A Multi-centre, Open-label Extension, Safety Study to Describe the Long-term Clinical Experience of Mepolizumab in Participants With Hypereosinophilic Syndrome (HES) From Study 200622
Phase: PHASE3
Conditions: Hypereosinophilic Syndrome
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A multi-centre, open-label extension, safety study to describe the long-
term clinical experience of mepolizumab in participants with hypereosinophilic syndrome 
(HES) from Study 200622
Protocol Number: 205203/ 02
Short Title: A multi-centre, open-label extension, safety study of mepolizumab in 
participants with hypereosinophilic syndrome (HES) from Study 200622
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 can be found in the Study Reference 
Manual (SRM).
Regulatory Agency Identifying Number(s): IND#: BB-IND 011295, EudraCT#: 2017-
000184-32
Approval Date: 16-NOV-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 02
16-Nov-2017
Amendment 01
13-Jan-2017
Original Protocol
02-Nov-2016
Amendment 02 16-NOV-2017
Overall Rationale for the Amendment: To add the optional biomarker sub-study and 
update the text around the HES therapy adjustment after HES flare considering therapy 
reduction during the study.
Section # and 
Name
Description of Change
Brief Rationale
2. Schedule of 
Activities
9.8.2. Biomarker 
Sub-study
Information about the optional 
biomarker sub-study and sample 
collection schedule was added to 
the protocol.
The optional biomarker sub-study has 
been added.
9.1.1. HES Flare
The text was updated from 
“Investigators are encouraged, as 
medically appropriate, to return the 
subject’s treatment regimen to the 
baseline (Visit 2) after the flare has 
resolved.” to “Investigators are 
encouraged, as medically 
appropriate, to return the subject’s 
treatment regimen to level prior to 
the flare after the flare has 
resolved.”
The text around HES therapy 
adjustment after the HES flare has 
been updated considering that 
investigators may adjust the 
participants’ background HES therapy 
per standard of care starting at Visit 2 
(approximately 4 weeks after the first 
dose).
1. Synopsis, 2. 
Schedule of 
Activities, 3. 
Background, 5.1. 
Overall Design, 
7.7. Treatment 
after the End of the 
Study
‘MHE104317/MHE112562’ has 
been replaced with ‘mepolizumab 
HES expanded access’.
GSK tracking numbers have been 
replaced with the term, ‘mepolizumab 
HES expanded access’ to describe the 
program.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................12
3.1.
Study Rationale ..........................................................................................12
3.2.
Background ................................................................................................12
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................22
3.3.3.
Overall Benefit:Risk Conclusion...................................................22
4.
OBJECTIVES AND ENDPOINTS...........................................................................23
5.
STUDY DESIGN ....................................................................................................24
5.1.
Overall Design ............................................................................................24
5.2.
Number of Participants ...............................................................................25
5.3.
Participant and Study Completion...............................................................25
5.4.
Scientific Rationale for Study Design ..........................................................25
5.5.
Dose Justification........................................................................................26
6.
STUDY POPULATION...........................................................................................26
6.1.
Inclusion Criteria.........................................................................................26
6.2.
Exclusion Criteria........................................................................................27
6.3.
Screen Failures...........................................................................................28
7.
TREATMENTS.......................................................................................................29
7.1.
Treatments Administered............................................................................29
7.2.
Method of Treatment Assignment ...............................................................29
7.3.
Blinding.......................................................................................................30
7.4.
Preparation/Handling/Storage/Accountability..............................................30
7.5.
Treatment Compliance................................................................................30
7.6.
Concomitant Therapy..................................................................................31
7.7.
Treatment after the End of the Study ..........................................................31
8.
TREATMENT DISCONTINUATION CRITERIA......................................................31
8.1.
Discontinuation of Study Treatment ............................................................31
8.1.1.
Liver Chemistry Stopping Criteria ................................................32
8.1.2.
QTc Stopping Criteria ..................................................................33
8.1.3.
Temporary Discontinuation of Mepolizumab ................................33
8.1.4.
Rechallenge.................................................................................33
8.1.4.1.
Study Treatment Restart or Rechallenge....................33
8.2.
Withdrawal from the Study..........................................................................33
8.3.
Lost to Follow Up........................................................................................34
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
9.1.
Efficacy Assessments.................................................................................34

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9.1.1.
HES Flare....................................................................................34
9.1.2.
HES Core Assessments (Clinician Assessment)..........................35
9.2.
Adverse Events...........................................................................................37
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................38
9.2.2.
Method of Detecting AEs and SAEs.............................................38
9.2.3.
Follow-up of AEs and SAEs.........................................................38
9.2.4.
Regulatory Reporting Requirements for SAEs .............................38
9.2.5.
Cardiovascular and Death Events................................................39
9.2.6.
Pregnancy ...................................................................................39
9.3.
Treatment of Overdose...............................................................................39
9.4.
Safety Assessments ...................................................................................40
9.4.1.
Physical Examinations.................................................................40
9.4.2.
Vital Signs....................................................................................40
9.4.3.
Electrocardiograms......................................................................40
9.4.4.
Clinical Safety Laboratory Assessments ......................................41
9.5.
Pharmacokinetics .......................................................................................41
9.6.
Pharmacodynamics ....................................................................................41
9.7.
Genetics .....................................................................................................41
9.8.
Biomarkers .................................................................................................42
9.8.1.
Immunogenicity Assessments......................................................42
9.8.2.
Optional Biomarker Sub-study .....................................................42
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................42
10. STATISTICAL CONSIDERATIONS........................................................................42
10.1.
Sample Size Determination ........................................................................42
10.2.
Populations for Analyses ............................................................................43
10.3.
Statistical Analyses.....................................................................................43
10.3.1.
Safety Analyses...........................................................................43
10.3.2.
Efficacy, Pharmacodynamic, and Pharmacokinetic 
Analyses......................................................................................43
10.3.3.
Interim Analyses ..........................................................................43
11. REFERENCES.......................................................................................................44
12. APPENDICES........................................................................................................46
12.1.
Appendix 1: Abbreviations and Trademarks................................................46
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................49
12.3.
Appendix 3: Study Governance Considerations..........................................51
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................55
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................60
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................63
12.7.
Appendix 7: Anaphylaxis Criteria ................................................................66
12.8.
Appendix 8: Classification of Heart Failure..................................................67
12.9.
Appendix 9: Definition of Cardiovascular Events.........................................68
12.10. Appendix 10: Protocol Amendment History.................................................69

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1.
SYNOPSIS
Protocol Title: A multi-centre, open-label extension, safety study to describe the 
long-term clinical experience of mepolizumab in participants with hypereosinophilic 
syndrome (HES) from Study 200622
Short Title: A multi-centre, open-label extension, safety study of mepolizumab in 
participants with hypereosinophilic syndrome (HES) from Study 200622
Rationale:
Study 200622 is a 32-week treatment period, randomized, double-blind, placebo-
controlled, parallel group, multicentre study of mepolizumab in adolescent and adult 
participants with severe hypereosinophilic syndrome (HES) receiving standard of care 
(SoC) therapy.  Participants will be randomized in a 1:1 ratio to receive either 300 mg 
mepolizumab or placebo subcutaneously (SC) every 4 weeks while continuing their HES 
therapy.
The rationale for Study 205203 is to have Study 200622 participants continue 4-weekly 
dosing with open-label mepolizumab 300mg SC for an additional 20 weeks after 
completing the 32-week study assessments post-randomization.  While the 32-week 
phase 3 data from Study 200622 will be the basis to demonstrate the clinical benefit of 
mepolizumab and support the registration of mepolizumab for the indication of HES, 
combining the data from 205203 and 200622 will provide up to 52-week exposure data to 
further characterize the long-term safety profile of mepolizumab and provide additional 
data on the clinical benefit in HES patients beyond 32 weeks.
This study will provide Study 200622 participants who meet the current study eligibility 
criteria the option of receiving treatment with mepolizumab as an add-on to their SoC 
treatment for HES post-study.
Objectives and Endpoints:
Objectives
Endpoints
Primary - Safety

To describe the long-term safety profile of 
mepolizumab in participants with HES who 
took part in Study 200622.

Adverse events (AEs) [serious and non-
serious]

Anti-drug antibody
Other – Safety

To describe the long-term safety profile of 
mepolizumab in participants with HES who 
took part in Study 200622.

Vital signs

12-lead ECG

Hematological and clinical laboratory tests

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Objectives
Endpoints
Exploratory - Efficacy

To assess the effect of long-term use of 
mepolizumab on multiple clinical outcomes.

Rate of HES flare#

Change in the mean daily OCS dose from 
Weeks 0-4 to Weeks 16-20

Proportion of participants who achieve a
mean daily OCS (prednisone/prednisolone 
or equivalent) dose of 7.5mg during 
Weeks 16-20
Pharmacodynamic (PD)

To assess the effect of long-term use of 
mepolizumab on a PD marker

Blood eosinophil levels
# HES flare as defined in Section 9.1.1.
Overall Design:
This is a multi-centre, open-label extension, 20-week treatment period, safety study of 
mepolizumab in adolescent and adult participants with HES who took part in the 
phase 3 Study 200622.
Study 200622 participants who meet one of the following criteria will be screened to 
continue with Study 205203:
i. Completion of the 32-week treatment period in Study 200622,
or
ii. If the participant was withdrawn from study treatment prematurely during the 
200622 study, but continued in the study per protocol (including HES flare-
related assessments) until 32 weeks from randomization.
Eligible participants will receive 300mg SC mepolizumab every 4 weeks starting 
approximately 32 weeks after the first dose of study treatment in Study 200622.  In this 
OLE Study 205203, the final dose of mepolizumab will be administered at Visit 5 (Week 
16).  Assessments during the Visit 6 (20 weeks after first dose and 4 weeks after the last 
dose) will complete the study treatment period.
During Study 205203, investigators will be blinded to the blood eosinophil count 
(Section 12.2) for the sample collected at Visit 1 (1st dosing visit), after which blood 
eosinophil counts will be unblinded starting at Visit 2.  Investigators may adjust the 
participants’ background HES therapy per standard of care starting at Visit 2 
(approximately 4 weeks after the first dose).
Participants who complete assessments at Visit 6 (Week 20) may continue with 
mepolizumab treatment via mepolizumab HES expanded access (e.g., MHE104317, 

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MHE112562), where local regulation permits.  Study 205203 participants who do not 
continue with mepolizumab HES expanded access will have an additional follow-up 
assessment at Visit 7 (28 weeks after first dose and 12 weeks after the last dose of 
mepolizumab).
Number of Participants:
Approximately 80 participants will be randomized in the initial recruitment phase for 
Study 200622.  The proportion of participants that have an HES flare will be monitored 
and the total number of participants randomized may be increased if the blinded overall 
rate is predicted to be <30%.  The sample size may be increased up to a maximum of 
120 participants in total.  Participants who completed required assessments for 32 weeks 
starting from randomization in Study 200622 may be evaluated for eligibility to 
participate in Study 205203.
Treatment Groups and Duration:
All participants will receive 300mg mepolizumab SC every 4 weeks for the duration of 
20 weeks.

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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening/Baseline
20-Week Treatment Period
WD
(4 weeks 
post-last 
dose) 1 
wk
Study Visit 7
Additional 
follow-up
(12 weeks 
post-last dose
1 wk
Flare
Notes
Study Visit
1
2
3
4
5
6
Study Weeks
0
4

1 
wk
8
1 
wk
12
1 
wk
16
1 
wk
20
1 
wk
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including 
height and weight
X
Past and current medical conditions
X
Urine pregnancy test (WOCBP only) –
serum test if locally required
X
X
X
X
X
X
X
X
Test is required for WOCBP on study 
treatment until the last follow-up.
Clinical safety laboratory assessments 
(include liver chemistries)
1
2
2
2
2
1
1
2
1: Hematology, chemistry, aldolase, 
troponin, urinalysis
2: Hematology, chemistry, aldolase, 
troponin
PK
X
X
X
X
Immunogenicity (Anti-drug antibody)
X
X
X
X

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Procedure
Screening/Baseline
20-Week Treatment Period
WD
(4 weeks 
post-last 
dose) 1 
wk
Study Visit 7
Additional 
follow-up
(12 weeks 
post-last dose
1 wk
Flare
Notes
Study Visit
1
2
3
4
5
6
Study Weeks
0
4

1 
wk
8
1 
wk
12
1 
wk
16
1 
wk
20
1 
wk
Sample collection for optional biomarker 
sub-study
X
X
X
X
Sample collection for the optional 
biomarker sub-study should be done 
after obtaining a written consent.
12-lead ECG
X
X
X
Vital signs
X
X
X
X
X
X
X
X
HES Core Assessments/HES flare 
details
X
X
X
X
X
X
X
X
Study treatment
X
X
X
X
X
AE review
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
wk: week

The baseline visit is the exit visit (32 weeks after randomization) for Study 200622.  Assessments that are captured as part of the exit visit for Study 200622 do 
not have to be repeated.  Information will be transferred accordingly.

Biological sample collection (for clinical safety laboratory, PK, and immunogenicity) is done prior to administration of study treatment on dosing visits (Visits 1 
2, 3, 4, 5) as specified in the SoA.

WD: Prematurely discontinuation of mepolizumab (~4 weeks after the last dose of mepolizumab).

Visit 7 - Additional follow-up is required 12 weeks after the last dose of mepolizumab for participants who do not continue with mepolizumab via mepolizumab 
HES expanded access at that time.

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
Participants who prematurely discontinue study treatment will attend 4-weekly study visits (e.g., Visit 2, 3, 4, 5) to complete all assessments/procedures as noted 
in the SoA except for administration of study treatment and pre-dose pregnancy test for women of childbearing potential (WOCBP).  For additional assessments 
at 4 weeks and 12 weeks after the last dose of mepolizumab (duplicate assessments in 4-weekly study visits and 4 weeks/12 weeks post-last dose assessments are 
completed only once), refer to ‘WD’ and ‘Visit 7- Additional follow-up’.

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
Study 200622 is a 32-week treatment period, randomized, double-blind, placebo-
controlled, parallel group, multicentre study of mepolizumab in adolescent and adult 
participants with severe hypereosinophilic syndrome (HES) receiving standard of care 
(SoC) therapy.  Participants will be randomized in a 1:1 ratio to receive either 300 mg 
mepolizumab or placebo subcutaneously (SC) every 4 weeks while continuing their HES 
therapy.
The rationale for Study 205203 is to have Study 200622 participants continue 4-weekly 
dosing with open-label mepolizumab 300mg SC for an additional 20 weeks after 
completing the 32-week study assessments post-randomization.  While the 32-week 
phase 3 data from Study 200622 will be the basis to demonstrate the clinical benefit of 
mepolizumab and support the registration of mepolizumab for the indication of HES, 
combining the data from 205203 and 200622 will provide up to 52-week exposure data to 
further characterize the long-term safety profile of mepolizumab and provide additional 
data on the clinical benefit in HES patients beyond 32 weeks.
This study will provide Study 200622 participants who meet the current study eligibility 
criteria the option of receiving treatment with mepolizumab as an add-on to their SoC 
treatment for HES post-study.
3.2.
Background
HES is a heterogeneous group of chronic inflammatory disorders characterized by 
persistent eosinophilia (elevated blood eosinophil counts) and diverse organ involvement, 
punctuated by flares of disease worsening.  Inadequate HES treatment can lead to 
profound end-organ damage and increased mortality.  Given the clinical heterogeneity of 
HES, clinicians use diverse classes of medications (such as high doses of oral 
corticosteroids), most of which are not approved to treat HES, have detrimental side 
effects, and may not result in complete remission of disease.
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa, mAb) which is specific 
for human IL-5.  Mepolizumab blocks binding of human IL-5 (hIL-5) to the alpha chain 
of the IL-5 receptor complex expressed on the eosinophil cell surface.  In conditions 
where eosinophilia is considered to play an important part in the pathology, including 
severe eosinophilic asthma and Eosinophilic Granulomatosis with Polyangiitis (EGPA), a 
consistent reduction in blood eosinophil counts is observed in association with 
mepolizumab administration, with concomitant clinical improvement [Haldar, 2009; 
Kim, 2010; Moosig, 2011; Nair, 2009; Ortega, 2014; Pavord, 2012].  The potential 
benefit of mepolizumab in patients with HES has been supported by clinical data from 
previously completed clinical studies (MHE100185 [Rothenberg, 2008], MHE100901 
[Roufosse, 2013], CRT112446 [Stein, 2008]).  In addition, the ongoing mepolizumab 
HES expanded access program (MHE104317 as well as named patient supply 
[MHE112562 and 112000]) with over 200 patients (interim data cut-off date of 23 

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September 2013) demonstrated that mepolizumab is well tolerated and provides long-
term disease control to some patients with HES [Duncan, 2015].
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of mepolizumab may be found in the Investigator’s 
Brochure (IB).

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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) - mepolizumab
Risk of systemic reactions including allergic reactions

In the placebo-controlled severe asthma 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 (6% in the 
mepolizumab [all doses combined] group and 
3% in the mepolizumab [100 mg SC/75 mg IV] 
combined group as compared with 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 including 
anaphylaxis have been reported.

Reactions reported to date across the 
mepolizumab program are summarized in the IB 
‘Adverse Events of Special Interest’ section; see 
also ‘Special Warnings and Special Precautions 
for Use’ section located in Section 6 titled 
‘Summary of Data and Guidance for the 
Investigator’.

Daily monitoring of serious AEs (SAEs) by GSK 
Medical Monitor; regular systematic review of 
AE/SAE data from ongoing studies by a GSK 
study team and/or GSK safety review team.

Customized AE and SAE case report form 
(CRF) utilized for targeted collection of systemic 
reactions data.

Utilization of anaphylaxis diagnostic criteria as 
outlined by the 2006 Joint National Institute of 
Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network (NIAID/FAAN) 2nd 
Symposium on Anaphylaxis to collect data on 
reports of anaphylaxis (see Section 12.7).

Participants are monitored in clinic for 1 hour for 
the 1st three administrations following dosing 
with mepolizumab, then follow monitoring 
policies for the center.
Risk of local injection site reactions

In the placebo-controlled severe asthma studies 
an increase in the incidence of local injection 
site reactions has been observed with SC 
administration of mepolizumab compared with 

Daily monitoring of serious AEs (SAEs) by GSK 
Medical Monitor; regular systematic review of 
AE/SAE data from ongoing studies by a GSK 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
placebo (8% vs. 3%). There have been no 
reports of severe reactions. Pain, erythema, 
swelling, itching, and burning sensation were the 
most common symptoms reported.

Local injection site reactions reported to date 
across the mepolizumab program are 
summarized in the Adverse Events of Special 
Interest’ section of the IB; see also ‘Section 6
titled ‘Summary of Data and Guidance for the 
Investigator’.
study team and/or GSK safety review team. 

Customized AE and SAE case report form 
(CRF) will be utilized for targeted collection of 
systemic reactions data.
Potential risk of immunogenicity

Biopharmaceutical products may elicit anti-drug 
antibody (ADA) and neutralizing antibodies 
(NAB), which have the potential to modulate 
pharmacokinetics (PK), pharmacodynamics 
(PD) or produce adverse reactions. However, 
humanized and fully human antibodies are less 
immunogenic than mouse or chimeric 
monoclonal antibodies.

In the placebo controlled severe asthma studies 
low incidence (6% 100 mg SC and 2% all IV 
doses) and low titer of ADA and neutralizing 
antibodies have been reported. To date there 
have been no apparent association with adverse 
events, loss of disease control and/or markedly 
altered PK or PD profiles associated with anti-
mepolizumab antibodies in any participants.
Immunogenicity data reported to date across the 
mepolizumab development program are summarized 
in the IB; see Section 5.4. ‘Clinical Immunogenicity’ 
To characterize the potential risk of immunogenicity:

Blood samples are collected in clinical studies 
for detection of both ADA and NAB.

For participants who develop anti-mepolizumab 
antibodies systematic review of AE/SAE data at 
the end of the study will be conducted.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and a summary of immunogenicity findings in the 
‘Other Potentially Clinically Relevant Information for 
the Investigator’ section located in Section 6 titled 
‘Summary of Data and Guidance for the Investigator’.
Potential risk for adverse cardiovascular (CV) effects

Mepolizumab binding was restricted to human 
lymphoid tissues in an immunohistochemistry 
tissue binding study suggesting a low likelihood 
of non-pharmacologic effects on CV function.

No AEs concerning cardiac conduction or 
repolarization evident in cynomolgus monkeys 
at doses at least 10-fold in excess of humans 
dosed at 10 mg/kg or 750 mg.

No clinically relevant trends observed in 
electrocardiogram (ECG) data in humans.

In study MHE100185 HES participants received 
mepolizumab 750 mg IV every 4 weeks for up to 
36 weeks, cardiac events were reported by 7% 
of participants in both mepolizumab and placebo 
arm s.  There was 1 death, due to cardiac arrest 
in the mepolizumab group not considered 
related to mepolizumab treatment.  This subject 
had severe HES with multiple cardiovascular 
complications and concurrent renal failure.  
Other cardiac disorder AE occurred is palpitation
(2 participants in the mepolizumab group and 1 
subject in the placebo group).  The following 
events reported in the placebo arm only:  
cardiovascular disorder, arterial dilatation, 
ventricular dysfunction and ventricular 

Daily monitoring of SAEs by GSK Medical 
Monitor; regular systematic review of AE/SAE 
data from ongoing studies by GSK study team 
and/or GSK safety review team.

CV monitoring for study includes:
o
Enhanced baseline collection of CV risk 
factors & functional status;
o
Baseline evaluation of clinical symptoms of 
ischemic heart disease, if clinically indicated.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
hypertrophy.

In study MHE100901 (open-label extension 
[OLE] study to MHE100185 above), participants 
received mepolizumab 750 mg IV for up to 67 
months, 1 fatal and 2 non-fatal SAEs reported 
due to cardiac failure, none considered related 
to mepolizumab.

In study MHE104317 (compassionate use) 7% 
of patients reported SAEs of cardiac disorders. 3 
SAEs reported, 1 secondary to CHF, 1 due to 
cardiac arrest, & 1 due to MI, all were 
considered unrelated to mepolizumab.
Severe Asthma:

In Study MEA112997, a numeric imbalance in 
the number of serious cardiac events was 
observed for mepolizumab (7 participants: 2/153 
on 75 mg IV [3 events: myocardial ischemia, 
acute myocardial infarction, coronary artery 
thrombosis], 1/152 on 250 mg IV [1 event: 
coronary artery insufficiency] and 4/156 on 
750 mg IV [4 events: myocardial ischemia, atrial 
fibrillation, myocardial infarction and 
supraventricular tachycardia]) compared with 
placebo (1 of 155 participants reported atrial 
flutter). This imbalance was not replicated in 
subsequent Phase III placebo-controlled 
studies, MEA115588 and MEA115575, and it 
was not observed previously in other controlled 
asthma trials or in other populations studied 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
such as HES.

In the OLE studies, cardiovascular events were 
similar in frequency and type with those reported 
from the placebo-controlled severe asthma 
(PCSA) studies.
Cardiovascular events in the severe asthma program 
are summarized under AE of special interest (AESI) 
section of the IB.
Potential risk of alterations in immune response, 
potentially leading to increase in infections

This is a theoretical concern with biologics; 
however, critical review of preclinical toxicity 
data and pharmacological properties of 
mepolizumab suggests that the risk for potential 
immunotoxicity is low.

No evidence of increased incidence of infections 
in any preclinical studies.

Murine data demonstrate that IL-5 antagonism is 
unlikely to influence cellular or humoral 
immunity, particularly in response to parasitic 
infections.

No mepolizumab-related effects on lymphocyte 
immunophenotyping in monkeys or humans, 
including T-cell activation, distribution of 
CD4/CD8 subtypes or Th1/Th2 cytokine 
patterns, B-cells, NK cells or γδ-T-cells.

Across all PCSA, the frequency of participants 
with infections was similar between placebo 
(239/412 or 58%), mepolizumab 100 mg SC 

Eosinophils may be involved in the 
immunological response to some helminth 
infections.  Participants with recent parasitic 
(helminth) infections will be excluded from the 
study or required to be adequately treated for 
helminth infections before initiation of study 
treatment.  If a subject becomes infected whilst 
receiving study treatment and does not respond 
to anti-helminth treatment, temporary 
discontinuation of study treatment should be 
considered in consultation with GSK Medical 
Monitor.

Daily monitoring of SAE by GSK Medical 
Monitor; regular systematic review of AE/SAE 
data from ongoing studies by a GSK study team 
and/or GSK safety review team

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
(136/263 or 52%) and mepolizumab 75 mg IV 
(209/344 or 61%).

In the OLE studies, rates of infections, including 
all infections, serious and opportunistic 
infections, were similar to those from the PCSA 
studies

Infections reported to date across the 
mepolizumab development program are 
summarized in the IB; see ‘Special Precautions 
and Warnings’ (for exclusion of participants with 
underlying parasitic infections) and ‘Undesirable 
Effects’ HES subsection (for very common 
infections of nasopharyngitis, upper respiratory 
tract infection (URTI), rhinitis and bronchitis 
reported in other patient populations) sections 
located in Section 6 titled ‘Summary of Data and 
Guidance for the Investigator’.
Potential risk of alterations in immune response 
potentially leading to increase in malignancies

Non-clinical and clinical experience to date does 
not support a role for mepolizumab in the 
development of malignancies.  No evidence of 
defective tumor surveillance in IL-5 or 
eosinophil-deficient mice.  Mepolizumab is not 
believed to possess an inherent carcinogenic 
potential or increase the susceptibility to tumor 
formation secondary to significant 
immunosuppression, and there is no evidence to 
date that mepolizumab has produced 
immunosuppression in animals.

Reports of malignancies in the overall 

Participants with current malignancy or 
malignancy that developed during Study 
200622 will be excluded from the study.  
Participants who had localized carcinoma (i.e., 
basal or squamous cell) of the skin which was 
resected for cure will not be excluded.

Daily monitoring of SAEs by GSK Medical 
Monitor; regular systematic review of AE/SAE 
data from this study by GSK study team and/or 
GSK safety review team

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
mepolizumab program (including asthma, HES, 
other eosinophil-driven diseases & healthy 
participants) were similar across treatment 
groups and are those types common in the 
general population with a frequency rate of <1% 
at all individual doses and all doses of 
mepolizumab combined.
A review of a well-established cohort of patients 
with hyperoesinophilia including those with HES 
at the Mayo clinic showed that 5.1% developed 
hematologic malignancy over 13-year period; 
the median time the malignancy developed was 
10 months after the onset of hypereosinophilia.  
T-cell derived malignancies were most 
commonly diagnosed [Jin, 2015].
Malignancies, including lymphoma, reported to 
date across the mepolizumab program (severe 
asthma and HES) are summarized in the IB; see 
also  ‘Special Warnings and Special Precautions 
for Use’ section located in IB Section 6 titled 
‘Summary of Data and Guidance for the 
Investigator’.
Potential risk for exaggerated response of symptoms 
upon cessation of treatment

No apparent rebound eosinophilia observed in 
monkeys treated with mepolizumab.

Across the PCSA program, post-treatment AEs 
of asthma did not appear to occur at a 
significantly greater incidence following 
cessation of treatment with mepolizumab 
compared with placebo.  Clinical data in severe 

Daily monitoring of SAEs by GSK Medical 
Monitor; regular systematic review of AE/SAE 
data from ongoing studies by GSK study team 
and/or GSK safety review team

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
asthma did not show evidence of symptom 
rebound after cessation of mepolizumab.  
Participants enrolled in the OLE study 
MEA115666 study previously participated in the 
Phase III PCSA study MEA112997 and had a 
treatment break of a minimum of 12 months 
between studies.  Of the 347 participants 
enrolled in MEA115666, 22% received placebo 
in MEA112997 and 24%, 26%, and 28% 
received 75 mg, 250 mg, and 750 mg 
mepolizumab IV, respectively.  There was no 
increase in asthma exacerbations during the 
interim period between the end of MEA112997 
and the start of MEA115666.

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3.3.2.
Benefit Assessment
Study 205203 is an open-label extension study to Study 200622, a 32-week treatment 
period, randomized, placebo-controlled study during which participants with HES receive 
either 300mg SC mepolizumab or placebo every 4 weeks.  During the 20-week treatment 
period of Study 205203, all participants will receive active treatment, 300mg SC 
mepolizumab, every 4 weeks, while they continue with their background HES therapy 
per SoC.  The open-label, active treatment aspect of the study is anticipated to offer 
clinical benefit to participants based on the effectiveness and safety profile  in patients 
with HES reported in  previously completed studies as well as the ongoing mepolizumab 
HES expanded access which has been active for approximately 10 years [Rothenberg, 
2008; Roufosse, 2013; Stein, 2008; Duncan, 2015].
During Study 205203, investigators may adjust the participants’ background HES therapy 
per SoC starting 4 weeks after the first administration of study treatment.  Physician-
guided alteration of SoC can be expected since completed Study MHE100185 
demonstrated that participants with HES receiving mepolizumab 750mg IV every 
4 weeks (84%) were able to reduce the dose of maintenance OCS compared to those 
receiving placebo (43%) without increased clinical activity of HES [Rothenberg, 2008].  
Given long-term toxicity of current HES therapy including OCS, the ability to reduce 
their background HES therapy per SoC may offer benefit to participants.
In addition, participants will attend monthly visits and therefore may benefit from the 
additional disease monitoring and interaction with health care professionals.
Study 205203 will provide data on the long-term clinical experience of mepolizumab at 
300mg SC every 4 weeks in patients with HES.  Given the low prevalence of HES and 
the requirement to blind the blood eosinophil level during the randomized, placebo-
controlled study of mepolizumab, a single registration study of 32-week treatment period, 
Study 200622, was included in the clinical development plan.  Study 205203 will allow 
gathering clinical experience with mepolizumab up to a total of 52 weeks.
3.3.3.
Overall Benefit:Risk Conclusion
Data from mepolizumab preclinical and clinical development programs support the 
pharmacological action of mepolizumab to neutralize IL-5, and consequently treat 
conditions associated with eosinophilia, such as HES.  To date, the safety profile of
mepolizumab has been favorable.  Furthermore, there are no safety observations with 
mepolizumab that would preclude investigation in HES.  The Sponsor therefore 
maintains that investigation of mepolizumab in participants with HES is justified in Study 
205203.

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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary - Safety

To describe the long-term safety profile of 
mepolizumab in participants with HES who 
took part in Study 200622.

Adverse events (AEs) [serious and non-
serious]

Anti-drug antibody
Other – Safety

To describe the long-term safety profile of 
mepolizumab in participants with HES who 
took part in Study 200622.

Vital signs

12-lead ECG

Hematological and clinical laboratory tests
Exploratory - Efficacy

To assess the effect of long-term use of 
mepolizumab on multiple clinical outcomes.

Rate of HES flare#

Change in the mean daily OCS dose from 
Weeks 0-4 to Weeks 16-20

Proportion of participants who achieve a 
mean daily OCS (prednisone/prednisolone 
or equivalent) dose of 7.5mg during 
Weeks 16-20
Pharmacodynamic (PD)

To assess the effect of long-term use of 
mepolizumab on a PD marker

Blood eosinophil levels
# HES flare as defined in Section 9.1.1.

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5.
STUDY DESIGN
5.1.
Overall Design
Figure 1
Study schematic
This is a multi-centre, open-label extension, 20-week treatment period, safety study of 
mepolizumab in adolescent and adult participants with HES who took part in the 
phase 3 Study 200622 (Figure 1).
Study 200622 participants who meet one of the following criteria will be screened to 
continue with Study 205203:
i. Completion of the 32-week treatment period in Study 200622,
or
ii. If the participant was withdrawn from study treatment prematurely during the 
200622 study, but continued in the study per protocol (including HES flare-
related assessments) until 32 weeks from randomization.
Eligible participants will receive 300mg SC mepolizumab every 4 weeks starting 
approximately 32 weeks after the first dose of study treatment in Study 200622.  In this 
OLE Study 205203, the final dose of mepolizumab will be administered at Visit 5 (Week 
16).  Assessments during the Visit 6 (20 weeks after first dose and 4 weeks after the last 
dose) will complete the study treatment period.
During Study 205203, investigators will be blinded to the blood eosinophil count 
(Section 12.2) for the sample collected at Visit 1 (1st dosing visit), after which blood 
eosinophil counts will be unblinded starting at Visit 2.  Investigators may adjust the 
participants’ background HES therapy per standard of care starting at Visit 2 
(approximately 4 weeks after the first dose).

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Participants who complete assessments at Visit 6 (Week 20) may continue with 
mepolizumab treatment via mepolizumab HES expanded access (e.g., MHE104317, 
MHE112562), where local regulation permits.  Study 205203 participants who do not 
continue with mepolizumab HES expanded access will have an additional follow-up 
assessment at Visit 7 (28 weeks after first dose and 12 weeks after the last dose of 
mepolizumab).
5.2.
Number of Participants
Approximately 80 participants will be randomized in the initial recruitment phase for 
Study 200622.  The proportion of participants that have an HES flare will be monitored 
and the total number of participants randomized may be increased if the blinded overall 
rate is predicted to be <30%.  The sample size may be increased up to a maximum of 
120 participants in total.  Participants who completed required assessments for 32 weeks 
starting from randomization in Study 200622 may be evaluated for eligibility to 
participate in Study 205203.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit or the last scheduled procedure shown in the 
Schedule of Activities (SoA).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the study 
globally.
5.4.
Scientific Rationale for Study Design
The study treatment duration for the phase 3, Study 200622 is 32 weeks.  This treatment 
duration was considered adequate to demonstrate the treatment effect of mepolizumab 
compared to placebo.  However, it was not extended beyond 32 weeks in order to 
minimize the duration of time that investigators are blinded from blood eosinophil counts 
which are used in SoC to manage patients with HES.  The OLE Study 205203 will 
provide continuous data for up to 52 weeks (32 weeks 200622 plus 20 weeks 2005203) 
for 200622 participants who had been assigned to mepolizumab, and will provide 
additional 20 week mepolizumab exposure data for participants who received placebo 
during 200622
During the phase 3, randomized, placebo-controlled Study 200622, the same regimen of 
HES therapy is maintained throughout the 32-week study treatment period unless there is 
worsening of symptom(s) that requires an increase in therapy.  A reduction in dose of 
HES therapy for safety reasons, with return to the original dosing regimen if possible, is 
permitted in consultation with the GSK Medical Monitor.  By restricting titration of 
background therapy(ies) which could impact the subject’s clinical status, the phase 3 
study design mitigates a confounding element that could impact the assessment of the 
primary endpoint, HES flare.  HES flare is defined as HES-related clinical manifestation 
resulting in therapy escalation due to symptoms or receipt of two or more courses of 
blinded active OCS.  In the OLE Study 205203, the primary objective is to describe the 

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long-term safety profile of mepolizumab in participants with HES while all participants 
receive active treatment.  Therefore, during Study 205203, participants’ HES SoC 
therapy may be adjusted starting 4 weeks after the first dose of mepolizumab.
5.5.
Dose Justification
Based on the goal of obtaining up to 52-week clinical data at the 300mg SC every 
4 weeks regimen in participants with HES, the dose of mepolizumab in Study 205203 
will remain as 300mg SC every 4 weeks continued from the preceding Study 200622.  
The maintenance of the 300mg SC mepolizumab dose every 4 weeks during Study 
205203 will help further characterize the long-term safety profile of mepolizumab and 
provide additional data on the clinical benefit in HES patients.
6.
STUDY POPULATION
Participants will be evaluated based on the following study entry criteria detailed in 
Section 6.1 and Section 6.2.  Prospective approval of protocol deviations to recruitment 
and enrolment criteria, also known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Study 200622 requirements
1.
Age 12 years and older participants who were enrolled in Study 200622.
To be considered for Study 205203, Study 200622 participants must have completed 
32-week assessments since randomization:
(i)
Completion of the 32-week treatment period in Study 200622
OR
(ii)
If the participant was withdrawn from study treatment prematurely during the 
200622 study, but continued in the study per protocol (including HES flare-
related assessments) until 32 weeks from randomization.
Sex
2.
Male or female
Female participants:
A female participant who meets one of the following conditions:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 at 
least 30 days prior to the first dose of study treatment and until 16 weeks after 
the last dose of study treatment.

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Positive benefit:risk ratio
3.
The treating physician must confirm a positive benefit/risk ratio.  The anticipated 
clinical benefit from mepolizumab must outweigh any potential safety or tolerability 
risk in Study 205203.
Informed consent
4.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
1.
Participants with any history of hypersensitivity to any monoclonal antibody 
(including mepolizumab)
2.
Participants with current malignancy or malignancy that developed during Study 
200622.
NOTE:

Participants who had localized localized carcinoma (i.e., basal or squamous cell) 
of the skin which was resected for cure will not be excluded.
3.
Participant who is pregnant or breastfeeding.
NOTE:

Participants should not be considered for continued treatment if they plan to 
become pregnant during the course of treatment with mepolizumab.
4.
Participant who has other clinically significant medical conditions uncontrolled with 
SoC therapy not associated with HES, e.g., unstable liver disease, uncontrolled 
cardiovascular disease, ongoing active infectious disease
NOTE:

Participants with recent parasitic (helminth) infections will be excluded from the 
study or required to be adequately treated for helminth infections before 
initiation of mepolizumab.
5.
Participants with QTc >450 msec or QTc > 480 msec in participants with bundle 
branch block based on local EGC reading
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method.  It is either 
machine-read or manually over-read.

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
The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In 
other words, several different formulas cannot be used to calculate the QTc for an 
individual participant and then the lowest QTc value used to include or 
discontinue the participant from the trial.
6.
Liver abnormality/disease:

Participants who discontinue study treatment based on liver chemistry stopping 
criteria during Study 200622

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).
NOTE: 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.
Prior/concurrent clinical study experience
7.
Other investigational product/clinical study:

Participants who have received treatment with an investigational agent (biologic 
or non-biologic) within the past 30 days or 5 drug half-lives whichever is longer, 
prior to the first dose, other than Study 200622 study treatment.  The term 
“investigational” applies to any drug not approved for sale for the 
disease/indication to treat in the country in which it is being used or 
investigational formulations of marketed products

Participants who are currently participating in any other interventional clinical 
study
8.
Participant had an adverse event (serious or non-serious) considered related to study 
treatment while participating in Study 200622 which resulted in permanent 
withdrawal of study treatment.
6.3.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but subsequently have not received any study treatment.  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 (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only upon approval by the GSK Medical Monitor.

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7.
TREATMENTS
Study treatment is defined as any investigational treatment intended to be administered to 
a study participant according to the study protocol.
7.1.
Treatments Administered
Study Treatment Name
SB240563 (mepolizumab)
Dosage formulation
Mepolizumab 100 mg vial for injection contains target 
quantities of 10.3 mg sodium phosphate dibasic 
heptahydrate, 0.96 mg polysorbate 80 and 230.4 mg 
xucrose per vial
Unit dose strength(s)/Dosage 
level(s)
3 vials (100mg/vial) per administration
Route of Administration
3 SC injections per administration
Dosing instructions
Participants will be dosed with three 100 mg SC 
injections every 4 weeks.
Injections should be administered into the abdomen, 
upper arm, or thigh.
Packaging and Labeling
Study Treatment will be provided in a vial.  Each vial 
will be labelled as required per country requirement.
Manufacturer
GlaxoSmithKline
Participants will be monitored during SC administration and for 1 hour after the first 
three administrations and then follow monitoring policies for the center.  Such 
monitoring will include general safety monitoring including monitoring for both systemic 
reactions (e.g., hypersensitivity) and local site reactions.  In the event of an acute severe 
reaction (e.g., anaphylaxis) following administration of mepolizumab, there are 
personnel/staff onsite at the treatment facility who are appropriately trained in basic life 
support to manage the subject 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.
7.2.
Method of Treatment Assignment
Study treatment will be dispensed at the study visits summarized in SOA.

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7.3.
Blinding
This is an open-label treatment study.  All eligible participants will receive 300mg SC 
mepolizumab every 4 weeks for a total of 5 doses during the 20-week treatment period.
During Study 205203, investigators and the study team will be blinded to the blood 
eosinophil count (Section 12.2) for the sample collected at Visit 1 (1st dosing visit), after 
which blood eosinophil counts will be unblinded starting at Visit 2.
Blinding to previous treatment assignment as well as blood eosinophil counts in 
Study 200622 will be maintained until that study has reached DBF.
7.4.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all supply of mepolizumab received and any 
discrepancies are reported and resolved before use of mepolizumab.

Only participants enrolled in the study may receive mepolizumab and only authorized 
site staff may supply or administer study treatment.  All supply of mepolizumab must 
be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for mepolizumab accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Under normal conditions of handling and administration, mepolizumab it is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the GSK monitor, Medical Monitor 
and/or study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
Mepolizumab must be stored in a secure area under the appropriate physical conditions 
for the product, which includes storage in a refrigerator or at a temperature of 2-8C and 
protected from light.  Maintenance of a temperature log (manual or automated) is 
required.  Access to mepolizumab will be limited to the investigator’s authorized site 
staff.  Mepolizumab must be dispensed or administered only to participants enrolled in 
the study and in accordance with the protocol.
7.5.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

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
Participants will be dosed at the site 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 mepolizumab 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 mepolizumab.

Mepolizumab will be administered to participants as 3 SC injections per dosing visit 
at the site.  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 
enrollment 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
Concomitant therapy with another biological therapy (e.g., monoclonal antibodies or IV 
immunoglobulin therapy) should be discussed with the GSK Medical Monitor prior to 
beginning therapy.  If allowed, therapy should not be administered at the same time as the 
mepolizumab injection(s) and physicians should take measures to separate administration 
of another biological therapy as long as possible from administration of mepolizumab.
The GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.
Treatment after the End of the Study
Participants who complete assessments at Visit 6 (Week 20) in Study 205203 may 
continue with mepolizumab treatment via mepolizumab HES expanded access (e.g., 
MHE104317, MHE112562), where local regulation permits.
Participants who prematurely discontinue mepolizumab during Study 205203 will be 
considered for mepolizumab HES expanded access, if available, 20 weeks after the first 
dose.  This requirement is placed to encourage participants to continue mepolizumab 
treatment via the OLE Study 205203 rather than immediately transitioning from Study 
200622 to mepolizumab HES expanded access where relatively limited data are 
collected.
8.
TREATMENT DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who discontinue study treatment prematurely (for any reason) should, where 
possible, continue in the study per protocol (Refer to SoA) until 20 weeks after the first 
dose of mepolizumab in study 205203 (Visit 7), including the collection of biological 

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samples for laboratory assessments approximately 4 weeks and 12 weeks after the last 
dose of mepolizumab.
If a participant experiences an organ-threatening or a life-threatening event, the 
investigator should discuss continuation of mepolizumab with the GSK Medical Monitor.
Participants will be withdrawn from treatment with mepolizumab for any of the following 
reasons:

Pregnancy: Any female subject who becomes pregnant.

Meet the liver chemistry stopping criteria (Section 8.1.1)

Meet QTc stopping criteria (Section 8.1.2).
8.1.1.
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.
Figure 2
Liver Stopping and Monitoring Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
Both
ALT
≥8xULN
And
≥ 2X 
baseline 
value
Both
ALT≥3xULN
And
≥1.5x baseline 
value
Plus
Symptoms of 
liver injury or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
And ≥ 1.5x 
baseline 
value 
BUT
ALT<8xULN 
And <2x 
baseline 
value
And able to 
monitor for 4 
weeks
Yes
Yes
No
ALT ≥3xULN 
And ≥ 1.5x 
baseline value 
BUT
ALT<8xULN 
And <2x 
baseline value
persists for 
4 weeks or 
other stopping 
criteria met
No
Yes
If subject to be monitored weekly must refer to Liver Safety Required Actions and Follow up   
Assessments section in the Appendix
Refer to Section 12.6 for Liver Safety Required Actions and Follow-up Assessments.

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8.1.2.
QTc Stopping Criteria
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from mepolizumab:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
For patients 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
8.1.3.
Temporary Discontinuation of Mepolizumab
If a participant becomes infected with helminths while receiving mepolizumab and does 
not respond to anti-helminth treatment, temporary discontinuation of mepolizumab
should be considered in consultation with GSK Medical Monitor.
8.1.4.
Rechallenge
8.1.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

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 (WD visit and Visit 7 additional follow-up) for data to be collected 
at the time of withdrawal from the study and follow-up and for any further 
evaluations that need to be completed.

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8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study 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 (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes providing the procedure met the protocol-specified criteria and 
was performed within the time frame defined in the SoA.
9.1.
Efficacy Assessments
9.1.1.
HES Flare
A HES flare is defined as an HES-related clinical manifestation based on a physician-
documented change in clinical signs or symptoms (worsening symptoms and/or elevated 
blood eosinophil level) resulting in the need for either of the following:

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
An increase from the most recent dose in the maintenance OCS dose 
(prednisone/prednisolone equivalent) by at least 10mg/day for 5 days

An increase in or addition of any cytotoxic and/or immunosuppressive HES 
therapy from/to the most recent dose of HES therapy.
To be considered as an HES flare, the most recent dose of HES therapy must not have 
changed for at least 4 weeks.  This ensures that failed reductions in HES therapy are not 
misclassified as an HES flare.
The start date for an HES flare will be defined as the date of therapy escalation confirmed 
by the investigator attributable to an HES-related clinical manifestation.
When a subject experiences an HES flare, the investigator will monitor the change in 
disease control per routine medical care (e.g., follow-up call) and record the resolution of 
the flare including the end date.  Investigators are encouraged, as medically appropriate, 
to return the subject’s treatment regimen to the level prior to the flare after the flare has 
resolved.
In the event of disease worsening for which the investigator suspects an HES flare 
between scheduled clinic visits, when possible, the subject will return to the clinic to have 
the unscheduled ‘Flare’ visit assessment completed as described in the SoA.  When 
attending the clinic visit at the time of a suspected HES flare is not possible, the 
investigator should make every effort to evaluate the subject via telephone and complete 
the HES Core Assessments (Section 9.1.2).  If an escalation of therapy is initiated by a 
non-study physician, the investigator should confirm that the escalation in therapy is 
attributable to an HES-related clinical manifestation.
Investigators will be required to record details pertaining to the HES flare event in the 
CRF from Visit 1 until 20 weeks after the first dose of mepolizumab.  This should 
include details regarding the clinical symptoms resulting in the flare with detail of the 
required intervention(s), e.g., OCS dose increase, or addition or escalation of 
immunosuppressive or cytotoxic therapy.  In addition, all other relevant clinical, 
laboratory or other diagnostic investigations required to confirm the flare must be 
captured in the CRF.
The definition of HES flare for this study (205203) is different from that for the 
preceding, randomized Study 200622.  This difference in definitions is due to the 
requirement during Study 200622 to avoid decreases in background HES therapy that 
may confound a blinded subject’s clinical status.  In Study 205203, all participants will 
receive mepolizumab and investigators will be unblinded to blood eosinophil levels 
starting 4 weeks after the first dose (Visit 2) so that they may adjust background HES 
therapy as per SoC.
9.1.2.
HES Core Assessments (Clinician Assessment)
Clinical evaluation by the investigator will be guided by the HES Core Assessments, 
consisting of clinical signs and symptoms that reflect the heterogeneous nature of HES 
observed in clinical practice.  During the study, the investigator will evaluate participants 

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at each clinic visit using the HES Core Assessments and determine whether worsening of 
signs/symptoms supports an increase in HES therapy.  In addition, to further characterize 
the basis for determination of flare and increase in therapy, the investigator will prepare a 
narrative for each HES flare.
The HES Core Assessments will characterize each subject’s clinical manifestations at 
baseline and monitor for changes throughout the study.  The investigator will be asked to 
rule out other possible etiologies for the change in clinical symptoms, such as an 
infection, prior to diagnosing an HES flare.  For the “others” category in Table 1, specific 
components of the physical exam will be used as part of the baseline core assessments 
and throughout the study to monitor for the presence or absence of changes in exam 
findings.  Findings of the HES Core assessments will be recorded in the electronic 
device.
Table 1
HES Core Assessments
Symptoms
Assessment
Constitutional
Fatigue
Pain (including but not limited to muscle, joint, general pain) 
Angioedema (swelling under the skin)
Each symptom rated using a 0-3 scale
Dermatologic
Rash
Itch
Hives
Others (specify)
Each symptom rated using a 0-3 scale
Gastrointestinal
Average number of vomiting a day in the past week
Average number of diarrhea a day in the past week
Average number of stools a day in the past week
Abdominal pain
Difficulty in swallowing food
Each symptom rated using a 0-3 scale
Respiratory
Breathing symptoms such as shortness of breath and wheezing
0-3 scale
Dyspnea (shortness of breath)
0-3 scale
Cough
0-3 scale

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Symptoms
Assessment
Sinus-related symptoms:
Nasal congestion
Sinus headache/facial pain/pressure
Postnasal drip (drainage down the back of the throat)
Purulent rhinorrhea (discoloured & thick nasal discharge)
Ear fullness
Each symptom rated using a 0-3 scale
Cardiovascular
Heart failure classification for functional capacity
Classes I-IV
Heart failure classification for objective assessment
Classes: A-D
Neurologic
Sensory
Motor
Cognitive and Mental status change
Each symptom rated using a 0-3 scale
Others
Vascular, venous, arterial, loss of pulse, splinter hemorrhage, 
renal failure, splenomegaly, other (specify)
Each identified symptom rated using a 
0-3 scale
1.
0-3 scale symptom score: 0 for not present or no impact, 1 for present but minimal impact, 2 for significant 
impact on daily activities, 3 for incapacitating
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The following adverse events of special interest (AESI) 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 
Section 12.7 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 

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participation, or that caused the participant to discontinue the study treatment or study 
participation (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).

All AEs will be collected from the signing of the ICF until the follow-up visit 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 case report form (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.
9.2.2.
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.
9.2.3.
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 (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 4.
9.2.4.
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 

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investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.9 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 Medical 
Dictionary for Regulatory Activities (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.
9.2.6.
Pregnancy

Details of all pregnancies in female participants that occur from the first dose of 
study treatment and until at least 16 weeks post-last dose of study treatment will be 
collected.

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 12.5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
The dose of mepolizumab considered to be an overdose has not been defined.  There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose.  The investigator will use clinical judgment in treating the symptoms 
of a suspected overdose.
In the event that mepolizumab is administered more than as detailed in the protocol in 
terms of dose or frequency, the investigator should contact the GSK Medical Monitor 
immediately.

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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, assessments of the ear 
nose throat (ENT), Skin, Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems.  Height and weight will also be measured and recorded..

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Vital Signs

Temperature, pulse rate, and blood pressure will be assessed.

Vital signs will be measured prior to blood draws in a sitting position after 5 minutes 
rest.
9.4.3.
Electrocardiograms

Details of the cardiac monitoring procedures will be provided by the centralized 
cardiology service provider.

All sites will use standardized ECG equipment provided by a centralized external 
vendor.

Collection shortly after a meal or during sleep should be avoided since QT 
prolongation can occur at these times.  All ECG measurements will be made with the 
participant in a supine position having rested in this position for approximately 5 
minutes before each reading.

Paper ECG traces will be recorded at a standard paper speed of 25 mm/sec and gain 
of 10 mm/mV, with a lead II rhythm strip.  There will be electronic capture and 
storage of the data by a validated method, with subsequent transfer to the central 
laboratory for manual reading and calculation of the electrocardiographic parameters.  
Paper traces are required to be maintained at the site with other source documents.

The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG.  The investigator 
must provide his/her dated signature on the original paper tracing, attesting to the 
authenticity of the ECG machine interpretation.

All ECGs will be electronically transmitted to an independent cardiologist (contracted 
by GSK) and evaluated.  The independent cardiologist will be responsible for 
providing measurements of heart rate, QT intervals and an interpretation of all ECGs 
collected in this study.  A hard copy of these results will be sent to the investigator.  
The investigator must provide his/her dated signature on the confirmed report, 
attesting to his/her review of the independent cardiologist’s assessment to support the 
decision regarding the continuation or discontinuation of study treatment based on the 
ECG results (Section 8.1.2).

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
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  Refer to Section 8.1.2 for QTc stopping criteria.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Section 12.2 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 4 weeks 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 GSK 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 (e.g., SAE or AE or dose 
modification), then the results must be recorded in the CRF.
9.5.
Pharmacokinetics

Blood samples for determination of mepolizumab plasma concentration will be 
collected prior to dosing at the timepoints indicated in SoA.  The actual date and time 
of each blood sample collection will be recorded.

Processing, storage and shipping procedures are provided in the laboratory manual.
9.6.
Pharmacodynamics

Blood eosinophil counts will be recorded as part of the standard hematology 
assessments performed at the visits specified in the SoA.
9.7.
Genetics
Genetics are not evaluated in this study.

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9.8.
Biomarkers
9.8.1.
Immunogenicity Assessments

Blood samples will be collected prior to dosing at visits specified in the SoA.  
Samples will be analysed for the presence of anti-mepolizumab antibodies.

Processing, storage and shipping procedures are provided in the laboratory manual.
9.8.2.
Optional Biomarker Sub-study
With the subject’s consent, blood samples will be collected during this study and will be 
used for the optional biomarker sub-study.  In addition, the samples may be used for the 
purposes of measuring novel biomarkers to identify factors that may influence HES, 
and/or potentially medically related conditions (e.g., T-cell lymphoma), as well as the 
biological and clinical responses to study treatment.  If relevant, this approach will be 
extended to include the identification of biomarkers associated with adverse events.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with HES conditions that are medically related to HES, and/or the 
action of study treatment may be identified by application.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
There is no sample size calculation for this study.  The sample size will be determined by 
the number of available participants who were randomized in to Study 200622 and are 
eligible for the current study based on the inclusion and exclusion criteria.

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10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Subjects Enrolled (ASE)
All subjects who sign the ICF and for whom a record exists on the 
database.
Safety
All participants who take at least 1 dose of mepolizumab (study 
treatment).
10.3.
Statistical Analyses
10.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
AEs will be coded using MedDRA coding dictionary and summarised by preferred term. 
Separate summaries will be provided for all AEs, IP-related AEs, SAEs, events of special 
interest (including systemic reactions and local injection site reactions) and for AEs 
leading to permanent discontinuation of IP or withdrawal from the study.
The number of participants with anti-mepolizumab antibodies during the study will be 
summarized.
Further details of the analysis of safety will be provided in the Reporting and Analysis 
Plan (RAP).
10.3.2.
Efficacy, Pharmacodynamic, and Pharmacokinetic Analyses
Details of the analysis of exploratory efficacy endpoints will be provided in the RAP.
PD analyses will be described in the RAP.
To put into context the result of the immunogenicity assessment PK samples are collected 
in this study and mepolizumab PK concentrations will be summarized descriptively by 
immunogenicity status.
10.3.3.
Interim Analyses
Interim analysis will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in HES.

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11.
REFERENCES
American Heart Association. Classes of Heart Failure.  Available at: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp.  Accessed 03 November 2014.
Duncan EA, Ortega H, Gleich G, Price R, Klion A.  Observational experience describing 
the use of mepolizumab in patients with hypereosinophilic syndrome (abstract). 
American Thoracic Society International Conference.  May 2015.
Haldar P, Brightling C, Hargadon B, et al. Mepolizumab and exacerbations of refractory 
eosinophilic asthma. N Engl J Med. 2009; 360: 973-84.
Jin JJ, Butterfield JH, Weiler CR. Hematologic Malignancies Identified in Patients with 
Hypereosinophilia and Hypereosinophilic Syndromes. J Allergy Clin Immunol Pract.
2015; 3: 920-5.
Kim S, Marigowda G, Oren E, Israel E, Wechsler ME. Mepolizumab as a steroid-sparing 
treatment option in patients with Churg-Strauss Syndrome. J Allergy Clin Immunol. 
2010; 125: 1336-43. 
Moosig F, Gross WL, Herrmann K, Bremer JP. Targeting interleukin-5 in refractory and 
relapsing Churg–Strauss Syndrome. Ann Int Med. 2011; 155: 341-343.
Nair P, Pizzichini M, Kjarsgaard M et al. Mepolizumab for prednisone-dependent asthma 
with sputum eosinophilia. N Engl J Med. 2009; 360: 985-93.
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, 
Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab 
treatment in patients with severe eosinophilic asthma.  N Engl J Med. 2014; 371: 1198-
207.
Pavord ID, Korn S, Howarth P et al. Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380: 651–
59.
Rothenberg ME, Klion AD, Roufosse FE et al. Treatment of patients with 
hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008; 358: 1215-28.
Roufosse FE, Kahn J-E, Gleich GJ, et al. Long-term safety of mepolizumab for the 
treatment of hypereosinophilic syndromes. J Allergy Clin Immunol. 2013; 131: 461-7.
Sampson HA, Muñoz-Furlong A, Campbell R, et al. Second symposium on the definition 
and management of anaphylaxis: Summary report—Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol. 2006; 117: 391-7.

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Stein ML, Villaneuva JM, Buckmeier BK, et al. Anti-IL-5 (mepolizumab) therapy 
reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels. J 
Allergy Clin Immunol. 2008; 121: 1473-83.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADA
Anti-drug antibody
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ASE
All subjects enrolled
AST
Aspartate transaminase
BP
Blood pressure
CHF
Congestive heart failure
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DBF
Database freeze
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EGPA
Eosinophilic Granulomatosis with Polyangiitis
FAAN
Food Allergy and Anaphylaxis Network
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
hCG
human chorionic gonadotrophin
HES
Hypereosinophilic Syndrome
HF
Heart failure
HPLC
High performance liquid chromatography
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-Treat
LDH
Lactate dehydrogenase

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mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligrams
MSDS
Material Safety Data Sheet
Msec
millisecond
NAB
Neutralizing antibodies
NIAID
National Institute of Allergy and Infectious Disease
NYHA
New York Heart Association
NPS
Named Patient Supply
OCS
Oral corticosteroid
OLE
Open-label extension
PCR
Polymerase chain reaction
PCSA
Placebo-controlled severe asthma
PD
Pharmacodynamics
PEF
Peak expiratory flow
PK
Pharmacokinetics
PMS
Post marketing surveillance
PP
Per protocol
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SC
Subcutaneous(ly)
SDAC
Statistical analysis data center
SoA
Schedule of Activities
SOC
System Organ Class
SoC
Standard of care
SRM
Study reference manual
SUSAR
Suspected unexpected serious adverse reactions
TOC
Table of Contents
ULN
Upper limit of normal
URTI
Upper respiratory tract infection
WOCBP
Women of childbearing potential
WBC
White blood cell
WD
Withdrawal

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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None

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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in SoA 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.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 2
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with Differential:
Total white cell count#
Neutrophils (absolute and differential [%]#)
Lymphocytes (absolute and differential [%]#)
Monocytes (absolute and differential [%]#)
Eosinophils (absolute# and differential [%]#)
Basophils (absolute and differential [%]#)
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 (non-
fasting)
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones (by dipstick, if locally permitted)

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women 
of childbearing potential [WOCBP])2
All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of urine pregnancy tests

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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.  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.
3.
# (underlined and italicized) indicates the results that will not be sent to the investigators for blinding from the 
blood eosinophil counts for the samples collected prior to Visit 2.
Investigators, GSK personnel involved in the study, and participants will be blinded to 
the results of absolute blood eosinophil counts, total white blood cell counts, and white 
blood count differentials (%) from the sample collected at Visit 1.  This will ensure 
treatment blinding for Study 200622 of which last dose were given approximately 4 
weeks prior to Visit 1 of Study 205203.

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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 (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations.
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 
authorized representative.

Participants who are rescreened are required to sign a new ICF.
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.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
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 

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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 from the issue of the final Clinical 
Study Report(CSR)/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
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.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

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
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study 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 (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 (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.

The disease/disorder being studied or expected progression, signs, or symptoms of 

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the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
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 fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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 (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

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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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
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.

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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 
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.

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Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to ensure sending the data to GSK within 24 hours 
following knowledge of the SAE.

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 treatment/study participation (causality) within 
72 hours of SAE entry into the eCRF.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken 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 GSK Medical Monitor by telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK 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 SRM.

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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
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 as described in
Table 3.

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Table 3
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 (IUD)

Intrauterine hormone-releasing system (IUS)

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 at least 
30 days prior to the first dose of study treatment and until 16 weeks after the last dose of mepolizumab 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine (or serum, if locally required) pregnancy test

Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and at 4 weeks after the last dose of study treatment and as required 
locally.

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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 25 mIU/mL will be performed and assayed in 
a certified laboratory OR and assayed in the central laboratory OR using the test kit 
provided by the central laboratory / provided by the sponsor /approved by the 
sponsor and in accordance with instructions provided in its package insert.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study 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 
mepolizumab.

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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Liver chemistry stopping criteria
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
Both ALT 8xULN and 2X baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value  that 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
Both ALT 3xULN and ≥ 1.5x baseline value and cannot be monitored weekly for 4 
weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
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 
(laboratory assessments performed closest 
and prior to first dose of study treatment).

Do not restart/rechallenge participant with 
study treatment.

If restart/rechallenge not allowed, 
permanently discontinue study treatment and 
may continue participant in the study for any 
protocol-specified follow up assessments.

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 1 week of the liver event6.

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential 
to assess eosinophilia.  Note: the mechanism 
of action of mepolizumab is lowering the 
eosinophils.

Record the appearance or worsening of 
clinical symptoms of liver injury, or

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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.
hypersensitivity, on the AE report form

Record use of concomitant medications on the 
concomitant medications report formincluding 
acetaminophen, herbal remedies, other over 
the counter medications.

Record alcohol use on the liver event alcohol 
intake case report form (CRF) page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study 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 
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 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 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.

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Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and ≥ 1.5x baseline 
value but ALT <8x ULN and < 2x 
baseline value 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, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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12.7.
Appendix 7: Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis 
[Sampson, 2006].  The criteria do not make a distinction based on underlying mechanism. 
These criteria are summarized as follows:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

Reduced  blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline.

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12.8.
Appendix 8: Classification of Heart Failure
Physicians usually classify patients' heart failure according to the severity of their 
symptoms [American Heart Association, 2014].  The table below describes the most 
commonly used classification system, the NYHA Functional Classification.  It places 
patients in one of four categories based on how much they are limited during physical 
activity.
Class
Functional Capacity: How a patient with cardiac disease feels during physical 
activity
I
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest.
Class
Objective assessment
A
No objective evidence of cardiovascular disease. No symptoms and no limitation in 
ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. Marked limitation 
in activity due to symptoms, even during less-than-ordinary activity. Comfortable 
only at rest.
D
Objective evidence of severe cardiovascular disease. Severe limitations. 
Experiences symptoms even while at rest.
For Example:

A patient with minimal or no symptoms but a large pressure gradient across the 
aortic valve or severe obstruction of the left main coronary artery is classified: 
Function Capacity I, Objective Assessment D.

A patient with severe anginal syndrome but angiographically normal coronary 
arteries is classified: Functional Capacity IV, Objective Assessment A.

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12.9.
Appendix 9: 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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12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Information regarding the previous amendment is as follows:
Amendment 01 13-JAN-2017
Overall Rationale for the Amendment: To provide the correct EudraCT number in the 
protocol.
Section # 
and Name
Description of Change
Brief Rationale
Title Page
Regulatory Agency Identifying 
Number: EudraCT# was changed 
from 2014-001232-11 to 2017-
000184-32.
The change was made to reflect the correct 
EudraCT# associated with the protocol.
Numbering of Global Protocol Amendments
Type of Protocol Amendment
Numbering
Type of changes
Global
Amendment 02
New changes for all
Global
Amendment 01
New changes for all
Document History Table for Global Protocol Amendment
DOCUMENT HISTORY
Document
Date of Issue
Amendment 02
16-Nov-2017
Amendment 01
13-Jan-2017
Original Protocol
02-Nov-2016