start date and CM stop date ≥ IP start date
If IP start date < CM start Date < IP Stop Date + 28 days
Taken Post-
Treatment
If CM start date < IP stop date+28 days and CM stop date ≥ IP stop date +28 days
If CM start Date > IP stop date + 28 days
NOTES: If the IP stop date is missing and CM start date is on/after IP start date then CM considered taken during 
treatment
If CM start date is missing, then CM considered to be taken during treatment
 
 
 
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14.5.
Appendix 5: Data Display Standards & Handling 
Conventions
14.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
HARP Compound
Analysis Datasets 

Analysis datasets will be created according to CDISC standards [SDTM IG Version 3.2 & ADaM IG 
Version 1.0].

Analysis datasets will include variables to clearly indicate whether each observation was observed 
while the patient was on randomized treatment, observed after the patient discontinued randomized 
treatment, or was imputed or is missing.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
14.5.2.
Reporting Standards
General

All data displays (Tables, Figures & Listings) will use the term “Subject” rather than “Participant” which 
reflects CDISC and GSK Data Display Standards terminology.

Templates and standards within the current GSK Integrated Data Standards Library (IDSL) will be used
for reporting unless otherwise stated.
IDSL standards located at https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx (under supporting 
documentation/component/statistical displays) will be applied: 

4.03 to 4.24: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles for the precision to which data and summary statistics are to be 
presented will in general be adopted, these may be adjusted to a clinically interpretable number of 
decimal places (d.p.).

For Blood Eosinophil Counts displayed as GI/L the following will be applied:
Geometric Mean, Median, Min and Max (2 d.p.); SD Logs (3 d.p.)
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for data listings: 

Planned and actual time relative to study drug dosing will be shown in listings.

Unscheduled or unplanned readings will be presented within the subject’s listings.
 
 
 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures, however they will be included 
in listings.

Data from unscheduled visits may be included in summary tables/figures when the unscheduled visit 
has been reassigned (Section 14.3.2). 

Data from unscheduled visits will be included in any-time post-baseline summaries
Early Withdrawal from Interventional Product or from Study

Data recorded at the early withdrawal visit will be re-assigned to the next scheduled visit, 
unless information already exists at that visit. Early withdrawal data re-assigned to a 
scheduled visit will be included in analyses, summary tables and figures by scheduled visit. 
Early withdrawal visit data that is not re-assigned to a scheduled visit will not be included in 
analyses, summary tables or figures by scheduled visit.

Data recorded at early withdrawal visits will be included in the assessment of maximum or 
worst-case post-baseline for relevant endpoints.

Data from all early withdrawal visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
n, mean, standard deviation or standard error, median, minimum, maximum 
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals for Graphics 
14.5.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: BLQ concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics only.
NONMEM/Pop PK 
File
Pop-PK file (CSV and SAS format) for the POP-PK and POP-PKPD analyses 
performed by the Clinical Pharmacology Modelling and Simulation function will be 
created according to the POP-PKPD Dataset Specification document. 
Pharmacokinetic Parameter Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
 
 
 
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14.6.
Appendix 6: Derived and Transformed Data
14.6.1.
General
Multiple Measurements at One Analysis Time Point

Unless otherwise specified, if there are multiple measurements reported under the same nominal visit, 
the value of the first assessment will be used in any derivation of summary statistics, all individual 
measurements will be presented in any data listings.

Participants with post-baseline safety data in both High and Low categories with respect to the Normal 
Range/Potential Clinical Concern will be counted in each of the categories for the “Any visit post-
baseline” row of any related summary tables.
Study Day

Calculated as the number of days from the first dose of study medication (IP start date).

If Visit Date = Missing             → Study Day = Missing 

If Visit Date < First Dose Date → Study Day = Visit Date – IP Start Date

If Visit Date ≥ First Dose Date → Study Day = Visit Date – (IP Start Date) + 1    
14.6.2.
Analysis Population
Actual Treatment for Safety Population

Analysis of safety data will be by actual treatment arm.

For participants identified as having any discrepancies between the treatment group they were 
randomised to and the treatment received, the actual treatment arm will be derived based on the 
treatment received for more than 50% of all treatment administrations.  For all other participants, actual 
treatment arm will be the same as the randomised treatment arm.
14.6.3.
Study Population
Demographics
Age

Year of birth is collected as ‘YYYY’ and will be presented as collected in listings

Date of birth will be imputed as ‘30th June YYY’

Age is calculated according to GSK standard IDSL algorithms and is based on the imputed 
date of birth relative to the date of Visit 1 (Screening).
BMI

BMI will be calculated as Weight (kg) / [Height (m)]2
Exposure
Extent of Exposure (Therapeutic Coverage)

IP is administered 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:
o
Duration of Exposure (days) = (IP Stop Date – IP Start Date + 29)
o
Duration of Exposure (months) = (IP Stop Date – IP Start Date + 29) * 12/365.25
 
 
 
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Exposure
Extent of Exposure (Therapeutic Coverage)

Subject Years Exposure is calculated as follows; 
o
Subject Years Exposure = (IP Stop Date – IP Start Date + 29)/365.25

If the IP start date is missing and there is evidence the participant received at least one dose of IP, the 
IP start date will be taken to be the date of randomisation, if the IP end date is missing it will be taken to 
be the last on-treatment visit attended.

Randomised participants with no evidence of receiving at least one dose of IP will be considered as 
having zero days of exposure.
Exposure for treatment period and no-treatment follow-up
Number of years on and off-treatment or missing

All participants are expected to participate in the study for at least 52 weeks (±7 days)

The number of years on-treatment will be calculated as follows: 
o
(IP Stop Date – IP Start Date + 29)/365.25

The number of years off-treatment will be calculated as follows: 
o
Date of Phase Conclusion – (IP stop date +29)/365.25

The number of years missing will be calculated as follows: 
o
371/365.25 – (number of years on-treatment) – (number of years off-treatment)
Duration of time in no-treatment follow-up

This will be calculated in months as follows:
o
(Date of study end – Date of entering no-treatment follow up)/30.5
Concomitant Medications (CM)
Time since first dose (days) 

The time since first dose will be calculated as follows: 
If CM start date < IP start date = CM start date - IP start date
If CM start date ≥ IP start date = CM start date – IP Start Date +1
Missing otherwise.

The duration in days will be calculated as follows: 
CM end date – CM start date + 1
NOTES: Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates 
Subgroups
Participants With Asthma

Concurrent asthma: Subjects with a response of ‘Current’ for the medical condition of ‘Asthma’.

No concurrent asthma: Subjects with a response of ‘Past’, ‘Not Assessed’ or ‘No Medical Condition’ for 
the medical condition of ‘Asthma’.  Subjects with a missing response will also be included in this 
category.
Aspirin Exacerbated Respiratory Disease (AERDS)

Current AERDS: Subjects with a response of ‘Current’ for the medical condition of ‘Drug Allergy’.
 
 
 
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Subgroups

No Current AERDS: Subjects with a response of ‘Past’, ’Not Assessed’ or ‘No Medical Condition’ for the 
medical condition of ‘Drug Allergy’.  Subjects with a missing response will also be included in this 
category.
Number of previous surgeries

Participants will be categorised as follows based on data collected on the eCRF regarding number of 
previous surgeries: 1, 2, >2
Baseline Blood Eosinophil Categories

Categories for baseline blood eosinophils will be:
o
≤0.3 GI/L; >0.3 to ≤0.5 GI/L; >0.5 to ≤0.7 GI/L; >0.7 GI/L

Blood eosinophils are reported in GI/L, each category is rounded to 1 d.p. which is equivalent to 
rounding blood eosinophils to the nearest 100 cells/µL.
Region

Europe: Participants from sites in Germany, Netherlands, Romania, Sweden, UK

United States: Participants from sites in US

Rest of World: Participants from sites in South Korea, Argentina, Australia, Canada, Russia
Age Categories

Participants will be categorised as follows based on the derived age:

18-<40 years, 40 - < 65 years, ≥65 years.
Race Categories

Subjects will be categorised by Race based on the Geographic Ancestry reported on the eCRF:
Race Category
Geographic Ancestry reported on the eCRF
African American/African Heritage
African American/African Heritage
White
White – Arabic/North African Heritage
White – White/Caucasian/European Heritage
Asian
Asian – Central/South Asian Heritage
Asian – East Asian Heritage
Asian – Japanese Heritage
Asian – South East Asian Heritage
Other
American Indian or Alaskan Native
Native Hawaiian or Other Pacific Islander
Multiple Race
 
 
 
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14.6.4.
Change from Baseline
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Ratio to Baseline [1]
= Post-Dose Visit Value / Baseline
NOTES: Refer to Section 5.2 for definition of Baseline. Unless otherwise stated, if Baseline or the Post-Dose value is 
missing the result will be set to missing.
[1] For loge transformed data Ratio to Baseline is the back transformed change from baseline value 
14.6.5.
Efficacy
Total Endoscopic Nasal Score
Change from baseline categories

Categories for the change from baseline total endoscopic nasal score (centrally read) are detailed in 
Section 7.1.5.1, the same categories will be used for the investigator read scores.
Responder

A responder will be defined as a participant with a ≥1-point improvement from baseline in total 
endoscopic nasal score (centrally read).

Participants with no improvement/worsening or with missing data will be considered a non-responder 
for analysis.
VAS scores (individual and composite)
Individual VAS Scores

VAS scores are captured electronically using an eDiary, participants indicate their response on a line 

The final VAS scores for inclusion in summary and analysis tables will be derived from the electronically 
captured score by 
.
Change from baseline categories

Categories for the change from baseline in individual, overall and composite VAS scores are detailed in 
Section 7.2.2.4.

The baseline scores will be calculated as the mean of the scores reported between the 7 days prior to 
the first dose.

The scores for each 4-week period will be calculated as the mean of the scores reported between 
timepoints detailed in Section 14.3.3.
Composite VAS scores

Two separate composite VAS scores will be derived using the final VAS scores:

Composite of nasal obstruction, nasal discharge, mucus in the throat and loss of smell
o

Composite of nasal obstruction, nasal discharge, mucus in the throat, loss of smell and facial pain
o
 
 
 
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Nasal Surgery (reported on the disease related events page of the eCRF)
Time to first nasal surgery

Calculated as (Date of first nasal surgery – Date of first dose of study treatment) + 1

Analysis excluding data from the follow-up period after Week 52: 
For participants who withdraw from the study before Week 52 and before experiencing surgery, event 
times will be censored at the time of study withdrawal
For participants who complete to Week 52 without experiencing surgery, event times will be censored
at the time of the Week 52 visit.

Analysis including data from the follow-up period after Week 52: 
For participants who withdraw from the follow-up period before completion and before experiencing 
surgery, event times will be censored at the time of study withdrawal.
For participants who complete the follow-up period without experiencing surgery, event times will be 
censored at time of completion of follow-up.
Need for surgery(responder)

Need for surgery at Week 52 is based on the overall VAS symptoms score and the endoscopic NP 
score (centrally read).  Participants will be classified as not having a need for surgery if they meet the 
following:
o
Overall VAS symptoms score >7 (Weeks 49-52) and total endoscopic NP score ≥5 (Week 52, 
centrally read)

Participants who have undergone nasal polyps surgery at any time prior to the week 52 visit, or who 
have a missing endoscopic NP score (centrally read) at Week 52, or missing overall VAS symptom 
score (Weeks 49-52) will be identified for analysis as still having a need for surgery.
Rate of surgery

The crude rate of surgery will be presented for each treatment arm, this will be calculated as: 
*365.25
Systemic steroid use
Conversion of glucocorticoid dose to mgs of prednisolone equivalent OCS use

The total number of mgs of prednisolone equivalent OCS use per year will be calculated as follows and 
will be based on systemic steroids taken via the following routes: Oral, Intravenous, Intramuscular: 
*365.25
 
 
 
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Systemic steroid use

The following table from the study reference manual will be used for conversion of intravenous and oral 
steroid use into prednisolone equivalent OCS use in mgs:
Glucocorticoid
Approximate equivalent dose (mg)
Short-Acting
Cortisone
25
Hydrocortisone
20
Intermediate-Acting
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Triamcinolone
4
Long- Acting
Betamethasone
0.6-0.75
Dexamethasone
0.75

Participants who withdraw early from the study will have yearly use estimated based on use during the 
study.
Milligrams of use per year

Categories of total mgs prednisolone equivalent OCS dose used per year are detailed in Section 
7.2.4.4.
Courses of Therapy

A course of systemic steroid therapy is defined by the start and stop date of therapy.

If the start date of a course of systemic steroid therapy occurs <7 days from the stop date of the 
previous course, it will be considered a continuation of the same course.
Days on Therapy

The duration of a course of systemic steroids will be calculated as the number of days between the start 
and stop date of the course: stop date – start date +1

For each participant the total number of days on systemic steroids will be calculated as the sum of the 
duration of each of their courses of therapy.

For each participant the percentage of days on systemic steroids will be calculated as follows:
*100
 
 
 
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Nasal Surgery or Course of Systemic Steroids
Time to first nasal surgery or course of systemic steroids

Calculated as (Date of first nasal surgery/course of systemic steroids – Date of first dose of study 
treatment) + 1

Analysis excluding data reported in the follow-up period after Week 52: 
For participants who withdraw from the study before Week 52 and before experiencing either event,
event times will be censored at the time of study withdrawal
For participants who complete to Week 52 without experiencing either event, event times will be 
censored at the time of the Week 52 visit
Antibiotic Use
Courses of Therapy

A course of antibiotics is defined by the start and stop date of therapy.

If the start date of a course of antibiotics occurs <7 days from the stop date of the previous course, it 
will be considered a continuation of the same course.
SNOT-22
SNOT-22 Total Score

Each question of the SNOT-22 is graded on 
 
 
[Hopkins, 2009].


If a participant does not complete any questions at a visit the total score for that visit will be 
missing.

If a participant has some (but no more than 50%) missing responses to questions at a visit, 
then the missing responses will be imputed with the unrounded mean of the non-missing 
responses at that visit. The SNOT-22 total score for that visit will then be rounded to the 
nearest integer.
Change from baseline categories

Categories for the change from baseline in SNOT-22 total score are detailed in Section 7.2.3.4.
SNOT-22 Responder

A responder is defined as having a ≥9-point improvement (decrease) from baseline in SNOT-
22 total score.
UPSIT
UPSIT total score

The total score is calculated as the number of times the correct smell is identified out of a possible 4 
choices, for 40 different smells.
Change from baseline categories

Categories for the change from baseline in UPSIT total score are detailed in Section 7.3.8.4.
ACQ-5
ACQ-5 Score

ACQ-5 is a 5-item questionnaire developed as a measure of patient’s asthma control.  Response 
 
 
 
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ACQ-5
options for each question are on 

The questions are equally weighted, and the ACQ-5 score is calculated as the mean of the 5 questions, 
.

For a given visit, if the response to one of the 5 questions is missing then the ACQ-5 score will be 
calculated as the mean of the available responses.  If the response to more than one question is 
missing, then the ACQ-5 score will be set to missing.
Asthma exacerbations
Clinically significant asthma exacerbation

A clinically significant asthma exacerbation is defined as a worsening of asthma requiring systemic 
steroids (i.v. or oral) for at least 3 days or a single intra-muscular corticosteroid dose, and/or an ED visit 
and/or hospitalisation.
14.6.6.
Safety
Adverse Events
Drug Related AE’s

AEs where the response to “Is there a reasonable possibility that the AE may have been caused by the 
Study Treatment?” is “Yes” or it is missing
AE’s Leading to Permanent Discontinuation of Study Treatment or Withdrawal from Study

AE’s leading to permanent discontinuation of study treatment are defined as AEs where the response to 
“Most Clinically Significant Action Taken with Study Treatment(s) as a Result of the AE” is “Study 
Treatment(s) Withdrawn”.

AEs leading to withdrawal from study are defined as AEs where the response to “Did the subject 
withdraw from study as a result of this AE?” is “Yes”.
AE’s on Day of Dosing

These are defined as AEs with an onset date on the same day as dosing with interventional product 
and an onset time on or after the time of dosing with interventional product on the given day.
AE Time Since First Dose

If AE onset time is missing, calculate in days as follows:
o
If AE start date < Date of first dose of Interventional Product, then 
Time since first dose = AE start date - Date of first dose of Interventional Product
o
If AE start date ≥ Date of first dose of Interventional Product, then 
Time since first dose = AE start date – Date of first dose of Interventional Product +1
o
If AE start date or date of first dose of Interventional Product is missing time since first dose is 
missing.

If AE onset time is present, calculate as above but in days, hours, minutes using AE start date/time and 
date/time of first dose of interventional product
AE Duration in Days

If AE onset time is missing calculate in days: AE end date - AE start date + 1

If AE onset time is present calculate in days, hours, minutes as above but using AE end date/time and 
AE start date/time.

If AE start/end date is missing duration is missing.
 
 
 
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Adverse Events
Drug Related AE’s

AEs where the response to “Is there a reasonable possibility that the AE may have been caused by the 
Study Treatment?” is “Yes” or it is missing
AE’s Leading to Permanent Discontinuation of Study Treatment or Withdrawal from Study

AE’s leading to permanent discontinuation of study treatment are defined as AEs where the response to 
“Most Clinically Significant Action Taken with Study Treatment(s) as a Result of the AE” is “Study 
Treatment(s) Withdrawn”.

AEs leading to withdrawal from study are defined as AEs where the response to “Did the subject 
withdraw from study as a result of this AE?” is “Yes”.
AE’s on Day of Dosing

These are defined as AEs with an onset date on the same day as dosing with interventional product 
and an onset time on or after the time of dosing with interventional product on the given day.
AE Time Since First Dose

If AE onset time is missing, calculate in days as follows:
o
If AE start date < Date of first dose of Interventional Product, then 
Time since first dose = AE start date - Date of first dose of Interventional Product
o
If AE start date ≥ Date of first dose of Interventional Product, then 
Time since first dose = AE start date – Date of first dose of Interventional Product +1
o
If AE start date or date of first dose of Interventional Product is missing time since first dose is 
missing.

If AE onset time is present, calculate as above but in days, hours, minutes using AE start date/time and 
date/time of first dose of interventional product
AE Duration in Days

If AE onset time is missing calculate in days: AE end date - AE start date + 1

If AE onset time is present calculate in days, hours, minutes as above but using AE end date/time and 
AE start date/time.

If AE start/end date is missing duration is missing.
AE’s of Special Interest

Section 8.2 provides a full list of AEs of special interest for this compound.

AESIs of anaphylaxis reactions, systemic reactions, and local injection site reactions are collected via 
targeted eCRF.

The AESIs of potential opportunistic infections, malignancies, serious CVT events and serious ischemic 
events will be identified from a list of relevant preferred terms maintained within a project level 
reference dataset; created based on the latest version of the MedDRA dictionary available at the time of 
database freeze for this study (See Program Safety Analysis Plan for additional details).
ECG
Multiple Assessments

Where multiple assessments are performed at a given time point, the mean value over the replicate 
assessments will be used for summary statistics; the highest value amongst the individual replicate 
assessments will be used in the evaluation of the highest post-baseline value.
QTc values

A single 12-lead ECG machine will be used to assess heart rate and measure PR, QRS, QT and QTc 
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
QTc(F) will be derived from QT (uncorrected) and RR interval as: 

QTc(B) will be derived from QT (uncorrected) and RR interval as: 

If present the reported QTc value will be included in any summaries, else the derived QTc value will be 
included.
Categorised QTc values
Individual maximum QTc(F) and QTc(B) values and maximum change from baseline QTc(F) and QTc(B) will 
be categorised as follows: 
Lower
Upper
QTc Interval (msec)
≤ 450
> 450
≤ 480
> 480
≤ 500
> 500
QTc Change from 
Baseline (msec)
≤ 30
> 30
≤60
> 60
Laboratory Parameters
Character Values

If a laboratory value which is expected to have a numeric value for summary purposes has a non-
detectable level reported in the database, where the numeric value is missing, but instead a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, a numeric value will be imputed; the number of significant digits in the observed value will be 
used to determine how much to add or subtract to impute the corresponding numeric value: 
o
Example 1: 2 Significant Digits = ‘< x ‘imputed as x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ imputed as x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ imputed as x –1

Laboratory values with missing values due to being below the limit of quantification (BLQ) for that 
parameter will have a value imputed as half the lower limit of quantification for that measure (i.e. the 
lowest observed value for that measure within the entire study database).

Values of potential clinical concern and those outside the ≥2, ≥3 etc. limit of normal will be identified as 
detailed in Section 14.8.
Blood Eosinophils

Blood eosinophil counts will be log transformed (loge) prior to analysis.  The log transformation for 
values of 0GI/L will be based on a value of 0.005GI/L.
Biomarkers

No analyses of additional biomarker will be carried out as part of this RAP.
 
 
 
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14.7.
Appendix 7: Reporting Standards for Missing Data
14.7.1.
Premature Withdrawals
Element
Reporting Detail
General

The protocol objective is to collect data over the full study treatment period (up to Week 
52) for all participants, whether they continue on interventional product (IP) and 
complete Week 52 on-treatment, or whether they withdraw prematurely from IP.  
o
For the participants who withdraw prematurely from IP before Week 52 and 
agree to the continued collection of data off-treatment, data will be collected 
for up to 52 weeks after randomization (or up to 76 weeks if the participant 
enters the Follow-up period after Week 52) either through clinic visits or via 
phone contact, in accordance with the participants existing visit schedule.
o
Where available, off-treatment data will be included in the analysis of the co-
primary endpoints and, unless otherwise indicated, in the analysis of other 
efficacy endpoints.  

A participant will be considered to have completed study treatment if he/she continues 
to take study treatment until Visit 14 (Week 48) and completes Visit 15 (week 52). 

As specified in the protocol participants will be considered to have completed the study 
upon completion of Visit 15 (Week 52) regardless of whether they continue to take IP.

A participant eligible for the no-treatment follow-up will be considered to have 
completed follow-up if they continue to participate in the study until Visit 18 (Week 76)

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
Pre-
Screen/Scre
en and Run-
in Failures

Participants are assigned a subject number at the time of signing informed consent.

Pre-Screen Failure: A participant who is assigned a subject number but did not 
continue through to Visit 1. 

Screening Failure: Participant performs a Visit 1 procedure, but does not enter the run-
in period

Run-in Failure: Participant enters the run-in period, may perform a Visit 2 procedure,
but is not subsequently randomised.
14.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated using a “blank” in data listings. Where all data for 
a specific visit are missing the visit will be excluded from the listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed.
Values reported as ‘BLQ’ are not considered as missing data and are handled as detailed in 
 
 
 
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Element
Reporting Detail
Section 14.6.6, these values will be displayed in the listings and included in any
summary/analysis outputs.
Outliers

All data will be included in the summaries and analyses of each endpoint.  The 
exclusion of participants or participant data from any supplementary analyses will be 
documented within footnotes and where required the clinical study.report.
Covariate 
information

Participants with missing information for a covariate included in the analysis model will 
be excluded from the analysis.
14.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Start or end dates which are completely missing (i.e. no day, month or year is specified) will 
remain missing, with no imputation applied. 
Derivations requiring this information such as time to onset and duration will be set to 
missing.
14.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listings.
Adverse 
Events

The eCRF allows for the possibility of partial dates to be recorded for AE start and end 
dates.

For partial dates the following imputations will be applied:
o
Partial Start Date: '01' will be used for a missing day and ‘Jan’ will be used for 
a missing month.  If this results in a date prior to the start of study treatment, 
then the treatment start date will be used. The event will then be considered 
‘On-treatment’ as per Section 14.4.1.3.
o
Partial Stop Date: '28/29/30/31' will be used for a missing day (dependent on 
the month and year) and 'Dec' will be used for a missing month.  If this results 
in a date after the study stop date, then the study stop date will be used.

The above imputations will be applied when calculating the time to onset and duration 
of the event.
Concomitant 
Medications

For concomitant medications partial dates will be imputed as follows:
o
Partial start date: '01' will be used for a missing day and 'Jan' will be used for a 
missing month
o
Partial stop date: '28/29/30/31' will be used for a missing day (dependent on the 
month and year) and 'Dec' will be used for a missing month.
 
 
 
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14.7.2.3.
Missing Data for Statistical Analysis
Element
Reporting Detail
General

The study is designed to collect data for the 52 weeks following randomisation for all 
participants, including for participants who prematurely withdraw from interventional 
product.  The following scenarios may arise.
1) Participant completes interventional product and study
2) Participant prematurely withdrawn from interventional product and agrees to 
continued data collection off-treatment for 52 weeks following randomisation
3) Participant prematurely withdrawn from interventional product and initially 
agrees to continued off-treatment data collection, but subsequently withdraws from 
the study prior to 52 weeks following randomisation
4) Participant prematurely withdrawn from interventional product and does not 
agree to continued off-treatment data collection

For participants under any scenario missing data may arise intermittently due to 
nonattendance at scheduled visits.  For participants under scenarios 3 and 4 missing 
data will arise due to premature withdrawal from the study.

Unless otherwise specified on-treatment data and where available off-treatment data 
will be included in the analysis of efficacy endpoints.
 
 
 
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14.8.
Appendix 8: Values of Potential Clinical Importance
14.8.1.
Laboratory Values of Potential Clinical Concern
Haematology
Laboratory Parameter
Units
Age 
Category
(years)
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit
Ratio of 1
12+
0.201
0.599
Haemoglobin
G/L
12+
71
199
Platelet Count 
GI/L
1+
31
1499
While Blood Cell Count (WBC)
GI/L
12+
1.1
Clinical Chemistry
Laboratory Parameter
Units
Age 
Category
(years)
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
ALT
U/L
3-12
>143 (and Total 
Bilirubin >43)
U/L
13+
>239 (and Total 
Bilirubin >43)
Calcium
mmol/L
3+
1.50
3.24
Creatinine Phosphokinase
IU/L
12+
>5 x ULN
Glucose
mmol/L
1+
2.2
27.8
Phosphorus, Inorg
mmol/L
3+
0.32
Potassium
mmol/L
3+
2.8
6.5
Sodium
mmol/L
0+
120
160
Possible Hy’s Law Cases
Test Analyte
Units
Category
Clinical Concern Range
ALT, Bilirubin
ALT ≥ 3xULN and Bilirubin ≥ 2xULN
(>35% direct)
ALT, INR
ALT ≥ 3xULN and INR > 1.5
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14.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
14.9.1.
Population Pharmacokinetic (PopPK) Dataset Specification
Specifications for the generation of the dataset will be provided in a separate document.
14.9.2.
Population Pharmacokinetic (PopPK) Methodology
Mepolizumab plasma concentration-time data (samples collected at Weeks 4, 52 and 68; 
at the Early Withdrawal Visit and the additional follow-up 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).
14.9.2.1.
Base Model
In consideration of the sparse sampling (3 samples post-start of treatment over 68 weeks: 
Week 4, 52 and 68) and the wealth of mepolizumab PK knowledge, the most recent 
population PK model will be applied directly to the dataset without estimation (e.g. 
maxevals=0 in NONMEM) and predictions generated, against which the model will be 
validated prospectively using appropriate goodness of fit tests. For example, the 
Anderson-Darling and Cramér–von Mises tests are accepted methods of comparing 
Empirical Distribution Functions for model and data (i.e. PK concentrations) to evaluate 
whether independent observations (i.e. observed PK concentrations from the study) are 
adequately described by a model (i.e. most recent population PK model).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated;

Population mepolizumab plasma PK parameter estimates with 95% CI from the final 
model will be tabulated. Goodness of fit plots for the final model will be presented;

Individual post-hoc PK parameter estimates (such as area under the plasma 
concentration-time curve over the dosing interval [AUC (0-)], CAV [AUC (0-)/]) 
will be summarised descriptively and listed;

Individual post-hoc predicted plasma concentrations will be summarised descriptively 
and listed;

Accumulation ratio estimate will be assessed at Week 52.
The most recent model consists of a two-compartment pharmacokinetic model with first-
order absorption and elimination. Bodyweight is incorporated into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volumes, respectively. Albumin and creatinine clearance are also included as 
covariates of mepolizumab clearance on physiological grounds, however their effects are 
small and not of clinical relevance. Details of the model can be found in report 
GlaxoSmithKline Document Number 2015N238436_00.
 
 
 
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14.9.2.2.
Investigation of Covariates
The impact of the following prospectively selected covariates on mepolizumab exposure
(e.g. clearance) will be evaluated using the procedures described in Section 14.9.2.3.
Category
Covariates
Demographics
Weight (included in the structural model), age, race, 
gender, country
Baseline clinical status
Creatinine clearance, albumin (both already included in the 
current model), serum creatinine, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, bilirubin, 
total protein
Baseline disease status
Total endoscopic NP score (centrally read), blood 
eosinophils and baseline OCS dose
Concomitant medications
If data permits*, e.g. immunosuppressant therapies (e.g. 
methotrexate, azathioprine and mycophenolate mofetil), 
proton pump inhibitors, statins, pain relief (e.g. 
paracetamol, NSAIDs), interferon alfa and antihypertensive 
drugs
Others
Presence/absence of anti-drug antibodies and previous 
biologics use (monoclonal antibodies).
*Attempt to investigate those classes of drug will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PK parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.4 (or higher). Individual PK parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the procedures described in Section 14.9.2.3. If deemed 
appropriate box plots of systemic clearance versus covariates of interest (e.g. 
immunogenicity status) will be provided.
14.9.2.3.
Covariate Model Selection Procedures
The covariate model building will follow a step-wise process consisting of a forward and 
backward selection procedure. The likelihood ratio test will be used to evaluate the 
significance of incorporating or removing covariates into the population model based on 
alpha levels set a priori. For forward and backward selections, a significance level of 
0.05 and 0.01 for first order conditional estimation with interaction (FOCE-I) will be 
used, respectively, in line with criteria used in previous analyses.
 
 
 
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
Step-wise forward addition procedure
Each covariate will be included individually in the ‘base model’ to identify covariates 
resulting in a decrease in the objective function value (OFV) of > 3.84, χ2 < 0.05 for 1 
degree of freedom (df) using FOCE-I. The retained covariates will then be added to the 
base model one by one, starting with the most significant ones until all covariates have 
been tested. Note, if a covariate exponent estimate is numerically small, the covariate 
will not be retained; irrespective of objective function. This will also be supported by 
examination of the goodness of fit. This will constitute the full model.

Backward elimination procedure
From the full model, the significance of each covariate will be tested individually by 
removing covariates one by one until all non-significant covariates have been excluded. 
A covariate will be retained if upon removal, the OFV increase by more than 6.64 points 
(χ2< 0.01 for 1 df) using FOCE-I. Note, a covariate may be retained in the model despite 
being found non-statistically significant, if there is a strong rationale for its inclusion. 
This will constitute the final model.
Note: centering of continuous covariates may be considered, as appropriate. The mean or 
median value of the subjects included in the analysis may be used for example.
The impact of the presence of anti-mepolizumab antibodies may not be formally tested as 
a covariate in the model, considering the low incidence observed in the mepolizumab 
programme to date. Instead a graphical approach will be used, if deemed appropriate.
14.9.2.4.
Model Evaluation
The uncertainty in the parameter estimates will be assessed (e.g. from the standard error 
estimates provided by NONMEM or from the 95% CI estimates provided by other 
appropriate analysis conducted using other software). Furthermore, the model 
performance will be investigated using a set of goodness of fit plots as well as Visual 
Predictive Check (VPC) method. Other evaluation methods may be used (e.g. 
bootstrapping) if deemed appropriate.
 
 
 
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14.10.
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses
14.10.1.
Pharmacokinetic / Pharmacodynamic Dataset Specification
Specifications for the generation of the dataset will be provided in a separate document.
14.10.2.
Pharmacokinetic / Pharmacodynamic Methodology
Mepolizumab blood eosinophil count-time data (samples collected every 4 weeks from 
Baseline to Week 52, and at Weeks 60, 68 and 76) 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).
14.10.3.
Base Model
The most recent population PKPD model will be applied directly to the dataset without 
estimation (e.g. maxevals=0 in NONMEM) and predictions generated against which the 
model will be validated prospectively using appropriate goodness of fit tests as described 
in Section 14.9.2.1 (using the observed data from the study).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated.

The population PD parameter estimates with 95% CI from the final model will be 
tabulated. Goodness of fit plots for the final model will be presented.
The most recent population PKPD model consists of an indirect response model 
parameterised in term of baseline blood eosinophil count (KRO), rate of elimination of 
eosinophils in the blood (Kout), concentration resulting in 50% of maximum drug effect 
(IC50) and maximum effect (Imax). Observed baseline blood eosinophil count is included 
as covariates of both predicted baseline and mepolizumab inhibitory response; and 
disease for predicted baseline blood eosinophil count. Details of the model can be found 
in GlaxoSmithKline Document Number 2015N238436_00 and GlaxoSmithKline 
Document Number 2015N255079_00 (extension of the former report).
14.10.4.
Investigation of Covariates
The impact of the following prospectively selected plausible covariates on relevant 
parameters (i.e., baseline blood eosinophil count and maximum effect) will be evaluated.
Category
Covariates
Demographics
Age, race, gender
Baseline disease status
Total endoscopic NP score (centrally read), blood 
eosinophils (already included in the current model)
Others
Baseline OCS absolute dose, presence/absence of anti-drug 
antibodies*, immunosuppressant therapies* (e.g. 
 
 
 
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methotrexate, azathioprine and mycophenolate mofetil), 
interferon alfa*
*Attempt to investigate those covariates will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PD parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.4 (or higher). Individual PD parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the same procedures as described in Section 14.9.2.3 for 
the population PK model.
Model evaluation will be as described in Section 14.9.2.4 for the population PK model.
 
 
 
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14.11.
Appendix 11: Abbreviations & Trade Marks
14.11.1.
Abbreviations
Abbreviation
Description
ACQ
Asthma Control Questionnaire
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
ED
Emergency Department
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IP
Interventional Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
NP
Nasal Polyps
OCS
Oral Corticosteroid
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PnIF
Peak Nasal Inspiratory Flow
PP
Per Protocol
PopPK
Population PK
PopPKPD
Pharmacokinetic / Pharmacodynamic
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SC
Subcutaneous
SDSP
Study Data Standardization Plan
 
 
 
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Abbreviation
Description
SDTM
Study Data Tabulation Model
SF-36
Short Form-36
SNOT-22
Sino-Nasal Outcome Test -22
SoC
Standard of Care
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
UPSIT
University of Pennsylvania Smell Identification Test
VAS
Visual Analogue Scale
WPAI
Work Productivity and Impairment
14.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
WinNonlin
SAS
NONMEM
 
 
 
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14.12.
Appendix 12: List of Data Displays
14.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.22
1.1
Efficacy
2.1 to 2.69
2.1 to 2.25
Safety
3.1 to 3.68
3.1 to 3.3
Population Pharmacokinetic (PopPK)
4.1 to 4.7
4.1 to 4.9
Pharmacokinetic / Pharmacodynamic 
(PopPKPD)
5.1 to 5.6
5.1 to 5.10
Exposure-Efficacy
6.1 to 6.4
Section
Listings
ICH and Other Listings
1 to 51
14.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacokinetic / Pharmacodynamic
(PopPKPD)
POPPKPD_Fn
POPPKPD_Tn
POPPKPD_Ln
Efficacy Exposure
EE_Fn
EE_Tn
EE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL/Shell’ or ‘Programming Notes’ column with an associated 
reference.’
14.12.3.
Deliverables
Delivery Priority [1]
Description
SAC [1]
Headline Results
SAC [2]
Final Statistical Analysis Complete
NOTES: 
[1] Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
 
 
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14.12.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC [1]
1.2.
ITT
SHELL
Summary of Time On- and Off-Treatment by Withdrawal 
Scenario
Withdrawal scenarios are detailed in 
Section 14.7.2.3.  Add footnote to 
indicate exclusion of data from the 
follow-up period after Week 52
SAC [2]
1.3.
ITT
ES1
Summary of Subject Disposition (Week 52)
ICH E3, FDAAA, EudraCT
SAC [1]
1.4.
FU
ES1
Summary of Subject Disposition (Follow-Up Period after Week 
52)
SAC [1]
1.5.
FU
SHELL
Summary of Duration of Time in Follow-Up Period after Week 52
SAC [2]
1.6.
ENROLLED
ES6
Summary of Screening and Run-In Status and Reasons for 
Screen and Run-In Failures
Journal Requirements
SAC [2]
1.7.
ENROLLED
NS1/SHELL
Summary of Number of Subjects by Region, Country and Centre
EudraCT/Clinical Operations
Add in column for region, add a total for 
each region and a total for each 
country.
SAC [2]
Protocol Deviation
1.8.
ITT
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [2]
Population Analysed
1.9.
ENROLLED
SP1
Summary of Study Populations 
IDSL
SAC [1]
1.10.
Randomised
SP2A
Summary of Exclusions from the Intent-to-Treat and Safety 
Populations
IDSL
SAC [2]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
1.11.
ITT
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [1]
1.12.
ENROLLED
DM11
Summary of Age Ranges
EudraCT
SAC [2]
1.13.
ITT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [2]
1.14.
ITT
Shell
Summary of Nasal Polyps Disease History and Characteristics
Include Disease Duration 
(years/months); Number of previous 
surgeries; Number of Courses of OCS 
for NP in previous 12 months. Baseline 
Nasal Polyps endoscopy score 
(centrally read and investigator read); 
Baseline SNOT-22; Baseline SF-36.
SAC [1]
1.15.
ITT
Shell
Summary of Previous Exacerbation History
To include separate summary of 
information for Asthma and COPD 
Exacerbation History
SAC [2]
Medical Conditions
1.16.
ITT
MH4
Summary of Past Medical Conditions
ICH E3 
SAC [2]
1.17.
ITT
MH4
Summary of Current Medical Conditions
ICH E3 
SAC [2]
Prior and Concomitant Medications
1.18.
ITT
CM1
Summary of Medications Started Prior to Treatment
ICH E3; ATC classification to be 
displayed for combination medications 
(not for individual ingredients)
SAC [2]
1.19.
ITT
CM1
Summary of Concomitant Medications Started During Treatment
ICH E3; ATC classification to be 
displayed for combination medications 
(not for individual ingredients).
Footnote: Includes medications started 
after first dose and before last dose + 
28 days.
SAC [2]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.20.
ITT
CM1
Summary of Systemic Corticosteroids Started During Treatment
Footnote: Includes medications started 
after first dose and before last dose + 
28 days.
SAC [2]
Exposure
1.21.
ITT
SHELL
Summary of Exposure (Therapeutic Coverage) to Interventional 
Product
ICH E3
Range of Exposure (months): 1-<3, 3-
<6, 6-<9, 9-<12, >=12Also add subject 
years exposure
SAC [2]
1.22.
ITT
SHELL
Summary of Number of Treatments Administered
SAC [2]
14.12.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT
SHELL
Subject Withdrawal from Interventional Product
Footnote: Kaplan-Meier estimates of
time to withdrawal from IP. Subjects
are represented from Day 1 to Day of
withdrawal from IP
SAC [2]
 
 
 
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14.12.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Co-Primary Endpoints
2.1.
ITT
SHELL
Summary of Total Endoscopic Nasal Polyps Score (Centrally 
Read)
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include actual categories
SAC [1]
2.2.
ITT
SHELL
Analysis of Change from Baseline Total Endoscopic Nasal 
Polyps Score (Centrally Read)
SAC [1]
2.3.
ITT
SHELL
Sensitivity Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52: Subjects with 
Missing Data Included in the Actual Surgery Category
SAC [2]
2.4.
ITT
SHELL
Sensitivity Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52: Subjects with 
Missing Data Included in the 1-point Improvement Category
SAC [2]
2.5.
ITT
SHELL
Supplementary Analysis of Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52: 
Subjects with Early Withdrawal from Interventional Product 
Included in the Actual Surgery Category
All intercurrent events in least 
favourable treatment response category
SAC [2]
2.6.
PP
SHELL
Supplementary Analysis of Change from Baseline Total 
Endoscopic Nasal Polyps Score (Centrally Read) at Week 52: 
Per-Protocol Population
SAC [2]
2.7.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Participants 
with Asthma
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Aspirin 
Exacerbated Respiratory Disease (AERDS)
SAC [2]
2.9.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Number of 
Previous Surgeries
SAC [2]
2.10.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Baseline 
Blood Eosinophil Categories
SAC [2]
2.11.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Region
SAC [2]
2.12.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Age
SAC [2]
2.13.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Gender
SAC [2]
2.14.
ITT
SHELL
Subgroup Analysis of Change from Baseline Total Endoscopic 
Nasal Polyps Score (Centrally Read) at Week 52 by Race
SAC [2]
2.15.
ITT
SHELL
Predicted Change from Baseline Total Endoscopic Nasal Score 
(Centrally Read) at Week 52 by Baseline Blood Eosinophils
SAC [2]
2.16.
ITT
SHELL
Summary of Nasal Obstruction VAS score
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include actual categories
SAC [1]
2.17.
ITT
SHELL
Analysis of Change from Baseline Nasal Obstruction VAS Score
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18.
ITT
SHELL
Sensitivity Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) - Subjects with Missing Data included 
in the Actual Surgery Category 
SAC [2]
2.19.
ITT
SHELL
Sensitivity Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) – Subjects with Missing Data 
Included in the >0 to 1-point Improvement Category
SAC [2]
2.20.
ITT
SHELL
Supplementary Analysis of Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52): Subjects with Early 
Withdrawal from Interventional Product Included in the Actual 
Surgery Category
SAC [2]
2.21.
PP
SHELL
Supplementary Analysis of Change from Baseline Nasal 
Obstruction VAS Score (Weeks 49-52): Per-Protocol Population
SAC [2]
2.22.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Subjects with Asthma
SAC [2]
2.23.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Aspirin Exacerbated Respiratory 
Disease (AERDS)
SAC [2]
2.24.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Number of Previous Surgeries
SAC [2]
2.25.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Baseline Blood Eosinophil
Categories
SAC [2]
2.26.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Region
SAC [2]
2.27.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Age
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.28.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Gender
SAC [2]
2.29.
ITT
SHELL
Subgroup Analysis of Change from Baseline Nasal Obstruction 
VAS Score (Weeks 49-52) by Race
SAC [2]
2.30.
ITT
SHELL
Predicted Change from Baseline Nasal Obstruction VAS (Weeks
49-52) by Baseline Blood Eosinophils
SAC [2]
Secondary Endpoints
2.31.
ITT
SHELL
Analysis of Time to First Nasal Surgery
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
2.32.
ITT
SHELL
Sensitivity Analysis of Time to First Nasal Surgery: Tipping Point 
Analysis
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.33.
ITT
SHELL
Summary of Overall VAS score
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include actual categories
SAC [1]
2.34.
ITT
SHELL
Analysis of Change from Baseline Overall VAS Score
SAC [1]
2.35.
ITT
SHELL
Summary of SNOT-22 Total Score
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include actual categories
SAC [1]
2.36.
ITT
SHELL
Analysis of Change from Baseline SNOT-22
SAC [1]
2.37.
ITT
SHELL
Summary and Analysis of Total Prednisolone-equivalent OCS 
Use (mgs per year)
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.38.
ITT
SHELL
Subgroup Analysis of Total Prednisolone-equivalent OCS Use 
(mgs per year) by Participants with Asthma
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.39.
ITT
SHELL
Summary of P-values for Treatment Comparisons Adjusted for 
Multiplicity According to Hierarchy of Endpoints
SAC [1]
Other Endpoints
2.40.
ITT
SHELL
Summary of Total Endoscopic Nasal Score (Investigator Read)
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include actual and change from 
baseline categories
SAC [2]
2.41.
ITT
SHELL
Summary and Analysis of Total Endoscopic Nasal Polyps Score 
(Centrally Read) Responders
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.42.
ITT
SHELL
Summary and Analysis of SNOT-22 Responders
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.43.
ITT
SHELL
Summary and Analysis of Change from Baseline Individual VAS 
Symptom Scores
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Include data for nasal discharge, mucus 
in throat, loss of smell, facial pain
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.44.
ITT
SHELL
Summary and Analysis of Change from Baseline Composite 
VAS Scores
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Footnote: Composite includes nasal 
obstruction, nasal discharge, mucus in 
the throat and loss of smell
Include Composite Excluding Facial 
Pain and Composite Including Facial 
Pain
SAC [2]
2.45.
ITT
SHELL
Summary of University of Pennsylvania Smell Identification Test 
(UPSIT)
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Footnote: performed in UK, US and 
Canada only
Include actual categories
SAC [2]
2.46.
ITT
SHELL
Analysis of Change from Baseline University of Pennsylvania 
Smell Identification Test (UPSIT)
Footnote: performed in UK, US and 
Canada only
SAC [2]
2.47.
ITT
SHELL
Summary of Peak Nasal Inspiratory Flow (PNIF)
Include actual and change from 
baseline
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.48.
ITT
SHELL
Summary of Frequency and Rate of Nasal Surgery
Include n (%) with 0, 1, 2, etc surgeries 
and crude rate
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.49.
ITT
SHELL
Time to First Inclusion on Waiting List for Nasal Polyps Surgery
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.50.
ITT
SHELL
Summary of Subjects Placed on Waiting List for Surgery to 
Week 52
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.51.
ITT
SHELL
Summary and Analysis of Need for Surgery to Week 52
Footnote: Subjects no longer having a 
need for surgery based on 
improvements seen in total endoscopic 
nasal polyps score and overall VAS 
score
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.52.
ITT
SHELL
Summary of Number of Courses of Systemic Steroids
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Footnote: Courses of systemic steroids 
separated by <7 days are considered a 
continuation of the same course
Include n (%) with 0 vs ≥1 and 0, 1, 2,
etc courses and total number of 
courses
SAC [2]
2.53.
ITT
SHELL
Summary of Days on Systemic Steroids
Footnote: excludes data reported 
during the follow-up period after Week 
52
Include days on therapy and 
percentage of days on therapy
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.54.
ITT
SHELL
Time to First Course of Systemic Steroids
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.55.
ITT
SHELL
Analysis of Time to First Nasal Surgery or Course of Systemic 
Steroids
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.56.
ITT
SHELL
Summary of Number of Courses of Antibiotics
Footnote: Excludes data reported 
during the follow-up period after Week 
52
Footnote: Courses of antibiotics 
separated by <7 days are considered a 
continuation of the same course
Include n (%) with 0 vs ≥1 and 0, 1, 2, 
courses and total number of courses
SAC [2]
2.57.
ITT
SHELL
Summary of On-Treatment Blood Eosinophils (GI/L)
Include absolute and ratio to baseline 
values
SAC [1]
2.58.
ITT
SHELL
Analysis of On-Treatment Blood Eosinophils (GI/L) Ratio 
Compared to Baseline Mixed Model Repeated Measures
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Endpoints – Health Economics/Medical Resource Utilisation
2.59.
ITT
SHELL
Summary of SF-36 Domain Scores and Component Summary 
Scores
Include 8 domain scores bodily pain, 
general health, mental health, physical 
functioning, role emotional, role 
physical, social functioning and vitality
and Mental and Physical Component 
Summary scores.
Include actual and change from 
baseline
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.60.
ITT
SHELL
Summary of Work Productivity and Activity Impairment 
Questionnaire (WPAI)
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
Other Endpoints – Participants with Asthma
2.61.
ITT
SHELL
Summary of ACQ-5 in Participants with Asthma
Include actual and change from 
baseline
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.62.
ITT
SHELL
Summary of Frequency of Clinically Significant Asthma 
Exacerbations in Participants with Asthma
Provide n (%) with 0 vs ≥1 and 0, 1, 2 
etc exacerbations and total number of 
exacerbations
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Endpoints – Maintenance of Response Following Cessation of Interventional Product (Follow-Up Period After Week 52)
2.63.
FU
SHELL
Summary of Total Endoscopic Nasal Polyps Score (Centrally 
Read) for Subjects in the Follow-Up Period After Week 52
Include actual and change from 
baseline
SAC [2]
2.64.
FU
SHELL
Summary of Individual VAS Symptom Scores for Subjects in the 
Follow-Up Period After Week 52
Include actual and change from 
baseline
Include nasal obstruction, nasal 
discharge, mucus in throat, loss of 
smell, facial pain, overall VAS score
SAC [2]
2.65.
FU
SHELL
Summary of Total Prednisolone-equivalent OCS Use (mgs per 
year) for Subjects in the Follow-Up Period After Week 52
SAC [2]
2.66.
FU
SHELL
Summary of SNOT-22 for Subjects in the Follow-Up Period After 
Week 52
Include actual and change from 
baseline
SAC [2]
2.67.
FU
SHELL
Time to First Nasal Surgery for Subjects in the Follow-Up Period 
After Week 52
SAC [2]
2.68.
FU
SHELL
Summary of Number of Courses of Systemic Steroids for 
Subjects in the Follow-Up Period After Week 52
Footnote: Courses of systemic steroids 
separated by less than 7 days are 
considered a continuation of the same 
course
SAC [2]
2.69.
FU
SHELL
Summary of Blood Eosinophils (GI/L) for Subjects in the Follow-
up Period After Week 52
SAC [2]
14.12.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Co-Primary Endpoints
2.1.
ITT
SHELL
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) at Week 52
Show percentages in each category
SAC [1]
2.2.
ITT
SHELL
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) by Visit
OR and 95%CI
SAC [1]
2.3.
ITT
SHELL
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) at Week 52: Cumulative Distribution 
Function
SAC [2]
2.4.
ITT
SHELL
Figure of Change from Baseline Total Endoscopic Nasal Polyps 
Score (Centrally Read) at Week 52: Sensitivity and 
Supplementary Analyses
Include primary, sensitivity and 
supplementary analyses
SAC [2]
2.5.
ITT
SHELL
Figure of Predicted Change from Baseline Total Endoscopic 
Nasal Score (Centrally Read) at Week 52 by Baseline Blood 
Eosinophils
SAC [2]
2.6.
ITT
SHELL
Figure of Change from Baseline Nasal Obstruction VAS Score 
(Week 49-52)
Show percentages in each category
SAC [1]
2.7.
ITT
SHELL
Figure of Change from Baseline Nasal Obstruction VAS Score in 
each 4-Weekly Period
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.8.
ITT
SHELL
Figure of Nasal Obstruction VAS Score (Week 49-52): 
Sensitivity and Supplementary Analyses
Include primary, sensitivity and 
supplementary analyses
SAC [2]
2.9.
ITT
SHELL
Figure of Predicted Change from Baseline Nasal Obstruction 
VAS (Weeks 49-52) by Baseline Blood Eosinophils
SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Secondary Endpoints
2.10.
ITT
SHELL
Kaplan-Meier Time to First Nasal Surgery
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
2.11.
ITT
SHELL
Sensitivity Time to First Nasal Surgery: Tipping Point
Heat Map
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.12.
ITT
SHELL
Sensitivity Time to First Nasal Surgery (TBD): Tipping Point –
Fixed Assumption for Placebo
2-dimensional
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.13.
ITT
SHELL
Figure of Change from Baseline Overall VAS Score in Each 4-
Weekly Period
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
2.14.
ITT
SHELL
Figure of Change from Baseline SNOT-22 by Visit
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
Other Endpoints
2.15.
ITT
SHELL
Figure of Total Endoscopic Nasal Polyps Score (Centrally Read) 
Responders by Visit
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.16.
ITT
SHELL
Figure of University of Pennsylvania Smell Identification Test 
(UPSIT) Change from Baseline by Visit
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.17.
ITT
SHELL
Figure of SNOT-22 Responders by Visit
OR and 95%CI
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.18.
ITT
SHELL
Kaplan-Meier Time to First Inclusion on Waiting List for Nasal 
Polyps Surgery
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.19.
ITT
SHELL
Kaplan-Meier Time to First Course of Systemic Steroids
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.20.
ITT
SHELL
Kaplan-Meier Time to First Nasal Surgery or Course of Systemic 
Steroids
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
2.21.
ITT
SHELL
Figure of On-Treatment Blood Eosinophils Absolute Values
No reference line.
Include screening/baseline geometric 
mean values without 95% CI.
Week 4 onwards adjusted estimates 
from MMRM model with 95% CI.
SAC [2]
2.22.
ITT
SHELL
Figure of On-Treatment Blood Eosinophils Ratio to Baseline
Reference line at 1
SAC [2]
Other Endpoints – Maintenance of Response Following Cessation of Interventional Product (Follow-Up Period After Week 52)
2.23.
FU
SHELL
Kaplan-Meier Time to First Nasal Surgery for Subjects in the 
Follow-Up Period After Week 52
SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.24.
FU
SHELL
Kaplan-Meier Time to First Inclusion on Waiting List for Nasal 
Polyps Surgery for Subjects in the Follow-Up Period After Week 
52
SAC [2]
2.25.
FU
SHELL
Figure of Blood Eosinophils for Subjects in the Follow-Up Period 
After Week 52
SAC [2]
14.12.8.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE13/SHELL
Adverse Event Overview
SAC [1]
3.2.
Safety
AE1
Summary of On-Treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC [1]
3.3.
Safety
AE1
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
3.4.
FU
AE1
Summary of Adverse Events Reported During the Follow-Up 
Period After Week 52 by System Organ Class and Preferred 
Term
SAC [2]
3.5.
Safety
AE3
Summary of Common (>=3% in Any Treatment Group) On-
Treatment Adverse Events by Overall Frequency
ICH E3
≥3% (prior to rounding to nearest 
percent)
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
Safety
AE5a
Summary of On-Treatment Adverse Events by System Organ 
Class and Maximum Severity
Add a Total column across all severities
SAC [2]
3.7.
Safety
AE1
Summary of Drug-Related On-Treatment Adverse Events by 
System Organ Class and Preferred Term
ICH E3
SAC [2]
3.8.
Safety
AE5a
Summary of Drug Related On-Treatment Adverse Events by 
System Organ Class and Maximum Severity
Add a Total column across all 
severities
SAC [2]
3.9.
Safety
AE15
Summary of Common (>=3% In Any Treatment Group) Non-
Serious On-Treatment Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT≥3% (prior to 
rounding to nearest percent)
SAC [2]
3.10.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Post-
Baseline Anti-Drug Antibody Result
Add in row with n in each ADA result 
category.
Footnote: Highest Post-Baseline Anti-
Drug Antibody result excluding data 
from no-treatment follow-up period.
SAC [2]
3.11.
Safety
AE1
Summary of Post-Treatment Adverse Events by Highest Post-
Baseline Anti-Drug Antibody Result
Add in row with n in each ADA result 
category.
Footnote: Highest Post-Baseline Anti-
Drug Antibody result excluding data 
from no-treatment follow-up period.
Footnote: Excludes AEs reported 
during the follow-up period after Week 
52
SAC [2]
3.12.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by System Organ Class
IDSL
SAC [2]
3.13.
Safety
AE1
Summary of Adverse Events Leading to Withdrawal from Study
by System Organ Class
IDSL
SAC [2]
3.14.
Safety
AE1
Summary of Adverse Events Reported on Day of Dosing by 
System Organ Class
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
3.15.
Safety
AE3
Summary of Fatal Serious Adverse Events
SAC [1]
3.16.
Safety
AE3
Summary of Fatal Drug-Related Serious Adverse Events
SAC [2]
3.17.
Safety
AE1
Summary of Non-Fatal Serious Adverse Events by System 
Organ Class
Include on-treatment and post-
treatment
SAC [2]
3.18.
Safety
AE1
Summary of Non-Fatal Serious On-Treatment Adverse Events 
by System Organ Class
SAC [2]
3.19.
Safety
AE1
Summary of Non-Fatal Serious Post-Treatment Adverse Events 
by System Organ Class
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [1]
3.20.
Safety
AE1
Summary of Serious Adverse Events by System Organ Class
Include on-treatment and post-
treatment
SAC [1]
3.21.
Safety
AE1
Summary of Serious On-Treatment Adverse Events by System 
Organ Class
SAC [2]
3.22.
Safety
AE1
Summary of Serious Post-Treatment Adverse Events by System 
Organ Class
Footnote: Excludes data reported 
during the follow-up period after Week 
52
SAC [2]
3.23.
FU
AE1
Summary of Serious Adverse Events Reported During the 
Follow-Up Period After Week 52 by System Organ Class
SAC [2]
3.24.
Safety
AE1
Summary of Serious Drug-Related On-Treatment Adverse 
Events by System Organ Class
SAC [2]
3.25.
Safety
AE1
Summary of Pre-Treatment Serious Adverse Events by System 
Organ Class
SAC [2]
3.26.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.27.
Safety
SHELL
Summary of Deaths
Includes all deaths separating those 
reported in no-treatment follow-up
SAC [2]
Adverse Events of Special Interest
3.28.
Safety
SHELL
Summary of On-Treatment Serious AEs and AEs of Special 
Interest: Incidence, Relative Risk and Risk Difference (Placebo 
vs 100mg SC)
SAC [2]
3.29.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Systemic Reactions Reported by the Investigator as Meeting the 
Criteria for Anaphylaxis
SAC [2]
3.30.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Events Reported by the Investigator as Systemic Reactions –
Allergic (Type I Hypersensitivity) and Other Reactions
SAC [2]
3.31.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Events Defined by the Investigator as Systemic Reactions –
Allergic (Type I Hypersensitivity)
SAC [2]
3.32.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Events Defined by the Investigator as Systemic Reactions –
Other Reactions
SAC [2]
3.33.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Events Reported by the Investigator as Local Injection Site 
Reactions
SAC [2]
3.34.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Serious Cardiac, Vascular and Thromboembolic Events
SAC [2]
3.35.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Serious Ischemic Events
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.36.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Malignancies
SAC [2]
3.37.
Safety
AE1
Summary of On-Treatment Adverse Events of Special Interest:
Potential Opportunistic Infections
SAC [2]
3.38.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Systemic Reactions Reported by the Investigator as 
Meeting the Criteria for Anaphylaxis
SAC [2]
3.39.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Systemic 
Reactions – Allergic (Type I Hypersensitivity) and Other 
Reactions
SAC [2]
3.40.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Defined by the Investigator as Systemic 
Reactions – Allergic (Type I Hypersensitivity)
SAC [2]
3.41.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Defined by the Investigator as Systemic 
Reactions –Other Reactions
SAC [2]
3.42.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Events Reported by the Investigator as Local Injection 
Site Reactions
SAC [2]
3.43.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Serious Cardiac, Vascular and Thromboembolic Events
SAC [2]
3.44.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Serious Ischemic Events
SAC [2]
3.45.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Malignancies
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.46.
Safety
SHELL
Summary Profile of On-Treatment Adverse Events of Special 
Interest: Potential Opportunistic Infections
SAC [2]
Laboratory: Chemistry 
3.47.
Safety
LB1
Summary of On-Treatment Chemistry Changes from Baseline 
ICH E3
Includes Baseline values
SAC [2]
3.48.
Safety
LB3
Summary of On-Treatment Chemistry Shifts from Baseline 
Relative to Normal Range
ICH E3
Include Any Time Post Baseline
Add footnotes:
Note: Any Time Post Baseline –
Includes scheduled and any 
unscheduled assessments
Subjects may be counted in more than 
one category.
SAC [2]
3.49.
Safety
LB3
Summary of On-Treatment Chemistry Shifts from Baseline 
Relative to PCI Criteria
ICH E3
Include Any Time Post Baseline
Add footnotes:
Note: Any Time Post Baseline –
Includes scheduled and any 
unscheduled assessments
Subjects may be counted in more than 
one category.
SAC [2]
Laboratory: Hematology
3.50.
Safety
LB1
Summary of On-Treatment Haematology Changes from 
Baseline 
ICH E3
Includes Baseline values
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.51.
Safety
LB3
Summary of On-Treatment Haematology Shifts from Baseline 
Relative to Normal Range
ICH E3
Include Any Time Post Baseline
Add footnotes:
Note: Any Time Post Baseline –
Includes scheduled and any 
unscheduled assessments
Subjects may be counted in more than 
one category.
SAC [2]
3.52.
Safety
LB3
Summary of On-Treatment Haematology Shifts from Baseline 
Relative to PCI Criteria
ICH E3
Include Any Time Post Baseline
Add footnotes:
Note: Any Time Post Baseline –
Includes scheduled and any 
unscheduled assessments
Subjects may be counted in more than 
one category.
SAC [2]
 
 
 
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Laboratory: Urinalysis
3.53.
Safety
UR1
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline 
ICH E3
SAC [2]
Laboratory: Hepatobiliary (Liver)
3.54.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC [2]
3.55.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC [2]
ECG
3.56.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC [2]
3.57.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC [2]
3.58.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL
SAC [2]
3.59.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC [2]
Vital Signs
3.60.
Safety
VS1
Summary Vital Signs
SAC [2]
3.61.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC [2]
Immunogenicity
3.62.
Safety
SHELL
Summary of Binding Anti Drug Antibody Assay: Highest 
Confirmatory Result
Footnote: Excludes data from no-
treatment follow-up period
SAC [2]
3.63.
Safety
SHELL
Summary of Binding Anti Drug Antibody Assay: Highest 
Treatment Emergent Confirmatory Result
Footnote: Excludes data from no-
treatment follow-up period
SAC [2]
3.64.
Safety
SHELL
Summary of Neutralising Antibody Assay: Highest Result
Footnote: Excludes data from no-
treatment follow-up period
SAC [2]
3.65.
FU
SHELL
Summary of Binding Anti Drug Antibody Assay: Highest 
Confirmatory Result for Subjects in the Follow-up Period After 
Week 52
Footnote: Includes all available data
SAC [2]
 
 
 
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Laboratory: Urinalysis
3.66.
FU
SHELL
Summary of Binding Anti Drug Antibody Assay: Highest 
Treatment Emergent Confirmatory Results for Subjects in the 
Follow-up Period After Week 52
Footnote: Includes all available data
SAC [2]
3.67.
FU
SHELL
Summary of Neutralising Antibody Assay: Highest Result for 
Subjects in the Follow-up Period After Week 52
Footnote: Includes all available data
SAC [2]
3.68.
Safety
SHELL
Summary of On-Treatment Blood Eosinophils (GI/L) by Anti 
Drug Antibody Status
SAC [2]
14.12.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
AE10
Common (>=3% In Any Treatment Group) On-Treatment 
Adverse Events and Relative Risk 
IDSL
SAC [2]
3.2.
Safety
SHELL
On-treatment Serious Adverse Events and Adverse Events of 
Special Interest (Placebo vs Mepolizumab 100mg SC)
Provide relative risk with 95% CI
SAC [2]
Laboratory
3.3.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
SAC [2]
14.12.10. Pharmacokinetic Population (PopPK) Tables
Pharmacokinetic Population (POPPK): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
 
 
 
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Pharmacokinetic Population (POPPK): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK01
Summary of Plasma Mepolizumab Concentration-Time Data 
(Observed and Predicted)
SAC [2]
4.2.
PK
PK06
Summary Statistics of Individual Model Predicted Plasma 
Mepolizumab Pharmacokinetic Parameters (Non-transformed 
and Log-transformed)
SAC [2]
4.3.
PK
-
Description and Evaluation of Key PK Models Tested
Provided by CPMS
SAC [2]
4.4.
PK
-
Population PK Parameter Estimates with 95% CI of Final PK 
Model
Provided by CPMS
SAC [2]
4.5.
PK
-
Demographics Summary
Provided by CPMS
SAC [2]
4.6.
PK
-
Samples Summary
Provided by CPMS
SAC [2]
4.7.
PK
-
Accumulation Ratio Estimate at Week 52
Provided by CPMS
SAC [2]
14.12.11. Pharmacokinetic Population (PopPK) Figures
Pharmacokinetic Population (POPPK): Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
-
Plasma Mepolizumab Concentration-Time Profiles (by 
Treatment)
Provided by CPMS
SAC [2]
4.2.
PK
-
Model Goodness of Fit Plots
Provided by CPMS
SAC [2]
4.3.
PK
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC [2]
4.4.
PK
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC [2]
4.5.
PK
-
Automated Covariate Selection
Provided by CPMS
SAC [2]
4.6.
PK
-
Visual Predictive Check
Provided by CPMS
SAC [2]
 
 
 
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Pharmacokinetic Population (POPPK): Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.7.
PK
-
Observed Plasma Mepolizumab Concentration-Time Profiles by 
Anti-Drug Antibody Status
Provided by CPMS
SAC [2]
4.8.
PK
-
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Subject)
Provided by CPMS
SAC [2]
4.9.
PK
-
Box Plot of Systemic Clearance versus Covariates of Interest
Provided by CPMS
SAC [2]
14.12.12. Pharmacokinetic/Pharmacodynamic Population (PopPK/PD) Tables
Pharmacokinetic/Pharmacodynamic Population (POPPK/PD): Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.1.
PK and PD
-
Description and Evaluation of Key PKPD Models Tested
Provided by CPMS
SAC [2]
5.2.
PK and PD
-
Population PD Parameter Estimates with 95% CI of Final PKPD 
Model
Provided by CPMS
SAC [2]
5.3.
PK and PD
-
Demographics Summary
Provided by CPMS
SAC [2]
5.4.
PK and PD
-
Samples Summary
Provided by CPMS
SAC [2]
5.5.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic NP Score (Centrally Read) 
at Week 52 vs Dose/Body Weight
Post-SAC [2]
5.6.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic NP Score (Centrally Read) 
at Week 52 vs Cav
Post-SAC [2]
 
 
 
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14.12.13. Pharmacokinetic/Pharmacodynamic Population (PopPKPD) Figures
Pharmacokinetic/Pharmacodynamic Population (POPPK/PD): Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.1.
PK and PD
-
Blood Eosinophil Count-Time Profiles
Provided by CPMS
SAC [2]
5.2.
PK and PD
-
Model Goodness of Fit Plots
Provided by CPMS
SAC [2]
5.3.
PK and PD
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC [2]
5.4.
PK and PD
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC [2]
5.5.
PK and PD
-
Automated Covariate Selection
Provided by CPMS
SAC [2]
5.6.
PK and PD
-
Visual Predictive Check
Provided by CPMS
SAC [2]
5.7.
PK and PD
-
Observed Blood Eosinophil Count -Time Profiles by Anti-Drug 
Antibody Status
Provided by CPMS
SAC [2]
5.8.
PK and PD
-
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Subject)
Provided by CPMS
SAC [2]
5.9.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic Nasal Polyps Score (Centrally 
Read) at Week 52 vs Dose/Body Weight
Post-SAC [2]
5.10.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52) vs 
Dose/Body Weight
Post-SAC [2]
14.12.14. Exposure-Efficacy Figures
Exposure-Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
 
 
 
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Exposure-Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
6.1.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Total Endoscopic Nasal Polyps Score (Centrally 
Read) at Week 52 vs Dose/Body Weight
Post-SAC [2]
6.2.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52) vs 
Dose/Body Weight
Post-SAC [2]
6.3.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52) vs 
Week 52 Ctau
Post-SAC [2]
6.4.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of Change 
from Baseline Nasal Obstruction VAS Score (Weeks 49-52 vs 
Week 52 Ctau
Post-SAC [2]
 
 
 
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14.12.15. ICH and Other Listings
ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ENROLLED
ES7
Listing of Reasons for Screen and Run-In Failures
Journal Guidelines
SAC [2]
2.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [2]
3.
ITT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Include and identify withdrawals from 
no-treatment follow-up
SAC [2]
4.
ENROLLED
ES9
Listing of Subjects Who Were Rescreened
SAC [2]
5.
ITT
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC [2]
6.
ITT
TA1
Listing of Planned and Actual Treatments
IDSL
SAC [2]
Protocol Deviations
7.
ITT
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC [2]
8.
ITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC [2]
Populations Analysed
9.
Randomised
SP3
Listing of Subjects Excluded from Any Population
ICH E3
SAC [2]
Demographic and Baseline Characteristics
10.
ITT
DM2
Listing of Demographic Characteristics
ICH E3
SAC [2]
11.
ITT
DM9
Listing of Race
ICH E3
SAC [2]
 
 
 
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ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.
ITT
SHELL
Listing of Nasal Polyps Disease History and Baseline 
Characteristics
Include Disease Duration 
(years/months); Number of previous 
surgeries; Number of Courses of OCS 
for NP in previous 12 months; History 
of Sinusitis; Baseline Nasal Polyps 
endoscopy score (centrally read and 
investigator read); Nasal Obstruction 
VAS, Overall VAS, Baseline SNOT-22; 
Baseline SF-36. Include tobacco 
history.
SAC [2]
Prior and Concomitant Medications
13.
ITT
CM3
Listing of Concomitant Medications
IDSL
Include column to identify entries 
coming from the systemic corticosteroid 
eCRF page
SAC [2]
Exposure
14.
Randomised
SHELL/EX3
Listing of Exposure Data
ICH E3
SAC [2]
Adverse Events
15.
Safety
AE8
Listing of All Adverse Events
ICH E3
add Phase (pre/on/post-trt)
SAC [2]
16.
Safety
AE8
Listing of All Adverse Events on Day of Dosing
SAC [2]
17.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
Split on-treatment, post-treatment, 
reported during follow-up period after 
Week 52
SAC [2]
18.
Safety
AE8
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment or Withdrawal from Study
ICH E3
add Phase (pre/on/post-trt)
SAC [2]
 
 
 
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ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC [2]
Serious and Other Significant Adverse Events
20.
Safety
AE8
Listing of Fatal Serious Adverse Events
ICH E3
SAC [2]
21.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC [2]
22.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [2]
23.
Safety
DTH3
Listing of Deaths
SAC [2]
24.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events: 
All Cause Deaths
SAC [2]
25.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Arrhythmias
SAC [2]
26.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Congestive Heart Failure
SAC [2]
27.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Cerebrovascular Events/Stroke
SAC [2]
28.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Deep venous Thrombosis/Pulmonary Embolism
SAC [2]
29.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Myocardial Infarction/Unstable Angina
SAC [2]
30.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Peripheral Arterial Thrombosis Embolism
SAC [2]
31.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Pulmonary Hypertension
SAC [2]
 
 
 
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ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
32.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Revascularisation
SAC [2]
33.
Safety
IDSL
Patient Profiles of Investigator Reported Cardiovascular Events:
Valvulopathy
SAC [2]
Adverse Events of Special Interest
34.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Events Reported by the Investigator as Meeting the Criteria for 
Anaphylaxis
add Phase(on/post-trt)
add number of doses taken prior to the 
event and symptoms related to the 
event
SAC [2]
35.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Events Defined by the Investigator as Systemic Reactions –
Allergic (Type I Hypersensitivity)
add Phase(on/post-trt)
add number of doses taken prior to the 
event and symptoms related to the 
event
SAC [2]
36.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Events Defined by the Investigator as Systemic Reactions –
Other Reactions
add Phase(on/post-trt)
add number of doses taken prior to the 
event and symptoms related to the 
event
SAC [2]
37.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Events Reported by the Investigator as Local Injection Site 
Reactions
add Phase(on/post-trt)
add number of doses taken prior to the 
event and symptoms related to the 
event
SAC [2]
38.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Serious Cardiac, Vascular and Thromboembolic Events
add Phase(on/post-trt)
SAC [2]
39.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Serious Ischemic Events
add Phase(on/post-trt)
SAC [2]
40.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Malignancies
add Phase(on/post-trt)
SAC [2]
 
 
 
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ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
41.
Safety
AE8
Listing of On-Treatment Adverse Events of Special Interest:
Potential Opportunistic Infections
add Phase(on/post-trt)
SAC [2]
Hepatobiliary (Liver)
42.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
SAC [2]
43.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline
SAC [2]
44.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC [2]
45.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC [2]
All Laboratory
46.
Safety
LB5
Listing of Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC [2]
47.
Safety
LB5
Listing of Haematology Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC [2]
48.
Safety
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC [2]
49.
Safety
UR2A/UR2B
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC [2]
ECG
50.
Safety
EG3 / EG4
Listing of All ECG Values for Subjects with Protocol Defined
QTc Stopping Criteria
IDSL
SAC [2]
 
 
 
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ICH and Other Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunogenicity
51.
Safety
IMM2
Listing of Immunogenicity Data
Include column titled: Screening 
Binding Assay, Confirmation Antibody 
Assay, Confirmation Assay Titre, 
Neutralizing Antibody Assay
SAC [2]
 
 
 
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14.13.
Appendix 13: Example Mock Shells for Data Displays
Shells are available upon request.
 
 
 
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