A Single Arm, Multi-center Study to Assess the Long-term Real-world Safety and Effectiveness of Nucala in EGPA Patients Who Have Already Used Nucala for at Least 96 Weeks in Japan
Conditions: Churg-Strauss Syndrome, Eosinophilic Granulomatosis With Polyangiitis
Sponsor: GlaxoSmithKline

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NON-INTERVENTIONAL STUDY PROTOCOL
UNIQUE IDENTIFIER
213684
TITLE
A single arm, multi-center study to assess the long-term real-
world safety and effectiveness of Nucala in EGPA patients who 
have already used Nucala for at least 96 weeks in Japan.
STUDY ACCOUNTABLE 
PERSON
(Medical Japan)
CONTRIBUTING AUTHORS
Dr. 
 (Tohoku Univ.); Dr. 
; Dr 
 Dr. 
; Dr. 
; Dr.
;
 
; 
;
; 
; 
; 
ASSET ID
SB240563
GSK ASSET
Mepolizumab (Nucala)
INDICATION
Eosinophilic granulomatosis with polyangiitis (EGPA)
PHASE OF DEVELOPMENT
n/a
REVISION CHRONOLOGY:  
Date  
Version
Change(s) since last version
15-JUN-2020
Original
N/A
27-JUL-2020
Amendment 01

Addition of benefit/risk assessments

Addition of detailed description of each 
study period (screening period, 
observation period and follow-up period)

Change of time period for collecting AE

Change of Table for Schedule of activity

Removal of the opportunity of review by 
the identified investigator for the study 
reports

Change of a duration for retaining 
records and documents
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................5
TRADEMARK INFORMATION........................................................................................6
1.
BACKGROUND AND RATIONALE..........................................................................7
1.1.
Benefit/Risk Assessment ..............................................................................8
1.1.1.
Risk Assessment ...........................................................................8
1.1.2.
Benefit Assessment.......................................................................8
1.1.3.
Overall Benefit: Risk Conclusion....................................................8
2.
OBJECTIVES/ENDPOINTS .....................................................................................8
3.
RESEARCH METHODOLOGY ................................................................................9
3.1.
Study Design ................................................................................................9
3.2.
Data Source / Data Collection.....................................................................11
3.3.
Eligibility Criteria .........................................................................................12
3.3.1.
Inclusion Criteria..........................................................................12
3.3.2.
Exclusion Criteria.........................................................................12
3.3.3.
Withdrawal from Study.................................................................13
3.4.
Variables.....................................................................................................13
3.5.
Sample Size / Power Calculations ..............................................................15
4.
DATA ANALYSIS CONSIDERATIONS ..................................................................15
4.1.
Analysis Populations...................................................................................15
4.2.
Protocol Deviations.....................................................................................16
4.3.
Summary of Patient Characteristics............................................................16
4.4.
Interim Analysis ..........................................................................................16
4.5.
Primary Analysis.........................................................................................17
4.6.
Secondary and Exploratory Analyses .........................................................17
4.7.
Subgroup Analysis......................................................................................19
5.
LIMITATIONS.........................................................................................................20
6.
STUDY CONDUCT, MANAGEMENT & ETHICS....................................................20
6.1.
Legal Basis for Processing Individual Human Data.....................................21
6.2.
Adverse Events and Serious Adverse Events.............................................21
6.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................22
6.2.2.
Method of Detecting AEs and SAEs.............................................22
6.2.3.
Follow-up of AEs..........................................................................22
6.2.4.
Regulatory Reporting Requirements for AEs and SAEs...............23
6.2.5.
Pregnancy ...................................................................................23
6.2.6.
Medical Device Incidents (Including Malfunctions).......................23
6.2.6.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................24
6.2.6.2.
Follow-up of Medical Device Incidents........................24
6.2.6.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................24

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6.2.6.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................24
6.2.6.5.
Medical Device Malfunctions ......................................25
6.3.
Adverse Event (AE), Pregnancy Exposure, and Incident Reporting 
Related to Any GSK Product.......................................................................25
7.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS ..............................................................................................................25
8.
REFERENCES.......................................................................................................27
9.
APPENDIX.............................................................................................................29
9.1.
APPENDIX 1: SCHEDULE OF ACTIVITIES (SOA) ....................................29
9.2.
APPENDIX 2: STUDY OVERSIGHT CONSIDERATIONS..........................30
9.2.1.
Informed Consent Process ..........................................................30
9.2.2.
Data Protection............................................................................30
9.2.3.
Plans for Disseminating and Communicating Study 
Results ........................................................................................30
9.2.4.
Data Quality Assurance ...............................................................31
9.2.5.
Source Documents ......................................................................31
9.2.6.
Study and Site Closure ................................................................32
9.2.7.
Publication Policy.........................................................................32
9.3.
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING......................................................................................33
9.3.1.
Definition of an AE.......................................................................33
9.3.2.
Definition of an SAE.....................................................................34
9.3.3.
Recording and Follow-Up of AEs and SAEs ................................35
9.3.4.
Reporting of AE and SAE to GSK................................................36
9.4.
APPENDIX 4: Collection of Pregnancy Information.....................................38
9.5.
APPENDIX 5: Medical Device Incidents: Definition and Procedures 
for Recording, Evaluating, Follow-up, and Reporting ..................................38
9.6.
APPENDIX 6: STUDY-SPECIFIC PHARMACOVIGILANCE PLAN 
(SPVP) .......................................................................................................40

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ABBREVIATIONS
ADEs
Adverse device effects
ADRs
Adverse drug reactions
AEs
Adverse events
AESI
AEs of special interests
ASE
All Subjects Enrolled
CIOMS
Council for International Organizations of Medical Sciences
CROs
Contract Research Organisations
DBF
Database freeze
DBR
Database release
eCRF
Electronic case report form
EGPA
Eosinophilic granulomatosis with polyangiitis
ENT
Ear, nose, and throat
GSK
GlaxoSmithKline
HCP
Healthcare Professional
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IHD
Individual human data
IL-5
Interleukin-5
MedDRA
Medical Dictionary for Regulatory Activities
MPO
Myeloperoxidase
MT
Malignant tumour
OCS
Oral corticosteroid
PDMP
Protocol Deviation Management Plan
PML
Progressive multifocal leukoencephalopathy
PMS
Post marketing surveillance
RAP
Reporting and Analysis Plan
RCT
Randomized controlled trial
RMP
Risk management plan
SADEs
Serious adverse device effects
SAEs
Serious adverse events
SoA
Schedule of Activities
SRM
Study reference manual
sPVP
Study-specific pharmacovigilance plan
TP
Treated Population
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
Nucala
CCI

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1.
BACKGROUND AND RATIONALE
Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as the Churg-
Strauss syndrome, is a systemic necrotizing vasculitis that affects small and medium 
sized blood vessels [Groh, 2005]. It is characterized by asthma, sinusitis, pulmonary 
infiltrates, neuropathy, and eosinophilic vasculitis of one or more organs [Jennette, 2013; 
Churg, 1951; Cottin, 2016; Guillevin, 1999].
Eosinophils contribute to the pathophysiology of EGPA by tissue and vascular infiltration 
and inflammation through different kinds of mediators [Akuthota, 2012; Khoury, 2014].
The cytokine interleukin-5 (IL-5) plays a crucial role in regulating the life cycle of 
eosinophils [Lopez, 1988; Rothenberg, 2006; Clutterbuck, 1989], and is found in very 
high levels in patients with EGPA [Hellmich, 2005]. Therefore, neutralization of IL-5 
with mepolizumab, a humanized anti-IL5 monoclonal antibody, is a therapeutic option 
for EGPA [GlaxoSmithKline Document Number 2012N142276_03].
In Japan, 3401 patients with EGPA were certified as recipients of specific disease 
treatment [Japan Intractable Diseases Information Center, 2019]. According to a cross-
sectional nationwide survey conducted by Sada et al., the prevalence of EGPA in Japan
was estimated at 17.8 per 1,000,000 adults [Sada, 2014], which is similar to the 
prevalence reported in western countries (10.7-13 per 1,000,000 individuals) [Mahr, 
2004; Martin, 1999]. In Japan, EGPA is one of the designated intractable diseases for 
promoting research to clarify the pathogenesis and to develop pharmaceutical products 
and medical devices, as well as to financially support patients with these diseases [Japan 
Intractable Diseases Information Centre, 2019].
Nucala (mepolizumab 300 mg, subcutaneous administration) was approved in Japan in 
2018 for the treatment of EGPA in adult patients who inadequately respond to existing 
therapies [Nucala, 2020]. As the number of Japanese patients in clinical trials was 
limited, a Post marketing surveillance (PMS) study, special drug use investigation after 
its market launch, has been conducted in all patients administered Nucala for the 
treatment of EGPA in order to collect and assess information on the safety and 
effectiveness of the long-term use of Nucala in daily clinical practice in patients with 
EGPA [GlaxoSmithKline PMS protocol No. 208505]. However, the observation period 
of this PMS study is limited to up to 96 weeks (approximately 2 years) per patients from 
the start of Nucala administration. There have been no reports to date assessing the long-
term safety and effectiveness of Nucala when used continuously beyond 96 weeks 
(approximately 2 years). There exists no-evidence not only in Japan, but also worldwide.
This study aims to assess the long-term safety and effectiveness of Nucala in the real-
world setting in patients with EGPA who have already used Nucala for 96 weeks 
(approximately 2 years) after its market launch in Japan.

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1.1.
Benefit/Risk Assessment
1.1.1.
Risk Assessment
This study does not involve the administration of any study treatment intervention to
participants nor invasive study procedures. No potential risks beyond the routine clinical 
practice are considered in relate to participating in this study.
1.1.2.
Benefit Assessment
By participating in this study, participants will be contributing to the understanding of
long-term safety and efficacy of Nucala in a Japanese population, which may help
provide a treatment option in the future.
1.1.3.
Overall Benefit: Risk Conclusion
In the overall benefit-risk assessment, any risks that will affect the conduct of this study
are not identified.
2.
OBJECTIVES/ENDPOINTS
The objective of this study is to collect and assess information on the long-term (2 to 4 
years) safety and effectiveness of Nucala (mepolizumab 300 mg, subcutaneous 
administration) in patients with EGPA, who have already used Nucala for 96 weeks 
(approximately 2 years), in real-world settings in Japan.
Objectives
Endpoints
Primary
To investigate the long-term safety of 
Nucala in adult patients with EGPA

Frequency of Adverse events (AEs)/ serious 
adverse events (SAEs)

Frequency of AEs related to Nucala (adverse 
drug reactions, ADRs)

Frequency of AEs of special interests (AESI)
Secondary
To investigate the long-term 
effectiveness of Nucala in adult patients 
with EGPA

Proportion of participants with clinical 
symptoms as assessed by 9 organ-systems 
(i.e. systemic, skin, mucous membranes/eyes, 
ears/nose/throat, chest, cardiovascular, 
abdominal, renal, nervous system)

Proportion of participants with EGPA 
relapsea

Annualized rate (event/year) of 
hospitalization for EGPA-related events

Annualized rate (event/year) of emergency 

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room/unscheduled visit for EGPA-related 
events

Average daily dose (prednisolone-equivalent)
of oral corticosteroid (OCS) over 96 weeks.

The proportion of subjects in the dosing 
categories* relative to average daily OCS 
(prednisolone-equivalent) over 96 weeks
* Zero, >0 to 4.0 mg/day, >4.0 to 7.5
mg/day, >7.5 mg/day
Exploratory
a. EGPA relapse is defined as any of the following with worsening EGPA. 1) Increased dose of OCS. 2) Initiation/increased dose of 
immuno-suppressive agents. 3) EGPA treatment with hospitalization (Section 4.6).
b. EGPA recurrence is judged by investigator based on the following definitions (only in participants who have been withdrawn 
from/terminated the Nucala treatment and entered the follow-up period due to symptom improvement per clinical judgement):1)
Initiation/increased dose of OCS, 2) Initiation/increased dose of immuno-suppressive agents, 3) Hospitalization in association with the 
EGPA treatment (Section 3.4).
3.
RESEARCH METHODOLOGY
3.1.
Study Design
This is a single-arm, multi-center, prospective, non-interventional, observational study to
assess the long-term (2 to 4 years) real-world safety and effectiveness of Nucala in adult 
patients with EGPA who have already received Nucala treatment for 96 weeks 
(approximately 2 years) after its market launch in Japan and who completed the Nucala
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PMS study (special drug use investigation; Protocol No. 208505, NCT03557060). To 
reflect the real-world setting, inclusion and exclusion criteria as well as concomitant 
treatment criteria are limited to the minimum required. Approximately 120 participants 
will be enrolled in the study.
The primary objective is to investigate the long-term safety of Nucala, with special 
attention to AEs, AESI, and SAEs, in adult patients with EGPA in Japan. The 
effectiveness of Nucala will also be investigated as secondary and exploratory objectives. 
Endpoints for effectiveness are included in reference to endpoints in the PMS study.
The study schema is provided in Figure 1. The data in the routine clinical practice will be
collected in the study.
Figure 1
Study Schema
This study is an observational study that does not involve the administration of study 
treatment intervention. According to the Japanese prescribing information for Nucala, 
300 mg mepolizumab is injected subcutaneously every 4 weeks in adult patients with 
EGPA, who inadequately respond to other existing therapies. Participants receive
marketed products of Nucala in any of the approved formulations; lyophilized products
and/or liquid products (prefilled syringe/auto-injector pen).
This study is composed of three periods: screening period, observation period and follow-
up period. 
Screening period
During the screening period (0-4 weeks), all participants are assessed to determine 
whether they meet the eligibility criteria. Retrospective data are collected for reference
regarding the clinical symptoms/findings and laboratory parameters before the first dose 
of Nucala (at least 96 weeks [approximately 2 years] before). These retrospective data 
should be from physician source/medication record. By using the retrospective data, 

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information could be provided about the change from pre-Nucala exposure to the end of 
this study, of which a period would be approximately 4 years.
Any participant who completes assessments during the screening period but does not 
continue in the study beyond Baseline or is subsequently found to be ineligible for the 
study prior to Baseline, is classified as Screen Failure. Information collected for the 
participant classified as Screen Failure is detailed in the guideline for eCRF entry. Re-
screening is permitted once only.
Observation period
During the observation period, which is scheduled for 96 weeks (approximately 2 years)
at maximum, safety and effectiveness data are obtained at approximately 12-week 
intervals. The intervals may be shorter/longer or may be irregular depending on the usual 
pattern of healthcare visits.
Any data collected during the observation period are entered into eCRF. The assessments
in the routine clinical practice during the observation period are shown in Section 9.1 
(Appendix 1).
Follow-up period
The follow-up period is only applicable to participants who have discontinued the
treatment of Nucala due to any reason. The assessments in the routine clinical practice
during the follow-up period are shown in Section 9.1 (Appendix 1).
In case EGPA symptoms are deteriorated in a participant who previously discontinued 
the treatment of Nucala due to improvement of EGPA symptoms, the participant can 
receive the re-treatment of Nucala during the follow-up period. The participant who 
received the re-treatment of Nucala continues the assessments in the follow-up period.
3.2.
Data Source / Data Collection
CRF data
For this study, participant data will be entered into GlaxoSmithKline (GSK)-defined 
Electronic case report forms (eCRFs), transmitted electronically to GSK, and combined
with data provided from other sources in a validated data system. Personal information 
such as “participant name”, “participant initial” and “full date of birth” will not be 
collected in eCRF, and each participant will be managed with Subject ID in eCRF and 
clinical database for anonymization.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing
errors and inconsistencies in the data. 

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eCRFs (including queries and audit trails) will be retained by GSK and copies will be
provided to the investigator to be maintained.  Participant initials will not be collected 
and transmitted to GSK according to a GSK policy.
3.3.
Eligibility Criteria
3.3.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1.
Adult patients with EGPA of 20 years of age inclusive, at the time of signing the
informed consent.
2.
Participants must have a current clinical diagnosis of EGPA by physician.
3.
Participants have continuously used Nucala for at least 96 weeks for the treatment of 
EGPA as mentioned in the current label in Japan.

Participants thus were registered and completed the Nucala PMS study (special 
drug use investigation; Protocol No. 208505, NCT03557060) prior to be enrolled 
in this study.
4.
Physician’s decision to continue treatment with Nucala for the treatment of EGPA as 
mentioned in the current label in Japan.
5.
Prior to commencing any study related activities, participants must be able and 
willing to provide written informed consent.
3.3.2.
Exclusion Criteria
A participant will not be eligible for inclusion in this study if any of the following criteria
apply:
1.
Participants who have previously discontinued Nucala treatment for EGPA for more 
than 12 weeks.
2.
Participating in another clinical trial within the past 12 months, in which the 
participant has been exposed to an investigational or non-investigational 
pharmaceutical product.
3.
Participants with any reasons that in physician’s opinion would place the patients at 
risk.
4.
Participants who are pregnant or breastfeeding.

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3.3.3.
Withdrawal from Study

A participant may withdraw from the study and stop reporting data at any time at 
his/her own or physician’s request, or if they are lost to follow-up.

To determine the safety and effectiveness of Nucala administration in participants 
who discontinued the treatment, a follow-up investigation (up to planned Week 96 of 
observation period) should be conducted wherever possible.

If the participants enroll in another study involving investigational study treatment 
intervention while enrolled in this study, they will be withdrawn from the present 
study.
3.4.
Variables
The investigator will collect information about the following variables wherever possible 
and record it on the eCRF. The timing of collecting information is listed in Section 9.1
(Appendix 1) (SoA).

Demography: Age, sex, body weight, height, EGPA severity classification*, and 
medical history/comorbidity
*Defined by Japan Intractable Diseases Information Center (Japan Intractable Diseases 
Research Foundation)

Administration status of Nucala for EGPA, including product formulation
information

Concomitant medications and therapies

Adverse events, SAEs, and AESI *
*AESI: hypersensitivity (including anaphylaxis), infections and malignant tumors, 
defined as safety specifications in the Japanese RMP

Clinical symptoms (only disease activities relevant to EGPA in systemic vasculitis
assessed) of the following 9 organ systems [Sada, 2014]:
1) Systemic
2) Skin
3) Mucous membranes/eyes
4) Ear, nose and throat (ENT)
5) Chest
6) Cardiovascular

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7) Abdominal
8) Renal
9) Nervous

Hospitalization for EGPA-related events

Emergency room/unscheduled visit for EGPA-related events

Asthma exacerbation as defined below:
1) Exacerbation of bronchial asthma which requires hospitalization
2) Exacerbation of bronchial asthma which requires emergency room visit
3) Exacerbation of bronchial asthma which requires the use of systemic steroids*
*The standard definitions for the use of systemic steroids are as follows:
When a participant requires continuous administration of steroids systemically, in 
concrete terms, orally, intravenously or intramuscularly, for ≥3 days. However, as for 
intramuscular injection, it must also include a continuous administration of 
dexamethasone sodium phosphate or betamethasone sodium phosphate for ≥3 days, or 
one or more doses of triamcinolone acetonide.
When a participant receiving the maintenance therapy with systemic steroids requires 
doubling the maintenance dose for ≥ 3 days for exacerbation of bronchial asthma.
Exacerbations that occurred <7 days from the last exacerbation were treated as a
continuation of the same exacerbation.

Clinical laboratory parameters: 

Lung function: 
(with reason for examination of pulmonary function)
Pre- and post-bronchodilator values will be collected as respective separate categories. If 
it is not known whether the reading is pre- or post-bronchodilator, this will be collected 
as unknown.


EGPA recurrence is judged by investigator based on the following definitions (only 
in participants who have been withdrawn from/terminated the Nucala treatment and 
entered the follow-up period due to symptom improvement per clinical judgement):
1) Initiation/increased dose of OCS
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2) Initiation/increased dose of immuno-suppressive agents
3) Hospitalization in association with the EGPA treatment
Note that EGPA relapse is defined in Section 4.6.
3.5.
Sample Size / Power Calculations
In a global Phase 3 study (MIRRA study) [Wechsler, 2017] conducted in EGPA patients 
(mepolizumab group: 68 patients), the minimum frequency of AEs was 1.47% (1/68 
patients). Assuming a binominal distribution, 107 participants are required to detect at 
least one case of an AE occurring with the frequency of 1.5% or higher with the
probability of 80%. With an expected dropout rate of 10%, a total of approximately 120 
participants are needed as the safety analysis population.
A total of 80 and 153 participants are required to detect at least one case of an AE 
occurring with the frequency of 1.5% or higher with the probabilities of 70% and 90%, 
respectively.
No sample size re-estimation is planned.
4.
DATA ANALYSIS CONSIDERATIONS
All pre-specified analyses will be described in a full Reporting and Analysis Plan (RAP) 
which will be finalized prior to database release (DBR).
This is a descriptive study. The study is not powered to detect differences and no formal 
statistical hypothesis testing will be performed for any of the endpoints.
4.1.
Analysis Populations
The populations for analyses are defined as shown below.
Population
Definition / Criteria
Analyses Evaluated
All Subjects Enrolled (ASE)

All participants
enrolled into the study
meeting the eligibility
criteria for the study.

Study Population
Treated Population (TP)

All participants in the 
ASE study population 
who have received at 
least 1 injection of

Study Population

Safety

Efficacy

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Population
Definition / Criteria
Analyses Evaluated
Nucala.
4.2.
Protocol Deviations

This study does not include a per protocol population.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan (PDMP).

Data will be reviewed prior to Database freeze (DBF) to ensure that important 
deviations (for inclusion in the Clinical Study Report) are identified and captured in 
the deviations dataset.

The deviations dataset will be the basis for summaries and listings.
4.3.
Summary of Patient Characteristics
Characteristics of enrolled participants collected at baseline will be described. This will 
include demographic information as well as disease characteristics. Results will be used 
to describe ASE population. This analysis is planned to be performed prior to and/or at 
the last participant first visit, depending on recruitment, and will not require formal 
statistical analysis. This analysis will not lead to a decision to amend the design or stop 
the study, and will be described further in the RAP.
4.4.
Interim Analysis
The purpose of the interim analysis that for present results of the analysis for the primary 
outcome of the long-term safety of Nucala, and the secondary outcomes of the long-term 
effectiveness of Nucala using dataset including data until 48 weeks post-exposure. This
analysis will not lead to a decision to amend the design or to stop the study.
The interim analysis will be based on the TP Population, and the prespecified analyses
will be carried out using interim dataset.
All required database cleaning activities will be completed and interim DBR and DBF 
will be declared by Data Management.

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4.5.
Primary Analysis
The primary analysis will be based on the TP population. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by 
preferred terms. All AEs, SAEs, ADRs and AESIs will be summarized separately.
Exposure-adjusted AE rate for these AE will also be summarized.
The summary table will be also produced by the observation period, the follow-up period
and the total period (the observation period and the follow-up period), respectively.
4.6.
Secondary and Exploratory Analyses
The secondary and exploratory analyses will be performed for the TP population. All 
endpoints will be summarised by using appropriate descriptive statistics. 
The summary table will be also produced by the observation period and the follow-up 
period, respectively.
The endpoints selected for secondary and exploratory analyses are listed below by
objective:
To investigate the long-term effectiveness of Nucala in adult patients with EGPA in
Japan

Proportion of participants with clinical symptoms as assessed by 9 organ-systems 
(i.e. systemic, skin, mucous membranes/eyes, ears/nose/throat, chest, cardiovascular, 
abdominal, renal, nervous system) for the observation period of 96 weeks.

Proportion of participants with EGPA relapse for the observation period of 96 weeks.
EGPA relapse is defined as any of the following with worsening EGPA.*
1) Increased dose of OCS.
2) Initiation/increased dose of immuno-suppressive agents.**
3) EGPA treatment with hospitalization.
* Worsening of EGPA: new onset of EGPA symptoms or worsening of existing 
symptoms.
** Immunosuppressive agents: If the dose of immunosuppressive agents increases 
for the same formulation or if the number of immunosuppressive agents increases for 
EGPA treatment.

Annualized rate (event/year) of hospitalization for EGPA-related events

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
Annualized rate (event/year) of emergency room/unscheduled visit for EGPA-related 
events
The annualized rate of hospitalization for EGPA treatment will be analysed by using 
a negative binomial generalized linear model with logarithm of time as an offset 
variable, from which the estimated event per year and associated 95% CIs will be 
calculated.

Average daily dose (prednisolone-equivalent) of OCS over 96 weeks

The proportion of subjects in the dosing categories* relative to average daily OCS
(prednisolone-equivalent) over 96 weeks
* Zero, >0 to 4.0 mg/day, >4.0 to 7.5 mg/day, >7.5 mg/day
To investigate the maintenance of response after cessation of Nucala treatment

Time to EGPA recurrence up to Week 96 in participants who discontinued/withdrew 
from Nucala treatment due to symptom improvement.
Summaries and graphs of the Kaplan-Meier estimates of the proportion of 
participants with an EGPA recurrence over time will be produced. (Definition of 
EGPA recurrence: See Section 3.4).
To investigate the condition of complicated asthma

Annualized rate (event/year) of asthma exacerbation.
The annualized rate of asthma exacerbation will be analysed by using a negative 
binomial generalized linear model with logarithm of time as an offset variable, from 
which the estimated event per year and associated 95% CIs will be calculated.
CCI

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To explore the effect on pulmonary function
To explore the effect on the cardiac function
The statistical model was selected with reference to previous clinical studies of Nucala. 
However, for a model checking and diagnostics, the fit of the negative binomial 
generalized linear model will be investigated by calculating standardized deviance 
residuals and plotting these on a “Q-Q” plot with simulation-generated tolerance 
boundaries, where appropriate.
Further details of the secondary and exploratory analyses including covariates will be
provided in the RAP or the supplementary RAP, when needed.
4.7.
Subgroup Analysis
The following subgroups are of interest in this study. A separate exploratory analysis of 
the prespecified endpoints within each subgroup will be carried out. Subgroup categories 
may be further collapsed if there are a small number of participants within a subgroup.
The following subgroups are of interest:

Sex

Age

Duration of EGPA disease

Severity of EGPA disease

Adherence to recommended treatment regimen for Nucala

Current medical conditions (e.g., presence/absence of asthma, allergic rhinitis, 
etc.)

Medical history (e.g., presence/absence of asthma, allergic rhinitis, etc.)

Prior use of Nucala for asthma
CCI
CCI

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
Previous therapeutic regimen for EGPA disease (e.g., presence/absence of
plasma exchange therapy, operation, etc.)

Prior use of other biological medications

ANCA

Favourable treatment response with Nucala

Immuno-suppressive therapy

EGPA disease relapse

Clinical symptoms

COVID-19 infection
Further details of the subgroup analyses will be provided in the RAP.
5.
LIMITATIONS
This observational study aims at assessing outcomes in usual clinical settings, thereby 
characterizing the real-world treatment safety and effectiveness of Nucala in patients with 
EGPA. Nonetheless, there may be limitations on the generalizability of study results. The
patient recruitment to this study is biased toward those who have completed the PMS 
study prior to being enrolled in this study: the study enrolled only participants who have
responded well to Nucala and experienced no AEs leading to treatment discontinuation. 
This may lead to a patient selection bias affecting estimates of the long-term safety and 
effectiveness of Nucala obtained from the study. It might be helpful to compare patient 
backgrounds in this study with those from the PMS study in order to consider selection 
bias.
In addition, given that the sample size was estimated based on the anticipated occurrence 
of AEs, the study is unlikely to produce sufficient data for the analyses of effectiveness.
Therefore, it would be difficult to give a robust clinical interpretation regarding any of
the Nucala treatment-related outcomes in patients with EGPA. Hence, caution should be 
observed when interpreting the results of this study.
6.
STUDY CONDUCT, MANAGEMENT & ETHICS
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 the Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines;

Ethical Guidelines for Medical and Health Research Involving Human Subjects;

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
Applicable laws and regulations.
The protocol, protocol amendments, Informed consent form (ICF), and other relevant 
documents (e.g., advertisements) must be submitted to an Independent Ethics Committee 
(IEC) by the investigator and reviewed and approved by the IEC before the study is 
initiated.
Any amendments to the protocol will require IEC 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 IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IEC;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of the IEC, and all applicable regulations.
Other study oversight considerations (study conduct and management information) are
provided in Section 9.2 (Appendix 2).
6.1.
Legal Basis for Processing Individual Human Data
The authors confirm that study data is Individual Human Data (IHD) owned by GSK and 
that the proposed use of the IHD is Study Use* as outlined in the patient consent.
* Study Use means - the use of IHD is as stated in the original study protocol and/or 
aligned with the informed consent form to answer the study objectives and satisfy 
regulatory requirements and learn more about the Nucala studied and the 
disease/condition studied. This includes bringing the Nucala to market or maintaining 
market access which includes working with government agencies, insurers or health care
payers and aiding GSK’s understanding of clinical efficacy, safety, or effectiveness of the 
product.
6.2.
Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE are provided in Section 9.3 (Appendix 3).
The definitions of device-related safety events can be found in Section 9.5 (Appendix 5)
(Device deficiencies are covered in Section 6.2.6).

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The investigator and any qualified designees are responsible during the study 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, of special interest, or
considered related to Nucala.
Participants will be instructed to contact the investigator immediately should they 
manifest any signs or symptoms they perceive as serious.
6.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information
All AEs should be monitored throughout the study. All AEs and SAEs must be recorded 
in the eCRF.
All AEs and SAEs will be collected from the signing of the informed consent form until 
the final study visit.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours of 
recognition, as indicated in Section 9.3 (Appendix 3). The investigator will submit any
updated SAE data to the sponsor within 24 hours of it being available. AEs related to 
Nucala will be recorded and reported to the sponsor or designee within 5 work days of 
recognition.
Investigators are not obligated to actively seek AE/SAEs after the conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and they consider the event to 
be reasonably related to Nucala, the investigator must promptly notify the sponsor. As for 
death information, investigators are asked to report it to the sponsor throughout the study
period regardless of whether the death is related to Nucala or not.
6.2.2.
Method of Detecting AEs and SAEs

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Section 
9.3 (Appendix 3).

Care will be taken not to introduce bias when detecting an AE and/or an SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred method
to inquire about the occurrence of AE.
6.2.3.
Follow-up of AEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, AEs related to Nucala and AESIs will 

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be followed until the event is resolved, stabilized, or otherwise explained, or the 
participant is lost to follow-up. Further information on follow up procedures is given in 
Section 9.3 (Appendix 3).
6.2.4.
Regulatory Reporting Requirements for AEs and SAEs
Prompt notification by the investigator to the sponsor of AEs and SAEs are essential so 
that legal obligations and ethical responsibilities towards the safety of participants are
met.
6.2.5.
Pregnancy
No female participants who become pregnant while participating in the study are required 
to be withdrawn from the study.
Details of all pregnancies in female participants will be collected after obtaining informed 
consent and until the final study visit. There is no requirement to collect pregnancy 
information from female partners of male participants.
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 9.4
(Appendix 4).
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fatal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
6.2.6.
Medical Device Incidents (Including Malfunctions)
The Nucala solution are combination products comprising a medicine and a medical 
device.
The Nucala solutions are following;

Nucala subcutaneous injection 100 mg Syringe: a pre-filled syringe filled with the 
medicinal solution of mepolizumab which combined with a safety device.

Nucala subcutaneous injection 100 mg Pen: a pre-filled syringe filled with the 
medicinal solution of mepolizumab which combined with a pen-shaped inspirator.
In order to fulfil regulatory reporting obligations worldwide, the investigator is
responsible for the detection and documentation of events meeting the definitions of 
device incident that occurs during the study with such devices. 
The definition of a Medical Device Incident can be found in Section 9.5 (Appendix 5).

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NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 6.2.3 and Section 9.3 (Appendix 3) of the protocol. 
6.2.6.1.
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 
medical device is used. 

If the investigator learns of any device incident at any time after a participant has 
been discharged from the study, and such a device incident is considered reasonably 
related to a medical device provided for the study, the investigator will promptly 
notify the sponsor.

The method of documenting medical device incidents is provided in Section 9.5
(Appendix 5).
6.2.6.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE or SAE will be followed and reported 
in the same manner as for other AEs (see Section 6.2.3). Follow-up applies to all 
participants, including those who discontinue study intervention or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental
investigations as indicated to elucidate the nature and/or causality of the incident.
6.2.6.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Device incidents will be reported to the sponsor within 24 hours after the investigator
determines that the event meets the protocol definition of a device incident.

The Medical Device Incident Report Form will be sent to the sponsor by e-mail. If e-
mail is unavailable, then fax should be utilized.

The sponsor will be the contact for the receipt of device incident reports.
6.2.6.4.
Regulatory Reporting Requirements for Medical Device Incidents

Prompt notification by the investigator to the sponsor of safety information relating 
to medical devices is essential so that legal obligations and ethical responsibilities 
towards the safety of participants are met.

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6.2.6.5.
Medical Device Malfunctions

When medical devices (Nucala subcutaneous injection 100 mg Syringe/Pen) are
used, it may happen the malfunction (e.g., parts missing, device leaking, needle 
bent). The information provided in this section applies to occurrence and reporting of 
device malfunctions that are NOT associated with an AE/SAE.

Participants will be instructed to contact the investigator, when they experience a 
device malfunction.
6.3.
Adverse Event (AE), Pregnancy Exposure, and Incident
Reporting Related to Any GSK Product
All serious and non-serious AEs, pregnancy exposures, or incidents related to any GSK 
product will be collected and reported as described in the study-specific 
pharmacovigilance plan (sPVP). The sPVP is provided in Section 9.6 (Appendix 6). This
plan will include the following elements to ensure a comprehensive approach to safety 
event collection and reporting:

Supplier pharmacovigilance training

Investigator and site staff pharmacovigilance training 

Safety-specific roles

AEs, pregnancy exposures, and incidents collection and reporting processes

AE, pregnancy exposure, and incident collection forms

Frequency of data review

Reporting process and timelines

Interim reports

Reconciliation process

Study-specific PVP monitoring process

Provision of final study report
7.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Target audience
The information generated by this study will contribute to the published literature and 
provide Healthcare Professional (HCPs) with information about the use of Nucala in 
patients with EGPA. GSK stakeholders also have an interest in the information generated 
by this study. The results may be disseminated externally via manuscripts and/or 
presentations.

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Interim analysis and reporting
Interim analysis will be performed as specified in Section 4.4, and the corresponding
publications will be produced as necessary.
Final analyses and reporting
A final study report will be generated after the final analysis. The final report will 
encompass all planned analyses, including a description of the complete study 
population, as described in the RAP. The study protocol will be entered into the 
ClinicalTrials.gov. 
Any publication of the results from this study will be consistent with GSK’s publication
policy and guided by the International Committee of Medical Journal Editors
[International Committee of Medical Journal Editors, 2019].

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8.
REFERENCES
Akuthota P, Weller PF. Eosinophils and Disease Pathogenesis. Semin Hematol. 
2012;49:113-9.
Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am 
J Pathol. 1951;27:277-301. 
Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the 
production of eosinophils in human bone marrow cultures: comparison and interaction
with IL-1, IL-3, IL-6 and GMCSF. Blood. 1989;73:1504-12. 
Cottin V, Bel E, Bottero P, et al. Respiratory manifestations of eosinophilic 
granulomatosis with polyangiitis (Churg-Strauss). Eur Respir J. 2016;48:1429-41. 
GlaxoSmithKline Document Number 2012N142276_03 Study ID MEA115921. Protocol 
Amendment: A Double-blind, Randomised, Placebo-controlled Study to Investigate the 
Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis 
with Polyangiitis in Subjects Receiving Standard of Care Therapy. Report Date 24-JUN-
2016.
GlaxoSmithKline PMS protocol No. 208505 NUCALA Subcutaneous Injection Special
Drug Use Investigation (EGPA, Long-term) ver. 3.0. 30-Jul-2019.
Groh M, Paqnoux C, Baldini C, et al. Eosinophilic granulomatosis with polyangiitis
(Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and
management. Eur J Intern Med. 2015;26:545-53. 
Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. clinical study and 
long-term follow-up of 96 patients. Medicine (Baltimore). 1999;78:26-37. 
Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in 
Churg-Strauss syndrome. Ann N Y Acad Sci. 2005;1051:121-31.
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals. Available at
URL (2020.5.8), http://www.ICMJE.org; 2019. 
Japan Intractable Diseases Information Center. Eosinophilic granulomatosis with 
polyangiitis (designated intractable disease 45). Available at URL (2020.3.31), 
https://www.nanbyou.or.jp/entry/3879; 2019.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus 
Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1-11. 
Khoury P, Grayson PC, Klion AD. Eosinophils in vasculitis: characteristics and roles in 
pathogenesis. Nat Rev Rheumatol. 2014;10:474-83. 

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Lopez AF, Sanderson CJ, Gamble JR, et al. Recombinant human interleukin 5 is a 
selective activator of human eosinophil function. J Exp Med. 1988;167:219-24. 
Mahr A, Guillevin L, Poissonnet M, et al. Prevalences of polyarteritis nodosa, 
microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a 
French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis
Rheum. 2004;51 (1):92-9. 
Martin RM, Wilton LV, Mann RD. Prevalence of Churg-Strauss syndrome, vasculitis, 
eosinophilia and associated conditions: retrospective analysis of 58 prescription-event 
monitoring cohort studies. Pharmacoepidemiol Drug Saf. 1999;8 (3):179-89.
NUCALA FOR S.C. INJECTION (Mepolizumab) Product Information. 3, 2020.
Rothenberg ME, Hogan SA. The eosinophil. Annu Rev. Immunol. 2006;24:147-74. 
Sada KE, Amano K, Uehara R, et al. A nationwide survey on the epidemiology and 
clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in
Japan. Mod Rheumatol. 2014;24(4):640-4; doi: 10.3109/14397595.2013.857582. 
Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or Placebo for Eosinophilic 
Granulomatosis with Polyangiitis. N Engl J Med. 2017;376:1921-32.

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9.
APPENDIX
9.1.
APPENDIX 1: SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening
Observation period
Follow-up1
Time period for which data should be collected at
usual EGPA healthcare visits,
if this is possible
Up to 4 weeks before Week 02
Week 0
Baseline
Week 12 to 96;
no more frequently than
every 12 weeks (±4weeks)
Early 
withdrawal
Up to 96 weeks
after Week 0
(Screening2) (Retrospective data3
collection)
Informed consent
X4
Inclusion and exclusion criteria
X
Demography
X
Administration status of Nucala for EGPA
X
X
X
X
X5
Concomitant medication
X
X6
X
X
X
X
Concomitant therapies
X
X7
X
X
X
X
Adverse events
X
Clinical symptoms
X
X
X
X
X
Hospitalization for EGPA-related events
X8
X
X
X
X
ER/Unscheduled visit for EGPA-related events
X8
X
X
X
X
Asthma exacerbation
X8
X
X
X
X
Clinical laboratory parameters9, if performed
X
X
X
X
X
Lung function, if performed
X
X
X
X
X
Ejection fraction, if performed
X
X
X
X
X
Pregnancy reporting
EGPA recurrence
X
1.
The follow-up period is only applicable for participant who discontinued the treatment. If drug-related adverse events occurred, contact the sponsor.
2.
Screening and Week 0 can occur on the same day.
3.
Retrospective data within 12 weeks (otherwise specified) before the first dose of Nucala for EGPA.
4.
Informed consent must be obtained prior to start of any study's procedure.
5.
Only for in case of receiving the re-treatment of Nucala.
6.
Only for other biological products, Nucala for asthma, corticosteroid, immunosuppressants, and immunoglobulin.
7.
Only for EGPA therapies.
8.
Number of events within 48 weeks before the first dose of Nucala for EGPA.
9.
Haematological parameters tested are: CCI

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9.2.
APPENDIX 2: STUDY OVERSIGHT CONSIDERATIONS
9.2.1.
Informed Consent Process
The investigator or their representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of local 
regulations, where applicable, and the 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 authorised 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.
9.2.2.
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 their 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 their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities.
9.2.3.
Plans for Disseminating and Communicating Study Results
GSK will provide the investigator with the full summary of the study results.
The procedures and timing for public disclosure of the protocol and results summary and 
for development of a manuscript for publication for this study will be in accordance with
GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results
provide important scientific or medical knowledge. 

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9.2.4.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and
quality such as Risk Management and Mitigation Strategies and Analytical Risk 
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organisations [CROs]).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorised 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, Ethical Guidelines for Medical 
and Health Research Involving Human Subjects, 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 10 years from the issue of the final Clinical 
Study Report (CSR) or equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.
9.2.5.
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. 
The definition of what constitutes source data will be found in the source data agreement.

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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. 
9.2.6.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the sponsor's procedures, or Ethical Guidelines for Medical 
and Health Research Involving Human Subjects;

Inadequate recruitment of participants by the investigator. 
9.2.7.
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 multi-center studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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9.3.
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-
UP, AND REPORTING
9.3.1.
Definition of an AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with study participation, whether or not considered related to study 
participation.
NOTE: An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with study participation.
Events Meeting the AE Definition

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically
significant in the medical and scientific judgment of the investigator (i.e., not related
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study entry 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 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.

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. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

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
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.
9.3.2.
Definition of an SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe.
Requires inpatient hospitalisation or prolongation of existing hospitalisation
In general, hospitalisation 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 hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is
not considered an AE.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
Is a congenital anomaly/birth defect
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise 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 hospitalisation, or development of drug dependency or drug abuse.

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9.3.3.
Recording and Follow-Up of AEs and SAEs
SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant information on AE/SAEs in the eCRF.

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 eCRF page.

There may be instances when copies of medical records for certain cases are
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the
study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilised 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 participation 
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 participation 
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 they 

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have reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an AE/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 AE/SAE data to GSK.

The investigator may change their opinion of causality in light of follow-up 
information and send an AE/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 AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE 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, 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 eCRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.

The investigator will submit any updated drug related AE data to GSK within 5 work 
days of receipt of the information.
9.3.4.
Reporting of AE and SAE to GSK
AE and SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting AE/SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to 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 AE/SAE from a study participant or receives

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updated data on a previously reported AE/SAE after the electronic data collection 
tool has been taken off line, then the site can report this information on a paper SAE
form (see next section).

Contacts for AE/SAE reporting can be found in the SRM.
AE and SAE Reporting to GSK via Paper CRF

Facsimile or email transmission of the AE/SAE paper CRF is the preferred method 
to transmit this information to the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the AE/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 AE/SAE CRF pages within the designated reporting time 
frames.

Contacts for AE/SAE reporting can be found in the SRM.

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9.4.
APPENDIX 4: 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.

The initial information will be recorded on the appropriate form and submitted to 
GSK within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will
be reported as such. 

Any SAE occurring as a result of a post-study pregnancy which is considered
reasonably related to Nucala by the investigator, will be reported to GSK as 
described in Section 9.3 (Appendix 3). While the investigator is not obligated to
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating may request 
continuation of study intervention.
9.5.
APPENDIX 5: 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
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.

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
Not all incidents lead to death or serious deterioration in health. The non-occurrence
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 intervention 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.
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 Section 9.3 (Appendix 3).

GSK will ask to investigator about medical device incidents to complete the form.

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.

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
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.
9.6.
APPENDIX 6: STUDY-SPECIFIC PHARMACOVIGILANCE 
PLAN (SPVP)
sPVP Element
Study-Specific Pharmacovigilance Plan (sPVP)
(tick applicable statements)
Supplier/
Vendor PV training
N/A – No supplier/vendor involved that could be in receipt of serious 
and/or non-serious AEs, pregnancy exposures, and/or incidents related to 
any GSK product
Supplier/vendor PV training will be conducted using the agreed method
and current, approved content, prior to beginning the study. Training will be 
completed annually and documented.
Investigator and
site staff PV
training
N/A – No Investigator and/or site staff involved that could be in receipt of
serious and/or non-serious AEs, pregnancy exposures, and/or incidents 
related to any GSK product
Investigator and/or site staff PV training will be conducted using the 
agreed method and current, approved content, prior to beginning the study. 
Training will be completed annually and documented. 
Safety-specific 
roles
SAP is responsible for identifying, collecting, reporting and reconciling
AEs, pregnancy exposures, and/or incidents related to any GSK product
Investigator/monitoring staff is responsible for identifying, collecting, 
reporting and reconciling AEs, pregnancy exposures, and/or medical device 
incidents related to any GSK product
AEs, pregnancy 
exposures, and
incidents collection 
and reporting 
processes
The following will be identified, collected, and reported to GSK Japan safety:  

serious and/or non-serious AEs, related to any GSK
product 

pregnancy exposures to any GSK product (note: in the case
of a pregnancy registry, the registry will manage exposures)

incidents related to any GSK product
For studies that evaluate a GSK product, consult with SMG Pharma Safety 
SERM to determine if additional data is required and complete the 
information below:
Study does not evaluate a GSK product - No additional study-specific 
safety data is to be collected
Study evaluates a GSK product - No additional study-specific safety data 
is to be collected
Study evaluates a GSK product - additional study-specific safety data is 
to be collected
AE, pregnancy 
exposure, and 
GSK Global Adverse Event, Pregnancy Exposure, and Incident 
Reporting Form for Epidemiology and Health Outcome studies 

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sPVP Element
Study-Specific Pharmacovigilance Plan (sPVP)
(tick applicable statements)
incident collection 
forms
Alternative collection form(s) will be utilized 
Investigators will report using the following forms:
Adverse Event Report form (Japanese)
Pregnancy Initial Notification Form (Japanese)
Pregnancy Outcome Form (Japanese)
Monitoring staff will report using the following forms:
Safety Information Notification Form for CRAs (Japanese)
Incident Information Notification Form (Japanese)
Frequency of data
review
N/A – No batch reviewing of the data. 
Batch review will be conducted
Reporting process
and timelines for 
AEs, pregnancy 
exposures and 
medical device 
incidents
Severe adverse events, pregnancy exposures, and/or incidents related to 
any GSK product will be reported to SMG Pharma Safety within 24 hours of 
awareness of the event. Adverse events will be reported to SMG Pharma 
Safety within 5 work days of awareness of the event.
Interim study 
reports
N/A – No interim study reports are planned.
Interim study reports will be shared with the SERM product specialist / 
physician for review of the interim report safety data 
Reconciliation
process
A log of all AEs, pregnancy exposures, and incidents identified during 
the research will be provided to GSK central safety (for multiple country
studies) or local safety (for single country studies) on a Reconciliation Form. 
Central or local safety will confirm all reports listed on the log are included on 
the GSK Safety Database. 
Study-specific PVP 
monitoring process
SAP will review the sPVP elements and discuss during regular study
team and/or supplier meetings to ensure the plan is working effectively. 
Other, please describe.
Provision of final 
study report
A summary of AEs, pregnancy exposures, and/or incidents related to 
any GSK product will be included in the final study report.  The final draft 
study report will be provided to the SERM product specialist / physician for 
review and approval where a specific asset is involved.