A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of Efficacy of Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) With Eosinophilic Esophagitis (EoE)
Phase: PHASE3
Conditions: Eosinophilic Esophagitis (EoE)
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02736409 
 
Study Title:  
A Phase 3, Multicenter, Double-blind Extension Study to Evaluate 
Maintenance of Efficacy of Oral Budesonide Suspension (OBS) and Long-term 
Treatment Effect of OBS in Adolescent and Adult Subjects (11 to 55 Years of 
Age, Inclusive) with Eosinophilic Esophagitis (EoE) 
 
Study Number:  
SHP621-302 
 
 
Protocol Version and Date:  
 
Original Protocol:  
05 December 2015 
Amendment 1:  
22 June 2016 
Amendment 2:   
19 December 2016 
 

PROTOCOL:  SHP621-302
TITLE:
A Phase 3, Multicenter, Double-blind Extension Study to Evaluate 
Maintenance of Efficacy of Oral Budesonide Suspension (OBS) and 
Long-term Treatment Effect of OBS in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol:  05 Dec 2015
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only

Shire 
Protocol SHP621-302 
CONFIDENTIAL 
Version 1.0 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
Date: 
05 Dec 2015 
Page 2 of2 
 MD 
 
Acknowledgement 
I have read this protocol for Shire Study SHP621-302. 
Title: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of 
Efficacy of Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in 
Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) with Eosinophilic 
Esophagitis (EoE) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
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Protocol SHP621-302
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Page 3 of 96
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by 
the Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department.  Applicable fax numbers and e-mail address can be found on the 
form (sent under separate cover).  A copy of this form must also be sent to the contract 
research organization (CRO)/Shire Medical Monitor by fax or e-mail using the details below.
, MD
Email:  
Fax:  
For protocol- or safety-related issues during normal business hours (8 am to 5 pm 
Eastern Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile: 
Email:  
Fax:  
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile: 
Email:  
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Page 4 of 96
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
 or 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
EMERGENCY CONTACT INFORMATION ..........................................................................3
PRODUCT QUALITY COMPLAINTS ....................................................................................4
ABBREVIATIONS..................................................................................................................12
STUDY SYNOPSIS.................................................................................................................14
STUDY SCHEDULE(S) ..........................................................................................................24
1.
BACKGROUND INFORMATION.............................................................................28
1.1
Indication and Current Treatment Options...................................................................28
1.2
Product Background and Clinical Information ............................................................28
2.
STUDY OBJECTIVES AND PURPOSE....................................................................30
2.1
Rationale for the Study.................................................................................................30
2.2
Study Objectives...........................................................................................................30
2.2.1
Primary Objective..................................................................................................30
2.2.2
Secondary Objectives ............................................................................................30
3.
STUDY DESIGN.........................................................................................................32
3.1
Study Design and Flow Chart ......................................................................................32
3.2
Duration and Study Completion Definition .................................................................35
3.3
Sites and Regions .........................................................................................................36
4.
STUDY POPULATION...............................................................................................37
4.1
Inclusion Criteria..........................................................................................................37
4.2
Exclusion Criteria.........................................................................................................37
4.3
Restrictions...................................................................................................................39
4.4
Reproductive Potential .................................................................................................39
4.4.1
Female Contraception............................................................................................39
4.5
Discontinuation of Subjects..........................................................................................40
4.5.1
Subject Withdrawal Criteria ..................................................................................41
4.5.2
Reasons for Discontinuation..................................................................................41
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................42
4.5.4
Safety-related Stopping Rules ...............................................................................42
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................43
5.1
Prior Treatment.............................................................................................................43
5.2
Concomitant Treatment................................................................................................43
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5.2.1
Permitted Treatment ..............................................................................................43
5.2.2
Prohibited Treatment .............................................................................................44
6.
INVESTIGATIONAL PRODUCT ..............................................................................45
6.1
Identity of Investigational Product...............................................................................45
6.1.1
Blinding the Treatment Assignment......................................................................45
6.2
Administration of Investigational Product(s)...............................................................45
6.2.1
Interactive Response Technology for Investigational Product Management........46
6.2.2
Allocation of Subjects to Treatment......................................................................46
6.2.3
Dosing....................................................................................................................47
6.2.4
Unblinding the Treatment Assignment..................................................................48
6.3
Labeling, Packaging, Storage, and Handling ...............................................................48
6.3.1
Labeling .................................................................................................................48
6.3.2
Packaging...............................................................................................................49
6.3.3
Storages..................................................................................................................49
6.3.4
Special Handling....................................................................................................50
6.4
Drug Accountability.....................................................................................................50
6.5
Subject Compliance......................................................................................................51
7.
STUDY PROCEDURES..............................................................................................53
7.1
Study Schedule.............................................................................................................53
7.1.1
Screening Period (Weeks -4 to 0)..........................................................................53
7.1.1.1
Screening Visit (Visit 0) / Visit 4 of SHP621-301 Study............................54
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28 
and 36 (or Early Termination) ...............................................................................55
7.1.2.1
Randomization Visit (Visit 1): Week 0.......................................................56
7.1.2.2
Visits 2 and 3 (Weeks 4 and 8)....................................................................57
7.1.2.3
Visit 4 (Week 12) ........................................................................................58
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28)....................................................58
7.1.2.5
Visit 8 (Week 36) or Early Termination .....................................................59
7.1.3
Follow-up Period ...................................................................................................60
7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40.............................................61
7.2
Study Evaluations and Procedures ...............................................................................61
7.2.1
Efficacy..................................................................................................................61
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation.........................................................................61
7.2.1.2
Dysphagia Symptom Questionnaire............................................................62
7.2.2
Safety .....................................................................................................................63
7.2.2.1
Medical and Medication History.................................................................63
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7.2.2.2
Physical Examination (Including Height and Weight)................................64
7.2.2.3
Adverse Event Collection............................................................................64
7.2.2.4
Vital Signs ...................................................................................................64
7.2.2.5
Clinical Laboratory Evaluations..................................................................65
7.2.2.6
Pregnancy Test ............................................................................................66
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density..................66
7.2.3
Other Assessments.................................................................................................67
7.2.3.2
Severity of Disease Assessments ................................................................68
7.2.4
Volume of Blood to Be Drawn from Each Subject ...............................................68
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................69
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................69
8.1.1
Severity Categorization..........................................................................................69
8.1.2
Relationship Categorization...................................................................................70
8.1.3
Outcome Categorization ........................................................................................71
8.1.4
Symptoms of the Disease under Study ..................................................................71
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................71
8.1.6
Pregnancy...............................................................................................................72
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................72
8.2
Serious Adverse Event Procedures...............................................................................73
8.2.1
Reference Safety Information................................................................................73
8.2.2
Reporting Procedures.............................................................................................73
8.2.3
Serious Adverse Event Definition .........................................................................74
8.2.4
Serious Adverse Event Collection Time Frame ....................................................74
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................74
8.2.6
Fatal Outcome........................................................................................................75
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................75
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................76
9.1
Data Collection.............................................................................................................76
9.2
Clinical Data Management...........................................................................................76
9.3
Data Handling Considerations......................................................................................76
9.4
Statistical Analysis Process..........................................................................................76
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........77
9.6
Sample Size Calculation and Power Considerations....................................................77
9.7
Study Population ..........................................................................................................77
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9.8
Efficacy Analyses.........................................................................................................78
9.8.1
Primary Efficacy Endpoint ....................................................................................78
9.8.2
Secondary Efficacy Endpoints...............................................................................79
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................79
9.9
Safety Analyses ............................................................................................................81
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................83
10.1
Sponsor’s Responsibilities ...........................................................................................83
10.1.1 Good Clinical Practice Compliance.......................................................................83
10.1.2 Indemnity/Liability and Insurance.........................................................................83
10.1.3 Public Posting of Study Information .....................................................................83
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................84
10.1.5 Study Suspension, Termination, and Completion .................................................84
10.2
Investigator’s Responsibilities .....................................................................................84
10.2.1 Good Clinical Practice Compliance.......................................................................84
10.2.2 Protocol Adherence and Investigator Agreement..................................................85
10.2.3 Documentation and Retention of Records.............................................................85
10.2.3.1 Case Report Forms......................................................................................85
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................86
10.2.3.3 Audit/Inspection..........................................................................................87
10.2.3.4 Financial Disclosure....................................................................................87
10.3
Ethical Considerations..................................................................................................87
10.3.1 Informed Consent ..................................................................................................87
10.3.2 Institutional Review Board or Ethics Committee..................................................88
10.4
Privacy and Confidentiality..........................................................................................88
10.5
Study Results/Publication Policy .................................................................................89
11.
REFERENCES.............................................................................................................91
12.
APPENDIX ..................................................................................................................93
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LIST OF TABLES
Table 1-1: Schedule of Assessments.......................................................................................24
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject.........................68
Table 8-1: Adverse Event Relatedness....................................................................................70
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LIST OF FIGURES
Figure 3-1: Study Design Flow Chart.......................................................................................33
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LIST OF APPENDICES
Appendix 1
Scales and Assessments...............................................................................94
Appendix 2
Dysphagia Symptom Questionnaire ePRO for EoE....................................95
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ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
β-hCG
beta-human chorionic gonadotropin
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CYP450 3A4
cytochrome P450 3A4
DSQ
Dysphagia Symptom Questionnaire
DXA (DEXA)
dual-energy X-ray absorptiometry
EC
ethics committee
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
  
ePRO
electronic patient-reported outcome
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HPF
high-powered field
hs
at bedtime
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
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ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication information
MedDRA
Medical Dictionary for Regulatory Activities
OBS
oral budesonide suspension
pc
after meals
PP
per-protocol
PPI
proton pump inhibitor
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
TEAE
treatment-emergent adverse event
UK
United Kingdom
US
United States
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STUDY SYNOPSIS
Protocol number:  SHP621-302
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of 
Efficacy of Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in 
Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
Number of subjects (total and for each treatment arm):
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to 
complete the SHP621-301 study and enroll in this treatment extension study based on enrollment 
observed in the Phase 2 study (MPI 101-06).
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America
Study period (planned):
April 2016 – April 2019
Clinical phase:
3
Objectives
Primary:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak eosinophilic 
count and the Dysphagia Symptom Questionnaire (DSQ) score, through a randomized withdrawal 
design for subjects who responded to 12 weeks of OBS treatment (2 mg twice daily) with a peak 
count of ≤6 eosinophils (eos)/high-powered field (HPF) across all available esophageal levels at 
the final treatment visit and a ≥30% reduction in DSQ score from baseline during the SHP621-301 
induction study
Key Secondary:

To evaluate the long-term treatment response over an extended period of 36 weeks for subjects 
who were randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 
induction study (subject did not have a peak count of ≤6 eos/HPF across all available esophageal 
levels at the final treatment visit and/or a ≥30% reduction in DSQ score from baseline)
Secondary:

To evaluate the response to OBS treatment over 36 weeks for subjects who received placebo in 
the SHP621-301 induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being 
randomized to placebo in the randomized withdrawal period (treatment-withdrawal-treatment 
reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE Endoscopic 
Reference Score (EREFS)

To evaluate other response criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
Exploratory:

 
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
 
 
Rationale:
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is being 
conducted to determine response to withdrawal of OBS, maintenance of response, extended therapy 
response, and response to intermittent therapy by evaluating both eosinophil counts and DSQ in
adolescent and adults treated or withdrawn from OBS in this treatment extension study.
Investigational product, dose, and mode of administration:
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the 
screening assessments (Visit 0) of this treatment extension study. At the SHP621-301 final treatment 
evaluation visit, subjects will be dispensed blinded investigational product (based on treatment 
assignment in SHP621-301) that will last for up to 4 weeks prior to enrolling into this treatment 
extension study. A 4-week screening period is required to allow for blinded treatment response 
information (reduction in DSQ from baseline and eosinophilic count as determined by a central reader) 
collected during the SHP621-301 final treatment evaluation visit to be entered into the interactive web-
based response system (IWRS) by the unblinded data team who is independent from the blinded study 
team and not involved with the day-to-day conduct of the study. Once information is available, 
subjects will return for the randomization visit (Visit 1) to receive investigational product as follows:

Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the 
final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 
2 mg twice daily or placebo at a 1:1 ratio

Subjects who were assigned to OBS treatment and did not respond or partially responded to OBS 
treatment in the SHP621-301 study will receive OBS 2 mg twice daily

Subjects who were assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice 
daily
Subjects, site staff, and study team members will remain blinded to treatment assignment and 
individual subject histology and individual subject DSQ data from the SHP621-301 study (post
randomization) and this extension study until database lock occurs for this extension study.  
During the 36-week double-blind treatment extension study, subjects will receive oral administration 
of 10 mL of 0.2 mg/mL (2 mg) investigational product twice daily (every morning [qAM] after meals 
[breakfast, pc] and at bedtime [hs]; 4 mg total/day), with no ingestion of food or liquids permitted for 
30 minutes after investigational product administration. Dosing regimens are consistent with the 
regimens used in the Phase 2 MPI 101-06 study and Phase 3 SHP621-301 study:

Placebo twice daily group:  placebo qAM (pc) and hs

OBS twice daily group: OBS 10 mL of 0.2 mg/mL (2 mg) qAM (pc) and hs (4 mg OBS total/day)
The investigational product will be supplied in amber glass, multidose bottles with child-resistant caps
and refrigerated throughout the study (in the clinic and subject’s home). Each bottle will contain 
approximately 210 mL of suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL 
(matching placebo). 
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for 
each subject in the OBS treatment group (Total Daily Dose of OBS). 
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Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume 
per Dose
(mL)
Morning Dose 
(mg) 
(qAM, pc)
Evening 
Dose (mg) 
(hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10
0.0
0.0
0.0
OBS 
0.2
10
2.0
2.0
4.0
Abbreviations: hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every 
morning
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with biopsy to 
evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on placebo in the 
randomized withdrawal period who have relapsed will have their treatment assignment changed to 
OBS 2 mg twice daily. The criteria for relapse is having an eosinophilic count of ≥15 eos/HPF from at 
least 2 of 3 levels of the esophagus, as determined by central reader and having at least 4 days of 
dysphagia in the 2-week period prior to the scheduled visit, as determined by the DSQ. At least 8 daily 
diary entries must be completed over 14 consecutive days in order to determine the criterion for DSQ 
relapse. If fewer than 8 diary entries are reported within the 2-week period, then the 2-week period will 
be shifted backwards from the scheduled visit to include the most recent 2-week period with at least 
8 diary entries over 14 consecutive days; however, the 2-week period will not be shifted by more than 
2 weeks (ie, no more than 2-week period plus additional 2-week additional expansion). The criteria for 
relapse align with the related inclusion criteria for participation in the SHP621-301 study. The 
treatment assignment change will be performed in a blinded manner in IWRS by the independent 
unblinded data team. If both criteria for relapse are not met, the subject will remain assigned to 
placebo.
If at any time, the subject reports increased or worsening dysphagia symptoms to the investigator, the 
investigator may choose to perform an unscheduled EGD.  If an unscheduled EGD is performed prior 
to Week 12, an EGD does not have to be repeated at Week 12.  The independent, unblinded data team 
will review the blinded EGD and DSQ data to confirm the subject is on placebo in the randomized 
withdrawal period, determine if the subject meets relapse criteria, and change the subject’s treatment 
assignment to OBS 2 mg twice daily if relapse is confirmed.
If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 levels 
of the esophagus yet relapse is not confirmed due to the criterion for dysphagia symptoms not being 
met, the subject will remain assigned to placebo. If the criterion for dysphagia symptoms is met at a 
subsequent visit and both criteria for relapse are then confirmed, the subject’s treatment assignment 
will be changed to OBS 2 mg twice daily at the next scheduled visit.
Methodology:
This is a Phase 3, double-blind, multicenter study to evaluate the efficacy, safety, and tolerability of 
twice daily administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, 
inclusive, with EoE and dysphagia who completed the SHP621-301 induction study. 
This study will comprise 3 periods: 4-week screening period, 36-week double-blind treatment period, 
and a 4-week safety follow-up (Study Design Flow Chart). All subjects who have completed the 
SHP621-301 induction study will be eligible to enroll in this extension study. Approximately 
200 subjects (88%) who were randomized in the SHP621-301 study are estimated to complete the 
SHP621-301 study and will be enrolled in this treatment extension study based on enrollment observed 
in the Phase 2 study (MPI 101-06). Randomization into the randomized withdrawal period will be 
stratified by treatment assignment and treatment response in the SHP621-301 study. Subjects who are 
full responders (defined as ≤6 eos/HPF across all available esophageal levels and at least a 30% 
reduction in DSQ at the final treatment evaluation visit [Visit 4]) in the SHP621-301 induction study 
will be eligible to enter the randomized withdrawal period to receive either OBS 2 mg twice daily or 
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placebo at a 1:1 ratio. The randomization of subjects who are full responders will also be stratified by 
age (adults and adolescents) to ensure approximately equal number of subjects within each age group
are assigned to the treatment groups.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened 
(Visit 0); assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as 
the Visit 0 screening assessments of the treatment extension study. Subjects who meet eligibility 
criteria at the screening visit (Visit 0) will enter the 36-week double-blind period. Eligible subjects will 
receive investigational product based on treatment assignment in SHP621-301 for up to 4 weeks prior 
to enrollment in the treatment extension study. This 4-week screening period is required to allow for 
blinded treatment response information (reduction in DSQ from baseline and eosinophilic count as 
determined by a central reader) collected during the SHP621-301 final treatment evaluation visit to be 
entered into IWRS by the unblinded data team who is independent from the blinded study team and 
not involved with the day-to-day conduct of the study. Once information is available, subjects will 
return for the randomization visit (Visit 1) to receive investigational product.
During the 36-week treatment extension study, subjects who were assigned to, and fully responded to 
OBS treatment in the SHP621-301 study (≤6 eos/HPF across all available esophageal levels and at 
least a 30% reduction in DSQ at the final treatment evaluation visit) will enter a randomized 
withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio. Subjects who were 
assigned to OBS treatment in the SHP621-301 study and did not respond or partially responded, will 
receive OBS 2 mg twice daily. Subjects who were assigned to placebo in the SHP621-301 study will 
receive OBS 2 mg twice daily. At Week 12, all subjects will undergo an upper 
esophagogastroduodenoscopy (EGD) with biopsy to evaluate eosinophil counts. Upon receipt of 
blinded EGD and DSQ data, subjects on placebo in the randomized withdrawal period who have 
relapsed (>15 eos/HPF from at least 2 levels of the esophagus and specimens and 4 days of dysphagia 
over 2 weeks) will have their treatment assignment changed to OBS 2 mg twice daily at the next 
scheduled visit. The treatment assignment change will be performed in a blinded manner in IWRS by 
the independent unblinded data team. If both criteria for relapse are not met, the subject will remain 
assigned to placebo.
Subjects who report increased or worsening dysphagia symptoms to the investigator prior to the 
Week 12 EGD may have an unscheduled EGD to confirm whether relapse has occurred. If an 
unscheduled EGD is performed prior to Week 12, an EGD does not have to be repeated at Week 12. 
The independent, unblinded data team will review the EGD and DSQ data to confirm the subject is on 
placebo in the randomized withdrawal phase, determine if the subject meets relapse criteria, and 
change the subject’s treatment assignment to OBS 2 mg twice daily at the next scheduled visit if 
relapse is confirmed.
Subjects will have efficacy and safety assessments at each visit during the 36-week period. Subjects 
who fail to meet all eligibility criteria at Visits 0 or 1 will be considered screen failures. Subjects 
cannot be rescreened once they have been designated as a screen failure. Subjects who discontinue will 
not be replaced.
Subjects will be required to visit the site up to 8 times over up to a 36-week period. All subjects will 
have a Follow-up phone call 4-weeks post last dose of investigational product.
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Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
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Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria 
(including test results):
1.
Subject completed SHP621-301 induction study.
2.
Subject is able to provide written informed consent (subject, parent or legal guardian and, as 
appropriate, subject assent) to participate in the study before completing any study-related 
procedures. 
3.
Subject is male or female aged 11-55 years, inclusive, at time of consent for SHP621-301 study.
4.
Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical 
regimens (including gastric acid suppression; see exclusions below) in effect at the screening visit
(Visit 0). There should be no changes to these regimens during study participation. 
5.
All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential must 
agree to continue acceptable birth control measures (eg, abstinence, stable oral contraceptives, or 
double-barrier methods) throughout study participation and for 30 days following the last dose of 
investigational product.
6.
Subject is willing and has an understanding and ability to fully comply with study procedures
including DSQ compliance (completed the DSQ on ≥70% of days in any 2 consecutive weeks of 
the screening period) and restrictions defined in this protocol.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subject has changes in medications that could affect the study or diet in the weeks since the final 
treatment evaluation visit (Visit 4) of the SHP621-301 study.
2.
Subject using immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study or anticipated use of immunomodulatory therapy during the treatment period 
(except for any ongoing regimen of allergy shots); any temporary use (≤7 days) or initiation of 
new steroid treatment during the study should be documented and discussed with the medical 
monitor prospectively but cannot occur within 4 weeks of scheduled EGDs.
3.
Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated use during the treatment period; any temporary use (≤7 days) or initiation of new 
steroid treatment during the study should be documented and discussed with medical monitor 
prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
4.
Subject on inhaled or intranasal steroids and not on a stable dose between the baseline visit 
(Visit 1) of the SHP621-301 study and the screening EGD of this study. 
5.
Subject has initiated, discontinued, or changed dosage regimen of proton pump inhibitors (PPIs), 
H2 antagonists, antacids, antihistamines, or leukotriene inhibitors for any condition (such as 
gastroesophageal reflux disease, asthma or allergic rhinitis) since the final treatment evaluation 
visit (Visit 4) of the SHP621-301 study or anticipated changes in the use of such medications 
during the treatment period.  
6.
Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final 
treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of such 
medications during the treatment period.  
7.
Subject has an appearance on screening EGD of an esophageal stricture (high grade), as defined 
by the presence of a lesion that does not allow passage of a diagnostic adult upper endoscope 
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(eg, with an insertion tube diameter of >9mm). 
8.
Subject is on a pure liquid diet or the six-food elimination diet.
9.
Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit 
(Visit 4) of the SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including 
eosinophilic gastritis, enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including 
hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous treatment.  
Diagnosis with oropharyngeal or esophageal candidiasis at or since the final treatment evaluation 
visit (Visit 4) of the SHP621-301 study is not an exclusion as long as the subject received 
treatment for candidiasis and is expected to respond to treatment. 
13. Subject has acute or chronic infection or immunodeficiency condition, including tuberculosis, 
fungal, bacterial, viral/parasite infection, ocular herpes simplex, or chicken pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment evaluation 
visit (Visit 4) of the SHP621-301 study or since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or 
any other corticosteroids), or to any other ingredients of the study medication.
19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
Maximum duration of subject involvement in the study:

Planned duration of screening period: up to 4 weeks

Planned duration of treatment period: 36 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who are randomized and receive at least 1 dose of 
investigational product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of 
investigational product and had 1 post baseline efficacy assessment (biopsy and/or DSQ score).

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major 
protocol deviations. The PP set will be identified prior to unblinding the treatment assignments 
by a team consisting of, at a minimum, a physician and a statistician from Shire. 
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized 
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withdrawal period. Relapse, a binary response (either with a relapse or not), is defined as having an 
eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined by a 
central reader, and having at least 4 days of dysphagia in the 2-week period prior to the scheduled 
study visit, as determined by the DSQ.
Key Secondary Efficacy Endpoint
The key secondary endpoint is the long-term treatment response, a binary response, over an extended 
period of 36 weeks in adolescent and adult subjects who were randomized to OBS treatment but did 
not respond after 12 weeks in the SHP621-301 induction study (subject did not have peak count of 
≤6 eos/HPF across all available esophageal levels at the final treatment visit and/or ≥30% reduction in 
DSQ score from baseline) and met the following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all 
available esophageal levels at the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline of the SHP621-301 study and from baseline of this 
extension study to the final treatment period evaluation (Visit 8)
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at each assessment visit 

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions
2+3) at each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study

Change in the DSQ score and change in the peak eosinophilic count at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each assessment 
visit from baseline of the SHP621-301 study and from baseline of this extension study

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each assessment visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each assessment visit

Change in the peak eosinophil count at each assessment visit from baseline of the SHP621-301 
study and from baseline of this extension study for each available esophageal level (proximal, 
mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension 
study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), at each assessment visit from baseline of the SHP621-301 study 
and from baseline of this extension

Change in the DSQ combined score (questions 2+3) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study

Cumulative distribution function curves for the change and the percent change in the DSQ score 
at each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study
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
Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study 
For subjects who relapse on placebo during the randomized withdrawal period and who reinitiate 
treatment with OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for 
histological data and DSQ endpoints will be conducted at each assessment visit. Changes will be 
summarized over time from baseline of the SHP621-301 study and from the time of relapse. The same 
criteria for response will be applied to these subjects (≤6 eos/HPF across all available esophageal 
levels and at least a 30% reduction in DSQ from the SHP621-301 baseline score). 
Exploratory Efficacy Endpoints

 
Safety Endpoints 
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital signs
(temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height 
assessments, dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD) and 
body composition measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory tests 
(hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), and adrenocorticotropic 
hormone (ACTH) stimulation tests. To account for the effects of puberty in adolescent subjects (11-17 
years, inclusive), BMD z-scores will be adjusted for height z-scores using the Bone Mineral Density in 
Childhood Study calculator.
 
 
 
 
 
 
Statistical Methodology for Primary Efficacy Endpoint 
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse during the 
end of the double-blind randomized withdrawal period for the FAS, using a chi-square test comparing 
OBS 2 mg twice daily against placebo. The primary test of treatment effect will be two-sided, and 
conducted at the significance level of 0.05. The proportion of subjects with relapse for each treatment 
group and the corresponding 95% confidence interval (CI) will be estimated. In addition, the 
difference in the proportion of subjects with relapse between the 2 treatment groups and its 95% CI 
will be estimated.
Subjects who withdraw without providing efficacy data at the early termination (ET) visit will be 
classified as being a relapser in the primary efficacy analysis. The null hypothesis states that there is 
no difference in relapse proportions between OBS 2 mg twice daily and placebo, with the two-sided 
alternative of a nonzero difference between groups. Relapse proportions at each adjacent double-blind 
visit interval will also be assessed by applying the chi-square test to the observed data at each double-
blind visit.
Statistical Methodology for Key Secondary and Other Secondary Efficacy Endpoints
To evaluate the long-term treatment response over an extended period of 36 weeks for subjects who 
were randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 induction 
study (subject did not have peak count of ≤6 eos/HPF across all available esophageal levels at the final 
treatment visit and/or ≥30% reduction in DSQ score from baseline of SHP621-301), the proportion of 
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subjects who responded based on the histological data and the DSQ data at the final treatment period 
evaluation (Visit 8) and the corresponding 95% confidence interval (CI) will be estimated and 
summarized.
Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the change 
from baseline of the SHP621-301 study and from baseline of this extension study at the final treatment 
period evaluation (Visit 8) will be summarized by each assessment visit.  
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo in the 
SHP621-301 induction study, the proportion of subjects who responded based on the histological data 
and the DSQ data at the final treatment period evaluation (Visit 8) and the corresponding 95% CI will
be summarized. Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count 
and the change from baseline of the SHP621-301 study and from baseline of this extension study at the 
final treatment period evaluation (Visit 8) will be summarized by each assessment visit.  
To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being randomized to 
placebo in the randomized withdrawal period (intermittent therapy), the proportion of subjects who 
responded based on the histological data and the DSQ data at the final treatment period evaluation 
(Visit 8) and the corresponding 95% CI will be summarized.
Summary statistics will be provided for all the secondary endpoints.
Statistical Methodology for Safety Endpoints 
All safety measures, including AEs, physical examination, stadiometry, vital signs (temperature, 
systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA 
scans for BMD and body composition measurements (for adolescents aged 11-17 years, inclusive), 
clinical laboratory results (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), 
and ACTH stimulation will be descriptively summarized by treatment group at baseline and for each 
post baseline visit.
The number and percent of subjects with TEAEs will be presented. TEAEs are defined as AEs that 
start or deteriorate on or after the date of the first dose of investigational product (Visit 1) and no later 
than 3 days following the last dose of investigational product. However, for any subjects who die 
during the study (ie, the date of death is between the date of first dose of investigational product and 
the date of study discontinuation entered by the site, inclusive), all AEs (including those resulting in 
death) that occur during the study will be considered as TEAEs irrespective of the last dose and will be 
included in the TEAE summaries. 
Sample Size Justification
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to 
complete the SHP621-301 study and enroll in this treatment extension study based on enrollment 
observed in the Phase 2 study (MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse during the 
double-blind randomized withdrawal period. Relapse, a binary response (either with relapse or not), is 
defined as having an eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus 
(determined by a central reader) and having at least 4 days of dysphagia in a 2-week period prior to the 
scheduled visit (determined by the DSQ). To be considered as a subject with relapse, both criteria must 
be met.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or 
approximately 40 subjects, who were assigned to OBS treatment in the SHP621-301 study are 
anticipated to respond fully after 12 weeks in the SHP621-301 study.  
For this study, to detect a 50 percentage point difference between relapse proportions of 20% and 70% 
in the OBS and placebo groups, respectively, at 80% power and a significance level of 0.05 
(two-sided) using a Chi-Square test with equal allocation to treatment groups, it is necessary to assess 
the primary efficacy measure for approximately 38 subjects (19 subjects in each of the OBS and 
placebo groups). 
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STUDY SCHEDULE(S)
Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-Blind Treatment Period
Safety 
Follow-Up 
Contacto
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETn
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6 days
±3 days
Informed consent/assent
X
Medical history review
X
X
Inclusion/exclusion criteria 
review
X
X
Vital signsb; heightc, and weight 
assessment
X
X
X
X
X
X
X
X
X
EGD with endoscopy score 
(EREFS) and biopsyd
X
X
X
Issue/Retrieve DSQ handset
X
X
DSQ completion
Once daily completion
DSQ compliance assessment
X
X
X
X
X
X
X
X
X
 
 
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-Blind Treatment Period
Safety 
Follow-Up 
Contacto
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETn
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6 days
±3 days
 
Physical examination
X
X
X
X
X
X
X
X
X
Tanner Staging Assessmentf
X
X
Clinical laboratory testsg
X
X
X
X
X
X
X
X
X
Urinalysish
X
X
X
X
X
X
X
X
X
Pregnancy testi
X
X
X
X
X
X
X
X
X
Morning cortisol (target 6:00-
9:00 am)
X
X
X
X
X
X
X
X
X
ACTH Stimulation Testing 
X
X
DXA Scan (subjects 11 to 
17 years of age)j
X
X
Randomizationk
X
Study medication supplied 
Xl
X
X
X
X
X
X
X
Study medication administration
Twice daily administration of study medication
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-Blind Treatment Period
Safety 
Follow-Up 
Contacto
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETn
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6 days
±3 days
Study medication compliance 
assessment
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures recorded 
X
X
X
X
X
X
X
X
X
X
Review of adverse eventsm
X
X
X
X
X
X
X
X
X
X
Abbreviations: 
ACTH=adrenocorticotropic 
hormone; 
DSQ=Dysphagia 
Symptom 
Questionnaire; 
DXA=dual-energy 
X-ray 
absorptiometry; 
EGD=esophagogastroduodenoscopy; 
EREFS=EoE Endoscopic Reference Score; hs=at bedtime; IWRS=interactive web-based response system; 
a
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the screening assessments (Visit 0) of this treatment extension 
study. 
b
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood 
pressure (systolic and diastolic), heart rate, respirations, and temperature.
c
Height to be collected at screening (Visit 0) and Visit 8 only. Stadiometers will be used to measure height for subjects aged 11-17 years, inclusive. 
d
Endoscopy must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Endoscopies at Visit 4 and Visit 8
should occur at or within 7 days of the scheduled visit. Unscheduled endoscopies may be performed at the discretion of the investigator.
 
f
Tanner staging assessments will be performed for all subjects ≥11 years of age until investigator confirms subject is post puberty.
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-Blind Treatment Period
Safety 
Follow-Up 
Contacto
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETn
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6 days
±3 days
g
Clinical laboratory tests will include the following: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein, 
albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, carbon dioxide, hemoglobin, hematocrit, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, mean corpuscular volume, erythrocyte count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and platelet count). All subjects must fast overnight prior to collection.
h
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
i
The serum pregnancy test will be performed for all female subjects at screening (Visit 0) and Visit 8. Urine pregnancy tests will be performed at all other visits.
j
Dual-energy X-ray absorptiometry scans should be performed using the same machine and software as used in the SHP621-301 study. Dual-energy X-ray
absorptiometry scan at Visit 8 should occur at or within 7 days of the scheduled visit.
k
Randomization will occur via IWRS at Visit 1 once the subject's eligibility is confirmed. 
l
Study medication is supplied at the SHP621-301 final treatment visit based on treatment assignment in SHP621-301.  
m
Adverse event assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, acne, 
hirsutism, mood swings, insomnia, and depression).
n
If subject discontinues study prematurely during the treatment period, the evaluations listed for Visit 8 are to be performed as completely as possible.
o
A safety follow-up contact by phone will be performed 4 weeks following the last dose of study medication for all subjects (including subjects who fail screening, 
who discontinue early, or who complete the study).
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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al., 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and 
adults present with dysphagia and food impaction. When these symptoms are present, the 
diagnosis is confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered
field (HPF) on at least 1 esophageal biopsy and when other causes such as proton pump 
inhibitor (PPI)-responsive esophageal eosinophilia are excluded (Dellon et al., 2014a; Furuta 
et al., 2007). The standards of care are diet therapies and off-label use of glucocorticosteroids.
Esophageal dilation is used to temporarily relieve symptoms but does not address underlying 
inflammation. Given the clinical outcomes associated with EoE, including severe dysphagia, 
esophageal stricture, food impaction, and esophageal perforation (Hirano and Aceves, 2014;
Liacouras et al., 2011) and the fact that there are currently no FDA-approved treatments, there 
is a clear unmet medical need for an approved treatment that induces and maintains remission
for patients with EoE (Furuta and Katzka, 2015).  
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a nonviscous suspension. Shire is developing OBS as a 
first-line therapy for EoE in adolescents and adults.
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the 
management of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, 
and for induction of remission in patients with active, mild to moderate ulcerative colitis. 
Budesonide has strong glucocorticoid receptor affinity and is subject to considerable first pass 
metabolism by the liver with a short half-life. These attributes permit budesonide to act 
rapidly and locally in the gut mucosa for treatment of inflammatory disorders such as Crohn’s 
disease and ulcerative colitis. Once absorbed into the systemic circulation, budesonide is 
rapidly metabolized in the liver and inactivated (FDA, 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in 2 Phase 2 studies in 
the OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the 
efficacy of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in 
adolescents and adults aged 11-40 years, respectively, by measuring histological response 
(defined as mean peak eosinophil count ≤6 eos/HPF after treatment). Study MPI 101-06 also 
evaluated symptom response as measured by the Dysphagia Symptom Questionnaire (DSQ). 
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The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia 
and its severity, as well as pain. The DSQ score is calculated only from responses to the
questions related to dysphagia, and this clinical outcome assessment was considered to be fit 
for purpose as a result of the MPI 101-06 study. Results from Study MPI 101-01 
demonstrated a statistically significant histologic response (eosinophil count ≤6 eos/HPF) and 
remission (eosinophil count ≤1 eos/HPF) in the medium-dose (1.4-2.0 mg daily) and high-
dose (2.8-4.0 mg daily) OBS groups compared to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both 
the coprimary efficacy endpoints of histologic response and change from baseline in 
dysphagia symptoms. Following 12 weeks of twice daily treatment (once every morning after 
meals [qAM, pc] and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent 
reduction from baseline values for cellular (mean peak eosinophil count and histopathology 
features), organ (endoscopy score), and holistic measures (Physician Global Assessment and 
DSQ scores); these results were independent of the type of rater/reviewer (central pathologist, 
physician at the study site, or subject). 
This Phase 3 extension study follows the SHP621-301 induction study, a Phase 3 randomized, 
double-blind, multicenter, study to evaluate the efficacy, safety, and tolerability of twice daily 
administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, 
inclusive, with EoE and dysphagia. Study SHP621-301 is designed to provide safety and 
efficacy data demonstrating histologic response (as measured by eosinophilic count 
≤6 eos/HPF) and improvement in dysphagia symptoms (as measured by the DSQ) following 
12 weeks of treatment with OBS in adolescent and adult subjects with EoE. This extension
study will evaluate maintenance of treatment and treatment withdrawal in subjects who 
complete the induction study.
Always refer to the latest version of the SHP621 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP621. 
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is 
being conducted to determine response to withdrawal of OBS, maintenance of response, 
extended therapy response, and response to intermittent therapy by evaluating both eosinophil 
counts and DSQ in adolescent and adults treated or withdrawn from OBS in this treatment 
extension study.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak 
eosinophilic count and the Dysphagia Symptom Questionnaire (DSQ) score, through a 
randomized withdrawal design for subjects who responded to 12 weeks of OBS treatment 
(2 mg twice daily) with a peak count of ≤6 eosinophils (eos)/high-powered field (HPF) 
across all available esophageal levels at the final treatment visit and a ≥30% reduction in 
DSQ score from baseline during the SHP621-301 induction study
2.2.2
Secondary Objectives
The key secondary objective of this study is:

To evaluate the long-term treatment response over an extended period of 36 weeks for 
subjects who were randomized to OBS treatment but did not respond after 12 weeks in the 
SHP621-301 induction study (subject did not have a peak count of ≤6 eos/HPF across all 
available esophageal levels at the final treatment visit and/or a ≥30% reduction in DSQ 
score from baseline)
Additional secondary objectives of the study are:

To evaluate the response to OBS treatment over 36 weeks for subjects who received
placebo in the SHP621-301 induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being 
randomized 
to 
placebo 
in 
the 
randomized 
withdrawal 
period
(treatment-
withdrawal-treatment reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE 
Endoscopic Reference Score (EREFS)

To evaluate other responding criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
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2.2.3
Exploratory Objectives
The exploratory objectives of this study are:

 

 
 
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, multicenter, double-blind study to evaluate the efficacy, safety and 
tolerability of OBS treatment administered twice daily (qAM, pc, and hs) for 36 weeks. The 
study will be conducted in adolescents and adults, aged 11-55 years, inclusive, with EoE and 
dysphagia who completed the SHP621-301 induction study.
Approximately 200 subjects (88%) who were randomized in the SHP621-301 study are 
estimated to complete the SHP621-301 study and will be enrolled in this treatment extension 
study based on enrollment observed in the Phase 2 study (MPI 101-06). Randomization into 
the randomized withdrawal period will be stratified by treatment assignment and treatment 
response in the SHP621-301 study. Subjects who are full responders (defined as ≤6 eos/HPF
across all available esophageal levels and at least a 30% reduction in DSQ at the final 
treatment evaluation visit [Visit 4]) in the SHP621-301 induction study will be eligible to 
enter the randomized withdrawal period to receive either OBS 2 mg twice daily or placebo at 
a 1:1 ratio. The randomization of subjects who are full responders will also be stratified by 
age (adults and adolescents) to ensure approximately equal number of subjects within each 
age group are assigned to the treatment groups.
This study will consist of 3 periods:  4-week screening period, 36-week double-blind 
treatment period, and 4-week safety follow-up (Figure 3-1).
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Figure 3-1:
Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
Subjects will be required to visit the site up to 8 times over up to a 36-week period. Following 
completion of the screening visit, subjects will be evaluated for eligibility and safety at 
Week 0 (Visit 1). Subjects who are eligible and randomized will have efficacy and safety 
assessments at Weeks 4, 8, 12, 16, 20, 28, and 36 (Visits 2-8) and additional safety 
assessments at follow-up at Week 40 (Visit 9). Subjects who fail to meet all eligibility criteria 
at Visits 0 or 1 will be considered screen failures. These subjects will receive a follow-up 
safety phone call 4 weeks after the last dose of investigational product. Subjects cannot be 
rescreened once they have been designated as a screen failure. Subjects who discontinue will 
not be replaced.
The screening period will start when subjects sign informed consent (or assent as applicable 
for subjects <18 years of age; screening visit [Visit 0]) and will be ≤4 weeks in duration. 
During the screening period, assessments from the SHP621-301 final treatment evaluation 
visit (Visit 4) will be used as the Visit 0 screening assessments of the treatment extension 
study. At the screening visit (Visit 0), subjects who are on a PPI must remain on the same 
dose of the PPI throughout the study; if they are not taking a PPI, they must remain off of a 
PPI for the remainder of the study. Eligible subjects will receive investigational product based 
on treatment assignment in SHP621-301 for up to 4 weeks prior to enrollment in the treatment 
extension study. This 4-week screening period is required to allow for blinded treatment 
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response information (reduction in DSQ from baseline and eosinophilic count as determined 
by a central reader) collected during the SHP621-301 final treatment evaluation visit to be 
entered into the interactive web-based response system (IWRS) by the unblinded data team
who is independent from the blinded study team and not involved with the day-to-day conduct 
of the study. Once response information is available, subjects will return for the 
randomization visit (Visit 1) to receive investigational product. Subjects who continue to meet 
eligibility criteria after the screening visit (Visit 0) will enter the 36-week double-blind 
treatment period.
Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 
study (≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ 
at the final treatment evaluation visit) will enter a randomized withdrawal period to receive 
either OBS 2 mg twice daily or placebo at a 1:1 ratio. These subjects will also be stratified by 
age (adults and adolescents). Subjects who were assigned to OBS treatment and did not 
respond or partially responded in the SHP621-301 study will receive OBS 2 mg twice daily. 
Subjects who were assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice 
daily. Subjects, site staff, and study team members will remain blinded to treatment 
assignment and individual subject histology, and individual subject DSQ data from the
SHP621-301 (post randomization) and this extension study until the database locks occurs for
this extension study.  
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily at the next scheduled visit. The criteria for 
relapse is having an eosinophilic count of ≥15 eos/HPF from at least 2 of 3 levels of the 
esophagus, as determined by central reader and having at least 4 days of dysphagia in the 
2-week period prior to the scheduled visit, as determined by the DSQ. The criteria for relapse 
align with the related inclusion criteria for participation in the SHP621-301 study. The 
treatment assignment change will be performed in a blinded manner in IWRS by the 
independent unblinded data team. If both criteria for relapse are not met, the subject will 
remain assigned to placebo. The upper EGD with esophageal biopsies will be repeated at the 
Week 36 visit (Visit 8) or at early termination (ET), to evaluate eosinophil counts. If an 
unscheduled EGD is performed between Week 12 and Week 36, the Week 36 EGD should 
still be performed.
All subjects will have a follow-up phone call 4-weeks post last dose of investigational product
to query for SAEs, AEs, and concomitant treatments.
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al., 2014a) and the fact that as EoE persists, it 
becomes more fibrostenotic in older patients and would not be amenable to anti-inflammatory 
treatment alone (Dellon et al., 2014b). A natural history study demonstrated that for every 
decade of life, the odds of developing the fibrostenotic phenotype of EoE more than doubles 
(Dellon et al., 2014b). By age 55, fibrostenotic EoE occurs in approximately 80% of patients. 
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Fibrostenotic disease is treated with dilatation and is not amenable to anti-inflammatory 
treatment alone. Therefore, budesonide is not expected to be an effective treatment for the 
majority of patients above age 55.
The design of this study combines randomized withdrawal and long-term extension elements 
in a manner that selects appropriate patients for placebo withdrawal and maintains 
double-blinding of subjects in all treatment groups. Only subjects who are full responders to 
OBS 2 mg twice daily in the SHP621-301 induction study (≤6 eos/HPF across all available 
esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation visit 
of SHP621-301), will be eligible for randomized withdrawal. The randomized withdrawal 
period is required to assess maintenance of efficacy in these subjects. The continuation of 
OBS 2 mg twice daily treatment for subjects in SHP621-301 who did not respond or partially 
responded to treatment, will evaluate whether these subjects might respond to OBS 2 mg 
twice daily if their treatment is extended for an additional 36 weeks. This aspect of the study 
is supported by the possibility that the response of EoE to topical corticosteroids may require 
more than 12 weeks of induction treatment. 
As described, the protocol also provides multiple mechanisms for switch from placebo and 
potential study discontinuation of relapsing and nonresponding subjects in order to evaluate 
the effect of reinitiating OBS treatment in these subjects. For subjects who relapse on placebo 
during the randomized withdrawal and who reinitiate treatment with OBS 2 mg twice daily 
(intermittent therapy), separate descriptive analyses for histological data and DSQ endpoints 
will be conducted at each assessment visit, as described in Section 9.8.2. For all subjects, an
esophageal stricture requiring dilation would be considered a treatment failure and result in 
withdrawal of the subject from the study. Subject withdrawal criteria are provided in 
Section 4.5.1.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 44 weeks, 
including the 4-week screening period. Including potential treatment in SHP621-301 and the 
screening period of this study, the maximum total duration of OBS 2 mg twice daily may be 
approximately 52 weeks.
The study will be completed in approximately 36 months.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including 
Visit 8 (Week 36), inclusive of the final treatment evaluation EGD. All subjects will have a 
follow-up phone call 4-weeks post last dose of investigational product.
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3.3
Sites and Regions
Approximately 60 sites in North America, the same sites participating in the SHP621-301 
study, will participate in this extension study.
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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject completed SHP621-301 induction study.
2. Subject is able to provide written informed consent (subject, parent or legal guardian and, 
as appropriate, subject assent) to participate in the study before completing any 
study-related procedures. 
3. Subject is male or female aged 11-55 years, inclusive, at time of consent for the 
SHP621-301 study. 
4. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at 
the screening visit (Visit 0). There should be no change to these regimens during study 
participation.
5. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing 
potential must agree to continue acceptable birth control measures (eg, abstinence, stable 
oral contraceptives or double-barrier methods) throughout study participation and for 
30 days following the last dose of investigational product.
6. Subject is willing and has an understanding and ability to fully comply with study 
procedures (completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period) and restrictions defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subject has changes in medications that could affect the study or diet in the weeks since 
the final treatment evaluation visit (Visit 4) of the SHP621-301 study.
2. Subject using immunomodulatory therapy since the final treatment evaluation visit 
(Visit 4) of the SHP621-301 study or anticipated use of immunomodulatory therapy 
during the treatment period (except for any ongoing regimen of allergy shots); any 
temporary use (≤7 days) or initiation of new steroid treatment during the study should be 
documented and discussed with the medical monitor prospectively but cannot occur 
within 4 weeks of scheduled EGDs.
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3. Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated use during the treatment period; any temporary use (≤7 days) or initiation of 
new steroid treatment during the study should be documented and discussed with medical 
monitor prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
4. Subject on inhaled or intranasal steroids and not on a stable dose between the baseline 
visit (Visit 1) of the SHP621-301 study and the screening EGD of this study.
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, antihistamines, or leukotriene inhibitors for any condition (such as 
gastroesophageal reflux disease, asthma or allergic rhinitis) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or anticipated changes in the use of 
such medications during the treatment period.
6. Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since 
the final treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of 
such medications during the treatment period.
7. Subject has an appearance on screening EGD of an esophageal stricture (high grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9mm). 
8. Subject is on a pure liquid diet or the six-food elimination diet.
9. Subject has presence of esophageal varices at the EGD at the final treatment evaluation 
visit (Visit 4) of the SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including 
eosinophilic gastritis, enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac 
disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including 
hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic 
infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous 
treatment. Diagnosis with oropharyngeal or esophageal candidiasis at or since the final 
treatment evaluation visit (Visit 4) of the SHP621-301 study is not an exclusion as long as 
the subject is expected to respond to candidiasis treatment.
13. Subject has acute or chronic infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, or chicken 
pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or since the final treatment evaluation 
visit (Visit 4) of the SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
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16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) 
of the SHP621-301 study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to 
budesonide (or any other corticosteroids), or to any other ingredients of the study 
medication.
19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No changes in medications or diet since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.

Temporary use (≤7 days) or initiation of new steroid treatment is permitted but cannot 
occur within the 4 weeks of the scheduled EGDs.

Stable treatment with intranasal or inhaled corticosteroids. For subjects with perennial 
allergic rhinitis and stable asthma, the topical corticosteroid must be maintained at the 
same dose throughout the study.  For subjects with seasonal allergic rhinitis, it is 
permissible after enrollment to resume (or discontinue) intranasal corticosteroids based on 
the subject's usual treatment regimen for allergy season.  (In these subjects, intranasal 
corticosteroids must not be changed between the baseline visit [Visit 1] of the 
SHP621-301 study and the screening EGD of this study). Topical corticosteroid dosing 
changes should be avoided within 4 weeks prior to EGD. Subjects who require a change 
in inhaled corticosteroid treatment for an asthma exacerbation should be discussed with 
the medical monitor.

No change in use of PPIs, H2 antagonists, antacids, antihistamines, or leukotriene 
inhibitors for any condition (such as gastroesophageal reflux disease, asthma or allergic 
rhinitis).

No use of cytochrome P450 3A4 (CYP450 3A4) inhibitors (eg, ketoconazole, grapefruit 
juice, see details in Section 5.2.2).

No use of sucralfate during the study as this may interfere with the adherence of OBS.
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit 0), randomization
visit (Visit 1), and Visits 2-8. A serum pregnancy test will be performed at the screening visit
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(Visit 0) and final treatment evaluation (Visit 8). Urine pregnancy tests will be performed at 
all other visits.
Female subjects should be either:

Premenarchal and Tanner Stage 1, or

Post menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone 1 of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post sterilization, or

Females of childbearing potential must agree to use acceptable methods of contraception
throughout the study period and for 30 days following the last dose of investigational 
product.

Acceptable methods of contraception are:

Abstinence

Stable oral contraceptives

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or 
foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), 
stabilized for at least 30 days prior to the screening visit (Visit 0), plus condoms. If 
hormonal contraceptives are used, they should be administered according to the 
package insert. Note: If subjects become sexually active during the study, they should 
use 1 of the other acceptable methods noted above in addition to the hormonal 
contraceptive until it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 8 are to be performed as completely as 
possible. If investigational product is discontinued due to an AE, the subject may remain on 
study to allow for completion of study procedures. 
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Whenever possible, all discontinued subjects should also undergo the protocol-specified 
follow-up (Schedule of Assessments, Table 1-1). Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
termination, date of stopping investigational product, and total amount of investigational 
product taken must be recorded in the case report form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
an esophageal stricture requiring dilation and/or worsening signs and symptoms of EoE (eg, 
weight loss or increased dysphagia), would be considered a relapse and result in withdrawal 
of the subject from the study. Subjects with oropharyngeal or esophageal candidiasis that has 
failed to respond to treatment by the Week 12 EGD or upper GI bleeding at the Week 12 
EGD will be withdrawn from the study. 
4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF. If a subject is withdrawn for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Completed

Death

AE

Noncompliance with study drug

Noncompliance with study procedure

Withdrawal by subject

Withdrawal by parent/guardian

Physician decision

Study terminated by sponsor

Site terminated by sponsor

Lost to follow-up

Pregnancy

Study screen failure
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
Protocol deviation

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.5.4
Safety-related Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the 
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar MedDRA higher level group code), 
and considered related to the study drug
The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) physician and the PVRM 
therapeutic area (TA) Head. The PVRM TA Head, not the PVRM physician involved in the 
study, may be unblinded as part of this urgent safety review, if required. Following the 
sponsor’s review of safety data, one of the following actions will be taken with respect to 
study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment
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5.
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, and nonpharmacological treatment, such as psychotherapy, as appropriate) received 
at the screening visit (Visit 0) and through the final study contact (including protocol-defined 
follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment, including but not limited to herbal treatments, vitamins, 
and nonpharmacological treatment such as psychotherapy, as appropriate, received at the
screening visit (Visit 0). Prior treatment information must be recorded on the appropriate CRF 
page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in SHP621-302 (Visit 1) and the end of the follow-up period, 
inclusive. Concomitant treatment information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the 
prescribed medication is not prohibited by the protocol. In the event of an emergency, any 
needed medications may be prescribed without prior approval, but the medical monitor must 
be notified of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been 
on a stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
scheduled EGDs) and will continue this dosing regimen throughout study participation. The 
investigator must contact the medical monitor to discuss any changes to concomitant steroid 
regimens or for any medications not listed here that could impact the outcome of the study.
1. Inhaled or intranasal steroids (exception for seasonal allergic rhinitis, see Section 4.3)
2. PPIs
3. H2 antagonists
4. Antacids
5. Antihistamines
6. Leukotriene inhibitors
7. Maintenance immunotherapy (allergy shots)
Influenza and other routine required vaccinations are allowed during the study.
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5.2.2
Prohibited Treatment
The following medications and treatments are prohibited throughout the course of the study 
and prior to treatment, as specified:
1. Immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study or use within the 4 weeks of scheduled EGDs. Any temporary use 
(≤7 days) or initiation of new corticosteroid treatment during the study should be 
documented and discussed with the medical monitor prospectively. (Seasonal nasal 
corticosteroid use for seasonal allergic rhinitis is permitted; changes within 4 weeks of 
scheduled EGD should be avoided).
2. Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition 
since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or use within 
the 4 weeks of scheduled EGDs. Any temporary use (≤7 days) or initiation of new steroid 
treatment during the study should be documented and discussed with the medical monitor 
prospectively.
3. Initiation or change in dosing frequency to PPIs, H2 antagonists, antacids, antihistamines, 
or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma, or allergic rhinitis) since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study, or anticipated use of such medications during the treatment period.
4. CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study, or anticipated changes in the use of 
such medications during the treatment period. For an expanded list of CYP3A inhibitors, 
investigators should refer to the 2012 FDA Draft Guidance on Drug Interactions (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
5. Sucralfate at screening or anticipated to be used during the treatment period.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in
8 ounce amber glass, multidose bottles. Additional information is provided in the current 
SHP621 investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle
form with the same volume.
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in 8 ounce amber glass, multidose bottles with 
child-resistant caps and refrigerated throughout the study (in the clinic and subject’s home).
Each bottle contains OBS concentration of 0.2 mg/mL. Inactive ingredients in OBS include 
dextrose, disodium edetate, citric acid, sodium citrate, potassium sorbate, polysorbate 80, 
glycerin, sodium benzoate, cherry flavor, Magnasweet 110, acesulfame potassium, and water.
The placebo suspension will also be supplied in 8 ounce amber glass multidose bottles with 
child-resistant caps. Placebo consists of all components of the investigational product with the 
exception of budesonide.
6.2
Administration of Investigational Product(s)
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last 
until the subsequent visit. The first dose of investigational product for each subject will be 
administered in the clinic. The subject will continue with the evening dosing regimen at 
home. 
Oral budesonide suspension and placebo will be supplied in amber glass bottles and must be 
shaken well prior to administration. OBS and placebo should be refrigerated at 2-8ºC 
(36-46ºF) throughout the study (in the clinic and subject’s home). The appropriate dose will 
be dispensed using the graduated dosing spoon provided. For subjects who are minors 
(<18 years), a parent/guardian will be responsible for ensuring that the subjects take their 
investigational product appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during 
this time interval. After 30 minutes, subjects will be instructed to rinse with water and spit, 
particularly after the bedtime dose.
Please refer to the investigational product Administration Manual for additional details.
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6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation 
and management, inventory management and supply ordering, investigational product 
expiration tracking and management, return of investigational product, and emergency 
unmasking. Please refer to the Study Manual for additional details regarding the IWRS.
During the 4-week screening period, blinded treatment response information (reduction in 
DSQ from baseline and eosinophilic count as determined by a central reader) collected during 
the SHP621-301 final treatment evaluation visit will be entered into the IWRS by an 
independent, unblinded data team. Details on the unblinded data team will be provided in a 
separate charter. Once information is available, subjects will return for the randomization visit 
(Visit 1) to be assigned to investigational product (OBS 2 mg twice daily or placebo). While 
only SHP621-301 OBS 2 mg twice daily responders will be randomized to continued OBS 2 
mg twice daily or placebo, all subjects will be assigned to investigational product via IWRS to 
maintain double-blinding of subjects, investigators, the blinded monitoring team and the 
sponsor (ie, sham randomization).
At the randomization visit (Visit 1), the investigator or designee will access the IWRS to 
either document a screen failure or, if the subject has met all entry criteria, to randomize the 
subject. Sites will enter eligibility criteria information prior to randomization. For randomized 
subjects, the IWRS will provide a medication identification (Med ID) number (ie, kit number 
to dispense for treatment).  
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be 
provided to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a 4-week screening period and a double-blind treatment period. The 
actual treatment given to individual subjects during the double-blind treatment period will be 
determined by the blinded treatment response information entered at the SHP621-301 final 
treatment evaluation visit.
Subjects will be randomized via a computer-generated randomization schedule at the 
randomization visit (Visit 1) following a 4-week screening period and confirmation of study 
eligibility. Subjects who fully responded to OBS treatment in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the 
final treatment evaluation visit) will enter a randomized withdrawal period to receive either 
OBS 2 mg twice daily or placebo at a 1:1 ratio. Subjects who did not respond or partially 
responded to OBS treatment in the SHP621-301 study will receive OBS 2 mg twice daily. 
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Subjects who were assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice 
daily. Subjects, site staff, and study team members will remain blinded to treatment 
assignment and individual subject histology and individual subject DSQ data from the 
SHP621-301 study (post randomization) and until database lock occurs for this extension 
study.  
Randomization of subjects in the randomized withdrawal period will also be stratified by age 
(adults and adolescents) to ensure approximately equal number of subjects within each age 
group are assigned to the treatment groups.
Subject numbers are assigned to all subjects as they consent to take part in the study. The 
subject number consists of the 3 digit study identifier, the 4 digit site identifier, and the 4 digit 
subject identifier. For the SHP621-302 study, the 3 digit site and 4 digit subject numbers will 
be the same as the SHP621-301 study.
The randomization number represents a unique number corresponding to investigational 
product allocated to the subject once eligibility has been determined at the randomization 
visit.  
Individual subject treatment is automatically assigned by the IWRS.
6.2.3
Dosing
During the 4-week screening period, all subjects will receive 10 mL of blinded investigational 
product twice daily based on treatment assignment in SHP621-301. During the 36-week 
double-blind treatment period, oral administration of 10 mL of investigational product will 
occur twice daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 
30 minutes after study drug administration. Subjects randomized to OBS will receive 10 mL 
of 0.2 mg/mL of OBS (2 mg) twice daily for a total daily dose of 4 mg.
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily. The criteria for relapse is having an eosinophil 
count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined by a central 
reader, and having at least 4 days of dysphagia in the 2-week period prior to the scheduled 
visit, as determined by the DSQ. At least 8 daily diary entries must be completed over 14 
consecutive days in order to determine the criterion for relapse. If fewer than 8 diary entries 
are reported within the 2-week period, the DSQ window can be expanded as described in 
Section 7.2.1.2. The criteria for relapse align with the related inclusion criteria for 
participation in the SHP621-301 study. The treatment assignment change will be performed in 
a blinded manner in IWRS by the independent, unblinded data team. If both criteria for 
relapse are not met, the subject will remain assigned to placebo.
If at any time the subject reports increased or worsening dysphagia symptoms to the 
investigator, the investigator may choose to perform an unscheduled EGD.  If an unscheduled 
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EGD is performed prior to Week 12, an EGD does not have to be repeated at Week 12.  The 
independent, unblinded data team will review the blinded EGD and DSQ data to confirm the 
subject is on placebo in the randomized withdrawal period, determine if the subject meets 
relapse criteria, and change the subject’s treatment assignment to OBS 2 mg twice daily if 
relapse is confirmed.
If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 
levels of the esophagus yet relapse is not confirmed due to the criterion for dysphagia 
symptoms not being met, the subject will remain assigned to placebo.  If the criterion for 
dysphagia symptoms is met at a subsequent visit and both criteria for relapse are then 
confirmed, the subject’s treatment assignment will be changed to OBS 2 mg twice daily at the 
next scheduled visit. 
Investigational product doses that are required to be administered at the clinic include the first 
dose of randomized investigational product (OBS or placebo) administered at the 
randomization visit (Visit 1) and all morning doses of investigational product administered at 
Visits 2-8. Subjects will be required to eat breakfast at the clinic prior to self-administering 
these doses. Subjects can self-administer all other doses of placebo and investigational 
product at home. 
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor and the sponsor as soon as 
possible after the investigator has been unblinded.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
There will be a provision for unblinding to ensure adequate treatment of the subject in the 
case of an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
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All investigational product is labeled with a minimum of the protocol number, Med ID, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the 
statements “For clinical study use only” and/or “CAUTION: New Drug - Limited by Federal 
(or US) Law to Investigational Use,” “Keep out of reach of children,” and the sponsor’s name 
and address. Any additional labeling requirements for participating countries and/or 
controlled substances will also be included on the label.
Space is allocated on the label so that the site representative can record subject information. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8 ounce amber glass bottle for multiple use. Bottles of OBS 
0.2 mg/mL or placebo will be packaged in an appropriately labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement 
in advance by the sponsor.
6.3.3
Storages
The investigator has overall responsibility for ensuring that investigational product is stored in 
a secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  
OBS and placebo must be refrigerated at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
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Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be 
notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the investigational product and 
will provide supportive documentation as necessary. Under no circumstances should the 
product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be stored under refrigeration at 2-8°C/36-46°F at all times.
The investigational product should be protected from light and shaken well immediately prior 
to each dose.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational 
product. Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) 
who is adequately trained in the protocol and who works under the direct supervision of the 
investigator. This delegation must be documented in the applicable study delegation of 
authority form.
The investigator or his/her designee (as documented by the investigator in the applicable 
study delegation of authority form) will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will 
be given only the investigational product carrying his/her treatment assignment. All dispensed 
medication will be documented on the CRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects. The 
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investigator or his/her designee will enter the unique subject identifier and initials on the 
investigational product kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and 
the sponsor (or designated CRO). For unused supplies where the original supplied 
tamper-evident feature is verified as intact, the tamper-evident feature must not be broken,
and the labeled amount is to be documented in lieu of counting. Shipment return forms, when 
used, must be signed prior to shipment from the site. Validated electronic return systems (ie,
IWRS) do not require a shipment form. Returned investigational product must be packed in a 
tamper-evident manner to ensure product integrity. Contact the sponsor for authorization to 
return any investigational product prior to shipment. Shipment of all returned investigational 
product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational 
product packaging to every visit.
Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container (eg, bottles) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel.
Site personnel must review the returned investigational product to assess compliance at every 
visit prior to dispensing additional investigational product. Any discrepancies should be 
reconciled with the subject immediately. Subjects who do not return their used and unused 
investigational product should be reminded to bring all used and unused investigational 
product at their next visit.
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Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. Please 
refer to the Pharmacy Manual for additional details.
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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined 
in the Schedule of Assessments (Table 1-1) and must be referred to in conjunction with the 
instructions provided in this section. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). There must be documentation of consent (as per local requirements) 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions, prior to performing any study-related procedures.
7.1.1
Screening Period (Weeks -4 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise up to 4 weeks, during which all procedures listed for the screening visit (Visit 0) in 
Table 1-1 shall be completed. The screening period will allow for the determination of 
eligibility of each subject’s inclusion into the study. A subject should not be instructed to 
discontinue use of any medication or treatment to participate in this study until informed 
consent has been obtained. Subjects should not stop permitted medications or treatments that 
are effective and well tolerated to participate in this study (Section 5.2.1).
Assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as 
the screening assessments (Visit 0) of this treatment extension study. Screening assessments 
may take place across several days to allow an appropriate time frame in which to complete 
all procedures and confirm study eligibility. At the SHP621-301 final treatment evaluation 
visit, subjects will be dispensed blinded investigational product (based on treatment 
assignment in SHP621-301) that will last for up to 4 weeks prior to enrolling into this 
treatment extension study. The 4-week screening period is required to allow for blinded 
treatment response information (reduction in DSQ from baseline and eosinophilic count as 
determined by a central reader) collected during the SHP621-301 final treatment evaluation 
visit to be entered into the IWRS by the independent, unblinded data team.
After the screening period, subjects who meet eligibility criteria at the end of the screening 
visit (Visit 0) will enter the 36-week double-blind treatment period. This period should not 
commence until all screening assessments required to confirm initial eligibility have been 
completed. If the subject does not meet eligibility criteria following completion of screening 
assessments, the investigator or designee will document the subject as a screen failure in the 
IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening or 
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randomized visits. Subjects cannot be rescreened once they have been designated as a screen 
failure.
7.1.1.1
Screening Visit (Visit 0) / Visit 4 of SHP621-301 Study
The screening visit (Visit 0) assessments and procedures, beginning with informed consent, 
will be performed as outlined in Table 1-1.
The following procedures will be performed at the screening visit:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review current use of concomitant medications and procedures. Note: Subjects who are 
on a PPI must remain on the same dose of the PPI throughout the study, and if they are not 
taking a PPI, they must remain off of a PPI for the remainder of the study.

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly 
completion and train the subject on its use. 
The following procedures will be performed at the final treatment evaluation visit (Visit 4) of 
SHP621-301 and will be used as the screening assessments for this extension study:

Review investigational product dosing compliance.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight. Perform stadiometry in subjects aged
11-17 years, inclusive. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of 
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing.

 
 
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
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging 
Assessment.

Serum pregnancy test will be performed on all female subjects. 

Perform EGD and biopsy either at the investigative site or by a referring physician. 
Esophagogastroduodenoscopy should be completed at or within 7 days of the scheduled 
visit. Biopsy specimens must be available to be sent to the central pathology lab at least 
2 weeks prior to Visit 1 to allow sufficient time for processing and central review and 
determination of eligibility.

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD)
and body composition measurements in subjects aged 11-17 years, inclusive. Baseline and 
post treatment DXA scans should be performed using the same machine and software.

Dispense blinded investigational product (OBS or placebo; based on treatment assignment 
in SHP621-301) and review administration instructions. The subject will continue with the 
twice daily (morning and evening) dosing regimen. For subjects who are minors 
(<18 years), a parent/guardian will be responsible for ensuring subject takes their 
investigational product appropriately.
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28 and 36
(or Early Termination)
The double-blind treatment period will comprise 36 weeks, during which all assessments and 
procedures listed for Visits 1-8 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted between Visits 1-6 (Weeks 0-20) 
and a 6-day visit window will be permitted between Visits 7-8 (Weeks 28-36), unless 
otherwise specified. Visit windows are calculated based upon the date of the randomization 
visit (Visit 1).
Once information for blinded treatment response is available, subjects will return for the 
randomization visit (Visit 1) to receive investigational product. Subjects who continue to meet 
all eligibility criteria and complete the 4-week screening period will have the opportunity to 
enroll in the treatment extension study. Subjects will receive either OBS twice daily (qAM, 
pc, and hs) or placebo twice daily (qAM, pc, and hs).
Subjects who fully responded to OBS treatment in the SHP621-301 study (≤6 eos/HPF across 
all available esophageal levels and at least a 30% reduction in DSQ at the final treatment 
evaluation visit) will enter a randomized withdrawal period to receive either OBS 2 mg twice 
daily or placebo at a 1:1 ratio. Subjects who did not respond or partially responded to OBS 
treatment in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were 
assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily. The 
investigator or assigned site staff will access the IWRS to randomize the subject and dispense 
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the investigational product. Subjects who fail to meet eligibility criteria at the randomization 
visit (Visit 1) will be documented as screen failures in the IWRS and discontinue study drug.
A safety follow-up contact by phone will be performed 4 weeks following the last dose of 
study medication for all subjects (including subjects who fail screening, who discontinue 
early, or who complete the study).
7.1.2.1
Randomization Visit (Visit 1): Week 0
Subjects will return to the site for the randomization visit (Visit 1) to confirm eligibility. The 
randomization visit (Visit 1) assessments and procedures will be performed as outlined in 
Table 1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight. Vital signs will be assessed after the subject has 
been in a supine position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review investigational product dosing compliance.

Review DSQ compliance; provide subject with instruction to continue completion of the 
DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will 
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record the date and time of the first randomized dose in the source documents. Beginning 
on the evening of Visit 1, the subject will take their first dose at home and continue with 
the twice daily (morning and evening) dosing regimen. For subjects who are minors 
(<18 years), a parent/guardian will be responsible for ensuring subject takes their 
investigational product appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.2
Visits 2 and 3 (Weeks 4 and 8)
Subjects will return to the site for Visit 2 (Week 4) and Visit 3 (Week 8). Assessments at 
these visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight. Vital signs will be assessed after the subject has 
been in a supine position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of study medication until after the morning cortisol test has 
been performed. 
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.

 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) and review investigational product 
dosing compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
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7.1.2.3
Visit 4 (Week 12)
Subjects will return to the site for Visit 4 (Week 12). Assessments at this visit will be 
performed as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), and weight. Vital signs will be assessed after the subject 
has been in a supine position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects.

Dispense investigational product (OBS or placebo) and review investigational product 
dosing compliance.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. In addition, an earlier EGD may also occur if the subject exhibits signs of relapse 
(Section 6.2.3).  
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28)
Subjects will return to the site for Visits 5, 6, and 7 (Weeks 16, 20, and 28). Assessments at 
these visits will be performed as outlined in Table 1-1.
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The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight. Vital signs will be assessed after the subject has 
been in a supine position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of study medication until after the morning cortisol test has 
been performed. 
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) and review investigational product 
dosing compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.5
Visit 8 (Week 36) or Early Termination
Subjects will return to the site for Visit 8 (Week 36). Assessments at this visit will be 
performed as outlined in Table 1-1. If a subject discontinues prematurely, the assessments for 
Visit 8 are to be performed as completely as possible.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight. Perform stadiometry in subjects aged 
11-17 years, inclusive. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
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excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review current use of concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection. Any subject with an abnormal 
urinary or serum glucose level will be followed closely until resolution (Section 7.2.2.5).

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of 
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing. Any subject 
with an abnormal ACTH stimulation test will be followed closely until resolution 
(Section 7.2.2.5).
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Retrieve DSQ handset and review DSQ compliance.
 
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging 
Assessment.

Serum pregnancy test will be performed on all female subjects.

Perform DXA scan for BMD and body composition measurements in subjects aged 
11-17 years, inclusive. Dual-energy X-ray absorptiometry scans should be performed at 
this visit or within 7 days of the scheduled visit using the same machine and software as 
used in the SHP621-301 study.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. An earlier EGD may occur if the subject exhibits signs of relapse (Section 6.2.3); 
however, the Week 36 EGD must be completed.

Review investigational product dosing compliance.
7.1.3
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational 
product. Subjects will receive a follow-up phone call at Visit 9 (Week 40) to query for SAEs, 
AEs, and concomitant treatments (Section 7.1.3.1).
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7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40
Assessments at this time, as outlined in Table 1-1, will include the following:

Review concomitant medications and procedures.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE; all AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in 
Appendix 1.
All assessments listed below will be performed by the subject and/or a qualified/trained site 
staff as indicated in the assessment description. For subject-completed assessments, trained 
site staff should not assist the subject in completing any of the questions as this can influence 
their responses. Site staff should review the completed assessment to ensure completeness.
If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales 
after the visit has been completed. Assessments are to be performed according to the schedule 
shown in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and Histopathologic 
Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
The screening EGD with biopsies will be performed by a physician at the investigative site at 
the final treatment evaluation visit in the SHP621-301 study. Biopsy specimens must be taken 
and provided to the central pathology lab by at least 2 weeks prior to the planned Visit 1 to 
allow sufficient time for processing and central review and determination of eligibility. The 
independent unblinded data team will receive data from the central reader and will use it to 
confirm whether the subject meets the eligibility criteria for this study. Subjects, site staff, and 
study team members will remain blinded to eosinophil counts and histopathologic findings by 
the central reader throughout the duration of the study.
At the Week 12 visit (Visit 4), and Week 36 visit (Visit 8) or at early termination (ET), an 
EGD with esophageal biopsies is required for all subjects. If at any time, the subject reports 
increased or worsening dysphagia symptoms to the investigator, the investigator may choose
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to perform an unscheduled EGD. If an unscheduled EGD is performed prior to Week 12, an 
EGD does not have to be repeated at Week 12. If an unscheduled EGD is performed between 
Week 12 and Week 36, the Week 36 EGD should still be performed. Multiple specimens (at 
least 2 biopsies from each of 3 levels, 6 specimens total) will be obtained from the proximal 
(3 cm below the cricopharyngeus muscle), midesophagus (midpoint between the 
cricopharyngeus muscle and the gastroesophageal junction), and distal (3 cm above the 
gastroesophageal junction). Biopsy tissue will be placed in 3 separate vials (1 vial for each of 
the levels) and sent to the central pathology laboratory for processing of tissue into slides. 
Eosinophil counts and, histopathologic features will be evaluated by the central reader and
scored for each EGD. Eight histopathologic epithelial features (basal layer hyperplasia, 
eosinophil density, eosinophil microabscesses,
eosinophil surface layering, dilated 
intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, lamina propria 
fibrosis) will be scored on a 4-point scale (0=normal, 3=worst) for both the severity of the 
abnormality (ie, grade) and the amount of tissue affected by the abnormality (ie, stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 
2) fixed esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed 
for each anatomic location (proximal and distal). The maximum endoscopy score is 10 points 
for each location, and a total endoscopy score is the sum of the scores for the proximal and 
distal locations.
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. At the investigator’s discretion, biopsies will be taken from the stomach and 
duodenum as follows: gastric body (greater curvature): 2 specimens, gastric antrum: 
2 specimens, and duodenum (third part or distal): 2 specimens. Biopsies from the stomach 
should be submitted in 1 vial; biopsies from the duodenum should be submitted in a separate 
vial to the central pathology laboratory for processing of tissue into slides. 
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 2). 
The questionnaire will be completed by subjects daily during the screening period and during 
the 36-week treatment period. Each evening before bedtime, subjects will be asked to indicate 
if they experienced dysphagia symptoms (eg, food passing slowly or food sticking) during 
that day. Subjects must fill out the DSQ at least 5 or more days during a given week in order 
to be compliant. Visit to visit compliance of DSQ completion will also be assessed by site 
personnel. Protocol deviations will be documented for subjects who fail to complete the DSQ 
for 3 or more days in a given week.
To meet relapse criteria, the subject must have at least 4 days of dysphagia as determined by 
the DSQ in the 2-week period prior to the scheduled visit in addition to meeting the 
eosinophil histology criterion (≥15 eos/HPF from at least 2 of 3 levels of the esophagus). At 
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least 8 daily diary entries must be completed over 14 consecutive days in order to determine 
the criterion for relapse. If fewer than 8 diary entries are reported within the 2-week period, 
then the 2-week period will be shifted backwards from the scheduled visit to include the most 
recent 2-week period with at least 8 diary entries over 14 consecutive days; however, the 
2-week period will not be shifted by more than 2 weeks (ie, no more than 2-week period plus 
additional 2-week additional expansion).
Calculations will be performed on daily ePRO entries during a 2-week interval prior to each 
study visit during the treatment period. The DSQ score for the coprimary endpoint and 
secondary endpoints will be calculated by summing the scores of responses to questions 2 and 
3 only. Questions 1 and 4 will be excluded from the DSQ score:

DSQ score =   (Sum of points from questions 2+3 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores 
of responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score = (Sum of points from questions 2+3+4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score = (Sum of points from question 4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
Medical History
The investigator must record all new clinically or medically relevant information which arose 
after the recording of the medical history in the antecedent study. New medical history will be 
collected at the screening visit (Visit 0) of this study. Medical history will be classified as EoE
or non-EoE by the investigator. Adverse events recorded during the SHP621-301 study may 
be added as medical history at the investigator’s discretion.
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Medication History
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, 
or other), must be recorded on the appropriate CRF page.
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit 0) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit 0)
will be captured as AEs on the AE CRF page, as deemed by the investigator.
Physical examination assessments at each visit should also include specific assessments for 
signs of glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swings, insomnia, and 
depression). Physical examination at the screening visit (Visit 0) will also include Tanner 
Staging Assessments for subjects <18 years of age.
Height will be collected at the screening visit (Visit 0) and Visit 8 for all subjects. 
Stadiometers will be used to measure height for subjects aged 11-17 years, inclusive. Statural 
height will be measured by trained site staff using a stabilized stadiometer. The same 
stadiometer should be used for the baseline and post treatment measurements. Standard 
measuring procedures should be followed (eg, removal of socks, shoes, and hats). The 
stadiometer must be calibrated at least once daily, and as feasible, within 4 hours of each 
measurement. All measurements should be recorded to the nearest 10th of a centimeter
(1 mm). Please refer to the study manual for additional details.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). AEs are collected from the time informed consent is signed. (Please refer to 
Section 8.) Any AE that is ongoing from the SHP621-301 study must be recorded on the CRF 
for this study. 
AE assessments at each visit should also include specific assessments for signs of 
glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and 
depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes 
immediately prior to the assessment and will include blood pressure (systolic and diastolic), 
heart rate, respirations, and temperature. Blood pressure should be determined by cuff (using 
the same method, the same arm, and in the same position throughout the study). Any 
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clinically significant deviations from baseline in vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. All subjects must fast overnight prior to collection of clinical laboratory tests.
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose 

blood urea nitrogen 

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

bilirubin

ketones

hemoglobin
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
pH

nitrite

urobilinogen

leukocyte esterase
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
Adrenocorticotropic hormone stimulation testing will be performed by measuring the levels of 
cortisol in the blood following the injection of a synthetic form of ACTH. The type of 
synthetic and route of administration will be per local lab discretion. Blood samples will be 
collected just prior to and approximately 30 and 60 minutes following the injection. 
Administration of ACTH stimulation testing and sample collection should follow the same 
procedures used in the SHP621-301 study.
In the event of clinically significant abnormal laboratory test results, follow-up laboratory 
tests may be conducted. All subjects with an abnormal ACTH stimulation test or urinary or 
serum glucose level must be followed closely until resolution. For subjects who discontinue 
from the treatment period at any time and have an abnormal ACTH stimulation test at the 
early termination visit, subjects will be scheduled for repeat testing approximately 6 weeks 
post last dose of investigational product to ensure that ACTH levels have normalized.  Any 
clinically significant abnormalities noted in the laboratory tests will be discussed with the 
medical monitor.
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit
(Visit 0) and the final treatment evaluation visit (Visit 8) or ET visit. A urine pregnancy test is 
performed on all female subjects at all other visits or if pregnancy is suspected.
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density
Dual-energy X-ray absorptiometry (also referred to as DEXA) scans for determination of 
BMD and body composition measurements will be performed in subjects aged 11-17 years, 
inclusive, as outlined in Table 1-1.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body 
less head (Bachrach, 2011; Gordon et al., 2008; International Society for Clinical 
Densitometry, 2013). Dual-energy X-ray absorptiometry body composition measurements 
will also be collected. The same DXA machine and software should be used for the baseline 
and post treatment scans. The DXA manufacturer, model, and software version should be 
recorded in the CRF.
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7.2.3
Other Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2.4
Volume of Blood to Be Drawn from Each Subject
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Safety
Biochemistry and -hCGa
6
9
54
ACTH
2
4
8
Cortisol
2
9
18
Hematology
2
9
18
Total mL
-
-
98
Abbreviations: ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropina -hCG testing 
is for females only.
During this study, it is expected that approximately 98 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of 
blood to be drawn may vary according to the instructions provided by the manufacturer or 
laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 98 mL. When more than 1 blood assessment is to be done 
at the time point/period, if they require the same type of tube, the assessments may be 
combined.  
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH Guidance E2A 1995).  
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening period of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pretreatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to dosing of investigational product, but the dyspepsia becomes severe and 
more frequent after first dose of investigational product has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate CRF).
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The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention.  
The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product 
for each AE. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for 
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related” based on the definitions 
in Table 8-1. The causality assessment must be documented in the source document.
Table 8-1: Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent 
disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or 
other drugs and chemicals and which follows a clinically reasonable response on 
dechallenge. The association of the clinical event or laboratory abnormality must 
also have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (dechallenge), and reappears upon 
repeated exposure (rechallenge). Note that this is not to be construed as requiring 
reexposure of the patient to study drug; however, the determination of definitely 
related can only be used when recurrence of event is observed.
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8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign assessment can represent an AE if 
the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening 
of an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing 
treatment or after the end of treatment with the investigational product, and the range of 
variation of the respective parameter within its reference range, must be taken into 
consideration.
If, at the end of the treatment period, there are abnormal clinical laboratory or vital sign 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign parameter is clinically 
significant and therefore represents an AE.
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8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
the Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event 
Form for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is 
not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)
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
Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of 4 mg of the product.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parents/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO medical monitor within 
24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (Section 
8.1.7) unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form 
for SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 
Pharmacovigilance and Risk Management Department. A copy of the Shire Clinical Study 
Adverse Event Form for SAEs and Non-serious AEs as Required by Protocol (and any 
applicable follow-up reports) must also be sent to the CRO medical monitor using the details
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

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 was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should 
not be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be 
reported to the Shire Global Pharmacovigilance and Risk Management Department and the 
medical monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Global Pharmacovigilance and Risk Management Department within 24 hours of the first 
awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
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resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, leading up to the onset date of the SAE, or following the resolution date of the 
SAE must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have “fatal” checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered as not resolved, without a resolution date 
recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, 
unless another investigational product action was previously taken (eg, drug interrupted, 
reduced, withdrawn), the action taken with the investigational product should be recorded as 
“dose not changed” or “not applicable” (if the subject never received investigational product). 
The investigational product action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and the clinical CRO are responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP621
program.  
The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy.
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability 
data) will be handled with special care during the data cleaning and review process. These 
data will be handled in such a way that, prior to unblinding, any data that may unblind study 
team personnel will be presented as blinded information or otherwise will not be made 
available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be 
performed using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
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SAP will also include a description of how missing, unused and spurious data will be 
addressed.
The SAP will be finalized prior to final database lock and performing analysis (ie, unblinding)
to preserve the integrity of the statistical analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis is planned.
9.6
Sample Size Calculation and Power Considerations
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are 
estimated to complete the SHP621-301 study and enroll in this treatment extension study 
based on enrollment observed in the Phase 2 study (MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse 
during the double-blind randomized withdrawal period, defined as having an eosinophil count 
of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus (as determined by a central 
reader) and at least 4 days of dysphagia in the 2-week period prior to the scheduled visit (as 
determined by the DSQ). To be considered as a subject with relapse, both criteria must be 
met. To determine whether a subject meets the criterion for dysphagia, at least 8 daily diary 
entries must be completed over 14 consecutive days, as described in Section 7.2.1.2.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or 
approximately 40 subjects, who were assigned to OBS treatment in the SHP621-301 study are 
anticipated to respond fully after 12 weeks in the SHP621-301 study. For this study, to detect 
a 50 percentage point difference between relapse proportions of 20% and 70% in the OBS and 
placebo groups, respectively, at 80% power and a significance level of 0.05 (two-sided) using 
a Chi-Square test with equal allocation to treatment groups, it is necessary to assess the 
primary efficacy measure for approximately 38 subjects (19 subjects in each of the OBS and 
placebo groups).  
9.7
Study Population
The safety set will include all subjects who are randomized and receive at least 1 dose of 
investigational product.
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose 
of investigational product and had 1 post baseline efficacy assessment (biopsy and/or DSQ 
score).
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The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major 
protocol deviations. The PP set will be identified prior to unblinding the treatment 
assignments by a team consisting of, at a minimum, a physician and a statistician from Shire. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized 
withdrawal period. Relapse, a binary response (either with a relapse or not), is defined as 
having an eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as 
determined by a central reader, and having at least 4 days of dysphagia in the 2-week period 
prior to the scheduled visit, as determined by the DSQ. To determine whether a subject meets 
the criterion for dysphagia, at least 8 daily diary entries must be completed over 14 
consecutive days, as described in Section 7.2.1.2.
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse
during the double-blind randomized withdrawal period for the FAS, using a Chi-Square test 
comparing OBS 2 mg twice daily against placebo. The primary test of treatment effect will be 
two-sided, and conducted at the significance level of 0.05. The proportion of subjects with 
relapse for each treatment group and the corresponding 95% confidence interval (CI) will be 
estimated. In addition, the difference in the proportion of subjects with relapse between the 2
treatment groups and its 95% CI will be estimated.
Subjects who withdraw without providing efficacy data at the ET visit will be classified as 
being relapsers in the primary efficacy analysis. The null hypothesis states that there is no 
difference in relapse proportions between OBS 2 mg twice daily and placebo, with the two-
sided alternative of a nonzero difference between groups. Relapse proportions at each 
adjacent double-blind visit interval will also be assessed by applying the chi-square test to the 
observed data at each double-blind visit.
The following sensitivity and supportive analyses will be performed for the primary endpoint 
to evaluate the robustness of the results from the primary analysis methods.
Similar analyses used for the ITT population will be repeated using the FAS and the PP 
datasets. Sensitivity analyses will be performed using the ITT population by classifying 
subjects who withdraw without providing efficacy data at the ET visit as non-relapsers. In 
addition, the subjects who were prematurely withdrawn from the study without the primary 
efficacy endpoint will be imputed randomly according to the distribution of relapsers with 
available data; and the similar statistical test will be performed using the imputed data.
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9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the long-term treatment response, a binary response
over an extended period of 36 weeks in adolescent and adult subjects who were randomized to 
OBS treatment but did not respond after 12 weeks in the SHP621-301 induction study
(subject did not have peak count of ≤6 eos/HPF across all available esophageal levels at the 
final treatment visit and/or ≥30% reduction in DSQ score from baseline) and met the 
following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline of the SHP621-301 study and from baseline of this 
extension study to the final treatment period evaluation (Visit 8)
The key secondary efficacy endpoint will be analyzed as the proportion of subjects who 
responded based on the histological data and the DSQ data at the final treatment period 
evaluation (Visit 8). The proportion of subjects with long-term treatment response and the 
corresponding 95% confidence interval (CI) will be estimated and summarized. 
The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at each assessment visit

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study 

Change in the DSQ score and change in the peak eosinophilic count at each assessment 
visit from baseline of the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study 

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each 
assessment visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each 
assessment visit 

Change in the peak eosinophil count at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study at each assessment visit for 
each available esophageal level (proximal, mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at 
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each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), at each assessments visit from baseline of the 
SHP621-301 study and from baseline of this extension study

Change in the DSQ combined score (questions 2+3) at each assessment from baseline of 
the SHP621-301 study and from baseline of this extension study 

Cumulative distribution function curves for the change and the percent change in the DSQ 
score at each assessment visit from baseline of the SHP621-301 study and from baseline 
of this extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline 
of the SHP621-301 study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study 
Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the 
change from baseline of the SHP621-301 study and from baseline of this extension study at 
the final treatment period evaluation (Visit 8) will be summarized by each assessment visit.  
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo 
in the SHP621-301 induction study, the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the 
corresponding 95% CI will be summarized. Summary statistics of the DSQ score (questions 
2+3) and the peak eosinophil count and the change from baseline of the SHP621-301 study 
and from baseline of this extension study at the final treatment period evaluation (Visit 8) will 
be summarized by each assessment visit.  
For subjects who relapse on placebo during the randomized withdrawal and who reinitiate 
treatment with OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for 
histological data and DSQ endpoints will be conducted at each assessment visit. Changes will 
be summarized over time from baseline of the SHP621-301 study and from the time of 
relapse. The same criteria for response will be applied to these subjects (≤6 eos/HPF across all 
available esophageal levels and at least a 30% reduction in DSQ from SHP621-301 baseline 
score).
Summary statistics will be provided for all other secondary endpoints.
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9.8.3
Exploratory Efficacy Endpoints
The exploratory endpoints that will be explored are the following:

 
 
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the randomization visit (Visit 1), or at the screening visit (Visit 0) 
if not collected at Visit 1, will be used as the baseline value for safety analyses.
TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product and no later than 3 days following the last dose of investigational product. However, 
for any subjects who die during the study (ie, the date of death is between the date of first 
dose of investigational product and the date of study discontinuation entered by the site, 
inclusive), all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs irrespective of the last dose and will be included in the TEAE 
summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of 
TEAEs will be calculated overall by system organ class, preferred term, and treatment group.
TEAEs will be further summarized by severity and relationship to investigational product. 
AEs related to investigational product, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized/listed.
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight 
and height assessments, DXA scans for BMD and body composition measurements (for 
adolescents aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, 
urinalysis; serum pregnancy test, if appropriate), and ACTH stimulation tests. To account for 
the effects of puberty in adolescent subjects (11-17 years of age, inclusive), BMD z-scores 
will be adjusted for height z-scores using the Bone Mineral Density in Childhood Study 
calculator (Bone Mineral Density in Childhood Study, 2015). Safety parameters will be 
descriptively summarized by treatment group at baseline and for each post baseline visit.
 
 
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third-party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ 
names and contact information.
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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for nonpediatric 
studies as per guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any 
reason. If the study is suspended or terminated, the sponsor will ensure that applicable sites, 
regulatory agencies and
IRBs/ECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical study, which has been posted to a designated public 
website, will be updated accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6 (1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification. Curriculum vitae for investigators and subinvestigators are 
provided to the study sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
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10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The data from the central pathologist will be recorded directly onto paper CRF.
All other data will have separate source documentation; no data will be recorded directly onto 
the CRF. The following data collected for assessments and procedures performed at the 
SHP621-301 final treatment evaluation visit (Visit 4) will not be recollected in the 
SHP621-302 database as follows (Section 7.1.1.1):

Vital signs, height, and weight assessment

EGD with endoscopy score (EREFS) and biopsy

DSQ compliance assessment
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
Physical examination

Tanner Staging Assessment

Clinical laboratory tests

Urinalysis

Pregnancy test

Morning cortisol

ACTH Stimulation Testing

DXA Scan (subjects 11 to 17 years of age)
All other data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to
subject’s medical file, original clinical laboratory reports, and histology and pathology 
reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective 
national, local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities 
and have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
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10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment,
retainer for ongoing consultation, or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 
2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (or assent as 
applicable for subjects <18 years of age) from all study subjects prior to any study-related 
procedures including screening assessments. All consent documentation must be in 
accordance with applicable regulations and GCP. Each subject or the subject’s legally
authorized representative, as applicable, is requested to sign and date the subject’s informed 
consent form or a certified translation, if applicable, after the subject has received and read (or 
been read) the written subject information and received an explanation of what the study 
involves, including but not limited to the objectives, potential benefits and risk, 
inconveniences, and the subject’s rights and responsibilities. A copy of the informed consent 
documentation (ie, a complete set of subject information sheets and fully executed signature 
pages) must be given to the subject or the subject’s legally authorized representative, as 
applicable. This document may require translation into the local language. Signed consent 
forms must remain in each subject’s study file and must be available for verification at any 
time.
Within the source documents, site personnel should document instruction of and 
understanding by the parents/legally authorized representative/caregiver of the safe, 
responsible storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and 
received their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor, prior to the start of the 
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study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification 
of the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator 
or, for multicenter studies, the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
Investigational product supplies will not be released until the CRO has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
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register, or market SHP621; national or local regulatory authorities; and the IRBs/ECs which 
gave approval for the study to proceed. The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purposes of any such transfer would 
include supporting regulatory submissions, conducting new data analyses to publish or 
present the study results, or answering questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a noncommercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this 
policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) 
the copyright on his/her publications. To the extent that the principal investigator has such 
sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
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confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the International Committee of Medical Journal 
Editors current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11.
REFERENCES
Bachrach LK, Sills IN, Section on Endocrinology. Clinical report—bone densitometry in 
children and adolescents. Pediatrics. 2011;127(1):189-94.
Bone 
Mineral 
Density 
in 
Childhood 
Study
(BMDCS). 
Available 
at:
http://www.bmdcspublic.com. Accessed August 5, 2015. 
Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in the United 
States. Clin Gastroenterol Hepatol. 2014a;12(4):589-96.
Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic 
esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc. 2014b;79(4):577-85.
 
Food and Drug Administration. Uceris pharmacology review. NDA 203-634. 2011.
Food and Drug Administration. Draft Guidance: Drug Interaction Studies – Study Design, 
Data Analysis, Implications for Dosing, and Labeling Recommendations. US Department of 
Health and Human Services, Center for Drug Evaluation and Research (CDER), February 
2012.
 
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: 
a systematic review and consensus recommendations for diagnosis and treatment. 
Gastroenterology. 2007;133(4):1342-63.
Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17):1640-48.
Gordon CM, Bachrach LK, Carpenter TO, et al. Duel energy X-ray absorptiometry 
interpretation and reporting in children and adolescents: the 2007 ISCD pediatric official 
positions. J Clin Densitom. 2008;11(1):43-58.
Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterol Clin North Am. 2014;43(2):297-316.
International Society for Clinical Densitometry. 2013 Official Positions—Adult & Pediatric. 
2014:1-20.
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3-20. 
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. 
 
 
 
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12.
APPENDIX
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Appendix 1
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Tanner Staging Assessment
Site
EREFS
Site
Abbreviations: DSQ=Dysphagia Symptom Questionnaire; 
 
EREFS=EoE Endoscopic Reference Score; 
 
A separate master file containing each scale/assessment listed above will be provided to the 
site. Updates to scales/assessments during the study (if applicable) will be documented in the 
table above, and a new master file containing the revised scale/assessment will be provided to 
the site. 
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Appendix 2
Dysphagia Symptom Questionnaire ePRO for EoE
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For non-commercial use only

PROTOCOL: SHP621-302
TITLE:
A Phase 3, Multicenter, Double-blind Extension Study to Evaluate 
Maintenance of Efficacy of Oral Budesonide Suspension (OBS) and 
Long-term Treatment Effect of OBS in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 05 Dec 2015
Protocol Amendment 1: 22 Jun 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only

-------------------------------------------
Shire 
CONFIDENTIAL 
Protocol SHP621-302, Amendment 1 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
, MD 
 
Acknowledgement 
I have read this protocol for Shire Study SHP621-302. 
Date: 
Page2 
22 Jun 2016 
Title: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of 
Efficacy of Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in 
Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis 
(Eo E) 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: _______________ Date: 
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Protocol SHP621-302, Amendment 1
22 Jun 2016
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The SHP621-302 protocol is amended to address the following items:

Clarification of relapse criterion based on days of dysphagia reported on the Dysphagia 
Symptom Questionnaire prior to study visits with consideration of the potential for missing 
diary entries 

Additional safety monitoring added for subjects with clinical evidence of adverse HPA 
effects

Clarification of withdrawal criteria to ensure that only subjects with severe signs and 
symptoms of EoE are withdrawn from the study

Methods for primary efficacy analysis updated from chi-square test to Fisher’s Exact test
Additional edits, as captured in the below table, were made to Protocol Amendment 1 to improve 
the clarity of the protocol and/or correct minor inconsistencies. Note that correction of typos and 
grammatical errors are not captured in the below table.
New text indicated in bold; deleted text indicated in strikethrough.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
Changed from:
 
To:
Emergency Contact Information 
Page
A 4-week screening period is required to allow for blinded treatment 
response information (reduction in DSQ from baseline and eosinophilic count 
as determined by a central reader) collected during the SHP621-301 final 
treatment evaluation visit to be entered into the interactive web-based 
response system (IWRS) by. Only the unblinded data team who is 
independent from the blinded study team and not involved with the day-to-
day conduct of the study will have restricted access to blinded treatment
response information. 
Rationale: This text has been clarified to emphasize that access to blinded 
treatment response information will be restricted to the unblinded data team. 
Blinded treatment response data will not be accessed by the study team; 
therefore, the double-blind will be maintained.
Synopsis: Investigational 
product, dose, and mode of 
administration;
Synopsis: Methodology;
Section 3.1: Study Design and
Flow Chart
At least 8 daily diary entries must be completed over 14 consecutive days in 
order to determine the criterion for DSQ relapse. Considering the potential 
for missing diary entries, the determination of relapse based on days of 
dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in order
Synopsis: Investigational 
product, dose, and mode of 
administration;
Section 6.2.3: Dosing;
Section 7.2.1.2: Dysphagia 
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Protocol SHP621-302, Amendment 1
22 Jun 2016
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
the 2-week period prior to the visit, the subject would meet the 
criterion for dysphagia symptom relapse. If fewer

If less than 4 days of dysphagia are reported and at least 8 diary 
entries are recorded within the 2-week period, the subject would 
not meet criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and less
fewer than 8 diary entries are reported recorded within the 2-week 
period, then the 2-week period will be shifted backwards from the 
scheduled visit, 1 day at a time, to include the most recent 2-week 
period with at least 8 diary entries confirm if the most recent 2-
week period with at least 8 diary entries subject meets the criteria 
for dysphagia symptom relapse over 14 consecutive days; 
however, the 2-week period will not be shifted further if at least 8 
diary entries are recorded in the 14-day period and will not be 
shifted by more than 2 weeks in total (ie, no more than 2-week 
period plus additional 2-week additional expansion). 
The criteria for relapse align with the related inclusion criteria for 
participation in the SHP621-301 study. If both histology and dysphagia 
symptom relapse criteria are met, then the treatment assignment change 
will be performed in a blinded manner in IWRS at the subsequent study 
visit by the independent unblinded data team.
Rationale: Additional text is provided to clarify the evaluation of dysphagia 
symptoms for determination of relapse based on days of dysphagia reported 
on the DSQ prior to study visits with the potential for missing diary entries.
Symptom Questionnaire
The independent, unblinded data team will review the blinded EGD and DSQ 
data to confirm the If a subject is on placebo in the randomized withdrawal 
period, determine if the subject meets relapse the criteria, and change for 
relapse, the subject’s treatment assignment will be changed in a blinded 
manner from placebo to OBS 2 mg twice daily if relapse is confirmed at 
the subsequent study visit.
Synopsis: Investigational 
product, dose, and mode of 
administration
Synopsis: Methodology;
Section 6.2.3: Dosing
6.
Subject is willing and has an understanding and ability to fully 
comply with study procedures including DSQ compliance (completed the 
DSQ on ≥70% of days in any 2 consecutive weeks of the screening period)
and restrictions defined in this protocol.
Synopsis: Inclusion Criteria;
Section 4.1: Inclusion Criteria
5.
Subject has initiated, discontinued, or changed dosage regimen of 
proton pump inhibitors (PPIs), H2 antagonists, antacids, antihistamines, or 
leukotriene inhibitors for any condition (such as gastroesophageal reflux 
disease, asthma or allergic rhinitis) since the final treatment evaluation visit 
(Visit 4) of the SHP621-301 study or anticipated changes in the use of such 
medications during the treatment period. 
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
12.
Subject has oropharyngeal or esophageal candidiasis that failed to 
respond to previous treatment. Diagnosis with oropharyngeal or esophageal 
candidiasis at or since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study is not an exclusion as long as the subject received is
treatment for candidiasis and is expected to respond to treatment. 
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
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Protocol SHP621-302, Amendment 1
22 Jun 2016
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
13.
Subject has a potentially serious acute or chronic infection or 
immunodeficiency condition, including tuberculosis, fungal, bacterial, 
viral/parasite infection, ocular herpes simplex, or chicken pox/measles.
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
The primary efficacy endpoint will be analyzed as the proportion of subjects 
with relapse during the end of the double-blind randomized withdrawal 
period for the FAS, using Fisher’s Exact a chi-square test comparing OBS 2 
mg twice daily against placebo.
Relapse proportions at each adjacent double-blind visit interval will also be 
assessed by applying the Fisher’s Exact chi-square test to the observed data 
at each double-blind visit.
Rationale: The primary efficacy analysis method has been changed from the 
Chi-square test to Fisher’s exact test. Considering the expected number of 
subjects in the randomized withdrawal portion of the study, and the very 
small number of subjects who are expected to relapse in the OBS group, the 
Fisher’s exact test is considered a more appropriate method.
Synopsis: Statistical 
Methodology for Primary 
Efficacy Endpoint
Section 9.8.1: Primary Efficacy 
Endpoint
For this study, to detect a 50 percentage point difference between relapse 
proportions of 20% and 70% in the OBS and placebo groups, respectively, at 
more than 80% power and a significance level of 0.05 (2-sided) using the 
Fisher’s Exact a Chi-Square test with equal allocation to treatment groups, it 
is necessary to assess the primary efficacy measure for approximately 38 
subjects (19 subjects in each of the OBS and placebo groups)
Synopsis: Sample Size 
Justification;
Section 9.6: Sample Size 
Calculation and Power 
Considerations
c  Height to be collected at screening (Visit 0) and Visit 8 only  Stadiometers 
will be used to measure height for all subjects aged. Height to be collected 
at Visit 4 for adolescents only (11-17 years, inclusive). Height 
measurements for adolescents should be measured in triplicate using
stadiometers. will be used to measure height for subjects aged 11-17 years, 
inclusive.
Table 1-1, Footnote c;
Section 7.1.2.3: Visit 4 (Week 
12)
d  Weight measurements for adolescents (11-17 years, inclusive) should 
be measured in duplicate.
Table 1-1, Footnote d
The treatment assignment change will be performed in a blinded manner in 
IWRS at the subsequent study visit by the independent unblinded data 
team.
Section 3.1: Study Design and 
Flow Chart
•
No change in use of PPIs, H2 antagonists, antacids, antihistamines,
or leukotriene inhibitors for any condition (such as gastroesophageal reflux 
disease, asthma or allergic rhinitis).
Section 4.3: Restrictions
•
Acceptable methods of contraception are:
•
Surgically sterile male partner
Section 4.4.1: Female 
Contraception
Medically important events that in the opinion of the investigator or medical 
monitor would compromise the subject’s ability to safely continue in the 
study, including but not limited to severe signs and symptoms of EoE, such
as an esophageal stricture requiring dilation, weight loss due to severe 
dysphagia, and/or upper GI bleed worsening signs and symptoms of EoE 
(eg, weight loss or increased dysphagia), would be considered a relapse and
result in withdrawal of the subject from the study.
Section 4.5.1: Subject 
Withdrawal Criteria
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
Rationale: The terms “worsening signs and symptoms of EoE” have been 
more clearly defined as “severe signs and symptoms of EoE” to prevent 
subjects with only minor to moderate symptoms being withdrawn from the 
study.
Antihistamines
Rationale: Antihistamines were removed from the list of permitted 
medications that require consultation with the medical monitor prior to 
initiating changes in the dosing regimen. Antihistamine use, including any 
changes to the dosing regimen, is permitted during the course of the study.
Section 5.2.1: Permitted 
Treatment
3.
Initiation or change in dosing frequency to PPIs, H2 antagonists, 
antacids, antihistamines, or leukotriene inhibitors for any condition…
Section 5.2.2: Prohibited 
Treatment
During the 4-week screening period, blinded treatment response information 
(reduction in DSQ from baseline and eosinophilic count as determined by a 
central reader) collected during the SHP621-301 final treatment evaluation 
visit will be entered into the IWRS by an independent, unblinded data team in 
a blinded manner in a blinded manner. Details on the unblinded data team 
will be provided in a separate charter. Once information is available in
IWRS, subjects will return…
Sites will enter confirm eligibility criteria information prior to randomization
Section 6.2.1: Interactive 
Response Technology for 
Investigational Product 
Management
The 4-week screening period is required to allow for blinded treatment 
response information (reduction in DSQ from baseline and eosinophilic count 
as determined by a central reader) collected during the SHP621-301 final 
treatment evaluation visit to be entered into the IWRS by the independent, 
unblinded, data team.
Section 7.1.1: Screening Period 
(Weeks -4 to 0)
•
Record vital signs (including blood pressure [systolic and diastolic], 
heart rate, respirations, and temperature), height (measured in triplicate for 
adolescents 11-17 years, inclusive), and weight (measured in duplicate for 
adolescents 11-17 years, inclusive). Perform stadiometry in adolescent
subjects. aged 11-17 years, inclusive.
Section 7.1.1.1: Screening Visit 
(Visit 0)/Visit 4 of SHP621-301 
Study;
Section 7.1.2.3: Visit 4 
(Week 12);
Section 7.1.2.5: Visit 8 
(Week 36) or Early Termination
•
Record vital signs (including blood pressure [systolic and diastolic], 
heart rate, respirations, and temperature) and weight (measured in duplicate 
for adolescents 11-17 years, inclusive).
Section 7.1.2.1: Randomization 
Visit (Visit 1)/Week 0;
Section 7.1.2.2: Visits 2 and 3 
(Weeks 4 and 8);
Section 7.1.2.4: Visits 5, 6, and 
7 (Weeks 16, 20, and 28)
Any subject with clinical evidence of reduced height velocity and/or 
delayed Tanner staging will be followed closely until resolution (Section 
7.2.2.2).
Section 7.1.2.5: Visit 8 (Week 
36) or Early Termination
The independent unblinded data team will receive data from the central 
reader and will use it to confirm whether the subject meets the eligibility 
criteria for this study.
Section 7.2.1.1: 
Esophagogastroduodenoscopy 
with Esophageal Biopsy and 
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
Histopathologic Evaluation
Height will be collected at the screening visit (Visit 0) and Visit 8 for all 
subjects, and at Visit 4 for adolescents (11-17 years, inclusive) only.
Height will be measured in triplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF.
Weight will be measured in duplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF.
All subjects with clinical evidence of reduced height velocity and/or 
delayed Tanner Staging, as determined by the investigator, must be 
followed closely until resolution (ie, resumption of normal for age height 
velocity, or the resumption of Tanner Stage development). Subjects who 
discontinue from the treatment period at any time and have clinical 
evidence of reduced height velocity and/or delayed Tanner Stage 
development at the early termination visit will be monitored beyond the 
end of the study until resolution is established. 
Rationale: This text was added to ensure that any subjects demonstrating 
laboratory or clinical findings suggestive of adverse HPA effect will be 
appropriately monitored until resolution.
Section 7.2.2.2: Physical 
Examination (Including Height 
and Weight)
For Subjects who discontinue from the treatment period at any time and have 
an abnormal ACTH stimulation test at the early termination visit, subjects 
will be scheduled for repeat ACTH testing approximately 6 weeks post last 
dose of investigational product to ensure that ACTH levels have normalized
and followed to resolution of the abnormality. 
Section 7.2.2.5: Clinical 
Laboratory Evaluations
To determine whether a subject meets the criterion for dysphagia, refer to at 
least 8 daily diary entries must be completed over 14 consecutive days, as 
described in Section 7.2.1.2.
Section 9.6: Sample Size 
Calculation and Power 
Considerations
Section 9.8.1: Primary Efficacy 
Endpoint
See Appendix 1 for protocol history, including all amendments.
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire Medical Monitor by fax or e-mail using the details below.
, MD
Email: 
Fax: 
For protocol- or safety-related issues during normal business hours (8 am to 5 pm Eastern 
Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile: 
Email: 
Fax: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
or 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................8
PRODUCT QUALITY COMPLAINTS..........................................................................................9
TABLE OF CONTENTS...............................................................................................................10
LIST OF TABLES.........................................................................................................................14
LIST OF FIGURES .......................................................................................................................15
LIST OF APPENDICES................................................................................................................16
LIST OF ABBREVIATIONS........................................................................................................17
STUDY SYNOPSIS ......................................................................................................................19
STUDY SCHEDULE(S) ...............................................................................................................28
1.
BACKGROUND INFORMATION.......................................................................................32
1.1
Indication and Current Treatment Options...............................................................32
1.2
Product Background and Clinical Information ........................................................32
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................34
2.1
Rationale for the Study.............................................................................................34
2.2
Study Objectives ......................................................................................................34
2.2.1
Primary Objective..................................................................................................34
2.2.2
Secondary Objectives.............................................................................................34
3.
STUDY DESIGN ...................................................................................................................36
3.1
Study Design and Flow Chart ..................................................................................36
3.2
Duration and Study Completion Definition .............................................................38
3.3
Sites and Regions .....................................................................................................39
4.
STUDY POPULATION.........................................................................................................40
4.1
Inclusion Criteria......................................................................................................40
4.2
Exclusion Criteria.....................................................................................................40
4.3
Restrictions...............................................................................................................42
4.4
Reproductive Potential .............................................................................................42
4.4.1
Female Contraception............................................................................................42
4.5
Discontinuation of Subjects .....................................................................................43
4.5.1
Subject Withdrawal Criteria ..................................................................................43
4.5.2
Reasons for Discontinuation..................................................................................44
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................44
4.5.4
Safety-related Stopping Rules................................................................................44
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................46
5.1
Prior Treatment ........................................................................................................46
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5.2
Concomitant Treatment............................................................................................46
5.2.1
Permitted Treatment...............................................................................................46
5.2.2
Prohibited Treatment .............................................................................................47
6.
INVESTIGATIONAL PRODUCT ........................................................................................48
6.1
Identity of Investigational Product...........................................................................48
6.1.1
Blinding the Treatment Assignment......................................................................48
6.2
Administration of Investigational Product(s)...........................................................48
6.2.1
Interactive Response Technology for Investigational Product Management ........48
6.2.2
Allocation of Subjects to Treatment ......................................................................49
6.2.3
Dosing....................................................................................................................50
6.2.4
Unblinding the Treatment Assignment..................................................................51
6.3
Labeling, Packaging, Storage, and Handling ...........................................................51
6.3.1
Labeling .................................................................................................................51
6.3.2
Packaging...............................................................................................................52
6.3.3
Storages..................................................................................................................52
6.3.4
Special Handling....................................................................................................53
6.4
Drug Accountability.................................................................................................53
6.5
Subject Compliance..................................................................................................54
7.
STUDY PROCEDURES........................................................................................................55
7.1
Study Schedule.........................................................................................................55
7.1.1
Screening Period (Weeks -4 to 0)..........................................................................55
7.1.1.1
Screening Visit (Visit 0)/Visit 4 of SHP621-301 Study ........................56
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28, 
and 36 (or Early Termination) ...............................................................................57
7.1.2.1
Randomization Visit (Visit 1): Week 0..................................................58
7.1.2.2
Visits 2 and 3 (Weeks 4 and 8) ..............................................................59
7.1.2.3
Visit 4 (Week 12) ...................................................................................59
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28) ..............................................60
7.1.2.5
Visit 8 (Week 36) or Early Termination ................................................61
7.1.3
Follow-up Period ...................................................................................................62
7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40........................................62
7.2
Study Evaluations and Procedures ...........................................................................62
7.2.1
Efficacy..................................................................................................................63
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation....................................................................63
7.2.1.2
Dysphagia Symptom Questionnaire.......................................................64
7.2.2
Safety .....................................................................................................................65
7.2.2.1
Medical and Medication History............................................................65
7.2.2.2
Physical Examination (Including Height and Weight) ..........................65
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7.2.2.3
Adverse Event Collection.......................................................................66
7.2.2.4
Vital Signs..............................................................................................66
7.2.2.5
Clinical Laboratory Evaluations.............................................................66
7.2.2.6
Pregnancy Test .......................................................................................68
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density.............68
7.2.3
Other Assessments.................................................................................................68
7.2.3.2
Severity of Disease Assessments ...........................................................69
7.2.4
Volume of Blood to Be Drawn from Each Subject ...............................................70
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................71
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................71
8.1.1
Severity Categorization..........................................................................................71
8.1.2
Relationship Categorization...................................................................................72
8.1.3
Outcome Categorization ........................................................................................72
8.1.4
Symptoms of the Disease under Study ..................................................................72
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................73
8.1.6
Pregnancy...............................................................................................................73
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................74
8.2
Serious Adverse Event Procedures ..........................................................................74
8.2.1
Reference Safety Information................................................................................74
8.2.2
Reporting Procedures.............................................................................................74
8.2.3
Serious Adverse Event Definition .........................................................................75
8.2.4
Serious Adverse Event Collection Time Frame.....................................................75
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................76
8.2.6
Fatal Outcome........................................................................................................76
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................76
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................77
9.1
Data Collection.........................................................................................................77
9.2
Clinical Data Management.......................................................................................77
9.3
Data Handling Considerations..................................................................................77
9.4
Statistical Analysis Process......................................................................................77
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......78
9.6
Sample Size Calculation and Power Considerations................................................78
9.7
Study Population ......................................................................................................78
9.8
Efficacy Analyses.....................................................................................................78
9.8.1
Primary Efficacy Endpoint ....................................................................................78
9.8.2
Secondary Efficacy Endpoints...............................................................................79
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9.8.2.1
Key Secondary Efficacy Endpoint .........................................................79
9.9
Safety Analyses........................................................................................................81
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................83
10.1
Sponsor’s Responsibilities .......................................................................................83
10.1.1 Good Clinical Practice Compliance.......................................................................83
10.1.2 Indemnity/Liability and Insurance.........................................................................83
10.1.3 Public Posting of Study Information......................................................................83
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................83
10.1.5 Study Suspension, Termination, and Completion..................................................84
10.2
Investigator’s Responsibilities .................................................................................84
10.2.1 Good Clinical Practice Compliance.......................................................................84
10.2.2 Protocol Adherence and Investigator Agreement..................................................84
10.2.3 Documentation and Retention of Records .............................................................85
10.2.3.1
Case Report Forms.................................................................................85
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................86
10.2.3.3
Audit/Inspection.....................................................................................86
10.2.3.4
Financial Disclosure...............................................................................86
10.3
Ethical Considerations..............................................................................................87
10.3.1 Informed Consent...................................................................................................87
10.3.2 Institutional Review Board or Ethics Committee..................................................87
10.4
Privacy and Confidentiality......................................................................................88
10.5
Study Results/Publication Policy .............................................................................88
11. REFERENCES .......................................................................................................................90
12. APPENDIX.............................................................................................................................92
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LIST OF TABLES
Table 1-1:
Schedule of Assessments...............................................................................28
Table 7-1:
Approximate Volume of Blood to Be Drawn from Each Subject.................70
Table 8-1:
Adverse Event Relatedness ...........................................................................72
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LIST OF FIGURES
Figure 3-1: 
  Study Design Flow Chart ............................................................................36
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LIST OF APPENDICES
Appendix 1
Protocol History................................................................................................93
Appendix 2
Scales and Assessments....................................................................................94
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE.........................................95
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LIST OF ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
β-hCG
beta-human chorionic gonadotropin
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CYP450 3A4
cytochrome P450 3A4
DSQ
Dysphagia Symptom Questionnaire
DXA (DEXA)
dual-energy X-ray absorptiometry
EC
ethics committee
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
  
ePRO
electronic patient-reported outcome
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HPF
high-powered field
hs
at bedtime
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
ITT
intent-to-treat
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IWRS
interactive web-based response system
Med ID
medication information
MedDRA
Medical Dictionary for Regulatory Activities
OBS
oral budesonide suspension
pc
after meals
PP
per-protocol
PPI
proton pump inhibitor
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
TEAE
treatment-emergent adverse event
UK
United Kingdom
US
United States
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STUDY SYNOPSIS
Protocol number: SHP621-302
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of Efficacy of 
Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in Adolescent and Adult Subjects (11 
to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
Number of subjects (total and for each treatment arm):
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to complete the 
SHP621-301 study and enroll in this treatment extension study based on enrollment observed in the Phase 2 study 
(MPI 101-06).
Investigator(s): Multicenter study
Site(s) and Region(s):
Approximately 60 sites in North America
Study period (planned):
April 2016–April 2019
Clinical phase:
3
Objectives
Primary:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak eosinophilic count and the 
Dysphagia Symptom Questionnaire (DSQ) score, through a randomized withdrawal design for subjects who 
responded to 12 weeks of OBS treatment (2 mg twice daily) with a peak count of ≤6 eosinophils 
(eos)/high-powered field (HPF) across all available esophageal levels at the final treatment visit and a ≥30% 
reduction in DSQ score from baseline during the SHP621-301 induction study
Key Secondary:

To evaluate the long-term treatment response over an extended period of 36 weeks for subjects who were 
randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject 
did not have a peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit and/or 
a ≥30% reduction in DSQ score from baseline)
Secondary:

To evaluate the response to OBS treatment over 36 weeks for subjects who received placebo in the SHP621-301 
induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being randomized to placebo 
in the randomized withdrawal period (treatment-withdrawal-treatment reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE Endoscopic Reference Score 
(EREFS)

To evaluate other response criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
Exploratory:

 

 
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Rationale:
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is being conducted to 
determine response to withdrawal of OBS, maintenance of response, extended therapy response, and response to 
intermittent therapy by evaluating both eosinophil counts and DSQ in adolescent and adults treated or withdrawn 
from OBS in this treatment extension study.
Investigational product, dose, and mode of administration:
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the screening 
assessments (Visit 0) of this treatment extension study. At the SHP621-301 final treatment evaluation visit, subjects 
will be dispensed blinded investigational product (based on treatment assignment in SHP621-301) that will last for 
up to 4 weeks prior to enrolling into this treatment extension study. A 4-week screening period is required to allow 
for blinded treatment response information (reduction in DSQ from baseline and eosinophilic count as determined 
by a central reader) collected during the SHP621-301 final treatment evaluation visit to be entered into the 
interactive web-based response system (IWRS). Only the unblinded data team who is independent from the blinded 
study team and not involved with the day-to-day conduct of the study will have restricted access to blinded 
treatment response information. Once information is available in IWRS, subjects will return for the randomization 
visit (Visit 1) to receive investigational product as follows:

Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 study (≤6 eos/HPF
across all available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation visit) 
will enter a randomized withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio

Subjects who were assigned to OBS treatment and did not respond or partially responded to OBS treatment in 
the SHP621-301 study will receive OBS 2 mg twice daily

Subjects who were assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily
Subjects, site staff, and study team members will remain blinded to treatment assignment and individual subject
histology and individual subject DSQ data from the SHP621-301 study (post randomization) and this extension 
study until database lock occurs for this extension study. 
During the 36-week double-blind treatment extension study, subjects will receive oral administration of 10 mL of 
0.2 mg/mL (2 mg) investigational product twice daily (every morning [qAM] after meals [breakfast, pc] and at 
bedtime [hs]; 4 mg total/day), with no ingestion of food or liquids permitted for 30 minutes after investigational 
product administration. Dosing regimens are consistent with the regimens used in the Phase 2 MPI 101-06 study and 
Phase 3 SHP621-301 study:

Placebo twice-daily group: placebo qAM (pc) and hs

OBS twice-daily group: OBS 10 mL of 0.2 mg/mL (2 mg) qAM (pc) and hs (4 mg OBS total/day)
The investigational product will be supplied in amber glass, multidose bottles with child-resistant caps and 
refrigerated throughout the study (in the clinic and subject’s home). Each bottle will contain approximately 210 mL 
of suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL (matching placebo). 
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for each subject in 
the OBS treatment group.
Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume per 
Dose (mL)
Morning Dose 
(mg) 
(qAM, pc)
Evening Dose 
(mg) (hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10
0.0
0.0
0.0
OBS 
0.2
10
2.0
2.0
4.0
Abbreviations: hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every morning
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At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with biopsy to evaluate 
eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on placebo in the randomized withdrawal 
period who have relapsed will have their treatment assignment changed to OBS 2 mg twice daily. The criteria for 
relapse is having an eosinophilic count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined 
by central reader and having at least 4 days of dysphagia in the 2-week period prior to the scheduled visit, as 
determined by the DSQ. Considering the potential for missing diary entries, the determination of relapse based on 
days of dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, the subject would 
meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within the 2-week period, 
the subject would not meet criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and less than 8 diary entries are recorded within the 
2-week period, then the 2-week period will be shifted backwards from the scheduled visit, 1 day at a time, to 
confirm if the subject meets the criteria for dysphagia symptom relapse over 14 consecutive days; however, the 
2-week period will not be shifted further if at least 8 diary entries are recorded in the 14-day period and will not 
be shifted by more than 2 weeks in total (ie, no more than 2-week period plus additional 2-week additional 
expansion). 
The criteria for relapse align with the related inclusion criteria for participation in the SHP621-301 study. If both 
histology and dysphagia symptom relapse criteria are met, the treatment assignment change will be performed in a 
blinded manner in IWRS at the subsequent study visit. If both criteria for relapse are not met, the subject will remain 
assigned to placebo.
If at any time, the subject reports increased or worsening dysphagia symptoms to the investigator, the investigator 
may choose to perform an unscheduled EGD. If an unscheduled EGD is performed prior to Week 12, an EGD does 
not have to be repeated at Week 12. If a subject on placebo meets the criteria for relapse, the subject’s treatment 
assignment will be changed in a blinded manner from placebo to OBS 2 mg twice daily at the subsequent study visit. 
If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 levels of the 
esophagus yet relapse is not confirmed due to the criterion for dysphagia symptoms not being met, the subject will 
remain assigned to placebo. If the criterion for dysphagia symptoms is met at a subsequent visit and both criteria for 
relapse are then confirmed, the subject’s treatment assignment will be changed to OBS 2 mg twice daily at the next 
scheduled visit.
Methodology:
This is a Phase 3, double-blind, multicenter study to evaluate the efficacy, safety, and tolerability of twice daily
administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, inclusive, with EoE and 
dysphagia who completed the SHP621-301 induction study. 
This study will comprise 3 periods: 4-week screening period, 36-week double-blind treatment period, and a 4-week 
safety follow-up (Study Design Flow Chart). All subjects who have completed the SHP621-301 induction study will 
be eligible to enroll in this extension study. Approximately 200 subjects (88%) who were randomized in the 
SHP621-301 study are estimated to complete the SHP621-301 study and will be enrolled in this treatment extension 
study based on enrollment observed in the Phase 2 study (MPI 101-06). Randomization into the randomized 
withdrawal period will be stratified by treatment assignment and treatment response in the SHP621-301 study.
Subjects who are full responders (defined as ≤6 eos/HPF across all available esophageal levels and at least a 30% 
reduction in DSQ at the final treatment evaluation visit [Visit 4]) in the SHP621-301 induction study will be eligible 
to enter the randomized withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio. The 
randomization of subjects who are full responders will also be stratified by age (adults and adolescents) to ensure 
approximately equal number of subjects within each age group are assigned to the treatment groups.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened (Visit 0); 
assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the Visit 0 screening 
assessments of the treatment extension study. Subjects who meet eligibility criteria at the screening visit (Visit 0) 
will enter the 36-week double-blind period. Eligible subjects will receive investigational product based on treatment 
assignment in SHP621-301 for up to 4 weeks prior to enrollment in the treatment extension study. This 4-week 
screening period is required to allow for blinded treatment response information (reduction in DSQ from baseline 
and eosinophilic count as determined by a central reader) collected during the SHP621-301 final treatment 
evaluation visit to be entered into IWRS. Only the unblinded data team who is independent from the blinded study 
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team and not involved with the day-to-day conduct of the study will have restricted access to blinded treatment 
response information. Once information is available in IWRS, subjects will return for the randomization visit (Visit 
1) to receive investigational product.
During the 36-week treatment extension study, subjects who were assigned to, and fully responded to OBS 
treatment in the SHP621-301 study (≤6 eos/HPF across all available esophageal levels and at least a 30% reduction 
in DSQ at the final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 2 mg 
twice daily or placebo at a 1:1 ratio. Subjects who were assigned to OBS treatment in the SHP621-301 study and did 
not respond or partially responded, will receive OBS 2 mg twice daily. Subjects who were assigned to placebo in the 
SHP621-301 study will receive OBS 2 mg twice daily. At Week 12, all subjects will undergo an upper 
esophagogastroduodenoscopy (EGD) with biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and 
DSQ data, subjects on placebo in the randomized withdrawal period who have relapsed (>15 eos/HPF from at least 
2 levels of the esophagus and specimens and 4 days of dysphagia over 2 weeks) will have their treatment assignment 
changed to OBS 2 mg twice daily at the next scheduled visit. The treatment assignment change will be performed in 
a blinded manner in IWRS at the subsequent study visit. If both criteria for relapse are not met, the subject will 
remain assigned to placebo.
Subjects who report increased or worsening dysphagia symptoms to the investigator prior to the Week 12 EGD may 
have an unscheduled EGD to confirm whether relapse has occurred. If an unscheduled EGD is performed prior to 
Week 12, an EGD does not have to be repeated at Week 12. If a subject on placebo meets the criteria for relapse, the 
subject’s treatment assignment will be changed in a blinded manner from placebo to OBS 2 mg twice daily at the 
subsequent study visit. 
Subjects will have efficacy and safety assessments at each visit during the 36-week period. Subjects who fail to meet 
all eligibility criteria at Visits 0 or 1 will be considered screen failures. Subjects cannot be rescreened once they have 
been designated as a screen failure. Subjects who discontinue will not be replaced.
Subjects will be required to visit the site up to 8 times over up to a 36-week period. All subjects will have a follow-
up phone call 4-weeks post last dose of investigational product.
Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
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Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria (including test 
results):
1.
Subject completed SHP621-301 induction study.
2.
Subject is able to provide written informed consent (subject, parent or legal guardian and, as appropriate, 
subject assent) to participate in the study before completing any study-related procedures. 
3.
Subject is male or female aged 11-55 years, inclusive, at time of consent for SHP621-301 study.
4.
Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical regimens 
(including gastric acid suppression; see exclusions below) in effect at the screening visit (Visit 0). There should 
be no changes to these regimens during study participation. 
5.
All female subjects must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) 
prior to enrollment into the study. Females of childbearing potential must agree to continue acceptable birth 
control measures (eg, abstinence, stable oral contraceptives, or double-barrier methods) throughout study 
participation and for 30 days following the last dose of investigational product.
6.
Subject is willing and has an understanding and ability to fully comply with study procedures including DSQ 
compliance and restrictions defined in this protocol.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subject has changes in medications that could affect the study or diet in the weeks since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study.
2.
Subject using immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the SHP621-301 
study or anticipated use of immunomodulatory therapy during the treatment period (except for any ongoing 
regimen of allergy shots); any temporary use (≤7 days) or initiation of new steroid treatment during the study 
should be documented and discussed with the medical monitor prospectively but cannot occur within 4 weeks 
of scheduled EGDs.
3.
Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use during the treatment period; 
any temporary use (≤7 days) or initiation of new steroid treatment during the study should be documented and 
discussed with medical monitor prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
4.
Subject on inhaled or intranasal steroids and not on a stable dose between the baseline visit (Visit 1) of the 
SHP621-301 study and the screening EGD of this study. 
5.
Subject has initiated, discontinued, or changed dosage regimen of proton pump inhibitors (PPIs), H2 
antagonists, antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma or allergic rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated changes in the use of such medications during the treatment period. 
6.
Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of such medications during the treatment 
period. 
7.
Subject has an appearance on screening EGD of an esophageal stricture (high grade), as defined by the presence 
of a lesion that does not allow passage of a diagnostic adult upper endoscope (eg, with an insertion tube 
diameter of >9 mm). 
8.
Subject is on a pure liquid diet or the six-food elimination diet.
9.
Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including eosinophilic gastritis, 
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enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous treatment. Diagnosis 
with oropharyngeal or esophageal candidiasis at or since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study is not an exclusion as long as the subject is expected to respond to treatment. 
13. Subject has a potentially serious acute or chronic infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, or chicken pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment evaluation visit (Visit 4) 
of the SHP621-301 study or since the final treatment evaluation visit (Visit 4) of the SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) of the SHP621-301 
study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or any other 
corticosteroids), or to any other ingredients of the study medication.
19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
Maximum duration of subject involvement in the study:

Planned duration of screening period: up to 4 weeks

Planned duration of treatment period: 36 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who are randomized and receive at least 1 dose of investigational 
product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of investigational 
product and had 1 post baseline efficacy assessment (biopsy and/or DSQ score).

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major protocol 
deviations. The PP set will be identified prior to unblinding the treatment assignments by a team consisting of, 
at a minimum, a physician and a statistician from Shire. 
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized withdrawal period. 
Relapse, a binary response (either with a relapse or not), is defined as having an eosinophil count of ≥15 eos/HPF 
from at least 2 of 3 levels of the esophagus, as determined by a central reader, and having at least 4 days of 
dysphagia in the 2-week period prior to the scheduled study visit, as determined by the DSQ.
Key Secondary Efficacy Endpoint
The key secondary endpoint is the long-term treatment response, a binary response, over an extended period of 36 
weeks in adolescent and adult subjects who were randomized to OBS treatment but did not respond after 12 weeks
in the SHP621-301 induction study (subject did not have peak count of ≤6 eos/HPF across all available esophageal 
levels at the final treatment visit and/or ≥30% reduction in DSQ score from baseline) and met the following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available esophageal levels at 
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the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 2+3) from 
baseline of the SHP621-301 study and from baseline of this extension study to the final treatment period 
evaluation (Visit 8)
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available esophageal levels at 
each assessment visit 

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 2+3) at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension study

Change in the DSQ score and change in the peak eosinophilic count at each assessment visit from baseline of 
the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each assessment visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each assessment visit

Change in the peak eosinophil count at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study for each available esophageal level (proximal, mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at each assessment visit 
from baseline of the SHP621-301 study and from baseline of this extension study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ combined score 
(questions 2+3), at each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension

Change in the DSQ combined score (questions 2+3) at each assessment visit from baseline of the SHP621-301 
study and from baseline of this extension study

Cumulative distribution function curves for the change and the percent change in the DSQ score at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak eosinophil count of ≤6
eos/HPF across all esophageal levels at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak eosinophil count of ≤6
eos/HPF across all esophageal levels at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study

Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline of the SHP621-301 
study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the SHP621-301 study and 
from baseline of this extension study 
For subjects who relapse on placebo during the randomized withdrawal period and who reinitiate treatment with 
OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for histological data and DSQ endpoints 
will be conducted at each assessment visit. Changes will be summarized over time from baseline of the SHP621-301 
study and from the time of relapse. The same criteria for response will be applied to these subjects (≤6 eos/HPF
across all available esophageal levels and at least a 30% reduction in DSQ from the SHP621-301 baseline score). 
Exploratory Efficacy Endpoints

Safety Endpoints 
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital signs (temperature, 
systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, dual-energy X-ray 
absorptiometry (DXA) scans for bone mineral density (BMD) and body composition measurements (for adolescents 
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aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum pregnancy test, if 
appropriate), and adrenocorticotropic hormone (ACTH) stimulation tests. To account for the effects of puberty in 
adolescent subjects (11-17 years, inclusive), BMD z-scores will be adjusted for height z-scores using the Bone 
Mineral Density in Childhood Study calculator.
 
 
Statistical Methodology for Primary Efficacy Endpoint 
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse during the end of the 
double-blind randomized withdrawal period for the FAS, using Fisher’s Exact test comparing OBS 2 mg twice daily
against placebo. The primary test of treatment effect will be 2-sided, and conducted at the significance level of 0.05.
The proportion of subjects with relapse for each treatment group and the corresponding 95% confidence interval 
(CI) will be estimated. In addition, the difference in the proportion of subjects with relapse between the 2 treatment 
groups and its 95% CI will be estimated.
Subjects who withdraw without providing efficacy data at the early termination (ET) visit will be classified as being 
a relapser in the primary efficacy analysis. The null hypothesis states that there is no difference in relapse
proportions between OBS 2 mg twice daily and placebo, with the 2-sided alternative of a nonzero difference 
between groups. Relapse proportions at each adjacent double-blind visit interval will also be assessed by applying 
the Fisher’s Exact test to the observed data at each double-blind visit.
Statistical Methodology for Key Secondary and Other Secondary Efficacy Endpoints
To evaluate the long-term treatment response over an extended period of 36 weeks for subjects who were 
randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject did 
not have peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit and/or ≥30% 
reduction in DSQ score from baseline of SHP621-301), the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the corresponding 95% 
confidence interval (CI) will be estimated and summarized.
Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the change from baseline of 
the SHP621-301 study and from baseline of this extension study at the final treatment period evaluation (Visit 8) 
will be summarized by each assessment visit. 
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo in the SHP621-301 
induction study, the proportion of subjects who responded based on the histological data and the DSQ data at the 
final treatment period evaluation (Visit 8) and the corresponding 95% CI will be summarized. Summary statistics of 
the DSQ score (questions 2+3) and the peak eosinophil count and the change from baseline of the SHP621-301 
study and from baseline of this extension study at the final treatment period evaluation (Visit 8) will be summarized 
by each assessment visit. 
To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being randomized to placebo in 
the randomized withdrawal period (intermittent therapy), the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the corresponding 95% CI 
will be summarized.
Summary statistics will be provided for all the secondary endpoints.
Statistical Methodology for Safety Endpoints 
All safety measures, including AEs, physical examination, stadiometry, vital signs (temperature, systolic and 
diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA scans for BMD and body 
composition measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory results (hematology, 
chemistry, urinalysis; serum pregnancy test, if appropriate), and ACTH stimulation will be descriptively 
summarized by treatment group at baseline and for each post baseline visit.
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The number and percent of subjects with TEAEs will be presented. TEAEs are defined as AEs that start or 
deteriorate on or after the date of the first dose of investigational product (Visit 1) and no later than 3 days following 
the last dose of investigational product. However, for any subjects who die during the study (ie, the date of death is 
between the date of first dose of investigational product and the date of study discontinuation entered by the site, 
inclusive), all AEs (including those resulting in death) that occur during the study will be considered as TEAEs 
irrespective of the last dose and will be included in the TEAE summaries. 
Sample Size Justification
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to complete the 
SHP621-301 study and enroll in this treatment extension study based on enrollment observed in the Phase 2 study 
(MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse during the double-blind 
randomized withdrawal period. Relapse, a binary response (either with relapse or not), is defined as having an 
eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus (determined by a central reader) and 
having at least 4 days of dysphagia in a 2-week period prior to the scheduled visit (determined by the DSQ). To be 
considered as a subject with relapse, both criteria must be met.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or approximately 40 
subjects, who were assigned to OBS treatment in the SHP621-301 study are anticipated to respond fully after 12 
weeks in the SHP621-301 study. 
For this study, to detect a 50 percentage point difference between relapse proportions of 20% and 70% in the OBS 
and placebo groups, respectively, at more than 80% power and a significance level of 0.05 (2-sided) using the 
Fisher’s Exact test with equal allocation to treatment groups, it is necessary to assess the primary efficacy measure 
for approximately 38 subjects (19 subjects in each of the OBS and placebo groups). 
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STUDY SCHEDULE(S)
Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
Informed consent/assent
X
Medical history review
X
X
Inclusion/exclusion criteria 
review
X
X
Vital signsb; heightc, and weight 
assessmentd
X
X
X
X
X
X
X
X
X
EGD with endoscopy score 
(EREFS) and biopsye
X
X
X
Issue/Retrieve DSQ handset
X
X
DSQ completion
Once-daily completion
DSQ compliance assessment
X
X
X
X
X
X
X
X
X
 
 
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
 
Physical examination
X
X
X
X
X
X
X
X
X
Tanner Staging Assessmentg
X
X
Clinical laboratory testsh
X
X
X
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
X
X
X
X
Pregnancy testj
X
X
X
X
X
X
X
X
X
Morning cortisol (target 6:00-
9:00 am)
X
X
X
X
X
X
X
X
X
ACTH Stimulation Testing 
X
X
DXA Scan (subjects 11 to 
17 years of age)k
X
X
Randomizationl
X
Study medication supplied 
Xm
X
X
X
X
X
X
X
Study medication administration
Twice-daily administration of study medication
Study medication compliance 
assessment
X
X
X
X
X
X
X
X
X
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
Concomitant medications and 
procedures recorded 
X
X
X
X
X
X
X
X
X
X
Review of adverse eventsn
X
X
X
X
X
X
X
X
X
X
Abbreviations: ACTH=adrenocorticotropic hormone; DSQ=Dysphagia Symptom Questionnaire; DXA=dual-energy X-ray absorptiometry; 
EGD=esophagogastroduodenoscopy; 
 
EREFS=EoE Endoscopic Reference Score; hs=at bedtime; IWRS=interactive web-based response system; 
a
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the screening assessments (Visit 0) of this treatment 
extension study. 
b
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood 
pressure (systolic and diastolic), heart rate, respirations, and temperature.
c
Height to be collected at screening (Visit 0) and Visit 8 for all subjects. Height to be collected at Visit 4 for adolescents only (11-17 years, inclusive). Height 
measurements for adolescents should be measured in triplicate using stadiometers.
d
Weight measurements for adolescents (11-17 years, inclusive) should be measured in duplicate.
e
Endoscopy must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Endoscopies at Visit 4 and 
Visit 8 should occur at or within 7 days of the scheduled visit. Unscheduled endoscopies may be performed at the discretion of the investigator.
 
g
Tanner staging assessments will be performed for all subjects ≥11 years of age until investigator confirms subject is post puberty.
h
Clinical laboratory tests will include the following: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein, 
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Table 1-1: Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, carbon dioxide, hemoglobin, hematocrit, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, erythrocyte count, leukocyte count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and platelet count). All subjects must fast overnight prior to collection.
i
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
j
The serum pregnancy test will be performed for all female subjects at screening (Visit 0) and Visit 8. Urine pregnancy tests will be performed at all other 
visits.
k
Dual-energy X-ray absorptiometry scans should be performed using the same machine and software as used in the SHP621-301 study. Dual-energy X-ray 
absorptiometry scan at Visit 8 should occur at or within 7 days of the scheduled visit.
l
Randomization will occur via IWRS at Visit 1 once the subject’s eligibility is confirmed. 
m
Study medication is supplied at the SHP621-301 final treatment visit based on treatment assignment in SHP621-301. 
n
Adverse event assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, 
acne, hirsutism, mood swings, insomnia, and depression).
o
If subject discontinues study prematurely during the treatment period, the evaluations listed for Visit 8 are to be performed as completely as possible.
p
A safety follow-up contact by phone will be performed 4 weeks following the last dose of study medication for all subjects (including subjects who fail 
screening, who discontinue early, or who complete the study).
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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al. 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and adults 
present with dysphagia and food impaction. When these symptoms are present, the diagnosis is 
confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered field (HPF) on 
at least 1 esophageal biopsy and when other causes such as proton pump inhibitor (PPI)-
responsive esophageal eosinophilia are excluded (Dellon et al. 2014a; Furuta et al. 2007). The 
standards of care are diet therapies and off-label use of glucocorticosteroids. Esophageal dilation 
is used to temporarily relieve symptoms but does not address underlying inflammation. Given 
the clinical outcomes associated with EoE, including severe dysphagia, esophageal stricture, 
food impaction, and esophageal perforation (Hirano and Aceves 2014; Liacouras et al. 2011) and 
the fact that there are currently no FDA-approved treatments, there is a clear unmet medical need 
for an approved treatment that induces and maintains remission for patients with EoE 
(Furuta and Katzka 2015). 
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a nonviscous suspension. Shire is developing OBS as a first-line 
therapy for EoE in adolescents and adults.
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the management 
of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, and for 
induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide 
has strong glucocorticoid receptor affinity and is subject to considerable first pass metabolism by 
the liver with a short half-life. These attributes permit budesonide to act rapidly and locally in the 
gut mucosa for treatment of inflammatory disorders such as Crohn’s disease and ulcerative 
colitis. Once absorbed into the systemic circulation, budesonide is rapidly metabolized in the 
liver and inactivated (FDA 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in 2 Phase 2 studies in the 
OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the efficacy 
of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in adolescents 
and adults aged 11-40 years, respectively, by measuring histological response (defined as mean 
peak eosinophil count ≤6 eos/HPF after treatment). Study MPI 101-06 also evaluated symptom 
response as measured by the Dysphagia Symptom Questionnaire (DSQ). The DSQ contains 4 
questions related to consumption of solid food, the presence of dysphagia and its severity, as
well as pain. The DSQ score is calculated only from responses to the questions related to 
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dysphagia, and this clinical outcome assessment was considered to be fit for purpose as a result 
of the MPI 101-06 study. Results from Study MPI 101-01 demonstrated a statistically significant 
histologic response (eosinophil count ≤6 eos/HPF) and remission (eosinophil count ≤1 eos/HPF) 
in the medium-dose (1.4-2.0 mg daily) and high-dose (2.8-4.0 mg daily) OBS groups compared 
to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both the 
coprimary efficacy endpoints of histologic response and change from baseline in dysphagia 
symptoms. Following 12 weeks of twice daily treatment (once every morning after meals [qAM, 
pc] and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent reduction from 
baseline values for cellular (mean peak eosinophil count and histopathology features), organ 
(endoscopy score), and holistic measures (Physician Global Assessment and DSQ scores); these 
results were independent of the type of rater/reviewer (central pathologist, physician at the study 
site, or subject). 
This Phase 3 extension study follows the SHP621-301 induction study, a Phase 3 randomized, 
double-blind, multicenter, study to evaluate the efficacy, safety, and tolerability of twice daily 
administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, inclusive, 
with EoE and dysphagia. Study SHP621-301 is designed to provide safety and efficacy data 
demonstrating histologic response (as measured by eosinophilic count ≤6 eos/HPF) and 
improvement in dysphagia symptoms (as measured by the DSQ) following 12 weeks of 
treatment with OBS in adolescent and adult subjects with EoE. This extension study will 
evaluate maintenance of treatment and treatment withdrawal in subjects who complete the 
induction study.
Always refer to the latest version of the SHP621 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP621. 
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is being 
conducted to determine response to withdrawal of OBS, maintenance of response, extended 
therapy response, and response to intermittent therapy by evaluating both eosinophil counts and 
DSQ in adolescent and adults treated or withdrawn from OBS in this treatment extension study.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak eosinophilic 
count and the Dysphagia Symptom Questionnaire (DSQ) score, through a randomized 
withdrawal design for subjects who responded to 12 weeks of OBS treatment (2 mg twice 
daily) with a peak count of ≤6 eosinophils (eos)/high-powered field (HPF) across all 
available esophageal levels at the final treatment visit and a ≥30% reduction in DSQ score 
from baseline during the SHP621-301 induction study
2.2.2
Secondary Objectives
The key secondary objective of this study is:

To evaluate the long-term treatment response over an extended period of 36 weeks for 
subjects who were randomized to OBS treatment but did not respond after 12 weeks in the 
SHP621-301 induction study (subject did not have a peak count of ≤6 eos/HPF across all 
available esophageal levels at the final treatment visit and/or a ≥30% reduction in DSQ score 
from baseline)
Additional secondary objectives of the study are:

To evaluate the response to OBS treatment over 36 weeks for subjects who received placebo 
in the SHP621-301 induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being 
randomized to placebo in the randomized withdrawal period (treatment-withdrawal-treatment 
reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE Endoscopic 
Reference Score (EREFS)

To evaluate other responding criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
2.2.3
Exploratory Objectives
The exploratory objectives of this study are:

 
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
 
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, multicenter, double-blind study to evaluate the efficacy, safety and tolerability
of OBS treatment administered twice daily (qAM, pc, and hs) for 36 weeks. The study will be 
conducted in adolescents and adults, aged 11-55 years, inclusive, with EoE and dysphagia who 
completed the SHP621-301 induction study.
Approximately 200 subjects (88%) who were randomized in the SHP621-301 study are 
estimated to complete the SHP621-301 study and will be enrolled in this treatment extension 
study based on enrollment observed in the Phase 2 study (MPI 101-06). Randomization into the 
randomized withdrawal period will be stratified by treatment assignment and treatment response 
in the SHP621-301 study. Subjects who are full responders (defined as ≤6 eos/HPF across all 
available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation 
visit [Visit 4]) in the SHP621-301 induction study will be eligible to enter the randomized 
withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio. The 
randomization of subjects who are full responders will also be stratified by age (adults and 
adolescents) to ensure approximately equal number of subjects within each age group are 
assigned to the treatment groups.
This study will consist of 3 periods: 4-week screening period, 36-week double-blind treatment 
period, and 4-week safety follow-up (Figure 3-1).
Figure 3-1:
  Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
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Subjects will be required to visit the site up to 8 times over up to a 36-week period. Following 
completion of the screening visit, subjects will be evaluated for eligibility and safety at Week 0
(Visit 1). Subjects who are eligible and randomized will have efficacy and safety assessments at 
Weeks 4, 8, 12, 16, 20, 28, and 36 (Visits 2-8) and additional safety assessments at follow-up at 
Week 40 (Visit 9). Subjects who fail to meet all eligibility criteria at Visits 0 or 1 will be 
considered screen failures. These subjects will receive a follow-up safety phone call 4 weeks 
after the last dose of investigational product. Subjects cannot be rescreened once they have been 
designated as a screen failure. Subjects who discontinue will not be replaced.
The screening period will start when subjects sign informed consent (or assent as applicable for 
subjects <18 years of age; screening visit [Visit 0]) and will be ≤4 weeks in duration. During the 
screening period, assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will 
be used as the Visit 0 screening assessments of the treatment extension study. At the screening 
visit (Visit 0), subjects who are on a PPI must remain on the same dose of the PPI throughout the 
study; if they are not taking a PPI, they must remain off of a PPI for the remainder of the study. 
Eligible subjects will receive investigational product based on treatment assignment in 
SHP621-301 for up to 4 weeks prior to enrollment in the treatment extension study. This 4-week 
screening period is required to allow for blinded treatment response information (reduction in 
DSQ from baseline and eosinophilic count as determined by a central reader) collected during 
the SHP621-301 final treatment evaluation visit to be entered into the interactive web-based
response system (IWRS). Only the unblinded data team who is independent from the blinded 
study team and not involved with the day-to-day conduct of the study will have restricted access 
to blinded treatment response information. Once response information is available, subjects will 
return for the randomization visit (Visit 1) to receive investigational product. Subjects who 
continue to meet eligibility criteria after the screening visit (Visit 0) will enter the 36-week 
double-blind treatment period.
Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the 
final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 
2 mg twice daily or placebo at a 1:1 ratio. These subjects will also be stratified by age (adults and 
adolescents). Subjects who were assigned to OBS treatment and did not respond or partially 
responded in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were 
assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects, site 
staff, and study team members will remain blinded to treatment assignment and individual 
subject histology, and individual subject DSQ data from the SHP621-301 (post randomization) 
and this extension study until the database locks occurs for this extension study. 
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily at the next scheduled visit. The criteria for relapse 
is having an eosinophilic count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as 
determined by central reader and having at least 4 days of dysphagia in the 2-week period prior 
to the scheduled visit, as determined by the DSQ. The criteria for relapse align with the related 
inclusion criteria for participation in the SHP621-301 study. The treatment assignment change 
will be performed in a blinded manner in IWRS at the subsequent study visit. If both criteria for 
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relapse are not met, the subject will remain assigned to placebo. The upper EGD with esophageal 
biopsies will be repeated at the Week 36 visit (Visit 8) or at early termination (ET), to evaluate 
eosinophil counts. If an unscheduled EGD is performed between Week 12 and Week 36, the 
Week 36 EGD should still be performed.
All subjects will have a follow-up phone call 4-weeks post last dose of investigational product to 
query for SAEs, AEs, and concomitant treatments.
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al. 2014a) and the fact that as EoE persists, it 
becomes more fibrostenotic in older patients and would not be amenable to anti-inflammatory 
treatment alone (Dellon et al. 2014b). A natural history study demonstrated that for every decade 
of life, the odds of developing the fibrostenotic phenotype of EoE more than doubles 
(Dellon et al. 2014b). By age 55, fibrostenotic EoE occurs in approximately 80% of patients. 
Fibrostenotic disease is treated with dilatation and is not amenable to anti-inflammatory 
treatment alone. Therefore, budesonide is not expected to be an effective treatment for the 
majority of patients above age 55.
The design of this study combines randomized withdrawal and long-term extension elements in a 
manner that selects appropriate patients for placebo withdrawal and maintains double-blinding of 
subjects in all treatment groups. Only subjects who are full responders to OBS 2 mg twice daily
in the SHP621-301 induction study (≤6 eos/HPF across all available esophageal levels and at 
least a 30% reduction in DSQ at the final treatment evaluation visit of SHP621-301), will be 
eligible for randomized withdrawal. The randomized withdrawal period is required to assess 
maintenance of efficacy in these subjects. The continuation of OBS 2 mg twice daily treatment 
for subjects in SHP621-301 who did not respond or partially responded to treatment, will 
evaluate whether these subjects might respond to OBS 2 mg twice daily if their treatment is 
extended for an additional 36 weeks. This aspect of the study is supported by the possibility that 
the response of EoE to topical corticosteroids may require more than 12 weeks of induction 
treatment. 
As described, the protocol also provides multiple mechanisms for switch from placebo and 
potential study discontinuation of relapsing and nonresponding subjects in order to evaluate the 
effect of reinitiating OBS treatment in these subjects. For subjects who relapse on placebo during 
the randomized withdrawal and who reinitiate treatment with OBS 2 mg twice daily (intermittent 
therapy), separate descriptive analyses for histological data and DSQ endpoints will be 
conducted at each assessment visit, as described in Section 9.8.2. For all subjects, an esophageal 
stricture requiring dilation would be considered a treatment failure and result in withdrawal of 
the subject from the study. Subject withdrawal criteria are provided in Section 4.5.1.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 44 weeks, 
including the 4-week screening period. Including potential treatment in SHP621-301 and the 
screening period of this study, the maximum total duration of OBS 2 mg twice daily may be 
approximately 52 weeks.
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The study will be completed in approximately 36 months.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including Visit 
8 (Week 36), inclusive of the final treatment evaluation EGD. All subjects will have a follow-up 
phone call 4-weeks post last dose of investigational product.
3.3
Sites and Regions
Approximately 60 sites in North America, the same sites participating in the SHP621-301 study, 
will participate in this extension study.
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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject completed SHP621-301 induction study.
2. Subject is able to provide written informed consent (subject, parent or legal guardian and, as 
appropriate, subject assent) to participate in the study before completing any study-related 
procedures. 
3. Subject is male or female aged 11-55 years, inclusive, at time of consent for the SHP621-301 
study. 
4. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at the 
screening visit (Visit 0). There should be no change to these regimens during study 
participation.
5. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential 
must agree to continue acceptable birth control measures (eg, abstinence, stable oral 
contraceptives or double-barrier methods) throughout study participation and for 30 days 
following the last dose of investigational product.
6. Subject is willing and has an understanding and ability to fully comply with study procedures 
including DSQ compliance and restrictions defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subject has changes in medications that could affect the study or diet in the weeks since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study.
2. Subject using immunomodulatory therapy since the final treatment evaluation visit (Visit 4) 
of the SHP621-301 study or anticipated use of immunomodulatory therapy during the 
treatment period (except for any ongoing regimen of allergy shots); any temporary use (≤7 
days) or initiation of new steroid treatment during the study should be documented and 
discussed with the medical monitor prospectively but cannot occur within 4 weeks of 
scheduled EGDs.
3. Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated use during the treatment period; any temporary use (≤7 days) or initiation of new 
steroid treatment during the study should be documented and discussed with medical monitor 
prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
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4. Subject on inhaled or intranasal steroids and not on a stable dose between the baseline visit 
(Visit 1) of the SHP621-301 study and the screening EGD of this study.
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma or allergic rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-
301 study or anticipated changes in the use of such medications during the treatment period.
6. Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of such 
medications during the treatment period.
7. Subject has an appearance on screening EGD of an esophageal stricture (high grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9mm). 
8. Subject is on a pure liquid diet or the six-food elimination diet.
9. Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit
(Visit 4) of the SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including 
eosinophilic gastritis, enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac 
disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including 
hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic 
infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous 
treatment. Diagnosis with oropharyngeal or esophageal candidiasis at or since the final 
treatment evaluation visit (Visit 4) of the SHP621-301 study is not an exclusion as long as 
the subject is expected to respond to treatment.
13. Subject has a potentially serious acute or chronic infection or immunodeficiency condition, 
including tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, or 
chicken pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or since the final treatment evaluation visit
(Visit 4) of the SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) of 
the SHP621-301 study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide 
(or any other corticosteroids), or to any other ingredients of the study medication.
19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
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4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No changes in medications or diet since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.

Temporary use (≤7 days) or initiation of new steroid treatment is permitted but cannot occur 
within the 4 weeks of the scheduled EGDs.

Stable treatment with intranasal or inhaled corticosteroids. For subjects with perennial 
allergic rhinitis and stable asthma, the topical corticosteroid must be maintained at the same 
dose throughout the study. For subjects with seasonal allergic rhinitis, it is permissible after 
enrollment to resume (or discontinue) intranasal corticosteroids based on the subject's usual 
treatment regimen for allergy season. (In these subjects, intranasal corticosteroids must not 
be changed between the baseline visit [Visit 1] of the SHP621-301 study and the screening 
EGD of this study). Topical corticosteroid dosing changes should be avoided within 4 weeks 
prior to EGD. Subjects who require a change in inhaled corticosteroid treatment for an 
asthma exacerbation should be discussed with the medical monitor.

No change in use of PPIs, H2 antagonists, antacids, or leukotriene inhibitors for any 
condition (such as gastroesophageal reflux disease, asthma or allergic rhinitis).

No use of cytochrome P450 3A4 (CYP450 3A4) inhibitors (eg, ketoconazole, grapefruit 
juice; see details in Section 5.2.2).

No use of sucralfate during the study as this may interfere with the adherence of OBS.
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit 0), randomization
visit (Visit 1), and Visits 2-8. A serum pregnancy test will be performed at the screening visit
(Visit 0) and final treatment evaluation (Visit 8). Urine pregnancy tests will be performed at all 
other visits.
Female subjects should be either:

Premenarchal and Tanner Stage 1, or

Post menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post sterilization, or

Females of childbearing potential must agree to use acceptable methods of contraception
throughout the study period and for 30 days following the last dose of investigational 
product.

Acceptable methods of contraception are:
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
Abstinence

Surgically sterile male partner

Stable oral contraceptives

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for 
at least 30 days prior to the screening visit (Visit 0), plus condoms. If hormonal 
contraceptives are used, they should be administered according to the package insert.
Note: If subjects become sexually active during the study, they should use 1 of the 
other acceptable methods noted above in addition to the hormonal contraceptive until 
it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 8 are to be performed as completely as 
possible. If investigational product is discontinued due to an AE, the subject may remain on 
study to allow for completion of study procedures. 
Whenever possible, all discontinued subjects should also undergo the protocol-specified follow-
up (Schedule of Assessments, Table 1-1). Comments (spontaneous or elicited) or complaints 
made by the subject must be recorded in the source documents. The reason for termination, date 
of stopping investigational product, and total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
severe signs and symptoms of EoE, such as an esophageal stricture requiring dilation, weight 
loss due to severe dysphagia, and/or upper GI bleed, would be considered a relapse and result in 
withdrawal of the subject from the study. Subjects with oropharyngeal or esophageal candidiasis 
that has failed to respond to treatment by the Week 12 EGD or upper GI bleeding at the Week 12 
EGD will be withdrawn from the study. 
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4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
Reasons for discontinuation include but are not limited to:

Completed

Death

AE

Noncompliance with study drug

Noncompliance with study procedure

Withdrawal by subject

Withdrawal by parent/guardian

Physician decision

Study terminated by sponsor

Site terminated by sponsor

Lost to follow-up

Pregnancy

Study screen failure

Protocol deviation

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
4.5.4
Safety-related Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the 
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar MedDRA higher level group code), 
and considered related to the study drug
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The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) physician and the PVRM therapeutic 
area (TA) Head. The PVRM TA Head, not the PVRM physician involved in the study, may be 
unblinded as part of this urgent safety review, if required. Following the sponsor’s review of 
safety data, one of the following actions will be taken with respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment
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5.
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, and nonpharmacological treatment, such as psychotherapy, as appropriate) received at 
the screening visit (Visit 0) and through the final study contact (including protocol-defined 
follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment, including but not limited to herbal treatments, vitamins, 
and nonpharmacological treatment such as psychotherapy, as appropriate, received at the
screening visit (Visit 0). Prior treatment information must be recorded on the appropriate CRF 
page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in SHP621-302 (Visit 1) and the end of the follow-up period, inclusive.
Concomitant treatment information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been on a 
stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
scheduled EGDs) and will continue this dosing regimen throughout study participation. The 
investigator must contact the medical monitor to discuss any changes to concomitant steroid 
regimens or for any medications not listed here that could impact the outcome of the study.
1.
Inhaled or intranasal steroids (exception for seasonal allergic rhinitis; see Section 4.3)
2.
PPIs
3.
H2 antagonists
4.
Antacids
5.
Leukotriene inhibitors
6.
Maintenance immunotherapy (allergy shots)
Influenza and other routine required vaccinations are allowed during the study.
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5.2.2
Prohibited Treatment
The following medications and treatments are prohibited throughout the course of the study and 
prior to treatment, as specified:
1.
Immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study or use within the 4 weeks of scheduled EGDs. Any temporary use 
(≤7 days) or initiation of new corticosteroid treatment during the study should be 
documented and discussed with the medical monitor prospectively. (Seasonal nasal 
corticosteroid use for seasonal allergic rhinitis is permitted; changes within 4 weeks of 
scheduled EGD should be avoided).
2.
Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition since 
the final treatment evaluation visit (Visit 4) of the SHP621-301 study or use within the 4 
weeks of scheduled EGDs. Any temporary use (≤7 days) or initiation of new steroid 
treatment during the study should be documented and discussed with the medical monitor 
prospectively.
3.
Initiation or change in dosing frequency to PPIs, H2 antagonists, antacids, or leukotriene 
inhibitors for any condition (such as gastroesophageal reflux disease, asthma, or allergic 
rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-301 study, or 
anticipated use of such medications during the treatment period.
4.
CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study, or anticipated changes in the use of such 
medications during the treatment period. For an expanded list of CYP3A inhibitors, 
investigators should refer to the 2012 FDA Draft Guidance on Drug Interactions (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
5.
Sucralfate at screening or anticipated to be used during the treatment period.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in 8 
ounce amber glass, multidose bottles. Additional information is provided in the current SHP621 
investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle form
with the same volume.
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in 8 ounce amber glass, multidose bottles with 
child-resistant caps and refrigerated throughout the study (in the clinic and subject’s home). Each 
bottle contains OBS concentration of 0.2 mg/mL. Inactive ingredients in OBS include dextrose, 
disodium edetate, citric acid, sodium citrate, potassium sorbate, polysorbate 80, glycerin, sodium 
benzoate, cherry flavor, Magnasweet 110, acesulfame potassium, and water.
The placebo suspension will also be supplied in 8 ounce amber glass multidose bottles with 
child-resistant caps. Placebo consists of all components of the investigational product with the 
exception of budesonide.
6.2
Administration of Investigational Product(s)
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last until 
the subsequent visit. The first dose of investigational product for each subject will be 
administered in the clinic. The subject will continue with the evening dosing regimen at home. 
Oral budesonide suspension and placebo will be supplied in amber glass bottles and must be 
shaken well prior to administration. OBS and placebo should be refrigerated at 2-8ºC (36-46ºF)
throughout the study (in the clinic and subject’s home). The appropriate dose will be dispensed 
using the graduated dosing spoon provided. For subjects who are minors (<18 years), a 
parent/guardian will be responsible for ensuring that the subjects take their investigational 
product appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during this 
time interval. After 30 minutes, subjects will be instructed to rinse with water and spit, 
particularly after the bedtime dose.
Please refer to the investigational product Administration Manual for additional details.
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
management, inventory management and supply ordering, investigational product expiration 
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tracking and management, return of investigational product, and emergency unmasking. Please 
refer to the Study Manual for additional details regarding the IWRS.
During the 4-week screening period, blinded treatment response information (reduction in DSQ 
from baseline and eosinophilic count as determined by a central reader) collected during the 
SHP621-301 final treatment evaluation visit will be entered into the IWRS in a blinded manner. 
Once information is available in IWRS, subjects will return for the randomization visit (Visit 1) 
to be assigned to investigational product (OBS 2 mg twice daily or placebo). While only 
SHP621-301 OBS 2 mg twice daily responders will be randomized to continued OBS 2 mg twice 
daily or placebo, all subjects will be assigned to investigational product via IWRS to maintain 
double-blinding of subjects, investigators, the blinded monitoring team and the sponsor (ie, sham 
randomization).
At the randomization visit (Visit 1), the investigator or designee will access the IWRS to either 
document a screen failure or, if the subject has met all entry criteria, to randomize the subject. 
Sites will confirm eligibility criteria information prior to randomization. For randomized 
subjects, the IWRS will provide a medication identification (Med ID) number (ie, kit number to 
dispense for treatment). 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a 4-week screening period and a double-blind treatment period. The actual 
treatment given to individual subjects during the double-blind treatment period will be 
determined by the blinded treatment response information entered at the SHP621-301 final 
treatment evaluation visit.
Subjects will be randomized via a computer-generated randomization schedule at the 
randomization visit (Visit 1) following a 4-week screening period and confirmation of study 
eligibility. Subjects who fully responded to OBS treatment in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the
final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 
2 mg twice daily or placebo at a 1:1 ratio. Subjects who did not respond or partially responded to 
OBS treatment in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were 
assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects, site 
staff, and study team members will remain blinded to treatment assignment and individual 
subject histology and individual subject DSQ data from the SHP621-301 study (post
randomization) and until database lock occurs for this extension study. 
Randomization of subjects in the randomized withdrawal period will also be stratified by age 
(adults and adolescents) to ensure approximately equal number of subjects within each age group 
are assigned to the treatment groups.
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Subject numbers are assigned to all subjects as they consent to take part in the study. The subject 
number consists of the 3 digit study identifier, the 4 digit site identifier, and the 4 digit subject 
identifier. For the SHP621-302 study, the 3 digit site and 4 digit subject numbers will be the 
same as the SHP621-301 study.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject once eligibility has been determined at the randomization visit. 
Individual subject treatment is automatically assigned by the IWRS.
6.2.3
Dosing
During the 4-week screening period, all subjects will receive 10 mL of blinded investigational 
product twice daily based on treatment assignment in SHP621-301. During the 36-week double-
blind treatment period, oral administration of 10 mL of investigational product will occur twice 
daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 30 minutes after study 
drug administration. Subjects randomized to OBS will receive 10 mL of 0.2 mg/mL of OBS 
(2 mg) twice daily for a total daily dose of 4 mg.
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily. The criteria for relapse is having an eosinophil 
count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined by a central 
reader, and having at least 4 days of dysphagia in the 2-week period prior to the scheduled visit, 
as determined by the DSQ. Considering the potential for missing diary entries, the determination 
of relapse based on days of dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, 
the subject would meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within 
the 2-week period, the subject would not meet criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and fewer than 8 diary entries are 
recorded within the 2-week period, the DSQ window can be expanded as described in 
Section 7.2.1.2. 
The criteria for relapse align with the related inclusion criteria for participation in the SHP621-
301 study. If both histology and dysphagia symptom relapse criteria are met, then the treatment 
assignment change will be performed in a blinded manner in IWRS at the subsequent study visit.
If both criteria for relapse are not met, the subject will remain assigned to placebo.
If at any time the subject reports increased or worsening dysphagia symptoms to the investigator, 
the investigator may choose to perform an unscheduled EGD. If an unscheduled EGD is 
performed prior to Week 12, an EGD does not have to be repeated at Week 12. If a subject on 
placebo meets the criteria for relapse, the subject’s treatment assignment will be changed in a 
blinded manner from placebo to OBS 2 mg twice daily at the subsequent study visit. 
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If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 
levels of the esophagus yet relapse is not confirmed due to the criterion for dysphagia symptoms 
not being met, the subject will remain assigned to placebo. If the criterion for dysphagia 
symptoms is met at a subsequent visit and both criteria for relapse are then confirmed, the 
subject’s treatment assignment will be changed to OBS 2 mg twice daily at the next scheduled 
visit. 
Investigational product doses that are required to be administered at the clinic include the first 
dose of randomized investigational product (OBS or placebo) administered at the randomization
visit (Visit 1) and all morning doses of investigational product administered at Visits 2-8.
Subjects will be required to eat breakfast at the clinic prior to self-administering these doses.
Subjects can self-administer all other doses of placebo and investigational product at home. 
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor and the sponsor as soon as possible 
after the investigator has been unblinded.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
There will be a provision for unblinding to ensure adequate treatment of the subject in the case of 
an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the protocol number, Med ID, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
study use only” and/or “CAUTION: New Drug - Limited by Federal (or US) Law to 
Investigational Use,” “Keep out of reach of children,” and the sponsor’s name and address. Any 
additional labeling requirements for participating countries and/or controlled substances will also 
be included on the label.
Space is allocated on the label so that the site representative can record subject information. 
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Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8 ounce amber glass bottle for multiple use. Bottles of OBS 
0.2 mg/mL or placebo will be packaged in an appropriately labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storages
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
OBS and placebo must be refrigerated at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
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The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be stored under refrigeration at 2-8°C/36-46°F at all times.
The investigational product should be protected from light and shaken well immediately prior to 
each dose.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product.
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication
will be documented on the CRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects. The investigator or 
his/her designee will enter the unique subject identifier and initials on the investigational product 
kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken, and the labeled 
amount is to be documented in lieu of counting. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IWRS) do not 
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require a shipment form. Returned investigational product must be packed in a tamper-evident 
manner to ensure product integrity. Contact the sponsor for authorization to return any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational product 
packaging to every visit. Drug accountability must be assessed at the container/packaging level 
for unused investigational product that is contained within the original tamper-evident sealed 
container (eg, bottles) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel. Site 
personnel must review the returned investigational product to assess compliance at every visit 
prior to dispensing additional investigational product. Any discrepancies should be reconciled 
with the subject immediately. Subjects who do not return their used and unused investigational 
product should be reminded to bring all used and unused investigational product at their next 
visit.
Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. Please 
refer to the Pharmacy Manual for additional details.
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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1-1) and must be referred to in conjunction with the 
instructions provided in this section. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). There must be documentation of consent (as per local requirements) 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions, prior to performing any study-related procedures.
7.1.1
Screening Period (Weeks -4 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise up to 4 weeks, during which all procedures listed for the screening visit (Visit 0) in 
Table 1-1 shall be completed. The screening period will allow for the determination of eligibility 
of each subject’s inclusion into the study. A subject should not be instructed to discontinue use 
of any medication or treatment to participate in this study until informed consent has been 
obtained. Subjects should not stop permitted medications or treatments that are effective and well 
tolerated to participate in this study (Section 5.2.1).
Assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the 
screening assessments (Visit 0) of this treatment extension study. Screening assessments may 
take place across several days to allow an appropriate time frame in which to complete all 
procedures and confirm study eligibility. At the SHP621-301 final treatment evaluation visit, 
subjects will be dispensed blinded investigational product (based on treatment assignment in 
SHP621-301) that will last for up to 4 weeks prior to enrolling into this treatment extension 
study. The 4-week screening period is required to allow for blinded treatment response 
information (reduction in DSQ from baseline and eosinophilic count as determined by a central 
reader) collected during the SHP621-301 final treatment evaluation visit to be entered into the 
IWRS.
After the screening period, subjects who meet eligibility criteria at the end of the screening visit
(Visit 0) will enter the 36-week double-blind treatment period. This period should not commence 
until all screening assessments required to confirm initial eligibility have been completed. If the 
subject does not meet eligibility criteria following completion of screening assessments, the 
investigator or designee will document the subject as a screen failure in the IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening or 
randomized visits. Subjects cannot be rescreened once they have been designated as a screen 
failure.
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7.1.1.1
Screening Visit (Visit 0)/Visit 4 of SHP621-301 Study
The screening visit (Visit 0) assessments and procedures, beginning with informed consent, will 
be performed as outlined in Table 1-1.
The following procedures will be performed at the screening visit:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review current use of concomitant medications and procedures. Note: Subjects who are on a 
PPI must remain on the same dose of the PPI throughout the study, and if they are not taking 
a PPI, they must remain off of a PPI for the remainder of the study.

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly completion 
and train the subject on its use. 
The following procedures will be performed at the final treatment evaluation visit (Visit 4) of 
SHP621-301 and will be used as the screening assessments for this extension study:

Review investigational product dosing compliance.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of synthetic 
and route of administration will be per local lab discretion. Additional cortisol samples will 
be drawn at 30 and 60 minutes following stimulation testing.
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging Assessment.
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
Serum pregnancy test will be performed on all female subjects. 

Perform EGD and biopsy either at the investigative site or by a referring physician. 
Esophagogastroduodenoscopy should be completed at or within 7 days of the scheduled visit. 
Biopsy specimens must be available to be sent to the central pathology lab at least 2 weeks 
prior to Visit 1 to allow sufficient time for processing and central review and determination 
of eligibility.

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD) and 
body composition measurements in subjects aged 11-17 years, inclusive. Baseline and post
treatment DXA scans should be performed using the same machine and software.

Dispense blinded investigational product (OBS or placebo; based on treatment assignment in 
SHP621-301) and review administration instructions. The subject will continue with the 
twice daily (morning and evening) dosing regimen. For subjects who are minors (<18 years), 
a parent/guardian will be responsible for ensuring subject takes their investigational product 
appropriately.
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28, and 
36 (or Early Termination)
The double-blind treatment period will comprise 36 weeks, during which all assessments and 
procedures listed for Visits 1-8 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted between Visits 1-6 (Weeks 0-20) 
and a 6-day visit window will be permitted between Visits 7-8 (Weeks 28-36), unless otherwise 
specified. Visit windows are calculated based upon the date of the randomization visit (Visit 1).
Once information for blinded treatment response is available, subjects will return for the 
randomization visit (Visit 1) to receive investigational product. Subjects who continue to meet all 
eligibility criteria and complete the 4-week screening period will have the opportunity to enroll 
in the treatment extension study. Subjects will receive either OBS twice daily (qAM, pc, and hs) 
or placebo twice daily (qAM, pc, and hs).
Subjects who fully responded to OBS treatment in the SHP621-301 study (≤6 eos/HPF across all 
available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation 
visit) will enter a randomized withdrawal period to receive either OBS 2 mg twice daily or 
placebo at a 1:1 ratio. Subjects who did not respond or partially responded to OBS treatment in 
the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were assigned to 
placebo in the SHP621-301 study will receive OBS 2 mg twice daily. The investigator or 
assigned site staff will access the IWRS to randomize the subject and dispense the investigational 
product. Subjects who fail to meet eligibility criteria at the randomization visit (Visit 1) will be 
documented as screen failures in the IWRS and discontinue study drug.
A safety follow-up contact by phone will be performed 4 weeks following the last dose of study 
medication for all subjects (including subjects who fail screening, who discontinue early, or who 
complete the study).
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7.1.2.1
Randomization Visit (Visit 1): Week 0
Subjects will return to the site for the randomization visit (Visit 1) to confirm eligibility. The 
randomization visit (Visit 1) assessments and procedures will be performed as outlined in Table 
1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate in adolescents, 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review investigational product dosing compliance.

Review DSQ compliance; provide subject with instruction to continue completion of the 
DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will record 
the date and time of the first randomized dose in the source documents. Beginning on the 
evening of Visit 1, the subject will take their first dose at home and continue with the twice 
daily (morning and evening) dosing regimen. For subjects who are minors (<18 years), a 
parent/guardian will be responsible for ensuring subject takes their investigational product 
appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
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7.1.2.2
Visits 2 and 3 (Weeks 4 and 8)
Subjects will return to the site for Visit 2 (Week 4) and Visit 3 (Week 8). Assessments at these 
visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate for adolescents, 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of study medication until after the morning cortisol test has been 
performed. 
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.3
Visit 4 (Week 12)
Subjects will return to the site for Visit 4 (Week 12). Assessments at this visit will be performed 
as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
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position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects.

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. In addition, an earlier EGD may also occur if the subject exhibits signs of relapse 
(Section 6.2.3). 
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28)
Subjects will return to the site for Visits 5, 6, and 7 (Weeks 16, 20, and 28). Assessments at these 
visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate for adolescents 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.
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
Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of study medication until after the morning cortisol test has been 
performed. 
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.5
Visit 8 (Week 36) or Early Termination
Subjects will return to the site for Visit 8 (Week 36). Assessments at this visit will be performed 
as outlined in Table 1-1. If a subject discontinues prematurely, the assessments for Visit 8 are to 
be performed as completely as possible.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review current use of concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection. Any subject with an abnormal 
urinary or serum glucose level will be followed closely until resolution (Section 7.2.2.5).

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of synthetic 
and route of administration will be per local lab discretion. Additional cortisol samples will 
be drawn at 30 and 60 minutes following stimulation testing. Any subject with an abnormal 
ACTH stimulation test will be followed closely until resolution (Section 7.2.2.5).
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The following order is recommended for the remaining procedures that will be performed at this 
visit:

Retrieve DSQ handset and review DSQ compliance.
 
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging Assessment.
Any subject with clinical evidence of reduced height velocity and/or delayed Tanner staging 
will be followed closely until resolution (Section 7.2.2.2).

Serum pregnancy test will be performed on all female subjects.

Perform DXA scan for BMD and body composition measurements in subjects aged 
11-17 years, inclusive. Dual-energy X-ray absorptiometry scans should be performed at this 
visit or within 7 days of the scheduled visit using the same machine and software as used in 
the SHP621-301 study.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. An earlier EGD may occur if the subject exhibits signs of relapse (Section 6.2.3); 
however, the Week 36 EGD must be completed.

Review investigational product dosing compliance.
7.1.3
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational product. 
Subjects will receive a follow-up phone call at Visit 9 (Week 40) to query for SAEs, AEs, and 
concomitant treatments (Section 7.1.3.1).
7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40
Assessments at this time, as outlined in Table 1-1, will include the following:

Review concomitant medications and procedures.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE; all 
AEs and SAEs that are not resolved at the time of this contact will be followed to closure.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in
Appendix 2.
All assessments listed below will be performed by the subject and/or a qualified/trained site staff 
as indicated in the assessment description. For subject-completed assessments, trained site staff 
should not assist the subject in completing any of the questions as this can influence their 
responses. Site staff should review the completed assessment to ensure completeness.
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If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales after 
the visit has been completed. Assessments are to be performed according to the schedule shown 
in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
The screening EGD with biopsies will be performed by a physician at the investigative site at the 
final treatment evaluation visit in the SHP621-301 study. Biopsy specimens must be taken and 
provided to the central pathology lab by at least 2 weeks prior to the planned Visit 1 to allow 
sufficient time for processing and central review and determination of eligibility. Subjects, site 
staff, and study team members will remain blinded to eosinophil counts and histopathologic 
findings by the central reader throughout the duration of the study.
At the Week 12 visit (Visit 4), and Week 36 visit (Visit 8) or at early termination (ET), an EGD 
with esophageal biopsies is required for all subjects. If at any time, the subject reports increased 
or worsening dysphagia symptoms to the investigator, the investigator may choose to perform an 
unscheduled EGD. If an unscheduled EGD is performed prior to Week 12, an EGD does not 
have to be repeated at Week 12. If an unscheduled EGD is performed between Week 12 and 
Week 36, the Week 36 EGD should still be performed. Multiple specimens (at least 2 biopsies 
from each of 3 levels, 6 specimens total) will be obtained from the proximal (3 cm below the 
cricopharyngeus muscle), midesophagus (midpoint between the cricopharyngeus muscle and the 
gastroesophageal junction), and distal (3 cm above the gastroesophageal junction). Biopsy tissue 
will be placed in 3 separate vials (1 vial for each of the levels) and sent to the central pathology 
laboratory for processing of tissue into slides. Eosinophil counts and, histopathologic features 
will be evaluated by the central reader and scored for each EGD. Eight histopathologic epithelial 
features (basal layer hyperplasia, eosinophil density, eosinophil microabscesses, eosinophil 
surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial 
cells, lamina propria fibrosis) will be scored on a 4-point scale (0=normal, 3=worst) for both the 
severity of the abnormality (ie, grade) and the amount of tissue affected by the abnormality (ie, 
stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 2) 
fixed esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed for 
each anatomic location (proximal and distal). The maximum endoscopy score is 10 points for 
each location, and a total endoscopy score is the sum of the scores for the proximal and distal 
locations.
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In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. At the investigator’s discretion, biopsies will be taken from the stomach and 
duodenum as follows: gastric body (greater curvature): 2 specimens, gastric antrum: 
2 specimens, and duodenum (third part or distal): 2 specimens. Biopsies from the stomach should 
be submitted in 1 vial; biopsies from the duodenum should be submitted in a separate vial to the 
central pathology laboratory for processing of tissue into slides. 
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 3). 
The questionnaire will be completed by subjects daily during the screening period and during the 
36-week treatment period. Each evening before bedtime, subjects will be asked to indicate if they 
experienced dysphagia symptoms (eg, food passing slowly or food sticking) during that day.
Subjects must fill out the DSQ at least 5 or more days during a given week in order to be 
compliant. Visit to visit compliance of DSQ completion will also be assessed by site personnel. 
Protocol deviations will be documented for subjects who fail to complete the DSQ for 3 or more 
days in a given week.
To meet relapse criteria, the subject must have at least 4 days of dysphagia as determined by the 
DSQ in the 2-week period prior to the scheduled visit in addition to meeting the eosinophil 
histology criterion (≥15 eos/HPF from at least 2 of 3 levels of the esophagus). Considering the 
potential for missing diary entries, the determination of relapse based on days of dysphagia 
reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, 
the subject would meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within 
the 2-week period, the subject would not meet criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and less than 8 diary entries are recorded within 
the 2-week period, then the 2-week period will be shifted backwards from the scheduled 
visit, 1 day at a time, to confirm if the subject meets the criteria for dysphagia symptom
relapse over 14 consecutive days; however, the 2-week period will not be shifted further if at 
least 8 diary entries are recorded in the 14-day period and will not be shifted by more than 2 
weeks (ie, no more than 2-week period plus additional 2-week additional expansion).
Calculations will be performed on daily ePRO entries during a 2-week interval prior to each 
study visit during the treatment period. The DSQ score for the coprimary endpoint and secondary 
endpoints will be calculated by summing the scores of responses to questions 2 and 3 only. 
Questions 1 and 4 will be excluded from the DSQ score:
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
DSQ score =   (Sum of points from questions 2+3 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores of 
responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score = (Sum of points from questions 2+3+4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score = (Sum of points from question 4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
MEDICAL HISTORY
The investigator must record all new clinically or medically relevant information which arose 
after the recording of the medical history in the antecedent study. New medical history will be 
collected at the screening visit (Visit 0) of this study. Medical history will be classified as EoE or 
non-EoE by the investigator. Adverse events recorded during the SHP621-301 study may be
added as medical history at the investigator’s discretion.
MEDICATION HISTORY
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, or 
other), must be recorded on the appropriate CRF page.
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit 0) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit 0) 
will be captured as AEs on the AE CRF page, as deemed by the investigator.
Physical examination assessments at each visit should also include specific assessments for signs 
of glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swings, insomnia, and 
depression). Physical examination at the screening visit (Visit 0) will also include Tanner 
Staging Assessments for subjects <18 years of age.
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Height will be collected at the screening visit (Visit 0) and Visit 8 for all subjects and at Visit 4 
for adolescents (11-17 years, inclusive) only. Stadiometers will be used to measure height for
subjects aged 11-17 years, inclusive. Statural height will be measured by trained site staff using a 
stabilized stadiometer. Height will be measured in triplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF. The same stadiometer should be used for the baseline and 
post treatment measurements. Standard measuring procedures should be followed (eg, removal 
of socks, shoes, and hats). The stadiometer must be calibrated at least once daily, and as feasible, 
within 4 hours of each measurement. All measurements should be recorded to the nearest 10th of 
a centimeter (1 mm). Please refer to the study manual for additional details.
Weight will be measured in duplicate in adolescents (11-17 years, inclusive) and recorded in the 
CRF.
All subjects with clinical evidence of reduced height velocity and/or delayed Tanner Staging, as 
determined by the investigator, must be followed closely until resolution (ie, resumption of 
normal for age height velocity, or the resumption of Tanner Stage development). Subjects who 
discontinue from the treatment period at any time and have clinical evidence of reduced height 
velocity and/or delayed Tanner Stage development at the early termination visit will be 
monitored beyond the end of the study until resolution is established. 
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
AEs are collected from the time informed consent is signed. (Please refer to Section 8) Any AE 
that is ongoing from the SHP621-301 study must be recorded on the CRF for this study. 
AE assessments at each visit should also include specific assessments for signs of glucocorticoid 
excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment and will include blood pressure (systolic and diastolic), heart rate, 
respirations, and temperature. Blood pressure should be determined by cuff (using the same 
method, the same arm, and in the same position throughout the study). Any clinically significant 
deviations from baseline in vital signs that are deemed clinically significant in the opinion of the 
investigator are to be recorded as an AE.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures.
All subjects must fast overnight prior to collection of clinical laboratory tests.
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
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discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose 

blood urea nitrogen 

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
Adrenocorticotropic hormone stimulation testing will be performed by measuring the levels of 
cortisol in the blood following the injection of a synthetic form of ACTH. The type of synthetic 
and route of administration will be per local lab discretion. Blood samples will be collected just 
prior to and approximately 30 and 60 minutes following the injection. Administration of ACTH 
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stimulation testing and sample collection should follow the same procedures used in the 
SHP621-301 study.
In the event of clinically significant abnormal laboratory test results, follow-up laboratory tests 
may be conducted. All subjects with an abnormal ACTH stimulation test or urinary or serum 
glucose level must be followed closely until resolution. Subjects who discontinue from the 
treatment period at any time and have an abnormal ACTH stimulation test at the early 
termination visit will be scheduled for repeat ACTH testing approximately 6 weeks post last dose 
of investigational product and followed to resolution of the abnormality. Any clinically 
significant abnormalities noted in the laboratory tests will be discussed with the medical monitor.
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit (Visit 0) 
and the final treatment evaluation visit (Visit 8) or ET visit. A urine pregnancy test is performed 
on all female subjects at all other visits or if pregnancy is suspected.
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density
Dual-energy X-ray absorptiometry (also referred to as DEXA) scans for determination of BMD 
and body composition measurements will be performed in subjects aged 11-17 years, inclusive,
as outlined in Table 1-1.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body less 
head (Bachrach 2011; Gordon et al. 2008; International Society for Clinical Densitometry 2013). 
Dual-energy X-ray absorptiometry body composition measurements will also be collected. The 
same DXA machine and software should be used for the baseline and post treatment scans. The 
DXA manufacturer, model, and software version should be recorded in the CRF.
7.2.3
Other Assessments
 
 
 
 
 
 
 
 
 
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7.2.4
Volume of Blood to Be Drawn from Each Subject
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Safety
Biochemistry and -hCGa
6
9
54
ACTH
2
4
8
Cortisol
2
9
18
Hematology
2
9
18
Total mL
-
-
98
Abbreviations: ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropina -hCG testing 
is for females only.
During this study, it is expected that approximately 98 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 98 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined. 
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening period of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related” based on the definitions in Table 8-1. The 
causality assessment must be documented in the source document.
Table 8-1: Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or other 
drugs and chemicals and which follows a clinically reasonable response on 
dechallenge. The association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (dechallenge), and reappears upon 
repeated exposure (rechallenge). Note that this is not to be construed as requiring 
reexposure of the patient to study drug; however, the determination of definitely 
related can only be used when recurrence of event is observed.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
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data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign assessment can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment period, there are abnormal clinical laboratory or vital sign values 
which were not present at the pretreatment value observed closest to the start of study treatment, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign parameter is clinically significant 
and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form
for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is not 
considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
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8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of 4 mg of the product.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parents/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO medical monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
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not apply to reports of abuse, misuse, overdose, or medication errors (Section 8.1.7) unless they 
result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol (and any applicable follow-up reports) must
also be sent to the CRO medical monitor using the details specified in the emergency contact 
information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

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 was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the medical 
monitor within 24 hours of the first awareness of the event. 
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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, leading up to the onset date of the SAE, or following the resolution date of the SAE must 
be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have “fatal” checked as an outcome with the date of death recorded as the resolution date.
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered as not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and the clinical CRO are responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP621
program. 
The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel.
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
The SAP will be finalized prior to final database lock and performing analysis (ie, unblinding) to 
preserve the integrity of the statistical analysis and study conclusions. 
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9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis is planned.
9.6
Sample Size Calculation and Power Considerations
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated 
to complete the SHP621-301 study and enroll in this treatment extension study based on 
enrollment observed in the Phase 2 study (MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse during
the double-blind randomized withdrawal period, defined as having an eosinophil count of 
≥15 eos/HPF from at least 2 of 3 levels of the esophagus (as determined by a central reader) and 
at least 4 days of dysphagia in the 2-week period prior to the scheduled visit (as determined by 
the DSQ). To be considered as a subject with relapse, both criteria must be met. To determine 
whether a subject meets the criterion for dysphagia, refer to Section 7.2.1.2.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or 
approximately 40 subjects, who were assigned to OBS treatment in the SHP621-301 study are 
anticipated to respond fully after 12 weeks in the SHP621-301 study. For this study, to detect a 
50 percentage point difference between relapse proportions of 20% and 70% in the OBS and 
placebo groups, respectively, at more than 80% power and a significance level of 0.05 (2-sided) 
using the Fisher’s Exact test with equal allocation to treatment groups, it is necessary to assess 
the primary efficacy measure for approximately 38 subjects (19 subjects in each of the OBS and 
placebo groups). 
9.7
Study Population
The safety set will include all subjects who are randomized and receive at least 1 dose of 
investigational product.
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of 
investigational product and had 1 post baseline efficacy assessment (biopsy and/or DSQ score).
The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major 
protocol deviations. The PP set will be identified prior to unblinding the treatment assignments 
by a team consisting of, at a minimum, a physician and a statistician from Shire. 
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized 
withdrawal period. Relapse, a binary response (either with a relapse or not), is defined as having 
an eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined 
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by a central reader, and having at least 4 days of dysphagia in the 2-week period prior to the 
scheduled visit, as determined by the DSQ (refer to Section 7.2.1.2).
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse during
the double-blind randomized withdrawal period for the FAS, using a Fisher’s Exact test 
comparing OBS 2 mg twice daily against placebo. The primary test of treatment effect will be 
2-sided, and conducted at the significance level of 0.05. The proportion of subjects with relapse 
for each treatment group and the corresponding 95% confidence interval (CI) will be estimated. 
In addition, the difference in the proportion of subjects with relapse between the 2 treatment 
groups and its 95% CI will be estimated.
Subjects who withdraw without providing efficacy data at the ET visit will be classified as being
relapsers in the primary efficacy analysis. The null hypothesis states that there is no difference in 
relapse proportions between OBS 2 mg twice daily and placebo, with the 2-sided alternative of a 
nonzero difference between groups. Relapse proportions at each adjacent double-blind visit 
interval will also be assessed by applying the Fisher’s Exact test to the observed data at each 
double-blind visit.
The following sensitivity and supportive analyses will be performed for the primary endpoint to 
evaluate the robustness of the results from the primary analysis methods.
Similar analyses used for the ITT population will be repeated using the FAS and the PP datasets. 
Sensitivity analyses will be performed using the ITT population by classifying subjects who 
withdraw without providing efficacy data at the ET visit as non-relapsers. In addition, the
subjects who were prematurely withdrawn from the study without the primary efficacy endpoint 
will be imputed randomly according to the distribution of relapsers with available data; and the 
similar statistical test will be performed using the imputed data.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the long-term treatment response, a binary response over 
an extended period of 36 weeks in adolescent and adult subjects who were randomized to OBS 
treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject did not 
have peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit 
and/or ≥30% reduction in DSQ score from baseline) and met the following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline of the SHP621-301 study and from baseline of this extension 
study to the final treatment period evaluation (Visit 8)
The key secondary efficacy endpoint will be analyzed as the proportion of subjects who 
responded based on the histological data and the DSQ data at the final treatment period 
evaluation (Visit 8). The proportion of subjects with long-term treatment response and the 
corresponding 95% confidence interval (CI) will be estimated and summarized. 
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The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at each assessment visit

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study 

Change in the DSQ score and change in the peak eosinophilic count at each assessment visit 
from baseline of the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension 
study 

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each assessment 
visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each assessment 
visit 

Change in the peak eosinophil count at each assessment visit from baseline of the SHP621-
301 study and from baseline of this extension study at each assessment visit for each 
available esophageal level (proximal, mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at 
each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), at each assessments visit from baseline of the SHP621-301 
study and from baseline of this extension study

Change in the DSQ combined score (questions 2+3) at each assessment from baseline of the 
SHP621-301 study and from baseline of this extension study 

Cumulative distribution function curves for the change and the percent change in the DSQ 
score at each assessment visit from baseline of the SHP621-301 study and from baseline of 
this extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline of 
the SHP621-301 study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study 
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Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the 
change from baseline of the SHP621-301 study and from baseline of this extension study at the 
final treatment period evaluation (Visit 8) will be summarized by each assessment visit. 
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo in 
the SHP621-301 induction study, the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the 
corresponding 95% CI will be summarized. Summary statistics of the DSQ score (questions 2+3) 
and the peak eosinophil count and the change from baseline of the SHP621-301 study and from 
baseline of this extension study at the final treatment period evaluation (Visit 8) will be 
summarized by each assessment visit. 
For subjects who relapse on placebo during the randomized withdrawal and who reinitiate 
treatment with OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for 
histological data and DSQ endpoints will be conducted at each assessment visit. Changes will be 
summarized over time from baseline of the SHP621-301 study and from the time of relapse. The 
same criteria for response will be applied to these subjects (≤6 eos/HPF across all available 
esophageal levels and at least a 30% reduction in DSQ from SHP621-301 baseline score).
Summary statistics will be provided for all other secondary endpoints.
9.8.3
Exploratory Efficacy Endpoints
The exploratory endpoints that will be explored are the following:

 
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the randomization visit (Visit 1), or at the screening visit (Visit 0) if 
not collected at Visit 1, will be used as the baseline value for safety analyses.
TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product and no later than 3 days following the last dose of investigational product. However, for 
any subjects who die during the study (ie, the date of death is between the date of first dose of 
investigational product and the date of study discontinuation entered by the site, inclusive), all 
AEs (including those resulting in death) that occur during the study will be considered as TEAEs 
irrespective of the last dose and will be included in the TEAE summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of TEAEs 
will be calculated overall by system organ class, preferred term, and treatment group. TEAEs
will be further summarized by severity and relationship to investigational product. AEs related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
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Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and 
height assessments, DXA scans for BMD and body composition measurements (for adolescents 
aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum 
pregnancy test, if appropriate), and ACTH stimulation tests. To account for the effects of puberty
in adolescent subjects (11-17 years of age, inclusive), BMD z-scores will be adjusted for height 
z-scores using the Bone Mineral Density in Childhood Study calculator
(Bone Mineral Density in Childhood Study 2015). Safety parameters will be descriptively 
summarized by treatment group at baseline and for each post baseline visit.
 
 
 
 
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
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the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study, which has been posted to a designated public website, will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
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the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with instructions 
from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The data from the central pathologist will be recorded directly onto paper CRF.
All other data will have separate source documentation; no data will be recorded directly onto 
the CRF. The following data collected for assessments and procedures performed at the 
SHP621-301 final treatment evaluation visit (Visit 4) will not be recollected in the SHP621-302 
database as follows (Section 7.1.1.1):

Vital signs, height, and weight assessment

EGD with endoscopy score (EREFS) and biopsy

DSQ compliance assessment

Physical examination

Tanner Staging Assessment

Clinical laboratory tests

Urinalysis

Pregnancy test

Morning cortisol

ACTH Stimulation Testing
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
DXA Scan (subjects 11 to 17 years of age)
All other data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to subject’s 
medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (or assent as 
applicable for subjects <18 years of age) from all study subjects prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s legally authorized 
representative, as applicable, is requested to sign and date the subject’s informed consent form or 
a certified translation, if applicable, after the subject has received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parents/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and received 
their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable opinion/approval 
of these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible for 
this action. Additionally, if the IRB/EC requires modification of the sample subject information 
and consent document provided by the sponsor, the documentation supporting this requirement 
must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator or,
for multicenter studies, the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
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Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP621; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purposes of any such transfer would include 
supporting regulatory submissions, conducting new data analyses to publish or present the study 
results, or answering questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg,
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
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All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral, or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11.
REFERENCES
Bachrach LK, Sills IN, Section on Endocrinology. Clinical report—bone densitometry in 
children and adolescents. Pediatrics. 2011;127(1):189-94.
Bone Mineral Density in Childhood Study (BMDCS). Available at:
http://www.bmdcspublic.com. Accessed August 5, 2015. 
Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in the United 
States. Clin Gastroenterol Hepatol. 2014a;12(4):589-96.
Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic esophagitis 
is a progressive fibrostenotic disease. Gastrointest Endosc. 2014b;79(4):577-85.
 
Food and Drug Administration. Uceris pharmacology review. NDA 203-634. 2011.
Food and Drug Administration. Draft Guidance: Drug Interaction Studies – Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. US Department of Health 
and Human Services, Center for Drug Evaluation and Research (CDER), February 2012.
 
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a 
systematic review and consensus recommendations for diagnosis and treatment. 
Gastroenterology. 2007;133(4):1342-63.
Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17):1640-48.
Gordon CM, Bachrach LK, Carpenter TO, et al. Duel energy X-ray absorptiometry interpretation 
and reporting in children and adolescents: the 2007 ISCD pediatric official positions. J Clin 
Densitom. 2008;11(1):43-58.
Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterol Clin North Am. 2014;43(2):297-316.
International Society for Clinical Densitometry. 2013 Official Positions—Adult & Pediatric. 
2014:1-20.
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3-20. 
 
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12.
APPENDIX
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Protocol Amendment 1
22 Jun 2016
Global
Original Protocol
05 Dec 2015
Global
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Appendix 2
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Subject
Tanner Staging Assessment
Site
EREFS
Site
Abbreviations: DSQ=Dysphagia Symptom Questionnaire; 
 
 EREFS=EoE Endoscopic Reference Score; 
 
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above, and a new master file containing the revised scale/assessment will be provided to the site. 
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Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE
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PROTOCOL: SHP621-302
TITLE:
A Phase 3, Multicenter, Double-blind Extension Study to Evaluate 
Maintenance of Efficacy of Oral Budesonide Suspension (OBS) and 
Long-term Treatment Effect of OBS in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 05 Dec 2015
Protocol Amendment 1: 22 Jun 2016
Protocol Amendment 2: 19 Dec 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.
For non-commercial use only

PROTOCOL SIGNATURE PAGE 
·Date: 
Page2 
19 Dec 
Sponsor's (Shire) Approval 
, MD 
 
Acknowledgement 
I have read this protocol for Shire Study SHP621-302. 
Title: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of 
Efficacy of Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in 
Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis 
(Eo E) 
I have fully discussed the objective( s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ---------------Date: 
Shire 
Protocol Amendment 2 
SHP621-302
CONFIDENTIAL 
 
Page 2 
 
19 Dec 2016
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Protocol Amendment 2
SHP621-302
19 Dec 2016
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The SHP621-302 protocol is amended to address the following items:

Update the dysphagia relapse criterion as it pertains to missing diary data. This change to this 
criterion will result in subjects being considered a relapse for treatment assignment change 
from placebo if they meet the dysphagia symptom criterion by missing diary data and meet 
the eosinophil histology criterion.

Clarify the primary efficacy analyses, including providing for sensitivity analysis in which 
patients with missing diary data be treated as not being relapsed.
  
Additional edits, as captured in the below table, were made to Protocol Amendment 2 to improve 
the clarity of the protocol and/or correct minor inconsistencies. Note that correction of typos and 
grammatical errors are not captured in the below table.
New text indicated in bold; deleted text indicated in strikethrough.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
19 Dec 2016
Global Amendment
Description of Change
Section(s) Affected by Change

If less than 4 days of dysphagia are reported in the DSQ and less 
than 8 diary entries are recorded within the 2 week period, then the 
2-week period will be shifted backwards from the scheduled visit, 1 
day at a time, to confirm if the subject meets the criteria for 
dysphagia symptom relapse over 14 consecutive days; however, the 
2-week period will not be shifted further if at least 8 diary entries are 
recorded in the 14-day period and will not be shifted by more than 2 
weeks in total (ie, no more than 2-week period plus additional 2-
week additional expansion). the subject would be designated as 
meeting the criterion for dysphagia symptom relapse due to 
missing diary data.
Rationale: To update the dysphagia symptom relapse criterion to result in 
subjects being considered a relapse for treatment assignment change from 
placebo if they meet the dysphagia symptom criterion by missing diary data 
and meet the eosinophil histology criterion
Synopsis: Investigational 
product, dose, and mode of 
administration;
Section 6.2.3: Dosing;
Section 7.2.1.2: Dysphagia 
Symptom Questionnaire
4.
Subject on inhaled or intranasal steroids and not on a stable dose
between in the baseline visit (Visit 1) of the SHP621-301 study and 4 weeks 
before the screening EGD of this study
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
Sensitivity analyses will be performed using the ITT population by 
classifying subjects who met the histology relapse criterion and met the 
dysphagia symptom relapse criterion due to missing diary data as non-
relapsers.
Rationale: To provide for sensitivity analysis in which patients with missing 
Synopsis: Statistical 
Methodology for Primary 
Efficacy Endpoint
Section 9.8.1: Primary Efficacy 
Endpoint
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Protocol Amendment 2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
19 Dec 2016
Global Amendment
Description of Change
Section(s) Affected by Change
diary data are treated as not being relapsed.
The following sensitivity and supportive analyses will be performed for 
the primary endpoint to evaluate the robustness of the results from the 
primary analysis methods.
Similar analyses used for the ITT population will be repeated using the 
FAS and the PP datasets. Sensitivity analyses will be performed using 
the ITT population by classifying subjects who withdraw without 
providing efficacy data at the ET visit as non-relapsers.
In addition, the subjects who were prematurely withdrawn from the 
study without the primary efficacy endpoint will be imputed randomly 
according to the distribution of relapsers with available data; and the 
similar statistical test will be performed using the imputed data.  
Rationale: Added text to the synopsis describing sensitivity analyses for the 
primary endpoint to be consistent with text in Section 9.8.1.
Synopsis: Statistical 
Methodology for Primary 
Efficacy Endpoint
Section 9.8.1: Primary Efficacy 
Endpoint
•
Stable treatment with intranasal or inhaled corticosteroids. For 
subjects with perennial allergic rhinitis and stable asthma, the topical 
corticosteroid must be maintained at the same dose throughout the study. For 
subjects with seasonal allergic rhinitis, it is permissible after enrollment to 
resume (or discontinue) intranasal corticosteroids based on the subject's usual 
treatment regimen for allergy season. (In these subjects, intranasal 
corticosteroids must not be changed between the baseline visit [Visit 1] of the
SHP621 301 study and the screening EGD of this study).All topical 
corticosteroid dosing changes, including those for seasonal allergic 
rhinitis, should be avoided within 4 weeks prior to EGD. Subjects who 
require a change in inhaled corticosteroid treatment for an asthma 
exacerbation should be discussed with the medical monitor.
Section 4.3: Restrictions
Relapse, a binary response (either with a relapse or not), is defined as having 
an eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the 
esophagus, as determined by a central reader, and having at least 4 days of 
dysphagia in the 2-week period prior to the scheduled visit, as determined by 
the DSQ (refer to Section 7.2.1.2 for additional detail, including missing 
diary data handling).
Section 9.8.1: Primary Efficacy 
Endpoint
See Appendix 1 for protocol history, including all amendments.
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Protocol Amendment 2
SHP621-302
19 Dec 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the 
Protocol Form within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of this form must also be sent to the contract research organization 
(CRO)/Shire Medical Monitor by fax or e-mail using the details below.
, MD
Email: 
Fax: 
For protocol- or safety-related issues during normal business hours (8 am to 5 pm Eastern 
Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile:
Email: 
Fax: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile: 
Email: 
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Protocol Amendment 2
SHP621-302
19 Dec 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
 or 
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19 Dec 2016
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
LIST OF ABBREVIATIONS........................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................23
1.
BACKGROUND INFORMATION.......................................................................................27
1.1
Indication and Current Treatment Options...............................................................27
1.2
Product Background and Clinical Information ........................................................27
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................29
2.1
Rationale for the Study.............................................................................................29
2.2
Study Objectives ......................................................................................................29
2.2.1
Primary Objective..................................................................................................29
2.2.2
Secondary Objectives.............................................................................................29
3.
STUDY DESIGN ...................................................................................................................31
3.1
Study Design and Flow Chart ..................................................................................31
3.2
Duration and Study Completion Definition .............................................................33
3.3
Sites and Regions .....................................................................................................34
4.
STUDY POPULATION.........................................................................................................35
4.1
Inclusion Criteria......................................................................................................35
4.2
Exclusion Criteria.....................................................................................................35
4.3
Restrictions...............................................................................................................37
4.4
Reproductive Potential .............................................................................................37
4.4.1
Female Contraception............................................................................................37
4.5
Discontinuation of Subjects .....................................................................................38
4.5.1
Subject Withdrawal Criteria ..................................................................................38
4.5.2
Reasons for Discontinuation..................................................................................39
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................39
4.5.4
Safety-related Stopping Rules................................................................................39
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................41
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5.1
Prior Treatment ........................................................................................................41
5.2
Concomitant Treatment............................................................................................41
5.2.1
Permitted Treatment...............................................................................................41
5.2.2
Prohibited Treatment .............................................................................................42
6.
INVESTIGATIONAL PRODUCT ........................................................................................43
6.1
Identity of Investigational Product...........................................................................43
6.1.1
Blinding the Treatment Assignment ......................................................................43
6.2
Administration of Investigational Product(s)...........................................................43
6.2.1
Interactive Response Technology for Investigational Product Management ........43
6.2.2
Allocation of Subjects to Treatment ......................................................................44
6.2.3
Dosing....................................................................................................................45
6.2.4
Unblinding the Treatment Assignment..................................................................46
6.3
Labeling, Packaging, Storage, and Handling ...........................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................47
6.3.3
Storages..................................................................................................................47
6.3.4
Special Handling....................................................................................................48
6.4
Drug Accountability.................................................................................................48
6.5
Subject Compliance..................................................................................................49
7.
STUDY PROCEDURES........................................................................................................50
7.1
Study Schedule.........................................................................................................50
7.1.1
Screening Period (Weeks -4 to 0)..........................................................................50
7.1.1.1
Screening Visit (Visit 0)/Visit 4 of SHP621-301 Study ........................51
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28, 
and 36 (or Early Termination) ...............................................................................52
7.1.2.1
Randomization Visit (Visit 1): Week 0..................................................53
7.1.2.2
Visits 2 and 3 (Weeks 4 and 8) ..............................................................54
7.1.2.3
Visit 4 (Week 12) ...................................................................................54
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28) ..............................................55
7.1.2.5
Visit 8 (Week 36) or Early Termination ................................................56
7.1.3
Follow-up Period ...................................................................................................57
7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40........................................57
7.2
Study Evaluations and Procedures ...........................................................................57
7.2.1
Efficacy..................................................................................................................58
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation....................................................................58
7.2.1.2
Dysphagia Symptom Questionnaire.......................................................59
7.2.2
Safety .....................................................................................................................60
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7.2.2.1
Medical and Medication History............................................................60
7.2.2.2
Physical Examination (Including Height and Weight) ..........................60
7.2.2.3
Adverse Event Collection.......................................................................61
7.2.2.4
Vital Signs..............................................................................................61
7.2.2.5
Clinical Laboratory Evaluations.............................................................61
7.2.2.6
Pregnancy Test .......................................................................................63
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density.............63
7.2.3
Other Assessments.................................................................................................63
7.2.3.2
Severity of Disease Assessments ...........................................................64
7.2.4
Volume of Blood to Be Drawn from Each Subject ...............................................65
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................66
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................66
8.1.1
Severity Categorization..........................................................................................66
8.1.2
Relationship Categorization...................................................................................67
8.1.3
Outcome Categorization ........................................................................................67
8.1.4
Symptoms of the Disease under Study ..................................................................68
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................68
8.1.6
Pregnancy...............................................................................................................68
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................69
8.2
Serious Adverse Event Procedures ..........................................................................69
8.2.1
Reference Safety Information................................................................................69
8.2.2
Reporting Procedures.............................................................................................70
8.2.3
Serious Adverse Event Definition .........................................................................70
8.2.4
Serious Adverse Event Collection Time Frame.....................................................71
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................71
8.2.6
Fatal Outcome........................................................................................................71
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................71
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................72
9.1
Data Collection.........................................................................................................72
9.2
Clinical Data Management.......................................................................................72
9.3
Data Handling Considerations..................................................................................72
9.4
Statistical Analysis Process......................................................................................72
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......73
9.6
Sample Size Calculation and Power Considerations................................................73
9.7
Study Population ......................................................................................................73
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9.8
Efficacy Analyses.....................................................................................................74
9.8.1
Primary Efficacy Endpoint ....................................................................................74
9.8.2
Secondary Efficacy Endpoints...............................................................................74
9.8.2.1
Key Secondary Efficacy Endpoint .........................................................74
9.9
Safety Analyses........................................................................................................76
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................78
10.1
Sponsor’s Responsibilities .......................................................................................78
10.1.1 Good Clinical Practice Compliance.......................................................................78
10.1.2 Indemnity/Liability and Insurance.........................................................................78
10.1.3 Public Posting of Study Information......................................................................78
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................78
10.1.5 Study Suspension, Termination, and Completion..................................................79
10.2
Investigator’s Responsibilities .................................................................................79
10.2.1 Good Clinical Practice Compliance.......................................................................79
10.2.2 Protocol Adherence and Investigator Agreement..................................................79
10.2.3 Documentation and Retention of Records.............................................................80
10.2.3.1
Case Report Forms.................................................................................80
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................81
10.2.3.3
Audit/Inspection.....................................................................................81
10.2.3.4
Financial Disclosure...............................................................................81
10.3
Ethical Considerations..............................................................................................82
10.3.1 Informed Consent...................................................................................................82
10.3.2 Institutional Review Board or Ethics Committee..................................................82
10.4
Privacy and Confidentiality......................................................................................83
10.5
Study Results/Publication Policy .............................................................................83
11. REFERENCES .......................................................................................................................85
12. APPENDIX.............................................................................................................................87
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LIST OF TABLES
Table 1-1
Schedule of Assessments...............................................................................23
Table 7-1
Approximate Volume of Blood to Be Drawn from Each Subject.................65
Table 8-1
Adverse Event Relatedness ...........................................................................67
LIST OF FIGURES
Figure 3-1
  Study Design Flow Chart ............................................................................31
LIST OF APPENDICES
Appendix 1
Protocol History .....................................................................................88
Appendix 2
Scales and Assessments .........................................................................94
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE...............................95
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LIST OF ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
β-hCG
beta-human chorionic gonadotropin
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CYP450 3A4
cytochrome P450 3A4
DSQ
Dysphagia Symptom Questionnaire
DXA (DEXA)
dual-energy X-ray absorptiometry
EC
ethics committee
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
  
ePRO
electronic patient-reported outcome
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
HPF
high-powered field
hs
at bedtime
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
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ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication information
MedDRA
Medical Dictionary for Regulatory Activities
OBS
oral budesonide suspension
pc
after meals
PP
per-protocol
PPI
proton pump inhibitor
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
TEAE
treatment-emergent adverse event
UK
United Kingdom
US
United States
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STUDY SYNOPSIS
Protocol number: SHP621-302
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: A Phase 3, Multicenter, Double-blind Extension Study to Evaluate Maintenance of Efficacy of 
Oral Budesonide Suspension (OBS) and Long-term Treatment Effect of OBS in Adolescent and Adult Subjects (11 
to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis (EoE)
Number of subjects (total and for each treatment arm):
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to complete the 
SHP621-301 study and enroll in this treatment extension study based on enrollment observed in the Phase 2 study 
(MPI 101-06).
Investigator(s): Multicenter study
Site(s) and Region(s):
Approximately 60 sites in North America
Study period (planned):
April 2016–April 2019
Clinical phase:
3
Objectives
Primary:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak eosinophilic count and the 
Dysphagia Symptom Questionnaire (DSQ) score, through a randomized withdrawal design for subjects who 
responded to 12 weeks of OBS treatment (2 mg twice daily) with a peak count of ≤6 eosinophils 
(eos)/high-powered field (HPF) across all available esophageal levels at the final treatment visit and a ≥30% 
reduction in DSQ score from baseline during the SHP621-301 induction study
Key Secondary:

To evaluate the long-term treatment response over an extended period of 36 weeks for subjects who were 
randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject 
did not have a peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit and/or 
a ≥30% reduction in DSQ score from baseline)
Secondary:

To evaluate the response to OBS treatment over 36 weeks for subjects who received placebo in the SHP621-301 
induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being randomized to placebo 
in the randomized withdrawal period (treatment-withdrawal-treatment reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE Endoscopic Reference Score 
(EREFS)

To evaluate other response criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
Exploratory:

 

 
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Rationale:
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is being conducted to 
determine response to withdrawal of OBS, maintenance of response, extended therapy response, and response to 
intermittent therapy by evaluating both eosinophil counts and DSQ in adolescent and adults treated or withdrawn 
from OBS in this treatment extension study.
Investigational product, dose, and mode of administration:
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the screening
assessments (Visit 0) of this treatment extension study. At the SHP621-301 final treatment evaluation visit, subjects 
will be dispensed blinded investigational product (based on treatment assignment in SHP621-301) that will last for 
up to 4 weeks prior to enrolling into this treatment extension study. A 4-week screening period is required to allow 
for blinded treatment response information (reduction in DSQ from baseline and eosinophilic count as determined 
by a central reader) collected during the SHP621-301 final treatment evaluation visit to be entered into the 
interactive web-based response system (IWRS). Only the unblinded data team who is independent from the blinded 
study team and not involved with the day-to-day conduct of the study will have restricted access to blinded 
treatment response information. Once information is available in IWRS, subjects will return for the randomization 
visit (Visit 1) to receive investigational product as follows:

Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 study (≤6 eos/HPF
across all available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation visit) 
will enter a randomized withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio

Subjects who were assigned to OBS treatment and did not respond or partially responded to OBS treatment in 
the SHP621-301 study will receive OBS 2 mg twice daily

Subjects who were assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily
Subjects, site staff, and study team members will remain blinded to treatment assignment and individual subject
histology and individual subject DSQ data from the SHP621-301 study (post randomization) and this extension 
study until database lock occurs for this extension study. 
During the 36-week double-blind treatment extension study, subjects will receive oral administration of 10 mL of 
0.2 mg/mL (2 mg) investigational product twice daily (every morning [qAM] after meals [breakfast, pc] and at 
bedtime [hs]; 4 mg total/day), with no ingestion of food or liquids permitted for 30 minutes after investigational 
product administration. Dosing regimens are consistent with the regimens used in the Phase 2 MPI 101-06 study and 
Phase 3 SHP621-301 study:

Placebo twice-daily group: placebo qAM (pc) and hs

OBS twice-daily group: OBS 10 mL of 0.2 mg/mL (2 mg) qAM (pc) and hs (4 mg OBS total/day)
The investigational product will be supplied in amber glass, multidose bottles with child-resistant caps and 
refrigerated throughout the study (in the clinic and subject’s home). Each bottle will contain approximately 210 mL 
of suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL (matching placebo). 
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for each subject in 
the OBS treatment group.
Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume per 
Dose (mL)
Morning Dose 
(mg) 
(qAM, pc)
Evening Dose 
(mg) (hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10
0.0
0.0
0.0
OBS 
0.2
10
2.0
2.0
4.0
Abbreviations: hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every morning
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At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with biopsy to evaluate 
eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on placebo in the randomized withdrawal 
period who have relapsed will have their treatment assignment changed to OBS 2 mg twice daily. The criteria for 
relapse is having an eosinophilic count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined 
by central reader and having at least 4 days of dysphagia in the 2-week period prior to the scheduled visit, as 
determined by the DSQ. Considering the potential for missing diary entries, the determination of relapse based on 
days of dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, the subject would 
meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within the 2-week period, 
the subject would not meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and less than 8 diary entries are recorded within the 
2-week period, the subject would be designated as meeting the criterion for dysphagia symptom relapse due to 
missing diary data. 
The criteria for relapse align with the related inclusion criteria for participation in the SHP621-301 study. If both 
histology and dysphagia symptom relapse criteria are met, the treatment assignment change will be performed in a 
blinded manner in IWRS at the subsequent study visit. If both criteria for relapse are not met, the subject will remain 
assigned to placebo.
If at any time, the subject reports increased or worsening dysphagia symptoms to the investigator, the investigator 
may choose to perform an unscheduled EGD. If an unscheduled EGD is performed prior to Week 12, an EGD does 
not have to be repeated at Week 12. If a subject on placebo meets the criteria for relapse, the subject’s treatment 
assignment will be changed in a blinded manner from placebo to OBS 2 mg twice daily at the subsequent study visit. 
If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 levels of the 
esophagus yet relapse is not confirmed due to the criterion for dysphagia symptoms not being met, the subject will 
remain assigned to placebo. If the criterion for dysphagia symptoms is met at a subsequent visit and both criteria for 
relapse are then confirmed, the subject’s treatment assignment will be changed to OBS 2 mg twice daily at the next 
scheduled visit.
Methodology:
This is a Phase 3, double-blind, multicenter study to evaluate the efficacy, safety, and tolerability of twice daily
administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, inclusive, with EoE and 
dysphagia who completed the SHP621-301 induction study. 
This study will comprise 3 periods: 4-week screening period, 36-week double-blind treatment period, and a 4-week 
safety follow-up (Study Design Flow Chart). All subjects who have completed the SHP621-301 induction study will 
be eligible to enroll in this extension study. Approximately 200 subjects (88%) who were randomized in the 
SHP621-301 study are estimated to complete the SHP621-301 study and will be enrolled in this treatment extension 
study based on enrollment observed in the Phase 2 study (MPI 101-06). Randomization into the randomized 
withdrawal period will be stratified by treatment assignment and treatment response in the SHP621-301 study.
Subjects who are full responders (defined as ≤6 eos/HPF across all available esophageal levels and at least a 30% 
reduction in DSQ at the final treatment evaluation visit [Visit 4]) in the SHP621-301 induction study will be eligible 
to enter the randomized withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio. The 
randomization of subjects who are full responders will also be stratified by age (adults and adolescents) to ensure 
approximately equal number of subjects within each age group are assigned to the treatment groups.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened (Visit 0); 
assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the Visit 0 screening 
assessments of the treatment extension study. Subjects who meet eligibility criteria at the screening visit (Visit 0) 
will enter the 36-week double-blind period. Eligible subjects will receive investigational product based on treatment 
assignment in SHP621-301 for up to 4 weeks prior to enrollment in the treatment extension study. This 4-week 
screening period is required to allow for blinded treatment response information (reduction in DSQ from baseline 
and eosinophilic count as determined by a central reader) collected during the SHP621-301 final treatment 
evaluation visit to be entered into IWRS. Only the unblinded data team who is independent from the blinded study 
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team and not involved with the day-to-day conduct of the study will have restricted access to blinded treatment 
response information. Once information is available in IWRS, subjects will return for the randomization visit (Visit 
1) to receive investigational product.
During the 36-week treatment extension study, subjects who were assigned to, and fully responded to OBS 
treatment in the SHP621-301 study (≤6 eos/HPF across all available esophageal levels and at least a 30% reduction 
in DSQ at the final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 2 mg 
twice daily or placebo at a 1:1 ratio. Subjects who were assigned to OBS treatment in the SHP621-301 study and did 
not respond or partially responded, will receive OBS 2 mg twice daily. Subjects who were assigned to placebo in the 
SHP621-301 study will receive OBS 2 mg twice daily. At Week 12, all subjects will undergo an upper 
esophagogastroduodenoscopy (EGD) with biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and 
DSQ data, subjects on placebo in the randomized withdrawal period who have relapsed (>15 eos/HPF from at least 
2 levels of the esophagus and specimens and 4 days of dysphagia over 2 weeks) will have their treatment assignment 
changed to OBS 2 mg twice daily at the next scheduled visit. The treatment assignment change will be performed in 
a blinded manner in IWRS at the subsequent study visit. If both criteria for relapse are not met, the subject will 
remain assigned to placebo.
Subjects who report increased or worsening dysphagia symptoms to the investigator prior to the Week 12 EGD may 
have an unscheduled EGD to confirm whether relapse has occurred. If an unscheduled EGD is performed prior to 
Week 12, an EGD does not have to be repeated at Week 12. If a subject on placebo meets the criteria for relapse, the 
subject’s treatment assignment will be changed in a blinded manner from placebo to OBS 2 mg twice daily at the 
subsequent study visit. 
Subjects will have efficacy and safety assessments at each visit during the 36-week period. Subjects who fail to meet 
all eligibility criteria at Visits 0 or 1 will be considered screen failures. Subjects cannot be rescreened once they have 
been designated as a screen failure. Subjects who discontinue will not be replaced.
Subjects will be required to visit the site up to 8 times over up to a 36-week period. All subjects will have a follow-
up phone call 4-weeks post last dose of investigational product.
Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
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Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria (including test 
results):
1. Subject completed SHP621-301 induction study.
2. Subject is able to provide written informed consent (subject, parent or legal guardian and, as appropriate, 
subject assent) to participate in the study before completing any study-related procedures. 
3. Subject is male or female aged 11-55 years, inclusive, at time of consent for SHP621-301 study.
4. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical regimens 
(including gastric acid suppression; see exclusions below) in effect at the screening visit (Visit 0). There 
should be no changes to these regimens during study participation. 
5. All female subjects must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) 
prior to enrollment into the study. Females of childbearing potential must agree to continue acceptable birth 
control measures (eg, abstinence, stable oral contraceptives, or double-barrier methods) throughout study 
participation and for 30 days following the last dose of investigational product.
6. Subject is willing and has an understanding and ability to fully comply with study procedures including DSQ 
compliance and restrictions defined in this protocol.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subject has changes in medications that could affect the study or diet in the weeks since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study.
2.
Subject using immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the SHP621-301 
study or anticipated use of immunomodulatory therapy during the treatment period (except for any ongoing 
regimen of allergy shots); any temporary use (≤7 days) or initiation of new steroid treatment during the study 
should be documented and discussed with the medical monitor prospectively but cannot occur within 4 weeks 
of scheduled EGDs.
3.
Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use during the treatment period; 
any temporary use (≤7 days) or initiation of new steroid treatment during the study should be documented and 
discussed with medical monitor prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
4.
Subject on inhaled or intranasal steroids and not on a stable dose in the 4 weeks before the screening EGD of 
this study. 
5.
Subject has initiated, discontinued, or changed dosage regimen of proton pump inhibitors (PPIs), H2 
antagonists, antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma or allergic rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated changes in the use of such medications during the treatment period. 
6.
Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of such medications during the treatment 
period. 
7.
Subject has an appearance on screening EGD of an esophageal stricture (high grade), as defined by the presence 
of a lesion that does not allow passage of a diagnostic adult upper endoscope (eg, with an insertion tube 
diameter of >9 mm). 
8.
Subject is on a pure liquid diet or the six-food elimination diet.
9.
Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including eosinophilic gastritis, 
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enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous treatment. Diagnosis 
with oropharyngeal or esophageal candidiasis at or since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study is not an exclusion as long as the subject is expected to respond to treatment. 
13. Subject has a potentially serious acute or chronic infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, or chicken pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment evaluation visit (Visit 4) 
of the SHP621-301 study or since the final treatment evaluation visit (Visit 4) of the SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) of the SHP621-301 
study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or any other 
corticosteroids), or to any other ingredients of the study medication.
19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
Maximum duration of subject involvement in the study:

Planned duration of screening period: up to 4 weeks

Planned duration of treatment period: 36 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who are randomized and receive at least 1 dose of investigational 
product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed according to their 
assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of investigational 
product and had 1 post baseline efficacy assessment (biopsy and/or DSQ score).

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major protocol 
deviations. The PP set will be identified prior to unblinding the treatment assignments by a team consisting of, 
at a minimum, a physician and a statistician from Shire. 
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized withdrawal period. 
Relapse, a binary response (either with a relapse or not), is defined as having an eosinophil count of ≥15 eos/HPF 
from at least 2 of 3 levels of the esophagus, as determined by a central reader, and having at least 4 days of 
dysphagia in the 2-week period prior to the scheduled study visit, as determined by the DSQ.
Key Secondary Efficacy Endpoint
The key secondary endpoint is the long-term treatment response, a binary response, over an extended period of 36 
weeks in adolescent and adult subjects who were randomized to OBS treatment but did not respond after 12 weeks
in the SHP621-301 induction study (subject did not have peak count of ≤6 eos/HPF across all available esophageal 
levels at the final treatment visit and/or ≥30% reduction in DSQ score from baseline) and met the following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available esophageal levels at 
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the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 2+3) from 
baseline of the SHP621-301 study and from baseline of this extension study to the final treatment period 
evaluation (Visit 8)
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available esophageal levels at 
each assessment visit 

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 2+3) at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension study

Change in the DSQ score and change in the peak eosinophilic count at each assessment visit from baseline of 
the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each assessment visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each assessment visit

Change in the peak eosinophil count at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study for each available esophageal level (proximal, mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at each assessment visit 
from baseline of the SHP621-301 study and from baseline of this extension study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ combined score 
(questions 2+3), at each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension

Change in the DSQ combined score (questions 2+3) at each assessment visit from baseline of the SHP621-301 
study and from baseline of this extension study

Cumulative distribution function curves for the change and the percent change in the DSQ score at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak eosinophil count of ≤6
eos/HPF across all esophageal levels at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak eosinophil count of ≤6
eos/HPF across all esophageal levels at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study

Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline of the SHP621-301 
study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the SHP621-301 study and 
from baseline of this extension study 
For subjects who relapse on placebo during the randomized withdrawal period and who reinitiate treatment with 
OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for histological data and DSQ endpoints 
will be conducted at each assessment visit. Changes will be summarized over time from baseline of the SHP621-301 
study and from the time of relapse. The same criteria for response will be applied to these subjects (≤6 eos/HPF
across all available esophageal levels and at least a 30% reduction in DSQ from the SHP621-301 baseline score). 
Exploratory Efficacy Endpoints

Safety Endpoints 
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital signs (temperature, 
systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, dual-energy X-ray 
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absorptiometry (DXA) scans for bone mineral density (BMD) and body composition measurements (for adolescents 
aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum pregnancy test, if 
appropriate), and adrenocorticotropic hormone (ACTH) stimulation tests. To account for the effects of puberty in 
adolescent subjects (11-17 years, inclusive), BMD z-scores will be adjusted for height z-scores using the Bone 
Mineral Density in Childhood Study calculator.
 
 
Statistical Methodology for Primary Efficacy Endpoint 
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse during the end of the 
double-blind randomized withdrawal period for the FAS, using Fisher’s Exact test comparing OBS 2 mg twice daily
against placebo. The primary test of treatment effect will be 2-sided, and conducted at the significance level of 0.05.
The proportion of subjects with relapse for each treatment group and the corresponding 95% confidence interval 
(CI) will be estimated. In addition, the difference in the proportion of subjects with relapse between the 2 treatment 
groups and its 95% CI will be estimated.
Subjects who withdraw without providing efficacy data at the early termination (ET) visit will be classified as being 
a relapser in the primary efficacy analysis. The null hypothesis states that there is no difference in relapse
proportions between OBS 2 mg twice daily and placebo, with the 2-sided alternative of a nonzero difference 
between groups. Relapse proportions at each adjacent double-blind visit interval will also be assessed by applying 
the Fisher’s Exact test to the observed data at each double-blind visit.
The following sensitivity and supportive analyses will be performed for the primary endpoint to evaluate the 
robustness of the results from the primary analysis methods.
Similar analyses used for the ITT population will be repeated using the FAS and the PP datasets. Sensitivity 
analyses will be performed using the ITT population by classifying subjects who withdraw without providing 
efficacy data at the ET visit as non-relapsers. Sensitivity analyses will be performed using the ITT population by 
classifying subjects who met the histology relapse criterion and met the dysphagia symptom relapse criterion due to 
missing diary data as non-relapsers.  In addition, the subjects who were prematurely withdrawn from the study 
without the primary efficacy endpoint will be imputed randomly according to the distribution of relapsers with 
available data; and the similar statistical test will be performed using the imputed data.  
Statistical Methodology for Key Secondary and Other Secondary Efficacy Endpoints
To evaluate the long-term treatment response over an extended period of 36 weeks for subjects who were 
randomized to OBS treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject did 
not have peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit and/or ≥30% 
reduction in DSQ score from baseline of SHP621-301), the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the corresponding 95% 
confidence interval (CI) will be estimated and summarized.
Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the change from baseline of 
the SHP621-301 study and from baseline of this extension study at the final treatment period evaluation (Visit 8) 
will be summarized by each assessment visit. 
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo in the SHP621-301 
induction study, the proportion of subjects who responded based on the histological data and the DSQ data at the 
final treatment period evaluation (Visit 8) and the corresponding 95% CI will be summarized. Summary statistics of 
the DSQ score (questions 2+3) and the peak eosinophil count and the change from baseline of the SHP621-301 
study and from baseline of this extension study at the final treatment period evaluation (Visit 8) will be summarized 
by each assessment visit. 
To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being randomized to placebo in 
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the randomized withdrawal period (intermittent therapy), the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the corresponding 95% CI 
will be summarized.
Summary statistics will be provided for all the secondary endpoints.
Statistical Methodology for Safety Endpoints 
All safety measures, including AEs, physical examination, stadiometry, vital signs (temperature, systolic and 
diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA scans for BMD and body 
composition measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory results (hematology, 
chemistry, urinalysis; serum pregnancy test, if appropriate), and ACTH stimulation will be descriptively 
summarized by treatment group at baseline and for each post baseline visit.
The number and percent of subjects with TEAEs will be presented. TEAEs are defined as AEs that start or 
deteriorate on or after the date of the first dose of investigational product (Visit 1) and no later than 3 days following 
the last dose of investigational product. However, for any subjects who die during the study (ie, the date of death is 
between the date of first dose of investigational product and the date of study discontinuation entered by the site, 
inclusive), all AEs (including those resulting in death) that occur during the study will be considered as TEAEs 
irrespective of the last dose and will be included in the TEAE summaries. 
Sample Size Justification
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated to complete the 
SHP621-301 study and enroll in this treatment extension study based on enrollment observed in the Phase 2 study 
(MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse during the double-blind 
randomized withdrawal period. Relapse, a binary response (either with relapse or not), is defined as having an 
eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus (determined by a central reader) and 
having at least 4 days of dysphagia in a 2-week period prior to the scheduled visit (determined by the DSQ). To be 
considered as a subject with relapse, both criteria must be met.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or approximately 40 
subjects, who were assigned to OBS treatment in the SHP621-301 study are anticipated to respond fully after 12 
weeks in the SHP621-301 study. 
For this study, to detect a 50 percentage point difference between relapse proportions of 20% and 70% in the OBS 
and placebo groups, respectively, at more than 80% power and a significance level of 0.05 (2-sided) using the 
Fisher’s Exact test with equal allocation to treatment groups, it is necessary to assess the primary efficacy measure 
for approximately 38 subjects (19 subjects in each of the OBS and placebo groups). 
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STUDY SCHEDULE(S)
Table 1-1 Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
Informed consent/assent
X
Medical history review
X
X
Inclusion/exclusion criteria 
review
X
X
Vital signsb; heightc, and weight 
assessmentd
X
X
X
X
X
X
X
X
X
EGD with endoscopy score 
(EREFS) and biopsye
X
X
X
Issue/Retrieve DSQ handset
X
X
DSQ completion
Once-daily completion
DSQ compliance assessment
X
X
X
X
X
X
X
X
X
 
 
 
Physical examination
X
X
X
X
X
X
X
X
X
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Table 1-1 Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
Tanner Staging Assessmentg
X
X
Clinical laboratory testsh
X
X
X
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
X
X
X
X
Pregnancy testj
X
X
X
X
X
X
X
X
X
Morning cortisol (target 6:00-
9:00 am)
X
X
X
X
X
X
X
X
X
ACTH Stimulation Testing 
X
X
DXA Scan (subjects 11 to 
17 years of age)k
X
X
Randomizationl
X
Study medication supplied 
Xm
X
X
X
X
X
X
X
Study medication administration
Twice-daily administration of study medication
Study medication compliance 
assessment
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures recorded 
X
X
X
X
X
X
X
X
X
X
Review of adverse eventsn
X
X
X
X
X
X
X
X
X
X
Abbreviations: ACTH=adrenocorticotropic hormone; DSQ=Dysphagia Symptom Questionnaire; DXA=dual-energy X-ray absorptiometry; 
EGD=esophagogastroduodenoscopy; 
 
EREFS=EoE Endoscopic Reference Score; hs=at bedtime; IWRS=interactive web-based response system; 
 pc=after meals; 
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Table 1-1 Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
a
The assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the screening assessments (Visit 0) of this treatment 
extension study. 
b
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood 
pressure (systolic and diastolic), heart rate, respirations, and temperature.
c
Height to be collected at screening (Visit 0) and Visit 8 for all subjects. Height to be collected at Visit 4 for adolescents only (11-17 years, inclusive). Height 
measurements for adolescents should be measured in triplicate using stadiometers.
d
Weight measurements for adolescents (11-17 years, inclusive) should be measured in duplicate.
e
Endoscopy must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Endoscopies at Visit 4 and 
Visit 8 should occur at or within 7 days of the scheduled visit. Unscheduled endoscopies may be performed at the discretion of the investigator.
 
g
Tanner staging assessments will be performed for all subjects ≥11 years of age until investigator confirms subject is post puberty.
h
Clinical laboratory tests will include the following: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein, 
albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, carbon dioxide, hemoglobin, hematocrit, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, erythrocyte count, leukocyte count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, and platelet count). All subjects must fast overnight prior to collection.
i
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
j
The serum pregnancy test will be performed for all female subjects at screening (Visit 0) and Visit 8. Urine pregnancy tests will be performed at all other 
visits.
k
Dual-energy X-ray absorptiometry scans should be performed using the same machine and software as used in the SHP621-301 study. Dual-energy X-ray 
absorptiometry scan at Visit 8 should occur at or within 7 days of the scheduled visit.
l
Randomization will occur via IWRS at Visit 1 once the subject’s eligibility is confirmed. 
m
Study medication is supplied at the SHP621-301 final treatment visit based on treatment assignment in SHP621-301. 
n
Adverse event assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, 
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Table 1-1 Schedule of Assessments
Procedures
Screeninga
Double-blind Treatment Period
Safety 
Follow-up 
Contactp
Visit 0
Randomization/
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
or ETo
Visit 9
Week
-4
0
4
8
12
16
20
28
36
40
Window
≤4 weeks
--
±3 
days
±3 
days
±3 
days
±3 
days
±3 
days
±6
days
±6
days
±3 days
acne, hirsutism, mood swings, insomnia, and depression).
o
If subject discontinues study prematurely during the treatment period, the evaluations listed for Visit 8 are to be performed as completely as possible.
p
A safety follow-up contact by phone will be performed 4 weeks following the last dose of study medication for all subjects (including subjects who fail 
screening, who discontinue early, or who complete the study).
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1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al. 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and adults 
present with dysphagia and food impaction. When these symptoms are present, the diagnosis is 
confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered field (HPF) on 
at least 1 esophageal biopsy and when other causes such as proton pump inhibitor (PPI)-
responsive esophageal eosinophilia are excluded (Dellon et al. 2014a; Furuta et al. 2007). The 
standards of care are diet therapies and off-label use of glucocorticosteroids. Esophageal dilation 
is used to temporarily relieve symptoms but does not address underlying inflammation. Given 
the clinical outcomes associated with EoE, including severe dysphagia, esophageal stricture, 
food impaction, and esophageal perforation (Hirano and Aceves 2014; Liacouras et al. 2011) and 
the fact that there are currently no FDA-approved treatments, there is a clear unmet medical need 
for an approved treatment that induces and maintains remission for patients with EoE 
(Furuta and Katzka 2015). 
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a nonviscous suspension. Shire is developing OBS as a first-line 
therapy for EoE in adolescents and adults.
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the management 
of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, and for 
induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide 
has strong glucocorticoid receptor affinity and is subject to considerable first pass metabolism by 
the liver with a short half-life. These attributes permit budesonide to act rapidly and locally in the 
gut mucosa for treatment of inflammatory disorders such as Crohn’s disease and ulcerative 
colitis. Once absorbed into the systemic circulation, budesonide is rapidly metabolized in the 
liver and inactivated (FDA 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in 2 Phase 2 studies in the 
OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the efficacy 
of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in adolescents 
and adults aged 11-40 years, respectively, by measuring histological response (defined as mean 
peak eosinophil count ≤6 eos/HPF after treatment). Study MPI 101-06 also evaluated symptom 
response as measured by the Dysphagia Symptom Questionnaire (DSQ). The DSQ contains 4 
questions related to consumption of solid food, the presence of dysphagia and its severity, as
well as pain. The DSQ score is calculated only from responses to the questions related to 
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dysphagia, and this clinical outcome assessment was considered to be fit for purpose as a result 
of the MPI 101-06 study. Results from Study MPI 101-01 demonstrated a statistically significant 
histologic response (eosinophil count ≤6 eos/HPF) and remission (eosinophil count ≤1 eos/HPF) 
in the medium-dose (1.4-2.0 mg daily) and high-dose (2.8-4.0 mg daily) OBS groups compared 
to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both the 
coprimary efficacy endpoints of histologic response and change from baseline in dysphagia 
symptoms. Following 12 weeks of twice daily treatment (once every morning after meals [qAM, 
pc] and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent reduction from 
baseline values for cellular (mean peak eosinophil count and histopathology features), organ 
(endoscopy score), and holistic measures (Physician Global Assessment and DSQ scores); these 
results were independent of the type of rater/reviewer (central pathologist, physician at the study 
site, or subject). 
This Phase 3 extension study follows the SHP621-301 induction study, a Phase 3 randomized, 
double-blind, multicenter, study to evaluate the efficacy, safety, and tolerability of twice daily 
administration of OBS (qAM, pc, and hs) in adolescents and adults aged 11-55 years, inclusive, 
with EoE and dysphagia. Study SHP621-301 is designed to provide safety and efficacy data 
demonstrating histologic response (as measured by eosinophilic count ≤6 eos/HPF) and 
improvement in dysphagia symptoms (as measured by the DSQ) following 12 weeks of 
treatment with OBS in adolescent and adult subjects with EoE. This extension study will 
evaluate maintenance of treatment and treatment withdrawal in subjects who complete the 
induction study.
Always refer to the latest version of the SHP621 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy, and safety of SHP621. 
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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This Phase 3 study is being 
conducted to determine response to withdrawal of OBS, maintenance of response, extended 
therapy response, and response to intermittent therapy by evaluating both eosinophil counts and 
DSQ in adolescent and adults treated or withdrawn from OBS in this treatment extension study.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is:

To evaluate the maintenance of efficacy over 36 weeks, as measured by the peak eosinophilic 
count and the Dysphagia Symptom Questionnaire (DSQ) score, through a randomized 
withdrawal design for subjects who responded to 12 weeks of OBS treatment (2 mg twice 
daily) with a peak count of ≤6 eosinophils (eos)/high-powered field (HPF) across all 
available esophageal levels at the final treatment visit and a ≥30% reduction in DSQ score 
from baseline during the SHP621-301 induction study
2.2.2
Secondary Objectives
The key secondary objective of this study is:

To evaluate the long-term treatment response over an extended period of 36 weeks for 
subjects who were randomized to OBS treatment but did not respond after 12 weeks in the 
SHP621-301 induction study (subject did not have a peak count of ≤6 eos/HPF across all 
available esophageal levels at the final treatment visit and/or a ≥30% reduction in DSQ score 
from baseline)
Additional secondary objectives of the study are:

To evaluate the response to OBS treatment over 36 weeks for subjects who received placebo 
in the SHP621-301 induction study

To evaluate the effect of reinitiating OBS treatment for subjects who relapse after being 
randomized to placebo in the randomized withdrawal period (treatment-withdrawal-treatment 
reinitiation)

To assess endoscopically identified esophageal features as measured by the EoE Endoscopic 
Reference Score (EREFS)

To evaluate other responding criteria based on histology and DSQ

To evaluate the long-term safety and tolerability of OBS treatment
2.2.3
Exploratory Objectives
The exploratory objectives of this study are:
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
 

 
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, multicenter, double-blind study to evaluate the efficacy, safety and tolerability
of OBS treatment administered twice daily (qAM, pc, and hs) for 36 weeks. The study will be 
conducted in adolescents and adults, aged 11-55 years, inclusive, with EoE and dysphagia who 
completed the SHP621-301 induction study.
Approximately 200 subjects (88%) who were randomized in the SHP621-301 study are 
estimated to complete the SHP621-301 study and will be enrolled in this treatment extension 
study based on enrollment observed in the Phase 2 study (MPI 101-06). Randomization into the 
randomized withdrawal period will be stratified by treatment assignment and treatment response 
in the SHP621-301 study. Subjects who are full responders (defined as ≤6 eos/HPF across all 
available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation 
visit [Visit 4]) in the SHP621-301 induction study will be eligible to enter the randomized 
withdrawal period to receive either OBS 2 mg twice daily or placebo at a 1:1 ratio. The 
randomization of subjects who are full responders will also be stratified by age (adults and 
adolescents) to ensure approximately equal number of subjects within each age group are 
assigned to the treatment groups.
This study will consist of 3 periods: 4-week screening period, 36-week double-blind treatment 
period, and 4-week safety follow-up (Figure 3-1).
Figure 3-1   Study Design Flow Chart
Abbreviations: EGD=esophagogastroduodenoscopy; OBS=oral budesonide suspension
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Subjects will be required to visit the site up to 8 times over up to a 36-week period. Following 
completion of the screening visit, subjects will be evaluated for eligibility and safety at Week 0
(Visit 1). Subjects who are eligible and randomized will have efficacy and safety assessments at 
Weeks 4, 8, 12, 16, 20, 28, and 36 (Visits 2-8) and additional safety assessments at follow-up at 
Week 40 (Visit 9). Subjects who fail to meet all eligibility criteria at Visits 0 or 1 will be 
considered screen failures. These subjects will receive a follow-up safety phone call 4 weeks 
after the last dose of investigational product. Subjects cannot be rescreened once they have been 
designated as a screen failure. Subjects who discontinue will not be replaced.
The screening period will start when subjects sign informed consent (or assent as applicable for 
subjects <18 years of age; screening visit [Visit 0]) and will be ≤4 weeks in duration. During the 
screening period, assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will 
be used as the Visit 0 screening assessments of the treatment extension study. At the screening 
visit (Visit 0), subjects who are on a PPI must remain on the same dose of the PPI throughout the 
study; if they are not taking a PPI, they must remain off of a PPI for the remainder of the study. 
Eligible subjects will receive investigational product based on treatment assignment in 
SHP621-301 for up to 4 weeks prior to enrollment in the treatment extension study. This 4-week 
screening period is required to allow for blinded treatment response information (reduction in 
DSQ from baseline and eosinophilic count as determined by a central reader) collected during 
the SHP621-301 final treatment evaluation visit to be entered into the interactive web-based
response system (IWRS). Only the unblinded data team who is independent from the blinded 
study team and not involved with the day-to-day conduct of the study will have restricted access 
to blinded treatment response information. Once response information is available, subjects will 
return for the randomization visit (Visit 1) to receive investigational product. Subjects who 
continue to meet eligibility criteria after the screening visit (Visit 0) will enter the 36-week 
double-blind treatment period.
Subjects who were assigned to OBS treatment and who fully responded in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the 
final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 
2 mg twice daily or placebo at a 1:1 ratio. These subjects will also be stratified by age (adults and 
adolescents). Subjects who were assigned to OBS treatment and did not respond or partially 
responded in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were 
assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects, site 
staff, and study team members will remain blinded to treatment assignment and individual 
subject histology, and individual subject DSQ data from the SHP621-301 (post randomization) 
and this extension study until the database locks occurs for this extension study. 
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily at the next scheduled visit. The criteria for relapse 
is having an eosinophilic count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as 
determined by central reader and having at least 4 days of dysphagia in the 2-week period prior 
to the scheduled visit, as determined by the DSQ. The criteria for relapse align with the related 
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inclusion criteria for participation in the SHP621-301 study. The treatment assignment change 
will be performed in a blinded manner in IWRS at the subsequent study visit. If both criteria for 
relapse are not met, the subject will remain assigned to placebo. The upper EGD with esophageal 
biopsies will be repeated at the Week 36 visit (Visit 8) or at early termination (ET), to evaluate 
eosinophil counts. If an unscheduled EGD is performed between Week 12 and Week 36, the 
Week 36 EGD should still be performed.
All subjects will have a follow-up phone call 4-weeks post last dose of investigational product to 
query for SAEs, AEs, and concomitant treatments.
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al. 2014a) and the fact that as EoE persists, it 
becomes more fibrostenotic in older patients and would not be amenable to anti-inflammatory 
treatment alone (Dellon et al. 2014b). A natural history study demonstrated that for every decade 
of life, the odds of developing the fibrostenotic phenotype of EoE more than doubles 
(Dellon et al. 2014b). By age 55, fibrostenotic EoE occurs in approximately 80% of patients. 
Fibrostenotic disease is treated with dilatation and is not amenable to anti-inflammatory 
treatment alone. Therefore, budesonide is not expected to be an effective treatment for the 
majority of patients above age 55.
The design of this study combines randomized withdrawal and long-term extension elements in a 
manner that selects appropriate patients for placebo withdrawal and maintains double-blinding of 
subjects in all treatment groups. Only subjects who are full responders to OBS 2 mg twice daily
in the SHP621-301 induction study (≤6 eos/HPF across all available esophageal levels and at 
least a 30% reduction in DSQ at the final treatment evaluation visit of SHP621-301), will be 
eligible for randomized withdrawal. The randomized withdrawal period is required to assess 
maintenance of efficacy in these subjects. The continuation of OBS 2 mg twice daily treatment 
for subjects in SHP621-301 who did not respond or partially responded to treatment, will 
evaluate whether these subjects might respond to OBS 2 mg twice daily if their treatment is 
extended for an additional 36 weeks. This aspect of the study is supported by the possibility that 
the response of EoE to topical corticosteroids may require more than 12 weeks of induction 
treatment. 
As described, the protocol also provides multiple mechanisms for switch from placebo and 
potential study discontinuation of relapsing and nonresponding subjects in order to evaluate the 
effect of reinitiating OBS treatment in these subjects. For subjects who relapse on placebo during 
the randomized withdrawal and who reinitiate treatment with OBS 2 mg twice daily (intermittent 
therapy), separate descriptive analyses for histological data and DSQ endpoints will be 
conducted at each assessment visit, as described in Section 9.8.2. For all subjects, an esophageal 
stricture requiring dilation would be considered a treatment failure and result in withdrawal of 
the subject from the study. Subject withdrawal criteria are provided in Section 4.5.1.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 44 weeks, 
including the 4-week screening period. Including potential treatment in SHP621-301 and the 
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screening period of this study, the maximum total duration of OBS 2 mg twice daily may be 
approximately 52 weeks.
The study will be completed in approximately 36 months.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including Visit 
8 (Week 36), inclusive of the final treatment evaluation EGD. All subjects will have a follow-up 
phone call 4-weeks post last dose of investigational product.
3.3
Sites and Regions
Approximately 60 sites in North America, the same sites participating in the SHP621-301 study, 
will participate in this extension study.
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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject completed SHP621-301 induction study.
2. Subject is able to provide written informed consent (subject, parent or legal guardian and, as 
appropriate, subject assent) to participate in the study before completing any study-related 
procedures. 
3. Subject is male or female aged 11-55 years, inclusive, at time of consent for the SHP621-301 
study. 
4. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at the 
screening visit (Visit 0). There should be no change to these regimens during study 
participation.
5. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential 
must agree to continue acceptable birth control measures (eg, abstinence, stable oral 
contraceptives or double-barrier methods) throughout study participation and for 30 days 
following the last dose of investigational product.
6. Subject is willing and has an understanding and ability to fully comply with study procedures 
including DSQ compliance and restrictions defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subject has changes in medications that could affect the study or diet in the weeks since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study.
2. Subject using immunomodulatory therapy since the final treatment evaluation visit (Visit 4) 
of the SHP621-301 study or anticipated use of immunomodulatory therapy during the 
treatment period (except for any ongoing regimen of allergy shots); any temporary use (≤7 
days) or initiation of new steroid treatment during the study should be documented and 
discussed with the medical monitor prospectively but cannot occur within 4 weeks of 
scheduled EGDs.
3. Subject using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition since the final treatment evaluation visit (Visit 4) of the SHP621-301 study or 
anticipated use during the treatment period; any temporary use (≤7 days) or initiation of new 
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steroid treatment during the study should be documented and discussed with medical monitor 
prospectively but cannot occur within the 4 weeks of the scheduled EGDs. 
4. Subject on inhaled or intranasal steroids and not on a stable dose in the 4 weeks before the 
screening EGD of this study.
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma or allergic rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-
301 study or anticipated changes in the use of such medications during the treatment period.
6. Subject using Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the 
final treatment evaluation visit (Visit 4) of the SHP621-301 study or anticipated use of such 
medications during the treatment period.
7. Subject has an appearance on screening EGD of an esophageal stricture (high grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9mm). 
8. Subject is on a pure liquid diet or the six-food elimination diet.
9. Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit
(Visit 4) of the SHP621-301 study.
10. Subject has any current disease of the gastrointestinal tract, aside from EoE, including 
eosinophilic gastritis, enteritis, colitis, or proctitis, inflammatory bowel disease, or celiac 
disease. 
11. Subject has other diseases causing or associated with esophageal eosinophilia, including 
hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic 
infection.
12. Subject has oropharyngeal or esophageal candidiasis that failed to respond to previous 
treatment. Diagnosis with oropharyngeal or esophageal candidiasis at or since the final 
treatment evaluation visit (Visit 4) of the SHP621-301 study is not an exclusion as long as 
the subject is expected to respond to treatment.
13. Subject has a potentially serious acute or chronic infection or immunodeficiency condition, 
including tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, or 
chicken pox/measles.
14. Subject has upper gastrointestinal bleeding identified in the EGD at the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study or since the final treatment evaluation visit
(Visit 4) of the SHP621-301 study.
15. Subject has evidence of active infection with Helicobacter pylori.
16. Subject has evidence of unstable asthma since the final treatment evaluation visit (Visit 4) of 
the SHP621-301 study.
17. Subject is female and pregnant or nursing.
18. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide 
(or any other corticosteroids), or to any other ingredients of the study medication.
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19. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
20. Subject is on sucralfate or anticipates using sucralfate during the treatment period.
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No changes in medications or diet since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study.

Temporary use (≤7 days) or initiation of new steroid treatment is permitted but cannot occur 
within the 4 weeks of the scheduled EGDs.

Stable treatment with intranasal or inhaled corticosteroids. For subjects with perennial 
allergic rhinitis and stable asthma, the topical corticosteroid must be maintained at the same 
dose throughout the study. For subjects with seasonal allergic rhinitis, it is permissible after 
enrollment to resume (or discontinue) intranasal corticosteroids based on the subject's usual 
treatment regimen for allergy season. All topical corticosteroid dosing changes, including 
those for seasonal allergic rhinitis, should be avoided within 4 weeks prior to EGD. Subjects 
who require a change in inhaled corticosteroid treatment for an asthma exacerbation should 
be discussed with the medical monitor.

No change in use of PPIs, H2 antagonists, antacids, or leukotriene inhibitors for any 
condition (such as gastroesophageal reflux disease, asthma or allergic rhinitis).

No use of cytochrome P450 3A4 (CYP450 3A4) inhibitors (eg, ketoconazole, grapefruit 
juice; see details in Section 5.2.2).

No use of sucralfate during the study as this may interfere with the adherence of OBS.
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit 0), randomization
visit (Visit 1), and Visits 2-8. A serum pregnancy test will be performed at the screening visit
(Visit 0) and final treatment evaluation (Visit 8). Urine pregnancy tests will be performed at all 
other visits.
Female subjects should be either:

Premenarchal and Tanner Stage 1, or

Post menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone 1 of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post sterilization, or

Females of childbearing potential must agree to use acceptable methods of contraception
throughout the study period and for 30 days following the last dose of investigational 
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product.

Acceptable methods of contraception are:

Abstinence

Surgically sterile male partner

Stable oral contraceptives

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for 
at least 30 days prior to the screening visit (Visit 0), plus condoms. If hormonal 
contraceptives are used, they should be administered according to the package insert.
Note: If subjects become sexually active during the study, they should use 1 of the 
other acceptable methods noted above in addition to the hormonal contraceptive until 
it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 8 are to be performed as completely as 
possible. If investigational product is discontinued due to an AE, the subject may remain on 
study to allow for completion of study procedures. 
Whenever possible, all discontinued subjects should also undergo the protocol-specified follow-
up (Schedule of Assessments, Table 1-1). Comments (spontaneous or elicited) or complaints 
made by the subject must be recorded in the source documents. The reason for termination, date 
of stopping investigational product, and total amount of investigational product taken must be 
recorded in the case report form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
severe signs and symptoms of EoE, such as an esophageal stricture requiring dilation, weight 
loss due to severe dysphagia, and/or upper GI bleed, would be considered a relapse and result in 
withdrawal of the subject from the study. Subjects with oropharyngeal or esophageal candidiasis 
that has failed to respond to treatment by the Week 12 EGD or upper GI bleeding at the Week 12 
EGD will be withdrawn from the study. 
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4.5.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s
medical record and on the CRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
Reasons for discontinuation include but are not limited to:

Completed

Death

AE

Noncompliance with study drug

Noncompliance with study procedure

Withdrawal by subject

Withdrawal by parent/guardian

Physician decision

Study terminated by sponsor

Site terminated by sponsor

Lost to follow-up

Pregnancy

Study screen failure

Protocol deviation

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
4.5.4
Safety-related Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the 
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar MedDRA higher level group code), 
and considered related to the study drug
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The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) physician and the PVRM therapeutic 
area (TA) Head. The PVRM TA Head, not the PVRM physician involved in the study, may be 
unblinded as part of this urgent safety review, if required. Following the sponsor’s review of 
safety data, one of the following actions will be taken with respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment
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5.
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, and nonpharmacological treatment, such as psychotherapy, as appropriate) received at 
the screening visit (Visit 0) and through the final study contact (including protocol-defined 
follow-up period) must be recorded on the appropriate CRF page.
5.1
Prior Treatment
Prior treatment includes all treatment, including but not limited to herbal treatments, vitamins, 
and nonpharmacological treatment such as psychotherapy, as appropriate, received at the
screening visit (Visit 0). Prior treatment information must be recorded on the appropriate CRF 
page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product in SHP621-302 (Visit 1) and the end of the follow-up period, inclusive.
Concomitant treatment information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been on a 
stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
scheduled EGDs) and will continue this dosing regimen throughout study participation. The 
investigator must contact the medical monitor to discuss any changes to concomitant steroid 
regimens or for any medications not listed here that could impact the outcome of the study.
1.
Inhaled or intranasal steroids (exception for seasonal allergic rhinitis; see Section 4.3)
2.
PPIs
3.
H2 antagonists
4.
Antacids
5.
Leukotriene inhibitors
6.
Maintenance immunotherapy (allergy shots)
Influenza and other routine required vaccinations are allowed during the study.
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5.2.2
Prohibited Treatment
The following medications and treatments are prohibited throughout the course of the study and 
prior to treatment, as specified:
1.
Immunomodulatory therapy since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study or use within the 4 weeks of scheduled EGDs. Any temporary use 
(≤7 days) or initiation of new corticosteroid treatment during the study should be 
documented and discussed with the medical monitor prospectively. (Seasonal nasal 
corticosteroid use for seasonal allergic rhinitis is permitted; changes within 4 weeks of 
scheduled EGD should be avoided).
2.
Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition since 
the final treatment evaluation visit (Visit 4) of the SHP621-301 study or use within the 4 
weeks of scheduled EGDs. Any temporary use (≤7 days) or initiation of new steroid 
treatment during the study should be documented and discussed with the medical monitor 
prospectively.
3.
Initiation or change in dosing frequency to PPIs, H2 antagonists, antacids, or leukotriene 
inhibitors for any condition (such as gastroesophageal reflux disease, asthma, or allergic 
rhinitis) since the final treatment evaluation visit (Visit 4) of the SHP621-301 study, or 
anticipated use of such medications during the treatment period.
4.
CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) since the final treatment 
evaluation visit (Visit 4) of the SHP621-301 study, or anticipated changes in the use of such 
medications during the treatment period. For an expanded list of CYP3A inhibitors, 
investigators should refer to the 2012 FDA Draft Guidance on Drug Interactions (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
5.
Sucralfate at screening or anticipated to be used during the treatment period.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in 8 
ounce amber glass, multidose bottles. Additional information is provided in the current SHP621 
investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle form
with the same volume.
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in 8 ounce amber glass, multidose bottles with 
child-resistant caps and refrigerated throughout the study (in the clinic and subject’s home). Each 
bottle contains OBS concentration of 0.2 mg/mL. Inactive ingredients in OBS include dextrose, 
disodium edetate, citric acid, sodium citrate, potassium sorbate, polysorbate 80, glycerin, sodium 
benzoate, cherry flavor, Magnasweet 110, acesulfame potassium, and water.
The placebo suspension will also be supplied in 8 ounce amber glass multidose bottles with 
child-resistant caps. Placebo consists of all components of the investigational product with the 
exception of budesonide.
6.2
Administration of Investigational Product(s)
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last until 
the subsequent visit. The first dose of investigational product for each subject will be 
administered in the clinic. The subject will continue with the evening dosing regimen at home. 
Oral budesonide suspension and placebo will be supplied in amber glass bottles and must be 
shaken well prior to administration. OBS and placebo should be refrigerated at 2-8ºC (36-46ºF)
throughout the study (in the clinic and subject’s home). The appropriate dose will be dispensed 
using the graduated dosing spoon provided. For subjects who are minors (<18 years), a 
parent/guardian will be responsible for ensuring that the subjects take their investigational 
product appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during this 
time interval. After 30 minutes, subjects will be instructed to rinse with water and spit, 
particularly after the bedtime dose.
Please refer to the investigational product Administration Manual for additional details.
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
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management, inventory management and supply ordering, investigational product expiration 
tracking and management, return of investigational product, and emergency unmasking. Please 
refer to the Study Manual for additional details regarding the IWRS.
During the 4-week screening period, blinded treatment response information (reduction in DSQ 
from baseline and eosinophilic count as determined by a central reader) collected during the 
SHP621-301 final treatment evaluation visit will be entered into the IWRS in a blinded manner. 
Once information is available in IWRS, subjects will return for the randomization visit (Visit 1) 
to be assigned to investigational product (OBS 2 mg twice daily or placebo). While only 
SHP621-301 OBS 2 mg twice daily responders will be randomized to continued OBS 2 mg twice 
daily or placebo, all subjects will be assigned to investigational product via IWRS to maintain 
double-blinding of subjects, investigators, the blinded monitoring team and the sponsor (ie, sham 
randomization).
At the randomization visit (Visit 1), the investigator or designee will access the IWRS to either 
document a screen failure or, if the subject has met all entry criteria, to randomize the subject. 
Sites will confirm eligibility criteria information prior to randomization. For randomized 
subjects, the IWRS will provide a medication identification (Med ID) number (ie, kit number to 
dispense for treatment). 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a 4-week screening period and a double-blind treatment period. The actual 
treatment given to individual subjects during the double-blind treatment period will be 
determined by the blinded treatment response information entered at the SHP621-301 final 
treatment evaluation visit.
Subjects will be randomized via a computer-generated randomization schedule at the 
randomization visit (Visit 1) following a 4-week screening period and confirmation of study 
eligibility. Subjects who fully responded to OBS treatment in the SHP621-301 study 
(≤6 eos/HPF across all available esophageal levels and at least a 30% reduction in DSQ at the
final treatment evaluation visit) will enter a randomized withdrawal period to receive either OBS 
2 mg twice daily or placebo at a 1:1 ratio. Subjects who did not respond or partially responded to 
OBS treatment in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were 
assigned to placebo in the SHP621-301 study will receive OBS 2 mg twice daily. Subjects, site 
staff, and study team members will remain blinded to treatment assignment and individual 
subject histology and individual subject DSQ data from the SHP621-301 study (post
randomization) and until database lock occurs for this extension study. 
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Randomization of subjects in the randomized withdrawal period will also be stratified by age 
(adults and adolescents) to ensure approximately equal number of subjects within each age group 
are assigned to the treatment groups.
Subject numbers are assigned to all subjects as they consent to take part in the study. The subject 
number consists of the 3 digit study identifier, the 4 digit site identifier, and the 4 digit subject 
identifier. For the SHP621-302 study, the 3 digit site and 4 digit subject numbers will be the 
same as the SHP621-301 study.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject once eligibility has been determined at the randomization visit. 
Individual subject treatment is automatically assigned by the IWRS.
6.2.3
Dosing
During the 4-week screening period, all subjects will receive 10 mL of blinded investigational 
product twice daily based on treatment assignment in SHP621-301. During the 36-week double-
blind treatment period, oral administration of 10 mL of investigational product will occur twice 
daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 30 minutes after study 
drug administration. Subjects randomized to OBS will receive 10 mL of 0.2 mg/mL of OBS 
(2 mg) twice daily for a total daily dose of 4 mg.
At Week 12, all subjects will undergo an upper esophagogastroduodenoscopy (EGD) with 
biopsy to evaluate eosinophil counts. Upon receipt of blinded EGD and DSQ data, subjects on 
placebo in the randomized withdrawal period who have relapsed will have their treatment 
assignment changed to OBS 2 mg twice daily. The criteria for relapse is having an eosinophil 
count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined by a central 
reader, and having at least 4 days of dysphagia in the 2-week period prior to the scheduled visit, 
as determined by the DSQ. Considering the potential for missing diary entries, the determination 
of relapse based on days of dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, 
the subject would meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within 
the 2-week period, the subject would not meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and fewer than 8 diary entries are 
recorded within the 2-week period, the subject would be designated as meeting the criterion 
for dysphagia symptom relapse due to missing diary data as described in Section 7.2.1.2. 
The criteria for relapse align with the related inclusion criteria for participation in the SHP621-
301 study. If both histology and dysphagia symptom relapse criteria are met, then the treatment 
assignment change will be performed in a blinded manner in IWRS at the subsequent study visit.
If both criteria for relapse are not met, the subject will remain assigned to placebo.
If at any time the subject reports increased or worsening dysphagia symptoms to the investigator, 
the investigator may choose to perform an unscheduled EGD. If an unscheduled EGD is 
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performed prior to Week 12, an EGD does not have to be repeated at Week 12. If a subject on 
placebo meets the criteria for relapse, the subject’s treatment assignment will be changed in a 
blinded manner from placebo to OBS 2 mg twice daily at the subsequent study visit. 
If the Week 12 or an unscheduled EGD reveals an eosinophil count of ≥15 from at least 2 of 3 
levels of the esophagus yet relapse is not confirmed due to the criterion for dysphagia symptoms 
not being met, the subject will remain assigned to placebo. If the criterion for dysphagia 
symptoms is met at a subsequent visit and both criteria for relapse are then confirmed, the 
subject’s treatment assignment will be changed to OBS 2 mg twice daily at the next scheduled 
visit. 
Investigational product doses that are required to be administered at the clinic include the first 
dose of randomized investigational product (OBS or placebo) administered at the randomization
visit (Visit 1) and all morning doses of investigational product administered at Visits 2-8.
Subjects will be required to eat breakfast at the clinic prior to self-administering these doses.
Subjects can self-administer all other doses of placebo and investigational product at home. 
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor and the sponsor as soon as possible 
after the investigator has been unblinded.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
There will be a provision for unblinding to ensure adequate treatment of the subject in the case of 
an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the protocol number, Med ID, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
study use only” and/or “CAUTION: New Drug - Limited by Federal (or US) Law to 
Investigational Use,” “Keep out of reach of children,” and the sponsor’s name and address. Any 
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additional labeling requirements for participating countries and/or controlled substances will also 
be included on the label.
Space is allocated on the label so that the site representative can record subject information. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8 ounce amber glass bottle for multiple use. Bottles of OBS 
0.2 mg/mL or placebo will be packaged in an appropriately labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storages
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. 
OBS and placebo must be refrigerated at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
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site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be stored under refrigeration at 2-8°C/36-46°F at all times.
The investigational product should be protected from light and shaken well immediately prior to 
each dose.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product.
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication
will be documented on the CRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects. The investigator or 
his/her designee will enter the unique subject identifier and initials on the investigational product 
kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
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nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken, and the labeled 
amount is to be documented in lieu of counting. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IWRS) do not 
require a shipment form. Returned investigational product must be packed in a tamper-evident
manner to ensure product integrity. Contact the sponsor for authorization to return any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational product 
packaging to every visit. Drug accountability must be assessed at the container/packaging level 
for unused investigational product that is contained within the original tamper-evident sealed 
container (eg, bottles) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel. Site 
personnel must review the returned investigational product to assess compliance at every visit 
prior to dispensing additional investigational product. Any discrepancies should be reconciled 
with the subject immediately. Subjects who do not return their used and unused investigational 
product should be reminded to bring all used and unused investigational product at their next 
visit.
Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. Please 
refer to the Pharmacy Manual for additional details.
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7.
STUDY PROCEDURES
7.1
Study Schedule
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Assessments (Table 1-1) and must be referred to in conjunction with the 
instructions provided in this section. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). There must be documentation of consent (as per local requirements) 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions, prior to performing any study-related procedures.
7.1.1
Screening Period (Weeks -4 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise up to 4 weeks, during which all procedures listed for the screening visit (Visit 0) in 
Table 1-1 shall be completed. The screening period will allow for the determination of eligibility 
of each subject’s inclusion into the study. A subject should not be instructed to discontinue use 
of any medication or treatment to participate in this study until informed consent has been 
obtained. Subjects should not stop permitted medications or treatments that are effective and well 
tolerated to participate in this study (Section 5.2.1).
Assessments from the SHP621-301 final treatment evaluation visit (Visit 4) will be used as the 
screening assessments (Visit 0) of this treatment extension study. Screening assessments may 
take place across several days to allow an appropriate time frame in which to complete all 
procedures and confirm study eligibility. At the SHP621-301 final treatment evaluation visit, 
subjects will be dispensed blinded investigational product (based on treatment assignment in 
SHP621-301) that will last for up to 4 weeks prior to enrolling into this treatment extension 
study. The 4-week screening period is required to allow for blinded treatment response 
information (reduction in DSQ from baseline and eosinophilic count as determined by a central 
reader) collected during the SHP621-301 final treatment evaluation visit to be entered into the 
IWRS.
After the screening period, subjects who meet eligibility criteria at the end of the screening visit
(Visit 0) will enter the 36-week double-blind treatment period. This period should not commence 
until all screening assessments required to confirm initial eligibility have been completed. If the 
subject does not meet eligibility criteria following completion of screening assessments, the 
investigator or designee will document the subject as a screen failure in the IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening or 
randomized visits. Subjects cannot be rescreened once they have been designated as a screen 
failure.
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7.1.1.1
Screening Visit (Visit 0)/Visit 4 of SHP621-301 Study
The screening visit (Visit 0) assessments and procedures, beginning with informed consent, will 
be performed as outlined in Table 1-1.
The following procedures will be performed at the screening visit:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review current use of concomitant medications and procedures. Note: Subjects who are on a 
PPI must remain on the same dose of the PPI throughout the study, and if they are not taking 
a PPI, they must remain off of a PPI for the remainder of the study.

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly completion 
and train the subject on its use. 
The following procedures will be performed at the final treatment evaluation visit (Visit 4) of 
SHP621-301 and will be used as the screening assessments for this extension study:

Review investigational product dosing compliance.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of synthetic 
and route of administration will be per local lab discretion. Additional cortisol samples will 
be drawn at 30 and 60 minutes following stimulation testing.
 
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging Assessment.
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
Serum pregnancy test will be performed on all female subjects. 

Perform EGD and biopsy either at the investigative site or by a referring physician. 
Esophagogastroduodenoscopy should be completed at or within 7 days of the scheduled visit. 
Biopsy specimens must be available to be sent to the central pathology lab at least 2 weeks 
prior to Visit 1 to allow sufficient time for processing and central review and determination 
of eligibility.

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD) and 
body composition measurements in subjects aged 11-17 years, inclusive. Baseline and post
treatment DXA scans should be performed using the same machine and software.

Dispense blinded investigational product (OBS or placebo; based on treatment assignment in 
SHP621-301) and review administration instructions. The subject will continue with the 
twice daily (morning and evening) dosing regimen. For subjects who are minors (<18 years), 
a parent/guardian will be responsible for ensuring subject takes their investigational product 
appropriately.
7.1.2
Double-blind Treatment Period (Visits 1-8): Weeks 0, 4, 8, 12, 16, 20, 28, and 
36 (or Early Termination)
The double-blind treatment period will comprise 36 weeks, during which all assessments and 
procedures listed for Visits 1-8 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted between Visits 1-6 (Weeks 0-20) 
and a 6-day visit window will be permitted between Visits 7-8 (Weeks 28-36), unless otherwise 
specified. Visit windows are calculated based upon the date of the randomization visit (Visit 1).
Once information for blinded treatment response is available, subjects will return for the 
randomization visit (Visit 1) to receive investigational product. Subjects who continue to meet all 
eligibility criteria and complete the 4-week screening period will have the opportunity to enroll 
in the treatment extension study. Subjects will receive either OBS twice daily (qAM, pc, and hs) 
or placebo twice daily (qAM, pc, and hs).
Subjects who fully responded to OBS treatment in the SHP621-301 study (≤6 eos/HPF across all 
available esophageal levels and at least a 30% reduction in DSQ at the final treatment evaluation 
visit) will enter a randomized withdrawal period to receive either OBS 2 mg twice daily or 
placebo at a 1:1 ratio. Subjects who did not respond or partially responded to OBS treatment in 
the SHP621-301 study will receive OBS 2 mg twice daily. Subjects who were assigned to 
placebo in the SHP621-301 study will receive OBS 2 mg twice daily. The investigator or 
assigned site staff will access the IWRS to randomize the subject and dispense the investigational 
product. Subjects who fail to meet eligibility criteria at the randomization visit (Visit 1) will be 
documented as screen failures in the IWRS and discontinue study drug.
A safety follow-up contact by phone will be performed 4 weeks following the last dose of study 
medication for all subjects (including subjects who fail screening, who discontinue early, or who 
complete the study).
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7.1.2.1
Randomization Visit (Visit 1): Week 0
Subjects will return to the site for the randomization visit (Visit 1) to confirm eligibility. The 
randomization visit (Visit 1) assessments and procedures will be performed as outlined in Table 
1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate in adolescents, 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review investigational product dosing compliance.

Review DSQ compliance; provide subject with instruction to continue completion of the 
DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will record 
the date and time of the first randomized dose in the source documents. Beginning on the 
evening of Visit 1, the subject will take their first dose at home and continue with the twice 
daily (morning and evening) dosing regimen. For subjects who are minors (<18 years), a 
parent/guardian will be responsible for ensuring subject takes their investigational product 
appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
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7.1.2.2
Visits 2 and 3 (Weeks 4 and 8)
Subjects will return to the site for Visit 2 (Week 4) and Visit 3 (Week 8). Assessments at these 
visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate for adolescents, 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of study medication until after the morning cortisol test has been 
performed. 
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.3
Visit 4 (Week 12)
Subjects will return to the site for Visit 4 (Week 12). Assessments at this visit will be performed 
as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
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position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects.

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. In addition, an earlier EGD may also occur if the subject exhibits signs of relapse 
(Section 6.2.3). 
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.4
Visits 5, 6, and 7 (Weeks 16, 20, and 28)
Subjects will return to the site for Visits 5, 6, and 7 (Weeks 16, 20, and 28). Assessments at these 
visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight (measured in duplicate for adolescents 11-17 years, inclusive).
Vital signs will be assessed after the subject has been in a supine position for at least 5 
minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
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overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of study medication until after the morning cortisol test has been 
performed. 
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review DSQ dysphagia episodes and compliance; provide subject with instruction to 
continue completion of the DSQ nightly.
 

Perform a physical examination and assess any changes since screening.

Readminister urine pregnancy test for female subjects. 

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.2.5
Visit 8 (Week 36) or Early Termination
Subjects will return to the site for Visit 8 (Week 36). Assessments at this visit will be performed 
as outlined in Table 1-1. If a subject discontinues prematurely, the assessments for Visit 8 are to 
be performed as completely as possible.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height (measured in triplicate for adolescents 11-17 years, inclusive), and 
weight (measured in duplicate for adolescents 11-17 years, inclusive). Perform stadiometry 
in adolescent subjects. Vital signs will be assessed after the subject has been in a supine 
position for at least 5 minutes immediately prior to the assessment.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review current use of concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection. Any subject with an abnormal 
urinary or serum glucose level will be followed closely until resolution (Section 7.2.2.5).

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of synthetic 
and route of administration will be per local lab discretion. Additional cortisol samples will 
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be drawn at 30 and 60 minutes following stimulation testing. Any subject with an abnormal 
ACTH stimulation test will be followed closely until resolution (Section 7.2.2.5).
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Retrieve DSQ handset and review DSQ compliance.
 
 

Perform a physical examination on all subjects. Adolescents (subjects ≥11 years until the 
investigator confirms subject is post puberty) will also undergo Tanner Staging Assessment.
Any subject with clinical evidence of reduced height velocity and/or delayed Tanner staging 
will be followed closely until resolution (Section 7.2.2.2).

Serum pregnancy test will be performed on all female subjects.

Perform DXA scan for BMD and body composition measurements in subjects aged 
11-17 years, inclusive. Dual-energy X-ray absorptiometry scans should be performed at this 
visit or within 7 days of the scheduled visit using the same machine and software as used in 
the SHP621-301 study.

Perform EGD and biopsy; EGD should be completed at or within 7 days of the scheduled 
visit. An earlier EGD may occur if the subject exhibits signs of relapse (Section 6.2.3); 
however, the Week 36 EGD must be completed.

Review investigational product dosing compliance.
7.1.3
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational product. 
Subjects will receive a follow-up phone call at Visit 9 (Week 40) to query for SAEs, AEs, and 
concomitant treatments (Section 7.1.3.1).
7.1.3.1
Safety Follow-up Contact (Visit 9): Week 40
Assessments at this time, as outlined in Table 1-1, will include the following:

Review concomitant medications and procedures.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE; all 
AEs and SAEs that are not resolved at the time of this contact will be followed to closure.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in
Appendix 2.
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All assessments listed below will be performed by the subject and/or a qualified/trained site staff 
as indicated in the assessment description. For subject-completed assessments, trained site staff 
should not assist the subject in completing any of the questions as this can influence their 
responses. Site staff should review the completed assessment to ensure completeness.
If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales after 
the visit has been completed. Assessments are to be performed according to the schedule shown 
in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
The screening EGD with biopsies will be performed by a physician at the investigative site at the 
final treatment evaluation visit in the SHP621-301 study. Biopsy specimens must be taken and 
provided to the central pathology lab by at least 2 weeks prior to the planned Visit 1 to allow 
sufficient time for processing and central review and determination of eligibility. Subjects, site 
staff, and study team members will remain blinded to eosinophil counts and histopathologic 
findings by the central reader throughout the duration of the study.
At the Week 12 visit (Visit 4), and Week 36 visit (Visit 8) or at early termination (ET), an EGD 
with esophageal biopsies is required for all subjects. If at any time, the subject reports increased 
or worsening dysphagia symptoms to the investigator, the investigator may choose to perform an 
unscheduled EGD. If an unscheduled EGD is performed prior to Week 12, an EGD does not 
have to be repeated at Week 12. If an unscheduled EGD is performed between Week 12 and 
Week 36, the Week 36 EGD should still be performed. Multiple specimens (at least 2 biopsies 
from each of 3 levels, 6 specimens total) will be obtained from the proximal (3 cm below the 
cricopharyngeus muscle), midesophagus (midpoint between the cricopharyngeus muscle and the 
gastroesophageal junction), and distal (3 cm above the gastroesophageal junction). Biopsy tissue 
will be placed in 3 separate vials (1 vial for each of the levels) and sent to the central pathology 
laboratory for processing of tissue into slides. Eosinophil counts and, histopathologic features 
will be evaluated by the central reader and scored for each EGD. Eight histopathologic epithelial 
features (basal layer hyperplasia, eosinophil density, eosinophil microabscesses, eosinophil 
surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial 
cells, lamina propria fibrosis) will be scored on a 4-point scale (0=normal, 3=worst) for both the 
severity of the abnormality (ie, grade) and the amount of tissue affected by the abnormality (ie, 
stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 2) 
fixed esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed for 
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each anatomic location (proximal and distal). The maximum endoscopy score is 10 points for 
each location, and a total endoscopy score is the sum of the scores for the proximal and distal 
locations.
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. At the investigator’s discretion, biopsies will be taken from the stomach and 
duodenum as follows: gastric body (greater curvature): 2 specimens, gastric antrum: 
2 specimens, and duodenum (third part or distal): 2 specimens. Biopsies from the stomach should 
be submitted in 1 vial; biopsies from the duodenum should be submitted in a separate vial to the 
central pathology laboratory for processing of tissue into slides. 
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 3). 
The questionnaire will be completed by subjects daily during the screening period and during the 
36-week treatment period. Each evening before bedtime, subjects will be asked to indicate if they 
experienced dysphagia symptoms (eg, food passing slowly or food sticking) during that day.
Subjects must fill out the DSQ at least 5 or more days during a given week in order to be 
compliant. Visit to visit compliance of DSQ completion will also be assessed by site personnel. 
Protocol deviations will be documented for subjects who fail to complete the DSQ for 3 or more 
days in a given week.
To meet relapse criteria, the subject must have at least 4 days of dysphagia as determined by the 
DSQ in the 2-week period prior to the scheduled visit in addition to meeting the eosinophil 
histology criterion (≥15 eos/HPF from at least 2 of 3 levels of the esophagus). Considering the 
potential for missing diary entries, the determination of relapse based on days of dysphagia 
reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in the 2-week period prior to the visit, 
the subject would meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and at least 8 diary entries are recorded within 
the 2-week period, the subject would not meet the criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported and less than 8 diary entries are recorded within 
the 2-week period, the subject would be designated as meeting the criterion for dysphagia 
symptom relapse due to missing diary data.
Calculations will be performed on daily ePRO entries during a 2-week interval prior to each 
study visit during the treatment period. The DSQ score for the coprimary endpoint and secondary 
endpoints will be calculated by summing the scores of responses to questions 2 and 3 only. 
Questions 1 and 4 will be excluded from the DSQ score:
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
DSQ score =   (Sum of points from questions 2+3 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores of 
responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score = (Sum of points from questions 2+3+4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score = (Sum of points from question 4 in the daily DSQ)×14 days
Number of diaries reported with nonmissing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
MEDICAL HISTORY
The investigator must record all new clinically or medically relevant information which arose 
after the recording of the medical history in the antecedent study. New medical history will be 
collected at the screening visit (Visit 0) of this study. Medical history will be classified as EoE or 
non-EoE by the investigator. Adverse events recorded during the SHP621-301 study may be
added as medical history at the investigator’s discretion.
MEDICATION HISTORY
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, or 
other), must be recorded on the appropriate CRF page.
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit 0) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit 0) 
will be captured as AEs on the AE CRF page, as deemed by the investigator.
Physical examination assessments at each visit should also include specific assessments for signs 
of glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swings, insomnia, and 
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depression). Physical examination at the screening visit (Visit 0) will also include Tanner 
Staging Assessments for subjects <18 years of age.
Height will be collected at the screening visit (Visit 0) and Visit 8 for all subjects and at Visit 4 
for adolescents (11-17 years, inclusive) only. Stadiometers will be used to measure height for
subjects aged 11-17 years, inclusive. Statural height will be measured by trained site staff using a 
stabilized stadiometer. Height will be measured in triplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF. The same stadiometer should be used for the baseline and 
post treatment measurements. Standard measuring procedures should be followed (eg, removal 
of socks, shoes, and hats). The stadiometer must be calibrated at least once daily, and as feasible, 
within 4 hours of each measurement. All measurements should be recorded to the nearest 10th of 
a centimeter (1 mm). Please refer to the study manual for additional details.
Weight will be measured in duplicate in adolescents (11-17 years, inclusive) and recorded in the 
CRF.
All subjects with clinical evidence of reduced height velocity and/or delayed Tanner Staging, as 
determined by the investigator, must be followed closely until resolution (ie, resumption of 
normal for age height velocity, or the resumption of Tanner Stage development). Subjects who 
discontinue from the treatment period at any time and have clinical evidence of reduced height 
velocity and/or delayed Tanner Stage development at the early termination visit will be 
monitored beyond the end of the study until resolution is established. 
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
AEs are collected from the time informed consent is signed. (Please refer to Section 8) Any AE 
that is ongoing from the SHP621-301 study must be recorded on the CRF for this study. 
AE assessments at each visit should also include specific assessments for signs of glucocorticoid 
excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment and will include blood pressure (systolic and diastolic), heart rate, 
respirations, and temperature. Blood pressure should be determined by cuff (using the same 
method, the same arm, and in the same position throughout the study). Any clinically significant 
deviations from baseline in vital signs that are deemed clinically significant in the opinion of the 
investigator are to be recorded as an AE.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures.
All subjects must fast overnight prior to collection of clinical laboratory tests.
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Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose 

blood urea nitrogen 

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
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Adrenocorticotropic hormone stimulation testing will be performed by measuring the levels of 
cortisol in the blood following the injection of a synthetic form of ACTH. The type of synthetic 
and route of administration will be per local lab discretion. Blood samples will be collected just 
prior to and approximately 30 and 60 minutes following the injection. Administration of ACTH 
stimulation testing and sample collection should follow the same procedures used in the 
SHP621-301 study.
In the event of clinically significant abnormal laboratory test results, follow-up laboratory tests 
may be conducted. All subjects with an abnormal ACTH stimulation test or urinary or serum 
glucose level must be followed closely until resolution. Subjects who discontinue from the 
treatment period at any time and have an abnormal ACTH stimulation test at the early 
termination visit will be scheduled for repeat ACTH testing approximately 6 weeks post last dose 
of investigational product and followed to resolution of the abnormality. Any clinically 
significant abnormalities noted in the laboratory tests will be discussed with the medical monitor.
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit (Visit 0) 
and the final treatment evaluation visit (Visit 8) or ET visit. A urine pregnancy test is performed 
on all female subjects at all other visits or if pregnancy is suspected.
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density
Dual-energy X-ray absorptiometry (also referred to as DEXA) scans for determination of BMD 
and body composition measurements will be performed in subjects aged 11-17 years, inclusive,
as outlined in Table 1-1.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body less 
head (Bachrach 2011; Gordon et al. 2008; International Society for Clinical Densitometry 2013). 
Dual-energy X-ray absorptiometry body composition measurements will also be collected. The 
same DXA machine and software should be used for the baseline and post treatment scans. The 
DXA manufacturer, model, and software version should be recorded in the CRF.
7.2.3
Other Assessments
 
 
 
 
 
 
 
 
 
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7.2.4
Volume of Blood to Be Drawn from Each Subject
Table 7-1 Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Safety
Biochemistry and -hCGa
6
9
54
ACTH
2
4
8
Cortisol
2
9
18
Hematology
2
9
18
Total mL
-
-
98
Abbreviations: ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropina -hCG testing 
is for females only.
During this study, it is expected that approximately 98 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 98 mL. When more than 1 blood assessment is to be done at the time
point/period, if they require the same type of tube, the assessments may be combined. 
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening period of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related” based on the definitions in Table 8-1. The 
causality assessment must be documented in the source document.
Table 8-1 Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or other 
drugs and chemicals and which follows a clinically reasonable response on 
dechallenge. The association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (dechallenge), and reappears upon 
repeated exposure (rechallenge). Note that this is not to be construed as requiring 
reexposure of the patient to study drug; however, the determination of definitely 
related can only be used when recurrence of event is observed.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign assessment can represent an AE if the 
change is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment period, there are abnormal clinical laboratory or vital sign values 
which were not present at the pretreatment value observed closest to the start of study treatment, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign parameter is clinically significant 
and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form
for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is not 
considered an SAE.
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In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of 4 mg of the product.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parents/legally authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO medical monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
not apply to reports of abuse, misuse, overdose, or medication errors (Section 8.1.7) unless they 
result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol (and any applicable follow-up reports) must
also be sent to the CRO medical monitor using the details specified in the emergency contact 
information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

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 was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the medical 
monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, leading up to the onset date of the SAE, or following the resolution date of the SAE must 
be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have “fatal” checked as an outcome with the date of death recorded as the resolution date.
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered as not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory 
authorities/US central Institutional Review Boards (IRBs) of related, unexpected SAEs.
In addition, the sponsor and the clinical CRO are responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the SHP621
program. 
The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel.
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan.
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
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The SAP will be finalized prior to final database lock and performing analysis (ie, unblinding) to 
preserve the integrity of the statistical analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis is planned.
9.6
Sample Size Calculation and Power Considerations
Approximately 200 subjects (88%) who are randomized in the SHP621-301 study are estimated 
to complete the SHP621-301 study and enroll in this treatment extension study based on 
enrollment observed in the Phase 2 study (MPI 101-06).
The primary efficacy measure of the study will be the proportion of subjects who relapse during
the double-blind randomized withdrawal period, defined as having an eosinophil count of 
≥15 eos/HPF from at least 2 of 3 levels of the esophagus (as determined by a central reader) and 
at least 4 days of dysphagia in the 2-week period prior to the scheduled visit (as determined by 
the DSQ). To be considered as a subject with relapse, both criteria must be met. To determine 
whether a subject meets the criterion for dysphagia, refer to Section 7.2.1.2.
Based on observation in the Phase 2 study (MPI 101-06), approximately 26% of subjects, or 
approximately 40 subjects, who were assigned to OBS treatment in the SHP621-301 study are 
anticipated to respond fully after 12 weeks in the SHP621-301 study. For this study, to detect a 
50 percentage point difference between relapse proportions of 20% and 70% in the OBS and 
placebo groups, respectively, at more than 80% power and a significance level of 0.05 (2-sided) 
using the Fisher’s Exact test with equal allocation to treatment groups, it is necessary to assess 
the primary efficacy measure for approximately 38 subjects (19 subjects in each of the OBS and 
placebo groups). 
9.7
Study Population
The safety set will include all subjects who are randomized and receive at least 1 dose of 
investigational product.
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of 
investigational product and had 1 post baseline efficacy assessment (biopsy and/or DSQ score).
The per-protocol (PP) set will include all subjects in the FAS excluding subjects with major 
protocol deviations. The PP set will be identified prior to unblinding the treatment assignments 
by a team consisting of, at a minimum, a physician and a statistician from Shire. 
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9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint for each subject is relapse during the double-blind randomized 
withdrawal period. Relapse, a binary response (either with a relapse or not), is defined as having 
an eosinophil count of ≥15 eos/HPF from at least 2 of 3 levels of the esophagus, as determined 
by a central reader, and having at least 4 days of dysphagia in the 2-week period prior to the 
scheduled visit, as determined by the DSQ (refer to Section 7.2.1.2 for additional details).
The primary efficacy endpoint will be analyzed as the proportion of subjects with relapse during
the double-blind randomized withdrawal period for the FAS, using a Fisher’s Exact test 
comparing OBS 2 mg twice daily against placebo. The primary test of treatment effect will be 
2-sided, and conducted at the significance level of 0.05. The proportion of subjects with relapse 
for each treatment group and the corresponding 95% confidence interval (CI) will be estimated. 
In addition, the difference in the proportion of subjects with relapse between the 2 treatment 
groups and its 95% CI will be estimated.
Subjects who withdraw without providing efficacy data at the ET visit will be classified as being
relapsers in the primary efficacy analysis. The null hypothesis states that there is no difference in 
relapse proportions between OBS 2 mg twice daily and placebo, with the 2-sided alternative of a 
nonzero difference between groups. Relapse proportions at each adjacent double-blind visit 
interval will also be assessed by applying the Fisher’s Exact test to the observed data at each 
double-blind visit.
The following sensitivity and supportive analyses will be performed for the primary endpoint to 
evaluate the robustness of the results from the primary analysis methods.
Similar analyses used for the ITT population will be repeated using the FAS and the PP datasets. 
Sensitivity analyses will be performed using the ITT population by classifying subjects who 
withdraw without providing efficacy data at the ET visit as non-relapsers. Sensitivity analyses 
will be performed using the ITT population by classifying subjects who met the histology relapse 
criterion and met the dysphagia symptom relapse criterion due to missing diary data as non-
relapsers. In addition, the subjects who were prematurely withdrawn from the study without the 
primary efficacy endpoint will be imputed randomly according to the distribution of relapsers 
with available data; and the similar statistical test will be performed using the imputed data.  
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the long-term treatment response, a binary response over 
an extended period of 36 weeks in adolescent and adult subjects who were randomized to OBS 
treatment but did not respond after 12 weeks in the SHP621-301 induction study (subject did not 
have peak count of ≤6 eos/HPF across all available esophageal levels at the final treatment visit 
and/or ≥30% reduction in DSQ score from baseline) and met the following criteria:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
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esophageal levels at the final treatment period evaluation (Visit 8)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline of the SHP621-301 study and from baseline of this extension 
study to the final treatment period evaluation (Visit 8)
The key secondary efficacy endpoint will be analyzed as the proportion of subjects who 
responded based on the histological data and the DSQ data at the final treatment period 
evaluation (Visit 8). The proportion of subjects with long-term treatment response and the 
corresponding 95% confidence interval (CI) will be estimated and summarized. 
The following secondary efficacy endpoints will be analyzed in all subjects:

Histologic response, defined as a peak eosinophil count of ≤6 eos/HPF across all available 
esophageal levels at each assessment visit

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) at each assessment visit from baseline of the SHP621-301 study and from 
baseline of this extension study 

Change in the DSQ score and change in the peak eosinophilic count at each assessment visit 
from baseline of the SHP621-301 study and from baseline of this extension study

Change in total endoscopy score, as measured by the EREFS classification, at each 
assessment visit from baseline of the SHP621-301 study and from baseline of this extension 
study 

Peak eosinophil count <15 eos/HPF across all available esophagus levels at each assessment 
visit

Peak eosinophil count ≤1 eos/HPF across all available esophagus levels at each assessment 
visit 

Change in the peak eosinophil count at each assessment visit from baseline of the SHP621-
301 study and from baseline of this extension study at each assessment visit for each 
available esophageal level (proximal, mid-, and distal)

Change in the histopathologic epithelial features combined total score (grade and stage) at 
each assessment visit from baseline of the SHP621-301 study and from baseline of this 
extension study

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), at each assessments visit from baseline of the SHP621-301 
study and from baseline of this extension study

Change in the DSQ combined score (questions 2+3) at each assessment from baseline of the 
SHP621-301 study and from baseline of this extension study 

Cumulative distribution function curves for the change and the percent change in the DSQ 
score at each assessment visit from baseline of the SHP621-301 study and from baseline of 
this extension study

Overall binary response I, defined as a reduction in the DSQ score of ≥30% and a peak 
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eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Overall binary response II, defined as a reduction in the DSQ score of ≥50% and a peak 
eosinophil count of ≤6 eos/HPF across all esophageal levels at each assessment visit from 
baseline of the SHP621-301 study and from baseline of this extension study 

Change in the DSQ + pain score (question 2+3+4) at each assessment visit from baseline of 
the SHP621-301 study and from baseline of this extension study 

Change in the DSQ pain score (question 4) at each assessment visit from baseline of the 
SHP621-301 study and from baseline of this extension study 
Summary statistics of the DSQ score (questions 2+3) and the peak eosinophil count and the 
change from baseline of the SHP621-301 study and from baseline of this extension study at the 
final treatment period evaluation (Visit 8) will be summarized by each assessment visit. 
To evaluate the response to OBS treatment over 36 weeks for subjects who were on placebo in 
the SHP621-301 induction study, the proportion of subjects who responded based on the 
histological data and the DSQ data at the final treatment period evaluation (Visit 8) and the 
corresponding 95% CI will be summarized. Summary statistics of the DSQ score (questions 2+3) 
and the peak eosinophil count and the change from baseline of the SHP621-301 study and from 
baseline of this extension study at the final treatment period evaluation (Visit 8) will be 
summarized by each assessment visit. 
For subjects who relapse on placebo during the randomized withdrawal and who reinitiate 
treatment with OBS 2 mg twice daily (intermittent therapy), separate descriptive analyses for 
histological data and DSQ endpoints will be conducted at each assessment visit. Changes will be 
summarized over time from baseline of the SHP621-301 study and from the time of relapse. The 
same criteria for response will be applied to these subjects (≤6 eos/HPF across all available 
esophageal levels and at least a 30% reduction in DSQ from SHP621-301 baseline score).
Summary statistics will be provided for all other secondary endpoints.
9.8.3
Exploratory Efficacy Endpoints
The exploratory endpoints that will be explored are the following:

 
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the randomization visit (Visit 1), or at the screening visit (Visit 0) if 
not collected at Visit 1, will be used as the baseline value for safety analyses.
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TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product and no later than 3 days following the last dose of investigational product. However, for 
any subjects who die during the study (ie, the date of death is between the date of first dose of 
investigational product and the date of study discontinuation entered by the site, inclusive), all 
AEs (including those resulting in death) that occur during the study will be considered as TEAEs 
irrespective of the last dose and will be included in the TEAE summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of TEAEs 
will be calculated overall by system organ class, preferred term, and treatment group. TEAEs
will be further summarized by severity and relationship to investigational product. AEs related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and 
height assessments, DXA scans for BMD and body composition measurements (for adolescents 
aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum 
pregnancy test, if appropriate), and ACTH stimulation tests. To account for the effects of puberty
in adolescent subjects (11-17 years of age, inclusive), BMD z-scores will be adjusted for height 
z-scores using the Bone Mineral Density in Childhood Study calculator
(Bone Mineral Density in Childhood Study 2015). Safety parameters will be descriptively 
summarized by treatment group at baseline and for each post baseline visit.
 
 
 
 
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
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the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason.
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study, which has been posted to a designated public website, will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
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the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with instructions 
from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
The data from the central pathologist will be recorded directly onto paper CRF.
All other data will have separate source documentation; no data will be recorded directly onto 
the CRF. The following data collected for assessments and procedures performed at the 
SHP621-301 final treatment evaluation visit (Visit 4) will not be recollected in the SHP621-302 
database as follows (Section 7.1.1.1):

Vital signs, height, and weight assessment

EGD with endoscopy score (EREFS) and biopsy

DSQ compliance assessment

Physical examination

Tanner Staging Assessment

Clinical laboratory tests

Urinalysis

Pregnancy test

Morning cortisol

ACTH Stimulation Testing
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
DXA Scan (subjects 11 to 17 years of age)
All other data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to subject’s 
medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation, or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (or assent as 
applicable for subjects <18 years of age) from all study subjects prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s legally authorized 
representative, as applicable, is requested to sign and date the subject’s informed consent form or 
a certified translation, if applicable, after the subject has received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parents/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and received 
their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable opinion/approval 
of these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible for 
this action. Additionally, if the IRB/EC requires modification of the sample subject information 
and consent document provided by the sponsor, the documentation supporting this requirement 
must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator or,
for multicenter studies, the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
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Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP621; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purposes of any such transfer would include 
supporting regulatory submissions, conducting new data analyses to publish or present the study 
results, or answering questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg,
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
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All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral, or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11.
REFERENCES
Bachrach LK, Sills IN, Section on Endocrinology. Clinical report—bone densitometry in 
children and adolescents. Pediatrics. 2011;127(1):189-94.
Bone Mineral Density in Childhood Study (BMDCS). Available at:
http://www.bmdcspublic.com. Accessed August 5, 2015. 
Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in the United 
States. Clin Gastroenterol Hepatol. 2014a;12(4):589-96.
Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic esophagitis 
is a progressive fibrostenotic disease. Gastrointest Endosc. 2014b;79(4):577-85.
 
Food and Drug Administration. Uceris pharmacology review. NDA 203-634. 2011.
Food and Drug Administration. Draft Guidance: Drug Interaction Studies – Study Design, Data 
Analysis, Implications for Dosing, and Labeling Recommendations. US Department of Health 
and Human Services, Center for Drug Evaluation and Research (CDER), February 2012.
 
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: a 
systematic review and consensus recommendations for diagnosis and treatment. 
Gastroenterology. 2007;133(4):1342-63.
Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med. 2015;373(17):1640-48.
Gordon CM, Bachrach LK, Carpenter TO, et al. Duel energy X-ray absorptiometry interpretation 
and reporting in children and adolescents: the 2007 ISCD pediatric official positions. J Clin 
Densitom. 2008;11(1):43-58.
Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterol Clin North Am. 2014;43(2):297-316.
International Society for Clinical Densitometry. 2013 Official Positions—Adult & Pediatric. 
2014:1-20.
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3-20. 
 
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12.
APPENDIX
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Protocol Amendment 2
19 Dec 2016
Global
Protocol Amendment 1
22 Jun 2016
Global
Original Protocol
05 Dec 2015
Global
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
Changed from:
 
To:
Emergency Contact Information 
Page
A 4-week screening period is required to allow for blinded treatment 
response information (reduction in DSQ from baseline and eosinophilic count 
as determined by a central reader) collected during the SHP621-301 final 
treatment evaluation visit to be entered into the interactive web-based 
response system (IWRS) by. Only the unblinded data team who is 
independent from the blinded study team and not involved with the day-to-
day conduct of the study will have restricted access to blinded treatment 
response information. 
Rationale: This text has been clarified to emphasize that access to blinded 
treatment response information will be restricted to the unblinded data team. 
Blinded treatment response data will not be accessed by the study team; 
therefore, the double-blind will be maintained.
Synopsis: Investigational 
product, dose, and mode of 
administration;
Synopsis Methodology;
Section 3.1: Study Design and 
Flow Chart
At least 8 daily diary entries must be completed over 14 consecutive days in 
order to determine the criterion for DSQ relapse. Considering the potential 
for missing diary entries, the determination of relapse based on days of 
dysphagia reported on the DSQ will occur as follows:

If at least 4 days of dysphagia are reported on the DSQ in order
the 2-week period prior to the visit, the subject would meet the 
criterion for dysphagia symptom relapse. If fewer

If less than 4 days of dysphagia are reported and at least 8 diary 
entries are recorded within the 2-week period, the subject would 
not meet criterion for dysphagia symptom relapse. 

If less than 4 days of dysphagia are reported in the DSQ and less
fewer than 8 diary entries are reported recorded within the 2-week 
period, then the 2-week period will be shifted backwards from the 
scheduled visit, 1 day at a time, to include the most recent 2-week 
period with at least 8 diary entries confirm if the most recent 2-
week period with at least 8 diary entries subject meets the criteria 
for dysphagia symptom relapse over 14 consecutive days; 
however, the 2-week period will not be shifted further if at least 8 
diary entries are recorded in the 14-day period and will not be 
shifted by more than 2 weeks in total (ie, no more than 2-week 
period plus additional 2-week additional expansion). 
The criteria for relapse align with the related inclusion criteria for 
participation in the SHP621-301 study. If both histology and dysphagia 
symptom relapse criteria are met, then the treatment assignment change 
will be performed in a blinded manner in IWRS at the subsequent study 
visit by the independent unblinded data team.
Rationale: Additional text is provided to clarify the evaluation of dysphagia 
Synopsis: Investigational 
product, dose, and mode of 
administration;
Section 6.2.3: Dosing;
Section 7.2.1.2: Dysphagia 
Symptom Questionnaire
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Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
symptoms for determination of relapse based on days of dysphagia reported 
on the DSQ prior to study visits with the potential for missing diary entries.
The independent, unblinded data team will review the blinded EGD and DSQ 
data to confirm the If a subject is on placebo in the randomized withdrawal 
period, determine if the subject meets relapse the criteria, and change for 
relapse, the subject’s treatment assignment will be changed in a blinded 
manner from placebo to OBS 2 mg twice daily if relapse is confirmed at 
the subsequent study visit.
Synopsis: Investigational 
product, dose, and mode of 
administration
Synopsis: Methodology; 
Section 6.2.3: Dosing
6.
Subject is willing and has an understanding and ability to fully 
comply with study procedures including DSQ compliance (completed the 
DSQ on ≥70% of days in any 2 consecutive weeks of the screening period)
and restrictions defined in this protocol.
Synopsis: Inclusion Criteria;
Section 4.1: Inclusion Criteria
5.
Subject has initiated, discontinued, or changed dosage regimen of 
proton pump inhibitors (PPIs), H2 antagonists, antacids, antihistamines, or 
leukotriene inhibitors for any condition (such as gastroesophageal reflux 
disease, asthma or allergic rhinitis) since the final treatment evaluation visit 
(Visit 4) of the SHP621-301 study or anticipated changes in the use of such 
medications during the treatment period. 
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
12.
Subject has oropharyngeal or esophageal candidiasis that failed to 
respond to previous treatment. Diagnosis with oropharyngeal or esophageal 
candidiasis at or since the final treatment evaluation visit (Visit 4) of the 
SHP621-301 study is not an exclusion as long as the subject received is
treatment for candidiasis and is expected to respond to treatment. 
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
13.
Subject has a potentially serious acute or chronic infection or 
immunodeficiency condition, including tuberculosis, fungal, bacterial, 
viral/parasite infection, ocular herpes simplex, or chicken pox/measles.
Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
The primary efficacy endpoint will be analyzed as the proportion of subjects 
with relapse during the end of the double-blind randomized withdrawal 
period for the FAS, using Fisher’s Exact a chi-square test comparing OBS 2 
mg twice daily against placebo.
Relapse proportions at each adjacent double-blind visit interval will also be 
assessed by applying the Fisher’s Exact chi-square test to the observed data 
at each double-blind visit.
Rationale: The primary efficacy analysis method has been changed from the 
Chi-square test to Fisher’s exact test. Considering the expected number of 
subjects in the randomized withdrawal portion of the study, and the very 
small number of subjects who are expected to relapse in the OBS group, the 
Fisher’s exact test is considered a more appropriate method.
Synopsis: Statistical 
Methodology for Primary 
Efficacy Endpoint
Section 9.8.1: Primary Efficacy 
Endpoint
For this study, to detect a 50 percentage point difference between relapse 
proportions of 20% and 70% in the OBS and placebo groups, respectively, at 
more than 80% power and a significance level of 0.05 (2-sided) using the 
Fisher’s Exact a Chi-Square test with equal allocation to treatment groups, it 
is necessary to assess the primary efficacy measure for approximately 38 
Synopsis: Sample Size 
Justification;
Section 9.6: Sample Size 
Calculation and Power 
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Amendment Number 1
Amendment Date
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Global Amendment
Description of Change
Section(s) Affected by Change
subjects (19 subjects in each of the OBS and placebo groups)
Considerations
c  Height to be collected at screening (Visit 0) and Visit 8 only  Stadiometers 
will be used to measure height for all subjects aged. Height to be collected 
at Visit 4 for adolescents only (11-17 years, inclusive). Height 
measurements for adolescents should be measured in triplicate using
stadiometers. will be used to measure height for subjects aged 11-17 years, 
inclusive.
Table 1-1, Footnote c;
Section 7.1.2.3: Visit 4 (Week 
12)
d  Weight measurements for adolescents (11-17 years, inclusive) should 
be measured in duplicate.
Table 1-1, Footnote d
The treatment assignment change will be performed in a blinded manner in 
IWRS at the subsequent study visit by the independent unblinded data 
team.
Section 3.1: Study Design and 
Flow Chart
•
No change in use of PPIs, H2 antagonists, antacids, antihistamines,
or leukotriene inhibitors for any condition (such as gastroesophageal reflux 
disease, asthma or allergic rhinitis).
Section 4.3: Restrictions
•
Acceptable methods of contraception are:
•
Surgically sterile male partner
Section 4.4.1: Female 
Contraception
Medically important events that in the opinion of the investigator or medical 
monitor would compromise the subject’s ability to safely continue in the 
study, including but not limited to severe signs and symptoms of EoE, such 
as an esophageal stricture requiring dilation, weight loss due to severe 
dysphagia, and/or upper GI bleed worsening signs and symptoms of EoE 
(eg, weight loss or increased dysphagia), would be considered a relapse and 
result in withdrawal of the subject from the study.
Rationale: The terms “worsening signs and symptoms of EoE” have been 
more clearly defined as “severe signs and symptoms of EoE” to prevent 
subjects with only minor to moderate symptoms being withdrawn from the 
study.
Section 4.5.1: Subject 
Withdrawal Criteria
Antihistamines
Rationale: Antihistamines were removed from the list of permitted 
medications that require consultation with the medical monitor prior to 
initiating changes in the dosing regimen. Antihistamine use, including any 
changes to the dosing regimen, is permitted during the course of the study.
Section 5.2.1: Permitted 
Treatment
3.
Initiation or change in dosing frequency to PPIs, H2 antagonists, 
antacids, antihistamines, or leukotriene inhibitors for any condition…
Section 5.2.2: Prohibited 
Treatment
During the 4-week screening period, blinded treatment response information 
(reduction in DSQ from baseline and eosinophilic count as determined by a 
central reader) collected during the SHP621-301 final treatment evaluation 
visit will be entered into the IWRS by an independent, unblinded data team in 
a blinded manner in a blinded manner. Details on the unblinded data team 
will be provided in a separate charter. Once information is available in 
IWRS, subjects will return…
Sites will enter confirm eligibility criteria information prior to randomization
Section 6.2.1: Interactive 
Response Technology for 
Investigational Product 
Management
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Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
The 4-week screening period is required to allow for blinded treatment 
response information (reduction in DSQ from baseline and eosinophilic count 
as determined by a central reader) collected during the SHP621-301 final 
treatment evaluation visit to be entered into the IWRS by the independent, 
unblinded, data team.
Section 7.1.1: Screening Period 
(Weeks -4 to 0)
•
Record vital signs (including blood pressure [systolic and diastolic], 
heart rate, respirations, and temperature), height (measured in triplicate for 
adolescents 11-17 years, inclusive), and weight (measured in duplicate for 
adolescents 11-17 years, inclusive). Perform stadiometry in adolescent
subjects. aged 11-17 years, inclusive.
Section 7.1.1.1: Screening Visit 
(Visit 0)/Visit 4 of SHP621-301 
Study;
Section 7.1.2.3: Visit 4 
(Week 12);
Section 7.1.2.5: Visit 8 
(Week 36) or Early Termination
•
Record vital signs (including blood pressure [systolic and diastolic], 
heart rate, respirations, and temperature) and weight (measured in duplicate 
for adolescents 11-17 years, inclusive).
Section 7.1.2.1: Randomization 
Visit (Visit 1)/Week 0;
Section 7.1.2.2: Visits 2 and 3 
(Weeks 4 and 8);
Section 7.1.2.4: Visits 5, 6, and 
7 (Weeks 16, 20, and 28)
Any subject with clinical evidence of reduced height velocity and/or 
delayed Tanner staging will be followed closely until resolution (Section 
7.2.2.2).
Section 7.1.2.5: Visit 8 (Week 
36) or Early Termination
The independent unblinded data team will receive data from the central 
reader and will use it to confirm whether the subject meets the eligibility 
criteria for this study.
Section 7.2.1.1: 
Esophagogastroduodenoscopy 
with Esophageal Biopsy and 
Histopathologic Evaluation
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Amendment Number 1
Amendment Date
22 June 2016
Global Amendment
Description of Change
Section(s) Affected by Change
Height will be collected at the screening visit (Visit 0) and Visit 8 for all 
subjects, and at Visit 4 for adolescents (11-17 years, inclusive) only.
Height will be measured in triplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF.
Weight will be measured in duplicate in adolescents (11-17 years, 
inclusive) and recorded in the CRF.
All subjects with clinical evidence of reduced height velocity and/or 
delayed Tanner Staging, as determined by the investigator, must be 
followed closely until resolution (ie, resumption of normal for age height 
velocity, or the resumption of Tanner Stage development). Subjects who 
discontinue from the treatment period at any time and have clinical 
evidence of reduced height velocity and/or delayed Tanner Stage 
development at the early termination visit will be monitored beyond the 
end of the study until resolution is established. 
Rationale: This text was added to ensure that any subjects demonstrating 
laboratory or clinical findings suggestive of adverse HPA effect will be 
appropriately monitored until resolution.
Section 7.2.2.2: Physical 
Examination (Including Height 
and Weight)
For Subjects who discontinue from the treatment period at any time and have 
an abnormal ACTH stimulation test at the early termination visit, subjects 
will be scheduled for repeat ACTH testing approximately 6 weeks post last 
dose of investigational product to ensure that ACTH levels have normalized
and followed to resolution of the abnormality. 
Section 7.2.2.5: Clinical 
Laboratory Evaluations
To determine whether a subject meets the criterion for dysphagia, refer to at 
least 8 daily diary entries must be completed over 14 consecutive days, as 
described in Section 7.2.1.2.
Section 9.6: Sample Size 
Calculation and Power 
Considerations
Section 9.8.1: Primary Efficacy 
Endpoint
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Appendix 2
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Subject
Tanner Staging Assessment
Site
EREFS
Site
Abbreviations: DSQ=Dysphagia Symptom Questionnaire; 
 
EREFS=EoE Endoscopic Reference Score; 
 
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above, and a new master file containing the revised scale/assessment will be provided to the site. 
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Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE
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MEMORANDUM 
Page 1 of 3 
 
To: 
SHP621-302 Investigators and Study Coordinators 
From:  
, MD, 
 
Date: 
 
20 February 2019 
Re: 
SHP621-302 Protocol Amendment 2 - Administrative Change  
 
 
This memorandum provides an administrative change made to SHP621-302 Protocol Amendment 2 
(dated 19 December 2016). 
 
Rationale for changes:  
• 
To provide clarification on recording of adverse events (AEs) in the clinical database  
• 
To provide clarifications on statistical methods for the final analysis  
• 
To provide the accurate text of the Dysphagia Symptom Questionnaire (DSQ)  
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
7.1.1.1 Screening 
Visit (Visit 0)/Visit 
4 of SHP621-301 
Study 
 
Perform AE assessments, including 
specific assessments for signs of 
glucocorticoid excess.   Any AE that occurs 
during this visit will be recorded in the CRF 
and considered a TEAE. 
Perform AE assessments, including 
specific assessments for signs of 
glucocorticoid excess.  Any AE that 
occurs during this visit will be recorded in 
the CRF and considered a TEAE. 
7.2.2.3 Adverse 
Event Collection 
AEs are collected from the time informed 
consent is signed. 
AEs are collected from the time the 
informed consent is signed first dose of 
investigational product (Visit 1). 
8.1 Definition of 
Adverse Events, 
Period of 
Observation, 
Recording of 
Adverse Events 
All AEs are collected from the time the 
informed consent is signed until the 
defined follow-up period stated in Section 
7.1.3. This includes events occurring 
during the screening period of the study, 
regardless of whether or not investigational 
product is administered. 
All AEs are collected from the time the 
informed consent is signed first dose of 
investigational product (Visit 1) until the 
defined follow-up period stated in Section 
7.1.3. This includes events occurring 
during the screening period of the study, 
regardless of whether or not 
investigational product is administered if 
they are ongoing at the time of Visit 1.  
Any AE that occurs and resolves prior to 
Visit 1 will be recorded in the SHP621-301 
clinical database. 
8.1.6 Pregnancy 
All pregnancies are to be reported from the 
time informed consent is signed until the 
defined follow-up period stated in Section 
7.1.3. 
All pregnancies are to be reported from 
the time the informed consent is signed 
first dose of investigational product (Visit 
1) until the defined follow-up period stated 
in Section 7.1.3. 
8.2.4 Serious 
Adverse Event 
Collection Time 
Frame 
All SAEs (regardless of relationship to 
study) are collected from the time the 
subject signs the informed consent until 
the defined follow-up period stated in 
Section 7.1.3 and must be reported to the 
Shire Global Pharmacovigilance and Risk 
Management Department and the medical 
monitor within 24 hours of the first 
awareness of the event. 
All SAEs (regardless of relationship to 
study) are collected from the time the 
informed consent is signed first dose of 
investigational product (Visit 1)  until the 
defined follow-up period stated in Section 
7.1.3 and must be reported to the Shire 
Global Pharmacovigilance and Risk 
Management Department and the medical 
monitor within 24 hours of the first 
awareness of the event.   
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MEMORANDUM 
Page 2 of 3 
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
8.2.5 Serious 
Adverse Event 
Onset and 
Resolution Dates 
In addition, any signs or symptoms 
experienced by the subject after signing 
the informed consent form, leading up to 
the onset date of the SAE, or following the 
resolution date of the SAE must be 
recorded as an AE, if appropriate. 
In addition, any signs or symptoms 
experienced by the subject after signing 
the informed consent form the first dose 
of investigational product (Visit 1), leading 
up to the onset date of the SAE, or 
following the resolution date of the SAE 
must be recorded as an AE, if 
appropriate.   
9.7 Study 
Population 
The intent-to-treat (ITT) set will include all 
randomized subjects. Subjects will be 
analyzed according to their assigned 
treatment, regardless of the treatment 
actually received. 
The full analysis set (FAS) will include all 
randomized subjects who received at least 
1 dose of investigational product and had 1 
post baseline efficacy assessment (biopsy 
and/or DSQ score). 
The intent-to-treat (ITT) set will include all 
randomized subjects. Subjects will be 
analyzed according to their assigned 
treatment, regardless of the treatment 
actually received. 
The full analysis set (FAS) will include all 
randomized subjects who received at 
least 1 dose of investigational product and 
had 1 post baseline efficacy assessment 
(biopsy and/or DSQ score). 
9.8.1 Primary 
Efficacy Endpoints 
Similar analyses used for the ITT 
population will be repeated using the FAS 
and the PP datasets.  Sensitivity analyses 
will be performed using the ITT population 
by classifying subjects who withdraw 
without providing efficacy data at the ET 
visit as non-relapsers. Sensitivity analyses 
will be performed using the ITT population 
by classifying subjects who met the 
histology relapse criterion and met the 
dysphagia symptom relapse criterion due 
to missing diary data as nonrelapsers. 
Similar analyses used for the ITT FAS 
population will be repeated using the FAS 
and the PP datasets. Sensitivity analyses 
will be performed using the ITT FAS 
population by classifying subjects who 
withdraw without providing efficacy data at 
the ET visit as non-relapsers. Sensitivity 
analyses will be performed using the ITT 
FAS population by classifying subjects 
who met the histology relapse criterion 
and met the dysphagia symptom relapse 
criterion due to missing diary data as non-
relapsers. 
9.9  Safety 
Analyses 
TEAEs are defined as AEs that start or 
deteriorate on or after the first dose of 
investigational product and no later than 3 
days following the last dose of 
investigational product. 
TEAEs are defined as AEs that start or 
deteriorate on or after the first dose of 
investigational product (Visit 1) and no 
later than 3 days following through the 
Safety Follow-up Contact, or 31 days after 
the last dose of investigational product for 
subjects who do not have a Safety 
Follow-up Contact. 
Appendix 3 
Dysphagia 
Symptom 
Questionnaire 
ePRO for EoE 
Question 2 
Since you woke up this morning, has food 
done down slowly or been stuck in your 
throat or chest? 
Question 2 
Since you woke up this morning, has food 
done down slowly or been stuck in your 
throat or chest? 
 
The above administrative changes do not impact the overall study design or study conduct.  These 
changes will be documented in a forthcoming protocol amendment should the need arise.  In the 
meantime, please submit this memo to your IRB notifying them of these changes, if appropriate per local 
requirements, and please file this memo in your study file records.  
 
For non-commercial use only

MEMORANDUM 
Page 3 of 3 
 
If you have further questions, please do not hesitate to contact your PPD Clinical Research Associate, the 
PPD Remote Site Monitor, or Shire directly. 
 
Sincerely, 
, MD 
 
 
 
 
 
 
 
For non-commercial use only

MEMORANDUM 
 
Page 1 of 3 
 
To: 
SHP621-302 Investigators and Study Coordinators 
From:  
, MD, 
 
Date: 
 
9 December 2019 
Re: 
SHP621-302 Protocol Amendment 2 - Administrative Change  
 
 
This memorandum serves to provide administrative changes made to SHP621-301 Protocol Amendment 
2 (dated 19 Dec 2016) that do not impact the overall study design, safety, or study conduct and in 
accordance with Takeda procedures.  
 
Rationale for changes:  
• 
To update technical aspects of the statistical testing method for the primary endpoint 
• 
To describe the fixed sequence procedure for hierarchy testing of certain secondary endpoints 
• 
To provide clarification on the intent of the key secondary endpoint  
• 
To include additional exploratory endpoints 
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
9.6 Sample Size 
Calculation and 
Power 
Considerations 
For this study, to detect a 50 percentage 
point difference between relapse 
proportions of 20% and 70% in the OBS 
and placebo groups, respectively, at more 
than 80% power and a significance level 
of 0.05 (2-sided) using the Fisher’s Exact 
test with equal allocation to treatment 
groups, it is necessary to assess the 
primary efficacy measure for 
approximately 38 subjects (19 subjects in 
each of the OBS and placebo groups). 
For this study, to detect a 50 
percentage point difference between 
relapse proportions of 20% and 70% 
in the OBS and placebo groups, 
respectively, at more than 80% 
power and a significance level of 
0.05 (2-sided) 0.025 (1-sided) using 
the Fisher’s Exact test with equal 
allocation to treatment groups, it is 
necessary to assess the primary 
efficacy measure for approximately 
38 subjects (19 subjects in each of 
the OBS and placebo groups). 
Hierarchical testing with fixed 
sequence procedure will be used to 
control the Type I error for the 
multiple endpoints tested at one-
sided α = 0.025. For a test to be 
considered statistically significant 
within the testing hierarchy, it must 
be statistically significant at the one-
sided 0.025 level, and all previous 
tests within the testing hierarchy 
must be statistically significant at the 
one-sided 0.025 level, The fixed 
sequence of testing hierarchy is as 
follows: 
1. Relapse during the double-
blind randomized withdrawal 
period.  
2. Histologic response [peak 
eosinophil count of ≤6/high-
powered field (HPF) across 
all available esophageal 
levels] at Visit 8 (Week 36) 
For non-commercial use only

MEMORANDUM 
 
Page 2 of 3 
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
3. Dysphagia symptom 
response [≥30% reduction in 
the Dysphagia Symptom 
Questionnaire (DSQ) 
combined score (questions 
2+3) from baseline of the 
SHP621-301 study] at Visit 8 
(Week 36) 
4. Change in total endoscopy 
score from baseline of the 
SHP621-301 study, as 
measured by the EREFS 
classification, at Visit 8 
(Week 36) 
 
9.8.1 Primary 
Efficacy Endpoint 
The primary efficacy endpoint will be 
analyzed as the proportion of subjects 
with relapse during the double-blind 
randomized withdrawal period for the 
FAS, using a Fisher’s Exact test 
comparing OBS 2 mg twice daily against 
placebo. The primary test of treatment 
effect will be 2-sided, and conducted at 
the significance level of 0.05. 
The primary efficacy endpoint will be 
analyzed as the proportion of 
subjects with relapse during the 
double-blind randomized withdrawal 
period for the FAS, using a Fisher’s 
Exact test comparing OBS 2 mg 
twice daily against placebo. The 
primary test of treatment effect will 
be 2-sided 1-sided, and conducted at 
the significance level of 0.05 0.025. 
9.8.1 Primary 
Efficacy Endpoint 
(sensitivity 
analyses) 
In addition, the subjects who were 
prematurely withdrawn from the study 
without the primary efficacy endpoint will 
be imputed randomly according to the 
distribution of relapsers with available 
data; and the similar statistical test will be 
performed using the imputed data. 
In addition, the subjects who were 
prematurely withdrawn from the 
study without the primary efficacy 
endpoint will be imputed randomly 
according to the distribution of 
relapsers with available data; and the 
similar statistical test will be 
performed using the imputed data. 
Analysis will be repeated based on 
FAS using different missing data 
handling methods to assess the 
impact of missing data on relapse. 
9.8.2.1 Key 
Secondary 
Efficacy Endpoint 
Dysphagia symptom response, defined as 
≥30% reduction in the DSQ combined 
score (questions 2+3) from baseline of the 
SHP621-301 study and from baseline of 
this extension study to the final treatment 
period evaluation (Visit 8) 
Dysphagia symptom response, 
defined as ≥30% reduction in the 
DSQ combined score (questions 
2+3) from baseline of the SHP621-
301 study and separately from 
baseline of this extension study to 
the final treatment period evaluation 
(Visit 8) 
9.8.3 Exploratory 
Efficacy Endpoints 
The exploratory endpoints that will be 
explored are the following: 
 
The exploratory endpoints that will be 
explored are the following: 
• 
Eosinophil histology relapse for 
subjects in the SHP621-301 
BOS full responder group, 
defined as peak eosinophil count 
For non-commercial use only

MEMORANDUM 
 
Page 3 of 3 
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
of ≥15/high-powered field (HPF) 
from at least 2 of 3 levels of the 
esophagus) during the double-
blind randomized withdrawal 
period  
• 
 
 
 
  
 
As stated above, the administrative changes do not impact the overall study design, safety, or study 
conduct.  Please file this memo in your study file records.  If appropriate per local requirements, please 
submit this memo to your IRB notifying them of these changes.  
 
If you have further questions, please do not hesitate to contact your PPD Clinical Research Associate, the 
PPD Remote Site Monitor, or Takeda directly. 
 
Sincerely, 
, MD 
 
 
 
 
 
For non-commercial use only