Conditions: Dermatitis, Atopic
Keywords: subcutaneous safety mepolizumab efficacy atopic dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
Mepolizumab is a humanized Immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that acts on Interleukin-5 (IL-5), which is responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils; thereby reducing the production and survival of eosinophils which may be therapeutic in subjects with atopic dermatitis (AD). This study will investigate the efficacy and safety of mepolizumab (100 milligram \[mg\] subcutaneous \[SC\] administered every 4 weeks) compared with placebo in adult subjects with moderate to severe atopic dermatitis (AD). Subjects will be randomized 1:1 to either placebo SC or mepolizumab SC. The study will comprise of a pre-screening period of up to approximately 4 weeks, a screening period of up to 2 weeks, followed by a 16-Week study treatment period (16 weeks with the last dose of study treatment at Week 12) and follow-up period of up to 4-week. The total duration of subject participation will be approximately 26 weeks. (Note: For subjects, who may need to stop treatment with a biologic, the total Pre-Screening and Screening period may last up to 20 weeks and total duration of participation in the study may be up to 40 weeks).

Detailed description:

Arms:
arm 1: Eligible subjects will receive mepolizumab 100 mg subcutaneously every 4 weeks on Day 1, Week 4, Week 8, and Week 12 arm 2: Eligible subjects will receive matching placebo subcutaneously every 4 weeks on Day 1, Week 4, Week 8, and Week 12

Interventions: intervention 1: Mepolizumab 100 mg intervention 2: Placebo matching mepolizumab
Intervention descriptions: intervention 1: Mepolizumab is available as lyophilized powder in sterile vials for injection. The content is reconstituted with 1.2 milliliter (mL) Sterile Water just prior to use. Subjects will receive 1mL (100 mg/mL) bolus subcutaneous injections. intervention 2: Placebo is available as 0.9% sodium chloride solution. Subjects will receive 1mL bolus subcutaneous injections.

Protocol document:
Prot_000.pdf: 
2015N268158_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
205050
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Study 205050: A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Investigate the 
Efficacy and Safety of Mepolizumab Administered 
Subcutaneously in Subjects with Moderate to Severe Atopic 
Dermatitis
Compound Number:
SB240563
Development Phase:
IIa
Effective Date:
22-JUN-2017
Protocol Amendment Number: 02
Author (s):
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N268158_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
205050
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N268158_00
2016-AUG-25
Original
2015N268158_01
2016-DEC-26
Amendment No. 1
Protocol amendment 1 includes recommendations from the US Food and Drug 
Administration (FDA) and other clarifications.
2015N268158_02
2017-JUN-22
Amendment No. 2
Protocol amendment 2 includes:
-
The addition of administrative interim analyses to enable review of subject efficacy 
and safety data summaries.
-
Minor clarifications regarding: collection of ECGs in triplicate for all ECG time 
points; general order of study procedures; checks for BSA and EASI eligibility 
utilizing eCRF auto calculated totals at Screening and Baseline visits.
-
Increase in anticipated number of subjects screened from approximately 75 subjects
to approximately 140 subjects (no change in target number of subjects randomized).
-
Reminders inserted into the study schematic and Time and Events tables, indicating
no IP dose will be administered at Week 16 and Week 20.
-
Removed requirement for subject data entry into the Daily Sign and Symptom 
Severity Diary for at least 7 consecutive days immediately prior to the Baseline visit. 


2015N268158_02
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3
SPONSOR SIGNATORY
Angelo Secci, MD
        Date
Senior Medical Director
Dermatology TA, R&D


2015N268158_02
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4
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 MD
GlaxoSmithKline
1250 S. Collegeville 
Road,
Collegeville, PA
19426
Secondary 
Medical 
Monitor
 
 MD
GlaxoSmithKline
5 Moore Drive RTP, 
NC 27709-3398
Mailstop: 5.5 B 
SAE 
contact 
information 
Primary reporting method:

Inform electronic Case Report Form (eCRF)

Enter SAE information into the InForm SAE eCRF to trigger an alert to the GSK 
study team
If Inform is not available, secondary method: 

Complete the paper SAE form (found in Study Reference Manual) 

Send the form:
-
via fax or e-mail to both the Primary and Secondary Medical Monitors, and
-
via e-mail to GSK Case Management Group (e-mail: 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  IND 129605
PPD
PPD
PPD
PPD
PPD
PPD


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5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 205050: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Investigate the Efficacy and Safety of Mepolizumab 
Administered Subcutaneously in Subjects with Moderate to Severe Atopic Dermatitis
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2015N268158_02
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6
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205050........................................................9
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................18
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................20
4.2.1.
Pre-screening/Screening Periods ................................................21
4.2.2.
Treatment Period.........................................................................22
4.2.3.
Follow-up Period..........................................................................23
4.2.4.
Unscheduled Visit for Flare/Relapse............................................24
4.3.
Type and Number of Subjects.....................................................................24
4.4.
Design Justification.....................................................................................24
4.5.
Dose Justification........................................................................................25
4.6.
Benefit:Risk Assessment ............................................................................26
4.6.1.
Risk Assessment .........................................................................27
4.6.2.
Benefit Assessment.....................................................................32
4.6.3.
Overall Benefit:Risk Conclusion...................................................32
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............32
5.1.
Inclusion Criteria.........................................................................................32
5.2.
Exclusion Criteria........................................................................................34
5.3.
Screening/Baseline Failures .......................................................................36
5.4.
Withdrawal/Stopping Criteria.......................................................................36
5.4.1.
Early Withdrawal from Study Treatment.......................................36
5.4.2.
Early Withdrawal from Study........................................................37
5.4.3.
Postponement of Study Treatment...............................................38
5.4.4.
Liver Chemistry Stopping Criteria ................................................38
5.4.4.1.
Study Treatment Restart or Rechallenge....................39
5.4.5.
QTcF Stopping Criteria ................................................................39
5.5.
Subject and Study Completion....................................................................40
6.
STUDY TREATMENT ............................................................................................40
6.1.
Investigational Product and Other Study Treatment....................................40
6.1.1.
Study Treatment Administration...................................................41
6.1.2.
Observation Period......................................................................41
6.2.
Treatment Assignment................................................................................41
6.3.
Blinding.......................................................................................................42
6.4.
Packaging and Labeling..............................................................................44
6.5.
Preparation/Handling/Storage/Accountability..............................................44
6.6.
Compliance with Study Treatment Administration.......................................44
6.7.
Treatment of Study Treatment Overdose....................................................45
6.8.
Treatment after the End of the Study ..........................................................45
6.9.
Lifestyle Restrictions...................................................................................45


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6.10.
Concomitant Medications and Non-Drug Therapies....................................45
6.10.1.
Permitted Medications and Non-Drug Therapies..........................45
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................46
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
7.1.
Time and Events Tables .............................................................................49
7.2.
Screening and Critical Baseline Assessments ............................................58
7.3.
Efficacy.......................................................................................................58
7.3.1.
Investigator’s Global Assessment (IGA).......................................58
7.3.2.
Pruritus/Itch Severity....................................................................59
7.3.3.
Body Surface Area (BSA) ............................................................59
7.3.4.
Eczema Area and Severity Index (EASI)......................................59
7.3.5.
Clinician Global Impression of Change Item ................................60
7.4.
Safety .........................................................................................................60
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........60
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................60
7.4.1.2.
Method of Detecting AEs and SAEs ...........................61
7.4.1.3.
Follow-up of AEs and SAEs........................................61
7.4.1.4.
Cardiovascular and Death Events ..............................61
7.4.1.5.
Regulatory Reporting Requirements for SAEs............62
7.4.2.
Pregnancy ...................................................................................62
7.4.3.
Physical Exams ...........................................................................62
7.4.4.
Vital Signs....................................................................................62
7.4.5.
Electrocardiogram (ECG).............................................................63
7.4.6.
Clinical Safety Laboratory Assessments ......................................63
7.4.7.
Immunogenicity............................................................................64
7.5.
Pharmacokinetics .......................................................................................65
7.5.1.
Blood Sample Collection..............................................................65
7.5.2.
Sample Analysis ..........................................................................65
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................65
7.6.1.
Novel Biomarkers- Skin Biopsy Sub-study and Serum 
Biomarkers ..................................................................................65
7.6.1.1.
RNA Transcriptome Research....................................66
7.6.1.2.
RNA Expression Research of a Subset of RNA 
Species ......................................................................66
7.6.1.3.
Protein levels of biomarkers in serum.........................67
7.7.
Genetics .....................................................................................................67
7.8.
Patient-Reported Outcomes........................................................................67
7.8.1.
Daily Sign and Symptom Severity Diary.......................................67
7.8.2.
Patient Global Impression of Severity and Change Items ............67
8.
DATA MANAGEMENT ...........................................................................................68
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................68
9.1.
Hypotheses.................................................................................................68
9.2.
Sample Size Considerations.......................................................................68
9.2.1.
Sample Size Assumptions ...........................................................68
9.2.2.
Sample Size Sensitivity................................................................69
9.2.3.
Sample Size Re-estimation or Adjustment...................................69
9.3.
Data Analysis Considerations .....................................................................69
9.3.1.
Analysis Populations....................................................................69


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9.3.2.
Administrative Interim Analyses ...................................................70
9.3.3.
Formal Interim Analysis ...............................................................70
9.4.
Key Elements of Analysis Plan ...................................................................71
9.4.1.
Primary Analyses.........................................................................71
9.4.2.
Secondary Analyses ....................................................................71
9.4.3.
Exploratory Analyses ...................................................................72
10. STUDY GOVERNANCE CONSIDERATIONS........................................................74
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............74
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................74
10.3.
Quality Control (Study Monitoring) ..............................................................75
10.4.
Quality Assurance.......................................................................................75
10.5.
Study and Site Closure ...............................................................................76
10.6.
Records Retention......................................................................................76
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................77
11. REFERENCES.......................................................................................................78
12. APPENDICES........................................................................................................81
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................81
12.2.
Appendix 2 – Anaphylaxis Criteria ..............................................................83
12.3.
Appendix 3 – Criteria for Atopic Dermatitis Diagnosis .................................84
12.4.
Appendix 4 – Investigator’s Global Assessment (IGA) ................................85
12.5.
Appendix 5 – Body Surface Area (BSA)......................................................86
12.6.
Appendix 6 – Eczema Area and Severity Index (EASI)...............................87
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................88
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............88
12.7.2.
Collection of Pregnancy Information ............................................88
12.7.3.
References ..................................................................................89
12.8.
Appendix 8 – Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................91
12.9.
Appendix 9 – Daily Sign and Symptom Severity Diary ................................94
12.10. Appendix 10 – Clinician Global Impression of Change................................96
12.11. Appendix 11 – Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................97
12.11.1. Definition of Adverse Events........................................................97
12.11.2. Definition of Serious Adverse Events...........................................98
12.11.3. Definition of Cardiovascular Events .............................................99
12.11.4. Recording of Aes and SAEs.......................................................100
12.11.5. Evaluating Aes and SAEs..........................................................100
12.11.6. Reporting of SAEs to GSK.........................................................102
12.12. Appendix 12 – Genetic Research .............................................................103
12.13. Appendix 13 – Patient Global Impression of Severity and Change ...........106
12.13.1. Patient Global Impression of Severity (PGIS) ............................106
12.13.2. Patient Global Impression of Change (PGIC).............................106
12.14. Appendix 14 – Country Specific Requirements .........................................107
12.15. Appendix 15: Protocol Changes................................................................108


2015N268158_02
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1.
PROTOCOL SYNOPSIS FOR STUDY 205050
Rationale
Interleukin-5 (IL-5) is the major cytokine responsible for the growth and differentiation, 
recruitment, activation, and survival of eosinophils.  Elevated levels of serum IL-5 and 
peripheral blood eosinophils have been implicated in the pathogenesis of atopic 
dermatitis (AD).  Mepolizumab (SB-240563; NUCALA®) is a humanized monoclonal 
antibody (IgG1, kappa, mAb) that binds to human interleukin-5 (hIL-5) and blocks it 
from binding to the IL-5 receptor complex expressed on the eosinophil cell surface and 
thus inhibits signaling.  Mepolizumab neutralizes IL-5 leading to a reduction in the 
production and survival of eosinophils which may be therapeutic in subjects with AD.
Mepolizumab has been approved for the treatment of severe eosinophilic asthma in 
several regions and countries including the United States (US), Canada, European Union, 
Japan and Taiwan.
The purpose of this randomized, double-blind study is to investigate the efficacy and 
safety of mepolizumab (100 mg subcutaneous [SC] administered every 4 weeks) 
compared with placebo over a 16-week treatment period in adult subjects with moderate 
to severe AD.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
Primary 

To determine the efficacy of 
mepolizumab SC in subjects with 
moderate to severe AD 

Proportion of subjects who achieve treatment 
success defined as an Investigator’s Global 
Assessment (IGA) score of 0 or 1 and at least a 2-
grade improvement at Week 16.
Secondary

To estimate the efficacy of 
mepolizumab SC 

Mean percentage change in Eczema Area and 
Severity Index (EASI) score from baseline to each 
study visit.

Proportion of subjects with an IGA score of 0 or 1 
and at least a 2-grade improvement at each study 
visit.

To describe the safety and 
tolerability of mepolizumab SC

Incidence, frequency, and nature of adverse events 
(AEs) including local injection site reactions and 
systemic reactions.

Change from baseline in laboratory parameters 
(hematology and chemistry) and frequency of 
clinically significant abnormal test results.

Change from baseline in vital signs and frequency 
of clinically significant abnormal results.

Immunogenicity as measured by anti-mepolizumab 
antibodies.


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Objectives
Endpoints
Exploratory

To further estimate the efficacy of 
mepolizumab SC

Proportion of subjects with ≥50% improvement in 
EASI from baseline to each study visit.

Proportion of subjects with ≥75% improvement in 
EASI from baseline to each study visit.

Mean change in percent of total body surface area 
(% BSA) affected from baseline to each study visit.

Mean change in weekly average of daily 
itch/pruritus numeric rating scale [NRS] score 
(based on Item #1 of Daily Sign and Symptom 
Severity Diary) from baseline to Week 16. 

Mean change in weekly average of daily 
itch/pruritus NRS score (based on Item #1 of Daily 
Sign and Symptom Severity Diary) from baseline to 
each study visit.

To evaluate disease flare/relapse 
during and after treatment with 
mepolizumab SC 

Proportion of subjects who have an IGA score of 3 
or 4 after achieving an IGA score of 0 or 1 and at 
least a 2-grade improvement during the Treatment 
and Follow-up Periods. 

Proportion of subjects who have an increase in 
EASI score of 25% from baseline during the 
Treatment and Follow-up Periods. 

To characterize the relationship 
between efficacy and blood 
eosinophil counts

Proportion of subjects who have an IGA score of 0 
or 1 and at least a 2-grade improvement at each 
study visit by baseline blood eosinophil count.

Mean percentage change in EASI score from 
baseline to each study visit by baseline blood 
eosinophil count. 

Mean percentage change in EASI score compared 
to change in blood eosinophils at each visit.

To investigate the 
pharmacokinetics (PK) of 
mepolizumab in subjects with 
moderate to severe AD

Plasma concentration of mepolizumab

To investigate the 
pharmacodynamics of 
mepolizumab in the blood and in 
AD lesional skin biopsies

Ratio to baseline in blood eosinophil counts

IL-5 levels (serum free and total)

Levels of circulating biomarkers in the blood 
including IgE, eosinophilic cationic protein (ECP), 
and levels of chemokines such as thymus and 
activation-regulated chemokine (TARC) 

Gene expression biomarkers in skin biopsies

To describe the effect of 
mepolizumab SC on Patient-
reported Outcomes (PROs)

Change over time in Daily Sign and Symptom 
Severity Diary

Change over time in Patient Global Impression of 
Severity and Patient Global Impression of Change 


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Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel-
group study that will investigate the efficacy and safety of mepolizumab SC in adult 
subjects with moderate to severe AD.  At the Baseline visit on Day 1, subjects who meet 
all inclusion criteria including a screening blood eosinophil count 350 cells/L and none 
of the exclusion criteria will be randomized in a ratio of 1:1 (mepolizumab 100 mg SC: 
placebo SC).
Treatment Arms and Duration

This study will consist of 4 periods:
o
Pre-screening (up to 4 weeks)
o
Screening (1 to 2 weeks)
-
If an ineffective treatment is stopped for the purpose of study entry, 
informed consent should be obtained at the time the ineffective 
treatment is stopped.  Note:  For subjects who may need to stop 
treatment with a biologic, the total Pre-Screening and Screening period 
may last up to 20 weeks.  
o
Treatment (16 weeks with the last dose of study treatment at Week 12)
o
Follow-up (4 weeks).

The subject will participate in the study for a maximum total duration of 
approximately 26 weeks. (Note: Subjects who need to stop treatment with a biologic 
during the Pre-Screening Period may participate in the study for a maximum total 
duration of approximately 40 weeks).  

For at least 7 consecutive days immediately prior to the Baseline visit and throughout 
the Treatment and Follow-up Periods, subjects must apply a non-prescription, non-
medicated (without an active ingredient) emollient twice daily.  The same emollient 
will be used by the subject throughout the study.
Note: In order to facilitate the assessment of AD at study visits, the subject must 
not apply the emollient within the 2-hour period preceding the study visit.  If the 
emollient is applied less than 2 hours prior to the study visit, study procedures 
will be performed 2 hours after emollient application.

Subject participation in the following exploratory sub-studies is voluntary and will 
require additional informed consent:
1. Skin biopsy sub-study: skin biopsies (at pre-identified study centers only) to 
study the effect of mepolizumab on gene expression biomarkers in the skin.
2. Genetics sub-study: to investigate the relationship between genetic variants, 
response to medicine and susceptibility, severity and progression of AD and 
related conditions.

In order to maintain the blind, the results from the following laboratory assessments 
will be blinded during the study: PK, immunogenicity, IL-5, blood biomarkers, and 


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skin biopsy.  Additionally, the following will be blinded from the Baseline visit until 
the end of the study:  total white blood cell (WBC) count, absolute eosinophil count, 
and differential (%). Investigators will ensure that subjects and any physicians 
managing study subjects during the course of the study are informed of this 
requirement.  Absolute neutrophil, lymphocyte, monocyte, and basophil counts will 
be provided.

Subjects who experience a suspected AD flare/relapse between scheduled study visits 
in the Treatment and Follow-up Periods will return to the clinic for an unscheduled 
visit to determine if AD flare/relapse criteria are met.  If AD flare/relapse is 
confirmed at the time of the unscheduled visit, the assessments of the unscheduled 
visit for flare/relapse will be completed.  In the case of flare/relapse with intolerable 
AD symptoms where the use of prohibited medication is required, the subject will be 
permanently withdrawn from treatment and the procedures and visits described in the 
last two bullets of the Treatment Period (below) will apply.  AD flare/relapse is 
defined as:
o
an IGA score of 3 or 4 after achieving an IGA score of 0 or 1 and at least a 2-
grade improvement, OR
o
an increase in EASI score of 25% from Baseline.
Pre-screening/Screening Periods
Pre-Screening Period: Prohibited Medications Prior to Screening:

Selection and modification of the subject’s medications prior to study participation is 
based on the physician’s judgment according to sound medical practice and principles 
and each subject’s needs.  Effective medications and treatments should not be 
changed merely for the purpose of enabling the subject’s participation in the study. 

Informed consent should be obtained prior to performing any study assessments or 
procedures.

Certain medications and treatments are prohibited prior to the Screening visit and 
throughout the study in order to allow for the evaluation of mepolizumab as 
monotherapy for AD and to eliminate the possible confounding effects of the 
specified medications/treatments on the evaluation of the study endpoints.

Subjects who have used prohibited concomitant medications or non-drug therapies 
will complete a Pre-screening period.

Assessments for the Pre-screening Visit will be completed up to 4 weeks prior to the 
Screening Visit.
Screening Period:

The Screening Period will begin once the subject meets the criteria for prohibited 
concomitant medications and non-drug therapies. The Screening Period will last from 
a minimum of 1 week to a maximum of 2 weeks prior to the Baseline visit.

For subjects who have not used a prohibited medication or non-drug therapy the 
assessments for the Pre-Screening and Screening Periods will be combined. The total 


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time to complete the combined Pre-Screening and Screening assessments will be a 
minimum of 1 week to a maximum of 2 weeks prior to the Baseline visit.
For All Subjects:

Results of the blood eosinophil count obtained at the Screening visit, after 
requirements regarding previous use of prohibited medication and non-drug 
therapies are met, will be used to determine eligibility (350 cells/L) and 
therefore must be available prior to randomizing the subject. 

At the Screening visit, site personnel will train subjects on the use of the 
electronic Daily Sign and Symptom Severity Diary.  Subjects will complete the 
Daily Sign and Symptom Severity Diary starting at the Screening Visit and 
throughout the life of study  Site personnel will receive automated alerts based on 
subject data entry throughout life of study.  Subjects for whom an alert is received 
will be re-educated on the importance of completing their diary.  Every effort will 
be made to re-educate those subjects who continue to not complete their diary 
(see SRM for information regarding monitoring).

The results of all laboratory assessments must be available prior to randomization 
in order to determine the subject’s eligibility.  The Screening Period may be 
extended beyond 2 weeks, if needed, to obtain the results of all laboratory 
assessments.
Treatment Period

The Treatment Period will begin with the Baseline visit on Day 1.  Study visits 
will also occur at Week 4, Week 8, Week 12, and Week 16.

At the Baseline visit, eligible subjects will be randomized in a 1:1 ratio to receive 
either mepolizumab 100 mg SC or placebo SC.

Study treatment will be prepared by a designated, qualified, unblinded member of 
the site staff who is independent of the protocol-defined study assessments.

Study treatment will be administered by SC injection at the Baseline visit, 
Week 4, Week 8, and Week 12 (last dose) into the upper arm, abdomen, or thigh.  
Every effort should be made to inject each dose of study treatment into the same 
region of the body.  Each SC injection will be administered by a trained member 
of the site staff who is blinded to study treatment.  Each subject will receive one 
1 mL SC injection of study treatment at each visit where dosing is scheduled.

Subjects will remain in the clinic for safety monitoring one hour after each 
administration of study treatment. Subjects will be observed for adverse events 
(AEs) including systemic reaction (i.e., allergic (type 1 hypersensitivity) reaction 
and other systemic reactions) and local injection site reactions.

There are no planned dose adjustments during the study. 

The last dose of study treatment will be administered at Week 12.  Study 
treatment will not be administered at Week 16.  For those subjects randomized to 
mepolizumab, four doses will provide therapeutic coverage to Week 16 when 
efficacy assessments for the primary endpoint will occur.  For this reason, the 


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Week 16 visit is considered to be part of the Treatment Period while also serving 
as the first follow-up visit (Post-Treatment Visit 1).

Subjects who prematurely discontinue study treatment will be followed for 
8 weeks after the last dose and will be scheduled for the following visits: 
o
Early Withdrawal Visit (if the decision is made to prematurely discontinue 
study treatment <4 weeks after last dose of study treatment), 
o
Post-Treatment Visit 1 (4 weeks after last dose of study treatment), and 
o
Post-Treatment Visit 2 (8 weeks after last dose of study treatment).

Subjects who are withdrawn from the study will complete an Early Withdrawal 
visit and then exit the study.
Follow-up Period 
Following completion of the Week 16 visit (Post-Treatment Visit 1), subjects will 
enter the Follow-up Period with a visit at Week 20 (Post-Treatment Visit 2, 
occurring 8 weeks after the last dose of study treatment).
Type and Number of Subjects
Approximately 140 adult subjects (ages 18 to 70 years) with moderate to severe atopic 
dermatitis will be screened to achieve approximately 56 randomized and 50 evaluable 
subjects.
Analysis
The primary endpoint will be the proportion of subjects who achieve treatment success 
defined as an IGA score of 0 or 1 and at least a 2-grade improvement at Week 16.
Sample size is based on the objective to characterize the clinical activity of mepolizumab 
in subjects with moderate-to-severe atopic dermatitis.  In order to characterize this, we 
assume that a 40% IGA response rate in the mepolizumab group and a 10% IGA 
response in the placebo arm, as well as a at least 15 percentage point improvement over 
placebo, will constitute a clinically meaningful improvement.
Using Bayesian posterior probability and assuming a uniform prior from 0-1 for 
difference in response rate, 25 mepolizumab subjects (and 25 placebo subjects) will 
power the study to approximately 80% with predictive probability method and provide P 
(difference in response rate 15%|Data) greater than 70% if the true response rate is 40% 
for mepolizumab group and 10% for placebo group.  The 80% credible intervals for the 
difference in response rate will be presented.  No pair wise comparisons are planned.
Administrative and formal interim analyses may be performed. An administrative interim 
analysis may be performed to enable the review of subject efficacy and safety data. The 
formal interim analysis may be conducted to assess futility when approximately 50% of 
subjects have been randomized and completed the Week 8 visit.


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The primary analysis will be performed on the Intent-to-Treat (ITT) population, with a 
supporting analysis of the per protocol (PP) population.
2.
INTRODUCTION
2.1.
Study Rationale
Interleukin-5 (IL-5) is the major cytokine responsible for the growth and differentiation, 
recruitment, activation, and survival of eosinophils.  Elevated levels of serum IL-5 and 
peripheral blood eosinophils have been implicated in the pathogenesis of atopic 
dermatitis (AD).  Mepolizumab (SB-240563; NUCALA®) is a humanized monoclonal 
antibody (IgG1, kappa, mAb) that binds to human interleukin-5 (hIL-5) and blocks it 
from binding to the IL-5 receptor complex expressed on the eosinophil cell surface and 
thus inhibits signaling.  Mepolizumab neutralizes IL-5 leading to a reduction in the 
production and survival of eosinophils which may be therapeutic in subjects with AD. 
Mepolizumab has been approved for the treatment of severe eosinophilic asthma in 
several regions and countries including the United States (US), Canada, European Union, 
Japan, and Taiwan.
The purpose of this randomized, double-blind study is to investigate the efficacy and 
safety of mepolizumab (100 mg subcutaneous [SC] administered every 4 weeks) 
compared with placebo over a 16-week treatment period in adult subjects with moderate 
to severe AD.
2.2.
Brief Background
Atopic dermatitis is a common inflammatory skin condition characterized by chronic 
pruritus, lichenification, xerosis, erythematous papules and plaques.  The cause of AD is 
multifactorial, with genetic and environmental factors, deficient skin barrier function, and 
impaired immune response being the most predominant factors [Guttman-Yassky, 2011a; 
Guttman-Yassky, 2011b].  The prevalence of AD is increasing, affecting up to 20% of 
children and 2–10% of adults in industrialized countries [Schneider, 2013; Shaw, 2011; 
Silverberg, 2013].
Atopic dermatitis, IL-5 expression and eosinophilia
AD is considered to be a type 2 helper T-cell (Th-2) mediated disease that results in over 
production of interleukin (IL)-4, IL-5, and IL-13.  Elevated serum levels of IL-5 have 
been reported in patients with moderate and severe AD.  In a study of 25 AD patients, 
elevated serum levels of IL-5 were detected in 22 patients compared to minimal to no 
detectable levels of IL-5 in normal controls.  Serum levels of IL-5 decreased significantly 
with topical steroid treatment and a greater reduction in clinical severity (>40%) was 
associated with a greater decrease in IL-5 serum levels [Kondo, 2001].
IL-5 overproduction promotes the differentiation, activation, mobilization, and survival 
of eosinophils [Guttman-Yassky, 2011b].  In a study reported by Hamid et al., the 
number of activated eosinophils (EG2+) in the skin from both acute AD lesions (acute 
erythematous AD lesions <3 days onset) and chronic AD lesions (chronic lichenified AD 


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lesions >2 weeks duration) were significantly elevated compared to non-lesional skin and 
skin from normal controls [Hamid, 1994].  Expression of IL-5 messenger ribonucleic acid
(mRNA) levels was higher in chronic AD lesions compared to acute AD lesions or 
uninvolved skin (Figure 1).  As compared with normal control skin or uninvolved skin of 
patients with AD, acute and chronic skin lesions had significantly greater numbers of 
cells that were positive for IL-4 (p<0.01) and IL-5 (p<0.01) mRNA expressing cells.  
Chronic AD skin lesions had significantly fewer IL-4 mRNA-expressing cells (p<0.01), 
but significantly greater IL-5 mRNA (p<0.01) than acute AD lesions.  These data indicate 
that, although acute and chronic AD lesions are associated with increased activation of 
IL-4 and IL-5 genes, initiation of acute skin inflammation in AD is associated with a 
predominance of IL-4 expression whereas maintenance of chronic inflammation is 
predominantly associated with increased IL-5 expression and eosinophil infiltration.  In 
the transition from acute to chronic atopic disease, there is a rise in IL-5 expression in the 
activated eosinophils [Hamid, 1994].
Figure 1
In situ hybridization of AD skin lesions and normal skin, by using 
riboprobes for IL-4, IL-5, and interferon (IFN)-gamma
1.
Republished with permission of American Society for Clinical Investigation [Hamid, 1994]; permission conveyed 
through Copyright Clearance Center, Inc.  
2.
*p <0.05 or **p<0.01, respectively, as compared to the same cytokine mRNA in normal skin.
In another study, chronic AD lesions showed evidence of activated eosinophils 
[Kiehl, 2001].  These results provide further evidence that tissue eosinophilia may be 
important for development of chronic AD.
Effective AD treatment has been shown to impact the number of eosinophils as well as 
the level of IL-5 in the peripheral blood and skin.  For example, tacrolimus has been 
shown to decrease levels of IL-5 and activated eosinophils in the skin [Caproni, 2007].  
In a study of 20 children with AD, a significant relationship between pre-treatment 
peripheral blood eosinophil counts and disease severity as measured by the severity score 
atopic dermatitis (SCORAD) index was observed (p=0.0001) [La Grutta, 2005].  All 
patients achieved a clinical remission after 1 to 2 week pulse treatments with a topical 


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corticosteroid (mometasone furorate) with a significant decrease in blood eosinophil 
counts (p<0.0001).
Mepolizumab 
Mepolizumab (SB-240563) is a humanized monoclonal antibody (IgG1, kappa, mAb) 
that blocks human interleukin-5 (hIL-5) from binding to its receptor.  Mepolizumab has 
been shown to reduce blood and tissue eosinophils and provide clinical benefit in subjects 
with severe eosinophilic asthma [Ortega, 2014a] and potential clinical benefit in subjects 
with hypereosinophilic syndrome [Rothenberg, 2008] and eosinophilic granulomatosis 
with polyangiitis [Kim, 2010; Menzella, 2015].  A cluster analysis showed that responses 
in patients with severe eosinophilic asthma were correlated with an elevated baseline 
blood eosinophil count [Ortega, 2014b].  To date, there have been no safety concerns 
identified with mepolizumab that would preclude further investigation in the patient 
populations under study in the clinical development program.
In 2002, a phase 2 study (SB240563/045) evaluated the efficacy of mepolizumab 
administered intravenously in adult subjects with moderate AD [Oldhoff, 2005; 
GlaxoSmithKline Document Number 2014N217948_00, 2014].  Mepolizumab (750 mg) 
or placebo was administered via two intravenous (IV) injections one week apart.  The 
primary endpoint was the proportion of subjects with a Physician Global Assessment of 
Improvement (PGAI) score of “0=cleared”, “1=almost cleared”, or “2=marked 
improvement” at week 2.  While there was a higher proportion of responders in the 
mepolizumab group (4/18 subjects=22.2%) compared to placebo (1/22 subjects=4.6%), 
the difference was not statistically significant (p=0.115).  However, a Proportional Odds 
analysis for the PGAI at Week 2 (i.e., considering all six levels of response, PGAI 0-5) 
showed an odds ratio (90% confidence interval [CI]) of 3.6 (1.3, 10.2) in favor of 
mepolizumab which did achieve statistical significance (p=0.0193).  Mepolizumab was 
well tolerated and no safety signals were observed.  Statistical analysis of change from 
baseline in blood eosinophil counts at week 2 showed a mean difference (90% CI) 
between mepolizumab and placebo treatment groups of −489 (−648, −329) cells per 
microliter which was statistically significant (p<0.001).  The limited clinical effect in the 
primary endpoint analysis may have been due to the short duration of the clinical study 
(2 weeks).
The scientific data implicating the role of IL-5 and eosinophils in the pathogenesis of AD 
provide the basis for the investigation of mepolizumab for the treatment of moderate to 
severe AD in a study with a longer treatment duration than the prior phase 2 study 
(SB240563/045).


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
Primary 

To determine the efficacy of 
mepolizumab SC in subjects with 
moderate to severe AD 

Proportion of subjects who achieve treatment 
success defined as an Investigator’s Global 
Assessment (IGA) score of 0 or 1 and at least a 2-
grade improvement at Week 16.  
Secondary

To estimate the efficacy of 
mepolizumab SC 

Mean percentage change in Eczema Area and 
Severity Index (EASI) score from baseline to each 
study visit.

Proportion of subjects with an IGA score of 0 or 1 
and at least a 2-grade improvement at each study 
visit.

To describe the safety and 
tolerability of mepolizumab SC

Incidence, frequency, and nature of adverse events 
(AEs) including local injection site reactions and 
systemic reactions.

Change from baseline in laboratory parameters 
(hematology and chemistry) and frequency of 
clinically significant abnormal test results.

Change from baseline in vital signs and frequency 
of clinically significant abnormal results.

Immunogenicity as measured by anti-mepolizumab 
antibodies.
Exploratory

To further estimate the efficacy of 
mepolizumab SC

Proportion of subjects with ≥50% improvement in 
EASI from baseline to each study visit.

Proportion of subjects with ≥75% improvement in 
EASI from baseline to each study visit.

Mean change in percent of total body surface area 
(% BSA) affected from baseline to each study visit.

Mean change in weekly average of daily 
itch/pruritus numeric rating scale [NRS] score 
(based on Item #1 of Daily Sign and Symptom 
Severity Diary) from baseline to Week 16. 

Mean change in weekly average of daily 
itch/pruritus NRS score (based on Item #1 of Daily 
Sign and Symptom Severity Diary) from baseline to 
each study visit.

To evaluate disease flare/relapse 
during and after treatment with 
mepolizumab SC 

Proportion of subjects who have an IGA score of 3 
or 4 after achieving an IGA score of 0 or 1 and at 
least a 2-grade improvement during the Treatment 
and Follow-up Periods. 

Proportion of subjects who have an increase in 
EASI score of 25% from baseline during the 
Treatment and Follow-up Periods. 


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Objectives
Endpoints

To characterize the relationship 
between efficacy and blood 
eosinophil counts

Proportion of subjects who have an IGA score of 0 
or 1 and at least a 2-grade improvement at each 
study visit by baseline blood eosinophil count.  

Mean percentage change in EASI score from 
baseline to each study visit by baseline blood 
eosinophil count. 

Mean percentage change in EASI score compared 
to change in blood eosinophils at each visit.

To investigate the 
pharmacokinetics of mepolizumab 
in subjects with moderate to severe 
AD

Plasma concentration of mepolizumab

To investigate the 
pharmacodynamics of 
mepolizumab in the blood and in 
AD lesional skin biopsies

Ratio to baseline in blood eosinophil counts

IL-5 levels (serum free and total)

Levels of circulating biomarkers in the blood 
including immunoglobulin (IgE), eosinophilic 
cationic protein (ECP), and levels of chemokines 
such as thymus and activation-regulated chemokine 
(TARC) 

Gene expression biomarkers in skin biopsies

To describe the effect of 
mepolizumab SC on Patient-
reported Outcomes (PROs)

Change over time in Daily Sign and Symptom 
Severity Diary

Change over time in Patient Global Impression of 
Severity and Patient Global Impression of Change 
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel-
group study that will investigate the efficacy and safety of mepolizumab SC in adult 
subjects with moderate to severe AD.  At the Baseline visit on Day 1, subjects who meet 
all inclusion criteria including a screening blood eosinophil count 350 cells/L and none 
of the exclusion criteria will be randomized in a ratio of 1:1 (mepolizumab 100 mg SC: 
placebo SC).


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Figure 2
Study Schematic 
4.2.
Treatment Arms and Duration

This study will consist of 4 periods:
o
Pre-screening (up to 4 weeks)
o
Screening (1 to 2 weeks)

If an ineffective treatment is stopped for the purpose of study entry, 
informed consent should be obtained at the time the ineffective 
treatment is stopped.  Note:  For subjects who may need to stop 


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treatment with a biologic, the total Pre-Screening and Screening period 
may last up to 20 weeks. 
o
Treatment (16 weeks with the last dose of study treatment at Week 12)
o
Follow-up (4 weeks).

The subject will participate in the study for a maximum total duration of 
approximately 26 weeks (Note: Subjects who need to stop treatment with a 
biologic during the Pre-Screening Period may participate in the study for a 
maximum total duration of approximately 40 weeks).  

Subject participation in the following exploratory sub-studies is voluntary and will 
require additional informed consent: 
1. Skin biopsy sub-study: skin biopsies (at pre-identified study centers only) to 
study the effect of mepolizumab on gene expression biomarkers in the skin.
2. Genetics sub-study: to investigate the relationship between genetic variants, 
response to medicine and susceptibility, severity and progression of AD and 
related conditions 

In order to maintain the blind, the results from the following laboratory 
assessments will be blinded during the study: PK, immunogenicity, IL-5, blood 
biomarkers, and skin biopsy.  Additionally, the following will be blinded from the 
Baseline visit until the end of the study:  total white blood cell (WBC) count, 
absolute eosinophil count, and differential (%).  Investigators will ensure that 
subjects and any physicians managing study subjects during the course of the 
study are informed of this requirement.  Absolute neutrophil, lymphocyte, 
monocyte, and basophil counts will be provided.
4.2.1.
Pre-screening/Screening Periods
Pre-Screening Period: Prohibited Medications Prior to Screening:

Informed consent should be obtained prior to performing any study assessments 
or procedures.

Certain medications and treatments are prohibited prior to the Screening visit and 
throughout the study in order to allow for the evaluation of mepolizumab as 
monotherapy for AD and to eliminate the possible confounding effects of the 
specified medications/treatments on the evaluation of the study endpoints.

Selection and modification of the subject’s medications prior to study 
participation is based on the physician’s judgment according to sound medical 
practice and principles and each subject’s needs.  Effective medications and 
treatments should not be changed merely for the purpose of enabling the subject’s 
participation in the study.  See Table 1 for a list of Prohibited Concomitant 
Medications and Non-Drug Therapies prior to the Screening visit.  If an 
ineffective treatment is stopped for the purpose of study entry, informed consent 
should be obtained at the time the ineffective treatment is stopped. 


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
Subjects who have used prohibited concomitant medications or non-drug 
therapies will complete a Pre-screening period.   

Assessments for the Pre-screening period will be completed up to 4 weeks prior to 
the Screening Visit. 

Screening Period:
When the subject meets criteria listed in Table 1 for prohibited concomitant 
medications and non-drug therapies, the Screening Period will begin.  The 
Screening Period will last from a minimum of 1 week to a maximum of 2 weeks 
prior to the Baseline visit.
For subjects who have not used a prohibited medication or non-drug therapy, the 
assessments for the Pre-Screening and Screening Periods will be combined.  The 
total time to complete the combined Pre-Screening and Screening assessments 
will be a minimum of 1 week to a maximum of 2 weeks prior to the Baseline 
visit.

For All Subjects:

Results of the blood eosinophil count obtained at the Screening visit, after 
requirements regarding previous use of prohibited medication and non-drug 
therapies (Table 1) are met, will be used to determine eligibility (350 cells/L) 
and therefore must be available prior to randomizing the subject.

At the Screening visit, site personnel will train subjects on the use of the 
electronic Daily Sign and Symptom Severity Diary.  Subjects will complete the 
electronic Daily Sign and Symptom Severity Diary starting at the Screening Visit 
and throughout the life of study. Site personnel will receive automated alerts
based on subject data entry throughout life of study.  Subjects for whom an alert is 
received will be re-educated on the importance of completing their diary.  Every 
effort will be made to re-educate those subjects who continue to not complete 
their diary (see SRM for information regarding monitoring).

For at least 7 consecutive days immediately prior to the Baseline visit, all subjects 
must apply a non-prescription, non-medicated (without an active ingredient) 
emollient twice daily.  Examples of acceptable emollients are provided in the 
Study Reference Manual (SRM).  The same emollient will be used by the subject 
throughout the study.  On study visit days, the subject must not apply the 
emollient within the 2-hour period preceding the study visit.  See Section 6.10.1
for further details regarding emollient use.

The results of all laboratory assessments must be available prior to randomization 
in order to determine the subject’s eligibility.  The Screening Period may be 
extended beyond 2 weeks, if needed, to obtain the results of all laboratory 
assessments.
4.2.2.
Treatment Period

The Treatment Period will begin with the Baseline visit on Day 1.  Study visits 
will also occur at Week 4, Week 8, Week 12, and Week 16.


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
At the Baseline visit, eligible subjects will be randomized in a 1:1 ratio to receive 
either mepolizumab 100 mg SC or placebo SC.
Study treatment will be prepared by a designated, qualified, unblinded member of 
the site staff who is independent of the protocol-defined study assessments (See 
Section 6.1). 

Study treatment will be administered by SC injection at the Baseline visit, 
Week 4, Week 8, and Week 12 (last dose).  Each SC injection will be 
administered by a trained member of the site staff who is blinded to study 
treatment.  See Section 6.1.1 for injection site instructions and study treatment 
administration details. 
Subjects will remain in the clinic for safety monitoring one hour after each 
administration of study treatment. Subjects will be observed for adverse events 
(AEs) including systemic reactions (i.e., allergic (type I hypersensitivity) reaction 
and other systemic reaction) and local injection site reactions (See Section 6.1.2).
There are no planned dose adjustments during the study.
The last dose of study treatment will be administered at Week 12.  Study 
treatment will not be administered at Week 16.  For those subjects randomized to 
mepolizumab, four doses will provide therapeutic coverage to Week 16 when 
efficacy assessments for the primary endpoint will occur.  For this reason, the 
Week 16 visit is considered to be part of the Treatment Period while also serving 
as the first follow-up visit (Post-Treatment Visit 1).
Subjects will continue to apply the same non-prescription, non-medicated 
(without an active ingredient) emollient twice daily.  On study visit days, the 
subject must not apply the emollient within the 2-hour period preceding the study 
visit.  See Section 6.10.1 for further details regarding emollient use.
Subjects who prematurely discontinue study treatment will be followed for 
8 weeks after the last dose and will be scheduled for the following visits 
(Section 5.4 and Table 3):
o Early Withdrawal Visit (if the decision is made to prematurely discontinue 
study treatment <4 weeks after last dose of study treatment), 
o Post-Treatment Visit 1 (4 weeks after last dose of study treatment), and 
o Post-Treatment Visit 2 (8 weeks after last dose of study treatment).
Subjects who are withdrawn from the study will complete an Early Withdrawal 
visit and then exit the study.  See Section 5.4 and Table 3.
4.2.3.
Follow-up Period
Following completion of the Week 16 visit (Post-Treatment Visit 1), subjects will 
enter the Follow-up Period with a visit at Week 20 (Post-Treatment Visit 2, 
occurring 8 weeks after the last dose of study treatment).  

Subjects will continue to apply the same non-prescription non-medicated (without 
an active ingredient) emollient twice daily until the Week 20 visit.  On study visit 


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days, the subject must not apply the emollient within the 2-hour period preceding 
the study visit.  See Section 6.10.1 for further details regarding emollient use.
4.2.4.
Unscheduled Visit for Flare/Relapse

Subjects who experience a suspected AD flare/relapse between scheduled study 
visits in the Treatment and Follow-up Periods will return to the clinic for an 
unscheduled visit to determine if AD flare/relapse criteria are met.  AD 
flare/relapse is defined as:
o
an IGA score of 3 or 4 after achieving an IGA score of 0 or 1 and at least a 
2-grade improvement, OR
o
an increase in EASI score of 25% from Baseline.

If AD flare/relapse is confirmed at the time of the unscheduled visit, the 
assessments of the unscheduled visit for flare/relapse (Table 4) will be completed.

In the case of flare/relapse with intolerable AD symptoms where the use of 
prohibited medication is required (See Table 1) the subject will be permanently 
withdrawn from treatment.

If the subject permanently withdraws from study treatment or withdraws from the 
study, the procedures and visits described in Section 5.4 and Table 3 will apply.
4.3.
Type and Number of Subjects
Approximately 140 adult subjects (ages 18 to 70 years) with moderate to severe atopic 
dermatitis will be screened to achieve approximately 56 randomized and 50 evaluable 
subjects, assuming a drop-out rate of 10%.
4.4.
Design Justification
The randomized, double-blind, placebo-controlled study design was selected to minimize 
the potential for subjective bias in assessing patient response.  The inclusion of a placebo 
group will provide a control for comparison of safety and efficacy of mepolizumab in the 
AD patient population.
This study will investigate the efficacy of mepolizumab at a SC dose of 100 mg 
administered every 4 weeks in subjects with moderate to severe AD.  Subjects with mild 
AD will be excluded because they can be adequately treated with topical therapies.  
Published data have indicated elevated blood eosinophil counts in patients with moderate 
to severe AD [Tremp, 2011; Hon, 2007; La Grutta, 2005; Yoshida, 2002].  An inclusion 
criterion of blood eosinophils 350 cells/L has been selected based on data from Study 
SB240563/045 where approximately 70% of subjects had a baseline blood eosinophil 
count above this threshold.  This inclusion criterion has therefore been selected to ensure 
the enrollment of subjects with meaningfully high blood eosinophil counts.  The 
relationship between baseline blood eosinophil count and efficacy will be explored in this 


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study.  In addition, the value of baseline biomarkers (ECP, IgE, and levels of chemokines 
such as TARC) as predictors of response will be evaluated.
The use of a non-prescription, non-medicated (without an active ingredient) emollient is 
required twice daily for the 7 consecutive days preceding the Baseline visit.  Subjects 
whose disease is adequately managed by the non-prescription, non-medicated emollient 
during this 7-day period will not be eligible for the study.  The requirement for the 
continued use of the concurrent non-prescription, non-medicated emollient throughout 
the remainder of the study ensures a consistent standard of care treatment for all subjects.  
Examples of acceptable emollients will be supplied in the SRM.  The subject will use the 
same emollient throughout the study to ensure consistency.  If the investigator determines 
it is in the best interest of the subject to initiate treatment with a prohibited medication or 
therapy, study treatment will be discontinued (if applicable), and the procedures and 
visits described in Section 5.4 and Table 3 will be performed.
The study will be conducted at multiple study centers to increase the generalizability of 
the study results.
4.5.
Dose Justification
Mepolizumab pharmacology has been extensively investigated during clinical 
development across various eosinophilic conditions.  In studies conducted in patients 
with severe eosinophilic asthma, efficacy was observed at doses of 75 mg IV or 
100 mg SC administered every 4 weeks.  Both doses provide similar exposure in terms of 
area under the curve (AUC) based on mepolizumab SC absolute bioavailability. Higher 
doses (up to 750 mg IV) were well tolerated but provided similar clinical benefit.  
Characterization of the dose-response relationship for blood eosinophil reduction in 
Study MEA114092 conducted in subjects with moderate/severe asthma and blood 
eosinophils >300 cells/L identified approximately 100 mg SC (every 4 weeks) as the 
dose providing 90% of maximal blood eosinophil reduction (ID90) [Pouliquen, 2015].  A 
confirmatory phase 3 trial in severe asthma with eosinophilic inflammation (Study 
MEA115588; Ortega, 2014a) confirmed 100 mg SC as an effective therapeutic dose, and 
therefore the translation of pharmacology into the clinical endpoint.  Mepolizumab, at a 
dose of 100 mg SC administered once every 4 weeks, recently received regulatory 
approval in the treatment of patients with severe eosinophilic asthma.  The dose selection 
for the AD program is also supported by the knowledge of mepolizumab pharmacology 
and is consistent with the dose justification approach taken in other mepolizumab follow-
on indications.
Mean blood eosinophil count reported in the severe AD patient population varies greatly 
across publications (mean ranging from 292 to 1319 cells/L across 5 publications of 
various sample sizes [Tremp, 2011; Jenerowicz, 2007; La Grutta, 2005; Hon, 2007; 
Yoshida, 2002]).  This might reflect differences in concurrent therapies known to impact 
blood eosinophil count, such as steroids.  In a publication reporting the results of four 
dupilumab studies in subjects with AD, mean baseline blood eosinophils reported across 
groups (with or without concurrent therapies) and studies ranged from 200 to 
900 cells/L [Beck, 2014].


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In the previous phase 2 study of mepolizumab in subjects with moderate AD (Study 
SB240563/045), the median blood eosinophil count decreased from 432.5 to 
88.5 cells/L in the mepolizumab group and increased from 495 to 605 cells/L in the 
placebo group from Day 0 to Day 14.  Acknowledging the uncertainty around the true 
mean baseline blood eosinophil count in the targeted population in the absence of 
concurrent therapy, an assumed geometric mean baseline of 500 to 800 cells/L was 
considered reasonable.  Based on the established mepolizumab dose-response for blood 
eosinophil reduction, for such a geometric mean baseline range, a reduction to a predicted 
geometric mean absolute blood eosinophil count of 100 to 150 cells/L would be 
anticipated with a 100 mg SC dose administered every 4 weeks [GlaxoSmithKline 
Document Number 2015N238375_00, 2015].  Based on the results of studies in other 
diseases (e.g., asthma), this magnitude of decrease in blood eosinophil level is anticipated 
to be therapeutic in moderate to severe AD subjects.
This study utilizes a Treatment Period of 16 weeks with study treatment administered at 
the Baseline visit, Week 4, Week 8, and Week 12.  For those subjects randomized to 
mepolizumab, four doses will provide therapeutic coverage to Week 16.  A 16-week 
Treatment Period is expected to be sufficient to reduce eosinophils in the skin and to 
assess clinical disease response to study treatment. 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB-240563) can be found in the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number CM2003/00010/12, 2016].  The following section 
outlines the key risks and risk assessment and mitigation strategy for this protocol:


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4.6.1.
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
Biopharmaceutical products administered 
subcutaneously may elicit systemic (e.g. 
hypersensitivity) and local site 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 subjects:
54/915 subjects or 6% in the mepolizumab 
group [all doses combined]
7/263 subjects or 3% in the mepolizumab 
100 mg SC group
12/344 subjects or 3% in the mepolizumab 
75 mg IV group
20/412 subjects or 5% in the placebo group.
The most common symptoms reported with any 
systemic reaction included headache, rash, 
pruritus, fatigue, and dizziness.  While rare, 
serious systemic reactions including anaphylaxis 
have been reported.
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by a GlaxoSmithKline (GSK) 
study team and/or GSK Safety Review 
team. 
Customized AE and SAE case report form (CRF) 
utilized for targeted collection of information for 
systemic reaction adverse events.
Use of Joint National Institute of Allergy and 
Infectious Diseases (US) (NIAID)/ Food Allergy 
and Anaphylaxis Network (FAAN) 2nd 
Symposium on Anaphylaxis to collect data on 
reports of anaphylaxis (See Appendix 2).
Subjects are monitored in the clinic for 1 hour 
after each administration of study treatment. 
Subjects will be observed for adverse events 
(AEs) including systemic reactions (i.e., allergic 
(type I hypersensitivity) reaction and other 
systemic reactions) and local injection site 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Systemic 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’.
reactions.  
In the event of an acute severe reaction (e.g., 
anaphylaxis) following administration of study 
treatment, there are personnel/staff onsite at the 
treatment facility who are appropriately trained in 
basic life support to manage the patient including 
administration of medications (e.g., epinephrine), 
and have access to a system that can promptly 
transport the patient to another facility for 
additional care if appropriate.
Injection site reactions
In the placebo controlled severe asthma studies, 
the incidence of local injection site reactions with 
SC administration of mepolizumab was higher on 
mepolizumab 100 mg SC group (21/263 or 8%) 
compared to mepolizumab 75mg IV (10/344 or
3%) or placebo (13/412 or 3%). Symptoms 
included pain, erythema, swelling, itching, and 
burning sensation. 
Local injection site reactions reported to date 
across the mepolizumab program are 
summarized in the Adverse Events of Special 
Interest’ section of the IB; See also ‘Section 6
titled ‘Summary of Data and Guidance for the 
Investigator’.
Daily monitoring of SAEs by medical monitor; 
regular systematic review of AE/SAE data from 
ongoing studies by GSK study team and/or GSK 
Safety Review Team. 
Customized AE and SAE CRF pages utilized for 
targeted collection of information for local 
injection site reaction adverse events.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Potential risk of immunogenicity
Biopharmaceutical products may elicit anti-drug 
antibody (ADA) and neutralizing antibody (NAB), 
which have the potential to modulate 
pharmacokinetic (PK), pharmacodynamic (PD) or 
produce adverse reactions. 
Mepolizumab has low immunogenic potential. 
Both incidence and titer data from completed 
studies demonstrate a low risk for loss of efficacy 
associated with AEs and/or altered PK/PD.  
Immunogenicity data reported to date across the 
mepolizumab development program are 
summarized in the IB; See Section 5.4 ‘Clinical 
Immunogenicity’ and a summary of 
immunogenicity findings in Section 6 ‘Other 
Potentially Clinically Relevant Information for the 
Investigator’.
Blood samples will be collected for detection of 
both ADA and NAB.
For subjects who develop anti-mepolizumab 
antibodies, systematic review of AE/SAE data at 
the end of the study (after unblinding) will be 
conducted.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Study visits and procedures may be a burden on 
the subject and may impact study completion.
Study procedures may cause adverse events. 
There is the potential for subjects to experience 
adverse events from the blood draws or 
electrocardiograms (ECGs).  However, these are 
generally considered to be low risk procedures.
The protocol has been designed to minimize the 
burden to sites and subjects as much as possible 
while maintaining the integrity of the design to 
support the endpoints.  All study procedures will 
be performed by appropriately trained study staff 
and subjects will be informed of the potential 
risks.
Scarring/discomfort/complications from skin 
biopsy
Subjects who consent to participate in the skin 
biopsy sub-study may experience discomfort, 
pain, bleeding, bruising, and/or scarring from the 
skin biopsy. Complications may occur such as 
infection or damage of the structures in the 
vicinity of the biopsy site (e.g., vessels and skin 
nerves).
Only sites with experience in skin biopsy sample 
collection will participate in the skin biopsy sub-
study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other 
AD flare/relapse
Subjects may experience disease flare/relapse 
and need alternative treatment. 
Subjects who experience an AD flare/relapse 
between scheduled study visits will return to the 
clinic for an unscheduled visit to determine if AD 
flare/relapse criteria are met (Table 4). In the 
case of flare/relapse with intolerable AD 
symptoms where the use of prohibited 
medication is required (See Table 1), the subject 
will be permanently withdrawn from treatment. 
If the subject permanently withdraws from study 
treatment or withdraws from the study, the 
procedures and visits described in Section 5.4
and Table 3 will apply. 


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4.6.2.
Benefit Assessment
Subjects randomized to mepolizumab may experience improvement in their AD during 
the course of the study.
Mepolizumab has demonstrated clinical benefit in severe eosinophilic asthma 
[Ortega, 2014a].
4.6.3.
Overall Benefit:Risk Conclusion
Data from mepolizumab preclinical and clinical development support the ability of 
mepolizumab to inhibit IL-5 leading to consistent reduction in blood eosinophils, and 
consequently, improvement in conditions associated with eosinophilia.  To date, there are 
no safety concerns with mepolizumab that would preclude development in AD.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the mepolizumab 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
CM2003/00010/12, 2016].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE

Between 18 and 70 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

AD diagnosed by the Eichenfield revised criteria of Hanifin and Rajka 
[Eichenfield, 2014] (Appendix 3).

Diagnosis of AD 2 years prior to the Screening visit.

An IGA score 3 at the Screening and Baseline visits (Appendix 4).

AD involvement of 10% BSA at the Screening and Baseline visits (Appendix 5).

EASI score 16 at the Screening and Baseline visits (Appendix 6).


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
Absolute blood eosinophil count 350 cells/L at the Screening visit.

Applied the same non-prescription, non-medicated (without an active ingredient) 
emollient twice-daily for at least 7 days immediately before the Baseline visit.

Recent history (6 months prior to the Screening visit) of inadequate response to a 
stable regimen of prescription topical medication or for whom prescription topical 
medications are not tolerated or where there is a concern for potential side effects, 
such as skin thinning or increased risk of hypothalamic-pituitary-adrenal [HPA] 
suppression; as well as, inadequate response to optimization of nonpharmacological 
measures such as moisturizers
Note: Inadequate response to a stable regimen of prescription topical medication 
(such as medium to high potency topical corticosteroids or topical calcineurin 
inhibitors) is defined as failure to achieve and maintain remission or low disease 
activity state (equivalent to an IGA score =0 [clear] to 2 [mild]) despite treatment 
for the recommended duration as per label or for the maximum duration 
recommended for the subject treatment, whichever is shorter. 
SEX

Male OR Female
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one 
of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrollment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 


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Reproductive Potential (FRP) (See Appendix 7) from 30 days prior to the first dose of 
study medication and until 16 weeks after the last dose of study medication.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT

Subject is able to give signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Other types of eczema.
2. Any other concomitant skin disorder (e.g., generalized erythroderma such as 
Netherton’s Syndrome, or psoriasis), pigmentation, or extensive scarring that in the 
opinion of the investigator may interfere with the evaluation of AD lesions or 
compromise subject safety.
3. Immunocompromised (e.g., lymphoma, acquired immunodeficiency syndrome, 
Wiskott-Aldrich Syndrome) or has a history of malignant disease within 5 years 
before the Baseline visit. 
Note: Subjects with successfully treated basal cell carcinoma (no more than 
3 lesions), squamous cell carcinoma of the skin, or cervical carcinoma in situ, 
with no evidence of recurrence within the 3 years prior to the Baseline visit may 
participate in the study.
4. A positive history for human immunodeficiency virus (HIV) antibody.
5. Chronic or acute infection requiring treatment with oral or IV antibiotics, antivirals, 
anti-protozoals, or antifungals within 4 weeks before the Screening visit or anytime 
between the Screening and Baseline visits.  Also See Section 6.10.2 and Table 1.
6. Superficial skin infections within 1 week before the Screening visit.
7. Known, pre-existing or suspected parasitic infection within 6 months before the 
Screening visit.
8. Other known or suspected conditions that could lead to elevated eosinophils, for 
example, hypereosinophilic syndromes including eosinophilic granulomatosis with 
polyangiitis (EGPA, also known as Churg-Strauss Syndrome), eosinophilic 
esophagitis, or severe asthma.


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9. A history or ongoing serious illness or medical, physical, or psychiatric condition(s) 
that, in the investigator’s opinion, may interfere with the subject’s completion of the 
study.
10. ALT >2xULN 
11. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
12. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
13. QTcF >450 msec or QTcF >480 msec in subjects with Bundle Branch Block.  
14. Clinically significant abnormality in the hematological or biochemical screen, as 
judged by the investigator.
CONCOMITANT MEDICATIONS
15. Previously treated with mepolizumab or participated in a previous mepolizumab 
clinical study. 
16. Prior treatment with any of the medications or treatments listed in Table 1 within the 
indicated periods before the Screening visit.
RELEVANT HABITS
17. Prolonged exposure to natural (e.g, sunlight) ultraviolet (UV) radiation within 
4 weeks prior to the Baseline visit and/or intention to have such exposure during the 
study, which is thought by the investigator to potentially impact the subject’s AD.
18. More than 2 visits per week to a tanning booth or parlor in the 4 weeks prior to the 
Baseline visit.
19. Onset of a new exercise routine or major change to a previous exercise routine within 
2 weeks before randomization, or unwilling to maintain current level of physical 
activity throughout the length of participation in this study.
20. History of alcohol or other substance abuse within the last 2 years.
CONTRAINDICATIONS 
21. Hypersensitivity to mepolizumab or any of its excipients. 
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
22. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment. 
23. Exposure to more than 4 investigational medicinal products within 12 months prior to 
the Baseline visit.
24. Subject is a member of the investigational team or his/her immediate family.


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5.3.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (See Section 7.4.1.5).
Subjects who are screen failures may be re-screened one time.
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons.
5.4.1.
Early Withdrawal from Study Treatment
Subjects must permanently discontinue study treatment for any of the following 
reasons:

Subject presents with worsening AD or any other condition that requires 
treatment with a prohibited medication.

Subject experiences an adverse event(s) which is considered to be related to 
study treatment or study procedures and, in the investigator’s judgment, is 
severe enough in nature to warrant treatment discontinuation.

Subject experiences a cardiovascular or hematologic AE consistent with specific 
Common Terminology Criteria for AEs (CTCAE) version 4.02 Grade 2 
(moderate) or higher (See SRM).

The subject’s randomized treatment assignment is unblinded by the investigator 
or treating physician.

Subject becomes pregnant.

Sponsor request (after discussion with the investigator), for reasons such as a 
significant protocol deviations or subject noncompliance. 

Study is terminated by the sponsor.

Subject meets liver chemistry stopping criteria (See Section 5.4.4).

Subject meets QTcF stopping criteria (See Section 5.4.5).
Subjects who permanently discontinue study treatment will be followed for 8 weeks after 
the last dose of study treatment.  Every effort will be made by the investigator to 
encourage the subject to remain in the study to complete the two Post-Treatment visits 
providing that consent has not been withdrawn for subsequent visits.


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If the decision is made to permanently discontinue study treatment less than 4 weeks after 
the last dose, an Early Withdrawal Visit will be scheduled as soon as is reasonably 
possible.  Post-Treatment Visit 1 will then be scheduled 4 weeks after the last dose of 
study treatment, and Post-Treatment Visit 2 will be scheduled 8 weeks after the last dose 
of study treatment.
If the decision is made to permanently discontinue study treatment at a scheduled visit 
and approximately 4 weeks have elapsed since the last dose of study treatment, the 
procedures of Post-Treatment Visit 1 will be performed.  Post-Treatment Visit 2 will be 
scheduled 8 weeks following the last dose of study treatment. 
The investigator will record the primary reason for permanent discontinuation of study 
treatment and subsequent study withdrawal in the electronic Case Report Form (eCRF).
5.4.2.
Early Withdrawal from Study
The subject must discontinue study treatment and be withdrawn from the study for 
the following reasons:

Subject demonstrates significant noncompliance with the study procedures.  
(See the SRM for examples.)

Subject is lost to follow-up. 

Subject withdraws consent to participate in the study.  If specified by the 
subject, the investigator should document the reason for withdrawal of consent.

Study is terminated by the sponsor.

Sponsor request (after discussion with the investigator) for reasons such as a 
significant protocol deviations or subject noncompliance.
Subjects who are withdrawn from the study will be asked to return to the clinic for an 
Early Withdrawal Visit providing that consent has not been withdrawn for subsequent 
visits.
If a subject withdraws from the study, he/she may request destruction of any samples 
taken, and the investigator must document this in the site study records.  The investigator 
will record the primary reason for study withdrawal in the eCRF.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 
The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 
In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 


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possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
5.4.3.
Postponement of Study Treatment
Administration of study dose and scheduled study visit assessments will be postponed 
during treatment for acute infection with oral or IV non-cytotoxic antibiotics, antivirals, 
anti-protozoals or antifungals.  Upon completion of treatment of the acute infection, the 
postponed dose of study drug will be administered as soon as feasible but not further than 
2 weeks from the originally planned visit schedule.  
Successive administrations of study dose (if applicable) will resume as per the subject’s 
originally planned visit schedule. If dose cannot be administered within 2 weeks from the 
original schedule, subjects must be discontinued from study treatment. 
5.4.4.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Figure 3
Liver Chemistry Stopping and Increased Monitoring 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
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*


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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 8. 
Figure 4
Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Required Actions and Follow up Assessments for all subjects who meet liver chemistry 
stopping or increased monitoring criteria can be found in Appendix 8.
5.4.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.5.
QTcF Stopping Criteria
The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  Note:  QTcF will be 
utilized for this study.  This formula may not be changed or substituted once the 
subject has been enrolled.
The QTcF should be based on averaged QTcF values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:


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
QTcF >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTcF>60 msec
For patients with underlying bundle branch block, the discontinuation criteria listed 
below apply:
Baseline QTcF with Bundle Branch Block
Discontinuation QTcF with Bundle 
Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
Note: Unscheduled ECGs may be performed as clinically indicated during the study.
5.5.
Subject and Study Completion
A subject will be considered to have completed study treatment if he/she receives all 
planned doses of study treatment through Week 12 and completes the Week 16 visit 
(final primary endpoint visit).  A subject will be considered to have completed the study
if he/she receives all planned doses of study treatment and completes the Week 16 (Post-
Treatment 1) and Week 20 (Post-Treatment 2) visits.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Mepolizumab (SB-240563) is a humanized immunoglobulin G (IgG) monoclonal 
antibody (IgG1, kappa) with human heavy and light chain frameworks.  Mepolizumab 
will be provided as a lyophilized cake in sterile vials for individual use.  The vial will be 
reconstituted with 1.2 mL Sterile Water for Injection, just prior to use yielding a 1 mL, 
100 mg/mL extractable volume.  The placebo in this study will be 0.9% sodium chloride 
solution and will be provided by the study site.  Once prepared, mepolizumab and 
placebo will be identical in appearance.  The mepolizumab 100 mg and placebo 
treatments will be delivered as 1 mL bolus subcutaneous injections.
Study treatment will be prepared by a designated, qualified, unblinded member of the site 
staff who is independent of the protocol-defined study assessments.  Unblinded site staff 
cannot participate in blinded activities (e.g., may not transition to study coordinator role 
or other blinded role) at any point throughout the life of the study.  They must not have 


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any contact with the study subjects.  The unblinded site staff will be responsible for 
receipt, storage, reconstitution, labelling, and accountability of investigational product.
It is recommended that a second unblinded member of the site staff review the unblinded 
study treatment documentation to verify the treatment assignment prior to transferring 
blinded study treatment to blinded site staff for administration to the subject.
6.1.1.
Study Treatment Administration
Blinded site staff will administer the study treatment into the subject’s upper arm, 
abdomen, or thigh via SC injection at the following visits: Baseline, Week 4, Week 8, 
and Week 12.  Ideally, study treatment should be injected into the same region of the 
body (e.g., upper arm) throughout the study.  However, the injection site may be changed 
(e.g., from upper arm to thigh) based on the investigator’s judgment and the reason 
documented in the source documents.  The site of injection for each dose will be recorded 
in the eCRF.
The blinding of all those involved in the evaluation of the study treatment (e.g., 
physician/nurse as well as the subject) shall be maintained at all times; therefore, 
procedures must be in place at the study site to ensure that blinding is maintained.
Further details of study treatment preparation and administration can be found in the 
Investigator’s Brochure [GlaxoSmithKline Document Number CM2003/00010/12, 2016], 
SRM, and unblinded pharmacy manual.
6.1.2.
Observation Period
Subjects will remain in the clinic for safety monitoring 1 hour after each administration 
of study treatment.  Subjects will be observed for adverse events (AEs) including 
systemic reaction (i.e., allergic (type I hypersensitivity) reaction and other systemic 
reactions) and local injection site reactions.
Systemic reactions will be evaluated for anaphylaxis using the diagnostic criteria for 
anaphylaxis as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis 
[Sampson, 2006] (See Appendix 2).
In the event of an acute severe reaction (e.g., anaphylaxis) following administration of 
study treatment, there are personnel/staff onsite at the treatment facility who are 
appropriately trained in basic life support to manage the patient including administration 
of medications (e.g., epinephrine), and have access to a system that can promptly 
transport the patient to another facility for additional care if appropriate.
6.2.
Treatment Assignment
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized at the Baseline visit in a ratio of 1:1 (mepolizumab 100 mg SC: placebo SC). 


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A description of each regimen is provided in the table below:
Mepolizumab
OR
Placebo (0.9% sodium chloride)
One 100 mg SC injection administered 
at the following visits: Baseline, 
Week 4, Week 8, and Week 12
One SC injection administered at the 
following visits: Baseline, Week 4, 
Week 8, and Week 12
Subjects will be assigned to study treatment via an interactive voice response system 
(IVRS) in accordance with the randomization schedule generated by Clinical Statistics, 
prior to the start of the study, using validated internal software.  Once a randomization 
number has been assigned to a subject, it must not be re-assigned to a different subject.
6.3.
Blinding
This will be a double-blind (sponsor open) study and the following will apply: 

GSK will utilize a blinded study team which will include a blinded study medical 
monitor and a blinded Operations and Science Lead.  In addition, GSK will 
designate unblinded team members including an unblinded Medical Monitor and 
an unblinded Global Study Manager to respond to questions or issues involving 
study treatment assignment and preparation.  The unblinded medical monitor may 
also review unblinded abnormal lab values for safety monitoring.  Unblinded 
GSK study monitors will review unblinded study treatment documentation while 
blinded GSK study monitors will review blinded records.  Procedures will be in 
place to ensure blinded GSK team members remain blinded.

Formal Interim Analysis: A formal interim analysis may be performed to enable 
future planning and to assess futility.  It is expected that GSK’s study statistician, 
programmer, clinical scientist, project physician lead, and/or respective 
designee(s) will be unblinded to subject-level data for the subjects enrolled at the 
time the database is locked for the formal interim analysis. These persons will not 
share subject-level randomization assignments with anyone not involved in 
conducting the analyses.  The protection of the study blind and the dissemination 
plan for summary level results of the interim analyses will be described in the 
RAP.

Administrative Interim Analyses:  Unblinded in-stream data summaries will be 
generated by a GSK study statistician and study programmer.  The unblinded 
summaries will be provided to GSK senior manager(s) for their review of subject 
efficacy and safety data. The results and randomization assignments will only be 
shared with members involved in the review and conduct of the analysis.

Study treatment will be prepared by a designated qualified, unblinded member of 
the site staff who is independent of the protocol-defined study assessments.  
Unblinded site staff cannot participate in blinded activities (e.g., may not 


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transition to study coordinator role or other blinded role) at any point throughout 
the life of the study.  They must not have any contact with the study subjects.

Once prepared, mepolizumab and placebo (0.9% sodium chloride solution 
provided by the site) will be identical in appearance.

Blinded site staff will administer study treatment to the subject.

Procedures must be in place at the study site to ensure that blinding is maintained.

In order to maintain the blind, the results from the following laboratory 
assessments will be blinded during the study: PK, immunogenicity, IL-5, blood 
biomarkers, and skin biopsy.  Additionally, the following will be blinded from the 
Baseline visit until the end of the study:  total WBC count, absolute eosinophil 
count, and differential (%).  Investigators will ensure that subjects and any 
physicians managing study subjects during the course of the study are informed of 
this requirement.  Absolute neutrophil, lymphocyte, monocyte, and basophil 
counts will be provided.

In the event that a local laboratory analyzes a hematology sample for a study 
subject after the Baseline visit, procedures must be in place at the site to ensure 
that the results of the total WBC count, absolute eosinophil count, and differential 
(%) remain blinded to the blinded site staff.

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator.

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF.

A subject must permanently discontinue study treatment if that subject’s treatment 
assignment is unblinded by the investigator or treating physician (Section 5.4).  
The subject will be encouraged to complete the Post-Treatment visits.  The 
primary reason for study treatment discontinuation (the event or condition which 
led to the unblinding) will be recorded in the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 


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expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability

A description of the methods and materials required for reconstitution of 
mepolizumab and preparation of placebo are described in Section 6.1 and the 
unblinded pharmacy manual. 

Unblinded site staff must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to 
authorized unblinded site staff. 

The unblinded site staff is responsible for study treatment accountability, 
reconciliation, and record maintenance (i.e. receipt, reconciliation and final 
disposition records).

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM and unblinded pharmacy manual.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.

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.
6.6.
Compliance with Study Treatment Administration
Mepolizumab or placebo will be administered subcutaneously to subjects at the site by 
blinded site staff.  Administration will be documented (including date and time) in the 
source documents and reported in the eCRF.


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6.7.
Treatment of Study Treatment 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 study treatment is administered more than as detailed in the protocol in 
terms of dose or frequency, the blinded GSK Medical Monitor should be notified.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because: there is insufficient evidence of efficacy in this indication, the indication 
being studied is not life threatening or seriously debilitating, and other treatment options 
are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.9.
Lifestyle Restrictions
Prolonged exposure to natural (e.g., sunlight) sources of UV radiation, which is thought 
by the investigator to potentially impact the subject’s AD, is prohibited from 4 weeks 
prior to the Baseline visit and until the last follow-up visit.  A subject who visits a tanning 
booth or parlor more than 2 times per week within the 4 weeks before the Baseline visit 
will not be eligible for inclusion in the study.  Tanning booth or parlor use is prohibited 
from the Baseline visit through the Follow-up Period.
Subjects should maintain their baseline level of physical activity throughout the study.
6.10.
Concomitant Medications and Non-Drug Therapies
All concomitant medications and non-drug therapies received by the subject during the 
study must be recorded in the source documents and eCRF.
6.10.1.
Permitted Medications and Non-Drug Therapies
Subjects must apply a non-prescription, non-medicated (without an active ingredient) 
emollient twice-daily for at least 7 days immediately before the Baseline visit and 
throughout the Treatment and Follow-up Periods.  Examples of acceptable emollients are 
provided in the SRM.  The subject will apply the same emollient throughout the study. 
In order to facilitate the assessment of AD at study visits, the subject must not apply the 
emollient within the 2-hour period preceding the study visit.  If the subject applies an 
emollient less than 2 hours prior to the study visit, site personnel must wait at least 
2 hours after the emollient was applied before conducting any study procedures.  


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Alternatively, the study visit may be rescheduled within the visit window specified in the 
Time and Events Tables (Section 7.1). 
Other than the prohibited medications and non-drug therapies listed in Section 6.10.2, 
treatment with concomitant medications are permitted during the study if, in the opinion 
of the investigator, their use will not impact the study assessments.  This includes 
treatment with oral contraceptives; nasal, inhaled, and intraocular corticosteroids for any 
duration. Oral or IV non-cytotoxic antibiotics, antivirals, anti-protozoals, or antifungals 
are permitted after the Baseline visit for the acute treatment of infections (for a duration 
no longer than indicated to treat the infection) See Section 5.4.3 for required 
postponement of study treatment during the use of oral or IV non-cytotoxic antibiotics, 
antivirals, anti-protozoals or antifungals.
6.10.2.
Prohibited Medications and Non-Drug Therapies
The prohibited concomitant medications and non-drug therapies listed in Table 1 will not 
be used from the specified period before the Screening visit and thereafter for the 
duration of the study except as stated below.
After completing the Week 16 visit, or after Early Withdrawal from Treatment, subjects 
may use prohibited concomitant medications for the treatment of worsening AD.  The use 
of topical therapies after the Week 16 or Early Withdrawal visit is preferred.  The use of 
systemic therapies during this time is at the investigator’s discretion.
The subject must permanently discontinue study treatment if the subject presents with 
worsening AD or any other condition that requires treatment with a prohibited medication 
prior to administration of the Week 12 dose of study treatment, and the procedures 
described in Section 5.4 and Table 3 will apply.  If the subject takes a prohibited 
medication or uses a non-drug therapy for reasons other than worsening AD, the 
investigator should consult with the medical monitor to determine if the subject should be 
withdrawn from study treatment and/or the study.


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Table 1
Prohibited Concomitant Medications and Non-Drug Therapies
Prohibited Medication or Non-Drug Therapy
(Note: Examples are not all-inclusive.)
Prohibited period before 
the Screening visit
Allergen immunotherapy (desensitization therapy)
6 months
Biologic agents 
12 weeks or 5 half-lives, 
whichever is longer (e.g., 
18 weeks for omalizumab)
Other investigational products
30 days, 5 half-lives or twice 
the duration of the biological 
effect of the investigational 
product (whichever is 
longer)
Oral or systemic glucocorticoids (e.g., hydrocortisone, cortisol, prednisone, 
prednisolone, methylprednisolone, dexamethasone, betamethasone, etc.)
4 weeks
Oral or systemic cytotoxic antibiotics (e.g., actinomycin, bleomycin, 
plicamycin, mitomycin, etc.)
4 weeks
Oral or systemic antimetabolites (e.g., methotrexate, azathioprine, 
mercaptopurine, etc.)
4 weeks
Oral or systemic alkylating agents (e.g., mechlorethamine, 
cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, etc.)
4 weeks
Mycophenolate: mycophenolate mofetil
4 weeks
Oral or systemic drugs acting on immunophilins (e.g., oral calcineurin 
inhibitors, cyclosporin, etc.)
4 weeks
Interferon-gamma
4 weeks
Adrenocorticotropic hormone analogs
4 weeks
Phototherapy (See Section 6.9 for tanning booth/parlor restrictions.)
4 weeks
Coal tar
4 weeks
Oral antihistamines
1 week
Topical immunomodulators (e.g., pimecrolimus, tacrolimus, etc.)
1 week
World Health Organization (WHO) group I-VII topical corticosteroids (e.g., 
betamethasone, clobetasol, desoximetasone, flurandrenolide, fluticasone, 
hydrocortiosone, traimcinolone, etc.)
1 week
Topical retinoids (e.g., tretinoin, tazarotene, adapalene, etc.)
1 week
Topical antibiotics
1 week
Antibacterial or antiseptic cleansing body wash/soap
1 week
Treatment of AD with a medical device (e.g., Atopiclair, PruMyx, EpiCeram, 
CeraVe, etc.)
1 week
Bleach baths
1 week
Wet wraps
1 week
Note: Selection and modification of the subject’s medications prior to study participation is based on the 
physician’s judgment according to sound medical practice and principles and each subject’s needs.  
Effective medications and treatments should not be changed merely for the purpose of enabling the 
subject’s participation in the study.
If an ineffective treatment is stopped for the purpose of study entry, informed consent should be obtained at 
the time the ineffective treatment is stopped.  For subjects who may need to stop treatment with a biologic, 
the total screening period may last up to 20 weeks.


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Tables, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables, Section 7.1.
Assessments should occur prior to dosing on dosing days and in the following order to 
the extent possible:
1. Patient-Reported Outcomes in the following order (first to last): Patient Global 
Impression of Change and Patient Global Impression of Severity
2. Efficacy assessments (IGA, BSA, EASI, Clinician Global Impression of Change) 
3. Other safety assessments (such as 12-lead ECG, vital signs, physical examination, 
height, weight)
4. Laboratory assessments (such as blood draws, urine pregnancy test, parasitic 
screening, skin biopsy)
Note: Prior to study procedures, subjects will report if emollient was applied within the 2-
hour period preceding the study visit.


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7.1.
Time and Events Tables
Table 2
Time and Events Table:  Pre-Screening and Screening
Period:
Pre-Screening and Screening Period
Notes
Visits:
Pre-Screening
Screening
Up to 4 wks
prior to 
Screening Visit
1 to 2 wks
prior to 
Day 1 
Baseline 
Visit
Individual Pre-Screening and Screening Visits will be conducted for subjects who have 
used prohibited medications or non-drug therapies and need to fulfil the prohibited 
medications period prior to the Screening Visit (See Table 1). For these subjects, the Pre-
Screening Visit will be completed up to 4 weeks prior to the Screening Visit. After
requirements regarding previous use of prohibited medication and non-drug therapies are 
met (See Table 1), the Screening Visit will be completed. The Screening visit will be 
completed up to 2 weeks prior to the Baseline visit. 
Assessments for Pre-screening and Screening Periods will be combined into one 
Screening Visit for subjects who meet prohibited medications or non-drug therapies 
criteria in Table 1 at entry (total time to complete the combined assessments= 1 to 
2 weeks prior to Baseline). 
The period between the Screening Visit and Baseline Visit may be extended beyond 2 
weeks, if needed, to obtain the results of all screening laboratory assessments.
Perform procedures in the order listed in Section 7
Procedure
Informed consent
PS
Obtain informed consent prior to study participation. See Section 4.2.1 and Table 1 notes.
Demography
PS
Fitzpatrick Skin Type Classification
PS
Inclusion/exclusion criteria
PS
S
Medical history/Medical conditions 
PS
S
Includes drug and alcohol usage, smoking history, cardiovascular medical history, and 
family history of premature cardiovascular disease.
Safety Assessments
Vital Signs
S
See Section 7.4.4.
Concomitant medications
PS
S
The subject must apply the same non-prescription, non-medicated emollient twice daily for 
the 7 consecutive days immediately prior to the Baseline visit.  On study visit days,.


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Period:
Pre-Screening and Screening Period
Notes
Visits:
Pre-Screening
Screening
Up to 4 wks
prior to 
Screening Visit
1 to 2 wks
prior to 
Day 1 
Baseline 
Visit
Individual Pre-Screening and Screening Visits will be conducted for subjects who have 
used prohibited medications or non-drug therapies and need to fulfil the prohibited 
medications period prior to the Screening Visit (See Table 1). For these subjects, the 
Pre-Screening Visit will be completed up to 4 weeks prior to the Screening Visit. After
requirements regarding previous use of prohibited medication and non-drug therapies 
are met (See Table 1), the Screening Visit will be completed. The Screening visit will be 
completed up to 2 weeks prior to the Baseline visit. 
Assessments for Pre-screening and Screening Periods will be combined into one 
Screening Visit for subjects who meet prohibited medications or non-drug therapies 
criteria in Table 1 at entry (total time to complete the combined assessments= 1 to 
2 weeks prior to Baseline). 
The period between the Screening Visit and Baseline Visit may be extended beyond 2 
weeks, if needed, to obtain the results of all screening laboratory assessments.
Perform procedures in the order listed in Section 7
Procedure
emollient must not be applied within the 2-hour period preceding the study visit.  If 
emollient is applied <2 hours prior to the visit, wait 2 hours after application to perform 
study procedures. See Section 6.10.1
Serious Adverse Events (SAEs)
PS
S
Record SAEs related to study participation or to a GSK product from the time a subject 
consents to participate in the study up to and including any follow-up contact.  AEs will be 
collected from the start of study treatment until the follow-up contact (Section 7.4.1.1).  
ECG
S
Laboratory Assessments
Note: Results of all laboratory assessments must be available prior to randomization
HBsAG and hepatitis C antibody 
PS
Not required if test otherwise performed within 3 months prior to first dose of study 
treatment.
Pregnancy test (urine) 
PS
S
Females of reproductive potential. If urine pregnancy test is positive, collect serum hCG 
(central laboratory). See Section 7.4.2 and Appendix 7 for reporting requirements.
FSH and estradiol
PS
Females, if needed to confirm postmenopausal status (See Section 5.1).


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Period:
Pre-Screening and Screening Period
Notes
Visits:
Pre-Screening
Screening
Up to 4 wks
prior to 
Screening Visit
1 to 2 wks
prior to 
Day 1 
Baseline 
Visit
Individual Pre-Screening and Screening Visits will be conducted for subjects who have 
used prohibited medications or non-drug therapies and need to fulfil the prohibited 
medications period prior to the Screening Visit (See Table 1). For these subjects, the 
Pre-Screening Visit will be completed up to 4 weeks prior to the Screening Visit. After
requirements regarding previous use of prohibited medication and non-drug therapies 
are met (See Table 1), the Screening Visit will be completed. The Screening visit will be 
completed up to 2 weeks prior to the Baseline visit. 
Assessments for Pre-screening and Screening Periods will be combined into one 
Screening Visit for subjects who meet prohibited medications or non-drug therapies 
criteria in Table 1 at entry (total time to complete the combined assessments= 1 to 
2 weeks prior to Baseline). 
The period between the Screening Visit and Baseline Visit may be extended beyond 2 
weeks, if needed, to obtain the results of all screening laboratory assessments.
Perform procedures in the order listed in Section 7
Procedure
Hematology with differential 
S
Clinical Chemistry 
S
Parasitic screening
S
Parasitic screening is only required in countries with high-risk or for subjects who have 
visited high-risk countries in the past 6 months. Sites should use local laboratories.  
Selection of tests will be at the investigator’s judgment.
Efficacy Assessments and Patient-Reported Outcomes
Investigator’s Global Assessment
S
See Section 7.3 and SRM for rater requirements.
% BSA affected
S
Regional assessment. Total % BSA affected will be auto-calculated within the eCRF. The 
total %BSA score from the eCRF will be utilized to confirm inclusion criteria. See Section 
7.3 and SRM for rater requirements.
EASI
S
% BSA affected will be utilized to calculate the EASI score.  The EASI score will be auto-
calculated within the eCRF.  The EASI score from the eCRF will be utilized to confirm 
inclusion criteria. See Section 7.3 and SRM for rater requirements


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Period:
Pre-Screening and Screening Period
Notes
Visits:
Pre-Screening
Screening
Up to 4 wks
prior to 
Screening Visit
1 to 2 wks
prior to 
Day 1 
Baseline 
Visit
Individual Pre-Screening and Screening Visits will be conducted for subjects who have 
used prohibited medications or non-drug therapies and need to fulfil the prohibited 
medications period prior to the Screening Visit (See Table 1). For these subjects, the 
Pre-Screening Visit will be completed up to 4 weeks prior to the Screening Visit. After
requirements regarding previous use of prohibited medication and non-drug therapies 
are met (See Table 1), the Screening Visit will be completed. The Screening visit will be 
completed up to 2 weeks prior to the Baseline visit. 
Assessments for Pre-screening and Screening Periods will be combined into one 
Screening Visit for subjects who meet prohibited medications or non-drug therapies 
criteria in Table 1 at entry (total time to complete the combined assessments= 1 to 
2 weeks prior to Baseline). 
The period between the Screening Visit and Baseline Visit may be extended beyond 2 
weeks, if needed, to obtain the results of all screening laboratory assessments.
Perform procedures in the order listed in Section 7
Procedure
Daily Sign and Symptom Severity 
Diary (electronic) 
S
To be completed by the subject every evening before 12:00 AM (midnight).  If subject fails 
screening and does not continue in the study, the subject will return the electronic device to 
the site. (See SRM for guidance).
Abbreviations: AEs= adverse events; BSA= body surface area; EASI= Eczema Area and Severity Index; FSH= follicle stimulating hormone; HBsAG= hepatitis B surface antigen; 
SAEs= serious adverse events; SRM=Study Reference Manual.


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Table 3
Time and Events Table: Baseline through Follow-up Period
Period:
Treatment 
Follow-up 
Period
Notes
Post-Tx 
Visit 1
4 wks after 
last dose
Post-Tx 
Visit 2
8 wks after 
last dose
Early 
WD
Perform procedures in the order listed in Section 7.
Early WD visit: same procedures apply both to subjects 
discontinuing treatment but continuing with Post-Tx visits 
and to subjects withdrawing from the study.
Day/Week:
Day 1
Baseline Wk 4 Wk 8 Wk 12
Wk 16
(No IP 
dose)
Wk 20
(No IP 
dose)
Window (days):
3
3
3
3
3
Procedure
Inclusion/exclusion criteria
BL
Randomization (IVRS)
BL
Safety Assessments
Physical examination, height, weight
BL
20
EW
Perform/obtain pre-dose on dosing days. See Section 7.4.3.
Vital signs
BL
4
8
12
16
20
EW
Obtain pre-dose on dosing days. See Section 7.4.4.
ECG
4
16
EW
Obtain pre-dose at Week 4.  Unscheduled ECGs may also 
be performed as clinically indicated during the study.
Concomitant medications
BL
4
8
12
16
20
EW
See Section 6.10.1.  Subject must apply the same non-
prescription, non-medicated emollient twice daily during 
Treatment and Follow-up Periods. On study visit days, 
emollient must not be applied within the 2-hour period 
preceding the study visit.  If emollient is applied <2 hours 
prior to the visit, wait 2 hours after application to perform 
study procedures. 
Adverse events
BL
4
8
12
16
20
EW
Collect AEs from the start of study treatment until the follow-
up contact.  Record SAEs related to study participation or to 
a GSK product from the time a subject consents to 
participate in the study up to and including any follow-up
contact (Section 7.4.1.1). 


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Period:
Treatment 
Follow-up 
Period
Notes
Post-Tx 
Visit 1
4 wks after 
last dose
Post-Tx 
Visit 2
8 wks after 
last dose
Early 
WD
Perform procedures in the order listed in Section 7.
Early WD visit: same procedures apply both to subjects 
discontinuing treatment but continuing with Post-Tx visits 
and to subjects withdrawing from the study.
Day/Week:
Day 1
Baseline Wk 4 Wk 8 Wk 12
Wk 16
(No IP 
dose)
Wk 20
(No IP 
dose)
Window (days):
3
3
3
3
3
Procedure
Laboratory Assessments
Note: Labs are collected pre-dose on dosing days (includes blood draws, skin biopsies, and pregnancy testing)
Genetic sample- pre-dose
BL
Subject participation is voluntary.  Additional informed 
consent is required.
Hematology with differential
BL
4
8
12
16
20
EW
Total WBC, absolute eosinophil count, and differential (%) 
will be blinded from the Baseline visit until the end of the 
study.
Clinical Chemistry
BL
4
8
12
16
EW
Pregnancy test (urine)
BL
4
8
12
16
20
EW
Females of reproductive potential.  If urine pregnancy test is 
positive, collect serum hCG (central laboratory). See Section 
7.4.2 and Appendix 7 for reporting requirements.
Pharmacokinetic blood sample
4
8
12
16
20
EW
Results will be blinded during the study.
Blood sample for immunogenicity
BL
4
16
20
EW
Results will be blinded during the study.
Serum IL-5
BL
4
16
20
EW
Results will be blinded during the study.
Serum sample for biomarkers
BL
4
8
12
16
Results will be blinded during the study.
Skin biopsy sub-study-
pre-identified study centers only
BL
4
Subject participation is voluntary.  Additional informed 
consent is required.  Results will be blinded during the study. 
Collect 1 lesional sample (from chronic lesion) and 1 non-
lesional sample at each visit.
Efficacy Assessments and Patient-Reported Outcomes 
Patient Global Impression of Change 
4
8
12
16
EW
Complete pre-dose prior to other assessments or evaluation 
by the investigator. 


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Period:
Treatment 
Follow-up 
Period
Notes
Post-Tx 
Visit 1
4 wks after 
last dose
Post-Tx 
Visit 2
8 wks after 
last dose
Early 
WD
Perform procedures in the order listed in Section 7.
Early WD visit: same procedures apply both to subjects 
discontinuing treatment but continuing with Post-Tx visits and 
to subjects withdrawing from the study.
Day/Week:
Day 1
Baseline Wk 4 Wk 8 Wk 12
Wk 16
(No IP 
dose)
Wk 20
(No IP
dose)
Window (days):
3
3
3
3
3
Procedure
Patient Global Impression of Severity 
BL
4
8
12
16
20
EW
Complete pre-dose prior to other assessments or evaluation 
by the investigator. 
Daily Sign and Symptom Severity 
Diary (electronic)
---------------------------------------------------------------
EW
To be completed by the subject every evening before 
12:00 A.M.(midnight) during the Treatment and Follow-up 
Periods.  Site personnel will review subject compliance with 
the diary at each visit.
Investigator’s Global Assessment 
BL
4
8
12
16
20
EW
Complete pre-dose.  See Section 7.3 and SRM for rater 
requirements.
% BSA affected 
BL
4
8
12
16
20
EW
Complete pre-dose. Regional assessment. Total % BSA 
affected will be auto-calculated within the eCRF. See Section 
7.3 and SRM for rater requirements
EASI 
BL
4
8
12
16
20
EW
Complete pre-dose.  % BSA affected from each visit will be 
utilized to calculate the EASI score at each visit.  The EASI 
score will be auto-calculated within the eCRF. See Section 
7.3  and SRM for rater requirements
Clinician Global Impression of Change 
4
8
12
16
EW
Complete pre-dose.  See Section 7.3. and SRM for rater 
requirements


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Period:
Treatment 
Follow-up 
Period
Notes
Post-Tx 
Visit 1
4 wks after 
last dose
Post-Tx 
Visit 2
8 wks after 
last dose
Early 
WD
Perform procedures in the order listed in Section 7.
Early WD visit: same procedures apply both to subjects 
discontinuing treatment but continuing with Post-Tx visits and 
to subjects withdrawing from the study.
Day/Week:
Day 1
Baseline Wk 4 Wk 8 Wk 12
Wk 16
(No IP 
dose)
Wk 20
(No IP 
dose)
Window (days):
3
3
3
3
3
Procedure
Investigational Product and Other Study Treatment
Mepolizumab or Placebo 
Administration
BL
4
8
12
No IP dose No IP dose
See Section 6.1 and Section 6.1.1 for study treatment 
administration details. Observation of subject required for 
1 hour after administration of study treatment.  See Section 
6.1.2. Postponement of study treatment and visit assessment 
is required during course of antibiotic, antiviral or antifungal 
treatment for acute infection. Postponed doses can be 
administered no further than 2 weeks after the original 
scheduled dose (See Section 5.4.3).
Abbreviations: AE= adverse events; BSA= body surface area; EASI= Eczema Area and Severity Index; IL-5= interleukin-5; SAEs= Serious Adverse Events; Tx= Treatment; WBC= 
white blood cell; WD=withdrawal; Wk=Week; wks=weeks  


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Table 4
Time and Events Table:  Unscheduled Visit for Flare/Relapse
Period:
Treatment 
and Follow-
up
Notes
Week:
Unscheduled
This visit is for subjects who experience AD flare/relapse 
between scheduled study visits. See Section 4.2.4.  
In the case of flare/relapse with intolerable AD symptoms 
where the use of prohibited medication is required (See 
Table 1), the subject will be permanently withdrawn from 
treatment 
If the subject permanently discontinues study treatment or 
withdraws from the study, the procedures and visits 
described in Section 5.4 and Table 3 will apply.
Perform procedures in the order listed in Section 7.
Window (days):
+5
Visit window is from the time the subject notifies the site staff 
of potential AD flare/relapse.
Procedure
Safety Assessments
Physical examination, 
height, weight
U
To be performed only if needed, based on the investigator’s 
judgment. 
Vital signs
U
See Section 7.4.4.
Concomitant medications
U
Adverse events
U
See Appendix 11.  The disease under study (AD) or expected 
progression, signs, or symptoms of AD do not meet the 
definition of AE unless the worsening is more severe than 
expected for the subject’s condition.
Laboratory Assessments
Hematology with 
differential
U
Total WBC, absolute eosinophil count, and differential (%) will 
remain blinded.
Clinical Chemistry 
U
Performed only if needed, based on investigator’s judgment.
Efficacy Assessments and Patient-Reported Outcomes
Daily Sign and Symptom 
Severity Diary (electronic)
U
To be completed the by subject in the evening. 
Investigator’s Global 
Assessment 
U
% BSA affected
U
Regional assessment. Total % BSA affected will be auto-
calculated within the eCRF. See Section 7.3 and SRM for rater 
requirements.
EASI 
U
% BSA affected from each visit will be utilized to calculate the 
EASI score at each visit.  The EASI score will be auto-
calculated within the eCRF. See Section 7.3 and SRM for rater 
requirements.
Abbreviations: AD= atopic dermatitis; EASI= Eczema Area and Severity Index; WBC= white blood cell; WD=withdrawal


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7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.  The subject’s Fitzpatrick skin type (Table 5) will also be documented.
Table 5
Fitzpatrick Skin Type Classification
Type
Constitutive Skin Color (Unexposed) and 
Typical Characteristics
Response to Ultraviolet Light Exposure
I
White; very fair; red or blond hair; blue eyes; 
freckles
Always burns, never tans
II
White; fair; red, blond, or brown hair; 
blue, hazel, or green eyes
Usually burns, tans with difficulty
III
White; any eye or hair color; very common
Sometimes mild burn, gradually tans
IV
White or light brown; typical Mediterranean 
Caucasian skin
Rarely burns, tans with ease
V
Brown; mid-eastern skin types
Very rarely burns, tans very easily
VI
Black
Never burns, tans very easily
Source: Based on the characteristics originally described in Fitzpatrick, 1988
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.
Medical (including AD history), medication, family history will be assessed as related to 
the inclusion/exclusion criteria listed in Section 5.  
Results of the blood eosinophil count obtained at the Screening Visit, after requirements 
regarding previous use of prohibited medication and non-drug therapies (Table 1) are 
met, will be used to determine eligibility.
7.3.
Efficacy
To minimize inter-rater variability, raters will complete required training on each of the 
required assessments before enrolling subjects at their study center.  To the fullest extent 
possible, the same rater will perform all efficacy assessments for an individual subject 
throughout the study. A rater must be an investigator, subinvestigator, or qualified 
healthcare professional.  The SRM will specify the required rater qualifications.
Efficacy assessments will be performed at the visits specified in the Time and Events 
Tables (Section 7.1).  
7.3.1.
Investigator’s Global Assessment (IGA)
The IGA is a clinical tool for assessing the current state/severity of a subject’s AD 
[Rehal, 2011] (Appendix 4).  It is a static 5-point morphological assessment of overall 
disease severity, as determined by the investigator, subinvestigator, or trained healthcare 
professional with required qualifications (See SRM), using the clinical characteristics of 


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erythema, infiltration, papulation, oozing, and crusting as guidelines.  IGA is made 
without reference to previous scores.
7.3.2.
Pruritus/Itch Severity
Pruritus is the most frequent symptom of AD and potentially has the greatest effect on 
quality of life.  Subject-reported itch severity will be obtained from the Daily Sign and 
Symptom Severity Diary NRS (Appendix 9).
7.3.3.
Body Surface Area (BSA)
The assessment of % body surface area (% BSA) is an estimate of the percentage of total 
involved skin with AD (Appendix 5).  The % BSA assessment will be performed by 
looking at inflamed areas from within each of the 4 body surface regions separately: the 
head and neck, the upper extremities, the trunk and the lower extremities, and each of 
these body regions can potentially have up to 100% involvement.  The raters will 
estimate the percentage of involved skin for each of the regions for a % BSA area score 
that is then multiplied by the appropriate proportionality multiplier to yield the % BSA 
regional involved value (for subjects 8 years of age, 0.1 for head, 0.2 upper extremities, 
0.3 for trunk and 0.4 for lower extremities). The regional % BSA involved values are 
summed to generate the total involved % BSA.  The regional % BSA area score will also 
be utilized as part of the matrix to calculate the EASI score.  The SRM will contain more 
detailed instructions for this assessment.
The investigator, subinvestigator, or trained healthcare professional with required 
qualifications (See SRM) will perform this assessment.
7.3.4.
Eczema Area and Severity Index (EASI)
The EASI scoring system is a standardized clinical tool for the assessment of AD that 
takes into account the overall extent of the % body surface area (% BSA) involved and 
the severity scores for each of the clinical signs: erythema, induration/papulation, 
excoriation, and lichenification [Hanifin, 2001; Rullo, 2008] (Appendix 6).  The % BSA 
area score from the % BSA assessment is to be used as part of the matrix to calculate the 
EASI score.  Severity scores for each of the clinical signs (erythema, 
induration/papulation, excoriation, and lichenification) are graded on a 4-point scale (0 to 
3) for each of the 4 body regions (head and neck, upper extremities, lower extremities, 
and trunk).  The severity scores for each of the signs are summed for each region and 
multiplied by the % BSA area score and by the appropriate proportionality multiplier (for 
subjects 8 years of age, 0.1 for head, 0.2 upper extremities, 0.3 for trunk and 0.4 for 
lower extremities) to generate a regional EASI score.  The regional EASI scores are then 
summed to yield the final EASI score.  The EASI score is a static assessment made 
without reference to previous scores. 
The investigator, subinvestigator, or trained healthcare professional with required 
qualifications (see SRM) will perform this assessment.


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7.3.5.
Clinician Global Impression of Change Item
This is a single item that asks the investigator to rate the change from baseline in the 
subject’s overall AD symptoms (Appendix 10).  Response options range from “1=very 
improved” to “7=very worse”.  Results will be used as a clinical anchor in analyses of the 
minimally-important differences in itch and daily sign and symptom severity.  The 
investigator, subinvestigator, or trained healthcare professional with required 
qualifications (See SRM) will perform this assessment.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
A GSK study team and/or the GSK Safety Review Team review safety data from ongoing 
studies on a regular, systematic basis.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 11.
Additional information (i.e., corresponding symptoms) will be collected on the AE or 
SAE pages for the following AEs of special interest: systemic reactions and injection site 
reactions.
In addition, information whether an event met the diagnostic criteria for anaphylaxis as 
outlined by the Second Symposium on Anaphylaxis [Sampson, 2006] and in Appendix 2
will also be collected on the AE and SAE eCRF pages. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (i.e., the Week 20 visit) (See Section 7.4.1.3), at the timepoints specified 
in the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 11.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 11.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?” or “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or
“Has your child had any (other) medical problems or seem to act differently in 
any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” or “Has your child needed to take any medicines, 
other than those provided in this study, since his/her last visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, non-serious AEs of special interest (as 
defined in Section 4.6.1) and AEs leading to withdrawal from treatment, will be followed 
until resolution, until the condition stabilizes, until the event is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.4). Further information on 
follow-up procedures is given in Appendix 11.  
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 11 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of 
dosing and until 16 weeks after the last dose of study treatment.

If a pregnancy is reported then the investigator should inform GSK within 
2 weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7.
7.4.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
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.
7.4.4.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse. 
Three readings of blood pressure and pulse rate will be taken.
First reading should be rejected.
Second and third readings should be averaged to give the measurement to be 
recorded in the eCRF. 


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7.4.5.
Electrocardiogram (ECG)

Triplicate 12-lead ECGs will be obtained at time points indicated in the Time and 
Events Tables (Section 7.1) and as clinically indicated using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  Refer to Section 5.4.5 for QTcF withdrawal criteria and additional QTc 
readings that may be necessary.

All sites will use standardized ECG equipment provided by a centralized external 
vendor.  A central ECG reader will be utilized.  Details are provided in the SRM.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 6, must be conducted in 
accordance with the laboratory manual and protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), the results must be recorded in the CRF.
Refer to the laboratory manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Parasitic screening (will be performed at a local laboratory)

Urine hCG pregnancy testing (will be performed at the study site). 
Note: If a local laboratory analyzes a hematology sample for a study subject after the 
Baseline visit, procedures must be in place at the site to ensure that the results of the total 
WBC, absolute eosinophil count, and differential (%) remain blinded.
Hematology, clinical chemistry, and additional parameters to be tested are listed in Table 
6.  All laboratory samples are to be obtained pre-dose on dosing days.


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Table 6
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential: 1
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 2
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Other Tests

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 3

Parasitic screening 4
NOTES :
1.
Total WBC, absolute eosinophil count, and differential (%) will be blinded from the 
Baseline visit until the end of the study.
2.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.4 and 
Appendix 8.
3.
Urine pregnancy tests will be completed at each site. If a urine pregnancy test is 
positive, collect serum hCG sample (central laboratory) to confirm pregnancy. See 
Section 7.4.2 and Appendix 7 for reporting requirements
4.
Local laboratory will be used.  Only required for high-risk countries or for subjects 
who have visited high-risk countries in the 6 months prior to Screening visit.  The 
selection of the tests will be at the investigator’s judgment.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood 
urea nitrogen; hCG=human chorionic gonadotrophin; MCH=mean corpuscular hemoglobin; 
MCV=mean corpuscular volume; RBC=red blood cell; WBC=white blood cell
7.4.7.
Immunogenicity
Pre-dose blood samples will be collected for the determination of anti-mepolizumab 
antibodies at the visits specified in the Time and Events Table (Table 3).  Details for 
sample collection and processing are provided in the Laboratory Manual.  Results will be 
blinded during the study. 


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7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for determination of mepolizumab plasma concentration will be collected 
at the time points indicated in Table 3.  The PK samples will be drawn pre-dose on days 
when study treatment is scheduled to be administered.  The actual date and time of each 
blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.
Blood samples (approximately 2 mL) for determination of plasma concentrations of 
mepolizumab will be collected into plastic lithium heparin tubes.
Processing, storage and shipping procedures are provided in the laboratory manual.
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology and Science 
(PTS), GlaxoSmithKline, the details of which will be included in the laboratory manual.  
Concentrations of mepolizumab will be determined in plasma samples using the currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical site 
(detailed in the laboratory manual).
Once the plasma has been analyzed for mepolizumab, any remaining plasma may be 
analyzed for other compound-related material and the results reported under a separate 
PTS, GlaxoSmithKline protocol.
The results will be blinded during the study.
7.6.
Biomarker(s)/Pharmacodynamic Markers
Blood eosinophil counts will be assessed as part of the standard hematology assessments 
(Section 7.4.6) performed at the visits specified in the Time and Events Tables 
(Section 7.1).
Blood samples will be collected for measurement of serum free and total IL-5 levels at 
the visits specified in the Time and Events Table (Table 3).
Samples will be collected pre-dose on dosing days.  The results will be blinded during the 
study.  Collection, processing, and shipping instructions are detailed in the laboratory 
manual.
7.6.1.
Novel Biomarkers- Skin Biopsy Sub-study and Serum 
Biomarkers
Skin biopsy (3 mm) and blood samples will be collected during this study (Table 3) and 
may be used for the purposes of measuring novel biomarkers to identify factors that may 
influence AD as well as the biological and clinical responses to mepolizumab treatment.  


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If relevant, this approach will be extended to include the identification of biomarkers 
associated with adverse events.  
Skin biopsies from lesional and non-lesional skin will be collected at the Baseline visit 
and Week 4 from up to 20 subjects.  Subject participation in the skin biopsy sub-study is 
voluntary and will require additional subject informed consent.  The sub-study will be 
conducted only at pre-identified centers. 
Blood samples will be collected from all subjects for measurement of serum biomarkers. 
(See Section 7.6.1.3). 
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with AD and/or the action of mepolizumab treatment will be 
identified by application of:

RNA transcriptome analysis of skin biopsy samples.

Measurement of the levels of a subset of RNA species on skin biopsy samples.

Protein levels of biomarkers in serum samples.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.  
Skin biopsies and blood samples will be collected prior to dosing and at the time points 
indicated in Table 3.  Collection, processing, and shipping instructions are detailed in the 
SRM.
7.6.1.1.
RNA Transcriptome Research
Transcriptome studies will be conducted using microarray which facilitates the 
simultaneous measurement of the relative abundances of thousands of RNA species 
resulting in a transcriptome profile for each skin biopsy sample.  This will enable the 
evaluation of changes in transcriptome profiles that may correlate with biological 
response relating to atopic dermatitis or the action of mepolizumab treatment.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.6.1.2.
RNA Expression Research of a Subset of RNA Species
RNA expression studies may be conducted using quantitative reverse transcription-
polymerase chain reaction (RT-PCR) for each skin biopsy sample.  The RNAs assayed 
may be those involved with the pathogenesis of AD or in the subject’s response to 
mepolizumab treatment.  In addition, continuing research may identify other proteins or 
regulatory RNAs that may be involved in response to mepolizumab treatment or the 
pathogenesis of AD. This will enable the evaluation of changes in RNA expression 
profiles that may correlate with biological response relating to AD or the action of study 
treatment.


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7.6.1.3.
Protein levels of biomarkers in serum
Serum samples will be collected from all subjects at the time points indicated in the Time 
and Events Table (Table 3) to evaluate the PD effects of mepolizumab on biomarkers, 
such as total IgE, eosinophil cationic protein (ECP), circulating eosinophils, and 
chemokines such as TARC (CCL17), Eotaxin-1, Eotaxin-3, macrophage-derived 
chemokine (MDC), and CCL13.
The same samples may also be used to confirm findings by application of alternative 
technologies.
7.7.
Genetics
Information regarding genetic research is included in Appendix 12.
7.8.
Patient-Reported Outcomes 
All Patient-Reported Outcomes (PROs) will be completed as specified in the Time and 
Events Tables (Section 7.1).  
All PROs except the Daily Sign and Symptom Severity Diary will be completed:

at study visits,

prior to dosing,

prior to other assessments or evaluation by investigator, and 

in the order recommended in Section 7.
The Daily Sign and Symptom Severity Diary will be completed as described in 
Section 7.8.1.
7.8.1.
Daily Sign and Symptom Severity Diary
The self-administered sign and symptom severity diary (which is based on the content of 
the Patient-Oriented Eczema Measure) assesses the severity of 11 disease-related signs 
and symptoms (itching, discoloration, bleeding, oozing, cracking, scaling, flaking, 
dry/rough, painful, burning, and stinging) (Appendix 9).  An additional item assesses the 
impact of AD on sleep.  Response options are on an 11-point NRS and range from 
0 (Absent) to 10 (Worst Imaginable).  Question 1 of the diary will be used to assess itch.
An electronic diary will be utilized.  Subjects will complete the diary every evening 
before 12:00 AM at approximately the same time, if possible, using a recall period of the 
past 24 hours.
7.8.2.
Patient Global Impression of Severity and Change Items
At the Baseline visit, during the Treatment Period, Early Withdrawal visit, and Follow-up 
Period, subjects will be asked to rate the overall severity of their AD from “0=absent” to 
“4=very severe” (Appendix 13).


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At all visits in the Treatment Period subsequent to the Baseline visit and at the Early 
Withdrawal visit, the global impression of change items ask subjects to rate their change 
from baseline in overall severity of AD symptoms and in overall severity of itch.  
Response options range from “1=very improved” to “7=very worse” (Appendix 13).
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal hypothesis testing is planned. The primary objective of this study is to 
characterize the clinical activity of mepolizumab.  A Bayesian approach will be 
employed to estimate the posterior probability that 1) the IGA response rate for 
mepolizumab is 40% or greater, and 2) that the improvement over placebo in IGA 
response rate is at least 15 percentage points.
Descriptive statistics including point estimates and corresponding 90% confidence/ 
credible intervals will be provided for efficacy endpoints.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The primary endpoint will be the proportion of subjects who achieve treatment success 
defined as an IGA score of 0 or 1 and at least a 2-grade improvement at Week 16.  
Sample size is based on the objective to characterize the clinical activity of mepolizumab 
in subjects with moderate-to-severe atopic dermatitis.  In order to characterize this, we 
assume that a 40% IGA response rate in the mepolizumab group and a 10% IGA 
response in the placebo arm, as well as an at least 15 percentage point improvement over 
placebo, will constitute a clinically meaningful improvement.


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Using Bayesian posterior probability and assuming a flat large variance normal prior for 
difference in response rate, 25 mepolizumab subjects and 25 placebo subjects (single 
formal interim at 50% of subjects) will power the study to approximately 80% with 
predictive probability method based on the success criteria that P (difference in response 
rate 15%|Data) greater than 70% if the true response rate is 40% for mepolizumab group 
and 10% for placebo group. The 80% credible intervals for the difference in response 
rate will be presented. No pairwise comparisons are planned.
The primary analysis will be performed on the Intent-to-Treat (ITT) population, with a 
supporting analysis of the per protocol (PP) population. 
9.2.2.
Sample Size Sensitivity
If either the actual percentage of patients on placebo that achieve an IGA score of 0 or 1 
at Week 16 and at least a 2-grade improvement or the treatment effect of mepolizumab is 
different from the values assumed in Section 9.2.1, the power to detect a change in the 
proportion of subjects that achieve an IGA score of 0 or 1 and at least a 2-grade 
improvement at Week 16 will be affected.
Table 7
Sample Size Effects on the Predictive Probability of Success at the 
End of the Study
Prior used
Total Sample Size
Probability of Success
Consensus prior
40
0.745
50
0.799
60
0.833
70
0.866
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size adjustment is planned.
9.3.
Data Analysis Considerations
All pre-specified analyses will be described in a full RAP which will be finalized prior to 
unblinding.  The study will be unblinded once the final subject has completed the 
Week 20 visit, all queries for data collected up to this time are resolved, and the clinical 
study database is frozen.
9.3.1.
Analysis Populations
Intent-to-Treat Population:
The intent-to-treat (ITT) population will consist of all subjects who are randomized and 
who received at least one dose of trial medication.  Randomized subjects will be assumed 
to have received study treatment unless definitive evidence to the contrary exists. This 
will constitute the primary population for all analyses of efficacy measures.


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Per Protocol Population:
The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat 
population not identified as full protocol deviators with respect to criteria that are 
considered to impact the primary efficacy analysis.  The decision to exclude a subject 
from the PP population or exclude part of their data from the PP population analyses will 
be made prior to breaking the blind.  The PP population will be used for a supplementary 
analysis of the primary endpoint.  The PP population will not be analyzed if this 
population comprises more than 95% or less than 50% of the ITT population.
Safety Population:
All subjects who received at least one dose of a study treatment will be included in the 
safety population.  Data will be summarized by actual treatment received.  This 
population will be used in the evaluation of safety and tolerability. 
PK Population:
The PK population is defined as all subjects in the ITT population who received at least 
one dose of study medication and for whom at least a PK sample was obtained, analyzed 
and was measurable. This will be the primary population for assessing PK.
PD Population:
The PD population is defined as all subjects in the ITT population who received at least 
one dose of study treatment and who also have a baseline serum PD measurement and at 
least one post-treatment serum PD measurement.  This will be the primary population for 
assessing PD.
Biopsy Population:
The Biopsy population is defined as all subjects in the ITT population who have a 
baseline measurement and who also have at least one post-treatment PD biomarker 
measurement derived from skin biopsy samples.  This will be the population used for the 
biopsy sub-study.
9.3.2.
Administrative Interim Analyses

Unblinded in-stream study data summaries will be generated by a GSK study 
statistician and study programmer.  The unblinded summaries will be provided to 
GSK senior manager(s) for their review of subject efficacy and safety data.  These 
results and randomization assignments will only be shared with members
involved in the review and conduct of the analysis.
9.3.3.
Formal Interim Analysis
A formal interim analysis may be performed after approximately 50% of subjects have 
been randomized and have had the opportunity to complete the Week 8 visit for futility 
and to enable future planning.   If the study is anticipated to be fully enrolled at the 
projected time for this analysis, the interim may not be conducted.


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It is expected that GSK’s study statistician, programmer, clinical scientist, project 
physician lead, and/or respective designee(s) will be responsible for presenting the 
unblinded formal interim analyses.  To do so, they will be unblinded to subject level data 
for the subjects enrolled in the study at the time the database is locked for the purpose of 
the interim analyses. These persons will not share subject-level randomization 
assignments with anyone not involved in conducting the analyses.  The protection of the 
study blind and the dissemination plan for summary level results of the interim analyses 
will be described in the RAP.
The formal interim analyses will include an assessment of the proportion of subjects who 
have an IGA score of 0 or 1 and a minimum 2-grade improvement from baseline at 
Week 8 and later time points, and assessments of key secondary endpoints (e.g., change 
from baseline for EASI score) and key safety data.  The interim analysis will not be used 
to declare success.  Futility will be evaluated and may be declared if the predictive 
probability of meeting the assumptions in Section 9.2.1 is less than 10%.
A full database cleaning is not required for the interim analysis.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The primary efficacy endpoint is the IGA response rate at week 16.  The observed 
response rate and difference between mepolizumab and placebo and the 80% credible 
interval for the response rate and the difference in response rate will be presented.  The 
posterior probability that the IGA response rate for mepolizumab is 40% or greater and 
that the improvement over placebo is at least 15 percentage points will be calculated.
Subjects withdrawing prematurely from the study prior to the Week 16 visit will be 
assumed to be non-responders.
9.4.2.
Secondary Analyses
The secondary efficacy endpoints are defined in Section 3. 
IGA: Subjects’ change from baseline in IGA score and the proportion of subjects with a 
2-point decrease from baseline will be summarized by visit.  Point-estimates and 
90% confidence intervals for the differences between the experimental and vehicle arm at 
Week 16 will be presented. No formal hypothesis testing will be performed.
EASI:  Subject’s change from baseline/percent change from baseline will be summarized 
by visit.  Point-estimates and 90% confidence intervals for the differences between the 
experimental and vehicle arm at Week 16 will be presented.  No formal hypothesis 
testing will be performed.
Continuous endpoints will be presented as means and 90% confidence intervals. 


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Safety Analyses
AEs will be coded using the MedDRA coding dictionary and summarized by preferred 
term and treatment group.  SAEs occurring pre-treatment and Aes and SAEs occurring 
during active treatment and post-treatment will be summarized separately.  Separate 
summaries will be provided for all Aes, investigational product-related Aes, SAEs, Aes 
of special interest (including systemic reactions [allergic/type I hypersensitivity or 
Systemic Other] and local injection site reactions) and for Aes leading to permanent 
discontinuation of investigational product or withdrawal from the study.  All laboratory 
parameters for clinical chemistry and hematology will be summarized and tabulated.
Summary statistics of pulse rate and systolic and diastolic blood pressure will be 
presented by visit.
Immunogenicity will be summarized using appropriate descriptive statistics.
Full details of planned analyses of safety endpoints will be included in the RAP.
9.4.3.
Exploratory Analyses
Pharmacokinetic Analyses
Blood samples will be collected to determine mepolizumab plasma concentrations as per 
the Time and Events Table (Table 3).  
Sparse blood sampling is being implemented in this study and mepolizumab plasma 
concentrations will be analyzed by population PK methods using the current population 
PK model in order to determine, for example, the subject’s individual systemic exposure, 
and apparent clearance.  In addition to the covariates already included in the current 
population PK model, the effect on mepolizumab systemic exposure of other covariates 
of particular interest in subjects with AD may be explored if deemed appropriate.  
Furthermore, the model will be used to generate predictions against which the model will 
be validated prospectively using the observed data from the study (sparse sampling) in 
order to confirm the absence of AD disease impact on mepolizumab exposure.  The 
ability of the model to describe data in AD subjects will be assessed by prospective 
validation using appropriate goodness of fit tests.  
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively.  Full details of the analysis to be performed will be given in 
the RAP.
Pharmacodynamic (PD) Analyses
PD endpoints are defined in Section 3.  Full details of planned analyses of PD endpoints 
will be included in the RAP.
Patient-Reported Outcomes (PRO) Endpoints
PRO endpoints are defined in Section 3.  Full details of planned analyses of PRO 


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endpoints will be included in the RAP and/or a separate PRO RAP.
Efficacy Endpoints
“Exploratory” efficacy endpoints are defined in Section 3.  Full details of the planned 
analysis of all “Exploratory” efficacy endpoints will be included in the RAP.
EASI:  The proportion of subjects with cutpoints (e.g., −50%, −75%) for percent change 
from baseline will be summarized by visit.  Point-estimates and 90% confidence intervals 
for the differences between the experimental and vehicle arm at Week 16 will be 
presented. No formal hypothesis testing will be performed.
Itch (Daily Sign and Symptom Severity Diary NRS Question #1): Subject’s change from 
baseline/percent change from baseline in weekly average and the 90% confidence 
interval for the difference between the experimental and vehicle arm at Week 16 will be 
presented.  No formal hypothesis testing will be performed.
Itch (Daily Sign and Symptom Severity Diary NRS Question #1): Subject’s change from 
baseline/percent change from baseline and the proportion of subjects with cutpoints (e.g., 
−50%, −75%) for percent change from baseline will be summarized by visit.
Disease Flare/Relapse Endpoints
Disease flare/relapse endpoints are defined in Section 3.  Full details of the planned 
analysis of these endpoints will be included in the RAP.
Relationship between Efficacy and Blood Eosinophils
Endpoints to characterize the relationship between efficacy and blood eosinophil counts 
are described in Section 3.
If data permits, EASI percent change from baseline will be analyzed using a Mixed 
Model Repeated Measures (MMRM) analysis, fitting subject as a random effect, and 
baseline value, treatment group and baseline blood eosinophil count as fixed effects.  An 
unstructured variance-covariance matrix structure will be assumed. 
Further exploratory analyses to determine the impact of baseline blood eosinophils may 
be conducted.
Full details of the planned analysis of these endpoints will be included in the RAP.


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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:
IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable
Obtaining signed informed consent
Investigator reporting requirements (e.g., reporting of Aes/SAEs/protocol 
deviations to IRB/IEC).
GSK will provide full details of the above procedures, either verbally, in writing, 
or both.
Signed informed consent must be obtained for each subject prior to participation 
in the study.
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.

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 entered in the eCRFs that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, 
depending on the study; also current medical records must be available.

Definition of what constitutes source data can be found in the Source Document 
Agreement. 
GSK will monitor the study and site activity to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.


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10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK 
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.


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
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.  GSK will provide the investigator with the randomization codes for their 
site only after completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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11.
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Caproni M, Torchia D, Antiga E, Terranova M, Volpi W, Del Bianco E, et al.  The 
comparative effects of tacrolimus and hydrocortisone in adult atopic dermatitis: An 
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Eichenfield LF, Tom WL, Chamlin SL, Feldman SR, Hanifin JM, Simpson EL, et al.  
Guidelines of care of the management of atopic dermatitis: Section 1. Diagnosis and 
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Fitzpatrick TB.  The validity and practicality of sun-reactive skin types I through VI.  
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blood eosinophil count- a dose response meta-analysis. 2015-May-12. 
GlaxoSmithKline Document Number CM2003/00010/12. Mepolizumab (SB-240563) 
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Guttman-Yassky E, Nograles KE, Krueger JG.  Contrasting pathogenesis of atopic 
dermatitis and psoriasis - Part I: Clinical and pathologic concepts.  J Allergy and Clin 
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Guttman-Yassky E, Nograles KE, Krueger JG.  Contrasting pathogenesis of atopic 
dermatitis and psoriasis - Part II: Immune cell subsets and therapeutic concepts.  J 
Allergy and Clin Immunol. 2011b;127(6):1420-1432. 
Hamid Q, Boguniewicz M, Leung DYM.  Differential in situ cytokine gene expression in 
acute versus chronic atopic dermatitis.  J Clin Invest. 1994;94(2):870-876. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M.  The Eczema Area 
and Severity Index (EASI): an assessment of reliability in atopic dermatitis. Exp 
Dermatol. 2001;10:11-18.
Hon KL, Lam MC, Leung TF, Wong KY, Chow CM, Fok TF, et al. Are age-specific 
high serum IgE levels associated with worse symptomatology in children with atopic 
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Jenerowicz D, Czarnecka-Operacz M, Silny W. Peripheral blood eosinophilia in atopic 
dermatitis. Acta Dermatoven APA. 2007;16(2):47-52.


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Kiehl P, Falkenberg K, Vogelbruch M, Kapp A.  Tissue eosinophilia in acute and chronic 
atopic dermatitis: a morphometric approach using quantitative image analysis of 
immunostaining.  British Journal of Dermatology. 2001;145:720-729.
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;125:1336-1343. 
Kondo S, Yazawa H, Jimbow K. Reduction of serum interleukin-5 levels reflect clinical 
improvement in patients with atopic dermatitis. J Dermatol. 2001;28:237-243.
La Grutta S, Richiusa P, Pizzolanti G, Mattina A, Pajno GB, Citarrella R, et al. CD4+IL-
13+ cells in peripheral blood well correlates with the severity of atopic dermatitis in 
children. Allergy. 2005;60:391-395. 
Menzella F, Lusuardi M, Galeone C, Taddei S, Zucchi L.  Profile of anti-IL-5 mAb 
mepolizumab in the treatment of severe refractory asthma and hypereosinophilic 
diseases.  Journal of Asthma and Allergy. 2015;8:105-114.
Oldhoff JM, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui J, et al.  Anti-IL-5 
recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic 
dermatitis. Allergy. 2005;60:693-696. 
Ortega H, Li H, Suruki R, Algers F, Gordon D, Yancey S. Cluster analysis and 
characterization of response to mepolizumab: a step closer to personalized medicine for 
patients with severe asthma. Ann Am Thorac Soc. 2014b;11(7):1011-1017. 
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al.  
Mepolizumab treatment in patients with severe eosinophilic asthma. New Engl J Med. 
2014a;371(13):1198-1207.
Pouliquen IJ, Kornmann O, Barton SV, Price JA, Ortega HG.  Characterization of the 
relationship between dose and blood eosinophil response following subcutaneous 
administration of mepolizumab. Int J Clin Pharmacol Ther. 2015;53(12):1015-1027. 
Rehal B, Armstrong AW.  Health Outcome Measures in Atopic Dermatitis: A Systematic 
Review of Trends in Disease Severity and Quality-of-Life Instruments 1985-2010.  PloS 
ONE.  2011;6(4):e17520.
Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon H-U, et al. 
Treatment of patients with the hypereosinophilic syndrome with mepolizumab. New Engl 
J Med. 2008;358(12):1215-1228.
Rullo VEV, Segato A, Kirsh A, Sole D. Severity scoring of atopic dermatitis: a 
comparison of two scoring systems. Allergol et Immunopathol. 2008;36(4):201-211.
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report-second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.  J Allergy Clin Immunol 2006;117(2):391-397.
Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, LeBovidge J, et al. Atopic 
dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131:295 299.
Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United 
States:  data from the 2003 national survey of children’s health. J Investig Dermatol. 
2011;131:67-73. 
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other health and demographic factors: a US population-based study. J Allergy Clin 
Immunol. 2013;132:1132-1138. 
Tremp M, Knafla I, Burg G, Wüthrich B, Schmid-Grendelmeier P. ‘EASIdig’- a digital 
tool to document disease activity in atopic dermatitis. Dermatology. 2011;223:68-73. 
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AD
atopic dermatitis
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
BP
blood pressure
BSA
body surface area
BUN
blood urea nitrogen
CI
confidence interval
CRF
case report form
CV
cardiovascular
EASI
Eczema Area and Severity Index
ECGs
electrocardiograms
ECP
eosinophil cationic protein
eCRF
electronic case report form
EGPA
eosinophilic granulomatosis with polyangiitis
FAAN
Food Allergy and Anaphylaxis Network
FRP
females of reproductive potential
FSH
follicle stimulating hormone
GSK
GlaxoSmithKline
HbsAg
hepatitis B surface antigen
hCG
human chorionic gonadotrophin
HIV
human immunodeficiency virus
HPA
hypothalamic-pituitary-adrenal
HRT
hormone replacement therapy
ID50
dose resulting in 50% of the maximum achievable effect
ID90
dose resulting in 90% of the maximum achievable effect
IFN
interferon
IFN-
interferon-gamma
IGA
Investigator’s Global Assessment
IgE
immunoglobulin E
IgG
immunoglobulin G
IL
interleukin
INR
international normalized ratio
ITT
Intent-to-Treat
IV
intravenous
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume


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MDC
macrophage-derived chemokine
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger ribonucleic acid
NAB
neutralizing antibody
NIAID
National Institute of Allergy and Infectious Diseases (US)
NRS
numeric rating scale
PD
pharmacodynamic
PEF
Peak expiratory flow
PGAI
Physician Global Assessment of Improvement
PK
Pharmacokinetics
PP
Per Protocol
PROs
Patient-Reported Outcomes
PTS
Platform Technology and Science
QTc
QT interval corrected for heart rate
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
RT-PCR
reverse transcription-polymerase chain reaction
SAE
serious adverse event
SC
subcutaneous
SCORAD
severity score atopic dermatitis
SRM
Study Reference Manual
TARC
thymus and activation regulated chemokine
Th-2
type 2 helper T-cell
ULN
upper limit of normal
US
United States
UV
ultraviolet
WBC
white blood cell
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NUCALA
Atopiclair
CeraVe
EpiCeram
PruMyx


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12.2.
Appendix 2 – Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis 
[Sampson, 2006]. The criteria do not make a distinction based on underlying mechanism. 
These criteria are summarized as follows:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow (PEF), hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c.
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline


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12.3.
Appendix 3 – Criteria for Atopic Dermatitis Diagnosis
The diagnosis of atopic dermatitis is based on the Eichenfield revised criteria of Hanifin 
and Rajka [Eichenfield, 2014].
ESSENTIAL FEATURES- Must be present:

Pruritus

Eczema (acute, subacute, chronic)
o
Typical morphology and age-specific patterns*
o
Chronic or relapsing history
*Patterns include:
1. Facial, neck, and extensor involvement in infants and children
2. Current or previous flexural lesions in any age group
3. Sparing of the groin and axillary regions
IMPORTANT FEATURES- Seen in most cases, adding support to the diagnosis:

Early age of onset 

Atopy
o
Personal and/or family history
o
Immunoglobulin E reactivity

Xerosis
ASSOCIATED FEATURES- These clinical associations help to suggest the diagnosis 
of atopic dermatitis but are too nonspecific to be used for defining or detecting atopic 
dermatitis for research and epidemiologic studies:

Atypical vascular responses (e.g., facial pallor, white dermographism, delayed 
blanch response)

Keratosis pilaris/pityriasis alba/hyperlinear palms/ichthyosis

Ocular/periorbital changes

Other regional findings (e.g., perioral changes/periauricular lesions)

Perifollicular accentuation/lichenification/prurigo lesions
EXCLUSIONARY CONDITIONS-It should be noted that a diagnosis of atopic 
dermatitis depends on excluding conditions, such as:

Scabies

Seborrheic dermatitis

Contact dermatitis (irritant or allergic)

Ichthyoses

Cutaneous T-cell lymphoma

Psoriasis

Photosensitivity dermatoses

Immune deficiency diseases

Erythroderma of other causes


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12.4.
Appendix 4 – Investigator’s Global Assessment (IGA)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.5.
Appendix 5 – Body Surface Area (BSA)
This study protocol will follow the 3 steps depicted below to calculate total % 
BSA involvement. However, for purposes of this study, qualified raters will 
only need to complete Step 1: estimating % BSA involvement in each region. 
Steps 2 and 3 will be auto calculated within the eCRF after completion of Step 1 
(entry of estimated % BSA involvement values).
Note: This process should be followed to confirm % BSA eligibility at the 
Screening and Baseline Visit.

Complete % BSA prior to EASI at each study visit. 

Use visit-specific estimated % BSA involvement (Step 1) to determine the EASI 
area score at each visit.
Body Region
% Involvement
(0-100% each area)
% Involvement x 
Proportionality Multiplier
Regional % BSA
Involvement
Head and neck
____ x 0.1 
Upper extremities
____ x 0.2
Trunk
____ x 0.3
Lower extremities
____ x 0.4
Total Involved % BSA  (sum of the 4 area values) =
Estimate % BSA
involvement in
each body region
Multiply %
involvement by
fraction of total
body area
Estimate % BSA
involvement in
each body region
Multiply %
involvement by
fraction of total
body area
2
1
3
Calculate 
total involved 
% BSA


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12.6.
Appendix 6 – Eczema Area and Severity Index (EASI)
For purposes of this study, qualified raters will record the severity of signs 
(erythema, induration/papulation, excoriation, lichenification) by body region 
(head/neck, trunk, upper extremities, lower extremities). The severity scores 
will be entered into the eCRF for each visit.  The region score (0-6), score per 
body region, and final EASI score will be auto calculated within the eCRF.
The eCRF auto calculated final EASI score will be utilized to confirm eligibility 
at the Screening Visit and the Baseline Visit.  
Once a % BSA involvement for each region is determined, each percentage is translated 
to an area score based on the following definitions:
Reference:
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M.  The Eczema Area 
and Severity Index (EASI): an assessment of reliability in atopic dermatitis. Exp 
Dermatol. 2001;10:11-18.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study (from first dose and until 16 weeks after 
last dose of study treatment)

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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.


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
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 11. 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 subject who becomes pregnant while participating will discontinue 
study treatment.  
12.7.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 


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Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998].
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.8.
Appendix 8 – Liver Safety Required Actions and Follow up 
Assessments
Liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments 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 subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(See MONITORING below)

Do not restart/rechallenge. Permanently 
discontinue study treatment and may 
continue subject in the study for any protocol 
specified follow up assessments (refer to 
Section 5.4).

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4 weeks after last 
dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia.  Note:
This blood sample will be sent to the 
central laboratory to maintain the blind 
while study is ongoing. Results will be 
provided only if unblinding of a subject’s 
treatment assignment is required. Also 
note that the mechanism of action of 
mepolizumab leads to lowering of 
eosinophils.   


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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 subjects 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 subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
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 HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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 subjects 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 


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5.
PK sample may not be required for subjects 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 subject’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.  
Liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment.

Subject 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 subject meets the liver chemistry 
stopping criteria, proceed as described above.

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly.

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects 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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12.9.
Appendix 9 – Daily Sign and Symptom Severity Diary
Individuals with eczema may experience a variety of symptoms.
Please answer each question to the best of your ability.  Please indicate how severe each 
of the following eczema symptoms was in the past 24 hours:
1.
Itchy skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
2.
Red or 
discolored 
skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
3.
Bleeding 
skin 
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
4.
Oozing skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
5.
Cracked skin 
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
6.
Scaly skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
7.
Flaky skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
8.
Dry or rough 
skin 
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
9.
Painful skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
10. Burning skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable
11. Stinging skin
0
Absent
1
2
3
4
5
6
7
8
9
10
Worst 
imaginable


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Please respond to the following question about how much your eczema impacted your 
sleep in the past 24 hours by selecting the number to indicate your response.
In the past 24 hours, how much was your sleep impacted?
0
No impact
1
2
3
4
5
6
7
8
9
10
Worst sleep 
imaginable


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12.10.
Appendix 10 – Clinician Global Impression of Change
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.11.
Appendix 11 – Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.11.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition.


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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE.

Situations where 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.
12.11.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during 
hospitalization are Aes.  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.

Results in disability/incapacity

NOTE:

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, 


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influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption
d.
Is a congenital anomaly/birth defect
e.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition.  These should also be 
considered serious.

Examples of such events are 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
f.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.11.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following Aes and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism


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
Deep venous thrombosis/pulmonary embolism

Revascularization
12.11.4.
Recording of Aes and SAEs
Aes 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of 
the subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed patient-reported outcomes questionnaires and the collection of 
AE data are independent components of the study.

Responses to each question in the patient-reported outcomes questionnaire will be 
treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.11.5.
Evaluating Aes and SAEs
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is 
assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both Aes and SAEs can be 


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assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment 
and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of Aes and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as may be indicated or as 
requested by GSK to elucidate as fully as possible the nature and/or causality of 
the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory 
tests or investigations, histopathological examinations or consultation with other 
health care professionals.

If a subject 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.


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
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.11.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool

If the electronic system is unavailable, the site will use the paper SAE data 
collection tool and fax or e-mail it to the Medical Monitor within 24 hours.

Site will enter the serious adverse event data into the electronic system as soon as 
it becomes available.

The investigator will be required to confirm review of the SAE causality by 
ticking the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of 
submission of the SAE.

After the study is completed at a given site, the electronic data collection tool 
(e.g., InForm system) 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 subject or receives updated 
data on a previously reported SAE after the electronic data collection tool has 
been taken off-line, the site can report this information on a paper SAE form or to 
the Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.12.
Appendix 12 – Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 
Response to medicine, including mepolizumab or any concomitant medicines;
Atopic dermatitis susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 


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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the Baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:
Continue to participate in the genetic research in which case the genetic DNA 
sample is retained
Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 


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Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.
If a subject withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.
Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.13.
Appendix 13 – Patient Global Impression of Severity and 
Change
12.13.1.
Patient Global Impression of Severity (PGIS)
12.13.2.
Patient Global Impression of Change (PGIC)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.14.
Appendix 14 – Country Specific Requirements
No country-specific requirements exist.


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12.15.
Appendix 15: Protocol Changes
Protocol Amendment 02: 22-JUN-2017
Where the amendment applies
This protocol amendment applies to all sites and all countries.
Summary of amendment changes and rationale 
Section # and Name
Description of Change
Brief Rationale
Medical 
Monitor/Sponsor 
Information Page
Site address for Secondary 
Medical Monitor was updated
Change in site address 
Section 4.1- Overall 
Design, Figure 1 
Study Schematic
A boarder was placed around 
the Week 16 and Week 20 visits 
to highlight that no IP dose is 
administered at the two visits.
Reminder placed within the study 
schematic noting no IP dose is 
administered at Weeks 16 and 20.
Synopsis; Section 
4.2.1- Pre-
screening/Screening 
Periods; &.Section 
7.1- Time and Events 
Table
Removed requirement for 
subject data entry into the Daily 
Sign and Symptom Severity 
Diary for at least 7 consecutive 
days immediately prior to the 
Baseline visit. 
The process for monitoring 
subject data entry into the Daily 
Sign and Symptom Severity 
Diary has been added.
Under Amendment 1, the itch/pruritus 
endpoint (‘the mean change in weekly 
average of daily itch/pruritus numeric 
rating scale [NRS] score [captured 
within the Daily Sign and Symptom 
Severity Diary] from baseline to Week 
16’) was changed from a secondary 
endpoint to exploratory endpoint. 
Subject data entry will be monitored 
throughout the trial. Subjects who do 
not complete data entry will be re-
educated on the importance of diary 
completion.
Synopsis; Section 4.3-
Type and Number of 
Subjects
Increase in number of subjects 
screened from approximately 75 
to approximately 140.  
Increase in screen failure rate requires 
increase in approximate number of 
subjects screened. 
No change was applied to target 
number of subjects randomized.
Synopsis; Section 6.3-
Blinding and Section 
9.3.2-Administrative 
Interim Analyses; 
Section 9.3.3 Formal 
Interim Analysis
The ‘Interim analysis’ section 
updated to ‘Formal interim 
analysis’.
Added separate section on 
administrative interim analyses’.
Administrative interim analyses will be 
conducted to enable GSK senior 
manager(s) review of subject efficacy 
and safety data summaries. GSK 
study statistician, study programmer 
and senior manager(s) will review 
unblinded data. Administrative and 
formal interim analyses may be 
performed.
Section 7- Study 
Assessments and 
Clarification regarding order of 
assessments. Note added 
Clarification regarding recommended 
order of assessments.


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Section # and Name
Description of Change
Brief Rationale
Procedures
regarding subject report of 
emollient application within the 
2-hour period preceding the 
study visit.
Section 7.1 Table 2
Clarification added to Pre-
Screening column table header-
‘prior to the Screening Visit’ was 
added after ‘Up to 4 weeks’. 
Clarification added to Screening 
column table header- ‘prior to 
the Day 1 Baseline Visit’ was 
added after ‘1 to 2 weeks’.
Pre-Screening Visit will occur up to 4 
weeks prior to the Screening Visit.
Screening Visit will occur 1 to 2 weeks 
prior to the Day 1 Baseline Visit.
Section 7.1 Table 3-
Time and Events
‘No IP dose’ was added to the 
Week 16 and Week 20 column 
headers within the Time and 
Events table.
Reminder that IP dose is not 
administered at Week 16 and Week 
20.
Section 7.4.5-
Electrocardiograms
Clarification: Triplicate 12-lead 
ECGs are required for all ECG 
time points noted in Section 7 
(all Time and Event tables).  
Original language indicated 
triplicate ECGs were required 
for time points noted within Time 
and Events Table 3 only.
Triplicate 12-lead ECGs are required 
for all time points.
Section 12.5-
Appendix 5: Body 
Surface Area
Clarification: The process 
outlined for BSA calculation 
should be followed at both the 
Screening and Baseline Visits in 
order to confirm subject 
eligibility. 
Original language describing the 
process for BSA calculation,
only referenced confirmation of 
subject eligibility at the 
Screening Visit and not both the 
Screening and Baseline Visits.
The eCRF auto calculated BSA score 
will be used for confirmation of BSA 
eligibility at the Screening and 
Baseline Visits.
Section 12.6-
Appendix 6: EASI
Clarification: Qualified raters will 
assess the severity of signs by 
body region. The severity 
scores will be entered into the 
eCRF for each visit. The region 
score (0-6), score per body 
region, and final EASI score will 
be auto calculated within the 
eCRF.
The eCRF auto calculated final EASI 
score will be used for confirmation of 
EASI eligibility at the Screening and 
Baseline visits.


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Protocol Amendment 01: 26-December-2016
Where the amendment applies
This protocol amendment applies to all sites and all countries.
Summary of amendment changes and rationale 
Protocol amendment 1 includes recommendations from the US Food and Drug 
Administration (FDA). In addition, some protocol clarifications have been made.
Section # and Name
Description of Change
Brief Rationale
5.1 Inclusion Criteria & 
throughout document
Enrollment of adult subjects only 
(ages 18 – 70 years). 
US Food and Drug Administration 
(FDA) recommendation to obtain 
preliminary safety and efficacy data in 
adults with moderate to severe atopic 
dermatitis (AD) prior to initiation of 
studies in pediatric subjects.[1]
Table 3: Time and 
Events Table: Baseline 
through Follow-up 
Period
Collection of additional 
pharmacokinetic (PK) samples 
at Weeks 8 and 12.
FDA recommendation.[1] As this is the 
first study in subjects with atopic 
dermatitis (AD) receiving 
mepolizumab subcutaneous (SC) 
treatment, additional PK sampling 
would provide useful data to elucidate 
the steady state of mepolizumab in 
subjects with AD. 
6.1.2 Observation 
Period & throughout 
document
Addition of 1 hour observation 
period at Week 12 post dose.
FDA recommendation to standardize 
post-dose safety monitoring.[1] With 
Amendment 1, the 1 hour observation 
period will be required for each 
dosing visit, post dose
5.4.1 Early Withdrawal 
from Study Treatment 
& 
7.4.1 Aes and SAEs
Addition of stopping criteria for 
cardiovascular or hematologic 
Aes consistent with CTCAE 
grade 2 or higher.
FDA recommendation.[1]
Table 3 Time and 
Events Table: Baseline 
through Follow-up 
Period
Collection of electrocardiograms 
(ECGs) at Week 4 (pre-dose), 
Week 16 or Early Withdrawal
FDA recommendation.[1]
6.10.1 Permitted 
Medications and Non-
Drug Therapies; Table 
1 Prohibited 
Medications and Non-
Drug Therapies
Prohibit use of oral 
antihistamines 
FDA recommendation.[1] Minimize 
impact on efficacy evaluation of 
pruritus.
5.4.3 Postponement of 
Study Treatment
Require postponement of study 
medication during treatment with 
FDA recommendation.[1]


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Section # and Name
Description of Change
Brief Rationale
oral or IV non-cytotoxic 
antibiotics, antivirals, anti-
protozoals or antifungals.
5.1 Inclusion Criteria
Revised definition of ‘inadequate 
response to prior treatment’ to 
specify a minimum potency for 
topical corticosteroid failure. 
Added inadequate response to 
optimal use of 
nonpharmacologic measures 
such as moisturizers.
FDA recommendation to specify a 
minimum potency for topical 
corticosteroid failure and inadequate 
response to optimal use of 
nonpharmacologic measures such as 
moisturizers. [1]
4.2.4 Unscheduled 
Visit for Flare/Relapse 
& 
Table 4 Time and 
Events Table: 
Unscheduled Visit for 
Flare/Relapse
Clarification regarding the 
management of subjects who 
experience flare/relapse. In the 
case of flare/relapse with 
intolerable AD symptoms where 
the use of prohibited medication 
is required (See Table 1), the 
subject will be permanently 
withdrawn from treatment.
FDA recommendation to clarify how 
subjects experiencing flare/relapse 
will be managed.[1]
3 Objectives and 
Endpoints & 9.4.3 
Exploratory Analyses
Shift in itch/pruritus endpoint 
(‘mean change in weekly 
average of daily itch/pruritus 
numeric rating scale [NRS] 
score from baseline to Week 
16’) from secondary endpoint to 
exploratory endpoint. 
Insufficient data available to properly 
design this endpoint as secondary 
therefore shifted to exploratory.  
4.2 Treatment Arms 
and Duration & Table 2 
Prohibited Medications 
and Non-Drug 
Therapies
Clarification regarding timing for 
informed consent. If an 
ineffective treatment is stopped 
for the purpose of study entry, 
informed consent should be 
obtained at the time the 
ineffective treatment is stopped.  
Clarification.
4.2 Treatment Arms 
and Duration, Table 2 
Prohibited Medications 
and Non-Drug 
Therapies
Clarification regarding the total 
time in the Screening Period for 
subjects transitioning off a 
biologic at study entry.
Clarification. For subjects who may 
need to stop treatment with a 
biologic, the total Pre-Screening and 
Screening Period may last up to 20 
weeks thus the total approximate time 
in the study may last for up to 40 
weeks.
Table 3 Time and 
Events Table: Baseline 
through Follow-up 
Period; Appendix 12.5 
% BSA
Clarification regarding the need 
to enter %BSA affected and 
EASI scores in the eCRF in-
stream.  
Clarification. 


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Section # and Name
Description of Change
Brief Rationale
Table 2 Time and 
Events: Pre-Screening 
through Screening 
Period; Table 3 Time 
and Events: Treatment 
through Follow-up 
Period and Table 4 
Time and Events 
Table: Unscheduled 
Visit for Flare/Relapse
Replacement of timepoint 
markers from ‘X’ to visit type 
abbreviation (e.g. ‘S’ for 
Screening visit, ‘B’ for Baseline 
visit).
To facilitate review.
Table 2 Time and 
Events: Pre-Screening 
through Screening 
Period; Table 3 Time 
and Events: Treatment 
through Follow-up 
Period and Table 6 
Protocol Required 
Safety Lab 
Assessments
Collection of serum hCG for 
confirmation of positive urine 
pregnancy test
Confirmation of urine pregnancy test
4.6 Benefit:Risk 
Assessment; 5 
Selection of Study 
Population and 
Withdrawal Criteria; 
6.3 Blinding and 11 
References
Update to document number of 
Investigator’s Brochure (IB) 
[GlaxoSmithKline Document
Number CM2003/00010/12, 
2016 GlaxoSmithKline 
Document Number 
CM2003/00010/11, 2016].
An IB update was released on 5-
November-2016.  This 5-November-
2016 IB (version 15) replaces IB 
version 14 released 3-December-
2015 and IB Supplement released 1-
August-2016.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205050
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Investigate the Efficacy and Safety of Mepolizumab 
Administered Subcutaneously in Subjects with Moderate to 
Severe Atopic Dermatitis
Compound Number 
:
SB240563
Effective Date 
:
28-FEB-2018
Description:

The purpose of this RAP is to describe the planned analyses and outputs to be 
included in the Clinical Study Report for Protocol GSK Document Number 
2015N268158_02

This RAP is intended to describe the efficacy, safety and tolerability, 
pharmacokinetic and pharmacodynamic analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval 
Method
NA
NA
Associate Statistician (Immuno Inflammation,
Quantitative Sciences India)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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RAP Team Approvals:
Approver
Date
Approval Method
22-FEB-2018
eTMF
Clinical Investigation Leader (Immuno 
Inflammation, Immuno Immunology)
28-FEB-2018
E-Mail
Project Physician Leader (Clinical Pharmacology 
Modelling and Simulation)
26-FEB-2018
eTMF
SERM Director (CMO GCSP)
22-FEB-2018
eTMF
Operational Scientist Leader (PCPS)
28-FEB-2018
eTMF
Data Quality Leader (Immuno Inflammation and 
Dermatology, Data Management)
Pharmacokinetist (Clinical Pharmacology 
Modelling and Simulation)
24-FEB-2018
eTMF
28-FEB-2018
eTMF
Lead Programmer (Future Pipeline Discovery,
Quantitative Sciences India)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
25-FEB-2018
eTMF
Statistical Leader (Immuno Inflammation, 
Quantitative Sciences India)
  
23-FEB-2018
eTMF
Biostatistics and Programming Manager (Future 
Pipeline Discovery, Quantitative Sciences India)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.1.
Protocol Defined Objectives and Endpoints ...................................8
2.2.2.
Final Reporting Objectives & Endpoints Following Study 
Termination....................................................................................9
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................12
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
5.1.
Study Treatment & Sub-group Display Descriptors.....................................15
5.2.
Baseline Definitions ....................................................................................15
5.2.1.
Derivations and Handling of Missing Baseline Data.....................16
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................16
6.
STUDY POPULATION ANALYSES .......................................................................17
6.1.
Overview of Planned Study Population Analyses........................................17
7.
EFFICACY ANALYSES..........................................................................................17
7.1.
Primary Efficacy Analyses ..........................................................................17
7.1.1.
Endpoint / Variables.....................................................................17
7.1.2.
Summary Measure ......................................................................17
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events ................17
7.1.4.
Population of Interest...................................................................17
7.1.5.
Statistical Analyses / Methods .....................................................18
7.1.5.1.
Statistical Methodology Specification..........................18
7.2.
Secondary Efficacy Analyses......................................................................18
7.2.1.
Endpoint / Variables.....................................................................18
7.2.2.
Summary Measure ......................................................................18
7.2.3.
Strategy for Intercurrent (Post-Randomization) Events ................19
7.2.4.
Population of Interest...................................................................19
7.2.5.
Statistical Analyses / Methods .....................................................19
7.2.5.1.
Statistical Methodology Specification..........................19
7.3.
Exploratory Efficacy Analyses.....................................................................19
7.3.1.
Endpoint / Variables.....................................................................19
7.3.2.
Summary Measure ......................................................................19
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events ................20


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7.3.4.
Population of Interest...................................................................20
7.3.4.1.
Statistical Analyses / Methods ....................................20
7.3.4.2.
Statistical Methodology Specification..........................20
8.
SAFETY ANALYSES .............................................................................................20
8.1.
Adverse Events Analyses ...........................................................................20
8.2.
Adverse Events of Special Interest Analyses..............................................20
8.3.
Clinical Laboratory Analyses.......................................................................21
8.4.
Other Safety Analyses ................................................................................21
8.4.1.
ECG.............................................................................................21
8.5.
Immunogenicity Analyses ...........................................................................22
9.
PHARMACOKINETIC ANALYSES.........................................................................23
9.1.
Exploratory Pharmacokinetic Analyses .......................................................23
9.1.1.
Endpoint / Variables.....................................................................23
9.1.1.1.
Drug Concentration Measures....................................23
9.1.1.2.
Derived Pharmacokinetic Parameters.........................23
9.1.2.
Summary Measure ......................................................................23
9.1.3.
Population of Interest...................................................................23
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................23
9.1.5.
Statistical Analyses / Methods .....................................................23
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................24
10.1.
Exploratory Pharmacodynamic and Biomarker Analyses............................24
10.1.1.
Endpoint / Variables.....................................................................24
10.1.2.
Summary Measure ......................................................................24
10.1.3.
Population of Interest...................................................................24
10.1.4.
Statistical Analyses / Methods .....................................................24
10.1.4.1.
Statistical Methodology Specification..........................25
11. REFERENCES.......................................................................................................26
12. APPENDICES........................................................................................................27
12.1.
Appendix 1: Schedule of Activities ..............................................................27
12.2.
Appendix 2: Assessment Windows .............................................................31
12.2.1.
Definitions of Assessment Windows for Analyses........................31
12.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
12.3.1.
Study Phases ..............................................................................32
12.3.1.1.
Study Phases for Efficacy Assessments.....................32
12.3.2.
Treatment Emergent Flag for Adverse Events .............................32
12.4.
Appendix 4: Data Display Standards & Handling Conventions....................33
12.4.1.
Reporting Process .......................................................................33
12.4.2.
Reporting Standards....................................................................33
12.4.3.
Reporting Standards for Pharmacokinetic....................................34
12.5.
Appendix 5: Derived and Transformed Data ...............................................35
12.5.1.
General........................................................................................35
12.5.2.
Study Population..........................................................................35
12.5.3.
Efficacy........................................................................................35
12.5.4.
Safety ..........................................................................................37
12.5.5.
Pharmacokinetic ..........................................................................37
12.5.6.
Pharmacodynamic and Biomarker ...............................................37


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12.6.
Appendix 6: Reporting Standards for Missing Data.....................................38
12.6.1.
Premature Withdrawals................................................................38
12.6.2.
Handling of Missing Data.............................................................38
12.6.2.1.
Handling of Missing and Partial Dates ........................38
12.7.
Appendix 7: Values of Potential Clinical Importance ...................................39
12.7.1.
Laboratory Values........................................................................39
12.7.2.
Vital Signs....................................................................................39
12.8.
Appendix 8: Abbreviations & Trade Marks ..................................................40
12.8.1.
Abbreviations...............................................................................40
12.8.2.
Trademarks .................................................................................41
12.9.
Appendix 9: List of Data Displays ...............................................................42
12.9.1.
Data Display Numbering..............................................................42
12.9.2.
Mock Example Shell Referencing ................................................42
12.9.3.
Deliverables.................................................................................42
12.9.4.
Study Population Tables..............................................................43
12.9.5.
Efficacy Tables ............................................................................45
12.9.6.
Safety Tables...............................................................................46
12.9.7.
Safety Figures .............................................................................51
12.9.8.
Pharmacokinetic Tables...............................................................51
12.9.9.
Pharmacokinetic Figures .............................................................52
12.9.10. Pharmacodynamic and Biomarker Tables....................................52
12.9.11. Pharmacodynamic and Biomarker Figures ..................................53
12.9.12. ICH Listings .................................................................................54
12.9.13. Non-ICH Listings..........................................................................57
12.10. Appendix 10: Example Mock Shells for Data Displays ................................59


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2015N268158_00
2016-AUG-25
Original
2015N268158_01
2016-DEC-26
Amendment No. 1

Protocol amendment 1 includes recommendations from the US Food and Drug Administration (FDA) 
and other clarifications.
2015N268158_02
2017-JUN-22
Amendment No. 2

The addition of administrative interim analyses to enable review of subject efficacy and safety 
data summaries.

Minor clarifications regarding: collection of ECGs in triplicate for all ECG timepoints; general order 
of study procedures; checks for BSA and EASI eligibility utilizing eCRF auto calculated totals at 
Screening and Baseline visits.

Increase in anticipated number of subjects screened from approximately 75 subjects to 
approximately 140 subjects (no change in target number of subjects randomized).

Reminders inserted into the study schematic and Time and Events tables, indicating no IP dose 
will be administered at Week 16 and Week 20.

Removed requirement for subject data entry into the Daily Sign and Symptom

Severity Diary for at least 7 consecutive days immediately prior to the Baseline visit.
Following a formal interim analysis (10-NOV-2017) after approximately 50% of subjects 
were randomised and had the opportunity to complete the Week 8 visit, the study met the 
planned futility stopping criteria and the study was terminated. As a result of the study 
being terminated, only a sub-set of planned protocol defined objectives and endpoints 
will be included for the final reporting.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.


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Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Exploratory Objectives: 
Proportion of subjects who 
have an IGA score of 0 or 1 
and at least a 2-grade 
improvement at each study 
visit by baseline blood 
eosinophil count

Exploratory Objectives: Mean 
percentage change in EASI 
score compared to change in 
blood eosinophils at each visit

These endpoints are not 
being considered for final 
reporting

Due to the limited 
responders, these 
endpoints will not be 
summarised

Exploratory Objectives: Mean 
change in weekly average of 
daily itch/pruritus numeric 
rating scale [NRS] score 
(based on Item #1 of Daily 
Sign and Symptom Severity 
Diary) from baseline to Week 
16

This endpoint is not 
considered for final reporting

Mean change from baseline 
for all study visit will also 
include Week 16 and hence 
this is considered as out of 
scope for final reporting

Exploratory Objectives 

Additional Exploratory 
Objective included: Clinician 
Global Impression of Change
is an exploratory endpoint 
which is not included while 
defining the objective/ 
endpoint

This is collected as per 
protocol so included for final 
reporting

Section 9.3.1: In all population 
definitions “all subjects” term is 
used

In all population definition “all 
subjects” term has been 
changed to “all participants” 

Changed as per current 
RAP template definition

Section 9.3.1: Per-Protocol 
Population definition

Per-Protocol Population is 
removed

There is no planned 
sensitivity analysis for the 
primary objective

Section 9.3.1: PK Population 
definition

PK Population definition 
updated

Changed as per current 
RAP template definition and 
to take account of potential 
miss-dosed participants

Section 9.1: Mentions 90% 
Credible Interval for the 
response rate and the 
difference in response rate for 
primary efficacy endpoint and 
later in Section 9.4 mentions 
as 80% Credible Interval for 
the response rate and the 
difference in response rate

80% Credible Interval for the 
response rate and the 
difference in response rate is 
provided for primary efficacy 
endpoint

There was inconsistency in 
the protocol and should be 
specified as 80% Credible 
Interval for the response 
rate and the difference in 
response rate


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2.2.
Study Objective(s) and Endpoint(s)
2.2.1.
Protocol Defined Objectives and Endpoints
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the efficacy of 
mepolizumab SC in subjects with
moderate to severe AD

Proportion of subjects who achieve treatment success 
defined as an Investigator’s Global Assessment (IGA) 
score of 0 or 1 and at least a 2-grade improvement at 
Week 16.
Secondary Objectives
Secondary Endpoints

To estimate the efficacy of
mepolizumab SC

Mean percentage change in Eczema Area and Severity 
Index (EASI) score from baseline to each study visit.

Proportion of subjects with an IGA score of 0 or 1 and at 
least a 2-grade improvement at each study visit.

To describe the safety and
tolerability of mepolizumab SC

Incidence, frequency, and nature of adverse events (AEs) 
including local injection site reactions and systemic 
reactions.

Change from baseline in laboratory parameters
(hematology and chemistry) and frequency of clinically 
significant abnormal test results.

Change from baseline in vital signs and frequency of 
clinically significant abnormal results.

Immunogenicity as measured by anti-mepolizumab 
antibodies.
Exploratory Objectives
Exploratory Endpoints

To further estimate the efficacy of 
mepolizumab SC

Proportion of subjects with ≥50% improvement in EASI 
from baseline to each study visit.

Proportion of subjects with ≥75% improvement in EASI 
from baseline to each study visit.

Mean change in percent of total body surface area (% 
BSA) affected from baseline to each study visit.

Mean change in weekly average of daily itch/pruritus 
numeric rating scale [NRS] score (based on Item #1 of 
Daily Sign and Symptom Severity Diary) from baseline to 
Week 16.

Mean change in weekly average of daily itch/pruritus NRS 
score (based on Item #1 of Daily Sign and Symptom 
Severity Diary) from baseline to each study visit.          

To evaluate disease flare/relapse 
during and after treatment with 
mepolizumab SC

Proportion of subjects who have an IGA score of 3 or 4 
after achieving an IGA score of 0 or 1 and at least a 2-
grade improvement during the Treatment and Follow-up 
Periods.

Proportion of subjects who have an increase in EASI 
score of >=25% from baseline during the Treatment and 
Follow-up Periods.


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Objectives
Endpoints

To characterize the relationship
between efficacy and blood eosinophil 
count

Proportion of subjects who have an IGA score of 0 or 1 
and at least a 2-grade improvement at each study visit by 
baseline blood eosinophil count.

Mean percentage change in EASI score from
baseline to each study visit by baseline blood
eosinophil count.

Mean percentage change in EASI score compared to 
change in blood eosinophils at each visit.

To investigate the pharmacokinetics of 
mepolizumab in subjects with 
moderate to severe AD

Plasma concentration of mepolizumab

To investigate the pharmacodynamics 
of mepolizumab in the blood and in
AD lesional skin biopsies

Ratio to baseline in blood eosinophil counts

IL-5 levels (serum free and total)

Levels of circulating biomarkers in the blood
including immunoglobulin (IgE), eosinophilic
cationic protein (ECP), and levels of chemokines such as 
thymus and activation-regulated chemokine (TARC)

Gene expression biomarkers in skin biopsies

To describe the effect of
mepolizumab SC on Patient reported 
Outcomes (PROs)

Change over time in Daily Sign and Symptom
Severity Diary

Change over time in Patient Global Impression of 
Severity and Patient Global Impression of Change
2.2.2.
Final Reporting Objectives & Endpoints Following Study 
Termination
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the efficacy of
mepolizumab SC in subjects with
moderate to severe AD

Proportion of subjects who achieve treatment
success defined as an Investigator’s Global

Assessment (IGA) score of 0 or 1 and at least a 2-grade 
improvement at Week 16.
Secondary Objectives
Secondary Endpoints

To estimate the efficacy of
mepolizumab SC

Mean percentage change in Eczema Area and Severity 
Index (EASI) score from baseline to each study visit.

Proportion of subjects with an IGA score of 0 or 1 and at 
least a 2-grade improvement at each study visit.

To describe the safety and tolerability 
of mepolizumab SC

Incidence, frequency, and nature of adverse events (AEs) 
including local injection site reactions and systemic 
reactions.

Change from baseline in laboratory parameters 
(hematology and chemistry) and frequency of clinically 
significant abnormal test results.

Change from baseline in vital signs and frequency of 
clinically significant abnormal results.

Immunogenicity as measured by anti-mepolizumab 
antibodies.


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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints

To further estimate the efficacy of 
mepolizumab SC

Proportion of subjects with ≥50% improvement in EASI 
from baseline to each study visit.

Proportion of subjects with ≥75% improvement in EASI 
from baseline to each study visit.

Mean change in percent of total body surface area (% 
BSA) affected from baseline to each study visit.

Mean change in weekly average of daily itch/pruritus NRS 
score (based on Item #1 of Daily Sign and Symptom 
Severity Diary) from baseline to each study visit.          

To evaluate disease flare/relapse 
during and after treatment with 
mepolizumab SC

Proportion of subjects who have an IGA score of 3 or 4 
after achieving an IGA score of 0 or 1 and at least a 2-
grade improvement during the Treatment and Follow-up 
Periods.

Proportion of subjects who have an increase in EASI 
score of >=25% from baseline during the Treatment and 
Follow-up Periods

To characterize the relationship
between efficacy and blood eosinophil 
count

Mean percentage change in EASI score from
baseline to each study visit by baseline blood
eosinophil count

To investigate the pharmacokinetics 
of mepolizumab in subjects with 
moderate to severe AD

Plasma concentration of mepolizumab

To investigate the pharmacodynamics 
of mepolizumab in the blood and in
AD lesional skin biopsies

Ratio to baseline in blood eosinophil counts

IL-5 levels (serum free and total)

Levels of circulating biomarkers in the blood
including immunoglobulin (IgE), eosinophilic
cationic protein (ECP), and levels of chemokines such as 
thymus and activation-regulated chemokine (TARC)

Gene expression biomarkers in skin biopsies

To describe the effect of mepolizumab
SC on Patient reported Outcomes 
(PROs)

Change over time in Daily Sign and Symptom
Severity Diary

Change over time in Patient Global Impression of 
Severity and Patient Global Impression of Change


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multicenter, randomized, double-blind, placebo-controlled, 2-arm, 
parallel group study.

This study will consist of 4 periods:
o Pre-screening (up to 4 weeks)
o Screening (1 to 2 weeks)
o Treatment (16 weeks with the last dose of study treatment at Week 
12)
o Follow-up (4 weeks).

Note: For subjects who may need to stop treatment with a biologic, the 
total Pre-Screening and Screening period may last up to 20 weeks.


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Overview of Study Design and Key Features
Dosing

Study Treatment will be administered by SC injection at the Baseline 
visit, Week 4, Week 8, and Week 12 (last dose).
Time & 
Events
Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment
Subjects will be randomized in 1:1 ratio to receive either Mepolizumab 
100 mg SC or Placebo SC.
Interim 
Analysis
An interim analysis for futility was performed after approximately 50% of 
subjects were randomized and had the opportunity to complete the Week 8 
visit. Futility was evaluated and pre-specified stopping criteria were met 
and declared for termination of the study. Further detailed in Section 3.1
Final 
Analysis
Final analysis is planned for subjects who had enrolled into the study prior 
to the termination of the study.
2.4.
Statistical Hypotheses / Statistical Analyses

No formal hypothesis testing is planned. 

The primary objective of this study is to characterize the clinical activity of 
mepolizumab. A Bayesian approach will be employed to estimate the posterior 
probability that 
1) the IGA response rate for mepolizumab is 40% or greater, and 
2) that the improvement over placebo in IGA response rate is at least 15 
percentage points.

Descriptive statistics including point estimates and corresponding 90% confidence 
interval and 80% credible interval will be provided for efficacy endpoints.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim analysis for futility and to enable future planning was performed after 
approximately 50% of subjects were randomized and had the opportunity to complete the 
Week 8 visit. An interim analysis was not conducted to declare early success of the study.
The interim analyses included the following data:

An assessment of the proportion of subjects who have an IGA score of 0 or 1 and a 
minimum 2-grade improvement from baseline at Week 8 and later time points 

Assessments of the key secondary endpoint EASI score (change from baseline and 
percent change from baseline in EASI score) 

Key safety data which included Laboratory and Vital Signs data.
If a subject withdrew at a scheduled visit at which these data were not scheduled to be 
collected, or if a subject withdrew between scheduled visits, data were slotted to the next 
visit where the data were scheduled to be collected according to the study flowchart. 


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The criteria for futility was based on the predictive probability of success at the final 
analysis, given the data available at the interim analysis. 

If the posterior probability of at least a 15% difference in the IGA response rates 
between Mepolizumab and Placebo is greater than 70% then the study is declared 
successful.  

If the predicted probability of success is below the pre-specified threshold of 10%, 
then the study may stop for futility. i.e.,
Study Success: Success=Posterior Probability (difference in Response rates ≥0.15)> 
70%
Stop for Futility: if Probability(Success)< 10%
Steps to calculate the Probability of Success:

No predictions were made for data at Week 16 based on Week 8 data. 

It was deemed sufficient to use Week 8 as a surrogate for decision making at the 
interim based on the fact that we would require Mepolizumab to be effective at this 
earlier timepoint and then maintained out to Week 16.

Markov-Chain-Monte-Carlo (MCMC) method in SAS was used to derive the 
posterior distributions response rate between the Mepolizumab treatment group and 
the placebo group. 
o
From this distribution, a distribution of predicted number of responses post 
interim was calculated for each treatment group. 
o
The observed and predicted number of responders was added together to give a 
large number of predicted datasets which was analysed using PROC MCMC and 
the same Bayesian model with non-informative prior as above but with the 
“observed” final data being a combination of the observed data at the interim and 
the predicted data from the posterior distribution at the interim. 
o
The posterior probability of the response rate for Mepolizumab meeting the above
criteria and the posterior probability of success at the end of the study was
calculated and summarised accordingly.

Convergence diagnostics of MCMC sample was checked using the DIAGNOSTICS 
option in SAS.
Additional statistical summaries were calculated to enable future planning:

The 80% credible intervals for the response rate and difference in response rate was
presented.

The predicted posterior probability of at least a 50% response rate on Mepolizumab is 
greater than 60% was calculated based on observed data at the interim.
Pre-specified stopping criteria for futility were met during this analysis. There were no 
safety concerns. Study team had therefore terminated this study.


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3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants who had enrolled into the study prior to the termination of the study
as defined in the protocol will be part of final analysis.
2.
All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management.
3.
All protocol deviations have been confirmed.
4.
All criteria for unblinding the randomisation codes have been met.
5.
Source Data Lock has been declared by Data Management.
6.
Randomisation codes have been distributed according to RandAll NG procedures.
7.
Database freeze has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Screened

All participants who were screened for eligibility

Study Population
Enrolled

All participants who passed screening and entered the 
study including randomized participants 
Note: Screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into 
the study (Reserve, Not Used) are excluded from the Enrolled 
population as they did not enter the study.

Study Population
Intent-to-
Treat 

Comprises of all participants who are randomized and who 
received at least one dose of study treatment.
Note: This population will be based on the treatment the 
participants are randomized to.

Study Population

Efficacy
Safety

Comprises of all participants who received at least one dose 
of a study treatment will be included in the safety 
population.
Note: This population will be based on the treatment the 
participants actually received.

Safety
PK

All participants in the Safety population who received the 
active study treatment and had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be 
considered as non-missing values).

PK
PD

Comprises of all participants in the ITT population who 
received at least one dose of study treatment and who also 
have a baseline serum PD measurement and at least one 
post-treatment serum PD measurement.

PD 


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Population
Definition / Criteria
Analyses Evaluated
Biopsy

Comprises of all participants in the ITT population who have 
a baseline measurement and who also have at least one 
post-treatment PD biomarker measurement derived from 
skin biopsy samples.

Biopsy sub-study
Refer to Appendix 9: List of Data Displays which details the population used for each 
display.
Note: If any re-screened participants are randomized and received at least one dose then 
that subject will be counted in both Screened and ITT Populations.
4.1.
Protocol Deviations
Protocol deviations (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, patient management or patient assessment) will be listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (10 November 2016 V1 or 
higher).
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the listings of protocol deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
1
Placebo SC 
Placebo SC
1
2
Mepolizumab 100 mg SC
Mepolizumab 100 mg SC
2
NOTES:
1.
Order represents treatments being presented in TFL
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment. In case of 
missing pre-dose assessment screening would be considered as baseline. If both are 
missing, then baseline would be set to missing.


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Parameter
Study Assessments Considered as 
Baseline
Baseline Used in 
Data Display
Screening [1]
Day 1 (Baseline)
Efficacy Assessments
IGA
X
X
Day 1 (Baseline)
EASI
X
X
Day 1 (Baseline)
%BSA Affected
X
X
Day 1 (Baseline)
Daily Sign and Symptom Severity 
Diary (only for item #1) [2]
X
X
Patient Global Impression of Severity
X
Day 1 (Baseline)
Safety Assessments
Vital Signs 
X
X
Day 1 (Baseline)
Haematology with differential
Clinical Chemistry
X
X
Day 1 (Baseline)
ECG
X
Screening
Laboratory Assessments
Immunogenicity (blood samples)
X
Day 1 (Baseline)
[1] Screening = 1-2 Wks Prior to Baseline Visit (All Participants). 
[2] Baseline for Daily Sign and Symptom Severity Diary (only for item #1) is based on derivation mentioned in Section 
12.2.1
5.2.1.
Derivations and Handling of Missing Baseline Data
For untransformed data, change from baseline at each time point is expressed as a 
difference (value at time point – value at baseline). For log transformed data, change 
from baseline at each time point is expressed as a ratio (value at time point/value at 
baseline).
Definition
Reporting Details
Change from Baseline [1]
= Post-Baseline Visit Value – Baseline Value
% Change from Baseline [1]
= 100 x [(Post-Baseline Visit Value – Baseline) / Baseline]
Ratio to Baseline [2]
= Post-Baseline Visit Value/Baseline 
[1] If the baseline value is missing the change from baseline derivations will also be missing
[2] Ratio to baseline = Back transformed change from baseline of the loge transformed values
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:


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Section
Component
Section 12.2
Appendix 2: Assessment Windows
Section 12.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
Section 12.4
Appendix 4: Data Display Standards & Handling Conventions
Section 12.5
Appendix 5: Derived and Transformed Data
Section 12.6
Appendix 6: Reporting Standards for Missing Data
Section 12.7
Appendix 7: Values of Potential Clinical Importance
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Screened”, “Enrolled” and “ITT”
population, unless otherwise specified.
Study population analyses including analyses of participants’ disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards (displays).  Details of the 
planned displays are presented in Appendix 9: List of Data Displays.
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables

Proportion of subjects who achieve treatment success defined as an IGA score of 0 or 
1 and at least a 2-grade improvement at Week 16
7.1.2.
Summary Measure
Posterior mean and median response rate and difference between mepolizumab and 
placebo and the 80% credible interval for the response rate and the difference in response 
rate will be presented.
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events
There are no planned strategies for intercurrent events.
7.1.4.
Population of Interest 
The primary efficacy analyses will be based on the “Intent-To-Treat” population, unless 
otherwise specified.


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7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays. and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics and listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint

Proportion of subjects who achieve treatment success defined as an IGA score of 0 or 1 and at 
least a 2-grade improvement at Week 16
Model Specification

A non-informative prior will be assumed for the response rate for Mepolizumab and Placebo. 

Markov-Chain-Monte-Carlo (MCMC) method in SAS will be used to derive the posterior 
distributions for the response rates for Mepolizumab and placebo treatment groups and the 
difference in response rates between the Mepolizumab and placebo.
Model Checking & Diagnostics

Convergence diagnostics of MCMC sample will be checked using the DIAGNOSTICS option in 
SAS and the alternative method may be used in case convergence is not achieved.
Model Results Presentation

Posterior mean and median response rate and difference between mepolizumab and placebo 
and the 80% credible interval for the response rate and the difference in response rate will be 
presented. 

The posterior probability that the IGA response rate for mepolizumab is 40% or greater and 
that the improvement over placebo is at least 15 percentage points will be calculated.
Sensitivity and Supportive Analyses

There are planned sensitivity or supportive analyses.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables

EASI Score 

IGA Response rate
7.2.2.
Summary Measure

Mean Change from baseline & percentage change from baseline EASI score to each 
visit

Proportion of subjects with an IGA score of 0 or 1 and at least a 2-grade improvement 
from baseline to each visit


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7.2.3.
Strategy for Intercurrent (Post-Randomization) Events
There are no planned strategies for intercurrent events.
7.2.4.
Population of Interest 
The secondary efficacy analyses will be based on the “Intent-To-Treat” population, 
unless otherwise specified.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics and listed.
7.2.5.1.
Statistical Methodology Specification
There will be no planned statistical analysis.
7.3.
Exploratory Efficacy Analyses
7.3.1.
Endpoint / Variables

At least 50% and 75% improvement in EASI score from baseline

Total body surface area (% BSA)

Weekly average of daily itch/pruritus NRS score (based on Item #1 of Daily Sign and 
Symptom Severity Diary)

IGA score of 3 or 4 after achieving an IGA score of 0 or 1 and at least a 2-grade 
improvement during the Treatment and Follow-up Periods.

Increase in EASI score of >=25% from baseline during the Treatment and Follow-up 
Periods.

EASI score by baseline blood eosinophil count

Daily Sign and Symptom Severity Diary

Patient Global Impression of Change

Patient Global Impression of Severity

Clinician Global Impression of Change
7.3.2.
Summary Measure

Proportion of subjects with ≥50% improvement (i.e., -50% percent change from 
baseline) in EASI from baseline to each visit.

Proportion of subjects with ≥75% improvement (i.e., -75% percent change from 
baseline) in EASI from baseline to each visit.

Mean change in weekly average of daily itch/pruritus NRS score (based on Item #1 of 
Daily Sign and Symptom Severity Diary) from baseline to each visit.   


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
Mean Percentage Change in EASI score from Baseline to each visit by baseline blood 
eosinophil count quartiles.

Only listings will be presented for [1] IGA score of 3 or 4 after achieving an IGA 
score of 0 or 1 and at least a 2-grade improvement during the Treatment and Follow-
up Periods, [2] Increase in EASI score of >=25% from baseline during the Treatment 
and Follow-up Periods. [3] Total body surface area (% BSA), [4] Daily Sign and 
Symptom Severity Diary, [5] Patient Global Impression of Change and Severity and 
[6] Clinician Global Impression of Change endpoints.
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events
There are no planned strategies for intercurrent events.
7.3.4.
Population of Interest 
The exploratory efficacy analyses will be based on the “Intent-To-Treat” population, 
unless otherwise specified.
7.3.4.1.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints defined in Section 7.3.1 will be summarised using 
descriptive statistics and listed.
7.3.4.2.
Statistical Methodology Specification
There will be no statistical analysis, only descriptive statistics will be presented.
8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
Adverse events of special interest (AESIs) are adverse events associated with the 
identified and potential risks of mepolizumab. AESIs reported by the investigator as 
anaphylaxis reactions, systemic reactions (further categorised by the investigator as either 
allergic (type I hypersensitivity) or other systemic reactions) and local injection site 
reactions are collected via targeted eCRF within the study.


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The AESIs of opportunistic infections, malignancies, serious CVT events and serious 
ischemic events will be identified from a list of relevant preferred terms maintained 
within a project level reference dataset; created based on the latest version of the 
MedDRA dictionary available at the time of database freeze for this study. 
Separate summary tables showing the number and percent of subjects with type of AESI, 
broken down by preferred term will be created if at least one event is reported for an 
AESI category. For each type of AESI a profile summary table will be produced 
containing information including, but not limited to, the number of occurrences of the 
event, event characteristics, time to onset, intensity, outcome and action taken if more 
than one event is reported for an AESI category.
Listings of AESIs identified by the investigator as anaphylaxis, allergic (type I 
hypersensitivity), other systemic reactions and local injection site reactions, opportunistic 
infections, malignancies, serious CVT events and serious ischemic events if more than 
one event is reported under each AESI category.
The details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK data standards and statistical principles.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards. A scatter plot of maximum ALT vs baseline ALT, and maximum ALT vs total 
bilirubin will be produced. In addition, if any liver stopping or liver monitoring events 
occur during the study, then only listing of liver monitoring/stopping event reporting and 
hepatobiliary laboratory abnormalities will be produced. The details of the planned
displays are in Appendix 9: List of Data Displays.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on CDISC Data Standards, unless otherwise specified. The details of the planned
displays are presented in Appendix 9: List of Data Displays.
8.4.1.
ECG
All sites used a standardised ECG equipment provided by a centralised external vendor. 
A central ECG reader was used. The site and vendor provided ECG interpretation, while 
the site differentiates between “Abnormal – Not Clinically Significant and Abnormal –
Clinically significant”, the vendor only specifies ‘Abnormal’. There are differences 
between the site vs vendor interpretations (i.e. the site interpretation = abnormal vs 
vendor = normal and site = normal vs vendor = abnormal). 
As site interpretations also take into consideration assessment from investigators of 
patients, the site interpretations will be used for summaries (i.e. even though for patients, 
vendor = abnormal vs site = normal) but both the site and vendor interpretations will be 
listed.  


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Actual and change from baseline QTcF category values will be summarized for each 
visit. Actual QTcF value is categorized as: <=450, >450 to <=480, >480 to <=500, and 
>500. Change from baseline QTcF value is categorized as: <=30, >30 to ≤ 60 and >60. In 
addition, listing will be produced for subject meeting the criteria of actual QTcF >500 
msec or change from baseline >60 msec.
8.5.
Immunogenicity Analyses
Immunogenicity analyses will be based on GSK Core Data Standards, unless otherwise 
specified. The details of the planned displays are presented in Appendix 9: List of Data 
Displays in Section 12.9.6.
An immune response to a therapeutic drug can lead to generation of anti-drug antibodies 
within the blood.  For the immunogenicity assessment, two types of antibody assays will 
be performed, a binding antibody assay and a neutralizing antibody assay.
For the binding antibody assay, there will be three testing steps: screening, confirmation 
and titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point. For samples 
with a positive confirmation result, a titre value will also be obtained to quantify the 
degree of binding in a titration assay and the sample will be characterized as positive for 
the binding antibodies. Subjects who test positive for the binding antibody assay, will be 
tested in the neutralizing antibody assay, which also reports results as positive or 
negative.
Subjects will be categorized as negative or positive and positive binding antibody will be 
further categorized as transient positive or persistent positive at each visit and for anytime 
post baseline visit. Summary statistics for titer results will also be included for anytime 
post baseline visit. 
A summary of adverse events by highest post-baseline binding antibody result will be 
produced. A summary of treatment emergent positive confirmation binding ADA assay 
results in the subset of subjects who did not have a positive confirmation binding ADA 
assay result prior to the dosing of study treatment will also be presented. 
Neutralizing antibody assay results will be summarised by visit and will also be 
summarised by category (positive or negative). For anytime post baseline visit, highest 
result will be used, i.e. according to the following hierarchy: ADA result will be 
Persistent Positive > Transient Positive > Negative, NAB result will be Positive > 
Negative and highest titer value. A listing of all immunogenicity data will also be 
provided.


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9.
PHARMACOKINETIC ANALYSES
9.1.
Exploratory Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
Plasma concentration of mepolizumab.
9.1.1.1.
Drug Concentration Measures
Mepolizumab plasma concentrations will be summarised and listed by nominal time. 
Standard summary statistics will be calculated. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Standards for Pharmacokinetic).
9.1.1.2.
Derived Pharmacokinetic Parameters
As a result of study termination, there will be no derivation of Pharmacokinetic 
Parameters for this study.
9.1.2.
Summary Measure
There is no treatment comparison in this study since only one active study treatment was 
administered. Mepolizumab plasma Concentrations will be summarised descriptively.
9.1.3.
Population of Interest
The exploratory pharmacokinetic analyses will be based on the “Pharmacokinetic”
population, unless otherwise specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Missing concentrations and concentrations below the limit of quantification of the assay 
will be handled as described in Guidance Document GUI_51487.
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Core Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


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10.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
10.1.
Exploratory Pharmacodynamic and Biomarker Analyses
10.1.1.
Endpoint / Variables
Endpoint
Parameters
Biomarker(s) / 
Pharmacodynamic Markers

Blood Sample: Eosinophil counts

Blood Sample: IL5 levels (serum free and total)
Novel Biomarkers – Skin Biopsy Sub-study & Serum Biomarkers
RNA Transcriptome Research
(Cancelled)

N/A
RNA Expression Research of a 
Subset of RNA Species [1]

Gene expression biomarkers in skin biopsies
Protein Levels of Biomarkers in 
Serum [2]

Total IgE, eosinophil cationic protein (ECP) and 
chemokines Eotaxin-1, Eotaxin-3, TARC, MCP4
[1] Epistem will be providing a report to be include in the CSR. 
[2] MDC was dropped as an analyte due to assay issues)
10.1.2.
Summary Measure

Geometric Means for ratio to baseline in blood eosinophil counts and for absolute 
blood eosinophil count at each visit.

Only listings will be presented for biomarker endpoints.
10.1.3.
Population of Interest
The pharmacodynamics and biomarker analyses will be based on the “Safety”, 
“Pharmacodynamic” and “Biopsy” populations, unless otherwise specified.
Safety population will be used for summarizing blood eosinophil counts. Biopsy 
population will be used for skin biopsy. Pharmacodynamic population will be used for 
remaining endpoints.
10.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


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10.1.4.1.
Statistical Methodology Specification
Endpoint

Ratio to baseline blood eosinophil counts (Note: from standard haematology assessments) 
Model Specification

Mixed Models Repeated Measures (MMRM) analysis.

The analysis will include all measurements at scheduled visits

Terms in the model:

Response: Ratio to Baseline Blood eosinophil count (loge transformed prior to analysis) (see
Appendix 5: Derived and Transformed Data, Section 12.5.6).

Categorical: Treatment group, Visit.

Continuous/covariate: Baseline blood eosinophil count.

Interaction: Treatment group*Visit.

Repeated: Visit.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. An 
unstructured covariance structure for the R matrix will be used by specifying 'type=UN' on the 
REPEATED line.
Model Checking

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.
Model Results Presentation

The results of the analysis from the MMRM model will be presented for each visit as LS 
Geometric Mean (SE), LS Geometric Mean Ratio to Baseline (95% Confidence Interval) for 
each treatment group, Geometric Treatment Ratio (Mepolizumab/Placebo) and corresponding 
95% Confidence Interval.
Sensitivity and Supportive Analyses

There are no planned sensitivity or supportive analyses.


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11.
REFERENCES
GlaxoSmithKline Document Number 2015N268158_02, Study ID 205050, A 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Investigate the Efficacy and Safety of Mepolizumab Administered Subcutaneously in 
Subjects with Moderate to Severe Atopic Dermatitis. Effective Date: 22-JUN-2017.


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12.
APPENDICES
12.1.
Appendix 1: Schedule of Activities
Time and Events Table: Pre-Screening and Screening


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Time and Events Table: Baseline through Follow-up Period


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Time and Events Table: Unscheduled Visit for Flare/Relapse
Abbreviations: AEs= adverse events; BSA= body surface area; EASI= Eczema Area and 
Severity Index; FSH= follicle stimulating hormone; HBsAG= hepatitis B surface antigen;
SAEs= serious adverse events; SRM=Study Reference Manual. AD= atopic dermatitis; 
EASI= Eczema Area and Severity Index; WBC= white blood cell; WD=withdrawal; IL-
5= interleukin-5; Tx= Treatment; Wk=Week; wks=weeks


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12.2.
Appendix 2: Assessment Windows
Clinic visits are scheduled to take place as specified in the protocol. Unscheduled visit 
will be excluded from analyses on any population. For all clinic visits, nominal visit days 
and times will be used for reporting; for example, if a subject recorded value on the Week 
4 visit that were made on Week 3 of treatment, they will be presented as Week 4 values.
If a subject withdraws at a scheduled visit, and these data were scheduled to be collected 
at that visit, the data will be summarised and analysed (as appropriate) together with data 
from subjects who did not withdraw. If a subject withdraws at a scheduled visit at which 
these data were not scheduled to be collected, or if a subject withdraws between 
scheduled visits, data will be slotted to the next visit where the data was scheduled to be 
collected according to the study flowchart. The protocol visits windows of ±3 days 
should be applied to the assignment of withdrawal visits, so that if a subject withdraws 
within the appropriate number of days from the last visit where that data was scheduled 
to be collected, they would get that data slotted to that visit and otherwise the data will be 
slotted to the next scheduled visit.
The early withdrawal visit will then be re-labelled as the corresponding visit. The same 
approach will be followed to Post Treatment 1 and Post Treatment 2 visits.
If there is more than one assessment associated with a particular visit interval, then the 
latest assessment will be used for summary tables and analyses. Where two or more 
findings (e.g. ECG (i.e. site interpretations will be used), laboratory data) slot to the same 
visit interval, the most ‘abnormal’ results will be used, i.e. according to the following 
hierarchy: Abnormal-Clinically Significant > Abnormal – not clinically significant >
Normal.
12.2.1.
Definitions of Assessment Windows for Analyses
The daily itch/pruritus NRS score (based on Item #1 of Daily Sign and Symptom Severity 
Diary) is recorded daily and will be averaged for every week.
The 7-days average score will be calculated as:

If a subject is missing more than 3 daily itch/pruritus NRS scores out of the 7 days, 
then the average NRS score for that week will be recorded as missing.

7-days average score for baseline visit will be calculated based on 7 days prior to the 
day of dosing (i.e., from Day -7 to Day -1).

7-days average score for Week 1 visit will be 7 days after the day of dosing (i.e., from 
Day 1 to Day 7).

Similarly, for Week 2 (from Day 8 to Day 14) and henceforth till Week 20.


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12.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
12.3.1.
Study Phases
Safety assessments and events will be classified according to the time of occurrence 
relative to the first dose of investigational product.
The on-treatment phase for the presentation of exposure, adverse event and concomitant 
medications is defined as being from the day of the first administration to the day of the 
last administration of study treatment + another 28 days inclusive.
Treatment Phase
Definition
Pre-Treatment 
Date < IP start date
On-Treatment
Event onset date is on/after IP start date & on/before IP stop date + 28 days
(IP Start Date ≤ Date ≤ IP Stop Date + 28 days)
Post-Treatment
Event onset date is after the IP stop date + 28
(Date > IP stop date + 28)
IP = Investigational Product = Study Treatment
12.3.1.1.
Study Phases for Efficacy Assessments
Efficacy assessments and events will be classified according to the time of occurrence 
relative to the study periods defined below:
Period
Definition
Study Treatment Period
Date ≤ Week 16 date (or date of withdrawal from the study, if prior to Week 16)
Follow-up Period
Week 16 date < Date ≤ Week 20 date (or date of withdrawal from the study, if 
between Week 16 and 20)
12.3.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent
If AE onset date is on or after treatment start date & on or before treatment stop date. (plus
28 days)
(Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 28)
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


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12.4.
Appendix 4: Data Display Standards & Handling 
Conventions
12.4.1.
Reporting Process
Software

The currently supported versions of SAS software 9.4 or higher will be used.
Reporting Area
HARP Server
: uk1salx00175.corpnet2.com
HARP Compound
: sb240563\mid205050\final_02
QC Spreadsheet 
: sb240563\mid205050\ final_02\documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.0]. 

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for SAC.
12.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 


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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
12.4.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: BLQ Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics and summarized graphical displays only. 


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12.5.
Appendix 5: Derived and Transformed Data
12.5.1.
General
Multiple Measurements at One Analysis Time Point

If there are two values within a time window (as per Section 12.2.1) then the latest assessment will be 
used. 

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from Randomization Date:

Ref Date = Missing                    → Study Day = Missing 

Ref Date < Randomization Date → Study Day = Ref Date – Randomization Date

Ref Data ≥ Randomization Date → Study Day = (Ref Date – Randomization Date) + 1    
12.5.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  Duration of 
Exposure in Days = (Treatment Stop Date – Treatment Start Date) + 29

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

On-treatment phase will be calculated based on the formula: On-Treatment Phase = (Treatment Stop 
Date – Treatment Start Date) + 29
12.5.3.
Efficacy
Efficacy
Investigators Global Assessment (IGA)

A Responder is defined as a subject who has an IGA score of 0 or 1 and a minimum 2-grade 
improvement from baseline. This is calculated for each study visit.

As per protocol, a non-responder imputation will be used for all early withdrawal subjects where 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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Efficacy
subject’s data will be imputed as a Non-Responder for all post withdrawal visits. This imputation will be 
used for summary and analysis table for primary and secondary endpoints.

The observed IGA score classifications will be used for each visit. For all early withdrawal subjects the 
data from Post-Treatment 1/Post-Treatment 2/Early Withdrawal visits will be slotted using the algorithm 
detailed in Section 12.2

AD flare/relapse for IGA is defined as IGA score of 3 or 4 after achieving an IGA score of 0 or 1 and at 
least a 2- grade improvement from the baseline.
Body Surface Area
EASI

The observed EASI data will be used for each visit. For all early withdrawal subjects, data from Post-
Treatment 1/Post-Treatment 2/ Early Withdrawal visits will be slotted using the algorithm detailed in 
Section 12.2.

AD flare/relapse for EASI is defined as increase in EASI score of ≥25% from Baseline.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.5.4.
Safety
Adverse Events of Special Interest

Section 8.2: Adverse Events of Special Interest Analyses provides a full list of AEs of special interest for 
this compound. AESIs of anaphylaxis reactions, systemic reactions, and local injection site reactions are 
collected via targeted eCRF.

The AESIs of opportunistic infections, malignancies, serious CVT events and serious ischemic events 
will be identified from a list of relevant preferred terms maintained within a project level reference 
dataset; created based on the latest version of the MedDRA dictionary available at the time of database 
freeze for this study (See Program Safety Analysis Plan for additional details).
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Decimal Points = ‘< x’ becomes x – 0.01
o
Example 2: 1 Decimal Point = ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Points = ‘< x’ becomes x – 1    
Immunogenicity (Binding Antibody Assay Results)

Positive binding antibody assay results are to be categorised as transient positive or persistent positive 
accordingly to the following definitions:

For all post-baseline visits, other than final study assessment
o Transient positive = a single positive immunogenic response at a visit, where the previous visit was 
negative
o Persistent positive = a positive immunogenic response at a visit, where the previous visit was also 
positive

For the final assessment:

Any positive response will be considered a persistent response, regardless of the status at the 
previous visit
12.5.5.
Pharmacokinetic
There will be no derivation of Pharmacokinetic Parameters for this study.
12.5.6.
Pharmacodynamic and Biomarker
Pharmacodynamic 
Blood Eosinophils

Blood eosinophil counts will be log transformed (loge) prior to analysis. 

For the log transformation values of 0 GI/L will be imputed to a value of minimum for all non-missing 
results/2.


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12.6.
Appendix 6: Reporting Standards for Missing Data
12.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as if he/she 
receives all planned doses of study treatment and completes the Week 16 (Post-
Treatment 1) and Week 20 (Post-Treatment 2) visits.

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 2: Assessment Windows
12.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument:
o
These data will be indicated using a “blank” in subject listing displays. Unless all data 
for a specific visit are missing in which case the data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start date 
of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 3: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.


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12.7.
Appendix 7: Values of Potential Clinical Importance
12.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Age
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
12+
0.201
0.599 
Hemoglobin 
G/L
12+
71
199
Platelet Count 
GI/L
1+
31
1499 
While Blood Cell Count (WBC)
GI/L
12+
1.1
Clinical Chemistry
Laboratory Parameter
Units
Age
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
ALT
U/L
3-12
>143 (and Total 
Bilirubin >43)
U/L
13+
>239 (and Total 
Bilirubin >43)
Calcium
mmol/L
3+
1.50
3.24
Glucose
mmol/L
1+
2.2
27.8
Potassium
mmol/L
3+
2.8
6.5
Sodium
mmol/L
0+
120
160
Possible Hy’s Law Cases
Laboratory Parameter
Units
Category
Clinical Concern Range
ALT, Bilirubin
ALT ≥ 3xULN and Bilirubin ≥ 2xULN 
(>35% direct) 
ALT, INR
ALT ≥ 3xULN and INR > 1.5 
12.7.2.
Vital Signs
Vital Sign Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110


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12.8.
Appendix 8: Abbreviations & Trade Marks
12.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Events of Special Interest
AIC
Akaike's Information Criteria
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
EASI
Eczema Area and Severity Index
eCRF
Electronic Case Record Form
ECP
Eosinophilic Cationic Protein
EASI
Eczema Area and Severity Index
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IGA
Investigator’s Global Assessment
IGE
Immunoglobulin
ITT
Intent-To-Treat
MCMC
Markov-Chain-Monte-Carlo
MMRM
Mixed Model Repeated Measures
NRS
Numeric Rating Scale
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PRO
Patient reported Outcomes
QC
Quality Control
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TARC
Activation-regulated Chemokine
TA
Therapeutic Area
TFL
Tables, Figures & Listings 


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12.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS


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12.9.
Appendix 9: List of Data Displays
12.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.10
N/A
Efficacy
2.1 to 2.7
N/A
Safety
3.1 to 3.40
3.1 to 3.2
Pharmacokinetic
4.1
4.1 to 4.2
Pharmacodynamic and Biomarker
5.1 to 5.2
5.1 to 5.2
Section
Listings
ICH Listings
1 to 26
Other Listings
27 to 40
12.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and Biomarker
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.
12.9.3.
Deliverables
Delivery [Priority] [1]
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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12.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL/ Example 
Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
ITT
ES1
Subject Status and Reason for Study Withdrawal
ICH E3, FDAAA, EudraCT
SAC
1.2.
ITT
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
Add Footnote “Note: Re-screened 
participants who have been randomised 
are included both in ENROLLED as well 
as FAILED category.
SAC 
1.4.
Enrolled
NS1
Summary of Number of Participants Enrolled by Country and 
Site ID
EudraCT/Clinical Operations
SAC 
Population Analysed
1.5.
Screened
SP1
Summary of Study Populations 
IDSL
SAC
Demographic and Baseline Characteristics
1.6.
ITT
DM1
Summary of Demographic and Baseline Characteristics
ICH E3, FDAAA, EudraCT
Include: Baseline Eosinophil counts and 
Fitzpatrick skin type
SAC
1.7.
ITT
DM11
Summary of Age Ranges
EudraCT
Note: Include Age categories: Adult (18 –
64 years), >=65 – 84 years and >=85 
years.
SAC
1.8.
ITT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC


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Study Population Tables
No.
Population
IDSL/ Example 
Shell
Title
Programming Notes
Deliverable
Prior and Concomitant Medications
1.9.
ITT
MH1
Summary of Past Medical Conditions
ICH E3
SAC
Exposure
1.10.
Safety
POP_T1
Summary of Exposure to Study Treatment
ICH E3
SAC


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12.9.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL/ Example 
Shell
Title
Programming Notes
Deliverable
IGA 
2.1.
ITT
EFF_T1
Bayesian Posterior Probability for Comparison between Mepolizumab and 
Placebo
Note: Non-Responder
imputation will be used 
SAC 
2.2.
ITT
EFF_T2
Number (%) of Participants in Each Category of the Investigator’s Global 
Assessment Scale at Each Visit
SAC 
2.3.
ITT
EFF_T3
Summary of Proportion of Participants with IGA Score of 0 or 1 and at 
Least a 2-Grade Improvement from Baseline at Each Visit
Note: Non-Responder 
imputation will be used
SAC 
EASI
2.4.
ITT
EFF_T4
Summary of Change from Baseline/Percent Change from Baseline in 
EASI Score at Each Visit
Note: CFB, %CFB in bylines
SAC
2.5.
ITT
EFF_T4
Summary of Change from Baseline/Percent Change from Baseline in 
EASI Score at Each Visit by Baseline Blood Eosinophil Count Quartiles
Note: Include Quartiles
categories as <=Q1(x), >Q1(x) 
- <=Q2, >Q2(x) - <=Q3(x) and 
>Q3(x). Include all quartiles 
value(x) 
SAC
2.6.
ITT
EFF_T5
Summary of Proportion of Participants with >=50% and >=75% 
Improvement in EASI Score from Baseline at Each Visit
Note: >=50%, >=75% 
improvement in bylines.
SAC
Patient Reported Outcomes
2.7.
ITT
EFF_T4
Summary of Change from Baseline in Weekly Average of Daily 
Itch/pruritus NRS Score (based on Item #1 of Daily Sign and Symptom 
Severity Diary) at Each Visit
Includes Baseline values.
Note: Mean change from 
baseline will be presented to 
only Week 4, 8, 12, 16 and 20
SAC


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12.9.6.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC
3.2.
Safety
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Preferred Term
ICH E3
SAC
3.3.
Safety
AE15
Summary of Common (>=3%) On-Treatment Non-Serious 
Adverse Events by System Organ Class and Preferred Term 
(Number of Participants and Occurrences)
FDAAA, EudraCT
SAC
3.4.
Safety
AE1
Summary of Adverse Events Reported on the Day of Dosing by 
System Organ Class and Preferred Term
SAC
3.5.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Binding 
Antibody Result
SAC
Serious and Other Significant Adverse Events
3.6.
Safety
AE16
Summary of On-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Participants and 
Occurrences)
FDAA, EudraCT
SAC
3.7.
Safety
AE16
Summary of Post-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Participants and 
Occurrences)
FDAA, EudraCT
SAC
3.8.
Safety
AE3
Summary of Fatal Serious Adverse Events by Overall Frequency
SAC
Adverse Events of Special Interest (AESI’s)
3.9.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest 
Reported by the Investigator as Meeting the Criteria for 
Anaphylaxis
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.10.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Meeting the Criteria for Anaphylaxis
Produced only if more than one 
AESI reported in this category.
SAC
3.11.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest 
Reported by the Investigator as Systemic Reactions - Allergic 
(Type I Hypersensitivity) and Other Systemic
SAC
3.12.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity) and Other Systemic
Produced only if more than one 
AESI reported in this category.
SAC
3.13.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest 
Reported by the Investigator as Systemic Reactions - Allergic 
(Type I Hypersensitivity)
SAC
3.14.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity)
Produced only if more than one 
AESI reported in this category.
SAC
3.15.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest 
Reported by the Investigator as Systemic Reactions - Other 
Systemic
SAC
3.16.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Other Systemic
Produced only if more than one 
AESI reported in this category.
SAC
3.17.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest 
Reported by the Investigator as Local Injection Site Reactions
SAC
3.18.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Local Injection Site Reactions
Produced only if more than one 
AESI reported in this category.
SAC
3.19.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest
Categorised as Serious Cardiac, Vascular and Thromboembolic 
Events
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.20.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events of Special 
Interest Categorised as Serious Cardiac, Vascular and 
Thromboembolic Events
Produced only if more than one 
AESI reported in this category.
SAC
3.21.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest
Categorised as Serious Ischemic Events
SAC
3.22.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events of Special 
Interest Categorised as Serious Ischemic Events
Produced only if more than one 
AESI reported in this category.
SAC
3.23.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest
Categorised as Malignancies
SAC
3.24.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events of Special 
Interest Categorised as Malignancies
Produced only if more than one 
AESI reported in this category.
SAC
3.25.
Safety
SAF_T1
Summary of On-Treatment Adverse Events of Special Interest
Categorised as Opportunistic Infections
SAC
3.26.
Safety
SAF_T2
Summary Profile of On-Treatment Adverse Events of Special 
Interest Categorised as Opportunistic Infections
Produced only if more than one 
AESI reported in this category.
SAC
Laboratory: Chemistry 
3.27.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
Includes Baseline values.
SAC
3.28.
Safety
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
SAC
3.29.
Safety
LB3
Summary of Emergent Chemistry Results (Relative to the 
Potential Clinical Concern Range)
ICH E3
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Laboratory: Haematology
3.30.
Safety
LB1
Summary of Haematology Changes from Baseline
ICH E3
Includes Baseline values.
SAC
3.31.
Safety
LB3
Summary of Haematology Shifts from Baseline Relative to 
Normal Range
SAC
3.32.
Safety
LB17
Summary of Emergent Haematology Results (Relative to the 
Potential Clinical Concern Range)
ICH E3
SAC
ECG
3.33.
Safety
EG1
Summary of ECG Findings 
The ECG findings to be summarized 
are the ECG interpretation, clinical 
significance of abnormal ECGs
SAC
3.34.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
Includes Baseline values.
SAC 
3.35.
Safety
EG10
Summary of Actual and Change from Baseline QTc(F) Values
by Category
Category column will be replaced and 
created based on the information 
provided in the Section 8.4.1.
For Anytime Post-Baseline, the
highest post-baseline QTcF value and
the change from baseline for this
highest post-baseline QTc value is
categorised
SAC
Vital Signs
3.36.
Safety
VS1
Summary of Change from Baseline in Vital Signs
Includes Baseline values.
SAC 
3.37.
Safety
VS3
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Immunogenicity
3.38.
Safety
SAF_T3
Summary of Binding Antibody by Visit
SAC
3.39.
Safety
SAF_T4
Summary of Neutralising Antibody by Visit
SAC
3.40.
Safety
SAF_T5
Summary of Binding Antibody Assay Results: Highest Treatment 
Emergent Confirmatory Result Any Time Post Baseline
SAC


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12.9.7.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Laboratory
3.1.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT
IDSL
Note: Figure created as no liver events 
report, but such a plot may flag 
participants who were not reported.
SAC
3.2.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
IDSL
SAC
12.9.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
4.1.
PK
PKCT1
Summary of Plasma Mepolizumab Pharmacokinetic
Concentration-Time Data
SAC


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12.9.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
4.1.
PK
PK_F1
Scatter Plot of Individual Plasma Concentration Data by 
Participants’ ADA Status 
Note: Participants’ ADA status is 
highest ADA result (Positive or 
Negative) in any post bassline visit. 
SAC
4.2.
PK
PK_F1
Scatter Plot of Individual Plasma Concentration Data (with 
Mean SD)
Include Mean ± SD for each visit
along with the individual plasma 
conc. data
SAC
12.9.10.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophil Counts
5.1.
Safety
PD_T1
Summary of Blood Eosinophils Count at Each Visit
1. Include both absolute and ratio to 
baseline for log transformed blood 
eosinophil count. 
SAC
5.2.
Safety
PD_T2
Summary of Mixed Model Repeated Measures (MMRM) 
Analysis for Blood Eosinophils Count
SAC


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12.9.11.
Pharmacodynamic and Biomarker Figures
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophil Counts
5.1.
Safety
PD_F1
Scatter Plot of Individual Absolute Blood Eosinophils Count by 
Participants’ ADA status
Note: Participants’ ADA status is 
highest ADA result (Positive or 
Negative) in any post bassline visit.
SAC
5.2.
Safety
PD_F2
Plot of Least Squares Geometric Means and 95% CI of Ratio to 
Baseline in Blood Eosinophil Count
SAC


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12.9.12.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC 
2.
ITT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC 
3.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC 
4.
ITT
BL1
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC
5.
ITT
TA1
Listing of Planned and Actual Treatments
IDSL
SAC 
Protocol Deviations
6.
ITT
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC 
7.
ITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Demographic and Baseline Characteristics
8.
ITT
DM2
Listing of Demographic and Baseline Characteristics
ICH E3
Include Baseline Eosinophil Count and 
Fitzpatrick skin type
SAC
9.
ITT
DM9
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
10.
ITT
CM3
Listing of Concomitant Medications
ICH E3
SAC
Exposure
11.
Safety
EX3
Listing of Exposure Data
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
12.
Safety
AE8
Listing of All Adverse Events
ICH E3
SAC 
13.
Safety
AE7
Listing of Participant Numbers for Individual Adverse Events
ICH E3
SAC
14.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
15.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC
16.
Safety
AE8
Listing of Adverse Events Reported on the Day of Dosing
SAC
17.
Safety
AE8
Listing of All Adverse Events of Special Interest 
Produced only if more than one 
AESI reported.
All Laboratory
18.
Safety
LB5
Listing of All Chemistry Laboratory Data for Participants with Any 
Value of Potential Clinical Importance
ICH E3
SAC
19.
Safety
LB5
Listing of All Haematology Laboratory Data for Participants with 
Any Value of Potential Clinical Importance
ICH E3
SAC
20.
Safety
LB14
Listing of Laboratory Data with Character Results
SAC 
21.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting 
22.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline
ECG
23.
Safety
EG3
Listing of ECG Values (Participants with QTcF >500 msec or 
Increase > 60 msec from Baseline)
SAC
24.
Safety
EG5
Listing of Abnormal ECG Findings
IDSL
SAC 


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Vital Signs
25.
Safety
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IDSL
SAC
Immunogenicity
26.
Safety
IMM2
Listing of Immunogenicity Results
IDSL. Include columns for Screening 
Binding Assay, Confirmation Antibody 
Assay, Confirmation Assay Titre,
Transient/Persistent, Neutralizing
Antibody Assay
SAC


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12.9.13.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
IGA
27.
ITT
EFF_L1
Listing of Investigator’s Global Assessment (IGA) Score
Note: Include Character result, Numeric 
score & CFB
SAC
EASI and %BSA
28.
ITT
EFF_L2
Listing of Eczema Area and Severity Index (EASI) Score
Note: Include Character result, Numeric 
score, CFB & %CFB
SAC 
29.
ITT
EFF_L4
Listing of Total Body Surface Area (%BSA)
Note: Include Numeric score & CFB 
SAC 
Patient-Reported Outcomes
30.
ITT
EFF_L3
Listing of Weekly Average of Daily itch/ pruritus NRS score 
(based on Item #1 of Daily Sign and Symptom Severity Diary)
Note: Include Numeric score & CFB for 
all derived visits
SAC 
31.
ITT
EFF_L4
Listing of Daily Sign and Symptom Severity Diary
Note: Include Numeric score 
SAC 
32.
ITT
EFF_L4
Listing of Patient Global Impression of Change Scores
Note: Severity of eczema symptoms 
and Severity of itch in by-lines.
Note: Include Character result, Numeric 
score
SAC 
33.
ITT
EFF_L4
Listing of Patient Global Impression of Severity Scores
Note: Include Character result, Numeric 
score & CFB
SAC 
34.
ITT
EFF_L4
Listing of Clinician Global Impression of Change Scores
Note: Include Character result, Numeric 
score
SAC 
PK
35.
PK
PKCL1P
Listing of Plasma Mepolizumab Concentration Time Data
SAC


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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophil Counts and Biomarkers
36.
Safety
EFF_L4
Listing of Blood Eosinophil Counts
Include both absolute and ratio to 
baseline blood eosinophil count
37.
Safety
N/A
Listing of Raw SAS Output for Mixed Model Repeated Measures 
(MMRM) Analysis for Blood Eosinophils Count
38.
PD
EFF_L4
Listing of Serum Free and Total Serum IL-5 Levels 
39.
PD
EFF_L4
Listing of Serum Biomarker Endpoints
40.
ITT
N/A
Listing of Raw SAS output of Bayesian Analysis of Response 
Rate in Investigator’s Global Assessment (IGA) Score


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12.10.
Appendix 10: Example Mock Shells for Data Displays
Example: POP_T1
Page 1 of n
Protocol: 205050
Population: Safety
Table 1.10
Summary of Exposure to Study Treatment
                                                      Placebo SC      Mepolizumab 100mg SC
                                                            (N=xx)            (N=xx)
            -----------------------------------------------------------------------------
           Treatments Administered      n               68                  68
                                        Mean            11.6                12.7
                                        SD               3.30                1.33
                                        Median          13.0                13.0
                                        Min.             2                   4
                                        Max.            14                  14
           Number of Treatments         1                0                  0
                                        2                2 (3%)             0
                                        3                3 (4%)             0
                                        4                3 (4%)             1 (1%)
                                            
          Number of Days on Treatment  n                68                  68
                                        Mean            330.8               357.2
                                        SD               91.43               37.39
                                        Median          365.0               365.0
                                        Min.             57                 114
                                        Max.            394                 392


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Note: Number of Days on Treatment = (Treatment Stop Date – Treatment Start Date) + another 
28 days inclusive.


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Example: EFF_T1 
Page 1 of 1
Protocol: 205050
Population: Intent-to-Treat
Table 2.1
Bayesian Posterior Probability for Comparison between Mepolizumab and Placebo
Visit
Treatment
n
Posterior 
Mean 
Response 
Rate (80% 
Cred Int)
Posterior 
Median 
Response Rate
(80% Cred Int)
Posterior 
Mean 
Difference 
(80% Cred 
Int)
Posterior
Probability 
of Response 
Rate ≥ 40%
Posterior 
Probability 
of 
difference 
of Response 
Rate ≥ 15%
Week 
16
Mepolizumab 
100 mg SC
xx
xx.xx 
(xx.xx, 
xx.xx)
xx.xx 
(xx.xx, xx.xx)
xx.xx 
(xx.xx, 
xx.xx)
xx.xx 
xx.xx 
Placebo SC
xx
xx.x x
(xx.xx, 
xx.xx)
xx.xx
(xx.xx, xx.xx)
Note: A Responder is defined as a subject who has an IGA score of 0 or 1 and a minimum 2-
grade improvement from baseline. If a subject withdraws early from the study the due to lack 
of efficacy or disease progression, then all weeks after withdrawal they are assigned to be 
a non-responder.
Note: 0=Clear; 1=Almost Clear; 2=Mild; 3=Moderate; 4=Severe.


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Example: EFF_T2
Protocol: 205050                                                                 Page 1 of 1
Population: Intent-to-Treat
Table 2.2
Number (%) of Subjects in Each Category of the Investigator’s Global Assessment Scale at 
Each Visit
Visit
Category
Placebo SC
(N=XX)
Mepolizumab 100 mg SC
(N=XX)
Day 1
n
XX
XX
Clear
XX (XX%)
XX (XX%)
Almost Clear
XX (XX%)
XX (XX%)
Mild
XX (XX%)
XX (XX%)
Moderate
XX (XX%)
XX (XX%)
Severe
XX (XX%)
XX (XX%)
Programming note: Repeat for all study visits


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Example: EFF_T3
Protocol: 205050                                                                 Page 1 of 1
Population: Intent-to-Treat
Table 2.3
Summary of Proportion of Subjects with an IGA Score of 0 or 1 and at Least a 2-Grade 
Improvement from Baseline at Each Visit
Visit
IGA score of 0 or 
1 and at least a 
2-grade 
improvement
Placebo SC
(N=XX)
Mepolizumab 
100mg SC
(N=XX)
Proportions 
Difference
90% CI for 
the 
Proportions 
Difference
Week 4
n
XX
XX
Yes
XX (XX%)
XX (XX%)
XX%
(XX.X%, 
XX.X%)
No
XX (XX%)
XX (XX%)
Note: A Responder is defined as a subject who has an IGA score of 0 or 1 and a minimum 2-
grade improvement from baseline. If a subject withdraws early from the study the due to lack 
of efficacy or disease progression, then all weeks after withdrawal they are assigned to be 
a non-responder.
Note: Day 1 is considered as baseline.
Note: 0=Clear; 1=Almost Clear; 2=Mild; 3=Moderate; 4=Severe.
Programming note: Repeat for all available visits


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Example: EFF_T4
Protocol: 205050                                                                 Page 1 of 1
Population: Intent-to-Treat
Table 2.4
Summary of Change from Baseline/Percent Change from Baseline in EASI Score at Each Visit
Summary: Change from Baseline
Visit
Placebo SC
(N=XX)
Mepolizumab 100mg SC
(N=XX)
Day 1
n
XX
XX
Mean
x.x 
x.x 
SD
X.XX
X.XX
Median
x.x 
x.x 
Min.
X
X
Max.
X
X
Week 4
n
XX
XX
Mean
x.x 
x.x 
SD
X.XX
X.XX
Median
x.x 
x.x 
Min.
X
X
Max.
X
X
Summary: Percentage Change from Baseline
……[Format as Change from Baseline]
Note: Day 1 is considered as baseline and summarized for absolute value.
Programming note: Repeat for all available visits and include percent change from baseline


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Example: EFF_T5
Protocol: 205050                                                                 Page 1 of 1
Population: Intent-to-Treat
Table 2.6
Summary of Proportion of Subjects with >=50% and >=75% Improvement in EASI Score from 
Baseline at Each Visit
Visit
Improvement in 
EASI Score from 
baseline 
Placebo SC
(N=XX)
Mepolizumab 
100mg SC
(N=XX)
Proportions 
Difference
90% CI for the 
Proportions 
Difference
Week 4
n
XX
XX
>=50% improvement
   XX (XX%)
XX (XX%)
XX%
(XX.X%, XX.X%)
>=75% improvement
XX (XX%)
XX (XX%)
XX%
(XX.X%, XX.X%)


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Example: SAF_T1
                 Page 1 of n
Protocol: 205050
Population: Intent-to-Treat
Table 3.9
Summary of On-Treatment Adverse Events of Special Interest Reported by the Investigator as 
Meeting the Criteria for Anaphylaxis
Number of Subjects with Any Event
Hypersensitivity                 
Placebo SC
(N=XX)
xx (xx%)
Mepolizumab 100mg SC
(N=XX)
xx (xx%)
Number of Subjects with Any Event
XX (XX%)
XX (XX%)
Facial Paralysis
XX (XX%)
XX (XX%)
Flushing
XX (XX%)
XX (XX%)
Injection related reaction
XX (XX%)
XX (XX%)
Rash
XX (XX%)
XX (XX%)
Other Systemic Reactions
Number of Subjects with Any Event
XX (XX%)
XX (XX%)
Facial Paralysis
XX (XX%)
XX (XX%)
Flushing
XX (XX%)
XX (XX%)
Injection related reaction
XX (XX%)
XX (XX%)
Rash
XX (XX%)
XX (XX%)


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Example: SAF_T2
Protocol: 205050
Page 1 of n
Population: Safety
Table 3.10
Summary Profile of On-Treatment Adverse Events Reported by the Investigator as Meeting the 
Criteria for Anaphylaxis
                                                       Placebo            Mepolizumab 100 mg SC
                                                       (N=xx)             (N=xx)
           -------------------------------------------------------------------------------------
           All Events
             >=1 event [1]                             3/2 (3%)           5/5 (7%)
             1 event                                   1   (1%)           5   (7%)
             2 events                                  1   (1%)           0
             3 events                                  0                  0
             >=4 events                                0                  0
           Serious Events
             >=1 event [1]                             1/1 (1%)           0
           Events considered related to
Investigational Product
             >=1 event [1]                             1/1 (1%)           1/1 (1%)
           Intensity [1]
             Mild                                      0                  4/4 (6%)
             Moderate                                  2/2 (3%)           1/1 (1%)
             Severe                                    1/1 (1%)           0
           Outcome [1]
             Recovered/Resolved                        3/2 (3%)           5/5 (7%)
             Recovering/Resolving                      0                  0
             Not Recovered/Not Resolved                0                  0


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             Recovered/Resolved With Sequelae          0                  0
             Fatal                                     0                  0
           Action Taken [1]
             Drug withdrawn                            0                  0
             Dose reduced                              0                  0
             Dose increased                            0                  0
             Dose not changed                          3/2 (3%)           5/5 (7%)
             Dose interrupted                          0                  0
             Not applicable                            0                  0
           No. doses prior to event [1]
             1                                         0                  0
             2                                         0                  1/1 (1%)
             3                                         0                  0
             4                                         0                  1/1 (1%)
             
           No. doses prior to first event
             1                                         0                  0
             2                                         0                  1   (1%)
             3                                         0                  0
             4                                         0                  1   (1%)
      
[1] Information presented as number of events / number (%) participants with at least one event.
Subjects may be counted in more than one row.


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Example: SAF_T3
Protocol: 205050
Page 1 of 1
Population: Safety
Table 3.38
Summary of Binding Antibody by Visit 
                                              
Placebo     Mepolizumab 100 mg SC
       Visit            
Assay Result    
(N=68)        (N=68)
    --------------------------------------------------------------------------------------
      Baseline         
n            
xx            xx
                              Negative     
xx (xx%)     xx (xx%)            
                              Positive     
xx (xx%)      xx (xx%)
        
Titer Value    Median    32.0          32.0
                                             Min.      32            32
                                             Max.      32            32
      Week 4          
n            
xx            xx
                              Negative     
xx (xx%)     xx (xx%)            
                              Positive     
xx (xx%)      xx (xx%)
Transient Positive     xx (xx%)      xx (xx%)
  Persistent Positive     xx (xx%)      xx (xx%)
Titer Value    Median    32.0          32.0
                                             Min.      32            32
                                             Max.      32            32
             
      Anytime Post Baseline  n            
xx            xx
                              Negative     
xx (xx%)     xx (xx%)            
                              Positive     
xx (xx%)      xx (xx%)       
  Transient Positive     xx (xx%)      xx (xx%)


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  Persistent Positive     xx (xx%)      xx (xx%)
                              Titer Value    Median    32.0          32.0
                                             Min.      32            32
                                             Max.      32            32
Note: The values shown at the anytime post baseline visit are based on each participants 
highest post baseline titer.
Any time post baseline would be Positive for a participants who had Negative and Positive
post baseline results


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Example: SAF_T4
Protocol: 205050 
Page 1 of 1
Population: Safety
Table 3.39
Summary of Neutralising Antibody by Visit
                                                                Mepolizumab
                                      Assay       Placebo       100 mg SC
               Visit       
   Result      (N=xx)        (N=xx)
               -------------------------------------------------------------
               Baseline               n            xx            xx
                                      Negative     xx (xx%)     xx (xx%)            
                                      Positive     xx (xx%)      xx (xx%)       
               Week 4                 n            xx            xx
                                      Negative     xx (xx%)     xx (xx%)            
                                      Positive     xx (xx%)      xx (xx%)       
               
               Anytime Post Baseline
n            xx            xx
                                      Negative     xx (xx%)     xx (xx%)            
                                      Positive     xx (xx%)      xx (xx%)       
Note: NAb assay result only presented for participant with positive ADA assay.
Any time post baseline would be Positive for a participant who had both Negative and 
Positive post baseline results.


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Example: SAF_T5
Protocol: 205050 
Page 1 of 1
Population: Safety
Table 3.40
Summary of Binding Antibody Assay Results: Highest Treatment Emergent Confirmatory Result 
Any Time Post Baseline
                                                          
               Assay Result            Placebo       Mepolizumab 100 mg SC
               
(N=xx)        
(N=xx)
               -------------------------------------------------------------
               n            
xx            xx
               Negative     
xx (xx%)     xx (xx%)            
               Positive     
xx (xx%)      xx (xx%)
Transient Positive     xx (xx%)      xx (xx%)
Persistent Positive     xx (xx%)      xx (xx%)
Titer Value    
Median    
32.0          32.0
                    Min.      
32            32
                    Max.      
32            32
             
               
               
Note: Includes only results from subjects who do not have a positive ADA assay prior to
the first dose of investigational product.


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Example: PD_T1
Protocol: 205050                                                                Page 1 of x
Population: Intent-to-Treat                       
Table 5.1                        
                              Summary of Blood Eosinophil Count at Each Visit                         
                                                     Placebo SC   Mepolizumab 100 mg SC
  Visit                                            
    (N=68)        (N=68)
  ------------------------------------------------------------------------------------------
  Baseline  Blood Eosinophils (10^9/L)           n           68           68
                                                 Geo Mean     0.172        0.177
                                                 Std Logs     1.3522       1.2890
                                                 Median       0.215        0.190
                                                 Min.         0.00         0.01
                                                 Max.         4.45         6.72
  Week 4   Blood Eosinophils (10^9/L)            n           66           66
                                               
Geo Mean     0.141        0.035
                                                 Std Logs     1.4972       0.9999
                                                 Median       0.195        0.040
                                                 Min.         0.00         0.00
                                                 Max.         3.35         1.56
           Blood Eosinophils Ratio to Baseline   n           66           66
                                                 Geo Mean     0.796        0.189
                                                 Std Logs     1.2976       1.1936
                                                 Median       0.964        0.185
                                                 Min.         0.00         0.00
                                                 Max.        22.00         4.00
Note: Data were log transformed.
Note: Where a result of zero was recorded, a small value (i.e. minimum all non-missing 
results/2) was added prior to log transformation


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Example: PD_T2
Protocol: 205050
                                                             Page 1 of x
Population: Safety
Table 5.2
Summary of Mixed Model Repeated Measures (MMRM) Analysis for Blood Eosinophils Count
Visit
Statistic
Placebo SC
N=xx
Mepolizumab 100 mg SC
N=xx
Week 4
n
xx
xx
LS Geometric Mean (SE)
x.xx (xx.xxx)
x.xx (xx.xxx)
LS Geometric Mean Ratio to Baseline (SE)
x.xx (xx.xxx)
x.xx (xx.xxx)
  95% Confidence Interval 
(x.xx, x.xx)
(x.xx, x.xx)
Treatment Ratio 
x.xx
  95% Confidence Interval 
(x.xx, x.xx)
Week 8
n
xx
xx
LS Geometric Mean (SE)
x.xx (xx.xxx)
x.xx (xx.xxx)
LS Geometric Mean Ratio to Baseline (SE)
x.xx(xx.xxx)
x.xx (xx.xxx)
  95% Confidence Interval 
(x.xx, x.xx)
(x.xx, x.xx)
Treatment Ratio 
x.xx
  95% Confidence Interval 
(x.xx, x.xx)
Note: Treatment Ratio (Mepolizumab/Placebo) and 95% Confidence Intervals for Ratio to 
Placebo are obtained from MMRM model, with fixed categorical effects of Treatment, Visit, 
and Treatment-By-Visit Interaction and fixed continuous covariates of Baseline. ‘XX’ 
covariance structure was used.
Note: n is the number of participants with non-missing data at that visit.


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Example: EFF_L1
Protocol: 205050                   
Page 1 of x
Population: Intent-to-Treat
Listing 24
Listing of Investigator’s Global Assessment(IGA) Score
Treatment 
Site 
ID./
Subj.
Visit/
Analysis 
Visit
Date/
Study 
Day
IGA 
Character 
result 
IGA 
Score
Change from
Baseline 
score
Study 
Treatment 
Period
Follow-Up 
Period 
Relapsed
(Y/N)
[1]
XXX/
XXX
WEEK 2/
Moderate
XXX/
XXX
                         
  
[1] Participants who have an IGA score of 3 or 4 after achieving an IGA score of 0 or 1 and 
at least a 2-grade improvement during the Treatment and Follow-up Periods.


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Example: EFF_L2
Protocol: 205050                            
Page 1 of x
Population: Intent-to-Treat
Listing 25
Listing of Eczema Area and Severity Index (EASI) Score
Treatment 
Site ID./
Subj.
Visit/
Analysis 
Visit
Date/
Study 
Day
EASI 
Score
Change from 
Baseline 
Score
Study 
Treatment 
Period
Follow-Up 
Period
Relapsed(Y/N)
[1]
XXX/
XXX
WEEK 2/
XXX/
XXX
                         
  
[1]: Participants who have an increase in EASI score of >=25% from baseline during the 
Treatment and Follow-up Periods


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Example: EFF_L3
Protocol: 205050                                                             
Page 1 of x
Population: Intent-to-Treat
Listing 27
Listing of Weekly Average of Daily Itch/pruritus NRS score (based on Item #1 of Daily Sign 
and Symptom Severity Diary)
Treatment 
Site ID./
Subj.
Visit/
Analysis Visit
Numeric 
Score
Change from Baseline 
Score
XXX/
XXX
WEEK 2/
XXX/
XXX
                     


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Example: EFF_L4
Protocol: 205050       
Page 1 of x
Population: Intent-to-Treat
Listing of xxxxxx
Treatment 
Site ID./
Subj.
Visit/
Analysis Visit
[optional]
Date/
Study 
Day
Character 
result 
[optional]
Numeric 
Score
Change 
from 
Baseline
[optional] 
XXX/
XXX
WEEK 2/
XXX/
XXX
                         
  
Programming Note: Include optional columns as required.


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Example: PK_F1/PD_F1
Protocol: 205050                                                              
Page 1 of x
Population: Intent-to-Treat
Figure 4.1
Scatter plot of Individual Plasma Concentration Data by Participants’ ADA Status
      ADA+ Participants
ADA- Participants
                  
       
Conc. (unit)
Time (unit)


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Example: PD_F2
Protocol: 205050                                                              
Page 1 of x
Population: Intent-to-Treat
Figure 5.2
Plot of Least Squares Geometric Means and 95% CI of Ratio to Baseline in Blood Eosinophil 
Count
Treatment :              Placebo SC
Mepolizumab 100 mg SC                     
LS Geometric Mean (95% CI)
Visit