Clinical trial NCT03245840
Conditions: Eosinophilic Esophagitis (EoE)
Sponsor: Shire
Start date: 2017-10-05; Completion date: 2022-04-26
Enrollment: 133 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a continuation study of Budesonide Oral Suspension (BOS) in adults and adolescents with Eosinophilic Esophagitis (EoE) who have completed participation in the SHP621-302 extension study. The purpose of this study is to see if BOS is safe and well tolerated over the long-term in adolescents and adults with EoE.

Detailed description:

Arms: arm 1: Participants received 10 milliliters (mL) of budesonide oral suspension at a concentration of 0.2 milligram per milliliter (mg/mL), twice daily, for up to 4 years 5 months.
Interventions: intervention 1: Budesonide oral suspension
Intervention descriptions: intervention 1: BOS 10 mL twice daily.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT03245840 
Study Title:  
A Phase 3, Multicenter, Open-label Continuation Study with Budesonide Oral 
Suspension (BOS) for Adolescent and Adult Subjects with Eosinophilic 
Esophagitis (EoE) 
Study Number:  
SHP621-303 
Protocol Version and Date:  
Amendment 3: 
21 Jun 2021 
For non-commercial use only


TAKEDA DEVELOPMENT CENTER AMERICAS, INC.
PROTOCOL: SHP621-303
TITLE:
A Phase 3, Multicenter, Open-label Continuation Study with 
Budesonide Oral Suspension (BOS) for Adolescent and Adult Subjects 
with Eosinophilic Esophagitis (EoE)
DRUG:
SHP621, TAK-721, budesonide oral suspension (BOS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Takeda Development Center Americas, Inc. (TDC Americas, “Takeda”)
95 Hayden Avenue, Lexington, MA 02421 USA
+1-617-349-0200
PROTOCOL 
HISTORY:
Original Protocol: 12 Dec 2016
Protocol Amendment 1: 27 Jun 2017
Protocol Amendment 2: 10 Aug 2020
Protocol Amendment 3: 21 Jun 2021
This document contains confidential and proprietary information of Takeda 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 Takeda.
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SHP621-303 Protocol Amendment 3 
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21 Jun 2021 
PROTOCOL SIGNATURE PAGE 
Sponsor’s (Takeda) Approval 
Signature: 
Date: 
, MD 
 
Acknowledgement 
I have read this protocol for Takeda Study SHP621-303. 
Title: A Phase 3, Multicenter, Open-label Continuation Study with Budesonide Oral Suspension 
(BOS) for Adolescent and Adult Subjects 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: 
DocuSign Envelope ID: 
22-Jun-2021 | 02:11:45 JST
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
The SHP621-303 protocol has been amended to update the sponsor name and address from Shire 
ViroPharma (Shire) to Takeda Development Center Americas Inc. (Takeda). 
The corresponding sections affected by this change are listed below.
See Appendix 1 for protocol history, including all amendments.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
21 Jun 2021
Global Amendment
Description of Change
Section(s) Affected by Change
Changed from: 
Shire ViroPharma Inc. (Shire, now called Shire 
ViroPharma LLC)
300 Shire Way, Lexington, MA 02421 USA
To:
Takeda Development Center Americas, Inc. (TDC 
Americas, “Takeda”)
95 Hayden Avenue, Lexington, MA 02421 USA
Rationale: To update sponsor name and address.
Headers; Cover Page; Protocol Signature Page; 
Emergency Contact Information Page;
Product Quality Complaints; Section 1.2, Product 
Background and Clinical Information; Section 6.2, 
Administration of Investigational Product; Section 6.4, 
Drug Accountability; Section 10.5 Study 
Results/Publication Policy
Update of “Shire medical monitor” to “medical monitor’
Rationale: For consistent language throughout the 
protocol.
Section 7.2.1.3, Physical Examination; Section 7.2.1.5, 
Clinical Laboratory Evaluations; Section 8.1.6,  
Pregnancy; Section 8.2.2, Reporting Procedures 
Update of “Shire GDS” and “Shire Global 
Pharmacovigilance and Risk management Department” 
to “Takeda Global Patient Safety Evaluation 
Department”
Rationale: To reflect updated department name per 
sponsor name update.
Emergency Contact Information Page; Section 8.1.6,  
Pregnancy; Section 8.2.2, Reporting Procedures; 
Section 8.2.4, Serious Adverse Event Collection Time 
Frame
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Clinical 
Study Serious Adverse Event and Non-serious Adverse Events (AEs) Required by the Protocol 
Form within 24 hours to the Takeda Global Patient Safety Evaluation Department 
(GlobalPharmacovigilance@shire.com). A copy of this form must also be sent to the medical 
monitor by fax or e-mail using the details below.
, MD, 
Email:
 
For protocol- or safety-related issues during normal business hours (8 am to 5 pm Eastern 
Standard Time), the investigator must contact the medical monitor: 
, MD, 
Office phone: 
Mobile: 
Email:
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the medical monitor:
, MD, 
Office phone: 
Mobile:
Email:
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Takeda within 
24 hours. This includes any instances wherein the quality or performance of a Takeda 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
PQC@shire.com
European Union and Rest of World
PQCROW@shire.com
Telephone numbers (provided for reference if needed):
Takeda, Lexington, MA (USA)
1-888-300-6414 or 1-800-828-2088
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................18
1.
BACKGROUND INFORMATION.......................................................................................23
1.1
Indication and Current Treatment Options...............................................................23
1.2
Product Background and Clinical Information ........................................................23
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Study.............................................................................................26
2.2
Study Objectives ......................................................................................................26
2.2.1
Primary Objective..................................................................................................26
2.2.2
Secondary Objectives.............................................................................................26
2.2.3
Exploratory Objectives ..........................................................................................26
3.
STUDY DESIGN ...................................................................................................................27
3.1
Study Design and Flow Chart ..................................................................................27
3.2
Duration and Study Completion Definition .............................................................28
3.3
Sites and Regions .....................................................................................................28
4.
STUDY POPULATION.........................................................................................................29
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Restrictions...............................................................................................................30
4.4
Reproductive Potential .............................................................................................30
4.4.1
Female Contraception............................................................................................30
4.5
Discontinuation of Subjects .....................................................................................31
4.5.1
Subject Withdrawal Criteria ..................................................................................32
4.5.2
Reasons for Discontinuation..................................................................................32
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................32
4.5.4
Safety-related Stopping Rules................................................................................33
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5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................34
5.1
Prior Treatment ........................................................................................................34
5.2
Concomitant Treatment............................................................................................34
5.2.1
Permitted Treatment...............................................................................................34
5.2.2
Prohibited Treatment .............................................................................................34
6.
INVESTIGATIONAL PRODUCT ........................................................................................35
6.1
Identity of Investigational Product...........................................................................35
6.1.1
Blinding the Treatment Assignment......................................................................35
6.2
Administration of Investigational Product ...............................................................35
6.2.1
Interactive Response Technology for BOS Management......................................35
6.2.2
Allocation of Subjects to Treatment ......................................................................36
6.2.3
Dosing....................................................................................................................36
6.2.4
Unblinding the Treatment Assignment..................................................................37
6.3
Labeling, Packaging, Storage, and Handling ...........................................................37
6.3.1
Labeling .................................................................................................................37
6.3.2
Packaging...............................................................................................................37
6.3.3
Storage ...................................................................................................................38
6.3.4
Special Handling....................................................................................................38
6.4
Drug Accountability.................................................................................................38
6.5
Subject Compliance..................................................................................................39
7.
STUDY PROCEDURES........................................................................................................41
7.1
Study Schedule.........................................................................................................41
7.1.1
Screening/Enrollment/Visit 0 (Month 0) ...............................................................41
7.1.1.1
Screening/Enrollment Visit (Visit 0)/Visit 8 of SHP621-302 Study .....42
7.1.2
Open-label Treatment Period (Visits 1-12)............................................................43
7.1.2.1
Visits 1, 3, 5, 7, 9, 11 (Months 6, 18, 30, 42, 54, 66).............................43
7.1.2.2
Visits 2, 4, 6, 8, 10 (Months 12, 24, 36, 48, 60).....................................44
7.1.2.3
Visit 12 (Month 72) or Early Termination.............................................46
7.1.3
Safety Follow-up Telephone Contact/Visit 13: .....................................................47
7.2
Study Evaluations and Procedures ...........................................................................47
7.2.1
Safety .....................................................................................................................47
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation....................................................................48
7.2.1.2
Medical and Medication History............................................................48
7.2.1.3
Physical Examination (Including Height and Weight) ..........................49
7.2.1.4
Vital Signs..............................................................................................50
7.2.1.5
Clinical Laboratory Evaluations.............................................................50
7.2.1.6
Pregnancy Test .......................................................................................51
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7.2.1.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density.............51
7.2.2
Other Assessments.................................................................................................52
7.2.2.1
Health-related Quality-of-life Assessment.............................................52
7.2.2.2
Severity of Disease Assessments ...........................................................53
7.2.3
Volume of Blood to Be Drawn from Each Subject ...............................................53
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................54
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................54
8.1.1
Severity Categorization..........................................................................................54
8.1.2
Relationship Categorization...................................................................................55
8.1.3
Outcome Categorization ........................................................................................55
8.1.4
Symptoms of the Disease under Study ..................................................................56
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................56
8.1.6
Pregnancy...............................................................................................................56
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................57
8.2
Serious Adverse Event Procedures ..........................................................................57
8.2.1
Reference Safety Information................................................................................57
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................58
8.2.4
Serious Adverse Event Collection Time Frame.....................................................59
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................59
8.2.6
Fatal Outcome........................................................................................................59
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................59
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................60
9.1
Data Collection.........................................................................................................60
9.2
Clinical Data Management.......................................................................................60
9.3
Data Handling Considerations..................................................................................60
9.4
Statistical Analysis Process......................................................................................60
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......61
9.6
Sample Size Calculation and Power Considerations................................................61
9.7
Study Population ......................................................................................................61
9.8
Efficacy Analyses.....................................................................................................61
9.8.1
Primary Efficacy Endpoint ....................................................................................61
9.8.2
Secondary Efficacy Endpoints...............................................................................61
9.8.2.1
Key Secondary Efficacy Endpoint .........................................................61
9.8.3
Exploratory 
 Endpoints.............................................................................61
9.9
Safety Analyses........................................................................................................62
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9.10
Health-related Quality-of-life Analyses...................................................................63
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................64
10.1
Sponsor’s Responsibilities .......................................................................................64
10.1.1 Good Clinical Practice Compliance.......................................................................64
10.1.2 Indemnity/Liability and Insurance.........................................................................64
10.1.3 Public Posting of Study Information......................................................................64
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities
of Member States Concerned and Ethics Committees...........................................64
10.1.5 Study Suspension, Termination, and Completion..................................................65
10.2
Investigator’s Responsibilities .................................................................................65
10.2.1 Good Clinical Practice Compliance.......................................................................65
10.2.2 Protocol Adherence and Investigator Agreement..................................................65
10.2.3 Documentation and Retention of Records.............................................................66
10.2.3.1
Case Report Forms.................................................................................66
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................67
10.2.3.3
Audit/Inspection.....................................................................................67
10.2.3.4
Financial Disclosure...............................................................................68
10.3
Ethical Considerations..............................................................................................68
10.3.1 Informed Consent...................................................................................................68
10.3.2 Institutional Review Board or Ethics Committee..................................................69
10.4
Privacy and Confidentiality......................................................................................69
10.5
Study Results/Publication Policy .............................................................................70
11. REFERENCES .......................................................................................................................72
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LIST OF TABLES
Table 1-1
Schedule of Assessments...............................................................................18
Table 7-1
Approximate Volume of Blood to Be Drawn from Each Subject 
(Visits 1-12)...................................................................................................53
Table 8-1
Adverse Event Relatedness ...........................................................................55
LIST OF FIGURES
Figure 3-1
Study Design Flow Chart ..............................................................................27
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................74
Appendix 2
Scales and Assessments.................................................................................79
Appendix 3
Patient Global Impression of Severity...........................................................80
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LIST OF ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
β-hCG
beta-human chorionic gonadotropin
BMD
bone mineral density
BOS
budesonide oral suspension
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
EoE-QoL-A
Adult Eosinophilic Esophagitis Quality of Life
EQ-5D-3L
EuroQol-5 Dimensions 3-level
EQ-5D
EuroQol
EQ-5D-Y
EuroQol-5 Dimensions Youth
ET
early termination
EU
European Union
FDA
Food and Drug Administration
GDS
Global Drug Safety
GCP
Good Clinical Practice
GPSE
Global Patient Safety Evaluation
GSL
Global Safety Lead
HIPAA
Health Insurance Portability and Accountability Act
HPF
high-powered field
HRQoL
health-related quality of life
hs
at bedtime
ICH
International Conference on Harmonisation
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IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication identification
MedDRA
Medical Dictionary for Regulatory Activities
pc
after meals
PedsQL-EoE
Pediatric Quality of Life Inventory – EoE
PGI-S
Patient Global Impression of Severity
PPI
proton pump inhibitor
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
TA
therapeutic area
TEAE
treatment-emergent adverse event
UK
United Kingdom
US
United States
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STUDY SYNOPSIS
Protocol number: SHP621-303
Drug: SHP621, budesonide oral suspension (BOS)
Title of the study: A Phase 3, Multicenter, Open-Label Continuation Study with Budesonide Oral Suspension 
(BOS) for Adolescent and Adult Subjects with Eosinophilic Esophagitis (EoE)
Number of subjects (total):
Approximately 100 subjects who have completed the SHP621-302 study will be enrolled in this continuation study.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America
Study period (planned):
September 2017 – October 2023
Clinical phase:
3
Objectives
Primary: 

To evaluate the long-term safety and tolerability of budesonide oral suspension (BOS) treatment
Exploratory:
 
 
Rationale:
Currently there is no approved medication for the treatment of eosinophilic esophagitis (EoE). This study is being 
conducted in order to provide continued access to BOS to subjects who complete both the SHP621-301 induction 
and SHP621-302 extension studies and are considered by the investigator to potentially benefit from continued BOS 
investigational treatment until commercial product is available. As there are limited data available on the potential 
benefits and risks of maintenance treatment of EoE with topical corticosteroids, investigators should exercise 
discretion in determining the duration of BOS treatment in this study and the need for and frequency of dose 
regimen changes or dose interruption.
Investigational product, dose, and mode of administration:
Budesonide oral suspension will be administered in 10 mL at a concentration of 0.2 mg/mL (2 mg dose), twice-daily 
(in the morning [qAM] after meals [breakfast, pc] and at bedtime [hs]). The 0.2 mg/mL concentration of BOS and 
dosing regimens were selected for use in Phase 3 studies based on the results of Study MPI 101-06, a Phase 2 study 
in 93 subjects with EoE and symptoms of dysphagia. For the current study, 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. 
The daily dose and potential total treatment duration of the current formulation of BOS with long-term continuation 
treatment in this study (ie, beyond the maximal 1 year total treatment duration in the SHP621-301 and SHP621-302 
studies combined) may expose subjects to 21-dehydrobudesonide (21-DHB), a known breakdown product of 
budesonide, at a level that has an unknown risk of mutagenicity. 21-DHB is an in vitro mutagen that has been found 
to be negative for mutagenicity in in vivo animal studies. The relevance of this finding to humans is unknown; 
however, a risk of causing DNA damage or carcinogenicity cannot be excluded with long durations of treatment. 
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As described in the SHP621 investigator’s brochure, investigators should make an individualized risk/benefit 
decision with respect to long-term BOS investigational treatment at the time of informed consent and when 
monitoring and adjusting BOS treatment in this study. The protocol allows for individualized treatment with BOS, 
including a dose regimen change from 2 mg twice-daily to 2 mg once-daily (qAM, pc) or treatment interruption 
(with resumption of treatment and/or increase in the BOS dose regimen to 2 mg twice-daily permitted at a later date 
while on study).
Methodology:
This is a Phase 3, multicenter, open-label study to evaluate the safety and tolerability of twice-daily administration 
of BOS (qAM, pc, and hs) in adolescent and adults with EoE. 
Approximately 100 subjects who have completed the SHP621-302 study will be enrolled in this continuation study. 
Subjects who complete the SHP621-302 extension study are eligible to participate once they sign informed consent 
(or assent as applicable for subjects <18 years). Eligible subjects will be enrolled into the open-label treatment 
period and evaluated for safety every 6 months following the final treatment evaluation visit (Visit 8) in the 
SHP621-302 study until commercial product is available. Esophagogastroduodenoscopy with biopsies will be 
performed in all subjects annually (Month 12, Month 24, etc.).
Study Design Flow Chart
Abbreviations: BOS=budesonide oral suspension; EGD=esophagogastroduodenoscopy; Enr=Enrollment; ET=early 
termination; M=month; Scr=Screening; V=visit.
Subjects will be evaluated for eligibility for participation in this continuation study at the screening visit (Visit 0) 
which will also coincide with the final treatment evaluation visit (Visit 8) of SHP621-302. Subjects who consent and 
meet eligibility criteria at Visit 0 will enter the open-label treatment period in SHP621-303. Subjects may be 
enrolled and treated prior to receipt of results from SHP621-302 Visit 8 assessments, per investigator discretion; 
however, if they are subsequently determined to no longer meet eligibility criteria, they must be discontinued. Dose 
interruptions starting at the time of completion of the SHP621-302 study, due to administrative or other reasons, will 
be permitted; however, dosing should be reinitiated within 3 months of completion of treatment in SHP621-302 
unless discussed prospectively with the medical monitor.
Subjects who withdraw from the study will receive a follow-up telephone call 4 weeks post last dose of BOS to 
query for serious adverse events (SAEs), adverse events (AEs), and concomitant treatments. If a subject 
discontinues from the study prematurely or transitions to commercial product upon availability, the assessments for 
Visit 12 are to be performed as completely as possible. Subjects who discontinue (ie, positive result on serum
pregnancy test) will not be replaced.
BOS treatment may adjusted by a dose regimen change from 2 mg twice-daily to 2 mg once-daily (qAM, pc) or by 
treatment interruption (with resumption of treatment and/or increase in the BOS dose regimen to 2 mg twice-daily 
permitted at a later date while on study). Interruptions of up to 6 months are allowed. In their discretion with respect 
to individual subject investigational treatment adjustment, investigators should consider the subject’s response to 
previous and current treatment, risk of relapse, and the overall risk/benefit profile of long-term treatment with BOS 
greater than 1 year.
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Continued participation in the study (ie, complete study assessments as scheduled) is required to resume BOS. 
Subjects who are discontinued from the study may not reinitiate BOS treatment.
Inclusion and exclusion criteria:
Inclusion Criteria: 
The subject will not be considered eligible for the study without meeting all the following criteria:
1.
Subject completed SHP621-302 extension study and is considered by the investigator to potentially benefit from 
continued BOS investigational treatment.
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.
Females of childbearing potential must agree to continue acceptable birth control measures (eg, abstinence, 
surgically sterile male partner, stable oral contraceptives, or double-barrier methods) throughout study 
participation. 
4.
Subject is willing and has an understanding and ability to fully comply with study procedures 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 or diet during the SHP621-302 study that could affect participation in this 
continuation study.
2.
Subject anticipates using swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition 
during the treatment period; 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 should be avoided within 
4 weeks of the scheduled esophagogastroduodenoscopy (EGDs). 
3.
Subject anticipates use of Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) during the 
continuation study. 
4.
Subject has an appearance at the EGD at the final treatment evaluation visit of SHP621-302 (Visit 8) 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). 
5.
Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit (Visit 8) of the 
SHP621-302 study.
6.
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.
7.
Subject has other diseases causing or associated with esophageal eosinophilia, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
8.
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 8) of the 
SHP621-302 study is not an exclusion as long as the subject is expected to respond to treatment. 
9.
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.
10. Subject has upper gastrointestinal bleeding identified at the EGD at the final treatment evaluation visit (Visit 8) 
of the SHP621-302 study.
11. Subject has evidence of active infection with Helicobacter pylori.
12. Subject has evidence of unstable asthma.
13. Subject is female and pregnant or nursing.
14. 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.
15. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
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Maximum duration of subject involvement in the study:
Open-label treatment period for up to 6 years or until commercial product is available. 
Endpoints and statistical analysis:
Subject Populations

The full analysis set (FAS) set will include all subjects who are enrolled in the study and receive at least one 
dose of BOS. 

The safety set will include all subjects who receive at least 1 dose of BOS.
The primary population for safety will be the safety population 
 
. An additional per-protocol population analysis may also be performed as secondary 
sensitivity analysis. Applicable analysis populations will be defined in the statistical analysis plan (SAP).
Primary Efficacy Endpoint
Not applicable.
Secondary Efficacy Endpoints 
Not applicable. 
Exploratory 
 Endpoints 
 
 
Safety Endpoints 
Safety endpoints include adverse events (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) (for adolescents aged 11-17 years, inclusive), clinical 
laboratory tests (hematology, chemistry, urinalysis; urine 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.
Health Economics and Outcomes Research Endpoints 

Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score at all visits from baseline (last 
assessment prior to first dose of BOS)

Change in EuroQol (EQ-5D; EuroQol-5 Dimensions 3-level [EQ-5D-3L] or EuroQol-5 Dimensions Youth 
[EQ-5D-Y], according to subject’s age) score at all visits from baseline (last assessment prior to first dose of 
BOS)

Change in Pediatric Quality of Life Inventory (subjects 11-17 years of age, inclusive) – EoE (PedsQL-EoE) 
score at all visits from baseline (last assessment prior to first dose of BOS)

Change in Patient Global Impression of Severity (PGI-S) score at all visits from baseline (last assessment prior 
to first dose of BOS)
Statistical Methodology for Primary Efficacy Endpoint 
Not applicable. 
Statistical Methodology for Key Secondary and Other Secondary Efficacy Endpoints
Not applicable. 
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 (for 
adolescents aged 11 17 years, inclusive), clinical laboratory results (hematology, chemistry, urinalysis; urine 
pregnancy test, if appropriate), and ACTH stimulation will be descriptively summarized at baseline and at each 
post-baseline visit.
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The number and percent of subjects with treatment-emergent adverse events (TEAEs) will be presented. 
Treatment-emergent adverse events are defined as AEs that start or deteriorate on or after the time the informed 
consent is signed and through the Safety Follow-up Contact, or 31 days after the last dose of for subjects who do not 
have a Safety Follow-up Contact. However, for any subjects who die during the study (ie, the date of death is 
between the date of first dose of BOS 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. 
Statistical Methodology for Exploratory and Health Economics and Outcomes Research Endpoints 
No formal testing will be conducted for efficacy or Health Economics and Outcomes Research endpoints. All 
endpoints will be summarized using summary statistics at each visit. Continuous endpoints will be summarized 
using mean, standard deviation, median, minimum and maximum values. Categorical endpoints will be summarized 
using count and percentage. Ninety five percent confidence interval (CI) will be provided wherever appropriate. 
Listings for subject-level data will be presented. 
Sample Size Justification
Approximately 100 subjects who complete the SHP621-302 extension study are anticipated to enroll into this 
open-label continuation study. 
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STUDY SCHEDULE(S)
Table 1-1
Schedule of Assessments
Procedures
Open-label Treatment Phase
Safety 
Follow-Up 
Phone 
Contactr
Visit 
0a
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 10
Visit 
11
Visit 
12 
ETq
Visit 13
Months 
0
6
12
18
24
30
36
42
48
54
60
66
72
73
Window
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±3 days
Informed 
consent/assent
X
Medical history 
review
X
Inclusion/exclusion 
criteria review
X
Vital signsb; heightc, 
and weightd
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
EGD with
 
 and 
biopsye
X
X
X
X
X
X
X
EQ-5Df
X
X
X
X
X
X
X
X
X
X
X
X
X
PedsQL-EoE 
(subjects 11 to 
17 years of age)g
X
X
X
X
X
X
X
X
X
X
X
X
X
EoE-QoL-A 
(subjects ≥18 years 
of age)
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 1-1
Schedule of Assessments
Procedures
Open-label Treatment Phase
Safety 
Follow-Up 
Phone 
Contactr
Visit 
0a
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 10
Visit 
11
Visit 
12 
ETq
Visit 13
Months 
0
6
12
18
24
30
36
42
48
54
60
66
72
73
Window
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±3 days
PGI-S
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationh
X
X
X
X
X
X
X
X
X
X
X
X
X
Tanner staging 
assessmenti
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical laboratory 
assessmentj
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysisk
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testl
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning cortisol 
(target 6:00-9:00 am)
X
X
X
X
X
X
X
ACTH stimulation 
testingm
X
X
X
X
X
X
X
DXA Scan (subjects 
11 to 17 years of 
age)n
X
X
X
X
X
X
X
BOS suppliedo
X
X
X
X
X
X
X
X
X
X
X
BOS administrationp
Twice-daily administration
BOS compliance 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 1-1
Schedule of Assessments
Procedures
Open-label Treatment Phase
Safety 
Follow-Up 
Phone 
Contactr
Visit 
0a
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 10
Visit 
11
Visit 
12 
ETq
Visit 13
Months 
0
6
12
18
24
30
36
42
48
54
60
66
72
73
Window
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±3 days
Review of 
concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ACTH=adrenocorticotropic hormone; DXA=dual-energy X-ray absorptiometry; EGD=esophagogastroduodenoscopy; EoE-QoL-A=Adult Eosinophilic 
Esophagitis Quality of Life; EQ-5D=EuroQol; EQ-5D-3L=EuroQol-5 Dimension 3-level; EQ-5D-Y=EuroQol-5 Dimensions Youth; 
 
; hs=at bedtime; IWRS=interactive web-based response system; PedsQL-EoE=Pediatric Quality of Life Inventory – EoE; pc=after meals; 
PGI-S=Patient Global Impression of Severity; qAM=every morning
a
The assessments from the final treatment evaluation visit (Visit 8) in SHP621-302 will be used to determine eligibility for participation in this continuation 
study. Subjects may be enrolled and treated prior to receipt of results from SHP621-302 Visit 8 assessments, per investigator discretion; however, if they are 
subsequently determined to no longer meet eligibility criteria, they must be discontinued. Subjects, site staff, and study team members involved with the 
conduct of the study will remain blinded to treatment assignment and individual subject histology data from the SHP621-301 and SHP621-302 studies until 
database lock occurs for SHP621-302. 
b
Vital signs will be assessed after the subject has been resting (and in a supine position for Visit 0 only) 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 measurements for adolescents (11-17 years, inclusive) should be measured in triplicate using stadiometers at every visit. Height measurement for 
adults is required at Visits 2, 4, 6, 8, 10, and 12 only. 
d
Weight measurements for adolescents (11-17 years, inclusive) should be measured in duplicate.
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Table 1-1
Schedule of Assessments
Procedures
Open-label Treatment Phase
Safety 
Follow-Up 
Phone 
Contactr
Visit 
0a
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 10
Visit 
11
Visit 
12 
ETq
Visit 13
Months 
0
6
12
18
24
30
36
42
48
54
60
66
72
73
Window
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±3 days
e
Endoscopy must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Unscheduled endoscopies may 
be performed at the discretion of the investigator to assess relapse, to determine whether or not BOS treatment should be interrupted or restarted, or to adjust 
BOS dose (Section 7.2.1). Endoscopy does not have to be completed at scheduled visit if unscheduled endoscopy was performed within 3 months of the 
scheduled visit (ie, 3 months before or after Visit 2, 4, 6, 8, or 10). If an unscheduled endoscopy is performed within 3 months of Visit 12 or ET, the Visit 12
(or ET) endoscopy does not need to be completed if discussed prospectively with the medical monitor and determined to be unnecessary.
f
Subjects 11-17 years of age, inclusive, at the time of consent into the SHP621-301 study, will complete the EQ-5D-Y throughout study participation; 
subjects ≥18 years of age (at the time of consent into the SHP621-301 study) will complete the EQ-5D-3L. 
g
Subjects 11-17 years of age, inclusive, at the time of consent into the SHP621-301 study will complete the PedsQL-EoE throughout study participation.
h
Physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and 
depression). 
i
Tanner staging assessments will be performed for all subjects ≥11 years of age until investigator confirms subject is post puberty.
j
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.
k
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
l
Serum pregnancy tests will be performed for all female subjects at Visit 8 of SHP621-302. All females with a positive pregnancy test will be discontinued 
from the study. Urine pregnancy tests will be performed at subsequent scheduled visits starting with Visit 1 for all female subjects during the conduct of 
SHP621-303. 
m
Unscheduled ACTH stimulation tests may be performed at the investigator’s discretion.
n
Dual-energy X-ray absorptiometry scans should be performed using the same machine and software as used in the SHP621-301 and SHP621-302 studies. 
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Table 1-1
Schedule of Assessments
Procedures
Open-label Treatment Phase
Safety 
Follow-Up 
Phone 
Contactr
Visit 
0a
Visit 
1
Visit 
2
Visit 
3
Visit 
4
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 10
Visit 
11
Visit 
12 
ETq
Visit 13
Months 
0
6
12
18
24
30
36
42
48
54
60
66
72
73
Window
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±4 
weeks
±3 days
o
Investigational product may be supplied at unscheduled visits given the long duration in between scheduled visits and to assess subjects for treatment 
interruption or reinitiation (see Section 6.2.3). 
p
Subjects will receive oral administration of 10 mL of BOS twice-daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 30 minutes after 
investigational product administration. At the investigator’s discretion, administration may be stopped (allowable up to 6 months) and/or stopped and 
reinitiated (see Section 3.1 and Section 6.2.3). Dose interruptions (up to 3 months) due to administrative or other reasons will also be allowed at the time of 
completion of the SHP621-302 study. In such instances, unscheduled safety and efficacy assessments may be required prior to dispensing study drug 
considering the time off of investigational treatment and the study schedule.
q
If subject discontinues study prematurely or transitions to commercial product upon availability, the evaluations listed for Visit 12 should be performed as 
soon as possible.
r
For subjects who withdraw from the treatment period, a safety follow-up contact by telephone will be performed 4 weeks following the last dose of BOS. 
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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 signs 
and 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(eos)/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., 2014; 
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 Food 
and Drug Administration (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
Budesonide oral suspension (BOS) 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. Takeda is developing BOS 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 United States (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 (Food and Drug Administration 2011).
The efficacy of BOS for the treatment of EoE has been demonstrated in 2 Phase 2 studies in the
BOS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the efficacy 
of BOS 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
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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 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 mg to2.0 mg daily) and high-dose (2.8 mg to 4.0 mg daily) BOS groups 
compared to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for BOS 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]), BOS-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 open-label continuation study follows the SHP621-301 induction study and 
SHP621-302 extension study. Study SHP621-301 is a Phase 3 randomized, double-blind, 
multicenter, study to evaluate the efficacy, safety, and tolerability of twice-daily administration 
of BOS (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 BOS in 
adolescent and adult subjects with EoE. The SHP621-302 extension study is designed to evaluate 
maintenance of treatment and treatment withdrawal in subjects who complete the induction 
study.
As there are no currently approved medications for the treatment of EoE, the objective of this 
study is to provide continued access to BOS until commercial product is available. To date, there 
are limited data on the efficacy and safety on long-term swallowed corticosteroid therapy 
(Alexander, 2014). In light of evidence that long-term corticosteroid treatment may reduce 
esophageal inflammation (Straumann et al., 2011) and that untreated EoE may result in 
esophageal fibrosis and stricture (Furuta and Katzka, 2015), EoE treatment guidelines 
recommend an individualized approach to potential long-term maintenance swallowed 
corticosteroid treatment (Liacouras et al., 2011; Dellon et al., 2013). Subjects who are considered 
by the investigator to potentially benefit from continued BOS investigational treatment after 
completing SHP621-301 and SHP621-302 will be eligible to participate in this study. The 
proposed dose of BOS for this study is the same that is currently employed in Studies 
SHP621-301 and SHP621-302, 2 mg BOS twice-daily. To allow for continuation treatment to be 
individualized, this protocol allows for the BOS dosing regimen to be changed from 2 mg 
twice-daily to 2 mg once-daily (qAM, pc) or for BOS to be stopped (allowable up to 6 months) 
and reinitiated at the investigator’s discretion (Section 6.2.3). To ensure that safety monitoring is 
complete, subjects must continue to remain in the protocol to be eligible to reinitiate BOS after 
treatment interruption.
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The daily dose and potential total treatment duration of the current formulation of BOS with 
long-term continuation treatment in this study (ie, beyond the maximal 1 year total treatment 
duration in the SHP621-301 and SHP621-302 studies combined) may expose subjects to 
21-dehydrobudesonide (21-DHB), a known breakdown product of budesonide, at a level that has 
an unknown risk of mutagenicity. 21-DHB is an in vitro mutagen that has been found to be 
negative for mutagenicity in in vivo animal studies. The relevance of this finding to humans is 
unknown; however, a risk of causing DNA damage or carcinogenicity cannot be excluded with 
long durations of treatment. As described in the SHP621 investigator’s brochure, investigators 
should make an individualized risk/benefit decision with respect to long-term BOS 
investigational treatment at the time of informed consent and when monitoring and adjusting 
BOS treatment in this study. The protocol allows for individualized treatment with BOS, 
including a dose regimen change from 2 mg twice-daily to 2 mg once-daily (qAM, pc) or 
treatment interruption (with resumption of treatment and/or increase in the BOS dose regimen to 
2 mg twice-daily permitted at a later date while on 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. Budesonide oral suspension 
is under clinical development for the treatment of EoE through 2 ongoing Phase 3 studies: 
SHP62-301, a randomized, double-blind induction study, and SHP621-302, a double-blind 
extension study. Because EoE is considered a seriously debilitating disease and there is an unmet 
medical need, this open-label continuation study is proposed to provide continued access to BOS 
for subjects who complete both the SHP621-301 and SHP621-302 studies and are considered by 
the investigator to potentially benefit from continued BOS investigational treatment until 
commercial product is available.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of the study is to evaluate the long-term safety and tolerability of BOS 
treatment. 
2.2.2
Secondary Objectives
Not applicable.
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, open-label study to evaluate the safety and tolerability of 
twice-daily administration of BOS (qAM, pc, and hs) in adolescent and adults with EoE. 
Approximately 100 subjects who have completed the SHP621-302 study will be enrolled in this 
continuation study. Subjects who complete the SHP621-302 extension study are eligible to 
participate once they sign informed consent (or assent as applicable for subjects <18 years). 
Eligible subjects will be enrolled into the open-label treatment period and evaluated for safety 
every 6 months following the final treatment evaluation visit (Visit 8) in the SHP621-302 study 
until commercial product is available. Esophagogastroduodenoscopy with biopsies will be 
performed in all subjects annually (Month 12, Month 24, etc.) (Figure 3-1).
Figure 3-1
Study Design Flow Chart 
BOS=budesonide oral suspension; EGD=esophagogastroduodenoscopy; Enr=enrollment; ET=early termination; M=month; 
Scr=screening; V=visit
Subjects will be evaluated for eligibility for participation in this continuation study at the 
screening visit (Visit 0) which will also coincide with the final treatment evaluation visit 
(Visit 8) of SHP621-302. Subjects who consent and meet eligibility criteria at Visit 0 will enter 
the open-label treatment period in SHP621-303. Subjects may be enrolled and treated prior to 
receipt of results from SHP621-302 Visit 8 assessments, per investigator discretion; however, if 
they are subsequently determined to no longer meet eligibility criteria, they must be 
discontinued. Dose interruptions starting at the time of completion of the SHP621-302 study, due 
to administrative or other reasons, will be permitted; however, dosing should be reinitiated 
within 3 months of completion of treatment in SHP621-302 unless discussed prospectively with 
the medical monitor.
As there are limited data on the potential benefits and risks of maintenance treatment of EoE 
with topical corticosteroids, investigators should exercise discretion in determining the duration 
of BOS treatment in this study and the need for and frequency of dose regimen changes or dose 
interruption as described in Section 1.2. 
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BOS treatment may be adjusted by a dose regimen change from 2 mg twice-daily to 2 mg 
once-daily (qAM, pc) or by treatment interruption (with resumption of treatment and/or increase 
in the BOS dose regimen to 2 mg twice-daily permitted at a later date while on study). 
Interruptions of up to 6 months are allowed (see Section 6.2.3). In their discretion with respect to 
individual subject investigational treatment adjustment, investigators should consider the 
subject’s response to previous and current treatment, risk of relapse, and the overall risk/benefit 
profile of long-term treatment with BOS greater than 1 year (see Section 1.2). 
Continued participation in the study (ie, completion of scheduled study assessments) is required 
to resume BOS treatment. Subjects who are discontinued from the study may not reinitiate BOS 
treatment. 
Subjects, site staff, and study team members involved with the conduct of the study will remain 
blinded to treatment assignment and individual subject histology data from the SHP621-301 and 
SHP621-302 studies until database lock occurs for SHP621-302. 
Subjects who withdraw from the study will receive a follow-up telephone call 4 weeks post last 
dose of BOS to query for serious adverse events (SAEs), adverse events (AEs), and concomitant 
treatments. If a subject discontinues from the study prematurely or transitions to commercial 
product upon availability, the assessments for Visit 12 are to be performed as completely as 
possible. Subjects who discontinue (ie, positive result on serum pregnancy test) will not be 
replaced.
3.2
Duration and Study Completion Definition
No fixed duration of subject participation is specified. Subjects may participate in the study for 
up to 6 years or until commercial product is available. 
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.
3.3
Sites and Regions
Approximately 60 sites in North America, the same sites participating in the SHP621-301 and 
SHP621-302 studies, will participate in this open-label continuation 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 the following 
criteria:
1. Subject completed the SHP621-302 extension study and is considered by the investigator to 
potentially benefit from continued BOS investigational treatment.
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. Females of childbearing potential must agree to continue acceptable birth control measures 
(eg, abstinence, surgically sterile male partner, stable oral contraceptives, or double-barrier 
methods) throughout study participation.
4. Subject is willing and has an understanding and ability to fully comply with study procedures 
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 or diet during the SHP621-302 study that could affect 
participation in this continuation study. 
2. Subject anticipates using swallowed topical corticosteroid for EoE or systemic corticosteroid 
for any condition during the treatment period; 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 should be avoided within 4 weeks of the scheduled 
esophagogastroduodenoscopy (EGDs).
3. Subject anticipates use of Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit 
juice) during the continuation study.
4. Subject has an appearance at the EGD at the final treatment evaluation visit of SHP621-302 
(Visit 8) 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).
5. Subject has presence of esophageal varices at the EGD at the final treatment evaluation visit 
(Visit 8) of the SHP621-302 study.
6. 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.
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7. Subject has other diseases causing or associated with esophageal eosinophilia, including 
hypereosinophilic syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic 
infection.
8. 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 8) of the SHP621-302 study is not an exclusion as long as 
the subject is expected to respond to treatment.
9. 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.
10. Subject has upper gastrointestinal bleeding identified at the EGD at the final treatment 
evaluation visit (Visit 8) of the SHP621-302 study.
11. Subject has evidence of active infection with Helicobacter pylori.
12. Subject has evidence of unstable asthma.
13. Subject is female and pregnant or nursing.
14. 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.
15. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

Temporary use (≤7 days) or initiation of new steroid treatment is permitted but should be 
avoided within the 4 weeks of the scheduled EGDs.

No use of cytochrome P450 3A4 (CYP450 3A4) inhibitors (eg, ketoconazole, grapefruit 
juice, see details in Section 5.2.2).
4.4
Reproductive Potential
4.4.1
Female Contraception
Serum pregnancy tests will be performed for all female subjects at Visit 8 of SHP621-302. All 
females with a positive pregnancy test will be discontinued from the study (Section 4.5.2). 
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
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
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 BOS.

Acceptable methods of contraception are: 

Abstinence

Surgically sterile male partner

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 BOS with the medical monitor when 
possible.
If BOS is discontinued and results in subject discontinuation from the study, regardless of the 
reason, the evaluations listed for Visit 12/Early Termination are to be performed as completely 
as possible. If the investigator adjusts BOS treatment at their discretion by interrupting treatment 
(allowable for up to 6 months prior to restarting treatment, see Section 3.1), the subject may 
continue in the study (ie, complete study assessments as scheduled). If the investigator adjusts 
BOS treatment at their discretion by decreasing the frequency of BOS dose from 2 mg 
twice-daily to 2 mg once-daily, the duration of dose regimen change does not impact continued 
study participation. Subjects with BOS treatment interruptions greater than 6 months should be 
discontinued after completing the Visit 12/Early Termination evaluations. Once subjects are 
discontinued from the study, they may not be re-enrolled.
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 and date of stopping BOS must be recorded in the case report form (CRF) and source 
documents.
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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 high grade esophageal stricture (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], weight loss due to severe dysphagia, and/or upper GI bleed 
would result in withdrawal of the subject from the study. Subjects with oropharyngeal or 
esophageal candidiasis that has failed to respond to treatment, per investigator discretion, should 
have BOS treatment interrupted or 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 investigational product

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

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 BOS.
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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 investigational product

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code), and considered related to the investigational 
product
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Safety Lead (GSL), Global Patient Safety Evaluation (GPSE) and the GDS 
therapeutic area (TA) Head. 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 non-study 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 prior to 
providing consent for SHP621-303. 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 BOS in 
SHP621-303 (Visit 0) 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 investigator must contact the medical monitor either retrospectively or prospectively to 
discuss any changes to concomitant steroid regimens that may impact the outcome of the study. 
Maintenance immunotherapy (allergy shots of sublingual immunotherapy for allergies), 
influenzae, and other routine required vaccinations are allowed during the study. 
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. Swallowed topical corticosteroid for EoE (other than investigational product). Systemic 
corticosteroid for any condition since the final treatment evaluation visit (Visit 8) of the 
SHP621-302 study or use within the 4 weeks of scheduled EGDs should be avoided. Any 
temporary use (≤7 days) or initiation of new steroid treatment during the study should be 
documented and discussed with the medical monitor prospectively.
2. CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice, some herbal products) since the 
final treatment evaluation visit (Visit 8) of the SHP621-302 study, or anticipated 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 and use their 
clinical judgment with respect to specific medications.
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is BOS (budesonide oral 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.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product 
All BOS and supplies (eg, dosing spoons) will be provided by Takeda or its designee. At each 
visit, subjects will be supplied with enough BOS to last until the subsequent visit. If home 
storage is a factor, subjects may need to return to the clinic for an unscheduled visit(s) to obtain 
additional supply of BOS. The first dose of BOS for each subject will be administered in the 
clinic. The subject will continue with the evening dosing regimen at home. 
Budesonide oral suspension will be supplied in amber glass bottles and must be shaken well 
prior to administration. BOS should be refrigerated at 2ºC to 8ºC (36ºF to 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 BOS appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking BOS. 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 BOS Management 
An interactive web-based response system (IWRS) will be used for enrolling subjects, recording 
subject visits, investigational product supply dispensation and management, inventory 
management and supply ordering, investigational product expiration tracking and management, 
and return of investigational product. Please refer to the Study Manual for additional details 
regarding the IWRS. 
At Visit 0, the investigator or designee will access the IWRS to assign open-label treatment to a 
subject. Sites will confirm eligibility criteria information prior to treatment assignment. The 
IWRS will provide a medication identification (Med ID) number (ie, kit number to dispense for 
treatment). 
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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 an open-label continuous treatment period during which all subjects will 
receive BOS. 
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 3 digit site identifier, and the 4 digit subject 
identifier. For the SHP621-303 study, the 3 digit site and 4 digit subject numbers will be the 
same as the SHP621-301 and SHP621-302 studies. 
6.2.3
Dosing
All subjects will receive 10 mL of BOS at a concentration of 0.2 mg/mL (2 mg dose). 
Budesonide oral suspension will be administered twice-daily (in the morning [qAM] after meals 
[breakfast, pc] and at bedtime [hs]), with no ingestion of food or liquids permitted for 30 minutes 
after investigational product administration.
Budesonide oral suspension doses that are required to be administered at the clinic include the 
first dose of BOS administered at Visit 0 and all morning doses of BOS administered at 
scheduled bi-annual visits. Subjects will be required to eat breakfast at the clinic prior to 
self-administering these doses. Subjects can self-administer all other doses of BOS at home.
At the investigator's discretion, changes to the dosage regimen are allowable. BOS treatment 
may be changed from twice-daily administration (2 mg twice-daily) to once-daily administration 
(qAM, pc). In addition, BOS treatment may be interrupted by stopping and planning to reinitiate 
investigational product treatment up to 6 months later (see Section 3.1). In these instances, 
investigational product treatment will be stopped while the subject remains in the study and 
continues to have other protocol assessments. Investigational product must be resumed within 
6 months and multiple treatment interruptions are permitted throughout study participation (ie, 
3 months on and 3 months off treatment). BOS dose regimen changes and dose interruptions 
must be recorded by the subject and study site. Continued participation in the study is required to 
resume BOS.
Dose interruptions starting at the time of completion of the SHP621-302 study, due to 
administrative or other reasons, will also be permitted; however, dosing should be reinitiated 
within 3 months of completion of treatment in SHP621-302 unless discussed prospectively with 
the medical monitor (eg, in instances when SHP621-302 investigational treatment was 
completed more than 3 months prior to the investigator’s site initiation in this study). In such
instances, the visit schedule in this study will be based off the final treatment evaluation visit 
(Visit 8) in SHP621-302, regardless of dose interruption at the time of completion of 
SHP621-302 or timing of consent to participate in this study. 
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Unscheduled safety and efficacy assessments may be required and should be discussed 
prospectively with the medical monitor prior to dispensing study drug considering the time off of 
investigational treatment and the study schedule (see Table 1-1).
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
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. 
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
Budesonide oral suspension is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites: BOS 0.2 mg/mL in an 
8-ounce amber glass bottle for multiple uses. Bottles of BOS 0.2 mg/mL 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.
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6.3.3
Storage
The investigator has overall responsibility for ensuring that BOS 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. 
Budesonide oral suspension must be refrigerated at 2-8ºC (36-46ºF), protected from light.
Budesonide oral suspension is 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.
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.
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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. 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 Takeda-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.
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 contract research organization [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 product delivered with those used and returned. All investigational product 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.
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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.
Compliance will be assessed at each treatment visit. Please refer to the Pharmacy Manual for 
additional details. If BOS is discontinued at the investigator's discretion (for potential resumption 
later), the investigational product interruption period will not be counted in compliance 
determination.
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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.
In acknowledgement of hospital, local, state, or national government restrictions or other site 
related factors caused by unavoidable circumstances (eg, COVID-19 pandemic) which may 
prevent investigators from conducting the study according to the Schedule of Assessments at the 
clinical study site, investigators should consider the subject’s overall risk/benefit profile 
including overall response to previous and current treatment for EoE in deciding whether to 
continue subjects in the study. For delayed on-site visits, investigators should consider whether 
health status and study assessments (eg, review of adverse events, concomitant medications and 
procedures, IP compliance, and PGI-S) can be accurately and comprehensively collected via 
telephone or whether the subject (or caregivers) can complete the health-related QoL 
assessments at home during the scheduled window. Investigators should reach out to the medical 
monitor for any questions or concerns.
7.1.1
Screening/Enrollment/Visit 0 (Month 0)
Screening will begin once subjects sign informed consent. The screening visit 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 SHP621-302 final treatment evaluation visit (Visit 8) will be used as the 
screening assessments (Visit 0) for this open-label continuation study. Subjects may be enrolled 
and treated prior to receipt of results from SHP621-302 Visit 8 assessments, per investigator 
discretion; however, if they are subsequently determined to no longer meet eligibility criteria, 
they must be discontinued. At the SHP621-302 final treatment evaluation visit (ie, final 
assessment is completed in SHP621-302), subjects who meet eligibility criteria at Visit 0 will be 
dispensed BOS and enter the open-label treatment period. Dose interruptions starting at the time 
of completion of the SHP621-302 study, due to administrative or other reasons, will be 
permitted; however, dosing should be reinitiated within 3 months of completion of treatment in 
SHP621-302 unless discussed prospectively with the medical monitor (eg, in instances when 
SHP621-302 investigational treatment was completed more than 3 months prior to the 
investigator’s site initiation in this study). 
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In such instances, unscheduled safety and efficacy assessments may be required prior to 
dispensing study drug considering the time off of investigational treatment and the study 
schedule (Table 1-1).
Serum pregnancy tests will be performed as part of Visit 8 of SHP621-302. Subjects who test 
positive for pregnancy, via the serum pregnancy test will be discontinued from the SHP621-303 
study.
7.1.1.1
Screening/Enrollment Visit (Visit 0)/Visit 8 of SHP621-302 Study
The screening/enrollment 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.

Review current use of concomitant medications and procedures

Dispense BOS and review administration instructions. Subjects will self-administer the first 
dose of BOS in the clinic during this visit after breakfast. Site personnel will record the date 
and time of the first dose in the source documents. Beginning on the evening of Visit 0, the 
subject will take their first dose at home and continue with the twice-daily (morning and 
evening) dosing regimen. The subject will continue with the twice-daily (morning and 
evening) dosing regimen unless otherwise instructed by the investigator (Section 6.2.3). For 
subjects who are minors (<18 years), a parent/guardian will be responsible for ensuring 
subject takes BOS appropriately.
The following procedures will be performed at the final treatment evaluation visit (Visit 8) of 
SHP621-302 and will be used as the screening assessments for this open-label continuation 
study. Subjects may be enrolled and treated prior to receipt of results from SHP621-302 Visit 8 
assessments, per investigator discretion; however, if they are subsequently determined to no 
longer meet eligibility criteria, they must be discontinued.

Review BOS 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 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.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.
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
Morning cortisol (performed between 6:00 AM and 9:00 AM). Subjects should be instructed 
not to take the morning dose of BOS until after the morning cortisol test has been performed. 

Administer adrenocorticotropic hormone (ACTH, 250 mcg) stimulation testing; the type of 
synthetic and route of administration will be per investigator discretion. Additional cortisol 
samples will be drawn at 30- and 60-minutes following stimulation testing. 

Administer health-related quality-of-life (HRQoL) assessments including the EuroQol 
(EQ-5D), Pediatric Quality of Life Inventory – EoE (PedsQL-EoE), and Adult Eosinophilic 
Esophagitis Quality of Life (EoE-QoL-A) as age-appropriate.

Administer Patient Global Impression of Severity (PGI-S) of disease assessment 

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 as described in Section 7.2.1.3.

Serum pregnancy test will be performed on all female subjects; subjects who test positive for 
pregnancy will be discontinued from the study (Section 4.5.2). 

Perform EGD and biopsy either at the investigative site or by a referring physician. Refer to 
guidance provided in the SHP621-302 protocol for sending specimens for central review.

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD) in 
subjects aged 11-17 years, inclusive. Baseline and post treatment DXA scans should be 
performed using the same machine and software, when feasible.
7.1.2
Open-label Treatment Period (Visits 1-12)
There is no fixed duration to the open-label treatment period; subjects will continue to receive 
treatment (with potential treatment interruption at the investigator's discretion) until commercial 
product is available.
During this period, a 4-week visit window will be permitted between scheduled visits. Visit 
windows are calculated based upon the date of Visit 0. 
Subjects will continue to receive BOS twice-daily (qAM, pc, and hs) throughout the open-label 
treatment period. At the investigator’s discretion, the dose regimen may be changed from 
twice-daily to once-daily (qAM, pc) or may be stopped (allowable up to 6 months) and/or 
stopped and reinitiated (Section 6.2.3). Subjects may continue in the study (ie, complete study 
assessments as scheduled); however, they will not receive investigational product until the 
investigator restarts BOS. Subjects who are discontinued from the study may not reinitiate BOS 
treatment.
7.1.2.1
Visits 1, 3, 5, 7, 9, 11 (Months 6, 18, 30, 42, 54, 66)
Assessments and procedures listed for all visits that occur during the open-label treatment period 
will be completed as listed 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), height (measured in triplicate for adolescents 11 years to 17 years, 
inclusive), and weight (measured in duplicate for adolescents 11 years to 17 years, inclusive). 
Perform stadiometry in subjects aged 11 years to 17 years, inclusive. Vital signs will be 
assessed after the subject has been resting 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 7.2.1.5).
The following order is recommended for the remaining procedures that will be performed at 
these visits:

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S of disease assessment.

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 as described in Section 7.2.1.3.

Urine pregnancy test will be performed on all female subjects.

Review BOS dosing compliance.

Dispense BOS and review administration instructions. Subjects whose doses have been 
stopped or interrupted (allowable up to 6 months), per investigator’s discretion, will not 
receive BOS until dose has been reinitiated at the investigator’s discretion (Section 6.2.3).
Following all blood draws, subjects can eat breakfast and take their morning dose of BOS.
7.1.2.2
Visits 2, 4, 6, 8, 10 (Months 12, 24, 36, 48, 60)
Assessments and procedures listed for all visits that occur during the open-label treatment period 
will be completed as listed 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), height (measured in triplicate for adolescents 11 years to 17 years, 
inclusive), and weight (measured in duplicate for adolescents 11 years to 17 years, inclusive). 
Perform stadiometry in subjects aged 11 years to 17 years, inclusive. Vital signs will be 
assessed after the subject has been resting for at least 5 minutes immediately prior to the 
assessment.
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
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 7.2.1.5).

Morning cortisol (performed between 6:00 AM and 9:00 AM). Subjects should be instructed 
not to take the morning dose of BOS until after the morning cortisol test has been performed. 

Administer adrenocorticotropic hormone (ACTH, 250 mcg) stimulation testing; the type 
of synthetic and route of administration will be per investigator 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 7.2.1.5). (Unscheduled ACTH stimulation tests may be performed at the 
investigator’s discretion between scheduled visits).
The following order is recommended for the remaining procedures that will be performed at 
these visits:

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S of disease assessment.

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 as described in Section 7.2.1.3.

Urine pregnancy test will be performed on all female subjects.

Perform DXA scan for BMD in subjects aged 11 years to 17 years, inclusive. Dual-energy 
X-ray absorptiometry scans should be performed at this visit or within 28 days of the 
scheduled visit using the same machine and software, when feasible.

Perform EGD and biopsy; EGD should be completed at or within 28 days of the scheduled 
visit. An earlier EGD may occur at the investigator’s discretion if the subject exhibits signs 
of relapse, or increased, worsening or persistent dysphagia symptoms (Section 4.5.1). 

Review BOS dosing compliance.

Dispense BOS and review administration instructions. Subjects whose doses have been 
stopped or interrupted (allowable up to 6 months), per investigator’s discretion, will not 
receive BOS until dose has been reinitiated at the investigator’s discretion (Section 6.2.3).
Following all blood draws, subjects can eat breakfast and take their morning dose of BOS.
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7.1.2.3
Visit 12 (Month 72) or Early Termination
Assessments at this visit will be performed as outlined in Table 1-1. If a subject discontinues the 
trial prematurely or if the trial is terminated (eg, at commercial availability of BOS), the 
assessments for Visit 12 are to be performed as completely as possible. Subjects whose BOS 
treatment is interrupted at the investigator's discretion will continue in the study for potential 
resumption of BOS treatment; these subjects will not undergo Early Termination assessments 
when investigational product is interrupted.
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 years to 17 years, 
inclusive), and weight (measured in duplicate for adolescents 11 years to 17 years, inclusive). 
Perform stadiometry in subjects aged 11 years to 17 years, inclusive. Vital signs will be 
assessed after the subject has been resting 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 7.2.1.5).

Morning cortisol (performed between 6:00 AM and 9:00 AM). Subjects should be instructed 
not to take the morning dose of BOS until after the morning cortisol test has been performed. 

Administer adrenocorticotropic hormone (ACTH, 250 mcg) stimulation testing; the type of 
synthetic and route of administration will be per investigator 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 7.2.1.5). (Unscheduled ACTH stimulation tests may be performed at the 
investigator’s discretion between scheduled visits).
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S of disease assessment. 

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 as described in Section 7.2.1.3.

Urine pregnancy test will be performed on all female subjects.
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
Perform DXA scan for BMD and in subjects aged 11-17 years, inclusive. Dual-energy X-ray 
absorptiometry scans should be performed at this visit or within 28 days of the scheduled 
visit using the same machine and software when feasible.

Perform EGD and biopsy; EGD should be completed at or within 28 days of the scheduled 
visit. An earlier EGD may occur at the investigator’s discretion if the subject exhibits signs 
of relapse, or increased, worsening or persistent dysphagia symptoms (Section 4.5.1).

Review BOS dosing compliance.
7.1.3
Safety Follow-up Telephone Contact/Visit 13:
The follow-up period for this protocol is 4 weeks from the last dose of investigational product 
treatment. Subjects who withdraw from study treatment will receive a follow-up telephone call at 
Visit 13 to query for SAEs, AEs, and concomitant treatments.
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 
(Section 8.1).
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.
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
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.
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7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation
The EGD with 
 and biopsy will be performed during the study as outlined in 
Table 1-1. 
All EGDs with biopsies will be performed by a physician at the investigative site. For all EGDs 
after screening (after the SHP621-302 Visit 8 EGD), the local endoscopist will submit biopsy 
specimens to a clinical pathology laboratory for histopathology including assessment of 
eosinophil counts and histopathologic features of EoE per local procedures. 
An EGD with esophageal biopsies is required for all subjects prior to enrolling in the study and 
then every year thereafter until the subject either completes or withdraws from the study. If at 
any time, the subject exhibits signs of relapse, or increased, worsening or persistent dysphagia 
symptoms, the investigator may choose to perform an unscheduled EGD. Investigators may 
perform an unscheduled EGD to evaluate subjects in their determination to interrupt or restart 
treatment, or to change the BOS dose (see Section 3.1). An unscheduled EGD may replace a 
scheduled interim EGD if it occurs within 3 months of the latter (ie, 3 months before or after 
Visit 2, 4, 6, 8, or 10). If an unscheduled EGD is performed within 3 months of Visit 12 (or ET), 
the Visit 12 (or ET) does not need to be completed if discussed prospectively with the medical 
monitor and determined to be unnecessary.
 
 
 
 
 
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. At the investigator’s discretion, biopsies may be taken from the stomach and 
duodenum per local procedures. 
7.2.1.2
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 SHP621-302 final treatment evaluation visit (Visit 8). Medical history will be 
classified as EoE or non-EoE by the investigator. Adverse events recorded during the 
SHP621-302 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.
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Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, or 
other), must be recorded on the appropriate CRF page.
7.2.1.3
Physical Examination (Including Height and Weight)
Abnormalities identified at the SHP621-302 final treatment evaluation visit (Visit 8) will be 
documented in the subject’s source documents and on the medical history CRF. Changes after 
this visit 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 will also include Tanner Staging Assessments for subjects 
<18 years of age unless the investigator confirms subject is post puberty. 
Height will be measured in triplicate at all visits for adolescents (11 years to 17 years, inclusive). 
Height will be measured in adults annually at Visits 2, 4, 6, 8, 10, and 12. Statural height in 
adolescents will be measured at each visit 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. Subjects who turn 18 over the course of 
the study (ie, after providing consent for the SHP621-303 study), will be considered to be adults 
and triplicate readings using stadiometers will not be required. 
Weight will be measured in duplicate in adolescents (11 years to 17 years, inclusive) and 
recorded in the CRF. Subjects who turn 18 over the course of the study (ie, after providing 
consent for the SHP621-303 study), will be considered to be adults and duplicate measurements 
will no longer be required.
All subjects with clinical evidence of reduced height velocity and/or delayed Tanner Staging 
during the study should be followed up at investigator discretion and within 3 months with repeat 
follow-up as necessary until resolution. Such clinically significant findings should be discussed 
with the medical monitor. The investigator should determine whether it is appropriate for the 
subject to continue investigational product treatment (or have treatment interrupted for potential 
restart at a later date). Subjects who discontinue from the study or have treatment interrupted and 
have clinical evidence of reduced height velocity and/or delayed Tanner Stage development at a 
study visit (including the early termination visit) should be followed up at investigator discretion 
and within 3 months with repeat follow-up as necessary until resolution. 
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 SHP621-302 study must be recorded on the CRF for this study. 
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Adverse event assessments at each visit should also include specific assessments for signs of 
glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and 
depression).
7.2.1.4
Vital Signs
Vital signs will be conducted after the subject has been resting (and in a supine position for 
Visit 0 only) 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.
7.2.1.5
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 (Section 8.1.5). 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
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Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Other tests

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 (250 mcg). The type of 
synthetic and route of administration will be per investigator 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 SHP621-302 study.
Clinically significant abnormal laboratory test results during the study should be followed up at 
investigator discretion and within 3 months. All subjects with an abnormal ACTH stimulation 
test or urinary or serum glucose level must be followed closely during the study until resolution. 
The investigator, in consultation with the medical monitor, should determine whether it is 
appropriate for subjects to continue study drug treatment. Subjects who discontinue from the 
treatment period at any time and have abnormal ACTH stimulation test or urinary or serum 
glucose level should also be followed up at investigator discretion and within 3 months with 
repeat follow-up as necessary until resolution. 
7.2.1.6
Pregnancy Test 
A urine pregnancy test is performed on all female subjects at all visits, except Visit 0, or if 
pregnancy is suspected.
7.2.1.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density 
Dual-energy X-ray absorptiometry (also referred to as DEXA) scans for determination of BMD 
will be performed in subjects aged 11-17 years, inclusive, as outlined in Table 1-1. Subjects who 
turn 18 over the course of the study (ie, after providing consent for the SHP621-303 study) will 
be considered to be adults and DXA scans will not be required. 
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body less 
head (Bachrach and Sills, 2011; Gordon et al., 2008; 
International Society for Clinical Densitometry 2014). The same DXA machine and software 
should be used for the baseline and post treatment scans, when feasible. The DXA manufacturer, 
model, and software version should be recorded in the CRF.
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7.2.2
Other Assessments
7.2.2.1
Health-related Quality-of-life Assessment
EuroQol-5 Dimensions 3-level Questionnaire 
The EuroQol-5D Dimensions 3-level (EQ-5D-3L; for subjects ≥18 years) and the EuroQol-5 
Dimensions Youth (EQ-5D-Y; for subjects 11-17 years of age, inclusive) will be performed 
during the study as outlined in Table 1-1. Subjects who turn 18 after over the course of the study 
(ie, after providing consent for the SHP621-303 study), will continue to fill out the same 
questionnaire for continuity of data collection. 
The EQ-5D-3L is a standardized measure of health status for use in adult populations that was 
developed by the EuroQol Group in order to provide a simple, generic measure of health for 
clinical and economic appraisal (EuroQol, 1990). The EQ-5D-3L provides a simple descriptive 
profile and a single index value for health status that can be used in the clinical and economic 
evaluation of healthcare as well as in population health surveys. It consists of a 5-item 
descriptive system that measures 5 dimensions of health, including mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single 
item with 3 levels of responses. The EQ-5D-3L will be completed by the subject. The EQ-5D-3L 
should take the subject a few minutes to complete.
The EQ-5D-Y is a self-report version of the EQ-5D that was developed by the EuroQol Group 
for use in younger populations (Wille et al., 2010). The EQ-5D-Y provides a simple descriptive 
profile and a single index value for health status that can be used in the clinical and economic 
evaluation of healthcare as well as in population health surveys. It consists of a 5-item 
descriptive system that measures 5 dimensions of health, including mobility, looking after 
myself, doing usual activities, having pain or discomfort, and feeling worried, sad, or unhappy. 
Each dimension is represented by a single item with 3 levels of responses. The EQ-5D-Y will be 
completed by the subject and should take a few minutes to complete.
Pediatric Quality of Life – EoE Questionnaire
The PedsQL-EoE questionnaire will be completed by subjects 11-17 years of age, inclusive, and 
their parent or legal guardian, as outlined in Table 1-1. Subjects who turn 18 over the course of 
the study will continue to fill out the same questionnaire for continuity of data collection.
The PedsQL-EoE is a modular, disease-specific instrument designed to measure HRQoL in 
children and adolescents (2-18 years of age) with EoE (Franciosi et al., 2013; 
Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID). The 
PedsQL-EoE module consists of 35 items for children and teenagers encompassing the following 
7 scales: 1) Symptoms I (6 items; chest/throat/stomach pain and nausea/vomiting), 2) 
Symptoms II (4 items; trouble swallowing), 3) Treatment (5 items; treatment barriers), 4) Worry 
(6 items; worries about treatment and disease), 5) Communication (5 items; communication with 
others about EoE), 6) Food and Eating (4 items; food and eating allergies and limitations), and 7) 
Food Feelings (3 items; emotions associated with food allergies). The PedsQL-EoE should take 
the subject and parent approximately 10 minutes to complete. 
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Adult Eosinophilic Esophagitis Quality of Life Questionnaire 
The EoE-QoL-A will be performed in subjects ≥18 years of age as outlined in Table 1-1.
The EoE-QoL-A is a disease-specific measure of HRQoL in adult patients (≥18 years of age) 
with EoE (Taft et al., 2011). The EoE-QoL-A consists of a 30-item test with 5 subscales: 
eating/diet impact, social impact, emotional impact, disease anxiety, and choking anxiety. 
The EoE-QoL-A will be completed by the subject and should take the subject approximately 
15 minutes to complete.
7.2.2.2
Severity of Disease Assessments
Patient Global Impression of Severity 
The PGI-S will be performed in all subjects as outlined in Table 1-1.
The PGI-S is a global index (Appendix 3) that can be used to rate the severity of a specific 
condition–in this case, dysphagia in EoE. Subjects will be asked to rate the severity of their 
dysphagia over the last 7 days using a 5-point scale.
7.2.3
Volume of Blood to Be Drawn from Each Subject
Table 7-1
Approximate Volume of Blood to Be Drawn from Each Subject (Visits 1-12)
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Safety
Biochemistry and -hCGa
6
12
72
ACTH
2
12
24
Cortisol
2
6
12
Hematology
2
12
24
Total mL
12
-
132
ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropin
a -hCG testing is for females only.
During this study, at scheduled Visits 1 through 12, it is expected that approximately 132 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 132 mL. When more than one 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 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 investigational product.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of investigational product, 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 investigational product, 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 
investigational product, follows a known or suspected response pattern to the 
investigational product, is confirmed by improvement upon stopping the 
investigational product (dechallenge), and reappears upon repeated exposure 
(rechallenge). Note that this is not to be construed as requiring re-exposure of the 
patient to investigational product; 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 
Takeda Global Patient Safety Evaluation Department using the Investigational and Marketed 
Products Pregnancy Report Form. A copy of the Investigational and Marketed Products 
Pregnancy Report Form (and any applicable follow-up reports) must also be sent to the 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 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 Clinical Study Adverse Event Form for SAEs and Non-
serious AEs as Required by Protocol as well as the 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 Takeda Global 
Patient Safety Evaluation Department (GlobalPharmacovigilance@shire.com) and the 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 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 Takeda Global Patient Safety 
Evaluation Department. A copy of the 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 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 Takeda Global Patient Safety Evaluation 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 Takeda Global 
Patient Safety Evaluation 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 enrolled, 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
Eligibility for participation in this continuation study will be determined based on assessments 
performed at the final treatment evaluation visit (Visit 8) of SHP621-302. However, subjects, site 
staff, and study team members involved with the conduct of the study will remain blinded to 
treatment assignment and individual subject histology data from the SHP621-301 and 
SHP621-302 studies until database lock occurs for SHP621-302. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using statistical analysis system (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.
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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 100 subjects who complete the SHP621-302 extension study are anticipated to 
enroll into this open-label continuation study.
9.7
Study Population
The safety set will include all subjects who receive at least 1 dose of BOS.
The full analysis (FAS) set will include all subjects who are enrolled in the study and receive at 
least 1 dose of BOS. 
The primary population for safety will be the safety population 
 
. An additional per-protocol population 
analysis may also be performed as secondary sensitivity analysis. Applicable analysis 
populations will be defined in the statistical analysis plan (SAP).
9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
Not applicable.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
Not applicable.
9.8.3
Exploratory 
 Endpoints
The exploratory endpoints that will be explored are the following:
 
 
 
 
 
 
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9.9
Safety Analyses
All safety endpoints, including AEs, physical examinations, stadiometry, vital signs 
(temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height 
assessments, DXA scans for BMD (for adolescents aged 11 years to 17 years, inclusive), clinical 
laboratory tests (hematology, chemistry, urinalysis; urine pregnancy test, if appropriate), and 
ACTH stimulation tests, will be descriptively summarized at baseline and at each post-baseline 
visit. To account for the effects of puberty in adolescent subjects (11 years to 17 years of age, 
inclusive), BMD z-scores will be adjusted for height z-scores.
The number and percent of subjects with treatment-emergent adverse events (TEAEs) will be 
presented. Treatment-emergent adverse events are defined as AEs that start or deteriorate on or 
after the time the informed consent is signed and 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. 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.
Adverse events 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. 
Treatment-emergent adverse events will be further summarized by severity and relationship to 
BOS. Adverse events related to BOS, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized/listed.
The following adverse events of special interest (AESIs) related to corticosteroid use will be 
categorized with preferred terms (SOC where applicable):

Infections:
o
System Organ Classes of infections and infestations 
o
Candidiasis related: esophageal candidiasis, oral candidiasis, candidiasis, 
oropharyngeal candidiasis, tongue fungal infection, vulvovaginal mycotic 
infection, anal candidiasis.

Potential systemic effects of corticosteroid use (including adrenal function): 
o
Adrenal effects: adrenal suppression, adrenal insufficiency, ACTH stimulation 
test abnormal, and blood cortisol decrease or increase, blood cortisol abnormal, 
cushingoid
o
CNS/Mood effects: insomnia, mood swings, suicidal ideation, OCD, anxiety, 
depression, major depression, irritability, restlessness, sleep disorder, disturbance 
in attention, headache, dizziness, vertigo, lethargy, paranesthesia, hypoesthesia, 
psychomotor hyperactivity
o
Metabolic effects: blood glucose increased, blood glucose abnormal, glucose 
intolerance impaired, diabetes mellitus, intraocular pressure increased, acne, 
weight increased, weight fluctuation, hepatic steatosis, hirsutism, dermatitis 
acneiform, skin striae, skin texture abnormal, obesity, menopausal symptoms, 
metrorrhagia
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o
Cardiac effects: edema peripheral, peripheral swelling, hypertension, palpitations
o
Fractures: foot fracture, upper limb fracture, humerus fracture, rib fracture, wrist 
fracture

GI effects: 
o
Esophagitis pain, esophagitis, vomiting, nausea, diarrhea, abdominal pain, 
abdominal pain upper, constipation, abdominal distention, abdominal discomfort, 
hiatus hernia, dyspepsia, gastritis, gastritis erosive, chronic gastritis, dry mouth, 
erosive esophagitis, and gastroesophageal reflux disease, mouth ulceration, gastric 
ulcer, duodenal ulcer, erosive duodenitis, mouth ulceration, esophageal ulcer.
9.10 Health-related Quality-of-life Analyses
The health economics and outcomes research endpoints that will be explored are the following:

Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score at all visits 
from baseline (last assessment prior to first dose of BOS)

Change in EuroQol (EQ-5D; EuroQol-5 Dimensions 3-level [EQ-5D-3L] or EuroQol-5 
Dimensions Youth [EQ-5D-Y], according to subject's age) score at all visits from baseline 
(last assessment prior to first dose of BOS)

Change in Pediatric Quality of Life Inventory (subjects 11-17 years of age, inclusive) - EoE 
(PedsQL-EoE) score at all visits from baseline (last assessment prior to first dose of BOS)

Change in Patient Global Impression of Severity (PGI-S) score at all visits from baseline (last 
assessment prior to first dose of BOS)
No formal testing will be conducted for Health Economics and Outcomes Research endpoints. 
All endpoints will be summarized using summary statistics at each visit. Continuous endpoints 
will be summarized using mean, standard deviation, median, minimum and maximum values. 
Categorical endpoints will be summarized using count and percentage. Ninety five percent 
confidence interval (CI) will be provided wherever appropriate. Listings for subject-level data 
will be presented. 
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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, European Union 
(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 BOS 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. 
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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). 
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 BOS, containers, and other study materials to the sponsor. 
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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.
All 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 SHP621-302 
final treatment evaluation visit (Visit 8) will not be recollected in the SHP621-303 database as 
follows (Section 7.1.1.1):

Vital signs, height, and weight assessment

EGD with 
 and biopsy

EQ-5D

PedsQL-EoE (subjects 11 to 17 years of age)

EoE-QoL-A (subjects ≥18 years of age)

PGI-S

Physical examination

Tanner Staging Assessment

Clinical laboratory tests

Urinalysis

Serum Pregnancy test

Morning cortisol

ACTH Stimulation Testing

DXA Scan (subjects 11 to 17 years of age)
All data sent to the sponsor must be endorsed by the investigator.
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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, 
European Medicines Agency (EMA), United Kingdom (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.
Laboratory samples (blood and urine) will be stored by the clinical laboratory for as long as is 
required to:

Complete the study

Publish data related to the study

Support any regulatory applications for the study drug
Samples could be stored for up to about 15 years. 
Biopsy specimens should be stored by the local laboratory per federal and local regulations.
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.
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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 BOS; any significant equity 
interest in the sponsor or subsidiaries as defined in 21 Code of Federal Regulations (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 BOS 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.
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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.
Budesonide oral suspension 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 Health Insurance Portability and Accountability Act (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).
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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
Takeda 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, Takeda 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 
Takeda. 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 Takeda products or projects must undergo appropriate technical and 
intellectual property review, with Takeda 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 Takeda, 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. 
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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
Food and Drug Administration 2011. Uceris pharmacology review. NDA 203-634.
International Society for Clinical Densitometry 2014. 2013 Official Positions—Adult & 
Pediatric, 1-20.
Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID).
Alexander, J. A. 2014. Steroid treatment of eosinophilic esophagitis in adults. Gastroenterol Clin 
North Am, 43, 357-73.
Bachrach, L. K. & Sills, I. N. 2011. Clinical report-bone densitometry in children and 
adolescents. Pediatrics, 127, 189-94.
Dellon, E. S., Gonsalves, N., Hirano, I., Furuta, G. T., Liacouras, C. A. & Katzka, D. A. 2013. 
ACG clinical guideline: Evidenced based approach to the diagnosis and management of 
esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol, 108, 
679-92; quiz 693.
Dellon, E. S., Jensen, E. T., Martin, C. F., Shaheen, N. J. & Kappelman, M. D. 2014. Prevalence 
of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol, 12, 589-
96.e1.
EuroQol 1990. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy, 16, 199-208.
Franciosi, J. P., Hommel, K. A., Bendo, C. B., King, E. C., Collins, M. H., Eby, M. D., Marsolo, 
K., Abonia, J. P., von Tiehl, K. F., Putnam, P. E., Greenler, A. J., Greenberg, A. B., 
Bryson, R. A., Davis, C. M., Olive, A. P., Gupta, S. K., Erwin, E. A., Klinnert, M. D., 
Spergel, J. M., Denham, J. M., Furuta, G. T., Rothenberg, M. E. & Varni, J. W. 2013. 
PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity. J Pediatr 
Gastroenterol Nutr, 57, 57-66.
Furuta, G. T. & Katzka, D. A. 2015. Eosinophilic Esophagitis. N Engl J Med, 373, 1640-8.
Furuta, G. T., Liacouras, C. A., Collins, M. H., Gupta, S. K., Justinich, C., Putnam, P. E., Bonis, 
P., Hassall, E., Straumann, A. & Rothenberg, M. E. 2007. Eosinophilic esophagitis in 
children and adults: a systematic review and consensus recommendations for diagnosis 
and treatment. Gastroenterology, 133, 1342-63.
Gordon, C. M., Bachrach, L. K., Carpenter, T. O., Crabtree, N., El-Hajj Fuleihan, G., Kutilek, S., 
Lorenc, R. S., Tosi, L. L., Ward, K. A., Ward, L. M. & Kalkwarf, H. J. 2008. Dual 
energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 
2007 ISCD Pediatric Official Positions. J Clin Densitom, 11, 43-58.
Hirano, I. & Aceves, S. S. 2014. Clinical implications and pathogenesis of esophageal 
remodeling in eosinophilic esophagitis. Gastroenterol Clin North Am, 43, 297-316.
Liacouras, C. A., Furuta, G. T., Hirano, I., Atkins, D., Attwood, S. E., Bonis, P. A., Burks, A. 
W., Chehade, M., Collins, M. H., Dellon, E. S., Dohil, R., Falk, G. W., Gonsalves, N., 
Gupta, S. K., Katzka, D. A., Lucendo, A. J., Markowitz, J. E., Noel, R. J., Odze, R. D., 
Putnam, P. E., Richter, J. E., Romero, Y., Ruchelli, E., Sampson, H. A., Schoepfer, A., 
Shaheen, N. J., Sicherer, S. H., Spechler, S., Spergel, J. M., Straumann, A., Wershil, B. 
K., Rothenberg, M. E. & Aceves, S. S. 2011. Eosinophilic esophagitis: updated 
consensus recommendations for children and adults. J Allergy Clin Immunol, 128, 3-
20.e6; quiz 21-2.
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Straumann, A., Conus, S., Degen, L., Frei, C., Bussmann, C., Beglinger, C., Schoepfer, A. & 
Simon, H. U. 2011. Long-term budesonide maintenance treatment is partially effective 
for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol, 9, 400-9.e1.
Taft, T. H., Kern, E., Kwiatek, M. A., Hirano, I., Gonsalves, N. & Keefer, L. 2011. The adult 
eosinophilic oesophagitis quality of life questionnaire: a new measure of health-related 
quality of life. Aliment Pharmacol Ther, 34, 790-8.
Wille, N., Badia, X., Bonsel, G., Burstrom, K., Cavrini, G., Devlin, N., Egmar, A. C., Greiner, 
W., Gusi, N., Herdman, M., Jelsma, J., Kind, P., Scalone, L. & Ravens-Sieberer, U. 2010. 
Development of the EQ-5D-Y: a child-friendly version of the EQ-5D. Qual Life Res, 19, 
875-86.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Protocol Amendment 3
21 Jun 2021
Global
Protocol Amendment 2
10 Aug 2020
Global
Protocol Amendment 1
27 Jun 2017
Global
Original Protocol
05 Dec 2015
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
10 Aug 2020
Global Amendment
Description of Change
Section(s) Affected by Change
Changed from: 
, MD
To:
, MD
Added email address for Shire Global Pharmacovigilance 
and Risk Management Department
Rationale: To provide updated emergency contact 
information.
Protocol Signature Page; Emergency Contact 
Information Page
Updated study design flow chart and Schedule of 
Assessments to reflect addition of 2 new study visits
Rationale: To extend treatment period until product is 
commercially available.
Synopsis: Study Period Planned, Methodology; 
Table 1-1
Schedule of Assessments
Section 3.1: Study Design and Flow Chart;
Section 7.1.2.1: Visit 1, 3, 5, 7, 9, 11 (Months 6, 18, 30, 
42, 54, 66);
Section 7.1.2.2: Visits 2, 4, 6, 8, 10 (Months 12, 24, 36, 
48, 60);
Section 7.1.2.3: Visit 12 (Month 72);
Section 7.1.3:Safety Follow-up Telephone 
Contact/Visit 13 
Throughout document
Replaced intent-to-treat analysis set (ITT) with full 
analysis set (FAS). Indicated that exploratory
analyses will be performed on the FAS, not the ITT.
Rationale: To provide clarification on statistical 
methods for the final analysis.
Synopsis: Study Populations
Section 9.7: Study Population
Updated text describing analyses of Health Economics 
and Outcomes Research and exploratory endpoints to 
indicate they will not be summarized by duration of 
exposure.
Synopsis: Methodology; 
Section 9.8.3: Exploratory 
 Endpoints
Section 9.10: Health-related Quality-of-life Analyses
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
10 Aug 2020
Global Amendment
Description of Change
Section(s) Affected by Change
Rationale: To clarify that analyses will be summarized 
by visit, not by duration of exposure.
Corrected text describing collection of treatment-adverse 
events (TEAE) to indicate that they will be collected from 
the time of informed consent.
Rationale: To clarify TEAE collection period.
Synopsis: Statistical Methodology for Safety Endpoints
Section 9.9: Safety Analyses
Added language to guide investigators in anticipation of 
potential deviations from study procedures due to 
unavoidable circumstances such as the COVID-19 
pandemic. 
Rationale: To provide direction to investigators to 
allow for continuation of subjects in the study despite 
missed study visits/missed study assessments due to 
unavoidable circumstances (eg, COVID-19 pandemic).
Section 7: Study Procedures
Updated blood volumes.
Rationale: To provide clarification on approximate 
volume of blood to be drawn from each subject.
Section 7.2.3: Volume of Blood to Be Drawn from 
Each Subject
Removed the Bone Mineral Density in Childhood Study 
calculator as this reference is no longer available. 
Rationale: To remove an outdated reference.
Synopsis: Statistical Methodology for Safety Endpoints
Section 9.9: Safety Analyses
Added language describing how long laboratory samples 
(blood, urine, and biopsy samples) will be stored by the 
clinical laboratory. 
Rationale: To clarify the retention period for 
laboratory sample storage. 
Section 10.2.3.2: Recording, Access, and Retention of 
Source Data and Study Documents
Summary of Change(s) for Protocol Amendment 1
Amendment Number 1
Amendment Date
27 Jun 2017
Global Amendment
Description of Change
Section(s) Affected by Change
As there are limited data available on the potential benefits and risks of 
maintenance treatment of EoE with topical corticosteroids, investigators 
should exercise discretion in determining the duration of BOS treatment in 
this study and the need for and frequency of dose regimen changes or dose 
interruption.
Synopsis: Rationale;
Section 3.1: Study Design and 
Flow Chart
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SHP621 (budesonide)
21 Jun 2021
Summary of Change(s) for Protocol Amendment 1
Amendment Number 1
Amendment Date
27 Jun 2017
Global Amendment
Description of Change
Section(s) Affected by Change
At the investigator’s discretion, BOS administration may be stopped (allowable 
up to 6 months) and/or stopped and reinitiated. Continued participation in the 
study is required to resume BOS.
The daily dose and potential total treatment duration of the current 
formulation of BOS with long-term continuation treatment in this study 
(ie, beyond the maximal 1 year total treatment duration in the SHP621-301 
and SHP621-302 studies combined) may expose subjects to 
21-dehydrobudesonide (21-DHB), a known breakdown product of 
budesonide, at a level that has an unknown risk of mutagenicity. 21-DHB is 
an in vitro mutagen that has been found to be negative for mutagenicity in 
in vivo animal studies. The relevance of this finding to humans is unknown; 
however, a risk of causing DNA damage or carcinogenicity cannot be 
excluded with long durations of treatment. As described in the SHP621 
investigator’s brochure, investigators should make an individualized 
risk/benefit decision with respect to long-term BOS investigational 
treatment at the time of informed consent and when monitoring and 
adjusting BOS treatment in this study. The protocol allows for 
individualized treatment with BOS, including dose-regimen change from 
2 mg twice-daily to 2 mg once-daily (qAM, pc) or treatment interruption 
(with resumption of treatment and/or increase in the BOS dose regimen to 
2 mg twice-daily permitted at a later date while on study).
Synopsis: Investigational 
product, dose, and mode of 
administration;
Section 3.1: Product Background 
and Clinical Information
BOS treatment may be adjusted by a dose regimen change from 2 mg 
twice-daily to 2 mg once-daily (qAM, pc) or by treatment interruption 
(with resumption of treatment and/or increase in the BOS dose regimen to 
2 mg twice-daily permitted at a later date while on study). Interruptions of 
up to 6 months are allowed. In their discretion with respect to individual 
subject investigational treatment adjustment, investigators should consider 
the subject’s response to previous and current treatment, risk of relapse, 
and the overall risk/benefit profile of long-term treatment with BOS 
greater than 1 year.
At the investigator’s discretion, BOS administration may be stopped during the 
study (allowable up to 6 months) and/or stopped and reinitiated (Section 6.2.3).
Synopsis: Investigational 
product, dose, and mode of 
administration; Methodology;
Section 3.1: Study Design and 
Flow Chart
Edited footnote ‘b’ to indicate that vital signs may be assessed after the subject 
has been resting for at least 5 minutes.
Table 1-1, Footnote b
Edited footnote ‘e’ to clarify that unscheduled endoscopies may be performed to 
assess relapse or to determine whether modifications to the BOS dosing 
regimen are needed. Added language indicating that if unscheduled EGDs are 
performed within 3 months of Visit 8 or ET, the Visit 8 (or ET) EGD does not 
need to be performed if discussed prospectively with the medical monitor.
Table 1-1, Footnote e
Added footnote ‘n’: 
Dual-energy X-ray absorptiometry scans should be performed using the 
same machine and software as used in the SHP621-301 and SHP621-302 
studies.
Table 1-1, Footnote n
Edited footnote ‘o’ to clarify that investigational product may be provided at 
unscheduled visits to assess subjects for treatment interruption or re-initiation.
Table 1-1, Footnote o
Continued participation in the study (ie, completion of scheduled study 
Synopsis: Methodology; 
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SHP621 (budesonide)
21 Jun 2021
Summary of Change(s) for Protocol Amendment 1
Amendment Number 1
Amendment Date
27 Jun 2017
Global Amendment
Description of Change
Section(s) Affected by Change
assessments) is required to resume BOS treatment. Subjects who are 
discontinued from the study may not reinitiate BOS treatment.
Section 3.1: Study Design and 
Flow Chart
No fixed duration of subject participation is specified. Subjects may 
participate in the study will continue to receive open label treatment for up to 
4 years or until commercial product is available.
Section 3.2: Duration and Study 
Completion Definition
If the investigator adjusts BOS treatment at their discretion for potential 
reinitiation at a later date by interrupting treatment (allowable for up to 
6 months prior to restarting treatment, see Section 3.1), the subject may 
continue in the study (ie, complete study assessments as scheduled). If the 
investigator adjusts BOS treatment at their discretion by decreasing the 
frequency of BOS dose from 2 mg twice-daily to 2 mg once-daily, the 
duration of dose regimen change does not impact continued study 
participation. Subjects with BOS treatment interruptions greater than 
6 months should be discontinued after completing the Visit 8/Early 
Termination evaluations. 
Section 4.5: Discontinuation of 
Subjects
Dose interruptions starting at the time of completion of the SHP621-302 study, 
due to administrative or other reasons, will be permitted; however, dosing 
should be reinitiated within 3 months of completion of treatment in SHP621-
302 unless discussed prospectively with the medical monitor. At the 
investigator's discretion, changes to the dosage regimen are allowable. BOS 
treatment may be changed from twice-daily administration (2 mg twice-
daily) to once-daily administration (qAM, pc). In addition, BOS treatment 
may be interrupted by stopping and planning to reinitiate investigational 
product treatment up to 6 months later (see Section 3.1). In these instances, 
investigational product treatment will be stopped while the subject remains 
in the study and continues to have other protocol assessments. 
Investigational product must be resumed within 6 months and multiple 
treatment interruptions are permitted (ie, 3 months on and 3 months off 
treatment). BOS may also be stopped (allowable up to 6 months) and/or 
stopped and restarted at the investigator’s discretion. Ddose regimen changes 
and dose interruptions must be recorded by the subject and study site. 
Continued participation in the study is required to resume BOS.
Dose interruptions starting at the time of completion of the SHP621-302 
study, due to administrative or other reasons, will also be permitted; 
however, dosing should be reinitiated within 3 months of completion of 
treatment in SHP621-302 unless discussed prospectively with the medical 
monitor (eg, in instances when SHP621-302 investigational treatment was 
completed more than 3 month prior to the investigator’s site initiation in 
this study). In such instances, the visit schedule in this study will be based 
off the final treatment evaluation visit (Visit 8) in SHP621-302, regardless 
of dose interruption at the time of completion of SHP621-302 or timing of 
consent to participate in this study. Unscheduled safety and efficacy 
assessments may be required and should be discussed prospectively with 
the medical monitor prior to dispensing study drug considering the time off 
of investigational treatment and the study schedule (see Table 1 1).
Section 6.2.3: Dosing
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SHP621-303 Protocol Amendment 3
SHP621 (budesonide)
21 Jun 2021
Summary of Change(s) for Protocol Amendment 1
Amendment Number 1
Amendment Date
27 Jun 2017
Global Amendment
Description of Change
Section(s) Affected by Change
Dose interruptions starting at the time of completion of the SHP621-302 study, 
due to administrative or other reasons, will be permitted; however, dosing 
should be reinitiated within 3 months of completion of treatment in 
SHP621-302 unless discussed prospectively with the medical monitor (eg, in 
instances when SHP621-302 investigational treatment was completed more 
than 3 months prior to the investigator’s site initiation in this study).
In such instances, unscheduled safety and efficacy assessments may be 
required prior to dispensing study drug considering the time off of 
investigational treatment and the study schedule (see Table 1-1).
Section 7.1.1: 
Screening/Enrollment/Visit 0 
(Month 0)
Section 6.2.3: Dosing
The subject will continue with the twice-daily (morning and evening) dosing 
regimen unless otherwise instructed by the investigator (see Section 6.2.3).
Section 7.1.1.1: Screening/ 
Enrollment Visit (Visit 0)/Visit 8 
of SHP621-302 Study
At the investigator’s discretion, the dose regimen may be changed from 
twice-daily to once-daily (qAM, pc) or administration may be stopped 
(allowable up to 6 months) and/or stopped and reinitiated (Section 6.2.3).
Section 7.1.2: Open-label 
Treatment Period (Visits 1-8)
Edited text describing vital signs assessments to indicate that vital signs may be 
assessed after the subject has been resting for at least 5 minutes.
Section 7.1.2.1: Visits 1, 3, 5, 7 
(Months 6, 18, 30, 42); 
Section 7.1.2.2: Visits 2, 4, 6 
(Months 12, 24, 36); 
Section 7.1.2.3: Visit 8 
(Month 48) or Early 
Termination; 7.2.1.4, Vital Signs
Investigators may perform an unscheduled EGD to evaluate subjects in 
their determination to interrupt or restart treatment, or to change the BOS 
dose (see Section 3.1). An unscheduled EGD may replace a scheduled 
interim EGD if it occurs within 3 months of the latter (ie, 3 months before 
or after Visit 2, 4, or 6). If an unscheduled EGD is performed within 3 
months of Visit 8 or ET, the Visit 8 (or ET) does not need to be completed if 
discussed prospectively with the medical monitor and determined to be 
unnecessary.
Section 7.2.1.1:
Esophagogastroduodenoscopy 
with Esophageal Biopsy and 
Histopathologic Evaluation
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21 Jun 2021
Appendix 2
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
EQ-5D-3L (for subjects ≥18 years)
EQ-5D-Y (for subjects 11-17 years of age, inclusive)a
Subject
PedsQL-EoE (subjects 11-17 years of age, inclusive)b
Subject and parent or legal guardian
EoE-QoL-A (subjects ≥18 years of age)
Subject
PGI-S
Subject
Tanner Staging Assessment
Site
Site
EoE-QoL-A=Adult Eosinophilic Esophagitis Quality of Life; EQ-5D=EuroQol; 
 
; PedsQL-EoE=Pediatric Quality of Life Inventory – EoE; PGI-S=Patient Global Impression of Severity
a Subjects 11 to 17 years of age, inclusive, at the time of consent into the SHP621-301 study, will complete the 
EQ-5D-Y throughout study participation; subjects ≥18 years of age (at the time of consent into the SHP621-301 
study) will complete the EQ-5D-3L. 
b Subjects 11 to 17 years of age, inclusive, at the time of consent into the SHP621-301 study will complete the 
PedsQL-EoE throughout study participation.
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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21 Jun 2021
Appendix 3
Patient Global Impression of Severity
How would you rate the overall severity of your dysphagia (difficulty swallowing) over the past 
7 days?
Rating
Description
0
No dysphagia
1
Mild dysphagia
2
Moderate dysphagia
3
Severe dysphagia
4
Very severe dysphagia
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT03245840 
 
Study Title:  
A Phase 3, Multicenter, Open-label Continuation Study with Budesonide Oral 
Suspension (BOS) for Adolescent and Adult Subjects with Eosinophilic 
Esophagitis (EoE) 
 
Study Number:  
SHP621-303 
 
 
SAP Version and Date:   
Version 1.0: 
  
26 Jan 2021 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: SHP621-303 
Study Title: A Phase 3, Multicenter, Open-label Continuation Study with Budesonide 
Oral Suspension (BOS) for Adolescent and Adult Subjects with  
Eosinophilic Esophagitis (EoE) 
Phase: III 
Version: 1.0 
Date: 26-Jan-2021 
Prepared by:  
 BIOSTATISTICS 
PPD 
3900 N Paramount Parkway 
Morrisville, NC 27560 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 10-Aug-2020 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
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SHP621-303 Statistical Analysis Plan v1.0 
SHP621 
 
26 Jan 2021 
 
 
 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Version 1.0 
26-Jan-2021 
Not Applicable 
 
 
 
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SHP621 
 
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TABLE OF CONTENTS 
REVISION HISTORY.....................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF IN-TEXT TABLES ..........................................................................................................6 
LIST OF IN-TEXT FIGURES.........................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................................9 
1.1 Objectives ............................................................................................................................9 
1.1.1 Primary Objective .......................................................................................................9 
1.1.2 Secondary Objective ...................................................................................................9 
1.1.3 Exploratory Objectives ...............................................................................................9 
1.2 Endpoints .............................................................................................................................9 
1.2.1 Primary Efficacy Endpoint .........................................................................................9 
1.2.2 Secondary Efficacy Endpoint .....................................................................................9 
1.2.3 Exploratory 
 Endpoints ..................................................................................9 
1.2.4 Safety Endpoints .........................................................................................................9 
1.2.5 Other Endpoints ........................................................................................................10 
1.3 Estimands ...........................................................................................................................10 
2. STUDY DESIGN.......................................................................................................................11 
2.1 General Study Design ........................................................................................................11 
2.2 Randomization ...................................................................................................................12 
2.3 Blinding..............................................................................................................................12 
2.4 Schedule of Assessments ...................................................................................................12 
3. STATISTICAL HYPOTHESES AND DECISION RLUES .....................................................18 
4. SAMPLE-SIZE DETERMINATION ........................................................................................19 
5. ANALYSIS SETS .....................................................................................................................20 
5.1 Screened Set .......................................................................................................................20 
5.2 Enrolled Set ........................................................................................................................20 
5.3 Safety Analysis Set ............................................................................................................20 
5.4 Full Analysis Set ................................................................................................................20 
5.5 Treatment Group ................................................................................................................20 
6. STATISTICAL ANALYSIS .....................................................................................................22 
6.1 General Considerations ......................................................................................................22 
6.2 Discontinuation of Study Treatment ..................................................................................22 
6.3 Demographic and Other Baseline Characteristics .............................................................23 
6.3.1 Demographics ...........................................................................................................23 
6.3.2 General Medical History ...........................................................................................24 
PI
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6.3.3 Interim EoE Medical History ....................................................................................24 
6.4 Medication History and Concomitant Medications ...........................................................24 
6.4.1 Prior Medications ......................................................................................................24 
6.4.2 Concomitant Medications .........................................................................................25 
6.5 Efficacy Analysis ...............................................................................................................25 
6.5.1 Primary Efficacy Endpoint Analysis ........................................................................25 
6.5.2 Secondary Efficacy Endpoint Analysis ....................................................................25 
6.5.3 Exploratory 
 Endpoints and Analyses .........................................................25 
6.5.4 Subgroup Analyses ...................................................................................................27 
6.6 Safety Analysis ..................................................................................................................27 
6.6.1 Adverse Events .........................................................................................................28 
6.6.2 Adverse Events of Special Interest ...........................................................................29 
6.6.3 Clinical Laboratory Variables ...................................................................................29 
6.6.4 Vital Signs .................................................................................................................30 
6.6.5 Physical Examination ................................................................................................30 
6.6.6 Dual-energy X-ray Absorptiometry for Bone Mineral Density ................................31 
6.6.7 Extent of Exposure and Compliance .........................................................................31 
6.7 Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .......................................33 
6.8 Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints Analysis .....33 
6.9 Other Analyses ...................................................................................................................33 
6.9.1 Health-related Quality of Life Analyses ...................................................................33 
6.10 Interim Analyses ..............................................................................................................36 
6.11 Data Monitoring Committee/Internal Review Committee/Other Data Review 
Committees ...............................................................................................................36 
7. REFERENCES ..........................................................................................................................37 
8. CHANGES TO PROTOCOL PLANNED ANALYSES ...........................................................38 
9. APPENDIX ................................................................................................................................39 
9.1 Changes from the Previous Version of the SAP ................................................................39 
9.2 Data Handling Conventions ...............................................................................................39 
9.2.1 General Data Reporting Conventions .......................................................................39 
9.2.2 Definition of Baseline ...............................................................................................39 
9.2.3 Definition of Visit Windows .....................................................................................39 
9.2.4 Repeated or Unscheduled Assessments of Safety Parameters ..................................39 
9.2.5 Missing Date of Investigational Product...................................................................40 
9.2.6 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ...................................................................................40 
9.2.7 Missing Date Information for Adverse Events .........................................................42 
9.2.8 Missing Severity Assessment for Adverse Events....................................................42 
PI
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9.2.9 Missing Relationship to Investigational Product for Adverse Events ......................42 
9.2.10 Character Values of Clinical Laboratory Variables ................................................42 
9.3 AESI Categories.................................................................................................................43 
9.4 Calculation of Adult Eosinophilic Esophagitis Quality of Life  (EoE-QOL-A) 
Subscale Scores ........................................................................................................44 
9.5 Calculation of Pediatric Quality of Life – EoE (PedsQL-EoE, subjects 11–17 years 
of age) Subscale Scores ............................................................................................44 
9.6 Calculation of the EQ-5D Score ........................................................................................45 
9.7 Analysis Software ..............................................................................................................46 
10. ELECTRONIC SIGNATURE .................................................................................................47 
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LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Assessment ................................................................................13 
Table 2 
Examples for Coding of Special Character Values for Clinical 
Laboratory .....................................................................................................43 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design Flow Chart ..............................................................................11 
 
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SHP621-303 Statistical Analysis Plan v1.0 
SHP621 
 
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ABBREVIATIONS 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
AESI 
AEs of special interest  
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
BMD 
bone mineral density 
BMI 
body mass index 
BOS 
budesonide oral suspension 
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 
EoE-QoL-A 
Adult Eosinophilic Esophagitis Quality of Life  
 
 
EQ-5D-3L 
EuroQol-5 Dimensions 3-level 
EQ-5D 
EuroQol 
EQ-5D-3L 
EuroQol-5 Dimensions 3-level EQ 
EQ-5D-Y 
EuroQol-5 Dimensions Youth  
 
 
ET 
early termination 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GDS 
Global Drug Safety 
GCP 
Good Clinical Practice 
GSL 
Global Safety Lead 
HIPAA 
Health Insurance Portability and Accountability Act  
 
 
HRQoL 
health-related quality of life 
hs 
at bedtime 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
PI
PI
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SHP621 
 
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Med ID 
medication identification 
MedDRA 
Medical Dictionary for Regulatory Activities  
PBO 
placebo 
pc 
after meals 
PedsQL-EoE 
Pediatric Quality of Life Inventory – EoE  
PGI-S 
Patient Global Impression of Severity 
PPI 
proton pump inhibitor 
qAM 
every morning 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS® 
statistical analysis system 
TA 
therapeutic area 
TEAE 
treatment-emergent adverse event 
UK 
United Kingdom 
US 
United States 
VAS 
Visual Analog Scale 
 
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1. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1  
Objectives 
1.1.1  Primary Objective 
The primary objective of this study is: 
• To evaluate the long-term safety and tolerability of BOS treatment  
1.1.2  Secondary Objective 
Not applicable. 
1.1.3  Exploratory Objectives 
 
 
 
 
 
 
 
1.2  
Endpoints 
1.2.1  
Primary Efficacy Endpoint 
Not applicable. 
1.2.2  
Secondary Efficacy Endpoint 
Not applicable. 
1.2.3  
Exploratory 
 Endpoints 
 
 
 
 
 
 
 
 
 
1.2.4  
Safety Endpoints 
The safety endpoints of this study are: 
• Adverse events (AEs) 
PI
PI
PI
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• Physical examinations include specific assessments for signs of glucocorticoid excess 
(eg, moon faces, acne, hirsutism, mood swing, insomnia, and depression). Tanner staging 
assessments for all subjects <18 years of age until investigator confirms subject is post 
puberty. 
• Vital signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate) 
• Height, weight and BMI 
• Dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD) (for 
adolescents aged 11–17 years, inclusive) 
• Clinical laboratory tests (hematology, chemistry, urinalysis; urine pregnancy test, if 
appropriate), and adrenocorticotropic hormone (ACTH) stimulation tests. 
1.2.5  
Other Endpoints 
The health economics and outcomes research endpoints that will be explored are the 
following: 
• Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score at all visits 
from baseline (last assessment prior to first dose of BOS) 
• Change in EuroQol (EQ-5D; EuroQol-5 Dimensions 3-level [EQ-5D-3L] or EuroQol-5 
Dimensions Youth [EQ-5D-Y], according to subject’s age) score at all visits from 
baseline (last assessment prior to first dose of BOS) 
• Change in Pediatric Quality of Life Inventory (subjects 11–17 years of age, inclusive) – 
EoE (PedsQL-EoE) score at all visits from baseline (last assessment prior to first dose of 
BOS) 
• Change in Patient Global Impression of Severity (PGI-S) score at all visits from baseline 
(last assessment prior to first dose of BOS) 
1.3  
Estimands 
Not applicable. 
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2.  STUDY DESIGN 
2.1  
General Study Design 
This is a Phase 3, multicenter, open-label study to evaluate the safety and tolerability of 
treatment administered twice daily of budesonide oral suspension (BOS; every morning [qAM] 
after meals [pc] and at bedtime [hs]) in adolescent and adults, aged 11 to 55 years, inclusive, 
with EoE. 
Approximately 100 subjects who have completed the SHP621-302 study will be enrolled in this 
continuation study. Subjects who complete the SHP621-302 extension study are eligible to 
participate once they sign informed consent (or assent as applicable for subjects <18 years). 
Eligible subjects will be enrolled into the open-label treatment period and evaluated for safety 
every 6 months following the final treatment evaluation visit (Visit 8) in the SHP621-302 study 
until commercial product is available. Esophagogastroduodenoscopy with biopsies will be 
performed in all subjects annually (Month 12, Month 24, etc.) (see Figure 1). 
Figure 1 
Study Design Flow Chart 
 
BOS=budesonide oral suspension; EGD=esophagogastroduodenoscopy; Enr=enrollment; ET=early termination; M=month; 
Scr=screening; V=visit 
Subjects will be evaluated for eligibility for participation in this continuation study at the 
screening visit (Visit 0) which will also coincide with the final treatment evaluation visit (Visit 8) 
of SHP621-302. Subjects who consent and meet eligibility criteria at Visit 0 will enter the open-
label treatment period in SHP621-303. Subjects may be enrolled and treated prior to receipt of 
results from SHP621-302 Visit 8 assessments, per investigator discretion; however, if they are 
subsequently determined to no longer meet eligibility criteria, they must be discontinued. Dose 
interruptions starting at the time of completion of the SHP621-302 study, due to administrative 
or other reasons, will be permitted; however, dosing should be reinitiated within 3 months of 
completion of treatment in SHP621-302 unless discussed prospectively with the medical monitor. 
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BOS treatment may be adjusted by a dose regimen change from 2 mg twice-daily to 2 mg once-
daily (qAM, pc) or by treatment interruption (with resumption of treatment and/or increase in 
the BOS dose regimen to 2 mg twice daily permitted at a later date while on study). Interruptions 
of up to 6 months are allowed. 
Continued participation in the study (i.e., completion of scheduled study assessments) is required 
to resume BOS treatment. Subjects who are discontinued from the study may not reinitiate BOS 
treatment.  
Subjects who withdraw from the study will receive a follow-up telephone call 4 weeks post last 
dose of BOS to query for serious adverse events (SAEs), adverse events (AEs), and concomitant 
treatments. If a subject discontinues from the study prematurely or transitions to commercial 
product upon availability, the assessments for Visit 12 are to be performed as completely as 
possible. Subjects who discontinue (i.e., positive result on serum pregnancy test) will not be 
replaced. 
2.2  
Randomization 
Randomization is not applicable for this open-label single arm study. 
2.3  
Blinding  
This is an open-label study. Blinding is not applicable. 
2.4  
Schedule of Assessments 
Table 1 presents the schematic of the study design.
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26 Jan 2021 
 
Table 1 
Schedule of Assessment 
Procedures 
 
Open-label Treatment Phase 
Safety 
Follow-
Up 
Phone 
Contactr 
 
Visit 
0a 
 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
Visit 
10 
 
Visit 
11 
Visit 
12 
ETq 
 
 
Visit 13 
Months 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
73 
Window 
 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±3 days 
Informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb; 
heightc, and weightd 
assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EGD with 
 
and 
bi
e
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
EQ-5Df 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PedsQL-EoE 
(subjects 11 to 
17 years of 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EoE-QoL-A 
(subjects ≥18 
years of age) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
PGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Table 1 
Schedule of Assessment 
Procedures 
 
Open-label Treatment Phase 
Safety 
Follow-
Up 
Phone 
Contactr 
 
Visit 
0a 
 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
Visit 
10 
 
Visit 
11 
Visit 
12 
ETq 
 
 
Visit 13 
Months 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
73 
Window 
 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±3 days 
Physical 
examinationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tanner 
staging 
assessmenti
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical 
laboratory 
j
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Morning cortisol 
(target 6:00-9:00 
am) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ACTH 
stimulation 
testingm 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
DXA Scan 
(subjects 11 to 17 
years of age)n 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
BOS suppliedo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
BOS administrationp 
Twice-daily administration 
 
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Table 1 
Schedule of Assessment 
Procedures 
 
Open-label Treatment Phase 
Safety 
Follow-
Up 
Phone 
Contactr 
 
Visit 
0a 
 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
Visit 
10 
 
Visit 
11 
Visit 
12 
ETq 
 
 
Visit 13 
Months 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
73 
Window 
 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±3 days 
BOS compliance 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of 
concomitant 
medications and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH=adrenocorticotropic hormone; DXA=dual-energy X-ray absorptiometry; EGD=esophagogastroduodenoscopy; EoE-QoL-A=Adult Eosinophilic 
Esophagitis Quality of Life; EQ-5D=EuroQol; EQ-5D-3L=EuroQol-5 Dimension 3-level; EQ-5D-Y=EuroQol-5 Dimensions Youth;
 hs=at bedtime; IWRS=interactive web-based response system; PedsQL-EoE=Pediatric Quality of Life Inventory – EoE; 
pc=after meals; PGI-S=Patient Global Impression of Severity; qAM=every morning 
a 
The assessments from the final treatment evaluation visit (Visit 8) in SHP621-302 will be used to determine eligibility for participation in this 
continuation study. Subjects may be enrolled and treated prior to receipt of results from SHP621-302 Visit 8 assessments, per investigator discretion; 
however, if they are subsequently determined to no longer meet eligibility criteria, they must be discontinued.  
b 
Vital signs will be assessed after the subject has been resting (and in a supine position for Visit 0 only) 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 measurements for adolescents (11-17 years, inclusive) should be measured in triplicate using stadiometers at every visit. Height 
measurement for adults is required at Visits 2, 4, 6, 8, 10, and 12 only. 
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Table 1 
Schedule of Assessment 
Procedures 
 
Open-label Treatment Phase 
Safety 
Follow-
Up 
Phone 
Contactr 
 
Visit 
0a 
 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
Visit 
10 
 
Visit 
11 
Visit 
12 
ETq 
 
 
Visit 13 
Months 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
73 
Window 
 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±3 days 
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. Unscheduled endoscopies 
may be performed at the discretion of the investigator to assess relapse, to determine whether or not BOS treatment should be interrupted or restarted, 
or to adjust BOS dose.  Endoscopy does not have to be completed at scheduled visit if unscheduled endoscopy was performed within 3 months of the 
scheduled visit (i.e., 3 months before or after Visit 2, 4, 6, 8, or 10). If an unscheduled endoscopy is performed within 3 months of Visit 12 or ET, the 
Visit 12 (or ET) endoscopy does not need to be completed if discussed prospectively with the medical monitor and determined to be unnecessary. 
f 
Subjects 11-17 years of age, inclusive, at the time of consent into the SHP621-301 study, will complete the EQ-5D-Y throughout study 
participation; subjects ≥18 years of age (at the time of consent into the SHP621-301 study) will complete the EQ-5D-3L. 
g 
Subjects 11-17 years of age, inclusive, at the time of consent into the SHP621-301 study will complete the PedsQL-EoE throughout study participation. 
h 
Physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, 
insomnia, and depression). 
i 
Tanner staging assessments will be performed for all subjects ≥11 years of age until investigator confirms subject is post puberty. 
j 
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. 
k 
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase. 
l 
Serum pregnancy tests will be performed for all female subjects at Visit 8 of SHP621-302. All females with a positive pregnancy test will be discontinued 
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Table 1 
Schedule of Assessment 
Procedures 
 
Open-label Treatment Phase 
Safety 
Follow-
Up 
Phone 
Contactr 
 
Visit 
0a 
 
Visit 
1 
 
Visit 
2 
 
Visit 
3 
 
Visit 
4 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
Visit 
10 
 
Visit 
11 
Visit 
12 
ETq 
 
 
Visit 13 
Months 
0 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
66 
72 
73 
Window 
 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±4 
weeks 
±3 days 
from the study. Urine pregnancy tests will be performed at subsequent scheduled visits starting with Visit 1 for all female subjects during the conduct of 
SHP621-303. 
m 
Unscheduled ACTH stimulation tests may be performed at the investigator’s discretion. 
n 
Dual-energy X-ray absorptiometry scans should be performed using the same machine and software as used in the SHP621-301 and SHP621-302 studies. 
o 
Investigational product may be supplied at unscheduled visits given the long duration in between scheduled visits and to assess subjects for 
treatment interruption or reinitiation. 
p 
Subjects will receive oral administration of 10 mL of BOS twice-daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 30 minutes 
after investigational product administration. At the investigator’s discretion, administration may be stopped (allowable up to 6 months) and/or stopped 
and reinitiated. Dose interruptions (up to 3 months) due to administrative or other reasons will also be allowed at the time of completion of the 
SHP621-302 study. In such instances, unscheduled safety and efficacy assessments may be required prior to dispensing study drug considering the 
time off of investigational treatment and the study schedule. 
q 
If subject discontinues study prematurely or transitions to commercial product upon availability, the evaluations listed for Visit 12 should be 
performed as soon as possible. 
r 
For subjects who withdraw from the treatment period, a safety follow-up contact by telephone will be performed 4 weeks following the last dose of BOS 
 
.
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3.  STATISTICAL HYPOTHESES AND DECISION RLUES 
This section is not applicable because the statistical objective of this study does not involve any 
inference, but only estimation. 
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4.  
SAMPLE-SIZE DETERMINATION 
The primary analysis for the study does not involve any statistical inference. Consequently, the 
sample size was determined based on feasibility considerations instead of a formal statistical 
evaluation. Approximately 100 subjects who complete the SHP621-302 extension study are 
anticipated to enroll into this open-label continuation study. 
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5.  
ANALYSIS SETS 
5.1  
Screened Set  
The Screened Set will consist of all subjects who, upon completion of study SHP621-302, have 
signed informed consent and have conducted screening assessments. 
5.2  
Enrolled Set 
The Enrolled Set will consist of all subjects who have signed informed consent excluding screen 
failures. 
5.3  
Safety Analysis Set 
The safety set will consist of all subjects who received at least 1 dose of BOS. The Safety Set will 
be used for the primary safety analysis. 
5.4  
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all subjects who are enrolled in the study and receive 
at least 1 dose of BOS. 
 
 
5.5  
Treatment Group 
Based on treatment in SHP621-301, SHP621-302, and SHP621-303, the overall treatment 
integration can be categorized as the following: 
A. BOS-BOS-BOS (subjects who were randomized to BOS treatment in SHP621-301, 
continuously randomized to BOS in SHP621-302, and enrolled in SHP621-303 with 
BOS) 
B. BOS-PBO-BOS (subjects who were randomized to BOS treatment and fully responded to 
treatment in SHP621-301, randomized to placebo (PBO) in SHP621-302, and enrolled in 
SHP621-303 with BOS) 
C. PBO-BOS-BOS (subjects who were randomized to placebo in SHP621-301, assigned to 
BOS in SHP621-302, and enrolled in SHP621-303 with BOS) 
D. BOS-PBO-BOS-BOS (subjects who were randomized to BOS treatment and fully 
responded to treatment in SHP621-301, randomized to placebo treatment in SHP621-302, 
but relapsed during the randomized withdrawal and reinitiated treatment with BOS 
(intermittent therapy) in SHP621-302, and enrolled in SHP621-303 with BOS) 
The majority of the data display will be presented by the following in SHP621-303: 
• BOS-BOS: Group A, C and D 
• PBO-BOS: Group B 
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• Total: Combine both BOS-BOS and PBO-BOS  
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6.  
STATISTICAL ANALYSIS  
6.1  
General Considerations 
Continuous variables will be summarized using the following descriptive statistics: n, mean, SD, 
median, Q1, Q3, minimum, and maximum. Categorical and count variables will be summarized 
by the number of subjects (n) and the percent of subjects in each category. 
Unless specified otherwise, min/max will be presented to the same decimal places as the raw 
data. Percentage, mean, and median will be presented to 1 more decimal place than the raw data. 
Standard deviation and standard error will be presented to 2 more decimal places than the raw 
data. 
Body mass index (BMI) should be rounded to 1 decimal place for reporting. 
Derived questionnaire scores, and other similar efficacy parameters recorded as integers, should 
be rounded to 1 decimal place for reporting. 
Averaged laboratory and vital sign results eg, diastolic/systolic blood pressure and pulse (when 
taken in triplicate) should be rounded to 1 decimal place for reporting. 
Baseline of this study is determined using the screening visit (Visit 0, also Visit 8 of 
SHP621-302) or the last observation prior to the first dose of BOS in SHP621-303, whichever is 
later. 
Baseline of SHP621-302 is determined using the last assessment prior to the first dose of 
investigational product in SHP621-302. 
Baseline of SHP621-301 is determined using the last assessment prior to the first dose of 
investigational product in SHP621-301. 
Discontinuation of Study Treatment 
6.2  
Discontinuation of Study Treatment 
In the disposition summary table, the number of subjects in each defined analysis set (i.e., 
Screened, Enrolled, FAS, and Safety) will be included. The number and percentage of subjects 
who completed each visit, who completed the study, and those who prematurely discontinued 
from the study will be presented for the Screened Set. The study completion includes the 
completion of the final protocol-defined assessment and follow-up visit or contact. Reasons for 
premature discontinuation from the study as recorded on the study completion page of the eCRF 
will be summarized (number and percentage). All subjects who prematurely discontinued will be 
listed by discontinuation reason for the Safety Set and the Screened Set. 
The number of subjects who were screened, enrolled, and completed will be tabulated by site. In 
addition, the duration of enrollment, in days, will be summarized for each site. Duration of 
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enrollment will be calculated as (last date of contact for any subject at that site - the first date of 
informed consent for any subject at that site +1). 
The number and percentage of subjects reporting any protocol deviations and the incidence of 
each deviation type will be summarized. All reported protocol deviations will be presented in a 
data listing with major/minor severity for the Screened Set. Protocol deviations will be 
summarized by deviation level (major or minor) and by type (International Council for 
Harmonisation [ICH]/Good Clinical Practice [GCP] or Protocol Deviation) within each deviation 
level. All protocol deviations related to the COVID-19 pandemic will be listed separately. 
6.3  
Demographic and Other Baseline Characteristics 
6.3.1  
Demographics 
Demographic and other baseline characteristics will be summarized using descriptive statistics. 
The FAS will be used when summarizing demographic and baseline characteristics.  
Continuous variables will be summarized by descriptive statistics including number of subjects, 
mean, standard deviation (SD), median, Q1, Q3, minimum, and maximum. Categorical variables 
will be summarized by the count of subjects in each category and the percentage of subjects out 
of the total in the respective analysis set. 
Baseline characteristics will be obtained using assessments at the screening visit in SHP621-303.  
The demographic characteristics to be summarized (in the order shown) are: age (years), age 
category (<18 years, ≥18 years), sex, ethnicity, and race. 
 The following baseline characteristics will be summarized in the order shown: weight (kg), 
height (cm), BMI (kg/m2), Tanner stage, 
 
 final histology response in SHP621-302, 
treatment in SHP621-301, and treatment in SHP621-302.   
If there are multiple measurements of weight and height collected on the same visit (e.g., 
adolescent subjects), the average of multiple measurements will be presented.  
Age category is based on age at the SHP621-303 informed consent. Age is calculated as the 
difference between date of birth and date of the SHP621-303 informed consent: 
• Age = (date of informed consent – date of birth+1)/365.25. 
Height and weight will be used to calculate BMI using the formula below: 
• BMI = weight [kg]/(height [m])2.  
Subject-level listings will generated displaying the demographics and baseline characteristics for 
each subject subjects. 
PI
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6.3.2  
General 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 SHP621-302 final treatment evaluation visit (Visit 8). Adverse events recorded 
during the SHP621-302 study may be added as medical history at the investigator’s discretion. 
The medical history will be summarized by system organ class (SOC) and preferred term (PT) 
for the Safety Set. General medical history findings will also be listed for all subjects for the 
Safety Set. Medical history will be coded using MedDRA Version 18.0 or higher. 
6.3.3  
Interim EoE Medical History 
The following information associated with interim EoE history will be recorded in the eCRF at 
the screening visit: 
• Any changes in diet since the screening visit in the SHP621-302 study (yes/no answer). 
• Any changes in medical treatment for EoE since the screening visit in the SHP621-302 
study (yes/no answer). 
 Interim EoE history will be summarized and listed for the Safety Set.  
6.4  
Medication History and Concomitant Medications  
The World Health Organization-Drug Dictionary (WHODRUG) as of March 2015 or higher 
version will be used to classify prior and concomitant medications by therapeutic class. 
Both prior and concomitant medication usage and medical/surgical procedures will be 
summarized by the number and proportion of subjects in each treatment group receiving each 
medication/procedure for the Safety Set. Procedures can be counted both as prior and 
concomitant. Multiple medication/procedure received by a subject in the same category will be 
counted only once. 
All prior and concomitant medications and medical/surgical procedures will be listed for the 
FAS. 
6.4.1  
Prior Medications 
The prior medication is defined as any medication with the end date prior to the informed 
consent date of the SHP621-303 study. 
Medical/surgical procedures performed prior and during the treatment period will be recorded on 
the eCRF, along with the date and reason for the procedure. The prior medical/surgical procedure 
is defined as any procedure with the start date prior to the informed consent date of the 
SHP621-303 study.  
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6.4.2  
Concomitant Medications 
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of BOS in SHP621-303 (Visit 0) and continuing after the first dose of BOS in 
SHP621-303 (Visit 0) or with a start date between the dates of the first dose of BOS in 
SHP621-303 (Visit 0) and the Safety Follow-up Contact, or 31 days after the last dose of BOS 
for subjects who do not have a Safety Follow-up Contact.  
The concomitant medical/surgical procedure is defined as any procedure with the start date 
between the first dose of BOS (Visit 0) and the last dose of BOS in SHP621-303. 
6.5  
Efficacy Analysis 
There are no primary or secondary efficacy for SHP621-303. 
 
The most recent non-missing measurement 
(scheduled or unscheduled) collected prior to first dose of investigational product administered 
(based on dates or date/times) will be used as the baseline for all efficacy analyses. The baseline 
of SHP621-301, the baseline of SHP621-302 , and the baseline of this SHP621-303 study will be 
used in the efficacy summary. 
6.5.1  
Primary Efficacy Endpoint Analysis 
Not applicable. 
6.5.2  
Secondary Efficacy Endpoint Analysis 
Not applicable. 
6.5.3  
Exploratory 
 Endpoints and Analyses  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
PI
PI
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6.5.4  
Subgroup Analyses  
 
 
 
 
 
 
 
 
 
6.6  
Safety Analysis 
The safety analysis will be performed using the Safety Set. Safety variables include adverse 
events (AEs), physical examinations, tanner staging, vital signs (temperature, systolic and 
diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA scans 
for BMD (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-score using the Bone Mineral Density in Childhood Study. 
Continuous safety parameters will be descriptively summarized at baseline of SHP621-303 and 
for each postbaseline visit. The assessment done at screening visit (Visit 0) of the SHP621-303 
study or the last assessment prior to the first dose of investigational product will be used as 
baseline of SHP621-303. 
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Both SHP621-301 and SHP621-303 study baselines will be used for safety analyses. 
6.6.1  
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 18.0 or higher. 
All AEs will be collected from the time of the informed consent through the completion of the 
SHP621-303 study’s post-treatment follow-up as described below. For eligible subjects from 
SHP621-302 who consent to participate in SHP621-303, AEs will be collected in the 
SHP621-302 clinical database up to the date of the first dose of SHP621-303 investigational 
product (i.e., Visit 0 in the SHP621-303 study) or the Safety Follow-up Contact for subjects who 
screen fail prior to enrolling in SHP621-303. Adverse events that have a start date on or after the 
informed consent of SHP621-303 study will be collected in the SHP621-303 database. Adverse 
events which start during SHP621-302 and remain ongoing until informed consent is signed for 
SHP621-303 will be recorded in the SHP621-302 clinical and safety databases and as ongoing 
AEs in the SHP621-303 database. 
Pretreatment AEs are defined as AEs with a start date prior to the informed consent date of 
SHP621-303. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that start or deteriorate on or 
after the time the informed consent is signed and 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. However, for any subjects who dies during the study (i.e., 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.   
An overall summary of the number of participants in the Safety Set with AEs will be presented, 
including the number and percentage of participants with AEs, pretreatment AEs, any TEAEs, 
serious TEAEs, severe TEAEs, life-threatening TEAEs, TEAEs related to investigational 
product, TEAEs related to EoE, deaths and hospitalizations due to TEAEs, TEAEs leading to 
discontinuation of investigational product, and TEAEs leading to study discontinuation. 
The number, and percentage of subjects reporting TEAEs will be tabulated by system organ class 
(SOC)/preferred term, and maximum severity. Serious TEAEs, TEAEs related to investigational 
product, and TEAEs related to EoE will also be summarized by SOC and preferred term. If more 
than 1 AE occurs with the same preferred term for the same subject, the subject will be counted 
only once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to investigational product. 
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The incidence of most common TEAEs (≥5% of subjects) will be summarized by preferred term. 
6.6.2  
Adverse Events of Special Interest 
Adverse events of special interest (AESI) will be summarized. The AESIs are defined in 
Section 9.3. The following analyses for treatment-emergent AESIs will be performed for the 
Safety Set: 
• Incidence of treatment-emergent AESIs 
• Number and percentages of subjects by preferred terms 
• Number and percentages of subjects by maximum severity 
• Serious treatment-emergent AESIs  
• Drug-related serious treatment-emergent AESIs  
• Treatment-emergent AESIs leading to discontinuation of investigational product 
• Treatment-emergent AESIs leading to death 
6.6.3  
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in both SI units and conventional units), 
changes from baseline of SHP621-303 and changes from baseline of SHP621-301 at each 
assessment time point, and shift tables from baseline of SHP621-303 as well as shift tables from 
baseline of SHP621-301 to each visit for quantitative variables will be presented for the 
following clinical laboratory variables. All laboratory data will also be listed. 
Hematology 
hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, mean corpuscular volume, erythrocyte count, 
leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and platelet count. 
Biochemistry 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
total bilirubin, total protein, albumin, glucose, blood urea nitrogen, 
creatinine, sodium, potassium, chloride, calcium, carbon dioxide. 
Urinalysis 
glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, 
hemoglobin, urobilinogen, and leukocyte esterase. 
Other tests 
urine pregnancy, morning cortisol (6:00-9:00 AM collection), ACTH  
stimulation testing (serum cortisol collections at 30 and 60 minutes after 
synthetic ACTH injection in addition to baseline collection at 6:00-9:00 AM). 
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Pregnancy test results will only be listed. Serum pregnancy tests are performed on all female 
subjects at Visit 8 of the SHP621-302 study. Urine pregnancy tests are performed on all female 
subjects at all visits starting with Visit 1 during the conduct of SHP621-303 study. 
Adrenocorticotropic hormone stimulation testing (ACTH) will be performed by measuring the 
levels of cortisol in the blood following the injection of a synthetic form of ACTH (250 mcg). 
The type of synthetic and route of administration will be per investigator discretion. Blood 
samples will be collected just prior to and approximately 30 and 60 minutes following the 
injection at the screening visit (Visit 0), Visit 2, Visit 4, Visit 6, Visit 8, Visit 10 and Visit 12. 
Unscheduled ACTH stimulation tests may be performed at the investigator’s discretion between 
scheduled visits. 
All laboratory data will be listed for the Safety Set. 
6.6.4  
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, heart rate, respiration 
rate, temperature, BMI, and weight) and their changes from baseline at each postbaseline visit 
and at the end of study will be presented. Weight will be collected at every visit for all subjects. 
Height for adolescents (11–17 years of age, inclusive, at the time of the SHP621-301 study 
consent) will be collected at every visit. Height for adults will be collected at Visits 2, 4, 6, 8, 10, 
and 12 only.  
For adolescents (11–17 years of age, inclusive), 2 weight measurements per visit will be 
recorded, and 3 height measurements per visit using stadiometers will be collected. The average 
weight and average height per visit will be used in summary tables for adolescents. 
For the growth parameters (height, weight, and BMI), the changes from baselines (both 
SHP621-301 and SHP621-303) will be summarized by age group (<18 years or ≥18 years, at the 
time of SHP621-301 informed consent). The z-scores for growth parameters will be summarized 
descriptively at each visit for adolescents based on the subject’s age at each visit. 
Z-scores will be derived using the CDC growth charts (Kuczmarski et al., 2002). A SAS program 
for the 2000 CDC Growth Charts will be used to derive the percentiles and z-scores 
(www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm). 
All vital signs data will be listed for the Safety Set. 
6.6.5  
Physical Examination 
Physical examination assessments at each visit will include specific assessments for signs of 
glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swing, insomnia, and depression). 
Tanner staging assessments will be performed for all subjects <18 years of age until investigator 
confirms subject is post puberty. The number and percentage of subjects reporting symptoms 
described above will be presented by visit. 
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6.6.6  
Dual-energy X-ray Absorptiometry for Bone Mineral Density 
DXA (also referred to as DEXA) scans for determination of BMD and body composition will be 
performed in subjects aged 11–17 years, inclusive, at the screening visit (Visit 0), Visit 2, 
Visit 4, Visit 6, Visit 8, Visit 10, and Visit 12. The sites for DXA measurement will be the 
lumbar spine (L1–L4 preferred) and total body less head. To account for the effects of puberty in 
adolescent subjects (11–17 years of age, inclusive), BMD z-scores will be adjusted for height in 
the following manner. The subject’s height is compared to the 50th percentile on the CDC 
growth chart. The age on the CDC growth chart where the subject’s height is equal to the 50th 
percentile height on the growth chart will be used in lieu of the subject’s actual age to calculate a 
“height-adjusted” BMD z-score. For example, if a 10-year-old boy is 125 cm tall, according to 
the CDC growth chart for boys aged 2–20 years, 125 cm is the median height for a 7.5-year-old 
boy. When calculating the height-adjusted BMD z-score, an age of 7.5 years will be used rather 
than the boy’s actual age of 10 years. Mean z-scores at scheduled assessments and mean 
within-subjects changes from baselines (both SHP621-301 and SHP621-303) will be calculated 
for the DXA z-scores.  
Summary of baselines (both SHP621-301 and SHP621-303) and change from baselines of 
z-scores adjusted for height at Visit 0 (Month 0), Visit 2 (Month 12), Visit 4 (Month 24), Visit 6 
(Month 36), Visit 8 (Month 48), Visit 10 (Month 60), and Visit 12 (Month 72) will  be presented 
in a table by location of DXA. Measurements at each scheduled visit will also be listed. 
6.6.7  
Extent of Exposure and Compliance 
Exposure to Investigational Product: 
Exposure to investigational product for the Safety Set will be summarized in terms of treatment 
duration, which is calculated as the number of weeks from the date of first dose of 
investigational product taken to the date of the last dose of investigational product taken 
excluding treatment interruption, inclusively. BOS treatment may be adjusted by a dose regimen 
change between 2 mg twice-daily and 2 mg once-daily (qAM, pc) or by treatment interruption 
(with resumption of treatment and/or increase in the BOS dose regimen to 2 mg twice-daily 
permitted at a later date while on study). BOS treatment may be interrupted by stopping and 
planning to reinitiate investigational product treatment up to 6 months. Investigational product 
must be resumed within 6 months and multiple treatment interruptions are permitted throughout 
study participation (i.e., 3 months on and 3 months off treatment). No fixed duration of subject 
participation is specified. Subjects may participate in the study for up to 6 years or until 
commercial product is available. 
For all treated subjects, including those who terminated early, treatment exposure is the duration 
between the first dose date and last dose date excluding all treatment interruptions: 
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• Duration of the 1st interruption (days)  = Last date of 1st treatment interruption – First date 
of 1st treatment interruption +1 
• Duration of the 2nd interruption (days) = Last date of 2nd treatment interruption – First 
date of 2nd treatment interruption +1 
• Duration of the nth interruption (days) = Last date of nth treatment interruption – First date 
of nth treatment interruption +1 
• Total days of treatment interruption = Duration of the 1st interruption + Duration of the 
2nd interruption + … + Duration of the nth interruption 
• Duration of exposure (days) = Last dose date - First dose date + 1 - Total days of 
treatment interruption 
• Length of Exposure (weeks) = Duration of exposure (days)/7 
In addition, total dose administered (mL) and average daily dose will be calculated and 
summarized: 
• Actual Average Daily Dose (mL/day) = Sum of the doses (mL)/Duration of exposure 
(days).  
Continuous variables will be summarized by descriptive statistics (n, mean, SD, Q1, Q3, 
minimum, median, and maximum) for total dose, duration of exposure and average daily dose. 
Categorical variables will be summarized by the number of subjects in each category and the 
percentage of subjects out of the total for categories of length of exposure in weeks (0 to 
≤24, >24 to ≤48, >48 to ≤72, >72 to ≤96, >96 to ≤120, >120 to ≤168,  >168 to ≤216, >216 to 
≤264, and >264) for all subjects in the Safety Set. 
A listing will be created by subject number and visit giving the date and time of dose 
administration for the Safety Set. 
Measurements of Treatment Compliance: 
Compliance with investigational product will be assessed across all study visits. Subjects will be 
instructed to bring any remaining investigational product and empty bottles to each study visit. 
Designated site staff will evaluate compliance by questioning the subject and evaluating the 
amount of investigational product remaining. The subject will be questioned regarding any 
discrepancies. If BOS is discontinued at the investigator's discretion (for potential resumption 
later), the investigational product interruption period will not be counted in compliance 
determination. 
When a bottle is returned, the site will measure the amount of investigational product remaining 
in the bottle in centimeters and the remaining amount will be recorded as 9.375 cm if the 
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measured amount in the bottle is >9.375 cm. The volume taken in mL for each bottle will be 
determined in centimeters based on the equation below: 
• Volume in mL = 210 cm3 – [22.4 cm2 × height of remaining product cm]. 
The percent compliance at each study visit will be determined as follows: 
• (volume of investigational product taken in all returned bottles)/(expected volume of 
investigational product to be taken).  
Compliance rate calculation will be based on the actual dose regimen.  
Subjects will be considered compliant with investigational product if they received no less than 
70% and no more than 130% of the intended dosing as assessed during the treatment period. 
Study drug exposure and overall compliance will be summarized for the Safety Set. The number 
and percentage of subjects whose compliance is <70% or >130% as well as between 70% and 
130% will be summarized. The overall approximate compliance rates will be summarized using 
descriptive statistics for the Safety Set. 
6.7  
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
Not applicable. 
6.8  
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints Analysis 
Not applicable. 
6.9  
Other Analyses 
All other analyses will be performed using the FAS. 
 
 
  
6.9.1  
Health-related Quality of Life Analyses 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire 
The EoE-QoL-A will be performed in subjects ≥18 years of age at all scheduled visits, from 
screening visit (Visit 0) to the last visit in the treatment period. 
The EoE-QoL-A is a disease-specific measure of HRQoL in adult patients (≥18 years of age) 
with EoE (Taft et al., 2011). The EoE-QoL-A consists of a 30-item test with 5 subscales: 
eating/diet impact, social impact, emotional impact, disease anxiety, and swallowing anxiety.  
Results of the EoE-QoL-A questionnaire will be summarized for each of the 
5 scales/30 questions by presenting number of subjects and percentages at all scheduled visits.  
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Summary of change from baseline at all scheduled visits in EoE-QoL-A total score and each of 
the subscales will also be presented. Refer to Section 9.4 for derivation of EoE-QoL-A subscale 
scores. 
EuroQol-5 Dimensions 3-level Questionnaire  
The EuroQol-5D Dimensions 3-level (EQ-5D-3L; for subjects ≥18 years) and the EuroQol-5 
Dimensions Youth (EQ-5D-Y; for subjects 11–17 years of age, inclusive) will be performed 
during the study at all scheduled visits, from screening visit (Visit 0) to Visit 12.  
Subjects who turn 18 over the course of the study (i.e., after providing consent for SHP621-303), 
will continue to fill out the same questionnaire for continuity of data collection.  
The EQ-5D-3L is a standardized measure of health status for use in adult populations that was 
developed by the EuroQol Group in order to provide a simple, generic measure of health for 
clinical and economic appraisal (EuroQol, 1990). The EQ-5D-3L provides a simple descriptive 
profile and a single index value for health status that can be used in the clinical and economic 
evaluation of healthcare as well as in population health surveys. It consists of a 5-item 
descriptive system that measures 5 dimensions of health, including mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension is represented by a single 
item with 3 levels of responses. The EQ-5D-3L will be completed by the subject.  
The EQ-5D-Y is a self-report version of the EQ-5D that was developed by the EuroQol Group 
for use in younger populations (Wille et al., 2010). The EQ-5D-Y provides a simple descriptive 
profile and a single index value for health status that can be used in the clinical and economic 
evaluation of healthcare as well as in population health surveys. It consists of a 5-item 
descriptive system that measures 5 dimensions of health, including mobility, looking after 
myself, doing usual activities, having pain or discomfort, and feeling worried, sad, or unhappy. 
Each dimension is represented by a single item with 3 levels of responses. 
Results of both EQ-5D-3L and EQ-5D-Y descriptive system instruments will be summarized 
separately on each question by presenting number of subjects and percentages for all visits. 
Visual Analog Scale (VAS) at baseline and at each scheduled visit, and change from baseline at 
each scheduled visit will be summarized using the following descriptive statistics: the number of 
subjects, mean, standard deviation, standard error, minimum value, 25th percentile, median, 75th 
percentile, and maximum value. 
Descriptive summary of EQ-5D-3L composite index score at each scheduled visit from screening 
and change from baseline at each scheduled visit will also be presented. Refer to Section 9.6 for 
derivation of EQ-5D-3L composite index score. 
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Pediatric Quality of Life – EoE Questionnaire 
The PedsQL-EoE questionnaire will be completed by subjects 11–17 years of age, inclusive, and 
their parent or legal guardian at all scheduled visits, from screening visit (Visit 0) to Visit 12. 
Subjects who turn 18 over the course of the study will continue to fill out the same questionnaire 
for continuity of data collection. 
The PedsQL-EoE is a modular, disease-specific instrument designed to measure HRQoL in 
children and adolescents (2–18 years of age) with EoE (Franciosi et al., 2013). The PedsQL-EoE 
module consists of 35 items for children and teenagers encompassing the following 7 scales: 
1) Symptoms I (6 items; chest/throat/stomach pain and nausea/vomiting), 2) Symptoms II 
(4 items; trouble swallowing), 3) Treatment (5 items; treatment barriers), 4) Worry (6 items; 
worries about treatment and disease), 5) Communication (5 items; communication with others 
about EoE), 6) Food and Eating (4 items; food and eating allergies and limitations), and 7) Food 
Feelings (3 items; emotions associated with food allergies).  
Results of the PedsQL-EoE report (adolescents and parents separately) questionnaire will be 
summarized for each of the 7 scales/questions by presenting number of subjects and percentages 
for all visits. 
Summary of change from baseline at all visits in PedsQL-EoE total score (adolescents and 
parents separately) and each of subscales will also be presented. Refer to Section 9.5 for 
derivation of PedsQL-EoE total and subscale scores. 
Patient Global Impression of Severity (PGI-S) 
The PGI-S is a global index that can be used to rate the severity of a specific condition - in this 
case, dysphagia in EoE. The PGI-S will be performed in all subjects at every visit starting at 
screening visit (Visit 0) through the last visit in the open-label treatment phase. Subjects will be 
asked to rate the severity of their dysphagia over the last 7 days using a 5-point scale at each 
visit: 
• No dysphagia (0) 
• Mild dysphagia (1) 
• Moderate dysphagia (2) 
• Severe dysphagia (3) 
• Very severe dysphagia (4) 
Change from baseline in PGI-S value at each assessment visit will be calculated as PGI-S at each 
assessment visit. Negative change from baseline value will indicate an improvement of 
dysphagia symptoms while a positive change from baseline value will indicate worsening of the 
symptoms. 
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Responses of the PGI-S will be summarized by presenting number of subjects and percentages 
by visit. Frequency of PGI-S at baseline and each postbaseline assessment and the change from 
baseline values will be summarized. 
6.10  Interim Analyses 
No interim analyses are planned.  
Details on the statistical methods used for interim summaries generated for inclusion in 
regulatory filings (including safety updates) are provided in a separate Integrated Summary of 
Safety Statistical Analysis Plan (ISS SAP). 
6.11  Data Monitoring Committee/Internal Review Committee/Other Data Review 
Committees 
Not applicable. 
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7.  
REFERENCES 
EuroQol 1990. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy, 16, 199-208. 
Franciosi, J. P., Hommel, K. A., Bendo, C. B., King, E. C., Collins, M. H., Eby, M. D., Marsolo, 
K., Abonia, J. P., von Tiehl, K. F., Putnam, P. E., Greenler, A. J., Greenberg, A. B., 
Bryson, R. A., Davis, C. M., Olive, A. P., Gupta, S. K., Erwin, E. A., Klinnert, M. D., 
Spergel, J. M., Denham, J. M., Furuta, G. T., Rothenberg, M. E. & Varni, J. W. 2013. 
PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity. J Pediatr 
Gastroenterol Nutr, 57, 57-66. 
Kuczmarski, R. J., Ogden, C. L., Guo, S. S., Grummer-Strawn, L. M., Flegal, K. M., Mei, Z., 
Wei, R., Curtin, L. R., Roche, A. F. & Johnson, C. L. 2002. 2000 CDC Growth Charts for 
the United States: methods and development. Vital Health Stat 11, 1-190. 
Shaw, J. W., Johnson, J. A. & Coons, S. J. 2005. US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model. Med Care, 43, 203-20. 
Taft, T. H., Kern, E., Kwiatek, M. A., Hirano, I., Gonsalves, N. & Keefer, L. 2011. The adult 
eosinophilic oesophagitis quality of life questionnaire: a new measure of health-related 
quality of life. Aliment Pharmacol Ther, 34, 790-8. 
Wille, N., Badia, X., Bonsel, G., Burström, K., Cavrini, G., Devlin, N., Egmar, A. C., Greiner, 
W., Gusi, N., Herdman, M., Jelsma, J., Kind, P., Scalone, L. & Ravens-Sieberer, U. 2010. 
Development of the EQ-5D-Y: a child-friendly version of the EQ-5D. Qual Life Res, 19, 
875-86. 
 
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8.  
CHANGES TO PROTOCOL PLANNED ANALYSES 
Not applicable. 
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9.  
APPENDIX  
9.1  
Changes from the Previous Version of the SAP 
Not applicable. 
9.2  
Data Handling Conventions  
9.2.1  
General Data Reporting Conventions  
Continuous variables will be summarized using the following descriptive statistics: n, mean, SD, 
median, Q1, Q3, minimum, and maximum. Categorical and count variables will be summarized 
by the number of subjects (n) and the percent of subjects in each category. 
Unless specified otherwise, min/max will be presented to the same decimal places as the raw 
data. Percentage, mean, and median will be presented to 1 more decimal place than the raw data. 
Standard deviation and standard error will be presented to 2 more decimal places than the raw 
data. 
BMI should be rounded to 1 decimal place for reporting. 
Derived questionnaire scores, and other similar efficacy parameters recorded as integers, should 
be rounded to 1 decimal place for reporting. 
Averaged laboratory and vital sign results eg, diastolic/systolic blood pressure and pulse (when 
taken in triplicate) should be rounded to 1 decimal place for reporting. 
9.2.2  Definition of Baseline  
Baseline of SHP621-303 is determined using the screening visit (Visit 0, also Visit 8 of 
SHP621-302) or the last observation prior to the first dose of BOS in SHP621-303, whichever is 
later. 
Baseline of SHP621-302 is determined using the last assessment prior to the first dose of 
investigational product in SHP621-302. 
Baseline of SHP621-301 is determined using the last assessment prior to the first dose of 
investigational product in SHP621-301. 
9.2.3  Definition of Visit Windows 
Visit window will be applied for unscheduled assessments of EGD with 
 
 and biopsy. If the scheduled visits are missing for endoscopy, then the most closest 
unscheduled endoscopy which within 3 months will be mapped to the scheduled visits. 
9.2.4  Repeated or Unscheduled Assessments of Safety Parameters  
For safety parameters, the early termination visits will be mapped to the next scheduled visits. 
The last visits per subject will be summarized in “End of Study” visit, including both last visits 
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of completers and early termination visits. Repeated or unscheduled assessments of safety 
parameters will be handled as follows: 
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end of study assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the end of study assessment for generating descriptive statistics. If a 
subject has repeated assessments between the start of investigational product in the treatment 
period and the end of study visit, the assessments of unscheduled visits will be excluded in the 
table summary. However, all assessments will be presented in the data listings. 
9.2.5  
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the Safety 
Set, all efforts should be made to obtain the date from the investigator.  If it is still missing after 
all efforts, then the last visit date when investigational product was returned will be used in the 
calculation of treatment duration. 
9.2.6  
Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) 
For prior or concomitant medications (and/or therapies/procedures), including rescue 
medications, incomplete (i.e., partially missing) start date and/or stop date will be imputed.  
When the start date and the stop date are both incomplete for a subject, impute the start date first. 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields. If the stop date 
is complete and the imputed start date is after the stop date, then the start date will be 
imputed using the stop date. 
Missing day and month 
• If the year of the incomplete start date is the same as the year of the date of the first dose 
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields. 
• If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
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Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day. 
• If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day. 
• If either the year is after the year of the date of the first dose of investigational product or 
if both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of investigational product is missing, it will be replaced with the last visit date. If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. 
Missing day and month 
• If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields. 
• If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
 Missing month only 
• The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of investigational product, then the day of the date of the last 
dose of investigational product will be assigned to the missing day. 
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• If either the year is before the year of the date of the last dose of investigational product 
or if both years are the same but the month is before the month of the date of the last dose 
of investigational product, then the last day of the month will be assigned to the missing 
day. 
• If either the year is after the year of the last dose of investigational product or if both 
years are the same but the month is after the month of the date of the last dose of 
investigational product, then the first day of the month will be assigned to the missing 
day. 
9.2.7  Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates. Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol. If imputation of an incomplete stop date is required, and both the start date and the stop 
date are incomplete for a subject, the start date will be imputed first. 
Incomplete Start Date  
Follow the same rules as in Section 9.2.6. 
Incomplete Stop Date  
Follow the same rules as in Section 9.2.6. 
9.2.8  
Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while both the actual and the imputed values will be used in data listings. 
9.2.9  
Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “Related” will be assigned. The imputed 
values for relationship to investigational product will be used for incidence summaries, while 
both the actual and the imputed values will be presented in data listings. 
9.2.10  
Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, an alpha character string being reported for a numerical variable, the 
appropriately determined coded value will be used in the statistical analysis. However, the actual 
values as reported in the database will be presented in data listings. 
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Table 2 
Examples for Coding of Special Character Values for Clinical Laboratory 
Clinical Laboratory Test 
Possible Results 
(in SI units) 
Possible Results 
(in conventional units) 
Coded Value for 
Analysis 
Chemistry: ALT 
<5 U/L 
<5 U/L 
0 
Chemistry: AST 
<5 U/L 
<5 U/L 
0 
Chemistry: Total Bilirubin 
<2 umol/L 
<0.15 mg/dL 
0 
Urinalysis: Glucose 
≥50 mg/dL 
≥50 mg/dL 
Positive 
≤0 mg/dL 
≤0 mg/dL 
Negative 
Urinalysis: Ketones 
>0 mg/dL 
>0 mg/dL 
Positive 
Urinalysis: Protein 
>0 mg/dL 
>0 mg/dL 
Positive 
Urinalysis: pH 
≥9.0 
≥9.0 
9.0 
 
9.3  
AESI Categories 
The following AESIs are categorized with preferred terms (SOC where applicable) and will be 
summarized: 
• Infections: 
o System Organ Classes of infections and infestations 
o Candidiasis related: oesophageal candidiasis, oral candidiasis, candidiasis, 
oropharyngeal candidiasis, tongue fungal infection, vulvovaginal mycotic infection, 
anal candidiasis. 
• Potential systemic effects of corticosteroid use (including adrenal function): 
o Adrenal effects: adrenal suppression, adrenal insufficiency, ACTH stimulation test 
abnormal, and blood cortisol decrease or increase, blood cortisol abnormal, 
cushingoid 
o CNS/Mood effects: insomnia, mood swings, suicidal ideation, OCD, anxiety, 
depression, major depression, irritability, restlessness, sleep disorder, disturbance in 
attention, headache, dizziness, vertigo, lethargy, paraesthesia, hypoaesthesia, 
psychomotor hyperactivity 
o Metabolic effects: blood glucose increased, blood glucose abnormal, glucose 
intolerance impaired, diabetes mellitus, intraocular pressure increased, acne, weight 
increased, weight fluctuation, hepatic steatosis, hirsutism, dermatitis acneiform, skin 
striae, skin texture abnormal, obesity, menopausal symptoms, metrorrhagia 
o Cardiac effects: oedema peripheral, peripheral swelling, hypertension, palpitations 
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o Fractures: foot fracture, hand fracture, spinal fracture, upper limb fracture, humerus 
fracture, rib fracture, wrist fracture 
• GI  effects: 
o Oesophagitis pain, oesophagitis, vomiting, nausea, diarrhoea, abdominal pain, 
abdominal pain upper, constipation, abdominal distention, abdominal discomfort, 
hiatus hernia, dyspepsia, gastritis, gastritis erosive, chronic gastritis, dry mouth, 
erosive oesophagitis, and gastroesophageal reflux disease, mouth ulceration, gastric 
ulcer, duodenal ulcer, erosive duodenitis, mouth ulceration, esophageal ulcer, hepatic 
steatosis. 
9.4  
Calculation of Adult Eosinophilic Esophagitis Quality of Life  (EoE-QOL-A) 
Subscale Scores 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire Standard Version (30 items) 
The responses will be changed to a numeric equivalent using the following transformation: Not 
at all=4, Slightly=3, Moderately=2, Quite a Bit=1, Extremely=0. 
Subscales will be the sum of set questions: 
Eating/Diet Impact will be the sum of: Q2, Q9, Q16, Q24, Q25, Q26, Q27, Q28, Q29, Q30 and 
it will have a score range from 0–40. 
Social Impact will be the sum of: Q14, Q17, Q19, Q22 and it will have a score range from 0–16. 
Emotional Impact will be the sum of: Q1, Q5, Q6, Q7, Q11, Q13, Q21, Q23 and it will have a 
score range from 0–32. 
Disease Anxiety will be the sum of: Q4, Q10, Q12, Q15, Q18 and it will have a score range 
from 0–20. 
Swallowing Anxiety will be the sum of: Q3, Q8, Q20 and it will have a score range from 0–12. 
To compute subscale score, a weighted total sum will be used. Sum up the value of the response 
for each of the questions in that subscale and then divide by the total number of questions 
answered for that subscale. 
9.5  
Calculation of Pediatric Quality of Life – EoE (PedsQL-EoE, subjects 11–17 years 
of age) Subscale Scores 
Pediatric Quality of Life – EoE Questionnaire 
The responses will be transformed to a numeric equivalent using the following reverse scoring 
transformation: NEVER=100, ALMOST NEVER=75, SOMETIMES=50, OFTEN=25, 
ALMOST ALWAYS=0. 
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We will create dimensions by combining different questions to form the dimensions (Symptoms 
I, Symptoms II, Treatment, Worry, Communication, Food and Eating, Food Feelings, and 
Feeding Tube). Feeding Tube dimension will not be used for reporting or analyses. 
SYMPTOMS I will be the sum of CRF questions ("Burning in chest", "Chest pain, ache, or 
hurt", "Feel like Throwing up", "Food coming back up throat", "Stomach aches or belly aches", 
"Throwing up"). 
SYMPTOMS II will be the sum of CRF questions ("Need drink to help swallow food", 
"Needing more time to eat", "Trouble swallowing", "food stuck in throat or chest"). 
TREATMENT will be the sum of CRF questions ("Getting allergy testing", "Getting an 
endoscopy", "Going to the doctor", "Not wanting to take medicines", "Remembering to take 
medicines"). 
WORRY will be the sum of CRF questions ("Getting allergy testing", "Getting an endoscopy 
Worry", "Getting sick in front of other people", "Going to the doctor", "Having EoE", "other 
people think about me because of EoE"). 
COMMUNICATION will be the sum of CRF questions ("Tell people about EoE", "Telling 
adults how feels", "Telling nurses how feels", "Telling friends how feels", "Telling parents how 
feels"). 
FOOD AND EATING will be the sum of CRF questions ("following diet restriction", "not 
eating same as family", "not eating same as friends", "sneaking food") 
FOOD FEELINGS will be the sum of CRF questions ("Feeling Mad", "Feeling Sad", "Worry 
about foods allergic too"). 
FEEDING TUBE will be the sum of CRF questions ("Remember to use feeding tube", "Using a 
feeding tube"). 
The dimension score will not be calculated if more than 50% of the items in the scale are 
missing. To compute dimension score, a weighted total sum will be used. Sum up the value of 
the response for each of the questions in that dimension and then divide by the total number of 
questions answered for that dimension. 
A total score will be the sum of all the items scores except for FEEDING TUBE. 
Symptoms total scale score will be calculated as the sum of items scores when dimensions in 
Symptoms I and II divided by the number of items answered. 
9.6  
Calculation of the EQ-5D Score 
ED-5D 3L and ED-5D Y Composite Index Score for US-Based Population 
The US population-based EQ-5D index score ranges from -0.11 to 1.0 on a scale where 
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0.0 = death and 1.0 = perfect health. The negative index scores are regarded as worse than death. 
The calculations of the EQ-5D index scores are based on a regression equation derived from a 
large-scale survey of the general adult US population (Shaw et al., 2005). The regression 
equation for scoring is as follows: 
X = 1 - 0.146 *MO2 - 0.558 *MO3 - 0.175 *SC2 - 0.471* SC3 - 0.140 *UA2 - 0.374 *UA3 - 
0.173* PD2- 0.537* PD3 - 0.156* AD2 - 0.450* AD3 + 0.140 *D1 - 0.011 *I2-squared + 0.122* 
I3 + 0.015 *I3- squared 
Where X is the US EQ-5D index score, and the independent variables are listed below 
MO2: 1 if mobility is level 2; 0 otherwise  
MO3: 1 if mobility is level 3; 0 otherwise  
SC2: 1 if self-care is level 2; 0 otherwise  
SC3: 1 if self-care is level 3; 0 otherwise 
UA2: 1 if usual activities is level 2; 0 otherwise  
UA3: 1 if usual activities is level 3; 0 otherwise  
PD2: 1 if pain/discomfort is level 2; 0 otherwise  
PD3: 1 if pain/discomfort is level 3; 0 otherwise  
AD2: 1 if anxiety/depression is level 2; 0 otherwise  
AD3: 1 if anxiety/depression is level 3; 0 otherwise 
D1: number of dimensions beyond the first in level 2 or level 3 (i.e., 0 if 0, 1 if 1 dimension in 
level 2 or 3 or number of dimensions in level 2 or level 3 minus 1 otherwise) 
I2-squared: squared number of dimensions beyond the first in level 2 
I3: number of dimensions beyond the first in level 3 
I3-squared: squared I3 
9.7  
Analysis Software  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified environment.   
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10.0 
ELECTRONIC SIGNATURE 
  
 
 
 
 
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Statistical and Quantitative Sciences-GI 
Takeda 
 
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