Clinical trial NCT02605837
Conditions: Eosinophilic Esophagitis (EoE)
Sponsor: Shire
Start date: 2015-12-07; Completion date: 2019-02-15
Enrollment: 318 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study in adolescents and adults with eosinophilic esophagitis (EoE) to measure the histologic response and determine if any reduction in dysphagia is achieved.

Detailed description:

Arms: arm 1: Participants will receive Oral Budesonide Suspension (OBS) 10 milliliter (ml) of 0.2 milligram per milliliter (mg/ml) twice daily up to 16 weeks. arm 2: Participants will receive oral dose of 10 ml of placebo matched with the experimental drug twice daily up to 16 weeks.
Interventions: intervention 1: Oral Budesonide Suspension (OBS) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral Budesonide Suspension (OBS) 10 milliliter (ml) of 0.2 milligram per milliliter (mg/ml) twice daily up to 16 weeks. intervention 2: Oral dose of 10 ml of placebo matched with the experimental drug.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02605837 
 
Study Title:  
Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11 to 
55 Years of Age, Inclusive) with Eosinophilic Esophagitis: A Phase 3 
Randomized, Double-blind, Placebo-controlled Study 
 
 
Study Number:  
SHP621-301 
 
 
Protocol Version and Date:  
 
Original Protocol: 31 Aug 2015 
Protocol Amendment 1: 17 Dec 2015 
Protocol Amendment 2: 26 Jan 2018 


PROTOCOL:  SHP621-301
TITLE:
Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis: 
A Phase 3 Randomized, Double-blind, Placebo-controlled Study
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol:  31 Aug 2015
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations.  This information should be used solely for the purposes for 
which it was provided and should not be copied, shared with, or disclosed to any third party without the express 
written consent of Shire.


Shire 
Protocol SHP621-301 
CONFIDENTIAL 
Version 1.0 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD, PhD 
 
 Clinical Development 
Acknowledgement 
I have read this protocol for Shire Study SHP621-301. 
-
Date: 31 Aug 2015 
31 Aug 2015 
Page 2 of91 
Title: Oral budesonide suspension (OBS) in Adolescent and Adult Subjects (11 to 55 years 
of age, inclusive) with Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, 
Placebo-Controlled Study 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ---------------------------------- Date: 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 3 of 91
EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by 
Protocol within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of the Shire Clinical Study Adverse Event Form for SAEs and Non-
serious AEs as Required by Protocol must also be sent to the CRO medical monitor by fax or 
e-mail using the details below.
, MD
Email:  
Fax:  
For protocol- or safety-related issues during normal business hours (8am to 5 pm 
Eastern Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile: 
Email:  
Fax:  
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile: 
Email:  


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 4 of 91
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
 or 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 5 of 91
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
EMERGENCY CONTACT INFORMATION ..........................................................................3
PRODUCT QUALITY COMPLAINTS ....................................................................................4
ABBREVIATIONS..................................................................................................................11
STUDY SYNOPSIS.................................................................................................................13
STUDY SCHEDULE(S) ..........................................................................................................22
1.
BACKGROUND INFORMATION.............................................................................27
1.1
Indication and Current Treatment Options...................................................................27
1.2
Product Background and Clinical Information ............................................................27
2.
STUDY OBJECTIVES AND PURPOSE....................................................................28
2.1
Rationale for the Study.................................................................................................28
2.2
Study Objectives...........................................................................................................28
2.2.1
Primary Objectives ................................................................................................28
2.2.2
Secondary Objectives ............................................................................................29
2.2.3
Exploratory Objective............................................................................................29
3.
STUDY DESIGN.........................................................................................................29
3.1
Study Design and Flow Chart ......................................................................................29
3.2
Duration and Study Completion Definition .................................................................31
3.3
Sites and Regions .........................................................................................................32
4.
STUDY POPULATION...............................................................................................32
4.1
Inclusion Criteria..........................................................................................................32
4.2
Exclusion Criteria.........................................................................................................33
4.3
Restrictions...................................................................................................................35
4.4
Reproductive Potential .................................................................................................35
4.4.1
Female Contraception............................................................................................35
4.5
Discontinuation of Subjects..........................................................................................36
4.5.1
Subject Withdrawal Criteria ..................................................................................36


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 6 of 91
4.5.2
Reasons for Discontinuation..................................................................................36
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................37
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................37
5.1
Prior Treatment.............................................................................................................38
5.2
Concomitant Treatment................................................................................................38
5.2.1
Permitted Treatment ..............................................................................................38
5.2.2
Prohibited Treatment .............................................................................................39
6.
INVESTIGATIONAL PRODUCT ..............................................................................39
6.1
Identity of Investigational Product...............................................................................39
6.1.1
Blinding the Treatment Assignment......................................................................40
6.2
Administration of Investigational Product(s)...............................................................40
6.2.1
Interactive Response Technology for Investigational Product Management........40
6.2.2
Allocation of Subjects to Treatment......................................................................41
6.2.3
Dosing....................................................................................................................42
6.2.4
Unblinding the Treatment Assignment..................................................................42
6.3
Labeling, Packaging, Storage, and Handling ...............................................................43
6.3.1
Labeling .................................................................................................................43
6.3.2
Packaging...............................................................................................................43
6.3.3
Storage ...................................................................................................................44
6.3.4
Special Handling....................................................................................................44
6.4
Drug Accountability.....................................................................................................44
6.5
Subject Compliance......................................................................................................46
7.
STUDY PROCEDURES..............................................................................................46
7.1
Study Schedule.............................................................................................................46
7.1.1
Screening Period (Weeks -6 to 0)..........................................................................46
7.1.1.1
Screening Visit (Visit -1) ............................................................................47
7.1.2
Placebo Lead-in Period (Weeks 0 to 4) .................................................................48
7.1.2.1
Placebo Lead-in Visit (Visit 0)....................................................................48
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or 
Early Termination).................................................................................................49
7.1.3.1
Baseline Visit (Visit 1): Week 4..................................................................50


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 7 of 91
7.1.3.2
Visits 2 and 3 (Weeks 8 and 12)..................................................................51
7.1.3.3
Visit 4 (Week 16) ........................................................................................52
7.1.4
Follow-up Period ...................................................................................................53
7.1.4.1
Safety Follow-up Contact (Visit 5): Week 20.............................................53
7.1.5
Additional Care of Subjects after the Study ..........................................................53
7.2
Study Evaluations and Procedures ...............................................................................53
7.2.1
Efficacy..................................................................................................................54
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation.........................................................................54
7.2.1.2
Dysphagia Symptom Questionnaire............................................................55
7.2.2
Safety .....................................................................................................................56
7.2.2.1
Medical and Medication History.................................................................56
7.2.2.2
Physical Examination (Including Height and Weight)................................56
7.2.2.3
Adverse Event Collection............................................................................57
7.2.2.4
Vital Signs ...................................................................................................57
7.2.2.5
Clinical Laboratory Evaluations..................................................................57
7.2.2.6
Pregnancy Test ............................................................................................59
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density..................59
7.2.3
Other Assessments.................................................................................................59
7.2.3.1
Health-related Quality-of-life Assessment..................................................59
7.2.3.2
Severity of Disease Assessments ................................................................60
7.2.4
Clinical Pharmacology Assessments .....................................................................60
7.2.5
Volume of Blood to Be Drawn from Each Subject ...............................................61
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................62
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................62
8.1.1
Severity Categorization..........................................................................................63
8.1.2
Relationship Categorization...................................................................................63
8.1.3
Outcome Categorization ........................................................................................64
8.1.4
Symptoms of the Disease under Study ..................................................................64
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................65
8.1.6
Pregnancy...............................................................................................................65
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................66
8.2
Serious Adverse Event Procedures...............................................................................67


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 8 of 91
8.2.1
Reference Safety Information................................................................................67
8.2.2
Reporting Procedures.............................................................................................67
8.2.3
Serious Adverse Event Definition .........................................................................67
8.2.4
Serious Adverse Event Collection Time Frame ....................................................68
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................68
8.2.6
Fatal Outcome........................................................................................................68
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................69
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................69
9.1
Data Collection.............................................................................................................69
9.2
Clinical Data Management...........................................................................................69
9.3
Data Handling Considerations......................................................................................70
9.4
Statistical Analysis Process..........................................................................................70
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........70
9.6
Sample Size Calculation and Power Considerations....................................................71
9.7
Study Population ..........................................................................................................71
9.8
Efficacy Analyses.........................................................................................................71
9.8.1
Primary Efficacy Endpoints...................................................................................72
9.8.1.1
Missing Data Imputation.............................................................................73
9.8.2
Secondary Efficacy Endpoints...............................................................................73
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................73
9.8.3
Exploratory Efficacy Endpoint..............................................................................75
9.9
Safety Analyses ............................................................................................................75
9.10
Other Analyses .............................................................................................................76
9.10.1 Health-related Quality-of-life Analyses.................................................................76
9.10.2 Pharmacokinetic Analyses.....................................................................................76
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................77
10.1
Sponsor’s Responsibilities ...........................................................................................77
10.1.1 Good Clinical Practice Compliance.......................................................................77
10.1.2 Indemnity/Liability and Insurance.........................................................................77
10.1.3 Public Posting of Study Information .....................................................................77


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 9 of 91
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................78
10.1.5 Study Suspension, Termination, and Completion .................................................78
10.2
Investigator’s Responsibilities .....................................................................................78
10.2.1 Good Clinical Practice Compliance.......................................................................78
10.2.2 Protocol Adherence and Investigator Agreement..................................................79
10.2.3 Documentation and Retention of Records.............................................................79
10.2.3.1 Case Report Forms......................................................................................79
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................80
10.2.3.3 Audit/Inspection..........................................................................................80
10.2.3.4 Financial Disclosure....................................................................................80
10.3
Ethical Considerations..................................................................................................81
10.3.1 Informed Consent ..................................................................................................81
10.3.2 Institutional Review Board or Ethics Committee..................................................81
10.4
Privacy and Confidentiality..........................................................................................82
10.5
Study Results/Publication Policy .................................................................................83
11.
REFERENCES.............................................................................................................84
12.
APPENDICES..............................................................................................................86
LIST OF TABLES
Table 1-1: Schedule of Assessments.......................................................................................22
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject.........................61
Table 8-1: Adverse Event Relatedness....................................................................................64
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata......................................................................................................................73
Table 9-2: Pharmacokinetic Parameters..................................................................................76
LIST OF FIGURES
Figure 1:
Study Design Flow Chart.......................................................................................30


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 10 of 91
LIST OF APPENDICES
Appendix 1
Scales and Assessments...............................................................................87
Appendix 2
Dysphagia Symptom Questionnaire ePRO for EoE....................................88
Appendix 3
Patient Global Impression of Severity.........................................................89
Appendix 4
Biosciences Generic Clinical Protocol Insert..............................................90


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 11 of 91
ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
ANCOVA
analysis of covariance
Auctau
area under the curve for the defined interval between doses
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum concentration occurring at tmax
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CYP450 3A4
cytochrome P450 3A4
DSG1
desmoglein 1
DSQ
Dysphagia Symptom Questionnaire
DXA (DEXA)
dual-energy X-ray absorptiometry
EC
ethics committee
EGD
esophagogastroduodenoscopy
EIS
external independent statistical
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
EoE-QoL-A  
Adult Eosinophilic Esophagitis Quality of Life
ePRO
electronic patient-reported outcome
EQ-5D-3L
EuroQol-5 Dimensions 3-level
EQ-5D
EuroQol
EQ-5D-Y
EuroQol 5 Dimensions Youth
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 12 of 91
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
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication information
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
OBS
oral budesonide suspension
pc
after meals
PedsQL-EoE
Pediatric Quality of Life Inventory – EoE
PGA
Physician Global Assessment
PGI-S
Patient Global Impression of Severity
PP
per-protocol
PPI
proton pump inhibitor
PT
preferred term
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
SOC
system organ class
TEAE
treatment-emergent adverse event
tmax
time of maximum observed concentration sampled during a dosing 
interval
UK
United Kingdom
US
United States


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 13 of 91
STUDY SYNOPSIS
Protocol number:  SHP621-301
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11 to 
55 Years of Age, Inclusive) with Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, 
Placebo-controlled Study
Number of subjects (total and for each treatment arm):
Approximately 300 subjects will be enrolled into the placebo lead-in period to allow for 228 subjects 
(approximately 152 and 76 per OBS and placebo treatment group, respectively) to be randomized into 
the double-blind treatment period.
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America
Study period (planned):
Oct 2015 to July 2018
Clinical phase:
3
Objectives
Co-primary:
To demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/high-powered field [HPF]) in 
adolescent and adult subjects with eosinophilic esophagitis (EoE) over a 12-week course of 
therapy.

OBS reduces dysphagia, as measured by the Dysphagia Symptom Questionnaire (DSQ), by at 
least 30% from baseline in adolescent and adult subjects with EoE over a 12-week course of 
therapy.
Key Secondary:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final treatment period 
evaluation (Visit 4). 
Secondary:

To assess the response of endoscopically identified esophageal features to OBS as compared to 
placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ

To evaluate the safety and tolerability of OBS over a 12-week course of therapy

To obtain OBS pharmacokinetic data in adult subjects with EoE
Exploratory:


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 14 of 91
Rationale:
Currently there is no approved medication for the treatment of EoE. This study is being conducted in 
order to provide safety and efficacy data demonstrating histologic response (as measured by 
eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as measured by the DSQ) 
following 12 weeks of treatment with OBS in adolescent and adult subjects with EoE. 
Investigational product, dose, and mode of administration
OBS 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 OBS 
and dosing regimens were selected for use in this Phase 3 study based on the results of Study MPI 
101-06, a Phase 2 study in 93 adolescents and adult subjects with EoE and symptoms of dysphagia. 
Subjects were treated in Study MPI 101-06 with 2 mg OBS twice daily to investigate the co-primary 
endpoints of histologic response (defined as ≤6 eosinophils/HPF) and reduction in DSQ score from 
baseline to Week 12 of treatment. For the current study, the investigational product will be supplied in 
amber glass, multi-dose bottles with child-resistant caps. Each bottle will contain 210 mL of 
suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL (matching placebo). 
After the screening period, eligible subjects will enter a 4-week single-blind placebo lead-in period and
will receive 10 mL of OBS placebo twice daily (qAM, pc, and hs). At the end of the placebo lead-in
period, eligible subjects will enter a 12-week double-blind treatment period (baseline visit, Visit 1) and 
will be randomized to 1 of 2 treatment groups in a 2:1 ratio (approximately 152 and 76 subjects for 
OBS and placebo twice daily treatment groups, respectively). Subjects will receive oral administration 
of 10 mL of 2 mg investigational product twice daily (qAM, pc, and hs; 4 mg/day total), with no 
ingestion of food or liquids permitted for 30 minutes after study drug administration:

Placebo twice daily group:  placebo qAM (pc) and hs

OBS twice daily group: OBS 10 mL of 0.2 mg/mL (2 mg total) qAM (pc) and hs
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for 
each subject in the OBS treatment group (Table 1). 
Table 1: Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume 
per Dose
Morning Dose 
(qAM, pc)
Evening 
Dose (hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10 mL
0.0 mg
0.0 mg
0.0
OBS 
0.2
10 mL
2.0 mg
2.0 mg
4.0
Abbreviations: hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every 
morning
At the end of the 12-week double-blind treatment period (Visit 4), subjects who complete the study 
will have the opportunity to enroll in the treatment extension study. These subjects will continue on the 
blinded assigned treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment 
extension study. 
Methodology:
This is a Phase 3, randomized, double-blind, multicenter, parallel-group, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of twice daily administration of OBS (qAM, pc, and hs) 
in adolescents and adults aged 11-55 years, inclusive, with EoE and dysphagia. 
This study will comprise 3 periods: a 3- to 6-week screening period, 4-week single-blind placebo 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 15 of 91
lead-in period, and 12-week double-blind treatment period (Figure 1). Approximately 300 subjects will 
be enrolled into the placebo lead-in period to allow for approximately 228 subjects to be randomized 
in a 2:1 ratio (approximately 152 and 76 per OBS and placebo treatment group, respectively) into the 
double-blind treatment period. A minimum of 40 randomized subjects will be aged 11-17 years, 
inclusive.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened 
(Visit -1). Subjects who meet eligibility criteria at the screening visit (Visit -1) and at the placebo 
lead-in visit (Visit 0) will enter the 4-week placebo lead-in period to assess their ability to comply with 
twice daily medication administration and assess whether there is a placebo response. Upon 
completion of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to confirm 
eligibility. Eligible subjects will be randomized 2:1 into the double-blind treatment period and will be 
evaluated for efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4). Subjects who fail to meet all
eligibility criteria at Visits -1, 0, or 1 will be considered screen failures. Subjects cannot be rescreened 
once they have been designated as a screen failure unless due solely to the use of a concomitant 
medication which can be stopped prior to rescreening. Subjects who discontinue will not be replaced.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. A safety follow-up 
phone call will occur 4 weeks following the last dose of investigational product for subjects who 
discontinue prematurely during the double-blind treatment period or who do not enroll in the treatment 
extension study.
Figure 1: Study Design Flow Chart
Abbreviations: BID=twice daily; EGD=esophagogastroduodenoscopy; ET=early termination; 
OBS=oral budesonide suspension


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 16 of 91
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria 
(including test results):
1.
Subject 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. 
2.
Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3.
Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 of 3 
(proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4.
Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating problems, 
abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) intermittently or 
continuously at screening (Visit -1).
5.
Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period and in the 2 weeks prior to the baseline visit (Visit 1).
6.
Subject must not have proton pump inhibitor (PPI)–responsive EoE based on esophageal biopsies 
performed after the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose 
therapy refers to the total daily dose, which may have been administered as a once- or twice daily 
dosing regimen). This may occur at the time of the qualifying esophagogastroduodenoscopy 
(EGD; in which case the same PPI regimen must be continued), or this may have been done 
previously (in which case PPI therapy may have been stopped if there was no response to therapy 
based on esophageal biopsy results).
7.
Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit (Visit -1).
8.
Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical 
regimens (including gastric acid suppression; see exclusions below) in effect at the screening visit 
(Visit -1). There should be no change to these regimens during study participation.
9.
All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential must 
agree to continue acceptable birth control measures (eg, abstinence, stable oral contraceptives, or 
double-barrier methods) throughout study participation.
10. 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 any condition or abnormality (including laboratory abnormalities), current or past, 
that, in the opinion of the principal investigator or medical monitor, would compromise the safety 
of the subject or interfere with or complicate the assessment of signs or symptoms of EoE. Such 
conditions may include psychiatric problems; neurologic deficits or disease; developmental delay; 
cardiovascular, metabolic, or pulmonary disease; or previous gastroesophageal surgery. These 
should be discussed with the medical monitor.
2.
Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD or 
between the qualifying EGD and baseline visit (Visit 1) or anticipates using immunomodulatory 
therapy during the treatment period (except for any ongoing regimen of allergy shots). Use of 
long-acting immunomodulatory therapy (eg, Rituxan) within 3 months of the qualifying EGD 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 17 of 91
should be reviewed with the medical monitor.
3.
Subject has been using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit (Visit 1), or anticipates use during the treatment period; any temporary use or 
initiation of new steroid treatment during the study should be documented and discussed with the 
medical monitor prospectively but cannot occur within 4 weeks of the final EGD. 
4.
Subject has been on inhaled or intranasal steroids and not on stable treatment for ≥3 months prior
to screening visit (Visit -1). Subjects on intranasal or inhaled steroids need to stay on stable 
treatment during study participation.
5.
Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, antacids, 
antihistamines, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease 
asthma or allergic rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying 
EGD and baseline visit (Visit 1), or anticipates changes in the use of such medications during the 
treatment period.  
6.
Subject has been using cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) 
within the 2 weeks prior to the baseline visit (Visit 1) or within 5 half-lives (whichever is greater)
or anticipates using such medications during the treatment period.  
7.
Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as defined 
by the presence of a lesion that does not allow passage of a diagnostic adult upper endoscope (eg, 
with an insertion tube diameter of >9 mm). 
8.
Subject is on a pure liquid diet or the 6-food elimination diet.
9.
Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic syndrome, 
collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has acute or chronic viral infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes esophagitis, 
or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit (Visit -1) or 
between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit (Visit -1) and 
between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or 
any other corticosteroids) or to any other ingredients of the investigational product.
20. Subject has taken part in an investigational study within 6 months prior to the screening visit 
(Visit -1).
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
22. Subject has previously completed, discontinued, or withdrawn from this study.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 18 of 91
23. Subject has participated in a previous clinical study involving OBS (SHP621).
Maximum duration of subject involvement in the study:

Planned duration of screening period: 3-6 weeks

Planned duration of placebo lead-in period: 4 weeks

Planned duration of treatment period: 12 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of a 
double-blind investigational product and have both an evaluable post-baseline biopsy in the 
treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and a 
post-baseline DSQ score.

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with protocol 
violations. The PP set will be identified prior to unblinding the treatment assignments by a team 
consisting of, at a minimum, a physician and a statistician from Shire. 

The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 
2+3) from baseline to the final treatment period evaluation (Visit 4)
Key Secondary Efficacy Endpoint

Change in DSQ combined score (questions 2+3) from baseline to the final treatment period 
evaluation (Visit 4)
Secondary Efficacy Endpoints 

Change in total endoscopy score, as measured by the EREFS classification, from baseline to the 
final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment period 
evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment period 
evaluation (Visit 4)

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 19 of 91

Change from baseline in the histopathologic epithelial features combined total score (grade and 
stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation (Visit 4)

Change from baseline in the DSQ combined score (questions 2+3) over time including 
post-baseline visits

Cumulative distribution function curves for the change and the percent change in the DSQ score 
from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Symptom response on DSQ + pain score (binary response), defined as ≥30% and 50% reductions 
in the DSQ combined score (questions 2+3+4) from baseline to the final treatment period 
evaluation (Visit 4)

Symptom response on DSQ pain score (binary response), defined as a ≥30% and 50% reduction 
in the DSQ score (question 4), from baseline to the final treatment period evaluation (Visit 4)
Exploratory Efficacy Endpoint 
Safety Endpoints 
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital signs
(temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height 
assessments, dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD)
measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory tests (hematology, 
chemistry, urinalysis; serum pregnancy test, if appropriate), and adrenocorticotropic hormone (ACTH) 
stimulation tests. To account for the effects of puberty in adolescent subjects (11-17 years, inclusive), 
BMD z-scores will be adjusted for height z-scores using the Bone Mineral Density in Childhood Study 
calculator (http://www.bmdcspublic.com).
Health Economics and Outcomes Research Endpoints 

Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score from baseline to 
the final treatment period evaluation (Visit 4)

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 from baseline to the final 
treatment period evaluation (Visit 4)

Change in Pediatric Quality of Life Inventory – EoE (PedsQL-EoE) score from baseline to the 
final treatment period evaluation (Visit 4)
Pharmacokinetic Endpoints 
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis. The pharmacokinetic parameters will include, but not be 
limited to:


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 20 of 91
AUCtau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing 
interval
Statistical Methodology for Primary Efficacy Endpoint 
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the co-primary 
efficacy endpoints is a binary response (ie, responders vs non-responders); the endpoint will be 
analyzed using a logistic regression model with the effects of the treatment group, the age group
(either <18 years or ≥18 years), and their interaction. The main-effect model will be considered the 
final definitive model if the interaction between the treatment and age group is not statistically 
significant at the 10% level. The odds ratio of being a responder on each of the co-primary endpoints 
for the OBS 2 mg twice daily group vs placebo group and associated 95% confidence interval (CI) will 
be estimated from the final model. Subjects who withdraw without providing efficacy data at the final 
treatment period evaluation (Visit 4, Week 16) will be classified as non-responders in the primary 
efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized and their respective 95% CI will be reported. The difference in 
the proportion of responders between the 2 treatment groups and the corresponding 95% CI will also 
be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to evaluate the 
robustness of the results from the primary analysis methods: 

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing efficacy data 
at the final treatment period evaluation (Visit 4) will be classified as responders.
Statistical Methodology for Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4). The change from 
baseline DSQ score at the final treatment period evaluation (Visit 4) will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment group and age group as factors and the baseline DSQ 
score as a continuous covariate.
Statistical Methodology for Secondary Efficacy Endpoints
Secondary subjective efficacy endpoints that are defined as:

Binary response endpoints will be analyzed using the same logistic model as the co-primary 
efficacy endpoints.

Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model that 
includes treatment group and age group as factors and baseline score as a continuous covariate.
The analyses for all secondary efficacy endpoints (including the key secondary efficacy endpoint) will 
be carried out using 2-sided tests at the 5% level of significance. For each of the secondary efficacy 
endpoints, the treatment difference, corresponding 95% CI for the difference, and treatment 
comparison p-value for testing the null hypothesis of zero treatment effect based on the final statistical 
model (ie, either logistic regression model or ANCOVA model) will be provided.
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 measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory results 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 21 of 91
(hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), and ACTH stimulation will 
be descriptively summarized by treatment group at baseline and for each post-baseline visit.
The number and percent of subjects with TEAEs will be presented. TEAEs are defined as AEs that 
start or deteriorate on or after the date of the first dose of investigational product and no later than 
3 days following the last dose of investigational product. However, for any subjects who die during the 
study (ie, the date of death is between the date of first dose of investigational product and the date of 
study discontinuation entered by the site, inclusive), all AEs (including those resulting in death) that 
occur during the study will be considered as TEAEs irrespective of the last dose and will be included 
in the TEAE summaries. 
Statistical Methodology for Pharmacokinetic Endpoint(s) 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters by overall and by week. Plasma concentrations at each nominal sampling time will also be 
summarized using descriptive statistics.
Sample Size Justification
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected difference 
between treatment response proportions of 69% and 45% in the OBS 2 mg twice daily (qAM, pc, and 
hs) and placebo groups, respectively. A total of 228 subjects (152 subjects randomized to OBS and 
76 subjects randomized to placebo) are required to achieve 90% power at the significance level of 
0.0499 (2-sided) using a 2-group chi-square test with unequal allocation 2:1 to treatment groups (OBS 
2 mg twice daily and placebo). With the specified number of subjects per treatment group, the study 
will be powered at 99% assuming histological response proportions of 40% and 3% in the OBS 2 mg 
twice daily and placebo groups, respectively. The overall study power for the co-primary endpoints 
will be at least 85%. Therefore, approximately 228 (approximately 152:76 OBS and placebo subjects, 
respectively) will be randomized to the study to allow for a loss of approximately 5% of subjects due 
to dropouts or invalid data.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 22 of 91
STUDY SCHEDULE(S)
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety Follow-
up Telephone 
Contactp
Visit -1
Visit 0
Randomization
Baseline/Visit 1
Visit 2
Visit 3
Visit 4 or 
ETo
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consent/assent
X
Medical history review
X
Inclusion/exclusion criteria review
X
X
X
Vital signsa; heightb and weight assessment
X
X
X
X
X
X
EGD with endoscopy score (EREFS) and 
biopsyc
X
X
DSQ training and issue of handset
X
Retrieval of DSQ handset
X
DSQ compliance assessment
X
X
X
X
X
EQ-5Dd
X
X
PedsQL-EoE (subjects 11-17 years of age, 
inclusive)
X
X
EoE-QoL-A (subjects ≥18 years of age)
X
X
PGI-S
X
X
X
X


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 23 of 91
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety Follow-
up Telephone 
Contactp
Visit -1
Visit 0
Randomization
Baseline/Visit 1
Visit 2
Visit 3
Visit 4 or 
ETo
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Physical examination
X
X
X
X
X
X
Tanner Staging Assessmente
X
X
Clinical laboratory testsf
X
X
X
X
X
X
Urinalysisg
X
X
X
X
X
X
Pregnancy testh
X
X
X
X
X
X
Morning cortisol (target 6:00-9:00 AM)
X
X
X
X
ACTH stimulation testing 
X
X
Blood pharmacokinetic sampling (subjects 
≥18 years of age)i
X
X
DXA Scan for BMD (subjects 11-17 years of 
age, inclusive)j
X
X
Randomizationk
X
Investigational product supplied 
X
X
X
X
Xl
Investigational product administrationm
Twice-daily administration of investigational product
Investigational product compliance 
assessment
X
X
X
X
Concomitant medications and procedures 
X
X
X
X
X
X
X


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 24 of 91
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety Follow-
up Telephone 
Contactp
Visit -1
Visit 0
Randomization
Baseline/Visit 1
Visit 2
Visit 3
Visit 4 or 
ETo
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
recorded 
Review of adverse eventsn
X
X
X
X
X
X
Abbreviations: ACTH=adrenocorticotropic hormone; BMD=bone mineral density; DSQ=Dysphagia Symptom Questionnaire; 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; EREFS=EoE Endoscopic Reference Score; 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
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood 
pressure (systolic and diastolic), heart rate, respirations, and temperature.
b
Height to be collected at screening visit (Visit -1) and Visit 4 for all subjects. Stadiometers are required for subjects 11-17 years of age, inclusive, and will be 
used at Visit 1 and 4.
c
Pre-treatment endoscopy will be performed during the screening period (at least 2 weeks prior to placebo lead-in visit [Visit 0] to allow adequate time for 
processing and central review). Endoscopy should include esophageal (proximal, mid-, and/or distal), gastric, and duodenal biopsies. Final treatment 
evaluation EGD must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Final treatment evaluation 
EGD should occur at or within 7 days of the scheduled visit.  
d
Subjects 11-17 years of age, inclusive, will complete the EQ-5D-Y; subjects ≥18 years of age will complete the EQ-5D-3L. 
e
Tanner staging assessments will be performed for all subjects aged ≥11 years until investigator confirms subject is post puberty.
f
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 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 25 of 91
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety Follow-
up Telephone 
Contactp
Visit -1
Visit 0
Randomization
Baseline/Visit 1
Visit 2
Visit 3
Visit 4 or 
ETo
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
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.
g
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
h
The serum pregnancy test will be performed for all female subjects at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine pregnancy
tests will be performed at all other visits.
i
Blood samples for pharmacokinetic analysis will be taken from adult subjects (aged ≥18 years). Subjects who do not participate in pharmacokinetic sampling 
will not be discontinued from the study and lack of participation will not be a considered protocol deviation. Blood samples for pharmacokinetic analysis will 
be obtained at the Week 8 or Week 12 visit at the following time points: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose. 
j
The baseline DXA scan may be performed any time during the placebo lead-in period after the subject has met all screening criteria and prior to 
blinded-treatment randomization. Baseline and post-treatment DXA scans should be performed using the same machine and software. Post-treatment DXA 
scan should occur at or within 7 days of the scheduled visit.
k
Randomization will occur via IWRS at the baseline visit (Visit 1) once the subject’s eligibility for study entry is confirmed. 
l
Investigational product will be dispensed at Visit 4 to subjects who consent to enroll in the treatment extension study.
m
Subjects will receive oral administration of 10 mL of investigational product twice daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 
30 minutes after study drug administration.
n
AE assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, acne, hirsutism, 
mood swings, insomnia, and depression).


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 26 of 91
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety Follow-
up Telephone 
Contactp
Visit -1
Visit 0
Randomization
Baseline/Visit 1
Visit 2
Visit 3
Visit 4 or 
ETo
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
o
If subject discontinues study prematurely, the evaluations listed for Visit 4 are to be performed as completely as possible.
p
For subjects who withdraw from the study or do not continue into treatment extension study, a safety follow-up contact by phone will be performed 4 weeks 
following the last dose of investigational product.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 27 of 91
1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al., 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and 
adults present with dysphagia and food impaction. When these symptoms are present, the 
diagnosis is confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered
field (HPF) on at least 1 esophageal biopsy and when other causes such as proton pump 
inhibitor (PPI)-responsive esophageal eosinophilia are excluded (Dellon et al., 2014a; Furuta 
et al., 2007). The standards of care are diet therapies and off-label use of glucocorticosteroids.
Esophageal dilation is used to temporarily relieve symptoms but does not address underlying 
inflammation. Given the clinical outcomes associated with EoE, including severe dysphagia, 
esophageal stricture, food impaction, and esophageal perforation (Hirano and Aceves, 2014;
Liacouras et al., 2011) and the fact that there are currently no FDA-approved treatments, there 
is a clear unmet medical need for a novel treatment for this disease.  
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a non-viscous suspension. Shire is developing OBS as a 
first-line therapy for EoE in adolescents and adults.
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the 
management of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, 
and for induction of remission in patients with active, mild to moderate ulcerative colitis. 
Budesonide has strong glucocorticoid receptor affinity and is subject to considerable first pass 
metabolism by the liver with a short half-life. These attributes permit budesonide to act 
rapidly and locally in the gut mucosa for treatment of inflammatory disorders such as Crohn’s 
disease and ulcerative colitis. Once absorbed into the systemic circulation, budesonide is 
rapidly metabolized in the liver and inactivated (FDA, 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in two Phase 2 studies in 
the OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the 
efficacy of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in 
adolescents and adults aged 11-40 years, respectively, by measuring histological response 
(defined as mean peak eosinophil count ≤6/HPF after treatment). Study MPI 101-06 also 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 28 of 91
evaluated symptom response as measured by the Dysphagia Symptom Questionnaire (DSQ). 
The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia 
and its severity, as well as pain. The DSQ score is calculated only from responses to the
questions related to dysphagia, and this clinical outcome assessment was considered to be fit 
for purpose as a result of the MPI 101-06 study. Results from Study MPI 101-01 
demonstrated a statistically significant histologic response (eosinophil count ≤6/HPF) and 
remission (eosinophil count ≤1/HPF) in the medium-dose (1.4-2.0 mg daily) and high-dose 
(2.8-4.0 mg daily) OBS groups compared to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both 
the co-primary efficacy endpoints of histologic response and change from baseline in 
dysphagia symptoms. Following 12 weeks of twice daily treatment (once in the morning after 
meals [qAM, pc] and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent 
reduction from baseline values for cellular (mean peak eosinophil count and histopathology 
features), organ (endoscopy score), and holistic measures (Physician Global Assessment 
[PGA] and DSQ scores); these results were independent of the type of rater/reviewer (central 
pathologist, physician at the study site, or subject). 
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. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This study is being 
conducted in order to provide safety and efficacy data demonstrating histologic response (as 
measured by eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as 
measured by the DSQ) following 12 weeks of treatment with OBS in adolescent and adult 
subjects with EoE.
2.2
Study Objectives
2.2.1
Primary Objectives
The co-primary objectives of the study are to demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/HPF) in adolescent and adult 
subjects with EoE over a 12-week course of therapy.

OBS reduces dysphagia, as measured by the DSQ, by at least 30% from baseline in 
adolescent and adult subjects with EoE over a 12-week course of therapy.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 29 of 91
2.2.2
Secondary Objectives
The key secondary objective of this study is:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final 
treatment period evaluation (Visit 4). 
Additional secondary objectives of the study are:

To assess the response of endoscopically identified esophageal features to OBS as 
compared to placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ

To evaluate the safety and tolerability of OBS over a 12-week course of therapy 

To obtain OBS pharmacokinetic data in adult subjects with EoE
2.2.3
Exploratory Objective
The exploratory objective of this study is:
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of OBS treatment administered twice daily (qAM, 
pc, and hs) for 12 weeks. The study will be conducted in adolescents and adults, aged 
11-55 years, inclusive, with EoE and dysphagia. 
Approximately 300 subjects will be enrolled in the placebo lead-in period to allow for 
approximately 228 subjects to be randomized into the double-blind treatment period. A 
minimum of 40 randomized subjects will be aged 11-17 years, inclusive. Subjects will be 
randomized 2:1 (approximately 152 and 76 per OBS and placebo treatment group, 
respectively) to receive either OBS 2 mg twice daily (qAM, pc, and hs) or placebo twice daily 
(qAM, pc, and hs).  
This study will consist of 3 periods: a 3- to 6-week screening period, 4-week single-blind 
placebo lead-in period, and a 12-week double-blind treatment period (see Figure 1).


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 30 of 91
Figure 1:
Study Design Flow Chart
Abbreviations: BID=twice daily; EGD=esophagogastroduodenoscopy; ET=end of treatment; OBS=oral 
budesonide suspension
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al., 2014a) and the fact that the type of EoE that 
develops in older patients is not amenable to anti-inflammatory treatment alone (Dellon et al.,
2014b). A natural history study demonstrated that for every decade of life, the odds of 
developing the fibrostenotic phenotype of EoE more than doubles (Dellon et al., 2014b). By 
age 55, fibrostenotic EoE occurs in approximately 80% of patients. Fibrostenotic disease is 
treated with dilatation and is not amenable to anti-inflammatory treatment alone. Therefore, 
budesonide is not expected to be an effective treatment for the majority of patients above 
age 55.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. Following 
completion of the screening and placebo lead-in visits, subjects will be evaluated for 
eligibility and safety at Week 4 (Visit 1). Subjects who are eligible and randomized will be 
evaluated for efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4) and additionally for 
safety at follow-up at Week 20 (Visit 5; telephone contact). Subjects who fail to meet all 
eligibility criteria at Visits -1, 0, or 1 will be considered screen failures. Subjects cannot be 
rescreened once they have been designated as a screen failure unless due solely to the use of a 
concomitant medication which can be stopped prior to rescreening. Subjects who discontinue 
will not be replaced. 
The screening period will start when subjects sign informed consent (or assent as applicable 
for subjects <18 years of age; screening visit [Visit -1]) and will be approximately 3-6 weeks 
in duration. During the screening period, all subjects will receive an upper endoscopy with 
histologic analysis of biopsy specimens to confirm the diagnosis of EoE (eosinophil count of 
≥15/HPF from 2 of 3 [proximal, mid-, and/or distal] levels of the esophagus). In addition, 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 31 of 91
subjects must complete the DSQ daily during the screening period (3-6 weeks) and have at 
least 4 reported days with symptoms of dysphagia and completed the DSQ on ≥70% of days 
in any 2 consecutive weeks. At the screening visit (Visit -1), subjects who are on a PPI must 
remain on the same dose of the PPI throughout the study; if they are not taking a PPI, they 
must remain off of a PPI for the remainder of the study. After the screening period, eligible 
subjects will enter a 4-week single-blind placebo lead-in period and will receive 10 mL of 
OBS placebo twice daily (in the morning after meals/breakfast [qAM, pc] and at bedtime 
[hs]). The placebo lead-in period will enable assessment of the subject’s ability to comply 
with twice daily medication administration and assess whether the subject experiences a 
placebo response. 
At the end of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to 
confirm eligibility. Subjects who continue to meet all eligibility criteria (those with at least 
4 reported dysphagia days and who completed the DSQ on ≥70% of days in the 2 weeks prior 
to randomization per daily DSQ completion) will be randomized to receive either OBS or 
placebo during the 12-week double-blind treatment period. 
OBS will be administered in 10 mL at a concentration of 0.2 mg/mL (2 mg dose), twice daily. 
The 0.2 mg/mL concentration of OBS and dosing regimens were selected for use in this 
Phase 3 study based on the results of Study MPI 101-06, a Phase 2 study in 93 adolescent and 
adult
subjects with EoE and symptoms of dysphagia. Subjects were treated in 
Study MPI 101-06 with 2 mg OBS twice daily to investigate the co-primary endpoints of 
histologic response (defined as ≤6 eosinophils/HPF) and reduction in DSQ score from 
baseline to Week 12 of treatment. For the current study, the investigational product will be 
supplied in amber glass, multi-dose bottles with child-resistant caps. Each bottle will contain 
210 mL of suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL 
(matching placebo).
At the end of the 12-week double-blind treatment period (Visit 4, Week 16), subjects who 
complete the study will have the opportunity to enroll in the treatment extension study. These 
subjects will continue on the blinded assigned treatment for 2-4 weeks as part of the screening 
prior to enrolling into the treatment extension study. Subjects who do not enroll in the 
treatment extension study or who discontinue at any time during the SHP621-301 (Induction) 
study will receive a follow-up phone call 4 weeks post last dose of investigational product
(Visit 5).
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 26 weeks, 
depending on the 3- to 6-week screening period.
The study will be completed in approximately 32 months.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 32 of 91
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including 
Visit 4 (Week 16), inclusive of the final treatment evaluation EGD. Subjects who do not 
enroll in the treatment extension study or who discontinue prematurely at any time during the 
SHP621-301 (Induction) study will receive a follow-up phone call 4 weeks post last dose of 
the investigational product to which they were randomized.
3.3
Sites and Regions
Approximately 60 sites in North America will participate.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject 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.
2. Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3. Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 
of 3 (proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4. Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating 
problems, abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) 
intermittently or continuously at screening (Visit -1).
5. Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks 
of the screening period and in the last 2 weeks prior to the baseline visit (Visit 1). 
6. Subject must not have PPI-responsive EoE based on esophageal biopsies performed after 
the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose therapy refers 
to the total daily dose, which may have been administered as a once- or twice daily dosing 
regimen). This may occur at the time of the qualifying EGD (in which case the same PPI 
regimen must be continued), or this may have been done previously (in which case PPI 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 33 of 91
therapy may have been stopped if there was no response to therapy based on esophageal 
biopsy results).
7. Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit
(Visit -1).
8. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at 
the screening visit (Visit -1). There should be no change to these regimens during study 
participation.
9. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing 
potential must agree to continue acceptable birth control measures (eg, abstinence, stable 
oral contraceptives, or double-barrier methods) throughout study participation.
10. 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 any condition or abnormality (including laboratory abnormalities), current or 
past, that, in the opinion of the principal investigator or medical monitor, would 
compromise the safety of the subject or interfere with or complicate the assessment of 
signs or symptoms of EoE. Such conditions may include psychiatric problems; neurologic 
deficits or disease; developmental delay; cardiovascular, metabolic, or pulmonary disease; 
or previous gastroesophageal surgery. These should be discussed with the medical 
monitor.
2. Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD 
or between the qualifying EGD and baseline visit (Visit 1) or anticipates using
immunomodulatory therapy during the treatment period (except for any ongoing regimen 
of allergy shots). Use of long-acting immunomodulatory therapy (eg, Rituxan) within 
3 months of the qualifying EGD should be reviewed with the medical monitor.
3. Subject has been using swallowed topical corticosteroid for EoE or systemic 
corticosteroid for any condition within the 4 weeks prior to the qualifying EGD, between 
the qualifying EGD and baseline visit (Visit 1), or anticipates use during the treatment 
period; any temporary use or initiation of new steroid treatment during the study should be 
documented and discussed with the medical monitor prospectively but cannot occur 
within 4 weeks of the final EGD. 
4. Subject has been on inhaled or intranasal steroids and has not been on stable treatment for 
≥3 months prior to screening visit (Visit -1). Subjects on intranasal or inhaled steroids 
need to stay on a stable treatment during study participation.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 34 of 91
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, antihistamines,
or
leukotriene inhibitors for any condition (such as 
gastroesophageal reflux disease, asthma or allergic rhinitis) within the 4 weeks prior to the 
qualifying EGD, between the qualifying esophagogastroduodenoscopy (EGD) and 
baseline visit (Visit 1), or anticipates changes in the use of such medications during the 
treatment period.  
6. Subject has been using cytochrome P450 3A4
(CYP450 3A4)
inhibitors (eg,
ketoconazole, grapefruit juice) within the 2 weeks prior to the baseline visit (Visit 1) or 
within 5 half-lives (whichever is greater) or anticipates using such medications during the 
treatment period.  
7. Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9 mm). 
8. Subject is on a pure liquid diet or the 6-food elimination diet.
9. Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has acute or chronic viral infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes 
esophagitis, or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit
(Visit -1) or between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit
(Visit -1) and between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to 
budesonide (or any other corticosteroids) or to any other ingredients of the investigational 
product.
20. Subject has taken part in an investigational study within 6 months prior to the screening 
visit (Visit -1).
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 35 of 91
22. Subject has previously completed, discontinued, or withdrawn from this study.
23. Subject has participated in a previous clinical study involving OBS (SHP621).
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No change in exercise

No change in diet (liquid diet for 3 days or less is acceptable.)

Short course of systemic steroids are permitted to treat, for example, exacerbation of 
asthma but cannot be used 4 weeks prior to the final EGD.

No change in PPI use

No use of CYP450 3A4 inhibitors

An esophageal dilatation during the trial (Dilatation is considered a treatment failure, and 
the subject should be withdrawn from the study.)
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit -1), placebo 
lead-in visit (Visit 0), baseline visit (Visit 1), and Visits 1-4. A serum pregnancy test will be 
performed at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine 
pregnancy tests will be performed at all other visits.  
Female subjects should be either:

Pre-menarchal and Tanner Stage 1, or

Post-menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential must agree to abstain from sexual activity that could 
result in pregnancy or agree to use acceptable methods of contraception throughout the 
study period and for 30 days following the last dose of investigational product.

Acceptable methods of contraception are:

Intrauterine devices plus condoms


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 36 of 91

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 -1), 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 one of the other acceptable methods noted above in addition to the hormonal 
contraceptive until it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 4 are to be performed as completely as 
possible. If investigational product is discontinued due to an AE, the subject may remain on 
study to allow for completion of study procedures. 
Whenever possible, all discontinued subjects should also undergo the protocol-specified 
follow-up. Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination, date of stopping investigational 
product, and total amount of investigational product taken must be recorded in the case report 
form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
an esophageal stricture requiring dilation and/or worsening signs and symptoms of EoE (eg, 
weight loss or increased dysphagia), would be considered a treatment failure and result in 
withdrawal of the subject 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, 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 37 of 91
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

Non-compliance with study drug

Non-compliance 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

Trial screen failure

Placebo responder

Protocol deviation

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, and non-pharmacological treatment, such as psychotherapy, as appropriate)
received within 3 months prior to the screening visit (Visit -1) (or pharmacokinetic equivalent 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 38 of 91
of 5 half-lives, whichever is longer) 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 non-pharmacological treatment such as psychotherapy, as appropriate, received within 
3 months of the screening visit (Visit -1). Prior treatment information must be recorded on the 
appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the 
prescribed medication is not prohibited by the protocol. In the event of an emergency, any 
needed medications may be prescribed without prior approval, but the medical monitor must 
be notified of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been 
on a stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
endoscopy required for entrance to this study) and will continue this dosing regimen 
throughout study participation. The investigator must contact the medical monitor to discuss 
any changes to concomitant steroid regimens or for any medications not listed here that could 
impact the outcome of the study.
1. Inhaled or intranasal steroids for conditions other than EoE; subject must be on stable 
treatment for ≥3 months prior to screening visit (Visit -1).
2. PPIs
3. H2 antagonists
4. Antacids
5. Antihistamines or antileukotrienes
6. Maintenance immunotherapy (allergy shots)
Influenza and other routine required vaccinations are allowed during the study.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 39 of 91
5.2.2
Prohibited Treatment
The following medications and treatments are prohibited throughout the course of the study 
and prior to treatment, as specified:
1. Immunomodulatory therapy within 8 weeks prior to the qualifying EGD or between the 
qualifying EGD and baseline visit (Visit 1) or anticipated use of immunomodulatory 
therapy during the treatment period (except for any ongoing regimen of allergy shots). 
Use of long-acting immunomodulatory therapy (eg, Rituxan) within 3 months of the 
qualifying EGD should be reviewed with the medical monitor.
2. Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition 
within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and baseline 
visit (Visit 1) or anticipated use during the treatment period; any temporary use or 
initiation of new steroid treatment during study should be documented and discussed with 
the medical monitor prospectively but cannot occur within the 4 weeks of the final EGD.
3. Inhaled or intranasal steroids if <3 months prior to screening visit (Visit -1) 
4. PPIs, H2 antagonists, antacids, antihistamines, or leukotriene inhibitors for any condition 
(such as gastroesophageal reflux disease, asthma, or allergic rhinitis) within the 4 weeks 
prior to the qualifying EGD, between the qualifying EGD and baseline visit 1, or 
anticipated changes in the use of such medications during the treatment period.
5. CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) within the 2 weeks prior to the 
baseline visit (Visit 1) or within 5 half-lives (whichever is greater) 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 (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
6. Esophageal dilation within the 3 months prior to screening (Visit -1)
7. Investigational study treatment within 6 months prior to the screening visit (Visit -1)
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in
multi-dose amber glass bottles, each containing 210 mL. Additional information is provided 
in the current SHP621 investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle
form with the same volume.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 40 of 91
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in amber glass, multi-dose bottles with child-resistant 
caps. Each bottle contains 210 mL of suspension with a budesonide concentration of 
0.2 mg/mL. Inactive ingredients in OBS include dextrose, disodium edetate, citric acid, 
sodium citrate, potassium sorbate, polysorbate 80, glycerin, sodium benzoate, cherry flavor, 
Magnasweet 110, acesulfame potassium, and water.
The placebo solution will also be supplied in amber glass multi-dose bottles with 
child-resistant caps. Placebo consists of all components of the investigational product solution 
with the exception of budesonide.
6.2
Administration of Investigational Product(s)
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last 
until the subsequent visit. The first dose of investigational product (placebo) for each subject 
will be administered in the clinic at the placebo lead-in visit (Visit 0).  The subject will 
continue with the evening dosing regimen at home. 
OBS and placebo will be supplied in amber glass bottles and must be shaken well prior to 
administration. The appropriate dose will be dispensed using the graduated dosing spoon 
provided. For subjects who are minors (<18 years), a parent/guardian will be responsible for 
ensuring that the subjects take their investigational product appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during 
this time interval. After 30 minutes, it is recommended that the subjects rinse with water and 
spit.
Please refer to the Investigational Product Administration Manual for additional details.
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation 
and management, inventory management and supply ordering, investigational product 
expiration tracking and management, return of investigational product, and emergency 
unmasking. Please refer to the Study Manual for additional details regarding the IWRS.
The investigator or designee will access the IWRS at the screening visit (Visit -1) to record 
subject-specific information (ie, unique subject number, date of birth, etc.). Subjects will be 
entered as screen failures or as entering the placebo lead-in period. Subjects cannot be 
rescreened once they have been designated as a screen failure unless due solely to the use of a 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 41 of 91
concomitant medication that can be stopped prior to rescreening. For subjects who enter the 
placebo lead-in period, IWRS will provide the assignment of placebo lead-in period 
medication to dispense. 
At the baseline visit (Visit 1), the investigator or designee will again access the IWRS to 
either document a screen failure or, if the subject has met all entry criteria, to randomize the 
subject.  Sites will enter eligibility criteria information prior to randomization. For 
randomized subjects, the IWRS will provide a medication identification (Med ID) number (ie, 
kit number to dispense for treatment).  
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be 
provided to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a single-blind lead-in period followed by a double-blind 
placebo-controlled study period. The actual treatment given to individual subjects during the 
double-blind period is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational 
product allocated to the subject once eligibility has been determined following the placebo 
lead-in period.  
Individual subject treatment is automatically assigned by the IWRS.
Subjects will be randomized after confirmation of study eligibility in a ratio of 2:1 via a 
computer-generated randomization schedule to receive OBS 2 mg twice daily (qAM, pc, and 
hs) or placebo. The randomization will be performed centrally and stratified by age group 
(2 strata total: <18 years vs ≥18 years). The stratification will ensure a minimum of 
40 subjects in the pediatric group (11-17 years, inclusive). Permuted blocks of random sizes 
will be used to ensure that approximately equal numbers of patients are assigned each 
treatment within strata.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 42 of 91
6.2.3
Dosing
During the 4-week single-blind placebo lead-in period, all subjects will receive 10 mL of 
placebo twice daily (qAM, pc, and hs). During the 12-week double-blind treatment period, 
oral administration of 10 mL of investigational product will occur twice daily (qAM, pc, and 
hs), with no ingestion of food or liquids permitted for 30 minutes after study drug 
administration. Subjects randomized to OBS will receive 10 mL of 0.2 mg/mL of OBS (2 mg) 
twice daily for a total daily dose of 4 mg.  
Investigational product doses that are required to be administered at the clinic include the first 
dose of placebo administered at the placebo lead-in visit (Visit 0), the first dose of 
randomized investigational product (OBS or placebo) administered at the baseline visit
(Visit 1) and all morning doses of investigational product administered at Visits 2-4. Subjects 
will Subjects will be required to eat breakfast at the clinic prior to self-administering these 
doses. Subjects can self-administer all other doses of placebo and investigational product at 
home. 
During the visit where the pharmacokinetic blood samples are collected (Visit 2 or Visit 3), 
subjects will be required to eat a moderate-fat breakfast on-site and will be instructed to take 
their morning dose at a set time to establish the schedule for post-dose sample collection.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor and the sponsor as soon as 
possible after the investigator has been unblinded.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
There will be a provision for unblinding to ensure adequate treatment of the subject in the 
case of an emergency.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 43 of 91
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 trial use only” and/or “CAUTION: New Drug - Limited by Federal 
(or US) Law to Investigational Use,” “Keep out of reach of children,” and the sponsor’s name 
and address. Any additional labeling requirements for participating countries and/or 
controlled substances will also be included on the label.
Space is allocated on the label so that the site representative can record subject information. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8-ounce amber glass bottle for multiple use. Three bottles 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.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 44 of 91
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in 
a secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  
OBS and placebo must be stored at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified min/max
thermometer) would require manual resetting upon each recording. The sponsor must be 
notified immediately upon discovery of any excursion from the established range.  
Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the investigational product and 
will provide supportive documentation as necessary. Under no circumstances should the 
product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
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 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 45 of 91
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational 
product. Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) 
who is adequately trained in the protocol and who works under the direct supervision of the 
investigator. This delegation must be documented in the applicable study delegation of 
authority form.
The investigator or his/her designee (as documented by the investigator in the applicable 
study delegation of authority form) will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will 
be given only the investigational product carrying his/her treatment assignment. All dispensed 
medication will be documented on the CRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects. The 
investigator or his/her designee will enter the unique subject identifier and initials on the 
investigational product kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and 
the sponsor (or designated CRO). For unused supplies where the original supplied 
tamper-evident feature is verified as intact, the tamper-evident feature must not be broken,
and the labeled amount is to be documented in lieu of counting. Shipment return forms, when 
used, must be signed prior to shipment from the site. Validated electronic return systems (ie,
IWRS) do not require a shipment form. Returned investigational product must be packed in a 
tamper-evident manner to ensure product integrity. Contact the sponsor for authorization to 
return any investigational product prior to shipment. Shipment of all returned investigational 
product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 46 of 91
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational 
product packaging to every visit.
Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container (eg, bottles) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel.
Site personnel must review the returned investigational product to assess compliance at every 
visit prior to dispensing additional investigational product. Any discrepancies should be 
reconciled with the subject immediately. Subjects who do not return their used and unused 
investigational product should be reminded to bring all used and unused investigational 
product at their next visit.
Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. 
Visit to visit compliance of DSQ completion will also be assessed by site personnel. Protocol 
deviations will be documented for subjects who fail to complete the DSQ for 3 or more days 
in a given week.
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 (see Table 1-1) and must be referred to in conjunction with 
the instructions provided in this section. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). There must be documentation of consent (as per local requirements) 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions, prior to performing any study-related procedures.
7.1.1
Screening Period (Weeks -6 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise 3-6 weeks, during which all procedures listed for the screening visit (Visit -1) in 
Table 1-1 shall be completed. The screening period will allow for the determination of 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 47 of 91
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 (see Section 5.2.1).
Screening assessments may take place across several days to allow an appropriate time frame 
in which to complete all procedures and confirm study eligibility. 
After the screening period, subjects who meet eligibility criteria at the end of the screening 
visit (Visit -1) will enter the 4-week single-blind, placebo lead-in period. The placebo lead-in
period should not commence until all screening assessments required to confirm initial 
eligibility have been completed. If the subject does not meet eligibility criteria following 
completion of screening assessments, the investigator or designee will document the subject 
as a screen failure in the IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening, 
placebo lead-in, or baseline visits. Subjects cannot be rescreened once they have been 
designated as a screen failure unless the screen failure was due to a concomitant medication 
that can be discontinued; those subjects can be rescreened.
7.1.1.1
Screening Visit (Visit -1) 
The screening visit (Visit -1) assessments and procedures, beginning with informed consent, 
will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight.

Review current use of concomitant medications, including medications taken and 
procedures completed within 3 months prior to the biopsy required for entrance to this 
study. Note: Subjects who are on a PPI must remain on the same dose of the PPI 
throughout the study, and if they are not taking a PPI, they must remain off of a PPI for 
the remainder of the study.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 48 of 91
The following order is recommended for the remaining procedures that will be performed at 
this visit or within the 6-week screening period:

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly 
completion and train the subject on its use. In order to qualify for study entry, subjects 
must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks 
of the screening period.

Perform a physical examination on all subjects. Adolescents (subjects ≤17 years) will also 
undergo Tanner Staging Assessment.

Serum pregnancy test will be performed on all female subjects. 

Perform EGD and biopsy; both must be performed within the 6 weeks prior to the Placebo 
Lead-in Visit either at the investigative site or by a referring physician. Biopsy specimens 
must be available to be sent to the central pathology lab at least 2 weeks prior to the 
Placebo Lead-in Visit to allow sufficient time for processing and central review and 
determination of eligibility.
7.1.2
Placebo Lead-in Period (Weeks 0 to 4)
The placebo lead-in period will comprise 4 weeks, during which all procedures listed for the 
placebo visit (Visit 0) in Table 1-1 shall be completed.
During the 4-week single-blind placebo lead-in, all eligible subjects will self-administer 
10 mL of placebo twice daily (qAM, pc, and hs). 
At the end of the placebo lead-in period, eligible subjects (those with at least 4 reported 
dysphagia days and completion of DSQ on ≥70% of days in the 2 weeks prior to baseline  
[Visit 1]) will be randomized and enter the 12-week double-blind treatment period (baseline 
visit). Subjects must be administrated placebo during the placebo lead-in period for 4 weeks 
(±3 days) prior to Visit 1 (baseline) to be eligible for randomization into the 12-week double-
blind treatment period.
7.1.2.1
Placebo Lead-in Visit (Visit 0) 
The placebo lead-in visit (Visit 0) assessments and procedures will be performed as outlined 
in Table 1-1. 
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 49 of 91

Perform AE assessments.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

Perform a physical examination and assess any changes since screening.

Urine pregnancy test for female subjects.  

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD)
in subjects aged 11-17 years, inclusive; the DXA scan may be performed any time during 
the placebo lead-in period, after the subject has met all screening criteria and prior to 
blinded-treatment randomization. Baseline and post-treatment DXA scans should be 
performed using the same machine and software.

Dispense placebo study medication and review administration instructions. Subjects will 
self-administer the first dose of placebo in the clinic after eating breakfast. Site personnel 
will record the date and time of the first placebo dose in the source documents. Beginning 
on the evening of Visit 0, the subject will take their second dose at home and continue 
with the twice daily (qAM, pc, and hs) dosing regimen.
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or Early 
Termination)
The double-blind treatment period will comprise 12 weeks, during which all assessments and 
procedures listed for Visits 1-4 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted, unless otherwise specified. Visit 
windows are calculated based upon the date of the placebo lead-in visit (Visit 0).
Subjects who continue to meet all eligibility criteria will be randomized 2:1 to receive either 
OBS twice daily (qAM, pc, and hs) or placebo twice daily (qAM, pc, and hs). The 
investigator or assigned site staff will access the IWRS to randomize the subject and dispense 
the investigational product. Subjects who fail to meet eligibility criteria at the baseline visit
(Visit 1) will be documented as screen failures in the IWRS.
Subjects who complete the 12-week double-blind treatment period will have the opportunity 
to enroll in the treatment extension study. These subjects will continue on the blinded 
assigned treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment 
extension study. Subjects who do not enroll in the treatment extension study or who 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 50 of 91
discontinue prematurely at any time during the SHP621-301 (Induction) study will receive a 
follow-up phone call 4-weeks post last dose of investigational product.
7.1.3.1
Baseline Visit (Visit 1): Week 4
Subjects will return to the site for the baseline visit (Visit 1) to confirm eligibility. The 
baseline visit (Visit 1) assessments and procedures will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight. Perform stadiometry in subjects aged 
11-17 years, inclusive. 

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of 
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review study medication dosing compliance.

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

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 PGI-S of disease assessment. 

Perform a physical examination and assess any changes since screening.

Re-administer urine pregnancy test for female subjects.  


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 51 of 91

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will 
record the date and time of the first randomized dose in the source documents. Beginning 
on the evening of Visit 1, the subject will take their first dose at home and continue with 
the twice daily (morning and evening) dosing regimen. For subjects who are minors (<18 
years), a parent/guardian will be responsible for ensuring subject takes their 
investigational product appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.2
Visits 2 and 3 (Weeks 8 and 12)
Subjects will return to the site for Visit 2 (Week 8) and Visit 3 (Week 12). Assessments at 
these visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of study medication until after the morning cortisol test has 
been performed. 

Collect blood samples for pharmacokinetic analysis for adult subjects. Subjects will be 
instructed to take their morning dose at a set time to establish the schedule for post-dose 
sample collection.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

Administer PGI-S assessment. 

Perform a physical examination and assess any changes since screening.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 52 of 91

Re-administer urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) and review investigational product 
dosing compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.3
Visit 4 (Week 16)
Subjects will return to the site for Visit 4 (Week 16). Assessments at this visit will be 
performed as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight. Perform stadiometry in subjects aged 
11-17 years, inclusive.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing. 

Retrieve DSQ handset and review DSQ compliance.

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S assessment. 

Perform a physical examination and assess any changes since screening. Adolescents 
(subjects ≤17 years) will also undergo Tanner Staging Assessment.

Re-administer serum pregnancy test for female subjects.  

Perform DXA scan for BMD in subjects aged 11-17 years, inclusive. DXA scan should be 
completed at or within 7 days of this visit. Baseline and post-treatment DXA scans should 
be performed using the same machine and software.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 53 of 91

Perform EGD and biopsy. EGD should be completed at or within 7 days of the scheduled 
visit.

For eligible subjects continuing into the treatment extension study, obtain informed 
consent for the treatment extension study, dispense investigational product (OBS or 
placebo) according to IWRS randomization and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product if they are continuing in the treatment extension study.
7.1.4
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational 
product. Subjects who do not enroll in the treatment extension study or who discontinue 
prematurely at any time during the study will receive a follow-up 4 phone call at Visit 5 
(Week 20) to query for SAEs, AEs, and concomitant treatments (Section 7.1.4.1).
7.1.4.1
Safety Follow-up Contact (Visit 5): Week 20
Assessments at this time, as outlined in Table 1-1, will include the following:

Review concomitant medications and procedures.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE; all AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure.
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study for those subjects who do not enroll in the treatment 
extension study.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in 
Appendix 1.
All assessments listed below will be performed by the subject and/or a qualified/trained site 
staff as indicated in the assessment description. For subject-completed assessments, trained 
site staff should not assist the subject in completing assessments in such a manner that it 
would influence their responses. Site staff should review the completed assessment to ensure 
completeness.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 54 of 91
If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales 
after the visit has been completed. Assessments are to be performed according to the schedule 
shown in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and Histopathologic 
Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
An EGD with esophageal, gastric and duodenal biopsies will be required for study 
participation; the peak eosinophil count per HPF from each esophageal level will be used as a 
primary measure of efficacy. The qualifying/baseline EGD with biopsies must be performed 
by a physician at the investigative site within the 6 weeks prior to placebo lead-in visit 
(Visit 1). Biopsy specimens must be available to be sent to the central pathology lab by at 
least 2 weeks prior to the placebo lead-in visit to allow sufficient time for processing and 
central review and determination of eligibility.
Multiple specimens (at least 2 biopsies from each of 3 levels, 6 specimens total) will be 
obtained from the proximal (3 cm below the cricopharyngeus muscle), mid-esophagus (mid-
point between the cricopharyngeus muscle and the gastroesophageal junction), and distal 
(3 cm above the gastroesophageal junction). Biopsy tissue will be placed in 3 separate vials 
(1 vial for each of the levels) and sent to the central pathology laboratory for processing of 
tissue into slides. A central pathologist will determine histologic eligibility for study entry. 
Peak eosinophil counts of ≥15/HPF in specimens from 2 or more levels of the esophagus will 
be a requirement for study entry, as determined by a central pathologist. Eosinophil counts, 
histopathologic features, and gross endoscopic findings will be evaluated and scored for each 
EGD. Eight histopathologic epithelial features (basal layer hyperplasia, eosinophil density, 
eosinophil microabscesses, eosinophil surface layering, dilated intercellular spaces, surface 
epithelial alteration, dyskeratotic epithelial cells, lamina propria fibrosis) will be scored on a 
4-point scale (0=normal, 3=worst) for both the severity of the abnormality (ie grade) and the 
amount of tissue affected by the abnormality (ie, stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 
2) fixed esophageal rings (grade 0–3); 3) edema (grade 0–1); 4) furrows (grade 0–1); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed 
for each anatomic location (proximal and distal). The maximum endoscopy score is 10 points 
for each location, and a Total Endoscopy Score is the sum of the scores for the proximal and 
distal locations.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 55 of 91
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. Biopsies will be taken from the stomach and duodenum for the screening EGD 
as follows: gastric body (greater curvature): 2 specimens, gastric antrum: 2 specimens, and 
duodenum (third part or distal): 2 specimens. Biopsies from the stomach should be submitted 
in one vial; biopsies from the duodenum should be submitted in a separate vial to the central 
pathology laboratory for processing of tissue into slides. If the pre-treatment biopsy identifies 
eosinophilia in the stomach and/or duodenum, the subject will be excluded from the study. 
At the Week 16 visit (Visit 4) or at early termination (ET), and EGD with esophageal biopsies 
(at least 2 biopsies from each of 3 levels [proximal, mid-, and distal]) is required. Endoscopic 
findings will be recorded by the endoscopist.  Biopsies will be sent to the central laboratory 
for processing. A central pathologist will evaluate the slides. Gastric and duodenal biopsies 
may be repeated at the discretion of the investigator, but are not required.
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 2). 
The questionnaire will be completed by subjects daily for a minimum of 3 weeks during the 
screening period, during the 4-week placebo lead-in period, and during the 12-week treatment 
period. Each evening before bedtime, subjects will be asked to indicate if they experienced 
dysphagia symptoms (eg, food passing slowly or food sticking) during that day. Subject must 
have experienced dysphagia (response of “yes” to question 2 on DSQ) on a minimum of 
4 days total and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period and in the 2 weeks prior to the baseline visit (Visit 1). Subjects must fill out 
the DSQ at least 5 or more days during a given week in order to be compliant.
Calculations will be performed on daily ePRO entries from the screening period, during a 
2-week interval prior to the baseline period, and prior to each study visit during the baseline 
and treatment periods. The DSQ score for the co-primary endpoint and secondary endpoints 
will be calculated by summing the scores of responses to questions 2 and 3 only. Questions 1 
and 4 will be excluded from the DSQ score:

DSQ score=   (Sum of points from questions 2+3 in the daily DSQ)×14
Number of diaries reported with non-missing data
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores 
of responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score= (Sum of points from questions 2+3+4 in the daily DSQ)×14
Number of diaries reported with non-missing data


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 56 of 91
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score=(Sum of points from question 4 in the daily DSQ)×14
Number of diaries reported with non-missing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
Medical History
The investigator must record all clinically or medically relevant information regardless of 
how much time has elapsed since the date of any diagnosis. Medical history will be classified 
as EoE or non-EoE by the investigator. The EoE medical history must include any prior 
history of esophageal strictures and esophageal dilations.
Medication History
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, 
or other), must be recorded on the appropriate CRF page.
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit -1) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit -1) 
will be captured as AEs on the AE CRF page, as deemed by the investigator.
Physical examination assessments at each visit should also include specific assessments for 
signs of glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swings, insomnia, and 
depression). Physical examination at the screening visit (Visit -1) will also include Tanner 
Staging Assessments for subjects <18 years of age.
Height will be collected at the screening visit (Visit -1) and Visit 4 for all subjects. 
Stadiometers will be used to measure height at Visit 1 and Visit 4 for subjects aged 
11-17 years, inclusive. Statural height will be measured by trained site staff using a stabilized 
stadiometer. The same stadiometer should be used for the baseline and post treatment 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 57 of 91
measurements. Standard measuring procedures should be followed (eg, removal of socks, 
shoes, and hats; calibration frequency). Please refer to the study manual for additional details.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). AEs are collected from the time informed consent is signed. (Please refer to 
Section 8.)
AE assessments at each visit should also include specific assessments for signs of 
glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and 
depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes 
immediately prior to the assessment and will include blood pressure (systolic and diastolic), 
heart rate, respirations, and temperature. Blood pressure should be determined by cuff (using 
the same method, the same arm, and in the same position throughout the study). Any 
clinically significant deviations from baseline (Visit 1) vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. All subjects must fast overnight prior to collection of clinical laboratory tests.
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

blood urea nitrogen 

creatinine

sodium 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 58 of 91

total bilirubin

total protein

albumin

glucose 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
ACTH stimulation testing will be performed by measuring the levels of cortisol in the blood 
following the injection of a synthetic form of ACTH. The type of synthetic and route of 
administration will be per local lab discretion. Blood samples will be collected just prior to 
and approximately 30 and 60 minutes following the injection. 
In the event of clinically significant abnormal laboratory test results, follow-up laboratory 
tests may be conducted. Any clinically significant abnormalities noted in the laboratory tests 
will be discussed with the medical monitor.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 59 of 91
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit
(Visit -1) and the final treatment evaluation visit (Visit 4) or ET visit. A urine pregnancy test 
is performed on all female subjects at the placebo lead-in visit (Visit 0), baseline visit (Visit 
1), Visit 2, and Visit 3 or if pregnancy is suspected.
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density
DXA (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.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body 
less head (Bachrach, 2011; Gordon, 2008; International Society for Clinical Densitometry, 
2013). The same DXA machine and software should be used for the baseline and 
post-treatment scans. The DXA manufacturer, model, and software version should be 
recorded in the CRF.
7.2.3
Other Assessments
7.2.3.1
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.
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 Group, 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 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 60 of 91
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.
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, 2013; PROQOLID). The
PedsQL-EoE module consists of 33 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.
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 37-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.
7.2.3.2
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.
7.2.4
Clinical Pharmacology Assessments
Blood samples will be collected from adult subjects (≥18 years of age) as outlined in Table 
1-1 to measure plasma concentrations of budesonide. Subjects who do not participate in 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 61 of 91
pharmacokinetic sampling will not be discontinued from the study, and lack of participation 
will not be a considered protocol deviation. 
Actual pharmacokinetic blood sample collection times vs time of dosing will be monitored. 
The sponsor’s expectation is that the investigator will ensure that every effort will be made to 
collect all pharmacokinetic blood samples at the precise protocol scheduled time. 
Pharmacokinetic blood collection must not deviate from the nominal collection time set forth 
in the protocol by more than ± 5 minutes for samples drawn within 4 hours post-dose or by 
more than ± 15 minutes for samples drawn after 4 hours post-dose. Samples drawn outside 
these parameters will be considered a protocol deviation.
Blood samples (4 mL) for pharmacokinetic analysis will be drawn by direct venipuncture into 
K2EDTA tubes, capped and mixed by inversion (×3), and chilled immediately on crushed ice. 
The actual blood collection time will be recorded in the subject’s source documents and on 
the appropriate CRF page (24-hour format). After applying a tourniquet, venous blood will be 
drawn with a disposable needle. If a catheter is used, the first milliliter of blood on each 
sampling occasion will be discarded. Saline can be used to keep catheters patent.
Within 15 minutes following each sample collection, the blood tubes will be centrifuged at 
approximately 1500 g (15 minutes, 4°C). The separated plasma will be decanted into 
appropriately labeled primary and backup polypropylene tubes via a plastic pipette. All 
samples will be stored nominally at -20°C, and the freezer temperature will be controlled, 
monitored, and recorded during the storage period until the samples are shipped to the 
designated bioanalytical laboratory for analysis.
For additional information detailing sample handling, storage, and shipment, see Appendix 4.
7.2.5
Volume of Blood to Be Drawn from Each Subject
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Pharmacokinetic samplesa
5
9
45
Safety
Biochemistry and -hCGb
6
6
36
ACTH
2
4
8
Cortisol
2
4
8
Hematology
2
6
12
Total mL
109
Abbreviations: ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropin
a
If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for pharmacokinetic 
sample.  A total of 5 mL of blood drawn has been used in determination of sample volume.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 62 of 91
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
b
-hCG testing is for females only.
During this study, it is expected that approximately 109 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 109 mL. When more than 1 blood assessment is to be done 
at the time point/period, if they require the same type of tube, the assessments may be 
combined.  
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 7.1.4. This includes events occurring during the screening phase of 
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 63 of 91
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 pre-treatment 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.
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.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 64 of 91
Table 8-1: Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent 
disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or 
other drugs and chemicals and which follows a clinically reasonable response on 
de-challenge.  The association of the clinical event or laboratory abnormality must 
also have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (de-challenge), and reappears upon 
repeated exposure (re-challenge).  Note that this is not to be construed as requiring 
re-exposure of the patient to study drug; however, the determination of definitely 
related can only be used when recurrence of event is observed.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 65 of 91
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 phase, there are abnormal clinical laboratory or vital sign values 
which were not present at the pre-treatment 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 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
the Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire medical monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event 
Form for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is 
not considered an SAE.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 66 of 91
In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical 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 pre-specified 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 
parent/legally authorized representative/caregiver.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 67 of 91
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global
Pharmacovigilance and Risk Management Department and the CRO medical monitor within 
24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see Section 
8.1.7) unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form 
for SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 
Pharmacovigilance and Risk Management Department. A copy of the Shire Clinical Study 
Adverse Event Form for SAEs and Non-serious AEs as Required by Protocol (and any 
applicable follow-up reports) must also be sent to the CRO medical monitor using the details
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should 
not be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 68 of 91

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be 
reported to the Shire Global Pharmacovigilance and Risk Management Department and the 
medical monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Global Pharmacovigilance and Risk Management Department within 24 hours of the first 
awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The 
resolution date is the date the event no longer meets serious criteria, the date the symptoms 
resolve, or the event is considered chronic. In the case of hospitalizations, the hospital 
admission and discharge dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent form, leading up to the onset date of the SAE, or following the resolution date of the 
SAE must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of 
death) must have “fatal” checked as an outcome with the date of death recorded as the 
resolution date. For all other events ongoing at the time of death that did not contribute to the 
subject’s death, the outcome should be considered as not resolved, without a resolution date 
recorded.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 69 of 91
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).
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.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy.  
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 70 of 91
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability 
data) will be handled with special care during the data cleaning and review process. These 
data will be handled in such a way that, prior to unblinding, any data that may unblind study 
team personnel will be presented as blinded information or otherwise will not be made 
available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be 
performed using SAS® (SAS Institute, Cary, NC, USA) version 9.1 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.
In addition to a final SAP for the final analysis, a separate interim SAP for the interim 
analysis will be finalized prior to unblinding and performing the analysis to preserve the 
integrity of the statistical analysis and study conclusions. The SAP for the final analysis will 
be finalized prior to final database lock and performing analysis (ie, unblinding) to preserve 
the integrity of the statistical analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A planned interim analysis for each of the co-primary endpoints will take place after 50% of 
all randomized subjects have either completed the study or prematurely withdrawn from the 
study, whichever comes first. The purpose of the unblinded interim analysis is to reassess the 
appropriateness of assumptions used for each of co-primary efficacy endpoints when the 
study was designed. The reassessment of the sample size will utilize the conditional power 
approach under certain conditions that do not inflate the type I error (Mehta and Pocock,
2011). The planned interim analysis will be conducted by an external independent statistical 
(EIS) group; the individuals involved in the day-to-day conduct of the trial will not be 
involved in the interim analysis or have access to the results of the interim analysis. The 
Sponsor will only be notified by the EIS group if any recommendation of increasing the 
sample size is needed from the conditional power; this will be detailed in the pre-specified 
interim SAP including a potential maximum sample size to be increased if deemed necessary.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 71 of 91
A very minimal fraction of alpha (0.0001) will be spent at the interim analysis as the trial will 
not stop due to the interim results. The final analysis will use 4.99% for each of the 
co-primary endpoints in order to preserve an overall type I error at 5% level.
9.6
Sample Size Calculation and Power Considerations
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected 
difference between treatment response proportions of 69% and 45% in the OBS 2 mg twice 
daily (qAM, pc, and hs) and placebo groups, respectively. A total of 228 subjects 
(152 subjects randomized to OBS and 76 subjects randomized to placebo) are required to 
achieve 90% power at the significance level of 0.0499 (2-sided) using a 2-group chi-square 
test with unequal allocation 2:1 to treatment groups (OBS 2 mg twice daily and placebo). 
With the specified number of subjects per treatment group, the study will be powered at 99% 
assuming histological response proportions of 40% and 3% in the OBS 2 mg twice daily and 
placebo groups, respectively. The overall study power for the co-primary endpoints will be at 
least 85%. Therefore, approximately 228 (approximately 152:76 OBS and placebo subjects, 
respectively) will be randomized to the study to allow for a loss of approximately 5% of 
subjects due to dropouts or invalid data. 
9.7
Study Population
The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. 
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose 
of a double-blind investigational product and have both an evaluable post-baseline biopsy in 
the treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and 
a post-baseline DSQ score.
The per-protocol (PP) set will include all subjects in the FAS excluding subjects with 
protocol violations. The PP set will be identified prior to unblinding the treatment 
assignments by a team consisting of, at a minimum, a physician and a statistician from Shire. 
The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
9.8
Efficacy Analyses
The primary, key secondary, and secondary efficacy analyses will be performed on the ITT
set and presented by treatment group.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 72 of 91
Data collected at the baseline visit (Visit 1) will be used as the baseline for all efficacy 
analyses.
9.8.1
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4)
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the 
co-primary efficacy endpoints is a binary response (ie, responders vs non-responders); the 
endpoint will be analyzed using a logistic regression model with effects of treatment group, 
age group (either <18 years or ≥18 years), and their interaction. The main-effect model will be 
considered the final definitive model if the interaction between treatment and age group is not 
statistically significant at the 10% level. The odds ratio of being a responder on each of the 
co-primary endpoints for the OBS 2 mg twice daily group vs placebo group and associated 
95% confidence interval (CI) will be estimated from the final model. Subjects who withdraw 
without providing efficacy data at the final treatment period evaluation (Visit 4, Week 16) 
will be classified as non-responders in the primary efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized, and their respective 95% CI will be reported. The 
difference in the proportion of responders between the 2 treatment groups and the 
corresponding 95% CI will also be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to 
evaluate the robustness of the results from the primary analysis methods: 

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing 
efficacy data at the final treatment period evaluation (Visit 4) and will be classified as 
responders.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 73 of 91
9.8.1.1
Missing Data Imputation
Method 1: Distribution-based Imputation
The subjects with missing co-primary efficacy endpoints will be assigned randomly according 
to the distribution of responders with available data for each of the co-primary endpoints (ie, 
those with non-missing data) across the 2 treatment groups by strata (see Table 9-1). 
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata
Strata
No
Yes
<18 years
X0%
X1%
≥18 years
Y0%
Y1%
For instance, if there are N subjects with missing data in strata 1 (age <18 years), then 
X0%*N subjects will be randomly assigned as non-responders and X1%*N subjects will be 
randomly assigned as responders.
Conversely, if there are M subjects with missing data in strata 2 (age ≥18 years), the Y0%*M 
subjects will be randomly assigned as non-responders and Y1%*N subjects will be randomly 
assigned as responders.
Method 2: Multiple Imputations
Multiple imputation (MI) methods will utilize the SAS procedures PROC MI and PROC 
MIANALYZE. The MI procedure will involve fitting a logistic regression model with the 
binary outcome (responders vs non-responders) as the dependent variable and the age group 
and the treatment group as the independent variables. The MI procedure will generate 
10 version datasets with binary outcome imputed from the subjects with complete data. Once 
the missing values are imputed and each dataset is created, the results will be appropriately 
pooled across the multiply imputed estimated regression coefficients and their standard errors 
using PROC MIANALYZE.
Other sensitivity analyses will be explored, and details will be provided in the SAP.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4). The change 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 74 of 91
from baseline DSQ score at the final treatment period evaluation (Visit 4) will be analyzed 
using an analysis of covariance (ANCOVA) model with treatment group and age group as 
factors and the baseline DSQ score as a continuous covariate.
The additional secondary efficacy endpoints are the following:

Change in total endoscopy score, as measured by the EREFS classification, from baseline 
to the final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)

Change from baseline in the histopathologic epithelial features combined total score 
(grade and stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a  ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation 
(Visit 4)

Change from baseline in the DSQ combined score (questions 2+3) over time including 
post baseline visits

Cumulative distribution function curves for the change and the percent change in the DSQ 
score from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline 
to the final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF 
across all esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from 
baseline to the final treatment period evaluation (Visit 4) and a peak eosinophil count of 
≤6/HPF across all esophageal levels at the final treatment period evaluation (Visit 4)

Symptom response on DSQ + pain score (binary response), defined as ≥30% and 50% 
reductions in the DSQ combined score (questions 2+3+4) from baseline to the final 
treatment period evaluation (Visit 4)

Symptom response on DSQ + pain score (binary response), defined as a ≥30% and 50% 
reduction in the DSQ score (question 4), from baseline to the final treatment period 
evaluation (Visit 4)
The binary response endpoints will be analyzed using the same logistic model as the 
co-primary efficacy endpoints.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 75 of 91
Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model 
that includes treatment group and age group as factors and baseline score as a covariate.
The analyses for all secondary efficacy endpoints (including the key secondary efficacy 
endpoint) will be carried out using 2-sided tests at the 5% level of significance. For each of 
the secondary efficacy endpoints, the treatment difference, corresponding 95% CI for the 
difference, and treatment comparison p-value for testing the null hypothesis of zero treatment 
effect based on the final statistical model (ie, either logistic regression model or ANCOVA 
model) will be provided.
9.8.3
Exploratory Efficacy Endpoint
The exploratory endpoint that will be explored is the following:
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the baseline visit (Visit 1) or the last preceding visit if not 
collected at Visit 1 will be used as the baseline value for safety analyses.
TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product (Visit 1) and no later than 3 days following the last dose of investigational product.
However, for any subjects who die during the study (ie, the date of death is between the date 
of first dose of investigational product and the date of study discontinuation entered by the 
site, inclusive), all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs irrespective of the last dose and will be included in the TEAE 
summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of 
TEAEs will be calculated overall by system organ class (SOC), preferred term (PT), and 
treatment group. TEAEs will be further summarized by severity and relationship to 
investigational product. AEs related to investigational product, AEs leading to withdrawal, 
SAEs, and deaths will be similarly summarized/listed.
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight 
and height assessments, DXA scans for BMD measurements (for adolescents aged 
11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum 
pregnancy test, if appropriate), and ACTH stimulation tests. To account for the effects of 
puberty in adolescent subjects (11-17 years of age, inclusive), BMD z-scores will be adjusted 
for height z-scores using the Bone Mineral Density in Childhood Study calculator. Safety 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 76 of 91
parameters will be descriptively summarized by treatment group at baseline and for each post-
baseline visit.
9.10
Other Analyses
9.10.1
Health-related Quality-of-life Analyses
The health economics and outcomes research endpoints that will be explored are the 
following:

EoE-QoL-A Questionnaire (Taft et al., 2011)

EQ-5D (EQ-5D-3L or EQ-5D-Y, according to subject’s age)

PedsQL-EoE
The sub-modules of the EoE-QoL-A and PedsQL-EoE will be assessed in addition to the 
overall score with a focus on emotional and physical elements. For all HRQoL analyses, 
change from baseline to the final treatment period evaluation (Visit 4) will be assessed.
9.10.2
Pharmacokinetic Analyses
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis.  
The pharmacokinetic endpoints will include but not be limited to those listed in Table 9-2.
Table 9-2: Pharmacokinetic Parameters
Parameter
Definition
AUC0-tau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing interval
Summary statistics (number of observations, mean, standard deviation, coefficient of 
variation, median, maximum, minimum, and geometric mean) will be determined for all 
pharmacokinetic parameters by overall and by week. Plasma concentrations at each nominal 
sampling time will also be summarized using descriptive statistics.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 77 of 91
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third-party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ 
names and contact information.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 78 of 91
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
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 sub-investigators 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). 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 79 of 91
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the 
source data per the monitoring plan. If the data are unclear or contradictory, queries are sent 
for corrections or verification of data.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 80 of 91
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to
subject’s medical file, original clinical laboratory reports, and histology and pathology 
reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective 
national, local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities 
and have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment,
retainer for ongoing consultation, or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 
2(b) (1998).


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 81 of 91
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 parent/legally
authorized representative/caregiver of the safe, 
responsible storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and 
received their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor, prior to the start of the 
study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification 
of the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator 
or, for multicenter studies, the coordinating principal investigator or sponsor, according to 
national provisions.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 82 of 91
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
Investigational product supplies will not be released until the CRO has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market SHP621; national or local regulatory authorities; and the IRBs/ECs which
gave approval for the study to proceed. The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purposes of any such transfer would 
include supporting regulatory submissions, conducting new data analyses to publish or 
present the study results, or answering questions asked by regulatory or health authorities.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 83 of 91
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this 
policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) 
the copyright on his/her publications. To the extent that the principal investigator has such 
sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 84 of 91
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.
11.
REFERENCES 
Bachrach LK, Sills IN, Section on Endocrinology. Clinical report—Bone densitometry in 
children and adolescents. Pediatrics 2011;127:189-194.
Bone 
Mineral 
Density 
in 
Childhood 
Study 
(BMDCS). 
Available 
at:
http://www.bmdcspublic.com. Accessed August 5, 2015. 
Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in the United 
States. Clin Gastroenterol Hepatol 2014a;12(4):589-96.
Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic 
esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc 2014b;79(4):577-85.
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208.
Food and Drug Administration. Uceris pharmacology review. NDA 203-634. 2011.
Franciosi JP, Hommel KA, Bendo CB. PedsQL eosinophilic esophagitis module: feasibility, 
reliability, and validity. J Pediatr Gastroenterol Nutr 2013;57(1):57-66.
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: 
a systematic review and consensus recommendations for
diagnosis and treatment. 
Gastroenterology 2007;133(4):1342-63.
Gordon CM, Bachrach LK, Carpenter TO, et al. Duel energy X-ray absorptiometry 
interpretation and reporting in children and adolescents: The 2007 ISCD pediatric official 
positions. J Clin Densitometry 2008;11:43-58.
Hirano I, Aceves S. Clinical Implications and Pathogenesis of Esophageal Remodeling in 
Eosinophilic Esophagitis. Gastro Clin North Am 2014;43(2):297-316.
International Society for Clinical Densitometry. 2013 Official Positions—Adult & Pediatric. 
2014:1-20.
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
recommendations for children and adults. J Allergy Clin Immunol 2011;128 (1):3-20. 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 85 of 91
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med 2011;30(28):3267-84.
Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID). 
Available at: http://www.proqolid.org. Accessed August 24, 2015. 
Taft TH, Kern E, Kwiatek MA. The adult eosinophilic oesophagitis quality of life 
questionnaire: a new measure of health-related quality of life. Aliment Pharmacol Ther 
2011t;34(7):790-8.
Wille N, Badia X, Bonsel G, et al. Development of the EQ-5D-Y: a child-friendly version of
the EQ-5D. Qual Life Res 2010;19(6):875-86. 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 86 of 91
12.
APPENDICES


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 87 of 91
Appendix 1
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Subject
EQ-5D
Subject
PedsQL-EoE (subjects 11-17 years of age, inclusive)
Subject and parent or legal 
guardian
EoE-QoL-A (subjects ≥18 years of age)
Subject
PGI-S
Subject
Tanner Staging Assessment
Site
EREFS
Site
Abbreviations: DSQ=Dysphagia Symptom Questionnaire; EoE-QoL-A=Adult Eosinophilic Esophagitis Quality 
of Life; EQ-5D=EuroQol; EREFS=EoE Endoscopic Reference Score; PedsQL-EoE=Pediatric Quality of Life 
Inventory – EoE; PGI-S=Patient Global Impression of Severity
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. 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 88 of 91
Appendix 2
Dysphagia Symptom Questionnaire ePRO for EoE


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 89 of 91
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


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 90 of 91
Appendix 4
Biosciences Generic Clinical Protocol Insert
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1-1 to measure plasma 
concentrations of budesonide. Potential metabolites may also be determined as appropriate.
Blood samples 4 mL for pharmacokinetic analysis will be drawn by in-dwelling catheters or 
direct venipuncture into K2EDTA tubes, capped and mixed by inversion (x3), and chilled 
immediately on crushed ice. The actual time that the sample was obtained will be recorded in 
the subject’s source document and on the appropriate CRF page. After applying a tourniquet, 
venous blood will be drawn with a disposable needle. If a catheter is used, the first milliliter 
of blood on each sampling occasion will be discarded. Saline can be used to keep catheters 
patent.
1.1
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after 
collection within <15 minutes, unless advised otherwise by refrigerated centrifugation (4C, 
1500 rpm 15 minutes). The separated plasma will be decanted into appropriately labeled 
polypropylene tubes via a plastic pipette. All samples will be stored at approximately -20C 
or colder and the freezer temperature will be controlled, monitored, and recorded during the 
storage period until they are transferred in the frozen state to a designated bioanalytical 
contract laboratory. Samples will remain frozen at -20C or colder until analysis.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe 
labels provided by the central laboratory. The labels will contain the following information:

Study number

Subject identifier (randomization number)

Matrix identifier (plasma)

Visit

Nominal time
1.2
Shipment of Plasma Samples
Plasma samples should be double-bagged to contain leaks and packed with a sufficient 
quantity of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in 
shipment. All applicable shipping regulations must be followed. Shipments should be 
scheduled so that no samples arrive on the weekend and should be shipped Monday to
Wednesday only. 


Shire
CONFIDENTIAL
31 Aug 2015
Protocol SHP621-301
Version 1.0
Page 91 of 91
Plasma samples, along with the corresponding documentation, will be shipped to:
PPD
2 Tesseneer Drive
Highland Heights, KY 41076, USA
Email: 
Phone:  
 or 
, 
Fax:  
Plasma samples will be stored nominally at -20C prior to and after analysis at Covance until 
their disposal is authorized by Shire.
1.3
Assay Methodology
Drug analysis will be performed at Covance under the guidance of the NCE group at Shire. 
Plasma sample analysis will be performed according to the bioanalytical study plans prepared 
for the study. 
Plasma samples will be analyzed at Covance for budesonide using the most current validated 
bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample 
reproducibility (full details will be described in the bioanalytical study plan). The presence of 
other metabolites or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at Covance.


PROTOCOL:  SHP621-301
TITLE:
Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis: 
A Phase 3 Randomized, Double-blind, Placebo-controlled Study
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol:  31 Aug 2015
Protocol Amendment 1: 17 Dec 2015
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations.  This information should be used solely for the purposes for 
which it was provided and should not be copied, shared with, or disclosed to any third party without the express 
written consent of Shire.


Shire 
Protocol SHP621-301 
CONFIDENTIAL 
Amendment 1 
17 December 2015 
Page 2 of98 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
 MD 
 
 
 Clinical Development 
Date: 
Acknowledgement 
I have read this protocol for Shire Study SHP621-301. 
Title: Oral budesonide suspension (OBS) in Adolescent and Adult Subjects (11 to 55 years 
of age, inclusive) with Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, 
Placebo-Controlled Study 
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 pmticipate. 
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 pmticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate 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 
(please hand print or type) 
= 
Signature: --------------------------------- Date: 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 3 of 98
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The SHP621-301 protocol is amended to include the addition of safety-related stopping 
criteria and a diet stratification factor. Additional edits, as captured in the below table, were 
made to Protocol Amendment 1 to improve the clarity of the protocol and/or correct minor 
inconsistencies. Note that correction of typos and grammatical errors are not captured in the 
below table.
New text indicated in bold; deleted text indicated in strikethrough.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
16 Dec 2015
Global Amendment
Description of Change
Section(s) Affected by Change
Changed from:
, MD, PhD
, Clinical Development
To:
, MD
, Clinical Development
Protocol Signature page; Sponsor 
Medical Monitor
Changed from:
 
To:
Emergency Contact Information 
Page
“Each bottle contains approximately 210 mL of suspension…”
Study Synopsis, Investigational 
product, dose, and mode of 
administration; Section 3.1, Study 
Design; Section 6.1, Identity of 
Investigational Product
…the investigational product will be supplied in amber glass, multi-
dose bottles with child-resistant caps and refrigerated throughout the 
study (in the clinic and subject’s home).
Study Synopsis, Investigational 
product, dose, and mode of 
administration; Section 3.1, Study 
Design; Section 6.1.1, Blinding the 
Treatment Assignment
A minimum of 40 randomized subjects will be aged 11-17 years, 
inclusive.
The randomization will be performed centrally and stratified by 
age group (2 strata total: <18 years or ≥18 years) and diet 
restriction for EoE or other health-related conditions (no diet 
restriction or any diet restriction). The stratification by age will 
Study Synopsis, Methodology; 
Section


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 4 of 98
ensure a minimum of 40 subjects in the pediatric group (11-17 
years, inclusive). The stratification by age and diet restriction will 
ensure balance between treatment groups for the respective 
stratification factors.
Subjects cannot be rescreened once it is confirmed they do not meet 
inclusion/exclusion criteria unless the screen failure was due to a 
concomitant medication that can be discontinued prior to 
rescreening; those subjects may be rescreened. they have been 
designated as a screen failure unless due solely to the use of a 
concomitant medication which can be stopped prior to rescreening
Other reasons for rescreening (ie, reasons unrelated to 
inclusion/exclusion criteria) must be discussed prospectively with 
the medical monitor.
Study Synopsis, Methodology; 
Section; Section 3.1, Study Design; 
Section 6.2.1, Interactive Response 
Technology for Investigational 
Product Management; Section 7.1.1, 
Screening Period (Weeks -6 to 0)
6. If PPI responsiveness was excluded by a previous EGD and 
biopsy, the historical EGD and biopsy must have been performed 
after the patient had been on a minimum of 6 weeks of high-dose 
PPI therapy.
Rationale: Inclusion criterion is modified to allow entry of subjects 
with at least 6 weeks of historical data demonstrating PPI 
responsiveness since the duration of PPI needed to exclude PPI 
responsiveness may vary by local standard of care.
Study Synopsis, Inclusion Criteria; 
Section 4.1, Inclusion Criteria
4. Subject has been on inhaled or intranasal steroids and has not been 
on stable treatment for ≥3 months prior to screening visit (Visit -1). 
Subjects on intranasal or inhaled steroids need to stay on a stable 
treatment during study participation. Subject has been on intranasal 
steroids and has not been on stable treatment for a minimum of 
4 weeks prior to the qualifying EGD. After the qualifying EGD,
subjects with seasonal allergic rhinitis may resume (or discontinue) 
intranasal corticosteroids based on the subject's usual treatment 
regimen for allergy season.
Study Synopsis, Exclusion Criteria; 
Section 4.2, Exclusion Criteria
5. Subject has initiated, discontinued, or changed dosage regimen of 
PPIs, H2 antagonists, antacids, antihistamines, or leukotriene 
inhibitors.
Study Synopsis, Exclusion Criteria; 
Section 4.2, Exclusion Criteria
20. Subject has taken part in an interventional investigational study 
related to EoE within 6 months prior to the screening visit (Visit -1), 
and or investigational study within 30 days prior to the screening 
visit (Visit -1).
Study Synopsis, Exclusion Criteria; 
Section 4.2, Exclusion Criteria
24. Subject anticipates using sucralfate during the study.
Rationale: Sucralfate is added as an exclusionary medication since the 
medication may interfere with oral budesonide esophageal adherence 
and may potentially impact efficacy.
Study Synopsis, Exclusion Criteria; 
Section 4.2, Exclusion Criteria


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 5 of 98
Changed:
Symptom response on DSQ + pain score (binary response), defined as 
≥30% and 50% reductions in the DSQ combined score (questions 
2+3+4) from baseline to the final treatment period evaluation (Visit 4)
To:
Change in the DSQ + pain score (questions 2+3+4) from baseline to 
the final treatment period evaluation (Visit 4)
Rationale: The binary response criteria in the DSQ (30% and 50%) 
were intended only for the DSQ combined score (questions 2+3).  
Therefore, this secondary efficacy endpoint pertaining to DSQ + pain 
score (questions 2+3+4) has been corrected.  
Study Synopsis, Secondary Efficacy 
Endpoints; Section 9.8.2, Secondary 
Efficacy Endpoints
Changed:
Symptom response on DSQ pain score (binary response), defined as 
≥30% and 50% reductions in the DSQ score (question 4) from baseline 
to the final treatment period evaluation (Visit 4)
To:
Change in the DSQ pain score (question 4) from baseline to the final 
treatment period evaluation (Visit 4)
Rationale: The binary response criteria in the DSQ (30% and 50%) 
were intended only for the DSQ combined score (questions 2+3).  
Therefore, this secondary efficacy endpoint pertaining to DSQ pain 
score (question 4) has been corrected.  
Study Synopsis, Secondary Efficacy 
Endpoints; Section 9.8.2, Secondary 
Efficacy Endpoints
“dual-energy X-ray absorptiometry (DXA) scans for bone mineral 
density (BMD) and body composition measurements…”
Study Synopsis, Safety Endpoints, 
Statistical Methodology for Safety 
Endpoints; Section 7.1.2.1, Placebo 
Lead-in Visit (Visit 0);Section 7.1.3.3, 
Visit 4 (Week 16); Section 7.2.2.7, 
Dual -energy X-ray Absorptiometry 
for Bone Mineral Density; Section 
9.9, Safety Analyses
“…the endpoint will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test a logistic regression model with the effects of 
the treatment group adjusting for age group (either < 18 years or 
≥18 years) and diet restriction for EoE or other health-related 
conditions (no diet restriction or any diet restriction) and their 
interaction. The main effect model will be considered the final 
definitive model if the interactions between the treatment and age 
group is not statistically significant at the 10% level. The adjusted 
odds ratio of being a responder on each of the co-primary endpoints for 
the OBS 2 mg twice daily group vs placebo group and associated 95% 
confidence interval (CI) will be estimated from the final model 
provided.”

Each of the co-primary efficacy endpoints will be analyzed 
using a logistic regression with the effects of treatment 
group, age group (either <18 years or ≥18 years) and diet 
Synopsis, Statistical Methodology for 
Primary Efficacy Endpoint; 
Section 9.8.1, Primary Efficacy 
Endpoints


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 6 of 98
restriction for EoE or other health-related conditions (no 
diet restriction or any diet restriction). The odds ratio of 
being a responder on each of the co-primary endpoints for 
the OBS 2 mg twice daily group vs placebo group and 
associated 95% confidence interval (CI) will be estimated 
from the final model. Subjects who withdraw without 
providing efficacy data at the final treatment period 
evaluation (Visit 4, Week 16) will be classified as non-
responders in the primary efficacy analysis.
Expected response and dropout rates are based on observation 
from the Phase 2 study (MPI 101-06).
Synopsis, Sample Size Justification; 
Section  9.6, Sample Size Calculation 
and Power Considerations
Added row for continuous DSQ completion
Schedule of Assessments

No change in exercise (other than seasonal changes in sports or 
activities). Intense exercise should be avoided unless part of an 
established exercise routine.

Short course of systemic steroids (≤7 days) are permitted to 
treat…

Stable treatment with intranasal or inhaled corticosteroids. 
For subjects with perennial allergic rhinitis and stable asthma, 
the topical corticosteroid must be maintained at the same dose 
throughout the study.  For subjects with seasonal allergic 
rhinitis, it is permissible after the qualifying EGD to resume 
(or discontinue) intranasal corticosteroids based on the 
subject's usual treatment regimen for allergy season.  All 
topical corticosteroid dosing changes, including those for 
seasonal allergic rhinitis, should be avoided within 4 weeks 
prior to the Week 16 EGD. Subjects who require a change in 
inhaled corticosteroid treatment for an asthma exacerbation 
should be discussed with the medical monitor.

No use of sucralfate during the study as this may interfere with 
the adherence of OBS.
Section 4.3, Restrictions
An urgent safety review will be conducted within 7 days by the 
sponsor if one or more of the following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical 
Dictionary for Regulatory Activities [MedDRA] higher level 
group code) and considered related to the study drug
The urgent review will be performed by a sponsor safety review 
group, which will include the study Pharmacovigilance and Risk 
Management (PVRM) physician and the PVRM Therapeutic Area 
Head.  The PVRM Therapeutic Area Head, not the PVRM 
physician involved in the study, may be unblinded as part of this 
urgent safety review, if required.  Following the sponsor’s review 
of safety data, one of the following actions will be taken with 
respect to study status:
Section 4.5.4, Safety-related Stopping 
Rules


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 7 of 98

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.
Rationale: Safety-related stopping rules are added to provide for an 
urgent safety review if criteria for related SAEs are met.  
1. Inhaled or intranasal steroids for conditions other than EoE; subject 
must be on stable treatment for ≥3 months prior to screening visit 
(Visit -1), except for seasonal allergic rhinitis, see Section 4.3.
Section 5.2.1, Permitted Treatment
3.  Inhaled or intranasal steroids if initiated or changed in dose
<3 months prior to screening visit (Visit -1).   (Seasonal nasal 
corticosteroid use for seasonal allergic rhinitis is permitted; 
changes within 4 weeks of scheduled EGD should be avoided).
4.  Initiation or change in dosing frequency of PPIs, H2 antagonists, 
antacids, antihistamines, or leukotriene inhibitors…
8.  Sucralfate use during the treatment period
Section 5.2.2, Prohibited Treatment
OBS and placebo should be refrigerated at 2-8ºC (36 46ºF) 
throughout the study (in the clinic and subject’s home).
After 30 minutes, it is recommended that the subjects will be 
instructed to rinse with water and spit, particularly after the bedtime 
dose.
Section 6.2, Administration of 
Investigational Product(s)
The randomization will be performed centrally and stratified by age 
group (2 strata total: <18 years or vs ≥18 years) and diet restriction 
for EoE or other health-related conditions (no diet restriction or 
any diet restriction). The stratification by age will ensure a minimum 
of 40 subjects in the pediatric group (11-17 years, inclusive). The 
stratification by age and diet restriction will ensure balance 
between treatment groups for the respective stratification factors. 
Fixed block randomization will be used to ensure that approximately 
equal numbers of patients are assigned each treatment within strata. 
 
Rationale: As the presence of dietary therapy may impact a subject’s 
response to therapy, a stratification factor based on baseline diet is 
added to ensure balance between treatment groups. 
Section 6.2.2, Allocation of Subjects 
to Treatment
Visit to visit compliance of DSQ completion will also be assessed by 
site personnel. Protocol deviations will be documented for subjects 
who fail to complete the DSQ for 3 or more days in a given week.
Section 6.5, Subject Compliance
Perform stadiometry in subjects aged 11-17 years, inclusive.
Section 7.1.1.1, Screening Visit (Visit 
-1)
Perform stadiometry in subjects aged 11 17 years, inclusive.
Section 7.1.3.1, Baseline Visit (Visit 
1): Week 4


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 8 of 98
Endoscopic findings with separate evaluations of the proximal and 
distal esophagus will be recorded with respect to 5 categories by the 
endoscopist: 1) exudates or plaques (grade 0-2); 2) fixed esophageal 
rings (grade 0–3); 3) edema (grade 0-21); 4) furrows (grade 0–21)…
Section 7.2.1.1, 
Esophagogastroduodenoscopy with 
Esophageal Biopsy and 
Histopathologic Evaluation
Visit to visit compliance of DSQ completion will also be assessed by 
site personnel. Protocol deviations will be documented for subjects 
who fail to complete the DSQ for 3 or more days in a given week.
Calculations will be performed on daily ePRO entries from the 
screening period, during a 2 week interval prior to the baseline period, 
and prior to each study visit during the baseline and treatment periods.
Section 7.2.1.2, Dysphagia Symptom 
Questionnaire
Standard measuring procedures should be followed (eg, removal of 
socks, shoes, and hats; calibration frequency). The stadiometer must 
be calibrated at least once daily, and as feasible, within 4 hours of 
measurement. All measurements should be recorded to the nearest 
10th of a centimeter (1 mm).
Section 7.2.2.2,  Physical Examination 
(Including Height and Weight)
All subjects with an abnormal ACTH stimulation test or urinary 
or serum glucose level must be followed closely until resolution.  
For subjects who discontinue from the treatment period at any 
time and have an abnormal ACTH stimulation test at the early 
termination visit, subjects will be scheduled for repeat testing 
approximately 6 weeks post last dose of investigational product to 
ensure that ACTH levels have normalized.
Section 7.2.2.5, Clinical Laboratory 
Evaluations
PedsQL-EoE module consists of 33 35 items…
Section 7.2.3.1, Health-related 
Quality-of-life Assessment, Pediatric 
Quality of Life – EoE Questionnaire
The EoE-QoL-A consists of a 37 30-item test
Section 7.2.3.1, Health-related 
Quality-of-life Assessment, Adult 
Eosinophilic Esophagitis Quality of 
Life Questionnaire
All data from the investigator will have separate source…
The data from the central pathologist will be recorded directly 
onto paper CRFs.  
Section 10.2.3.1, Case Report Forms
Added protocol history details.
Section 12, Appendix 1 Protocol 
History
Edited former Appendix 1 to Appendix 2
Specified age groups for EQ-5D-3L, EQ-5D-Y and Tanner Staging 
assessments.
Section 12, Appendix 2 Scales and 
Assessments
See Appendix 1 for protocol history, including all amendments.


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 9 of 98
EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by 
Protocol within 24 hours to the Shire Global Pharmacovigilance and Risk Management 
Department. Applicable fax numbers and e-mail address can be found on the form (sent under 
separate cover). A copy of the Shire Clinical Study Adverse Event Form for SAEs and Non-
serious AEs as Required by Protocol must also be sent to the CRO medical monitor by fax or 
e-mail using the details below.
, MD
Email:  
Fax:  
For protocol- or safety-related issues during normal business hours (8am to 5 pm 
Eastern Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile: 
Email: 
Fax:  
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile: 
Email:  


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 10 of 98
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products).  For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
 or 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 11 of 98
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION ..................................................3
EMERGENCY CONTACT INFORMATION ..........................................................................9
PRODUCT QUALITY COMPLAINTS ..................................................................................10
ABBREVIATIONS..................................................................................................................17
STUDY SYNOPSIS.................................................................................................................19
STUDY SCHEDULE(S) ..........................................................................................................28
1.
BACKGROUND INFORMATION.............................................................................32
1.1
Indication and Current Treatment Options...................................................................32
1.2
Product Background and Clinical Information ............................................................32
2.
STUDY OBJECTIVES AND PURPOSE....................................................................33
2.1
Rationale for the Study.................................................................................................33
2.2
Study Objectives...........................................................................................................33
2.2.1
Primary Objectives ................................................................................................33
2.2.2
Secondary Objectives ............................................................................................34
2.2.3
Exploratory Objective............................................................................................34
3.
STUDY DESIGN.........................................................................................................34
3.1
Study Design and Flow Chart ......................................................................................34
3.2
Duration and Study Completion Definition .................................................................36
3.3
Sites and Regions .........................................................................................................37
4.
STUDY POPULATION...............................................................................................37
4.1
Inclusion Criteria..........................................................................................................37
4.2
Exclusion Criteria.........................................................................................................38
4.3
Restrictions...................................................................................................................40
4.4
Reproductive Potential .................................................................................................40
4.4.1
Female Contraception............................................................................................40
4.5
Discontinuation of Subjects..........................................................................................41


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 12 of 98
4.5.1
Subject Withdrawal Criteria ..................................................................................42
4.5.2
Reasons for Discontinuation..................................................................................42
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................43
4.5.4
Safety-related Stopping Rules ...............................................................................43
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................44
5.1
Prior Treatment.............................................................................................................44
5.2
Concomitant Treatment................................................................................................44
5.2.1
Permitted Treatment ..............................................................................................44
5.2.2
Prohibited Treatment .............................................................................................45
6.
INVESTIGATIONAL PRODUCT ..............................................................................46
6.1
Identity of Investigational Product...............................................................................46
6.1.1
Blinding the Treatment Assignment......................................................................46
6.2
Administration of Investigational Product(s)...............................................................46
6.2.1
Interactive Response Technology for Investigational Product Management........47
6.2.2
Allocation of Subjects to Treatment......................................................................47
6.2.3
Dosing....................................................................................................................48
6.2.4
Unblinding the Treatment Assignment..................................................................48
6.3
Labeling, Packaging, Storage, and Handling ...............................................................49
6.3.1
Labeling .................................................................................................................49
6.3.2
Packaging...............................................................................................................50
6.3.3
Storage ...................................................................................................................50
6.3.4
Special Handling....................................................................................................51
6.4
Drug Accountability.....................................................................................................51
6.5
Subject Compliance......................................................................................................52
7.
STUDY PROCEDURES..............................................................................................52
7.1
Study Schedule.............................................................................................................52
7.1.1
Screening Period (Weeks -6 to 0)..........................................................................53
7.1.1.1
Screening Visit (Visit -1) ............................................................................53
7.1.2
Placebo Lead-in Period (Weeks 0 to 4) .................................................................54
7.1.2.1
Placebo Lead-in Visit (Visit 0)....................................................................54


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 13 of 98
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or 
Early Termination).................................................................................................55
7.1.3.1
Baseline Visit (Visit 1): Week 4..................................................................56
7.1.3.2
Visits 2 and 3 (Weeks 8 and 12)..................................................................57
7.1.3.3
Visit 4 (Week 16) ........................................................................................58
7.1.4
Follow-up Period ...................................................................................................59
7.1.4.1
Safety Follow-up Contact (Visit 5): Week 20.............................................59
7.1.5
Additional Care of Subjects after the Study ..........................................................59
7.2
Study Evaluations and Procedures ...............................................................................59
7.2.1
Efficacy..................................................................................................................60
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation.........................................................................60
7.2.1.2
Dysphagia Symptom Questionnaire............................................................61
7.2.2
Safety .....................................................................................................................62
7.2.2.1
Medical and Medication History.................................................................62
7.2.2.2
Physical Examination (Including Height and Weight)................................62
7.2.2.3
Adverse Event Collection............................................................................63
7.2.2.4
Vital Signs ...................................................................................................63
7.2.2.5
Clinical Laboratory Evaluations..................................................................63
7.2.2.6
Pregnancy Test ............................................................................................65
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density..................65
7.2.3
Other Assessments.................................................................................................65
7.2.3.1
Health-related Quality-of-life Assessment..................................................65
7.2.3.2
Severity of Disease Assessments ................................................................66
7.2.4
Clinical Pharmacology Assessments .....................................................................67
7.2.5
Volume of Blood to Be Drawn from Each Subject ...............................................68
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................68
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................68
8.1.1
Severity Categorization..........................................................................................69
8.1.2
Relationship Categorization...................................................................................69
8.1.3
Outcome Categorization ........................................................................................70
8.1.4
Symptoms of the Disease under Study ..................................................................70
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................71


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 14 of 98
8.1.6
Pregnancy...............................................................................................................71
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................72
8.2
Serious Adverse Event Procedures...............................................................................73
8.2.1
Reference Safety Information................................................................................73
8.2.2
Reporting Procedures.............................................................................................73
8.2.3
Serious Adverse Event Definition .........................................................................73
8.2.4
Serious Adverse Event Collection Time Frame ....................................................74
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................74
8.2.6
Fatal Outcome........................................................................................................74
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting ...............................................................................................................75
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................75
9.1
Data Collection.............................................................................................................75
9.2
Clinical Data Management...........................................................................................75
9.3
Data Handling Considerations......................................................................................75
9.4
Statistical Analysis Process..........................................................................................76
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee..........76
9.6
Sample Size Calculation and Power Considerations....................................................77
9.7
Study Population ..........................................................................................................77
9.8
Efficacy Analyses.........................................................................................................77
9.8.1
Primary Efficacy Endpoints...................................................................................78
9.8.1.1
Missing Data Imputation.............................................................................79
9.8.2
Secondary Efficacy Endpoints...............................................................................79
9.8.2.1
Key Secondary Efficacy Endpoint ..............................................................79
9.8.3
Exploratory Efficacy Endpoint..............................................................................81
9.9
Safety Analyses ............................................................................................................81
9.10
Other Analyses .............................................................................................................82
9.10.1 Health-related Quality-of-life Analyses.................................................................82
9.10.2 Pharmacokinetic Analyses.....................................................................................82
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................82
10.1
Sponsor’s Responsibilities ...........................................................................................83


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 15 of 98
10.1.1 Good Clinical Practice Compliance.......................................................................83
10.1.2 Indemnity/Liability and Insurance.........................................................................83
10.1.3 Public Posting of Study Information .....................................................................83
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................84
10.1.5 Study Suspension, Termination, and Completion .................................................84
10.2
Investigator’s Responsibilities .....................................................................................84
10.2.1 Good Clinical Practice Compliance.......................................................................84
10.2.2 Protocol Adherence and Investigator Agreement..................................................85
10.2.3 Documentation and Retention of Records.............................................................85
10.2.3.1 Case Report Forms......................................................................................85
10.2.3.2 Recording, Access, and Retention of Source Data and Study 
Documents...................................................................................................86
10.2.3.3 Audit/Inspection..........................................................................................86
10.2.3.4 Financial Disclosure....................................................................................86
10.3
Ethical Considerations..................................................................................................87
10.3.1 Informed Consent ..................................................................................................87
10.3.2 Institutional Review Board or Ethics Committee..................................................87
10.4
Privacy and Confidentiality..........................................................................................88
10.5
Study Results/Publication Policy .................................................................................89
11.
REFERENCES.............................................................................................................90
12.
APPENDICES..............................................................................................................92
LIST OF TABLES
Table 1-1: Schedule of Assessments.......................................................................................28
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject .........................68
Table 8-1: Adverse Event Relatedness....................................................................................70
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata......................................................................................................................79
Table 9-2: Pharmacokinetic Parameters..................................................................................82


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 16 of 98
LIST OF FIGURES
Figure 1:
Study Design Flow Chart.......................................................................................35
LIST OF APPENDICES
Appendix 1
Protocol History ..........................................................................................93
Appendix 2
Scales and Assessments...............................................................................94
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE....................................95
Appendix 4
Patient Global Impression of Severity.........................................................96
Appendix 5
Biosciences Generic Clinical Protocol Insert..............................................97


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 17 of 98
ABBREVIATIONS
ACTH
adrenocorticotropic hormone
AE
adverse event
ANCOVA
analysis of covariance
Auctau
area under the curve for the defined interval between doses
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum concentration occurring at tmax
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CYP450 3A4
cytochrome P450 3A4
DSG1
desmoglein 1
DSQ
Dysphagia Symptom Questionnaire
DXA (DEXA)
dual-energy X-ray absorptiometry
EC
ethics committee
EGD
esophagogastroduodenoscopy
EIS
external independent statistical
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
EoE-QoL-A  
Adult Eosinophilic Esophagitis Quality of Life
ePRO
electronic patient-reported outcome
EQ-5D-3L
EuroQol-5 Dimensions 3-level
EQ-5D
EuroQol
EQ-5D-Y
EuroQol 5 Dimensions Youth
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 18 of 98
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
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication information
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
OBS
oral budesonide suspension
pc
after meals
PedsQL-EoE
Pediatric Quality of Life Inventory – EoE
PGA
Physician Global Assessment
PGI-S
Patient Global Impression of Severity
PP
per-protocol
PPI
proton pump inhibitor
PT
preferred term
PVRM
Pharmacovigilance and Risk Management
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
SOC
system organ class
TEAE
treatment-emergent adverse event
tmax
time of maximum observed concentration sampled during a dosing 
interval
UK
United Kingdom
US
United States


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 19 of 98
STUDY SYNOPSIS
Protocol number:  SHP621-301
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11 to 
55 Years of Age, Inclusive) with Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, 
Placebo-controlled Study
Number of subjects (total and for each treatment arm):
Approximately 300 subjects will be enrolled into the placebo lead-in period to allow for 228 subjects 
(approximately 152 and 76 per OBS and placebo treatment group, respectively) to be randomized into 
the double-blind treatment period.
Investigator(s):  Multicenter study
Site(s) and Region(s): 
Approximately 60 sites in North America
Study period (planned):
Oct 2015 to July 2018
Clinical phase:
3
Objectives
Co-primary:
To demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/high-powered field [HPF]) in 
adolescent and adult subjects with eosinophilic esophagitis (EoE) over a 12-week course of 
therapy.

OBS reduces dysphagia, as measured by the Dysphagia Symptom Questionnaire (DSQ), by at 
least 30% from baseline in adolescent and adult subjects with EoE over a 12-week course of 
therapy.
Key Secondary:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final treatment period 
evaluation (Visit 4). 
Secondary:

To assess the response of endoscopically identified esophageal features to OBS as compared to 
placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ pain score

To evaluate the safety and tolerability of OBS over a 12-week course of therapy

To obtain OBS pharmacokinetic data in adult subjects with EoE
Exploratory:


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 20 of 98
Rationale:
Currently there is no approved medication for the treatment of EoE. This study is being conducted in 
order to provide safety and efficacy data demonstrating histologic response (as measured by 
eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as measured by the DSQ) 
following 12 weeks of treatment with OBS in adolescent and adult subjects with EoE. 
Investigational product, dose, and mode of administration
OBS 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 OBS 
and dosing regimens were selected for use in this Phase 3 study based on the results of Study MPI 
101-06, a Phase 2 study in 93 adolescents and adult subjects with EoE and symptoms of dysphagia. 
Subjects were treated in Study MPI 101-06 with 2 mg OBS twice daily to investigate the co-primary 
endpoints of histologic response (defined as ≤6 eosinophils/HPF) and reduction in DSQ score from 
baseline to Week 12 of treatment. For the current study, the investigational product will be supplied in 
amber glass, multi-dose bottles with child-resistant caps and refrigerated throughout the study (in the 
clinic and subject’s home). Each bottle will contain approximately 210 mL of suspension with a 
budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL (matching placebo). 
After the screening period, eligible subjects will enter a 4-week single-blind placebo lead-in period and
will receive 10 mL of OBS placebo twice daily (qAM, pc, and hs). At the end of the placebo lead-in
period, eligible subjects will enter a 12-week double-blind treatment period (baseline visit, Visit 1) and 
will be randomized to 1 of 2 treatment groups in a 2:1 ratio (approximately 152 and 76 subjects for 
OBS and placebo twice daily treatment groups, respectively). Subjects will receive oral administration 
of 10 mL of 2 mg investigational product twice daily (qAM, pc, and hs; 4 mg/day total), with no 
ingestion of food or liquids permitted for 30 minutes after study drug administration:

Placebo twice daily group:  placebo qAM (pc) and hs

OBS twice daily group: OBS 10 mL of 0.2 mg/mL (2 mg total) qAM (pc) and hs
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for 
each subject in the OBS treatment group (Table 1). 
Table 1: Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume 
per Dose
Morning Dose 
(qAM, pc)
Evening 
Dose (hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10 mL
0.0 mg
0.0 mg
0.0
OBS 
0.2
10 mL
2.0 mg
2.0 mg
4.0
Abbreviations: hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every 
morning
At the end of the 12-week double-blind treatment period (Visit 4), subjects who complete the study 
will have the opportunity to enroll in the treatment extension study. These subjects will continue on the 
blinded assigned treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment 
extension study. 
Methodology:
This is a Phase 3, randomized, double-blind, multicenter, parallel-group, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of twice daily administration of OBS (qAM, pc, and hs) 
in adolescents and adults aged 11-55 years, inclusive, with EoE and dysphagia. 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 21 of 98
This study will comprise 3 periods: a 3- to 6-week screening period, 4-week single-blind placebo 
lead-in period, and 12-week double-blind treatment period (Figure 1). Approximately 300 subjects will 
be enrolled into the placebo lead-in period to allow for approximately 228 subjects to be randomized 
in a 2:1 ratio (approximately 152 and 76 per OBS and placebo treatment group, respectively) into the 
double-blind treatment period. The randomization will be performed centrally and stratified by age 
group (2 strata total: <18 years or ≥18 years) and diet restriction for EoE or other health-related 
conditions (no diet restriction or any diet restriction). The stratification by age will ensure a minimum 
of 40 subjects in the pediatric group (11-17 years, inclusive). The stratification by age and diet will 
ensure balance between treatment groups for the respective stratification factors.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened 
(Visit -1). Subjects who meet eligibility criteria at the screening visit (Visit -1) and at the placebo 
lead-in visit (Visit 0) will enter the 4-week placebo lead-in period to assess their ability to comply with 
twice daily medication administration and assess whether there is a placebo response. Upon 
completion of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to confirm 
eligibility. Eligible subjects will be randomized 2:1 into the double-blind treatment period and will be 
evaluated for efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4). Subjects who fail to meet all
eligibility criteria at Visits -1, 0, or 1 will be considered screen failures. Subjects cannot be rescreened 
once it is confirmed they do not meet inclusion/exclusion criteria unless the screen failure was due to a 
concomitant medication that can be discontinued prior to rescreening; those subjects may be 
rescreened. Other reasons for rescreening (ie, reasons unrelated to inclusion/exclusion criteria) must be 
discussed prospectively with the medical monitor. Subjects who discontinue will not be replaced.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. A safety follow-up 
phone call will occur 4 weeks following the last dose of investigational product for subjects who 
discontinue prematurely during the double-blind treatment period or who do not enroll in the treatment 
extension study.
Figure 1: Study Design Flow Chart
Abbreviations: BID=twice daily; EGD=esophagogastroduodenoscopy; ET=early termination; 
OBS=oral budesonide suspension


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 22 of 98
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria 
(including test results):
1.
Subject 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. 
2.
Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3.
Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 of 3 
(proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4.
Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating problems, 
abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) intermittently or 
continuously at screening (Visit -1).
5.
Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period and in the 2 weeks prior to the baseline visit (Visit 1).
6.
Subject must not have proton pump inhibitor (PPI)–responsive EoE based on esophageal biopsies 
performed after the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose 
therapy refers to the total daily dose, which may have been administered as a once- or twice daily 
dosing regimen). This may occur at the time of the qualifying esophagogastroduodenoscopy 
(EGD; in which case the same PPI regimen must be continued), or this may have been done 
previously (in which case PPI therapy may have been stopped if there was no response to therapy 
based on esophageal biopsy results). If PPI responsiveness was excluded by a previous EGD and 
biopsy, the historical EGD and biopsy must have been performed after the patient had been on a 
minimum of 6 weeks of high-dose PPI therapy.
7.
Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit (Visit -1).
8.
Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical 
regimens (including gastric acid suppression; see exclusions below) in effect at the screening visit 
(Visit -1). There should be no change to these regimens during study participation.
9.
All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential must 
agree to continue acceptable birth control measures (eg, abstinence, stable oral contraceptives, or 
double-barrier methods) throughout study participation.
10. 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 any condition or abnormality (including laboratory abnormalities), current or past, 
that, in the opinion of the principal investigator or medical monitor, would compromise the safety 
of the subject or interfere with or complicate the assessment of signs or symptoms of EoE. Such 
conditions may include psychiatric problems; neurologic deficits or disease; developmental delay; 
cardiovascular, metabolic, or pulmonary disease; or previous gastroesophageal surgery. These 
should be discussed with the medical monitor.
2.
Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD or 
between the qualifying EGD and baseline visit (Visit 1) or anticipates using immunomodulatory 
therapy during the treatment period (except for any ongoing regimen of allergy shots). Use of 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 23 of 98
long-acting immunomodulatory therapy (eg, Rituxan) within 3 months of the qualifying EGD 
should be reviewed with the medical monitor.
3.
Subject has been using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 
condition within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit (Visit 1), or anticipates use during the treatment period; any temporary use (≤7 days) 
or initiation of new steroid treatment during the study should be documented and discussed with 
the medical monitor prospectively but cannot occur within 4 weeks of the final EGD. 
4.
Subject has been on inhaled steroids and not on stable treatment for ≥3 months prior to screening 
visit (Visit -1). Subjects on inhaled steroids need to stay on stable treatment during study 
participation. Subject has been on intranasal steroids and has not been on stable treatment for a 
minimum of 4 weeks prior to the qualifying EGD. After the qualifying EGD, subjects with 
seasonal allergic rhinitis may resume (or discontinue) intranasal corticosteroids based on the 
subject's usual treatment regimen for allergy season.
5.
Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, antacids, 
or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease asthma or 
allergic rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit (Visit 1), or anticipates changes in the use of such medications during the treatment 
period.  
6.
Subject has been using cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) 
within the 2 weeks prior to the baseline visit (Visit 1) or within 5 half-lives (whichever is greater)
or anticipates using such medications during the treatment period.  
7.
Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as defined 
by the presence of a lesion that does not allow passage of a diagnostic adult upper endoscope (eg, 
with an insertion tube diameter of >9 mm). 
8.
Subject is on a pure liquid diet or the 6-food elimination diet.
9.
Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic syndrome, 
collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has acute or chronic viral infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes esophagitis, 
or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit (Visit -1) or 
between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit (Visit -1) and 
between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or 
any other corticosteroids) or to any other ingredients of the investigational product.
20. Subject has taken part in an interventional study related to EoE within 6 months prior to the 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 24 of 98
screening visit (Visit -1), or any investigational study within 30 days prior to the screening visit 
(Visit -1).
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
22. Subject has previously completed, discontinued, or withdrawn from this study.
23. Subject has participated in a previous clinical study involving OBS (SHP621).
24. Subject anticipates using sucralfate during the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 3-6 weeks

Planned duration of placebo lead-in period: 4 weeks

Planned duration of treatment period: 12 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of a 
double-blind investigational product and have both an evaluable post-baseline biopsy in the 
treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and a 
post-baseline DSQ score.

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with protocol 
violations. The PP set will be identified prior to unblinding the treatment assignments by a team 
consisting of, at a minimum, a physician and a statistician from Shire. 

The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 
2+3) from baseline to the final treatment period evaluation (Visit 4)
Key Secondary Efficacy Endpoint

Change in DSQ combined score (questions 2+3) from baseline to the final treatment period 
evaluation (Visit 4)
Secondary Efficacy Endpoints 

Change in total endoscopy score, as measured by the EREFS classification, from baseline to the 
final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment period 


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 25 of 98
evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment period 
evaluation (Visit 4)

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)

Change from baseline in the histopathologic epithelial features combined total score (grade and 
stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation (Visit 4)

Change from baseline in the DSQ combined score (questions 2+3) over time including 
post-baseline visits

Cumulative distribution function curves for the change and the percent change in the DSQ score 
from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Change in the DSQ + pain score (questions 2 +3+4) from baseline to the final treatment period 
evaluation (Visit 4)

Change in the DSQ pain score (question 4) from baseline to the final treatment period evaluation 
(Visit 4)
Exploratory Efficacy Endpoint 
Safety Endpoints 
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital signs
(temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height 
assessments, dual-energy X-ray absorptiometry (DXA) scans for bone mineral density (BMD) and 
body composition measurements (for adolescents aged 11-17 years, inclusive), clinical laboratory tests 
(hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), and adrenocorticotropic 
hormone (ACTH) stimulation tests. To account for the effects of puberty in adolescent subjects (11-17 
years, inclusive), BMD z-scores will be adjusted for height z-scores using the Bone Mineral Density in 
Childhood Study calculator (http://www.bmdcspublic.com).
Health Economics and Outcomes Research Endpoints 

Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score from baseline to 
the final treatment period evaluation (Visit 4)

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 from baseline to the final 
treatment period evaluation (Visit 4)

Change in Pediatric Quality of Life Inventory – EoE (PedsQL-EoE) score from baseline to the 
final treatment period evaluation (Visit 4)


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 26 of 98
Pharmacokinetic Endpoints 
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis. The pharmacokinetic parameters will include, but not be 
limited to:
AUCtau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing 
interval
Statistical Methodology for Primary Efficacy Endpoint 
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the co-primary 
efficacy endpoints is a binary response (ie, responders vs non-responders); the endpoint will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for age group (either <18 years or 
≥18 years) and diet restriction for EoE or other health-related conditions (no diet restriction or any diet 
restriction) . The adjusted odds ratio of being a responder on each of the co-primary endpoints for the 
OBS 2 mg twice daily group vs placebo group and associated 95% confidence interval (CI) will be 
provided. Subjects who withdraw without providing efficacy data at the final treatment period 
evaluation (Visit 4, Week 16) will be classified as non-responders in the primary efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized and their respective 95% CI will be reported. The difference in 
the proportion of responders between the 2 treatment groups and the corresponding 95% CI will also 
be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to evaluate the 
robustness of the results from the primary analysis methods: 

Each of the co-primary efficacy endpoints will be analyzed using a logistic regression with the 
effects of treatment group, age group (either <18 years or ≥18 years) and diet restriction for EoE 
or other health-related conditions (no diet restriction or any diet restriction). The odds ratio of 
being a responder on each of the co-primary endpoints for the OBS 2 mg twice daily group vs 
placebo group and associated 95% confidence interval (CI) will be estimated from the final 
model. Subjects who withdraw without providing efficacy data at the final treatment period 
evaluation (Visit 4, Week 16) will be classified as non-responders in the primary efficacy analysis.

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing efficacy data 
at the final treatment period evaluation (Visit 4) will be classified as responders.
Statistical Methodology for Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4). The change from 
baseline DSQ score at the final treatment period evaluation (Visit 4) will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment group and age group as factors and the baseline DSQ 
score as a continuous covariate.
Statistical Methodology for Secondary Efficacy Endpoints
Secondary subjective efficacy endpoints that are defined as:

Binary response endpoints will be analyzed using the same logistic model as the co-primary 
efficacy endpoints.


Shire
CONFIDENTIAL
17 December 2015
Protocol SHP621-301
Amendment 1
Page 27 of 98

Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model that 
includes treatment group and age group as factors and baseline score as a continuous covariate.
The analyses for all secondary efficacy endpoints (including the key secondary efficacy endpoint) will 
be carried out using 2-sided tests at the 5% level of significance. For each of the secondary efficacy 
endpoints, the treatment difference, corresponding 95% CI for the difference, and treatment 
comparison p-value for testing the null hypothesis of zero treatment effect based on the final statistical 
model (ie, either logistic regression model or ANCOVA model) will be provided.
Statistical Methodology for Safety Endpoints 
All safety measures, including AEs, physical examination, stadiometry, vital signs (temperature, 
systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA 
scans for BMD and body composition measurements (for adolescents aged 11-17 years, inclusive), 
clinical laboratory results (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), 
and ACTH stimulation will be descriptively summarized by treatment group at baseline and for each 
post-baseline visit.
The number and percent of subjects with TEAEs will be presented. TEAEs are defined as AEs that 
start or deteriorate on or after the date of the first dose of investigational product and no later than 
3 days following the last dose of investigational product. However, for any subjects who die during the 
study (ie, the date of death is between the date of first dose of investigational product and the date of 
study discontinuation entered by the site, inclusive), all AEs (including those resulting in death) that 
occur during the study will be considered as TEAEs irrespective of the last dose and will be included 
in the TEAE summaries. 
Statistical Methodology for Pharmacokinetic Endpoint(s) 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters by overall and by week. Plasma concentrations at each nominal sampling time will also be 
summarized using descriptive statistics.
Sample Size Justification
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected difference 
between treatment response proportions of 69% and 45% in the OBS 2 mg twice daily (qAM, pc, and 
hs) and placebo groups, respectively. A total of 228 subjects (152 subjects randomized to OBS and 
76 subjects randomized to placebo) are required to achieve 90% power at the significance level of 
0.0499 (2-sided) using a 2-group chi-square test with unequal allocation 2:1 to treatment groups (OBS 
2 mg twice daily and placebo). With the specified number of subjects per treatment group, the study 
will be powered at 99% assuming histological response proportions of 40% and 3% in the OBS 2 mg 
twice daily and placebo groups, respectively. The overall study power for the co-primary endpoints 
will be at least 85%. Therefore, approximately 228 (approximately 152:76 OBS and placebo subjects, 
respectively) will be randomized to the study to allow for a loss of approximately 5% of subjects due 
to dropouts or invalid data.  Expected response and dropout rates are based on observation in the Phase 
2 study (MPI 101-06).


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 28 of 98
STUDY SCHEDULE(S)
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactp
Visit -1
Visit 0
Randomization 
Baseline/Visit 1
Visit 2 
Visit 3 
Visit 4 
or ETo 
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consent/assent
X
Medical history review
X
Inclusion/exclusion criteria review
X
X
X
Vital signsa; heightb and weight 
assessment
X
X
X
X
X
X
EGD with endoscopy score (EREFS) and 
biopsyc
X
X
DSQ training and issue of handset
X
Retrieval of DSQ handset
X
DSQ completion
Once daily completion
DSQ compliance assessment
X
X
X
X
X
EQ-5Dd
X
X
PedsQL-EoE (subjects 11-17 years of 
age, inclusive)
X
X


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 29 of 98
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactp
Visit -1
Visit 0
Randomization 
Baseline/Visit 1
Visit 2 
Visit 3 
Visit 4 
or ETo 
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
EoE-QoL-A (subjects ≥18 years of age)
X
X
PGI-S
X
X
X
X
Physical examination
X
X
X
X
X
X
Tanner Staging Assessmente
X
X
Clinical laboratory testsf
X
X
X
X
X
X
Urinalysisg
X
X
X
X
X
X
Pregnancy testh
X
X
X
X
X
X
Morning cortisol (target 6:00-9:00 AM)
X
X
X
X
ACTH stimulation testing 
X
X
Blood pharmacokinetic sampling 
(subjects ≥18 years of age)i
X
X
DXA Scan 
(subjects 11-17 years of age, inclusive)j
X
X
Randomizationk
X
Investigational product supplied 
X
X
X
X
Xl
Investigational product administrationm
Twice-daily administration of investigational product


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 30 of 98
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactp
Visit -1
Visit 0
Randomization 
Baseline/Visit 1
Visit 2 
Visit 3 
Visit 4 
or ETo 
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Investigational product compliance 
assessment
X
X
X
X
Concomitant medications and procedures 
recorded 
X
X
X
X
X
X
X
Review of adverse eventsn
X
X
X
X
X
X
Abbreviations: 
ACTH=adrenocorticotropic 
hormone; 
DSQ=Dysphagia 
Symptom 
Questionnaire; 
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; EREFS=EoE Endoscopic Reference Score; 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
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood 
pressure (systolic and diastolic), heart rate, respirations, and temperature.
b
Height to be collected at screening visit (Visit -1) and Visit 4 for all subjects. Stadiometers are required for subjects 11-17 years of age, inclusive, and will be used 
at Visit -1 and 4.
c
Pre-treatment endoscopy will be performed during the screening period (at least 2 weeks prior to placebo lead-in visit [Visit 0] to allow adequate time for 
processing and central review). Endoscopy should include esophageal (proximal, mid-, and/or distal), gastric, and duodenal biopsies. Final treatment evaluation 
EGD must include esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Final treatment evaluation EGD should 
occur at or within (±) 7 days of the scheduled visit.  
d
Subjects 11-17 years of age, inclusive, will complete the EQ-5D-Y; subjects ≥18 years of age will complete the EQ-5D-3L. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 31 of 98
e
Tanner staging assessments will be performed for all subjects aged ≥11 years until investigator confirms subject is post puberty.
f
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.
g
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase.
h
The serum pregnancy test will be performed for all female subjects at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine pregnancy tests 
will be performed at all other visits.
i
Blood samples for pharmacokinetic analysis will be taken from adult subjects (aged ≥18 years). Subjects who do not participate in pharmacokinetic sampling will 
not be discontinued from the study and lack of participation will not be a considered protocol deviation. Blood samples for pharmacokinetic analysis will be 
obtained at the Week 8 or Week 12 visit at the following time points: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose. 
j
The baseline DXA scan may be performed any time during the placebo lead-in period after the subject has met all screening criteria and prior to blinded-treatment 
randomization. Baseline and post-treatment DXA scans should be performed using the same machine and software. Post-treatment DXA scan should occur at or 
within (±) 7 days of the scheduled visit.
k
Randomization will occur via IWRS at the baseline visit (Visit 1) once the subject’s eligibility for study entry is confirmed. 
l
Investigational product will be dispensed at Visit 4 to subjects who consent to enroll in the treatment extension study.
m
Subjects will receive oral administration of 10 mL of investigational product twice daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 
30 minutes after study drug administration.
n
AE assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, moon facies, acne, hirsutism, 
mood swings, insomnia, and depression).
o
If subject discontinues study prematurely, the evaluations listed for Visit 4 are to be performed as completely as possible.
p
For subjects who withdraw from the study or do not continue into treatment extension study, a safety follow-up contact by phone will be performed 4 weeks 
following the last dose of investigational product.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 32 of 98
1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al., 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and 
adults present with dysphagia and food impaction. When these symptoms are present, the 
diagnosis is confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered
field (HPF) on at least 1 esophageal biopsy and when other causes such as proton pump 
inhibitor (PPI)-responsive esophageal eosinophilia are excluded (Dellon et al., 2014a; Furuta 
et al., 2007). The standards of care are diet therapies and off-label use of glucocorticosteroids.
Esophageal dilation is used to temporarily relieve symptoms but does not address underlying 
inflammation. Given the clinical outcomes associated with EoE, including severe dysphagia, 
esophageal stricture, food impaction, and esophageal perforation (Hirano and Aceves, 2014;
Liacouras et al., 2011) and the fact that there are currently no FDA-approved treatments, there 
is a clear unmet medical need for a novel treatment for this disease.  
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a non-viscous suspension. Shire is developing OBS as a 
first-line therapy for EoE in adolescents and adults.
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the 
management of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, 
and for induction of remission in patients with active, mild to moderate ulcerative colitis. 
Budesonide has strong glucocorticoid receptor affinity and is subject to considerable first pass 
metabolism by the liver with a short half-life. These attributes permit budesonide to act 
rapidly and locally in the gut mucosa for treatment of inflammatory disorders such as Crohn’s 
disease and ulcerative colitis. Once absorbed into the systemic circulation, budesonide is 
rapidly metabolized in the liver and inactivated (FDA, 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in two Phase 2 studies in 
the OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the 
efficacy of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in 
adolescents and adults aged 11-40 years, respectively, by measuring histological response 
(defined as mean peak eosinophil count ≤6/HPF after treatment). Study MPI 101-06 also 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 33 of 98
evaluated symptom response as measured by the Dysphagia Symptom Questionnaire (DSQ). 
The DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia 
and its severity, as well as pain. The DSQ score is calculated only from responses to the
questions related to dysphagia, and this clinical outcome assessment was considered to be fit 
for purpose as a result of the MPI 101-06 study. Results from Study MPI 101-01 
demonstrated a statistically significant histologic response (eosinophil count ≤6/HPF) and 
remission (eosinophil count ≤1/HPF) in the medium-dose (1.4-2.0 mg daily) and high-dose 
(2.8-4.0 mg daily) OBS groups compared to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both 
the co-primary efficacy endpoints of histologic response and change from baseline in 
dysphagia symptoms. Following 12 weeks of twice daily treatment (once in the morning after 
meals [qAM, pc] and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent 
reduction from baseline values for cellular (mean peak eosinophil count and histopathology 
features), organ (endoscopy score), and holistic measures (Physician Global Assessment 
[PGA] and DSQ scores); these results were independent of the type of rater/reviewer (central 
pathologist, physician at the study site, or subject). 
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. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This study is being 
conducted in order to provide safety and efficacy data demonstrating histologic response (as 
measured by eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as 
measured by the DSQ) following 12 weeks of treatment with OBS in adolescent and adult 
subjects with EoE.
2.2
Study Objectives
2.2.1
Primary Objectives
The co-primary objectives of the study are to demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/HPF) in adolescent and adult 
subjects with EoE over a 12-week course of therapy.

OBS reduces dysphagia, as measured by the DSQ, by at least 30% from baseline in 
adolescent and adult subjects with EoE over a 12-week course of therapy.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 34 of 98
2.2.2
Secondary Objectives
The key secondary objective of this study is:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final 
treatment period evaluation (Visit 4). 
Additional secondary objectives of the study are:

To assess the response of endoscopically identified esophageal features to OBS as 
compared to placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ pain score

To evaluate the safety and tolerability of OBS over a 12-week course of therapy 

To obtain OBS pharmacokinetic data in adult subjects with EoE
2.2.3
Exploratory Objective
The exploratory objective of this study is:
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of OBS treatment administered twice daily (qAM, 
pc, and hs) for 12 weeks. The study will be conducted in adolescents and adults, aged 
11-55 years, inclusive, with EoE and dysphagia. 
Approximately 300 subjects will be enrolled in the placebo lead-in period to allow for 
approximately 228 subjects to be randomized into the double-blind treatment period. A 
minimum of 40 randomized subjects will be aged 11-17 years, inclusive. Subjects will be 
randomized 2:1 (approximately 152 and 76 per OBS and placebo treatment group, 
respectively) to receive either OBS 2 mg twice daily (qAM, pc, and hs) or placebo twice daily 
(qAM, pc, and hs).  
This study will consist of 3 periods: a 3- to 6-week screening period, 4-week single-blind 
placebo lead-in period, and a 12-week double-blind treatment period (see Figure 1).


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 35 of 98
Figure 1:
Study Design Flow Chart
Abbreviations: BID=twice daily; EGD=esophagogastroduodenoscopy; ET=end of treatment; OBS=oral 
budesonide suspension
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al., 2014a) and the fact that the type of EoE that 
develops in older patients is not amenable to anti-inflammatory treatment alone (Dellon et al.,
2014b). A natural history study demonstrated that for every decade of life, the odds of 
developing the fibrostenotic phenotype of EoE more than doubles (Dellon et al., 2014b). By 
age 55, fibrostenotic EoE occurs in approximately 80% of patients. Fibrostenotic disease is 
treated with dilatation and is not amenable to anti-inflammatory treatment alone. Therefore, 
budesonide is not expected to be an effective treatment for the majority of patients above 
age 55.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. Following 
completion of the screening and placebo lead-in visits, subjects will be evaluated for 
eligibility and safety at Week 4 (Visit 1). Subjects who are eligible and randomized will be 
evaluated for efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4) and additionally for 
safety at follow-up at Week 20 (Visit 5; telephone contact). Subjects who fail to meet all 
eligibility criteria at Visits -1, 0, or 1 will be considered screen failures. Subjects cannot be 
rescreened once it is confirmed they do not meet inclusion/exclusion criteria unless the screen 
failure was due to a concomitant medication that can be discontinued prior to rescreening; 
those subjects may be rescreened. Other reasons for rescreening (ie, reasons unrelated to 
inclusion/exclusion criteria) must be discussed prospectively with the medical monitor. 
Subjects who discontinue will not be replaced. 
The screening period will start when subjects sign informed consent (or assent as applicable 
for subjects <18 years of age; screening visit [Visit -1]) and will be approximately 3-6 weeks 
in duration. During the screening period, all subjects will receive an upper endoscopy with 
histologic analysis of biopsy specimens to confirm the diagnosis of EoE (eosinophil count of 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 36 of 98
≥15/HPF from 2 of 3 [proximal, mid-, and/or distal] levels of the esophagus). In addition, 
subjects must complete the DSQ daily during the screening period (3-6 weeks) and have at 
least 4 reported days with symptoms of dysphagia and completed the DSQ on ≥70% of days 
in any 2 consecutive weeks. At the screening visit (Visit -1), subjects who are on a PPI must 
remain on the same dose of the PPI throughout the study; if they are not taking a PPI, they 
must remain off of a PPI for the remainder of the study. After the screening period, eligible 
subjects will enter a 4-week single-blind placebo lead-in period and will receive 10 mL of 
OBS placebo twice daily (in the morning after meals/breakfast [qAM, pc] and at bedtime 
[hs]). The placebo lead-in period will enable assessment of the subject’s ability to comply 
with twice daily medication administration and assess whether the subject experiences a 
placebo response. 
At the end of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to 
confirm eligibility. Subjects who continue to meet all eligibility criteria (those with at least 
4 reported dysphagia days and who completed the DSQ on ≥70% of days in the 2 weeks prior 
to randomization per daily DSQ completion) will be randomized to receive either OBS or 
placebo during the 12-week double-blind treatment period. 
OBS will be administered in 10 mL at a concentration of 0.2 mg/mL (2 mg dose), twice daily. 
The 0.2 mg/mL concentration of OBS and dosing regimens were selected for use in this 
Phase 3 study based on the results of Study MPI 101-06, a Phase 2 study in 93 adolescent and 
adult
subjects with EoE and symptoms of dysphagia. Subjects were treated in 
Study MPI 101-06 with 2 mg OBS twice daily to investigate the co-primary endpoints of 
histologic response (defined as ≤6 eosinophils/HPF) and reduction in DSQ score from 
baseline to Week 12 of treatment. For the current study, the investigational product will be 
supplied in amber glass, multi-dose bottles with child-resistant caps and refrigerated 
throughout the study (in the clinic and subject’s home). Each bottle will contain 
approximately 210 mL of suspension with a budesonide concentration of 0.2 mg/mL, or 0.00 
mg/mL (matching placebo).
At the end of the 12-week double-blind treatment period (Visit 4, Week 16), subjects who 
complete the study will have the opportunity to enroll in the treatment extension study. These 
subjects will continue on the blinded assigned treatment for 2-4 weeks as part of the screening 
prior to enrolling into the treatment extension study. Subjects who do not enroll in the 
treatment extension study or who discontinue at any time during the SHP621-301 (Induction) 
study will receive a follow-up phone call 4 weeks post last dose of investigational product
(Visit 5).
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 26 weeks, 
depending on the 3- to 6-week screening period.
The study will be completed in approximately 32 months.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 37 of 98
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including 
Visit 4 (Week 16), inclusive of the final treatment evaluation EGD. Subjects who do not 
enroll in the treatment extension study or who discontinue prematurely at any time during the 
SHP621-301 (Induction) study will receive a follow-up phone call 4 weeks post last dose of 
the investigational product to which they were randomized.
3.3
Sites and Regions
Approximately 60 sites in North America will participate.
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject 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.
2. Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3. Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 
of 3 (proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4. Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating 
problems, abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) 
intermittently or continuously at screening (Visit -1).
5. Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks 
of the screening period and in the last 2 weeks prior to the baseline visit (Visit 1). 
6. Subject must not have PPI-responsive EoE based on esophageal biopsies performed after 
the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose therapy refers 
to the total daily dose, which may have been administered as a once- or twice daily dosing 
regimen). This may occur at the time of the qualifying EGD (in which case the same PPI 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 38 of 98
regimen must be continued), or this may have been done previously (in which case PPI 
therapy may have been stopped if there was no response to therapy based on esophageal 
biopsy results). If PPI responsiveness was excluded by a previous EGD and biopsy, the
historical EGD and biopsy must have been performed after the patient had been on a 
minimum of 6 weeks of high-dose PPI therapy.
7. Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit
(Visit -1).
8. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at 
the screening visit (Visit -1). There should be no change to these regimens during study 
participation.
9. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing 
potential must agree to continue acceptable birth control measures (eg, abstinence, stable 
oral contraceptives, or double-barrier methods) throughout study participation.
10. 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 any condition or abnormality (including laboratory abnormalities), current or 
past, that, in the opinion of the principal investigator or medical monitor, would 
compromise the safety of the subject or interfere with or complicate the assessment of 
signs or symptoms of EoE. Such conditions may include psychiatric problems; neurologic 
deficits or disease; developmental delay; cardiovascular, metabolic, or pulmonary disease; 
or previous gastroesophageal surgery. These should be discussed with the medical 
monitor.
2. Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD 
or between the qualifying EGD and baseline visit (Visit 1) or anticipates using
immunomodulatory therapy during the treatment period (except for any ongoing regimen 
of allergy shots). Use of long-acting immunomodulatory therapy (eg, Rituxan) within 
3 months of the qualifying EGD should be reviewed with the medical monitor.
3. Subject has been using swallowed topical corticosteroid for EoE or systemic 
corticosteroid for any condition within the 4 weeks prior to the qualifying EGD, between 
the qualifying EGD and baseline visit (Visit 1), or anticipates use during the treatment 
period; any temporary use (≤7 days) or initiation of new steroid treatment during the study 
should be documented and discussed with the medical monitor prospectively but cannot 
occur within 4 weeks of the final EGD. 
4. Subject has been on inhaled steroids and has not been on stable treatment for ≥3 months 
prior to screening visit (Visit -1). Subjects on inhaled steroids need to stay on a stable 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 39 of 98
treatment during study participation. Subject has been on intranasal steroids and has not 
been on stable treatment for a minimum of 4 weeks prior to the qualifying EGD. After the 
qualifying EGD, subjects with seasonal allergic rhinitis may resume (or discontinue) 
intranasal corticosteroids based on the subject's usual treatment regimen for allergy 
season.
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux 
disease, asthma or allergic rhinitis) within the 4 weeks prior to the qualifying EGD, 
between the qualifying esophagogastroduodenoscopy (EGD) and baseline visit (Visit 1), 
or anticipates changes in the use of such medications during the treatment period.  
6. Subject has been using cytochrome P450 3A4
(CYP450 3A4)
inhibitors (eg,
ketoconazole, grapefruit juice) within the 2 weeks prior to the baseline visit (Visit 1) or 
within 5 half-lives (whichever is greater) or anticipates using such medications during the 
treatment period.  
7. Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9 mm). 
8. Subject is on a pure liquid diet or the 6-food elimination diet.
9. Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has acute or chronic viral infection or immunodeficiency condition, including 
tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes 
esophagitis, or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit
(Visit -1) or between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit
(Visit -1) and between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to 
budesonide (or any other corticosteroids) or to any other ingredients of the investigational 
product.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 40 of 98
20. Subject has taken part in an interventional study related to EoE within 6 months prior to 
the screening visit (Visit -1), or any investigational study within 30 days prior to the 
screening visit (Visit -1).
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
22. Subject has previously completed, discontinued, or withdrawn from this study.
23. Subject has participated in a previous clinical study involving OBS (SHP621).
24. Subject anticipates using sucralfate during the study.
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No change in exercise (other than seasonal changes in sports or activities). Intense 
exercise should be avoided unless part of an established exercise routine. 

No change in diet (liquid diet for 3 days or less is acceptable).

Short course of systemic steroids (≤7 days) are permitted to treat, for example, 
exacerbation of asthma but cannot be used 4 weeks prior to the final EGD.

Stable treatment with intranasal or inhaled corticosteroids. For subjects with perennial 
allergic rhinitis and stable asthma, the topical corticosteroid must be maintained at the 
same dose throughout the study. For subjects with seasonal allergic rhinitis, it is 
permissible after the qualifying EGD to resume (or discontinue) intranasal corticosteroids 
based on the subject's usual treatment regimen for allergy season. All topical 
corticosteroid dosing changes, including those for seasonal allergic rhinitis, should be 
avoided within 4 weeks prior to the Week 16 EGD. Subjects who require a change in 
inhaled corticosteroid treatment for an asthma exacerbation should be discussed with the 
medical monitor.

No change in PPI use

No use of CYP450 3A4 inhibitors

No use of sucralfate during the study as this may interfere with the adherence of OBS

An esophageal dilatation during the trial (Dilatation is considered a treatment failure, and 
the subject should be withdrawn from the study.)
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit -1), placebo 
lead-in visit (Visit 0), baseline visit (Visit 1), and Visits 1-4. A serum pregnancy test will be 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 41 of 98
performed at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine 
pregnancy tests will be performed at all other visits.  
Female subjects should be either:

Pre-menarchal and Tanner Stage 1, or

Post-menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone one of the following surgical acts:  hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential must agree to abstain from sexual activity that could 
result in pregnancy or agree to use acceptable methods of contraception throughout the 
study period and for 30 days following the last dose of investigational product.

Acceptable methods of contraception are:

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 -1), 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 one of the other acceptable methods noted above in addition to the hormonal 
contraceptive until it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 4 are to be performed as completely as 
possible. If investigational product is discontinued due to an AE, the subject may remain on 
study to allow for completion of study procedures. 
Whenever possible, all discontinued subjects should also undergo the protocol-specified 
follow-up. Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for termination, date of stopping investigational 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 42 of 98
product, and total amount of investigational product taken must be recorded in the case report 
form (CRF) and source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
an esophageal stricture requiring dilation and/or worsening signs and symptoms of EoE (eg, 
weight loss or increased dysphagia), would be considered a treatment failure and result in 
withdrawal of the subject 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

Non-compliance with study drug

Non-compliance 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

Trial screen failure

Protocol deviation

Other 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 43 of 98
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up 
at any time point prior to the last scheduled contact (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s 
last known address via courier or mail (with an acknowledgement of receipt request) asking 
that they return to the site for final safety evaluations and return any unused investigational 
product.
4.5.4
Safety-related Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the 
following criteria are met:

Death that is considered related to the study drug

Two SAEs of similar type (defined as same or similar Medical Dictionary for Regulatory 
Activities [MedDRA] higher level group code) and considered related to the study drug
The urgent review will be performed by a sponsor safety review group, which will include the 
study Pharmacovigilance and Risk Management (PVRM) physician and the PVRM 
Therapeutic Area Head. The PVRM Therapeutic Area Head, not the PVRM physician 
involved in the study, may be unblinded as part of this urgent safety review, if required. 
Following the sponsor’s review of safety data, one of the following actions will be taken with 
respect to study status:

Continue study with protocol unchanged

Continue study with modifications to the protocol

Terminate study
Subject safety will be monitored on a continuous basis during this study until the last subject 
completes his or her last scheduled study visit/assessment. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 44 of 98
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, and non-pharmacological treatment, such as psychotherapy, as appropriate)
received within 3 months prior to the screening visit (Visit -1) (or pharmacokinetic equivalent 
of 5 half-lives, whichever is longer) 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 non-pharmacological treatment such as psychotherapy, as appropriate, received within 
3 months of the screening visit (Visit -1). Prior treatment information must be recorded on the 
appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the 
prescribed medication is not prohibited by the protocol. In the event of an emergency, any 
needed medications may be prescribed without prior approval, but the medical monitor must 
be notified of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been 
on a stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
endoscopy required for entrance to this study) and will continue this dosing regimen 
throughout study participation. The investigator must contact the medical monitor to discuss 
any changes to concomitant steroid regimens or for any medications not listed here that could 
impact the outcome of the study.
1. Inhaled or intranasal steroids for conditions other than EoE; subject must be on stable 
treatment for ≥3 months prior to screening visit (Visit -1), except for seasonal allergic 
rhinitis, see Section 4.3.
2. PPIs
3. H2 antagonists
4. Antacids


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 45 of 98
5. Antihistamines or antileukotrienes
6. Maintenance immunotherapy (allergy shots)
Influenza 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. Immunomodulatory therapy within 8 weeks prior to the qualifying EGD or between the 
qualifying EGD and baseline visit (Visit 1) or anticipated use of immunomodulatory 
therapy during the treatment period (except for any ongoing regimen of allergy shots). 
Use of long-acting immunomodulatory therapy (eg, Rituxan) within 3 months of the 
qualifying EGD should be reviewed with the medical monitor.
2. Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition 
within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and baseline 
visit (Visit 1) or anticipated use during the treatment period; any temporary use (≤7 days) 
or initiation of new steroid treatment during study should be documented and discussed 
with the medical monitor prospectively but cannot occur within the 4 weeks of the final 
EGD.
3. Inhaled steroids if initiated or changed in dose <3 months prior to screening visit
(Visit -1).  (Seasonal nasal corticosteroid use for seasonal allergic rhinitis is 
permitted; changes within 4 weeks of scheduled EGD should be avoided).
4. Initiation or change in dosing frequency of PPIs, H2 antagonists, antacids, or leukotriene 
inhibitors for any condition (such as gastroesophageal reflux disease, asthma, or allergic 
rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit 1, or anticipated changes in the use of such medications during the treatment 
period.
5. CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) within the 2 weeks prior to the 
baseline visit (Visit 1) or within 5 half-lives (whichever is greater) 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 (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
6. Esophageal dilation within the 3 months prior to screening (Visit -1)
7. Investigational study treatment within 6 months prior to the screening visit (Visit -1)
8. Sucralfate use during the treatment period


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 46 of 98
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in
multi-dose amber glass bottles, each containing approximately 210 mL.
Additional 
information is provided in the current SHP621 investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle
form with the same volume.
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in amber glass, multi-dose bottles with child-resistant 
caps and refrigerated throughout the study (in the clinic and subject’s home). Each bottle 
contains approximately 210 mL of suspension with a budesonide concentration of 0.2 mg/mL.
Inactive ingredients in OBS include dextrose, disodium edetate, citric acid, sodium citrate, 
potassium sorbate, polysorbate 80, glycerin, sodium benzoate, cherry flavor, Magnasweet 
110, acesulfame potassium, and water.
The placebo solution will also be supplied in amber glass multi-dose bottles with 
child-resistant caps. Placebo consists of all components of the investigational product solution 
with the exception of budesonide.
6.2
Administration of Investigational Product(s)
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last 
until the subsequent visit. The first dose of investigational product (placebo) for each subject 
will be administered in the clinic at the placebo lead-in visit (Visit 0).  The subject will 
continue with the evening dosing regimen at home. 
OBS and placebo will be supplied in amber glass bottles and must be shaken well prior to 
administration. OBS and placebo should be refrigerated at 2-8ºC (36-46ºF) throughout the 
study (in the clinic and subject’s home). The appropriate dose will be dispensed using the 
graduated dosing spoon provided. For subjects who are minors (<18 years), a parent/guardian 
will be responsible for ensuring that the subjects take their investigational product 
appropriately. 
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during 
this time interval. After 30 minutes, subjects will be instructed to rinse with water and spit, 
particularly after the bedtime dose.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 47 of 98
Please refer to the Investigational Product Administration Manual for additional details.
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation 
and management, inventory management and supply ordering, investigational product 
expiration tracking and management, return of investigational product, and emergency 
unmasking. Please refer to the Study Manual for additional details regarding the IWRS.
The investigator or designee will access the IWRS at the screening visit (Visit -1) to record 
subject-specific information (ie, unique subject number, date of birth, etc.). Subjects will be 
entered as screen failures or as entering the placebo lead-in period. Subjects cannot be 
rescreened once it is confirmed they do not meet inclusion/exclusion criteria unless the screen 
failure was due to a concomitant medication that can be discontinued prior to rescreening; 
those subjects may be rescreened. Other reasons for rescreening (ie, reasons unrelated to 
inclusion/exclusion criteria) must be discussed prospectively with the medical monitor. For 
subjects who enter the placebo lead-in period, IWRS will provide the assignment of placebo 
lead-in period medication to dispense. 
At the baseline visit (Visit 1), the investigator or designee will again access the IWRS to 
either document a screen failure or, if the subject has met all entry criteria, to randomize the 
subject.  Sites will enter eligibility criteria information prior to randomization. For 
randomized subjects, the IWRS will provide a medication identification (Med ID) number (ie, 
kit number to dispense for treatment).  
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be 
provided to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a single-blind lead-in period followed by a double-blind 
placebo-controlled study period. The actual treatment given to individual subjects during the 
double-blind period is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 48 of 98
The randomization number represents a unique number corresponding to investigational 
product allocated to the subject once eligibility has been determined following the placebo 
lead-in period.  
Individual subject treatment is automatically assigned by the IWRS.
Subjects will be randomized after confirmation of study eligibility in a ratio of 2:1 via a 
computer-generated randomization schedule to receive OBS 2 mg twice daily (qAM, pc, and 
hs) or placebo. The randomization will be performed centrally and stratified by age group 
(2 strata total: <18 years or ≥18 years) and diet restriction for EoE or other health-related 
conditions (no diet restriction or any diet restriction). The stratification by age will ensure a 
minimum of 40 subjects in the pediatric group (11-17 years, inclusive). The stratification by 
age and diet restriction will ensure balance between treatment groups for the respective 
stratification factors. Fixed block randomization will be used to ensure that approximately 
equal numbers of patients are assigned each treatment within strata.
 
 
6.2.3
Dosing
During the 4-week single-blind placebo lead-in period, all subjects will receive 10 mL of 
placebo twice daily (qAM, pc, and hs). During the 12-week double-blind treatment period, 
oral administration of 10 mL of investigational product will occur twice daily (qAM, pc, and 
hs), with no ingestion of food or liquids permitted for 30 minutes after study drug 
administration. Subjects randomized to OBS will receive 10 mL of 0.2 mg/mL of OBS (2 mg) 
twice daily for a total daily dose of 4 mg.  
Investigational product doses that are required to be administered at the clinic include the first 
dose of placebo administered at the placebo lead-in visit (Visit 0), the first dose of 
randomized investigational product (OBS or placebo) administered at the baseline visit
(Visit 1) and all morning doses of investigational product administered at Visits 2-4. Subjects 
will Subjects will be required to eat breakfast at the clinic prior to self-administering these 
doses. Subjects can self-administer all other doses of placebo and investigational product at 
home. 
During the visit where the pharmacokinetic blood samples are collected (Visit 2 or Visit 3), 
subjects will be required to eat a moderate-fat breakfast on-site and will be instructed to take 
their morning dose at a set time to establish the schedule for post-dose sample collection.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 49 of 98
subject. The investigator should contact the medical monitor and the sponsor as soon as 
possible after the investigator has been unblinded.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
There will be a provision for unblinding to ensure adequate treatment of the subject in the 
case of an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. 
All investigational product is labeled with a minimum of the protocol number, Med ID, 
dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiry date (if applicable), batch number and/or packaging reference, the 
statements “For clinical trial 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.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 50 of 98
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8-ounce amber glass bottle for multiple use. Three bottles will be 
packaged in an appropriately labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement 
in advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in 
a secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.  
OBS and placebo must be stored at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by 
manual means, such that both minimum and maximum thermometric values over a specific 
time period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be 
notified immediately upon discovery of any excursion from the established range.  
Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the investigational product and 
will provide supportive documentation as necessary. Under no circumstances should the 
product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
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.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 51 of 98
6.3.4
Special Handling
The investigational product should be stored under refrigeration at 2-8°C/36-46°F at all times.
The investigational product should be protected from light and shaken well immediately prior 
to each dose.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry 
out this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational 
product. Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) 
who is adequately trained in the protocol and who works under the direct supervision of the 
investigator. This delegation must be documented in the applicable study delegation of 
authority form.
The investigator or his/her designee (as documented by the investigator in the applicable 
study delegation of authority form) will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will 
be given only the investigational product carrying his/her treatment assignment. All dispensed 
medication will be documented on the CRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects. The 
investigator or his/her designee will enter the unique subject identifier and initials on the 
investigational product kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and 
the sponsor (or designated CRO). For unused supplies where the original supplied 
tamper-evident feature is verified as intact, the tamper-evident feature must not be broken,
and the labeled amount is to be documented in lieu of counting. Shipment return forms, when 
used, must be signed prior to shipment from the site. Validated electronic return systems (ie,


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 52 of 98
IWRS) do not require a shipment form. Returned investigational product must be packed in a 
tamper-evident manner to ensure product integrity. Contact the sponsor for authorization to 
return any investigational product prior to shipment. Shipment of all returned investigational 
product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational 
product packaging to every visit.
Drug accountability must be assessed at the 
container/packaging level for unused investigational product that is contained within the 
original tamper-evident sealed container (eg, bottles) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the 
drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel.
Site personnel must review the returned investigational product to assess compliance at every 
visit prior to dispensing additional investigational product. Any discrepancies should be 
reconciled with the subject immediately. Subjects who do not return their used and unused 
investigational product should be reminded to bring all used and unused investigational 
product at their next visit.
Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. 
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 (see 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.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 53 of 98
7.1.1
Screening Period (Weeks -6 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise 3-6 weeks, during which all procedures listed for the screening visit (Visit -1) in 
Table 1-1 shall be completed. The screening period will allow for the determination of 
eligibility of each subject’s inclusion into the study. A subject should not be instructed to 
discontinue use of any medication or treatment to participate in this study until informed 
consent has been obtained. Subjects should not stop permitted medications or treatments that 
are effective and well tolerated to participate in this study (see Section 5.2.1).
Screening assessments may take place across several days to allow an appropriate time frame 
in which to complete all procedures and confirm study eligibility. 
After the screening period, subjects who meet eligibility criteria at the end of the screening 
visit (Visit -1) will enter the 4-week single-blind, placebo lead-in period. The placebo lead-in
period should not commence until all screening assessments required to confirm initial 
eligibility have been completed. If the subject does not meet eligibility criteria following 
completion of screening assessments, the investigator or designee will document the subject 
as a screen failure in the IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening, 
placebo lead-in, or baseline visits. Subjects cannot be rescreened once it is confirmed they do 
not meet inclusion/exclusion criteria unless the screen failure was due to a concomitant 
medication that can be discontinued prior to rescreening; those subjects may be rescreened. 
Other reasons for rescreening (ie, reasons unrelated to inclusion/exclusion criteria) must be 
discussed prospectively with the medical monitor.
7.1.1.1
Screening Visit (Visit -1) 
The screening visit (Visit -1) assessments and procedures, beginning with informed consent, 
will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight.  Perform stadiometry in subjects aged 
11-17 years, inclusive.

Review current use of concomitant medications, including medications taken and 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 54 of 98
procedures completed within 3 months prior to the biopsy required for entrance to this 
study. Note: Subjects who are on a PPI must remain on the same dose of the PPI 
throughout the study, and if they are not taking a PPI, they must remain off of a PPI for 
the remainder of the study.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.
The following order is recommended for the remaining procedures that will be performed at 
this visit or within the 6-week screening period:

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly 
completion and train the subject on its use. In order to qualify for study entry, subjects 
must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks 
of the screening period.

Perform a physical examination on all subjects. Adolescents (subjects ≤17 years) will also 
undergo Tanner Staging Assessment.

Serum pregnancy test will be performed on all female subjects. 

Perform EGD and biopsy; both must be performed within the 6 weeks prior to the Placebo 
Lead-in Visit either at the investigative site or by a referring physician. Biopsy specimens 
must be available to be sent to the central pathology lab at least 2 weeks prior to the 
Placebo Lead-in Visit to allow sufficient time for processing and central review and 
determination of eligibility.
7.1.2
Placebo Lead-in Period (Weeks 0 to 4)
The placebo lead-in period will comprise 4 weeks, during which all procedures listed for the 
placebo visit (Visit 0) in Table 1-1 shall be completed.
During the 4-week single-blind placebo lead-in, all eligible subjects will self-administer 
10 mL of placebo twice daily (qAM, pc, and hs). 
At the end of the placebo lead-in period, eligible subjects (those with at least 4 reported 
dysphagia days and completion of DSQ on ≥70% of days in the 2 weeks prior to baseline  
[Visit 1]) will be randomized and enter the 12-week double-blind treatment period (baseline 
visit). Subjects must be administrated placebo during the placebo lead-in period for 4 weeks
(±3 days) prior to Visit 1 (baseline) to be eligible for randomization into the 12-week double-
blind treatment period.
7.1.2.1
Placebo Lead-in Visit (Visit 0) 
The placebo lead-in visit (Visit 0) assessments and procedures will be performed as outlined 
in Table 1-1. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 55 of 98
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight.

Perform AE assessments.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

Perform a physical examination and assess any changes since screening.

Urine pregnancy test for female subjects.  

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD)
and body composition in subjects aged 11-17 years, inclusive; the DXA scan may be 
performed any time during the placebo lead-in period, after the subject has met all 
screening criteria and prior to blinded-treatment randomization. Baseline and post-
treatment DXA scans should be performed using the same machine and software.

Dispense placebo study medication and review administration instructions. Subjects will 
self-administer the first dose of placebo in the clinic after eating breakfast. Site personnel 
will record the date and time of the first placebo dose in the source documents. Beginning 
on the evening of Visit 0, the subject will take their second dose at home and continue 
with the twice daily (qAM, pc, and hs) dosing regimen.
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or Early 
Termination)
The double-blind treatment period will comprise 12 weeks, during which all assessments and 
procedures listed for Visits 1-4 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted, unless otherwise specified. Visit 
windows are calculated based upon the date of the placebo lead-in visit (Visit 0).
Subjects who continue to meet all eligibility criteria will be randomized 2:1 to receive either 
OBS twice daily (qAM, pc, and hs) or placebo twice daily (qAM, pc, and hs). The 
investigator or assigned site staff will access the IWRS to randomize the subject and dispense 
the investigational product. Subjects who fail to meet eligibility criteria at the baseline visit
(Visit 1) will be documented as screen failures in the IWRS.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 56 of 98
Subjects who complete the 12-week double-blind treatment period will have the opportunity 
to enroll in the treatment extension study. These subjects will continue on the blinded 
assigned treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment 
extension study. Subjects who do not enroll in the treatment extension study or who 
discontinue prematurely at any time during the SHP621-301 (Induction) study will receive a 
follow-up phone call 4-weeks post last dose of investigational product.
7.1.3.1
Baseline Visit (Visit 1): Week 4
Subjects will return to the site for the baseline visit (Visit 1) to confirm eligibility. The 
baseline visit (Visit 1) assessments and procedures will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of 
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review study medication dosing compliance.

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

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 PGI-S of disease assessment. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 57 of 98

Perform a physical examination and assess any changes since screening.

Re-administer urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will 
record the date and time of the first randomized dose in the source documents. Beginning 
on the evening of Visit 1, the subject will take their first dose at home and continue with 
the twice daily (morning and evening) dosing regimen. For subjects who are minors (<18 
years), a parent/guardian will be responsible for ensuring subject takes their 
investigational product appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.2
Visits 2 and 3 (Weeks 8 and 12)
Subjects will return to the site for Visit 2 (Week 8) and Visit 3 (Week 12). Assessments at 
these visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature) and weight.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of study medication until after the morning cortisol test has 
been performed. 

Collect blood samples for pharmacokinetic analysis for adult subjects. Subjects will be 
instructed to take their morning dose at a set time to establish the schedule for post-dose 
sample collection.
The following order is recommended for the remaining procedures that will be performed at 
this visit:

Review DSQ dysphagia episodes and compliance; re-dispense DSQ device to subject with 
instruction to continue completion of the DSQ nightly.

Administer PGI-S assessment. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 58 of 98

Perform a physical examination and assess any changes since screening.

Re-administer urine pregnancy test for female subjects.  

Dispense investigational product (OBS or placebo) and review investigational product 
dosing compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.3
Visit 4 (Week 16)
Subjects will return to the site for Visit 4 (Week 16). Assessments at this visit will be 
performed as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, 
respirations, and temperature), height, and weight. Perform stadiometry in subjects aged 
11-17 years, inclusive.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed 
not to take the morning dose of investigational product until after the morning cortisol test 
has been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of 
synthetic and route of administration will be per local lab discretion. Additional cortisol 
samples will be drawn at 30 and 60 minutes following stimulation testing. 

Retrieve DSQ handset and review DSQ compliance.

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S assessment. 

Perform a physical examination and assess any changes since screening. Adolescents 
(subjects ≤17 years) will also undergo Tanner Staging Assessment.

Re-administer serum pregnancy test for female subjects.  

Perform DXA scan for BMD and body composition in subjects aged 11-17 years, 
inclusive. DXA scan should be completed at or within (±) 7 days of this visit. Baseline 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 59 of 98
and post-treatment DXA scans should be performed using the same machine and software.

Perform EGD and biopsy. EGD should be completed at or within (±) 7 days of the 
scheduled visit.

For eligible subjects continuing into the treatment extension study, obtain informed 
consent for the treatment extension study, dispense investigational product (OBS or 
placebo) according to IWRS randomization and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product if they are continuing in the treatment extension study.
7.1.4
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational 
product. Subjects who do not enroll in the treatment extension study or who discontinue 
prematurely at any time during the study will receive a follow-up 4 phone call at Visit 5 
(Week 20) to query for SAEs, AEs, and concomitant treatments (Section 7.1.4.1).
7.1.4.1
Safety Follow-up Contact (Visit 5): Week 20
Assessments at this time, as outlined in Table 1-1, will include the following:

Review concomitant medications and procedures.

Perform AE assessments, including specific assessments for signs of glucocorticoid 
excess. Any AE that occurs during this visit will be recorded in the CRF and considered a 
TEAE; all AEs and SAEs that are not resolved at the time of this contact will be followed 
to closure.
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study for those subjects who do not enroll in the treatment 
extension study.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in 
Appendix 1.
All assessments listed below will be performed by the subject and/or a qualified/trained site 
staff as indicated in the assessment description. For subject-completed assessments, trained 
site staff should not assist the subject in completing assessments in such a manner that it 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 60 of 98
would influence their responses. Site staff should review the completed assessment to ensure 
completeness.
If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales 
after the visit has been completed. Assessments are to be performed according to the schedule 
shown in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and Histopathologic 
Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
An EGD with esophageal, gastric and duodenal biopsies will be required for study 
participation; the peak eosinophil count per HPF from each esophageal level will be used as a 
primary measure of efficacy. The qualifying/baseline EGD with biopsies must be performed 
by a physician at the investigative site within the 6 weeks prior to placebo lead-in visit 
(Visit 1). Biopsy specimens must be available to be sent to the central pathology lab by at 
least 2 weeks prior to the placebo lead-in visit to allow sufficient time for processing and 
central review and determination of eligibility.
Multiple specimens (at least 2 biopsies from each of 3 levels, 6 specimens total) will be 
obtained from the proximal (3 cm below the cricopharyngeus muscle), mid-esophagus (mid-
point between the cricopharyngeus muscle and the gastroesophageal junction), and distal 
(3 cm above the gastroesophageal junction). Biopsy tissue will be placed in 3 separate vials 
(1 vial for each of the levels) and sent to the central pathology laboratory for processing of 
tissue into slides. A central pathologist will determine histologic eligibility for study entry. 
Peak eosinophil counts of ≥15/HPF in specimens from 2 or more levels of the esophagus will 
be a requirement for study entry, as determined by a central pathologist. Eosinophil counts, 
histopathologic features, and gross endoscopic findings will be evaluated and scored for each 
EGD. Eight histopathologic epithelial features (basal layer hyperplasia, eosinophil density, 
eosinophil microabscesses, eosinophil surface layering, dilated intercellular spaces, surface 
epithelial alteration, dyskeratotic epithelial cells, lamina propria fibrosis) will be scored on a 
4-point scale (0=normal, 3=worst) for both the severity of the abnormality (ie, grade) and the 
amount of tissue affected by the abnormality (ie, stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 
2) fixed esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 61 of 98
for each anatomic location (proximal and distal). The maximum endoscopy score is 10 points 
for each location, and a Total Endoscopy Score is the sum of the scores for the proximal and 
distal locations.
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. Biopsies will be taken from the stomach and duodenum for the screening EGD 
as follows: gastric body (greater curvature): 2 specimens, gastric antrum: 2 specimens, and 
duodenum (third part or distal): 2 specimens. Biopsies from the stomach should be submitted 
in one vial; biopsies from the duodenum should be submitted in a separate vial to the central 
pathology laboratory for processing of tissue into slides. If the pre-treatment biopsy identifies 
eosinophilia in the stomach and/or duodenum, the subject will be excluded from the study. 
At the Week 16 visit (Visit 4) or at early termination (ET), and EGD with esophageal biopsies 
(at least 2 biopsies from each of 3 levels [proximal, mid-, and distal]) is required. Endoscopic 
findings will be recorded by the endoscopist.  Biopsies will be sent to the central laboratory 
for processing. A central pathologist will evaluate the slides. Gastric and duodenal biopsies 
may be repeated at the discretion of the investigator, but are not required.
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 3). 
The questionnaire will be completed by subjects daily for a minimum of 3 weeks during the 
screening period, during the 4-week placebo lead-in period, and during the 12-week treatment 
period. Each evening before bedtime, subjects will be asked to indicate if they experienced 
dysphagia symptoms (eg, food passing slowly or food sticking) during that day. Subject must 
have experienced dysphagia (response of “yes” to question 2 on DSQ) on a minimum of 
4 days total and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period and in the 2 weeks prior to the baseline visit (Visit 1). Subjects must fill out 
the DSQ at least 5 or more days during a given week in order to be compliant.
Visit to visit compliance of DSQ completion will also be assessed by site personnel. Protocol 
deviations will be documented for subjects who fail to complete the DSQ for 3 or more days 
in a given week.
Calculations will be performed on daily ePRO entries during a 2-week interval prior to each 
study visit during the treatment periods. The DSQ score for the co-primary endpoint and 
secondary endpoints will be calculated by summing the scores of responses to questions 2 and 
3 only. Questions 1 and 4 will be excluded from the DSQ score:

DSQ score=   (Sum of points from questions 2+3 in the daily DSQ)×14
Number of diaries reported with non-missing data


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 62 of 98
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores 
of responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score= (Sum of points from questions 2+3+4 in the daily DSQ)×14
Number of diaries reported with non-missing data
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score=(Sum of points from question 4 in the daily DSQ)×14
Number of diaries reported with non-missing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
Medical History
The investigator must record all clinically or medically relevant information regardless of 
how much time has elapsed since the date of any diagnosis. Medical history will be classified 
as EoE or non-EoE by the investigator. The EoE medical history must include any prior 
history of esophageal strictures and esophageal dilations.
Medication History
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, 
or other), must be recorded on the appropriate CRF page.
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit -1) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit -1) 
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 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 63 of 98
depression). Physical examination at the screening visit (Visit -1) will also include Tanner 
Staging Assessments for subjects <18 years of age.
Height will be collected at the screening visit (Visit -1) and Visit 4 for all subjects. 
Stadiometers will be used to measure height at Visit -1 and Visit 4 for subjects aged 
11-17 years, inclusive. Statural height will be measured by trained site staff using a stabilized 
stadiometer. The same stadiometer should be used for the baseline and post treatment 
measurements. Standard measuring procedures should be followed (eg, removal of socks, 
shoes, and hats). The stadiometer must be calibrated at least once daily, and as feasible,
within 4 hours of measurement. All measurements should be recorded to the nearest 10th of a 
centimeter (1 mm).  Please refer to the study manual for additional details.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last 
visit?”). AEs are collected from the time informed consent is signed. (Please refer to 
Section 8.)
AE assessments at each visit should also include specific assessments for signs of 
glucocorticoid excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and 
depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes 
immediately prior to the assessment and will include blood pressure (systolic and diastolic), 
heart rate, respirations, and temperature. Blood pressure should be determined by cuff (using 
the same method, the same arm, and in the same position throughout the study). Any 
clinically significant deviations from baseline (Visit 1) vital signs that are deemed clinically 
significant in the opinion of the investigator are to be recorded as an AE.
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal 
procedures. All subjects must fast overnight prior to collection of clinical laboratory tests.
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 64 of 98
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase 

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose 

blood urea nitrogen 

creatinine

sodium 

potassium 

chloride 

calcium

carbon dioxide
Hematology

hemoglobin 

hematocrit 

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
ACTH stimulation testing will be performed by measuring the levels of cortisol in the blood 
following the injection of a synthetic form of ACTH. The type of synthetic and route of 
administration will be per local lab discretion. Blood samples will be collected just prior to 
and approximately 30 and 60 minutes following the injection. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 65 of 98
In the event of clinically significant abnormal laboratory test results, follow-up laboratory 
tests may be conducted. All subjects with an abnormal ACTH stimulation test or urinary or 
serum glucose level must be followed closely until resolution. For subjects who discontinue 
from the treatment period at any time and have an abnormal ACTH stimulation test at the 
early termination visit, subjects will be scheduled for repeat testing approximately 6 weeks 
post last dose of investigational product to ensure that ACTH levels have normalized.  Any 
clinically significant abnormalities noted in the laboratory tests will be discussed with the 
medical monitor.
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit
(Visit -1) and the final treatment evaluation visit (Visit 4) or ET visit. A urine pregnancy test 
is performed on all female subjects at the placebo lead-in visit (Visit 0), baseline visit (Visit 
1), Visit 2, and Visit 3 or if pregnancy is suspected.
7.2.2.7
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, as outlined in Table 1-1.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body 
less head (Bachrach, 2011; Gordon, 2008; International Society for Clinical Densitometry, 
2013). The same DXA machine and software should be used for the baseline and 
post-treatment scans. The DXA manufacturer, model, and software version should be 
recorded in the CRF.
7.2.3
Other Assessments
7.2.3.1
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.
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 Group, 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, 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 66 of 98
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.
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, 2013; 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.
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.
7.2.3.2
Severity of Disease Assessments
Patient Global Impression of Severity 
The PGI-S will be performed in all subjects as outlined in Table 1-1.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 67 of 98
The PGI-S is a global index (Appendix 4) 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.
7.2.4
Clinical Pharmacology Assessments
Blood samples will be collected from adult subjects (≥18 years of age) as outlined in Table 
1-1 to measure plasma concentrations of budesonide. Subjects who do not participate in 
pharmacokinetic sampling will not be discontinued from the study, and lack of participation 
will not be a considered protocol deviation. 
Actual pharmacokinetic blood sample collection times vs time of dosing will be monitored. 
The sponsor’s expectation is that the investigator will ensure that every effort will be made to 
collect all pharmacokinetic blood samples at the precise protocol scheduled time. 
Pharmacokinetic blood collection must not deviate from the nominal collection time set forth 
in the protocol by more than ± 5 minutes for samples drawn within 4 hours post-dose or by 
more than ± 15 minutes for samples drawn after 4 hours post-dose. Samples drawn outside 
these parameters will be considered a protocol deviation.
Blood samples (4 mL) for pharmacokinetic analysis will be drawn by direct venipuncture into 
K2EDTA tubes, capped and mixed by inversion (×3), and chilled immediately on crushed ice. 
The actual blood collection time will be recorded in the subject’s source documents and on 
the appropriate CRF page (24-hour format). After applying a tourniquet, venous blood will be 
drawn with a disposable needle. If a catheter is used, the first milliliter of blood on each 
sampling occasion will be discarded. Saline can be used to keep catheters patent.
Within 15 minutes following each sample collection, the blood tubes will be centrifuged at 
approximately 1500 g (15 minutes, 4°C). The separated plasma will be decanted into 
appropriately labeled primary and backup polypropylene tubes via a plastic pipette. All 
samples will be stored nominally at -20°C, and the freezer temperature will be controlled, 
monitored, and recorded during the storage period until the samples are shipped to the 
designated bioanalytical laboratory for analysis.
For additional information detailing sample handling, storage, and shipment, see Appendix 5.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 68 of 98
7.2.5
Volume of Blood to Be Drawn from Each Subject
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Pharmacokinetic samplesa
5
9
45
Safety
Biochemistry and -hCGb
6
6
36
ACTH
2
4
8
Cortisol
2
4
8
Hematology
2
6
12
Total mL
109
Abbreviations: ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropin
a
If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for pharmacokinetic 
sample.  A total of 5 mL of blood drawn has been used in determination of sample volume.
b
-hCG testing is for females only.
During this study, it is expected that approximately 109 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 109 mL. When more than 1 blood assessment is to be done 
at the time point/period, if they require the same type of tube, the assessments may be 
combined.  
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 7.1.4. This includes events occurring during the screening phase of 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 69 of 98
the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on
the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to normal), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. When appropriate, medical tests and examinations are 
performed so that resolution of event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each change in severity. An event that changes in severity should be captured as 
a new event. Worsening of pre-treatment 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.
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 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 70 of 98
suspecting a possible cause-and-effect relationship between the investigational product and 
the occurrence of the AE, then the AE should be considered “related” based on the definitions 
in Table 8-1. The causality assessment must be documented in the source document.
Table 8-1: Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent 
disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or 
other drugs and chemicals and which follows a clinically reasonable response on 
de-challenge.  The association of the clinical event or laboratory abnormality must 
also have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (de-challenge), and reappears upon 
repeated exposure (re-challenge).  Note that this is not to be construed as requiring 
re-exposure of the patient to study drug; however, the determination of definitely 
related can only be used when recurrence of event is observed.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within 
the normal day-to-day fluctuation or expected progression of the disease and are part of the 
efficacy data to be collected in the study; however, significant worsening of the symptoms 
should be recorded as an AE.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 71 of 98
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 phase, there are abnormal clinical laboratory or vital sign values 
which were not present at the pre-treatment 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 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
the Shire Global PVRM Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products 
Pregnancy Report Form (and any applicable follow-up reports) must also be sent to the 
CRO/Shire medical monitor using the details specified in the emergency contact information 
section of the protocol. The pregnant female study participant must be withdrawn from the 
study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information 
within 30 calendar days after the initial notification and approximately 30 calendar days 
postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event 
Form for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is 
not considered an SAE.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 72 of 98
In addition to the above, if the investigator determines that the pregnancy meets serious 
criteria, it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical 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 pre-specified 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 
parent/legally authorized representative/caregiver.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 73 of 98
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
PVRM Department and the CRO medical monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form 
for SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the 
information recorded on the form with the corresponding source documents (Note: Source 
documents are not to be sent unless requested) and fax or e-mail the form to the Shire Global 
PVRM Department. A copy of the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by Protocol (and any applicable follow-up reports) must also be 
sent to the CRO medical monitor using the details specified in the emergency contact 
information section of the protocol.
8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to 
be related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should 
not be classified as SAEs. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 74 of 98

Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; blood dyscrasias or convulsions 
that do not result in inpatient hospitalization; or the development of drug dependency or 
drug abuse.  
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be 
reported to the Shire Global PVRM Department and the medical monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by 
the investigator at any interval after the study has completed must be reported to the Shire 
Global PVRM 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, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 75 of 98
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.
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the 
protocol on the CRF. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy.  
Discrepancies between source data and data entered on the CRF will be addressed by 
qualified site personnel. When a data discrepancy warrants correction, the correction will be 
made by authorized site personnel. Data collection procedures will be discussed with the site 
at the site initiation visit and/or at the investigator’s meeting. Once a subject is randomized, it 
is expected that site personnel will complete the CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification 
are to be communicated to the site for resolution. Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 76 of 98
data) will be handled with special care during the data cleaning and review process. These 
data will be handled in such a way that, prior to unblinding, any data that may unblind study 
team personnel will be presented as blinded information or otherwise will not be made 
available. If applicable, unblinded data may be made available to quality assurance 
representatives for the purposes of conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be
performed using SAS® (SAS Institute, Cary, NC, USA) version 9.1 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.
In addition to a final SAP for the final analysis, a separate interim SAP for the interim 
analysis will be finalized prior to unblinding and performing the analysis. The SAP for the 
final analysis will be finalized prior to final database lock and performing analysis (ie, 
unblinding) to preserve the integrity of the statistical analysis and study conclusions. 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A planned interim analysis for each of the co-primary endpoints will take place after 50% of 
all randomized subjects have either completed the study or prematurely withdrawn from the 
study, whichever comes first. The purpose of the unblinded interim analysis is to reassess the 
appropriateness of assumptions used for each of co-primary efficacy endpoints when the 
study was designed. The reassessment of the sample size will utilize the conditional power 
approach under certain conditions that do not inflate the type I error (Mehta and Pocock,
2011). The planned interim analysis will be conducted by an external independent statistical 
(EIS) group; the individuals involved in the day-to-day conduct of the trial will not be 
involved in the interim analysis or have access to the results of the interim analysis. The 
Sponsor will only be notified by the EIS group if any recommendation of increasing the 
sample size is needed from the conditional power; this will be detailed in the pre-specified 
interim SAP including a potential maximum sample size to be increased if deemed necessary. 
A very minimal fraction of alpha (0.0001) will be spent at the interim analysis as the trial will 
not stop due to the interim results. The final analysis will use 4.99% for each of the 
co-primary endpoints in order to preserve an overall type I error at 5% level.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 77 of 98
9.6
Sample Size Calculation and Power Considerations
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected 
difference between treatment response proportions of 69% and 45% in the OBS 2 mg twice 
daily (qAM, pc, and hs) and placebo groups, respectively. A total of 228 subjects 
(152 subjects randomized to OBS and 76 subjects randomized to placebo) are required to 
achieve 90% power at the significance level of 0.0499 (2-sided) using a 2-group chi-square 
test with unequal allocation 2:1 to treatment groups (OBS 2 mg twice daily and placebo). 
With the specified number of subjects per treatment group, the study will be powered at 99% 
assuming histological response proportions of 40% and 3% in the OBS 2 mg twice daily and 
placebo groups, respectively. The overall study power for the co-primary endpoints will be at 
least 85%. Therefore, approximately 228 (approximately 152:76 OBS and placebo subjects, 
respectively) will be randomized to the study to allow for a loss of approximately 5% of 
subjects due to dropouts or invalid data. Expected response and dropout rates are based on 
observation from the Phase 2 study (MPI 101-06).
9.7
Study Population
The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. 
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose 
of a double-blind investigational product and have both an evaluable post-baseline biopsy in 
the treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and 
a post-baseline DSQ score.
The per-protocol (PP) set will include all subjects in the FAS excluding subjects with 
protocol violations. The PP set will be identified prior to unblinding the treatment 
assignments by a team consisting of, at a minimum, a physician and a statistician from Shire. 
The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
9.8
Efficacy Analyses
The primary, key secondary, and secondary efficacy analyses will be performed on the ITT
set and presented by treatment group.
Data collected at the baseline visit (Visit 1) will be used as the baseline for all efficacy 
analyses.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 78 of 98
9.8.1
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4)
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the 
co-primary efficacy endpoints is a binary response (ie, responders vs non-responders); the 
endpoint will be analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for age 
group (either <18 years or ≥18 years) and diet restriction for EoE or other health-related 
conditions (no diet restriction or any diet restriction). The adjusted odds ratio of being a 
responder on each of the co-primary endpoints for the OBS 2 mg twice daily group vs placebo
group and associated 95% confidence interval (CI) will be provided. Subjects who withdraw 
without providing efficacy data at the final treatment period evaluation (Visit 4, Week 16) 
will be classified as non-responders in the primary efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized, and their respective 95% CI will be reported. The 
difference in the proportion of responders between the 2 treatment groups and the 
corresponding 95% CI will also be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to 
evaluate the robustness of the results from the primary analysis methods: 

Each of the co-primary efficacy endpoints will be analyzed using a logistic regression 
with the effects of treatment group, age group (either <18 years or ≥18 years) and diet 
restriction for EoE or other health-related conditions (no diet restriction or any diet 
restriction). The odds ratio of being a responder on each of the co-primary endpoints 
for the OBS 2 mg twice daily group vs placebo group and associated 95% confidence 
interval (CI) will be estimated from the final model. Subjects who withdraw without 
providing efficacy data at the final treatment period evaluation (Visit 4, Week 16) will 
be classified as non-responders in the primary efficacy analysis.

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing 
efficacy data at the final treatment period evaluation (Visit 4) and will be classified as 
responders.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 79 of 98
9.8.1.1
Missing Data Imputation
Method 1: Distribution-based Imputation
The subjects with missing co-primary efficacy endpoints will be assigned randomly according 
to the distribution of responders with available data for each of the co-primary endpoints (ie, 
those with non-missing data) across the 2 treatment groups by strata (see Table 9-1). 
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata
Strata
No
Yes
<18 years
X0%
X1%
≥18 years
Y0%
Y1%
For instance, if there are N subjects with missing data in strata 1 (age <18 years), then 
X0%*N subjects will be randomly assigned as non-responders and X1%*N subjects will be 
randomly assigned as responders.
Conversely, if there are M subjects with missing data in strata 2 (age ≥18 years), the Y0%*M 
subjects will be randomly assigned as non-responders and Y1%*N subjects will be randomly 
assigned as responders.
Method 2: Multiple Imputations
Multiple imputation (MI) methods will utilize the SAS procedures PROC MI and PROC 
MIANALYZE. The MI procedure will involve fitting a logistic regression model with the 
binary outcome (responders vs non-responders) as the dependent variable and the age group 
and the treatment group as the independent variables. The MI procedure will generate 
10 version datasets with binary outcome imputed from the subjects with complete data. Once 
the missing values are imputed and each dataset is created, the results will be appropriately 
pooled across the multiply imputed estimated regression coefficients and their standard errors 
using PROC MIANALYZE.
Other sensitivity analyses will be explored, and details will be provided in the SAP.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4). The change 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 80 of 98
from baseline DSQ score at the final treatment period evaluation (Visit 4) will be analyzed 
using an analysis of covariance (ANCOVA) model with treatment group and age group as 
factors and the baseline DSQ score as a continuous covariate.
The additional secondary efficacy endpoints are the following:

Change in total endoscopy score, as measured by the EREFS classification, from baseline 
to the final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)

Change from baseline in the histopathologic epithelial features combined total score 
(grade and stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a  ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation 
(Visit 4)

Change from baseline in the DSQ combined score (questions 2+3) over time including 
post baseline visits

Cumulative distribution function curves for the change and the percent change in the DSQ 
score from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline 
to the final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF 
across all esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from 
baseline to the final treatment period evaluation (Visit 4) and a peak eosinophil count of 
≤6/HPF across all esophageal levels at the final treatment period evaluation (Visit 4)

Change in the DSQ + pain score (questions 2+3+4) from baseline to the final treatment 
period evaluation (Visit 4)

Change in the DSQ pain score (question 4) from baseline to the final treatment period 
evaluation (Visit 4)
The binary response endpoints will be analyzed using the same logistic model as the 
co-primary efficacy endpoints.
Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model 
that includes treatment group and age group as factors and baseline score as a covariate.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 81 of 98
The analyses for all secondary efficacy endpoints (including the key secondary efficacy 
endpoint) will be carried out using 2-sided tests at the 5% level of significance. For each of 
the secondary efficacy endpoints, the treatment difference, corresponding 95% CI for the 
difference, and treatment comparison p-value for testing the null hypothesis of zero treatment 
effect based on the final statistical model (ie, either logistic regression model or ANCOVA 
model) will be provided.
9.8.3
Exploratory Efficacy Endpoint
The exploratory endpoint that will be explored is the following:
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the baseline visit (Visit 1) or the last preceding visit if not 
collected at Visit 1 will be used as the baseline value for safety analyses.
TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product (Visit 1) and no later than 3 days following the last dose of investigational product.
However, for any subjects who die during the study (ie, the date of death is between the date 
of first dose of investigational product and the date of study discontinuation entered by the 
site, inclusive), all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs irrespective of the last dose and will be included in the TEAE 
summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of 
TEAEs will be calculated overall by system organ class (SOC), preferred term (PT), and 
treatment group. TEAEs will be further summarized by severity and relationship to 
investigational product. AEs related to investigational product, AEs leading to withdrawal, 
SAEs, and deaths will be similarly summarized/listed.
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight 
and height assessments, DXA scans for BMD and body composition measurements (for 
adolescents aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, 
urinalysis; serum pregnancy test, if appropriate), and ACTH stimulation tests. To account for 
the effects of puberty in adolescent subjects (11-17 years of age, inclusive), BMD z-scores 
will be adjusted for height z-scores using the Bone Mineral Density in Childhood Study 
calculator
(http://www.bmdcspublic.com).
Safety 
parameters 
will 
be 
descriptively 
summarized by treatment group at baseline and for each post-baseline visit.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 82 of 98
9.10
Other Analyses
9.10.1
Health-related Quality-of-life Analyses
The health economics and outcomes research endpoints that will be explored are the 
following:

EoE-QoL-A Questionnaire (Taft et al., 2011)

EQ-5D (EQ-5D-3L or EQ-5D-Y, according to subject’s age)

PedsQL-EoE
The sub-modules of the EoE-QoL-A and PedsQL-EoE will be assessed in addition to the 
overall score with a focus on emotional and physical elements. For all HRQoL analyses, 
change from baseline to the final treatment period evaluation (Visit 4) will be assessed.
9.10.2
Pharmacokinetic Analyses
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis.  
The pharmacokinetic endpoints will include but not be limited to those listed in Table 9-2.
Table 9-2: Pharmacokinetic Parameters
Parameter
Definition
AUC0-tau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing interval
Summary statistics (number of observations, mean, standard deviation, coefficient of 
variation, median, maximum, minimum, and geometric mean) will be determined for all 
pharmacokinetic parameters by overall and by week. Plasma concentrations at each nominal 
sampling time will also be summarized using descriptive statistics.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 83 of 98
The name and address of each third-party vendor (eg, CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their assigned roles for this study in 
compliance with all applicable industry regulations, ICH GCP Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start 
of the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ 
names and contact information.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 84 of 98
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities of 
Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with 
the community guideline on GCP. This requirement will be fulfilled within 6 months of the 
end of the study completion date for pediatric studies and within 1 year for non-pediatric 
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 sub-investigators 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). 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 85 of 98
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials 
to the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, 
and regulatory agency with final reports and summaries as required by (inter)national 
regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions 
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data from the investigator will have separate source documentation; no data will be 
recorded directly onto the CRF.  
All data sent to the sponsor must be endorsed by the investigator.
The data from the central pathologist will be recorded directly onto paper CRFs.  
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.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 86 of 98
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include but are not limited to
subject’s medical file, original clinical laboratory reports, and histology and pathology 
reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective 
national, local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities 
and have direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (eg, the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment,
retainer for ongoing consultation, or honoraria; any proprietary interest in investigational 
product; any significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 
2(b) (1998).


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 87 of 98
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 parent/legally
authorized representative/caregiver of the safe, 
responsible storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and 
received their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable 
opinion/approval of these documents must be provided to the sponsor, prior to the start of the 
study unless it is agreed to and documented (abiding by regulatory guidelines and national 
provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification 
of the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and 
all must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator 
or, for multicenter studies, the coordinating principal investigator or sponsor, according to 
national provisions.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 88 of 98
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
Investigational product supplies will not be released until the CRO has received written 
IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant 
AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market SHP621; national or local regulatory authorities; and the IRBs/ECs which 
gave approval for the study to proceed. The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth 
may also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies 
within the countries where this study is conducted. The purposes of any such transfer would 
include supporting regulatory submissions, conducting new data analyses to publish or 
present the study results, or answering questions asked by regulatory or health authorities.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 89 of 98
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this 
policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) 
the copyright on his/her publications. To the extent that the principal investigator has such 
sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral, or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be 
made by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter 
publication of the compiled and analyzed study results. If such a multicenter publication is not 
submitted to a journal for publication by the sponsor within an 18-month period after 
conclusion, abandonment, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section. 
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 90 of 98
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.
11.
REFERENCES
Bachrach LK, Sills IN, Section on Endocrinology. Clinical report—Bone densitometry in 
children and adolescents. Pediatrics 2011;127:189-194.
Bone Mineral Density in Childhood Study (BMDCS)
calculator. Available at:
http://www.bmdcspublic.com. Accessed August 5, 2015. 
Dellon ES, Jensen ET, Martin CF, et al. Prevalence of eosinophilic esophagitis in the United 
States. Clin Gastroenterol Hepatol 2014a;12(4):589-96.
Dellon ES, Kim HP, Sperry SL, et al. A phenotypic analysis shows that eosinophilic 
esophagitis is a progressive fibrostenotic disease. Gastrointest Endosc 2014b;79(4):577-85.
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208.
Food and Drug Administration. Uceris pharmacology review. NDA 203-634. 2011.
Franciosi JP, Hommel KA, Bendo CB. PedsQL eosinophilic esophagitis module: feasibility, 
reliability, and validity. J Pediatr Gastroenterol Nutr 2013;57(1):57-66.
Furuta GT, Liacouras CA, Collins MH, et al. Eosinophilic esophagitis in children and adults: 
a systematic review and consensus recommendations for diagnosis and treatment. 
Gastroenterology 2007;133(4):1342-63.
Gordon CM, Bachrach LK, Carpenter TO, et al. Duel energy X-ray absorptiometry 
interpretation and reporting in children and adolescents: The 2007 ISCD pediatric official 
positions. J Clin Densitometry 2008;11:43-58.
Hirano I, Aceves S. Clinical Implications and Pathogenesis of Esophageal Remodeling in 
Eosinophilic Esophagitis. Gastro Clin North Am 2014;43(2):297-316.
International Society for Clinical Densitometry. 2013 Official Positions—Adult & Pediatric. 
2014:1-20.
Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus 
recommendations for children and adults. J Allergy Clin Immunol 2011;128 (1):3-20. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med 2011;30(28):3267-84.


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 91 of 98
Patient-Reported Outcome and Quality of Life Instruments Database (PROQOLID). 
Available at: http://www.proqolid.org. Accessed August 24, 2015. 
Taft TH, Kern E, Kwiatek MA. The adult eosinophilic oesophagitis quality of life 
questionnaire: a new measure of health-related quality of life. Aliment Pharmacol Ther 
2011t;34(7):790-8.
Wille N, Badia X, Bonsel G, et al. Development of the EQ-5D-Y: a child-friendly version of 
the EQ-5D. Qual Life Res 2010;19(6):875-86. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 92 of 98
12.
APPENDICES


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 93 of 98
Appendix 1
Protocol History 
Document
Date
Global/Country/Site Specific
Protocol Amendment 1
16 Dec 2015
Global
Original Protocol
31 Aug 2015
Global


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 94 of 98
Appendix 2
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Subject
EQ-5D-3L (for subjects ≥18 years)
EQ-5D-Y (for subjects 11-17 years of age, inclusive)
Subject
PedsQL-EoE (subjects 11-17 years of age, inclusive)
Subject and parent or legal 
guardian
EoE-QoL-A (subjects ≥18 years of age)
Subject
PGI-S
Subject
Tanner Staging Assessment (for subjects 11-17 years of age, inclusive)
Site
EREFS
Site
Abbreviations: DSQ=Dysphagia Symptom Questionnaire; EoE-QoL-A=Adult Eosinophilic Esophagitis Quality 
of Life; EQ-5D=EuroQol; EREFS=EoE Endoscopic Reference Score; PedsQL-EoE=Pediatric Quality of Life 
Inventory – EoE; PGI-S=Patient Global Impression of Severity
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. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 95 of 98
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 96 of 98
Appendix 4
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


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 97 of 98
Appendix 5
Biosciences Generic Clinical Protocol Insert
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1-1 to measure plasma 
concentrations of budesonide. Potential metabolites may also be determined as appropriate.
Blood samples 4 mL for pharmacokinetic analysis will be drawn by in-dwelling catheters or 
direct venipuncture into K2EDTA tubes, capped and mixed by inversion (x3), and chilled 
immediately on crushed ice. The actual time that the sample was obtained will be recorded in 
the subject’s source document and on the appropriate CRF page. After applying a tourniquet, 
venous blood will be drawn with a disposable needle. If a catheter is used, the first milliliter 
of blood on each sampling occasion will be discarded. Saline can be used to keep catheters 
patent.
1.1
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after 
collection within <15 minutes, unless advised otherwise by refrigerated centrifugation (4C, 
1500 rpm 15 minutes). The separated plasma will be decanted into appropriately labeled 
polypropylene tubes via a plastic pipette. All samples will be stored at approximately -20C 
or colder and the freezer temperature will be controlled, monitored, and recorded during the 
storage period until they are transferred in the frozen state to a designated bioanalytical 
contract laboratory. Samples will remain frozen at -20C or colder until analysis.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe 
labels provided by the central laboratory. The labels will contain the following information:

Study number

Subject identifier (randomization number)

Matrix identifier (plasma)

Visit

Nominal time
1.2
Shipment of Plasma Samples
Plasma samples should be double-bagged to contain leaks and packed with a sufficient 
quantity of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in 
shipment. All applicable shipping regulations must be followed. Shipments should be 
scheduled so that no samples arrive on the weekend and should be shipped Monday to
Wednesday only. 


Shire
CONFIDENTIAL
17 Dec 2015
Protocol SHP621-301
Amendment 1
Page 98 of 98
Plasma samples, along with the corresponding documentation, will be shipped to:
PPD
2 Tesseneer Drive
Highland Heights, KY 41076, USA
Email:
Phone:  
 or 
, 
Fax:  
Plasma samples will be stored nominally at -20C prior to and after analysis at Covance until 
their disposal is authorized by Shire.
1.3
Assay Methodology
Drug analysis will be performed at Covance under the guidance of the NCE group at Shire. 
Plasma sample analysis will be performed according to the bioanalytical study plans prepared 
for the study. 
Plasma samples will be analyzed at Covance for budesonide using the most current validated 
bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample 
reproducibility (full details will be described in the bioanalytical study plan). The presence of 
other metabolites or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at Covance.


PROTOCOL: SHP621-301
TITLE:
Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects 
(11 to 55 Years of Age, Inclusive) with Eosinophilic Esophagitis: 
A Phase 3 Randomized, Double-blind, Placebo-controlled Study
DRUG:
SHP621, oral budesonide suspension (OBS)
IND:
103,173
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 31 Aug 2015
Protocol Amendment 1: 17 Dec 2015
Protocol Amendment 2: 26 Jan 2018
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and nondisclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.


Shire
CONFIDENTIAL
Page 2
Protocol Amendment 2
SHP621-301
26 Jan 2018
PROTOCOL SIGNATURE PAGE


Shire
CONFIDENTIAL
Page 3
Protocol Amendment 2
SHP621-301
26 Jan 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
The SHP621-301 protocol is amended to address the following items:

Increase the number of enrolled subjects to allow an adequate number of subjects to 
enroll in the treatment extension study (SHP621-302).

Administrative changes issued since Protocol Amendment 1.
Additional edits, as captured in the below table, were made to Protocol Amendment 2 to 
improve the clarity of the protocol and/or correct minor inconsistencies. Note that correction of 
typos and grammatical errors are not captured in the below table.
New text indicated in bold; deleted text indicated in strikethrough.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
26 Jan 2018
Global Amendment
Description of Change
Section(s) Affected by Change
Revised text to reflect increased enrollment of subjects in this study 
(from 300 to 420) to allow an adequate number of subjects to enroll in 
the treatment extension study. Updated number of subjects to be 
randomized (from 152 to 204 for OBS; from 76 to 102 for placebo) to 
reflect increase enrollment of subjects in this study.
Study Synopsis: Number of subjects
Section 3.1: Study Design and Flow 
Chart
Approximately 60 70 sites in North America
Study Synopsis: Sites and Region(s)
Section 3.3; Sites and Regions
Oct 2015 to July 2018 Nov 2018
Study Synopsis: Study Period 
(Planned)
14.
Subject has a potentially serious acute or chronic viral 
infection or immunodeficiency condition, including tuberculosis, 
fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes 
esophagitis, or chicken pox/measles.
Study Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
20.
Subject has taken part and received intervention in an
interventional study related to EoE (except for an interventional 
study for a topical swallowed steroid) within 6 months prior to the 
screening visit (Visit -1), or any investigational study within 30 days 
prior to the screening visit (Visit -1). An investigational topical 
swallowed steroid must have been discontinued at least 30 days 
prior to the screening visit (Visit -1).
Study Synopsis: Exclusion Criteria;
Section 4.2: Exclusion Criteria
Pharmacokinetic parameters will be determined from the plasma 
concentration-time data for budesonide by non-compartmental 
analysis. for subjects who provide sufficient numbers of intensive 
PK samples. For all subjects who provide PK samples (ie, limited 
or intensive samples) population PK analysis will be conducted.
A report for the population PK analysis will be provided 
Study Synopsis: Endpoints and 
Statistical Analysis; Pharmacokinetic 
Endpoints
Section 9.10.2: Pharmacokinetic 
Analysis
Section 9.10.2: Pharmacokinetic 


Shire
CONFIDENTIAL
Page 4
Protocol Amendment 2
SHP621-301
26 Jan 2018
separately from the clinical study report (CSR).
Analysis 
Height measurements for adolescent subjects 11-17 years of age, 
inclusive, should be measured in triplicate.
Table 1-1; Schedule of Assessments, 
footnote b
Section 7.2.2.2; Physical Examination 
(Including Height and Weight)
Weight measurements for adolescent subjects (11-17 years, 
inclusive) should be measured in duplicate.
Table 1-1; Schedule of Assessments, 
footnote c
Section 7.2.2.2; Physical Examination 
(Including Height and Weight)
DSQ assessment includes completion of reports on DSQ handset 
(ie, eligibility reports and visit confirmations). 
Table 1-1; Schedule of Assessments, 
footnote e
Blood samples for pharmacokinetic analysis will can be obtained at the
one time on any day starting 7 days after Visit 1 (Week 8 or 5) and 
through Visit 4 (Week 12 visit 16). PK samples should be drawn, 
ideally, at pre-dose, 0.5 and 1 hour post-dose, and at the following
additional post-dose time points: pre-dose and at 0.5, 1, if feasible (2, 
3, 4, 6, 8, and 12 hours post-dose).
Table 1-1, Schedule of Assessments, 
footnote k
Section 7.1.3.2; Visits 2 and 3 
(Weeks 8 and 12)
Section 7.1.3.3; Visit 4 (Week 16)
Subjects cannot be rescreened once it is confirmed they do not meet 
inclusion/exclusion criteria unless the screen failure was due to a 
temporary condition or incomplete information at the time of 
consent (Visit -1) that would make rescreening at a later date 
appropriate (eg, concomitant medication that can be discontinued 
prior to rescreening; those subjects may be rescreened. Other, review 
of subject medical records provides new information with respect 
to the date of a prior esophageal dilation or diet change, or subject 
has a minor illness such as an upper respiratory or urinary tract 
infection). All reasons for rescreening (ie, reasons unrelated to 
inclusion/exclusion criteria) must be discussed and approved
prospectively with the medical monitor. Subjects who discontinue will 
not be replaced.
Section 3.1: Study Design and Flow 
Chart
Section 7.1.1; Screening Period 
(Weeks -6 to 0)

Abstinence

Surgically sterile male partner

Stable oral contraceptives
Section 4.4.1; Female Contraception
Medically important events that in the opinion of the investigator or 
medical monitor would compromise the subject’s ability to safely 
continue in the study, including but not limited to severe signs and 
symptoms of EoE, such as an esophageal stricture requiring dilation 
and/or worsening signs and symptoms of EoE (eg, weight loss or 
increased due to severe dysphagia), and/or upper GI bleed would be 
considered a treatment failure and result in withdrawal of the subject 
from the study.
Section 4.5.1; Subject Withdrawal 
Criteria
6.
Maintenance immunotherapy (allergy shots or sublingual 
immunotherapy)
Section 5.2.1; Permitted Treatment
During the visit day where the pharmacokinetic blood samples are 
collected (Visit 2 or Visit 3), subjects will be required to eat a 
moderate-fat breakfast on-site
Section 6.2.3; Dosing

Review Confirm DSQ dysphagia episodes and compliance by 
completing baseline screening eligibility report on DSQ 
device;
Section 7.1.2.1; Placebo Lead-in Visit 
(Visit 0)
Section 7.1.3.1; Baseline Visit 


Shire
CONFIDENTIAL
Page 5
Protocol Amendment 2
SHP621-301
26 Jan 2018
(Visit 1)

Review DSQ dysphagia episodescompliance and complete 
visit confirmation on the DSQ device;
Section 7.1.3.2; Visits 2 and 3 (Weeks 
8 and 12)
Section 7.1.3.3; Visit 4 (Week 16)

If an esophageal dilatation is performed at Visit 4 
(treatment failure),
subjects will not be eligible to 
participate in the treatment extension study.
Following all safety blood draws, subjects can eat breakfast and take 
their morning dose of investigational product if they are continuing in 
the treatment extension study or staying in clinic for PK sampling (to 
be performed as described in Section 7.1.3.2 above).
Section 7.1.3.3; Visit 4 (Week 16)
Subjects must fill out the DSQ at least 5 4 or more days during a given 
week in order to be compliant.
Protocol deviations will be documented for subjects who fail to 
complete the DSQ for 3 4 or more days in a given week.
Section 7.2.1.2; Dysphagia Symptom 
Questionnaire
The original protocol noted that a total of 228 subjects (152 subjects 
randomized to OBS and 76 subjects randomized to placebo) are 
required to achieve 90% power at the significance level of 0.0499 (2-
sided)…
The overall study power for the co-primary endpoints will was 
estimated to be at least 85%. Therefore, approximately 228 
(approximately 152:76 OBS and placebo subjects, respectively) will 
were to be randomized to in the study to allow for a loss of 
approximately 5% of subjects due to dropouts or invalid data.
In this protocol amendment, in order to ensure that a sufficient 
number of subjects will complete this study and enroll in the 
treatment extension study, up to approximately 420 subjects will 
be enrolled in the placebo lead-in period to allow for 
approximately 306 subjects to be randomized into the double blind 
period of this study (approximately 204:102 OBS and placebo 
subjects, respectively). With a total of 306 randomized subjects in 
this study, using the same assumptions for the co-primary 
endpoints and the dropout rate, the overall study power for the co-
primary endpoints is estimated to be at least 95%.
Rationale: The sample size is increased to ensure that a sufficient 
number of subjects complete this study and enroll in the treatment 
extension study (SHP621-302). Approximately 200 subjects (65%) 
who are randomized in the SHP621-301 study are estimated to 
complete the SHP621-301 study and enroll in the treatment extension 
study.
Section 9.6; Sample Size and Power 
Considerations
Added text to clarify the retention period for laboratory samples (blood 
and urine).
Section 10.2.3.2; Recording, Access, 
and Retention of Source Data and 
Study Documents
See Appendix 1 for protocol history, including all amendments.


Shire
CONFIDENTIAL
Page 6
Protocol Amendment 2
SHP621-301
26 Jan 2018
EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Study Adverse 
Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 
within 24 hours to the Shire Global Drug Safety Department. Applicable fax numbers and e-mail 
address can be found on the form (sent under separate cover). A copy of the Shire Clinical Study
Adverse Event Form for SAEs and Non-serious AEs as Required by Protocol must also be sent 
to the CRO medical monitor by fax or e-mail using the details below.
, MD
Email:
Fax:
7
For protocol- or safety-related issues during normal business hours (8am to 5 pm Eastern 
Standard Time), the investigator must contact the CRO medical monitor:
, MD
Phone: 
Mobile: 
Email: 
Fax:
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact the CRO medical monitor:
, MD
Mobile:
Email:


Shire
CONFIDENTIAL
Page 7
Protocol Amendment 2
SHP621-301
26 Jan 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
or 


Shire
CONFIDENTIAL
Page 8
Protocol Amendment 2
SHP621-301
26 Jan 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULE(S) ...............................................................................................................24
1.
BACKGROUND INFORMATION.......................................................................................28
1.1
Indication and Current Treatment Options...............................................................28
1.2
Product Background and Clinical Information ........................................................28
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................30
2.1
Rationale for the Study.............................................................................................30
2.2
Study Objectives ......................................................................................................30
2.2.1
Primary Objectives.................................................................................................30
2.2.2
Secondary Objectives.............................................................................................30
2.2.3
Exploratory Objective............................................................................................30
3.
STUDY DESIGN ...................................................................................................................31
3.1
Study Design and Flow Chart ..................................................................................31
3.2
Duration and Study Completion Definition .............................................................33
3.3
Sites and Regions .....................................................................................................33
4.
STUDY POPULATION.........................................................................................................34
4.1
Inclusion Criteria......................................................................................................34
4.2
Exclusion Criteria.....................................................................................................35
4.3
Restrictions...............................................................................................................36
4.4
Reproductive Potential .............................................................................................37
4.4.1
Female Contraception............................................................................................37
4.5
Discontinuation of Subjects .....................................................................................38
4.5.1
Subject Withdrawal Criteria ..................................................................................38
4.5.2
Reasons for Discontinuation..................................................................................38
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................39
4.5.4
Safety-related Stopping Rules................................................................................39
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................41
5.1
Prior Treatment ........................................................................................................41


Shire
CONFIDENTIAL
Page 9
Protocol Amendment 2
SHP621-301
26 Jan 2018
5.2
Concomitant Treatment............................................................................................41
5.2.1
Permitted Treatment...............................................................................................41
5.2.2
Prohibited Treatment .............................................................................................42
6.
INVESTIGATIONAL PRODUCT ........................................................................................43
6.1
Identity of Investigational Product...........................................................................43
6.1.1
Blinding the Treatment Assignment......................................................................43
6.2
Administration of Investigational Product(s)...........................................................43
6.2.1
Interactive Response Technology for Investigational Product Management ........44
6.2.2
Allocation of Subjects to Treatment ......................................................................44
6.2.3
Dosing....................................................................................................................45
6.2.4
Unblinding the Treatment Assignment..................................................................45
6.3
Labeling, Packaging, Storage, and Handling ...........................................................46
6.3.1
Labeling .................................................................................................................46
6.3.2
Packaging...............................................................................................................46
6.3.3
Storage ...................................................................................................................46
6.3.4
Special Handling....................................................................................................47
6.4
Drug Accountability.................................................................................................47
6.5
Subject Compliance..................................................................................................48
7.
STUDY PROCEDURES........................................................................................................50
7.1
Study Schedule.........................................................................................................50
7.1.1
Screening Period (Weeks -6 to 0)..........................................................................50
7.1.2
Placebo Lead-in Period (Weeks 0 to 4) .................................................................51
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or 
Early Termination).................................................................................................53
7.1.4
Follow-up Period ...................................................................................................56
7.1.5
Additional Care of Subjects after the Study ..........................................................57
7.2
Study Evaluations and Procedures ...........................................................................57
7.2.1
Efficacy..................................................................................................................57
7.2.2
Safety .....................................................................................................................59
7.2.3
Other Assessments.................................................................................................62
7.2.4
Clinical Pharmacology Assessments .....................................................................64
7.2.5
Volume of Blood to Be Drawn from Each Subject ...............................................65
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................66
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................66
8.1.1
Severity Categorization..........................................................................................66
8.1.2
Relationship Categorization...................................................................................67
8.1.3
Outcome Categorization ........................................................................................67


Shire
CONFIDENTIAL
Page 10
Protocol Amendment 2
SHP621-301
26 Jan 2018
8.1.4
Symptoms of the Disease under Study ..................................................................68
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................68
8.1.6
Pregnancy...............................................................................................................68
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................69
8.2
Serious Adverse Event Procedures ..........................................................................70
8.2.1
Reference Safety Information................................................................................70
8.2.2
Reporting Procedures.............................................................................................70
8.2.3
Serious Adverse Event Definition .........................................................................70
8.2.4
Serious Adverse Event Collection Time Frame.....................................................71
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................71
8.2.6
Fatal Outcome........................................................................................................71
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................71
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................73
9.1
Data Collection.........................................................................................................73
9.2
Clinical Data Management.......................................................................................73
9.3
Data Handling Considerations..................................................................................73
9.4
Statistical Analysis Process......................................................................................73
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......74
9.6
Sample Size Calculation and Power Considerations................................................74
9.7
Study Population ......................................................................................................75
9.8
Efficacy Analyses.....................................................................................................75
9.8.1
Primary Efficacy Endpoints...................................................................................75
9.8.2
Secondary Efficacy Endpoints...............................................................................77
9.8.3
Exploratory Efficacy Endpoint ..............................................................................78
9.9
Safety Analyses........................................................................................................78
9.10
Other Analyses .........................................................................................................79
9.10.1 Health-related Quality-of-life Analyses.................................................................79
9.10.2 Pharmacokinetic Analyses.....................................................................................79
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................81
10.1
Sponsor’s Responsibilities .......................................................................................81
10.1.1 Good Clinical Practice Compliance.......................................................................81
10.1.2 Indemnity/Liability and Insurance.........................................................................81
10.1.3 Public Posting of Study Information......................................................................81
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................82
10.1.5 Study Suspension, Termination, and Completion..................................................82
10.2
Investigator’s Responsibilities .................................................................................82


Shire
CONFIDENTIAL
Page 11
Protocol Amendment 2
SHP621-301
26 Jan 2018
10.2.1 Good Clinical Practice Compliance.......................................................................82
10.2.2 Protocol Adherence and Investigator Agreement..................................................83
10.2.3 Documentation and Retention of Records.............................................................83
10.3
Ethical Considerations..............................................................................................85
10.3.1 Informed Consent...................................................................................................85
10.3.2 Institutional Review Board or Ethics Committee..................................................85
10.4
Privacy and Confidentiality......................................................................................86
10.5
Study Results/Publication Policy .............................................................................87
11. REFERENCES .......................................................................................................................89
12. APPENDICES ........................................................................................................................91
Appendix 1
Protocol History .....................................................................................92
Appendix 2
Scales and Assessments .........................................................................93
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE...............................94
Appendix 4
Patient Global Impression of Severity ...................................................95
Appendix 5
Biosciences Generic Clinical Protocol Insert.........................................96


Shire
CONFIDENTIAL
Page 12
Protocol Amendment 2
SHP621-301
26 Jan 2018
LIST OF TABLES
Table 1-1: Schedule of Assessments .......................................................................................24
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject .........................65
Table 8-1: Adverse Event Relatedness....................................................................................67
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata ......................................................................................................................76
Table 9-2: Pharmacokinetic Parameters..................................................................................80
LIST OF FIGURES
Figure 1:
Study Design Flow Chart.......................................................................................31


Shire
CONFIDENTIAL
Page 13
Protocol Amendment 2
SHP621-301
26 Jan 2018
ABBREVIATIONS 
ACTH
adrenocorticotropic hormone
AE
adverse event
ANCOVA
analysis of covariance
Auctau
area under the curve for the defined interval between doses
β-hCG
beta-human chorionic gonadotropin
BMD
bone mineral density
CFR
Code of Federal Regulations
CI
confidence interval
Cmax
maximum concentration occurring at tmax
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
EIS
external independent statistical
EMA
European Medicines Agency
EoE
eosinophilic esophagitis
EoE-QoL-A
Adult Eosinophilic Esophagitis Quality of Life
ePRO
electronic patient-reported outcome
EQ-5D-3L
EuroQol-5 Dimensions 3-level
EQ-5D
EuroQol
EQ-5D-Y
EuroQol 5 Dimensions Youth
EREFS
EoE Endoscopic Reference Score
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GDS
Global Drug Safety
HIPAA
Health Insurance Portability and Accountability Act


Shire
CONFIDENTIAL
Page 14
Protocol Amendment 2
SHP621-301
26 Jan 2018
HPF
high-powered field
HRQoL
health-related quality of life
hs
at bedtime
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web-based response system
Med ID
medication identification
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
OBS
oral budesonide suspension
pc
after meals
PedsQL-EoE
Pediatric Quality of Life Inventory – EoE
PGI-S
Patient Global Impression of Severity
PP
per-protocol
PPI
proton pump inhibitor
PT
preferred term
qAM
every morning
SAE
serious adverse event
SAP
statistical analysis plan
SAS®
statistical analysis system
SOC
system organ class
TEAE
treatment emergent adverse event
tmax
time of maximum observed concentration sampled during a dosing 
interval
UK
United Kingdom
US
United States


Shire
CONFIDENTIAL
Page 15
Protocol Amendment 2
SHP621-301
26 Jan 2018
STUDY SYNOPSIS
Protocol number: SHP621-301
Drug: SHP621, oral budesonide suspension (OBS)
Title of the study: Oral Budesonide Suspension (OBS) in Adolescent and Adult Subjects (11 to 
55 Years of Age, Inclusive) with Eosinophilic Esophagitis: A Phase 3 Randomized, Double-blind, 
Placebo-controlled Study
Number of subjects (total and for each treatment arm):
Approximately up to approximately 420 subjects will be enrolled into the placebo lead-in period to 
allow for approximately 306 subjects (approximately 204 and 102 per OBS and placebo treatment 
group, respectively) to be randomized into the double-blind treatment period.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 70 sites in North America
Study period (planned):
Oct 2015 to Nov 2018
Clinical phase:
3
Objectives
Co-primary: 
To demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/high-powered field [HPF]) in 
adolescent and adult subjects with eosinophilic esophagitis (EoE) over a 12-week course of 
therapy.

OBS reduces dysphagia, as measured by the Dysphagia Symptom Questionnaire (DSQ), by at 
least 30% from baseline in adolescent and adult subjects with EoE over a 12-week course of 
therapy.
Key Secondary:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final treatment period 
evaluation (Visit 4). 
Secondary:

To assess the response of endoscopically identified esophageal features to OBS as compared to 
placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ pain score

To evaluate the safety and tolerability of OBS over a 12-week course of therapy

To obtain OBS pharmacokinetic data in adult subjects with EoE
Exploratory:
 


Shire
CONFIDENTIAL
Page 16
Protocol Amendment 2
SHP621-301
26 Jan 2018
Rationale:
Currently there is no approved medication for the treatment of EoE. This study is being conducted in 
order to provide safety and efficacy data demonstrating histologic response (as measured by 
eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as measured by the DSQ) 
following 12 weeks of treatment with OBS in adolescent and adult subjects with EoE. 
Investigational product, dose, and mode of administration
OBS will be administered in 10 mL at a concentration of 0.2 mg/mL (2 mg dose), twice daily (every 
morning [qAM] after meals [breakfast, pc] and at bedtime [hs]). The 0.2 mg/mL concentration of OBS 
and dosing regimens were selected for use in this Phase 3 study based on the results of Study MPI 
101-06, a Phase 2 study in 93 adolescents and adult subjects with EoE and symptoms of dysphagia. 
Subjects were treated in Study MPI 101-06 with 2 mg OBS twice daily to investigate the co-primary 
endpoints of histologic response (defined as ≤6 eosinophils/HPF) and reduction in DSQ score from 
baseline to Week 12 of treatment. For the current study, the investigational product will be supplied in 
amber glass, multi-dose bottles with child-resistant caps and refrigerated throughout the study (in the 
clinic and subject’s home). Each bottle will contain approximately 210 mL of suspension with a 
budesonide concentration of 0.2 mg/mL, or 0.00 mg/mL (matching placebo). 
After the screening period, eligible subjects will enter a 4-week single-blind placebo lead-in period and 
will receive 10 mL of OBS placebo twice daily (qAM, pc, and hs). At the end of the placebo lead-in 
period, eligible subjects will enter a 12-week double-blind treatment period (baseline visit, Visit 1) and 
will be randomized to 1 of 2 treatment groups in a 2:1 ratio (approximately 152 and 76 subjects for 
OBS and placebo twice daily treatment groups, respectively). Subjects will receive oral administration 
of 10 mL of 2 mg investigational product twice daily (qAM, pc, and hs; 4 mg/day total), with no 
ingestion of food or liquids permitted for 30 minutes after study drug administration:

Placebo twice daily group: placebo qAM (pc) and hs

OBS twice daily group: OBS 10 mL of 0.2 mg/mL (2 mg total) qAM (pc) and hs
The total daily dose of budesonide will be 0 mg for each subject in the placebo group and 4 mg for 
each subject in the OBS treatment group (Table 1). 
Table 1: Total Daily Dose of OBS
Dose Group
OBS 
Concentration
(mg/mL)
Volume 
per Dose
Morning Dose 
(qAM, pc)
Evening 
Dose (hs)
Total 
Dose/Day
(mg/day)
Placebo 
0.0
10 mL
0.0 mg
0.0 mg
0.0
OBS 
0.2
10 mL
2.0 mg
2.0 mg
4.0
hs=at bedtime; OBS=oral budesonide suspension; pc=after meals; qAM=every morning
At the end of the 12-week double-blind treatment period (Visit 4), subjects who complete the study 
will have the opportunity to enroll in the treatment extension study. These subjects will continue on the 
blinded assigned treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment 
extension study. 
Methodology:
This is a Phase 3, randomized, double-blind, multicenter, parallel-group, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of twice daily administration of OBS (qAM, pc, and hs) 
in adolescents and adults aged 11-55 years, inclusive, with EoE and dysphagia. 
This study will comprise 3 periods: a 3- to 6-week screening period, 4-week single-blind placebo 
lead-in period, and 12-week double-blind treatment period (Figure 1). The original protocol (dated 
31 Aug 2015) planned for approximately 300 subjects to be enrolled into the placebo lead-in period to 


Shire
CONFIDENTIAL
Page 17
Protocol Amendment 2
SHP621-301
26 Jan 2018
allow for approximately 228 subjects to be randomized in a 2:1 ratio (approximately 152 and 76 per 
OBS and placebo treatment group, respectively) into the double-blind treatment period. Under this 
protocol amendment, up to 420 subjects will be enrolled in the double-blind period to allow for 
approximately 306 subjects to be randomized 2:1 in the double blind period (approximately 204 and 
102 per OBS and placebo group, respectively), in order to provide for at least 200 subjects who 
complete this study and enroll in the successive treatment extension study (SHP621-302). The 
randomization will be performed centrally and stratified by age group (2 strata total: <18 years or 
≥18 years) and diet restriction for EoE or other health-related conditions (no diet restriction or any diet 
restriction). The stratification by age will ensure a minimum of 40 subjects in the pediatric group 
(11-17 years, inclusive). The stratification by age and diet will ensure balance between treatment 
groups for the respective stratification factors.
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be screened 
(Visit -1). Subjects who meet eligibility criteria at the screening visit (Visit -1) and at the placebo 
lead-in visit (Visit 0) will enter the 4-week placebo lead-in period to assess their ability to comply with 
twice daily medication administration and assess whether there is a placebo response. Upon 
completion of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to confirm 
eligibility. Eligible subjects will be randomized 2:1 into the double-blind treatment period and will be 
evaluated for efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4). Subjects who fail to meet all 
eligibility criteria at Visits -1, 0, or 1 will be considered screen failures. Subjects cannot be rescreened 
once it is confirmed they do not meet inclusion/exclusion criteria unless the screen failure was due to a 
temporary condition or incomplete information at the time of consent (Visit -1) that would make 
rescreening at a later date appropriate (eg, concomitant medication that can be discontinued prior to 
rescreening, review of subject medical records provides new information with respect to the date of a 
prior esophageal dilation of diet change, or subject has a minor illness such as an upper respiratory or 
urinary tract infection). All reasons for rescreening (ie, reasons unrelated to inclusion/exclusion 
criteria) must be discussed and approved prospectively with the medical monitor. Subjects who 
discontinue will not be replaced.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. A safety follow-up 
phone call will occur 4 weeks following the last dose of investigational product for subjects who 
discontinue prematurely during the double-blind treatment period or who do not enroll in the treatment 
extension study.
Figure 1: Study Design Flow Chart
BID=twice daily; EGD=esophagogastroduodenoscopy; ET=early termination; OBS=oral budesonide 
suspension
Inclusion and exclusion criteria:
Inclusion Criteria: 


Shire
CONFIDENTIAL
Page 18
Protocol Amendment 2
SHP621-301
26 Jan 2018
The subject will not be considered eligible for the study without meeting all of the following criteria 
(including test results):
1.
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. 
2.
Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3.
Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 of 3 
(proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4.
Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating problems, 
abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) intermittently or 
continuously at screening (Visit -1).
5.
Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the 
screening period and in the 2 weeks prior to the baseline visit (Visit 1).
6.
Subject must not have proton pump inhibitor (PPI)–responsive EoE based on esophageal biopsies 
performed after the patient has been on at least 8 weeks of high-dose PPI therapy (high-dose 
therapy refers to the total daily dose, which may have been administered as a once- or twice daily 
dosing regimen). This may occur at the time of the qualifying esophagogastroduodenoscopy 
(EGD; in which case the same PPI regimen must be continued), or this may have been done 
previously (in which case PPI therapy may have been stopped if there was no response to therapy 
based on esophageal biopsy results). If PPI responsiveness was excluded by a previous EGD and 
biopsy, the historical EGD and biopsy must have been performed after the patient had been on a 
minimum of 6 weeks of high-dose PPI therapy.
7.
Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit (Visit -1).
8.
Subject is willing and able to continue any dietary therapy, environmental therapy, and/or medical 
regimens (including gastric acid suppression; see exclusions below) in effect at the screening visit 
(Visit -1). There should be no change to these regimens during study participation.
9.
All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential must 
agree to continue acceptable birth control measures (eg, abstinence, stable oral contraceptives, or 
double-barrier methods) throughout study participation.
10. 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 any condition or abnormality (including laboratory abnormalities), current or past, 
that, in the opinion of the principal investigator or medical monitor, would compromise the safety 
of the subject or interfere with or complicate the assessment of signs or symptoms of EoE. Such 
conditions may include psychiatric problems; neurologic deficits or disease; developmental delay; 
cardiovascular, metabolic, or pulmonary disease; or previous gastroesophageal surgery. These 
should be discussed with the medical monitor.
2.
Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD or 
between the qualifying EGD and baseline visit (Visit 1) or anticipates using immunomodulatory 
therapy during the treatment period (except for any ongoing regimen of allergy shots). Use of 
long-acting immunomodulatory therapy (eg, Rituxan) within 3 months of the qualifying EGD 
should be reviewed with the medical monitor.
3.
Subject has been using swallowed topical corticosteroid for EoE or systemic corticosteroid for any 


Shire
CONFIDENTIAL
Page 19
Protocol Amendment 2
SHP621-301
26 Jan 2018
condition within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit (Visit 1), or anticipates use during the treatment period; any temporary use (≤7 days) 
or initiation of new steroid treatment during the study should be documented and discussed with 
the medical monitor prospectively but cannot occur within 4 weeks of the final EGD. 
4.
Subject has been on inhaled steroids and not on stable treatment for ≥3 months prior to screening 
visit (Visit -1). Subjects on inhaled steroids need to stay on stable treatment during study 
participation. Subject has been on intranasal steroids and has not been on stable treatment for a 
minimum of 4 weeks prior to the qualifying EGD. After the qualifying EGD, subjects with 
seasonal allergic rhinitis may resume (or discontinue) intranasal corticosteroids based on the 
subject's usual treatment regimen for allergy season.
5.
Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, antacids, 
or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease asthma or 
allergic rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit (Visit 1), or anticipates changes in the use of such medications during the treatment 
period.
6.
Subject has been using cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) 
within the 2 weeks prior to the baseline visit (Visit 1) or within 5 half-lives (whichever is greater) 
or anticipates using such medications during the treatment period.
7.
Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as defined 
by the presence of a lesion that does not allow passage of a diagnostic adult upper endoscope (eg, 
with an insertion tube diameter of >9 mm). 
8.
Subject is on a pure liquid diet or the 6-food elimination diet.
9.
Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic syndrome, 
collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has a potentially serious acute or chronic viral infection or immunodeficiency condition, 
including tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes simplex, herpes 
esophagitis, or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit (Visit -1) or 
between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit (Visit -1) and 
between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide (or 
any other corticosteroids) or to any other ingredients of the investigational product.
20. Subject has taken part and received intervention in an interventional study related to EoE (except 
for an interventional study for a topical swallowed steroid) within 6 months prior to the screening 
visit (Visit -1), or any investigational study within 30 days prior to the screening visit (Visit -1). 
An investigational topical swallowed steroid must have been discontinued at least 30 days prior to 
the screening visit (Visit -1).


Shire
CONFIDENTIAL
Page 20
Protocol Amendment 2
SHP621-301
26 Jan 2018
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
22. Subject has previously completed, discontinued, or withdrawn from this study.
23. Subject has participated in a previous clinical study involving OBS (SHP621).
24. Subject anticipates using sucralfate during the study.
Maximum duration of subject involvement in the study:

Planned duration of screening period: 3-6 weeks

Planned duration of placebo lead-in period: 4 weeks

Planned duration of treatment period: 12 weeks

Planned duration of safety follow-up period: 4 weeks
Endpoints and statistical analysis:
Subject Populations

The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product. 

The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.

The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of a 
double-blind investigational product and have both an evaluable post-baseline biopsy in the 
treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and a 
post-baseline DSQ score.

The per-protocol (PP) set will include all subjects in the FAS excluding subjects with protocol 
violations. The PP set will be identified prior to unblinding the treatment assignments by a team 
consisting of, at a minimum, a physician and a statistician from Shire. 

The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score (questions 
2+3) from baseline to the final treatment period evaluation (Visit 4)
Key Secondary Efficacy Endpoint

Change in DSQ combined score (questions 2+3) from baseline to the final treatment period 
evaluation (Visit 4)
Secondary Efficacy Endpoints 

Change in total endoscopy score, as measured by the EREFS classification, from baseline to the 
final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment period 
evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment period 
evaluation (Visit 4)


Shire
CONFIDENTIAL
Page 21
Protocol Amendment 2
SHP621-301
26 Jan 2018

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)

Change from baseline in the histopathologic epithelial features combined total score (grade and 
stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation (Visit 4)

Change from baseline in the DSQ combined score (questions 2+3) over time including 
post-baseline visits

Cumulative distribution function curves for the change and the percent change in the DSQ score 
from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from baseline to the 
final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across all 
esophageal levels at the final treatment period evaluation (Visit 4)

Change in the DSQ + pain score (questions 2 +3+4) from baseline to the final treatment period 
evaluation (Visit 4)

Change in the DSQ pain score (question 4) from baseline to the final treatment period evaluation 
(Visit 4)
Exploratory Efficacy Endpoint
Safety Endpoints 
Safety parameters will include monitoring of 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) and body composition measurements (for adolescents aged 11-17 years, inclusive), 
clinical laboratory tests (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), and 
adrenocorticotropic hormone (ACTH) stimulation tests. To account for the effects of puberty in 
adolescent subjects (11-17 years, inclusive), BMD z-scores will be adjusted for height z-scores using 
the 
Bone 
Mineral 
Density 
in 
Childhood 
Study 
calculator
(BMDCS 
2015)
(http://www.bmdcspublic.com).
Health Economics and Outcomes Research Endpoints 

Change in Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) score from baseline to 
the final treatment period evaluation (Visit 4) 

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 from baseline to the final 
treatment period evaluation (Visit 4)

Change in Pediatric Quality of Life Inventory – EoE (PedsQL-EoE) score from baseline to the 
final treatment period evaluation (Visit 4)
Pharmacokinetic Endpoints 
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis for subjects who provide sufficient numbers of intensive 


Shire
CONFIDENTIAL
Page 22
Protocol Amendment 2
SHP621-301
26 Jan 2018
PK samples. For all subjects who provide PK samples (ie, limited or intensive samples) population PK 
analysis will be conducted. The pharmacokinetic parameters will include, but not be limited to:
AUCtau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing 
interval
Statistical Methodology for Primary Efficacy Endpoint 
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the co-primary
efficacy endpoints is a binary response (ie, responders vs non-responders); the endpoint will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for age group (either <18 years or 
≥18 years) and diet restriction for EoE or other health-related conditions (no diet restriction or any diet 
restriction) . The adjusted odds ratio of being a responder on each of the co-primary endpoints for the 
OBS 2 mg twice daily group vs placebo group and associated 95% confidence interval (CI) will be 
provided. Subjects who withdraw without providing efficacy data at the final treatment period 
evaluation (Visit 4, Week 16) will be classified as non-responders in the primary efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized and their respective 95% CI will be reported. The difference in 
the proportion of responders between the 2 treatment groups and the corresponding 95% CI will also 
be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to evaluate the
robustness of the results from the primary analysis methods: 

Each of the co-primary efficacy endpoints will be analyzed using a logistic regression with the 
effects of treatment group, age group (either <18 years or ≥18 years) and diet restriction for EoE 
or other health-related conditions (no diet restriction or any diet restriction). The odds ratio of 
being a responder on each of the co-primary endpoints for the OBS 2 mg twice daily group vs 
placebo group and associated 95% CI will be estimated from the final model. Subjects who 
withdraw without providing efficacy data at the final treatment period evaluation (Visit 4, Week 
16) will be classified as non-responders in the primary efficacy analysis.

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing efficacy data 
at the final treatment period evaluation (Visit 4) will be classified as responders.
Statistical Methodology for Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4). The change from 
baseline DSQ score at the final treatment period evaluation (Visit 4) will be analyzed using an analysis 
of covariance (ANCOVA) model with treatment group and age group as factors and the baseline DSQ 
score as a continuous covariate.
Statistical Methodology for Secondary Efficacy Endpoints
Secondary subjective efficacy endpoints that are defined as:

Binary response endpoints will be analyzed using the same logistic model as the co-primary
efficacy endpoints.

Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model that 
includes treatment group and age group as factors and baseline score as a continuous covariate.
The analyses for all secondary efficacy endpoints (including the key secondary efficacy endpoint) will 
be carried out using 2-sided tests at the 5% level of significance. For each of the secondary efficacy 


Shire
CONFIDENTIAL
Page 23
Protocol Amendment 2
SHP621-301
26 Jan 2018
endpoints, the treatment difference, corresponding 95% CI for the difference, and treatment 
comparison p-value for testing the null hypothesis of zero treatment effect based on the final statistical 
model (ie, either logistic regression model or ANCOVA model) will be provided.
Statistical Methodology for Safety Endpoints 
All safety measures, including AEs, physical examination, stadiometry, vital signs (temperature, 
systolic and diastolic blood pressure, pulse, and respiratory rate), weight and height assessments, DXA 
scans for BMD and body composition measurements (for adolescents aged 11-17 years, inclusive), 
clinical laboratory results (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), 
and ACTH stimulation will be descriptively summarized by treatment group at baseline and for each 
postbaseline visit.
The number and percent of subjects with treatment emergent adverse events (TEAEs) will be 
presented. TEAEs are defined as AEs that start or deteriorate on or after the date of the first dose of 
investigational product and no later than 3 days following the last dose of investigational product. 
However, for any subjects who die during the study (ie, the date of death is between the date of first 
dose of investigational product and the date of study discontinuation entered by the site, inclusive), all 
AEs (including those resulting in death) that occur during the study will be considered as TEAEs 
irrespective of the last dose and will be included in the TEAE summaries.
Statistical Methodology for Pharmacokinetic Endpoint(s) 
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters by overall and by week. Plasma concentrations at each nominal sampling time will also be 
summarized using descriptive statistics.
Sample Size Justification
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected difference 
between treatment response proportions of 69% and 45% in the OBS 2 mg twice daily (qAM, pc, and 
hs) and placebo groups, respectively. The original protocol noted that a total of 228 subjects 
(152 subjects randomized to OBS and 76 subjects randomized to placebo) are required to achieve 90% 
power at the significance level of 0.0499 (2-sided) using a 2-group chi-square test with unequal 
allocation 2:1 to treatment groups (OBS 2 mg twice daily and placebo). With the specified number of 
subjects per treatment group, the study will be powered at 99% assuming histological response 
proportions of 40% and 3% in the OBS 2 mg twice daily and placebo groups, respectively. The overall 
study power for the co-primary endpoints was estimated to be at least 85%. Therefore, approximately 
228 (approximately 152:76 OBS and placebo subjects, respectively) were to be randomized in the 
study to allow for a loss of approximately 5% of subjects due to dropouts or invalid data. Expected 
response and dropout rates are based on observation in the Phase 2 study (MPI 101-06).
In this protocol amendment, in order to ensure that a sufficient number of subjects will complete this 
study and enroll in the treatment extension study, up to approximately 420 subjects will be enrolled in 
the placebo lead-in period to allow for approximately 306 subjects to be randomized into the double 
blind period of this study (approximately 204:102 OBS and placebo subjects, respectively). With a 
total of 306 randomized subjects in this study, using the same assumptions for the co-primary
endpoints and the dropout rate, the overall study power for the co-primary endpoints is estimated to be 
at least 95%.


Shire
CONFIDENTIAL
Page 24
Protocol Amendment 2
SHP621-301
26 Jan 2018
STUDY SCHEDULE(S)
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactr
Visit -1
Visit 0
Randomization 
Baseline/Visit 
1
Visit 2 
Visit 3 
Visit 4 
or ETq
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Informed consent/assent
X
Medical history review
X
Inclusion/exclusion criteria review
X
X
X
Vital signsa; heightb and weightc
assessment
X
X
X
X
X
X
EGD with endoscopy score (EREFS)
and biopsyd
X
X
DSQ training and issue of handset
X
Retrieval of DSQ handset
X
DSQ completion
Once daily completion
DSQ compliance assessmente
X
X
X
X
X
EQ-5Df
X
X
PedsQL-EoE (subjects 11-17 years of 
age, inclusive)
X
X
EoE-QoL-A (subjects ≥18 years of age)
X
X
PGI-S
X
X
X
X
Physical examination
X
X
X
X
X
X
Tanner Staging Assessmentg
X
X


Shire
CONFIDENTIAL
Page 25
Protocol Amendment 2
SHP621-301
26 Jan 2018
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactr
Visit -1
Visit 0
Randomization 
Baseline/Visit 
1
Visit 2 
Visit 3 
Visit 4 
or ETq
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
Clinical laboratory testsh
X
X
X
X
X
X
Urinalysisi
X
X
X
X
X
X
Pregnancy testj
X
X
X
X
X
X
Morning cortisol (target 6:00-9:00 AM)
X
X
X
X
ACTH stimulation testing 
X
X
Blood pharmacokinetic sampling 
(subjects ≥18 years of age)k
X
X
X
DXA Scan 
(subjects 11-17 years of age, inclusive)l
X
X
Randomizationm
X
Investigational product supplied
X
X
X
X
Xl
Investigational product administrationo
Twice-daily administration of investigational product
Investigational product compliance 
assessment
X
X
X
X
Concomitant medications and 
procedures recorded 
X
X
X
X
X
X
X
Review of adverse eventsp
X
X
X
X
X
X


Shire
CONFIDENTIAL
Page 26
Protocol Amendment 2
SHP621-301
26 Jan 2018
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactr
Visit -1
Visit 0
Randomization 
Baseline/Visit 
1
Visit 2 
Visit 3 
Visit 4 
or ETq
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
ACTH=adrenocorticotropic hormone; DSQ=Dysphagia Symptom Questionnaire; 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; EREFS=EoE Endoscopic Reference Score; 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
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the 
assessment and will include blood pressure (systolic and diastolic), heart rate, respirations, and temperature.
b
Height to be collected at screening visit (Visit -1) and Visit 4 for all subjects. Stadiometers are required for subjects 11-17 years of 
age, inclusive, and will be used at Visit -1 and 4. Height measurements for adolescent subjects (11-17 years of age, inclusive) 
should be measured in triplicate.
c
Weight measurements for adolescent subjects (11-17 years, inclusive) should be measured in duplicate.
d
Pretreatment endoscopy will be performed during the screening period (at least 2 weeks prior to placebo lead-in visit [Visit 0] to 
allow adequate time for processing and central review). Endoscopy should include esophageal (proximal, mid-, and/or distal), 
gastric, and duodenal biopsies. Final treatment evaluation EGD must include esophageal biopsies; gastric and duodenal biopsies 
may be done at the discretion of the investigator. Final treatment evaluation EGD should occur at or within (±) 7 days of the
scheduled visit. 
e
DSQ assessment includes completion of reports on DSQ handset (ie, eligibility reports and visit confirmations).
f
Subjects 11-17 years of age, inclusive, will complete the EQ-5D-Y; subjects ≥18 years of age will complete the EQ-5D-3L.
g
Tanner staging assessments will be performed for all subjects aged ≥11 years until investigator confirms subject is post-puberty.
h
Clinical laboratory tests will include the following: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
total bilirubin, total protein, albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, carbon 
dioxide, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular 
volume, erythrocyte count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count. All 


Shire
CONFIDENTIAL
Page 27
Protocol Amendment 2
SHP621-301
26 Jan 2018
Table 1-1: Schedule of Assessments
Procedures
Screening
Placebo 
Lead-in 
Treatment Phase
Safety 
Follow-up 
Telephone 
Contactr
Visit -1
Visit 0
Randomization 
Baseline/Visit 
1
Visit 2 
Visit 3 
Visit 4 
or ETq
Visit 5
Week
-6
0
4
8
12
16
20
Window
≤6 weeks
--
±3 days
±3 days
±3 days
±3 days
±3 days
subjects must fast overnight prior to collection.
i
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and 
leukocyte esterase.
j
The serum pregnancy test will be performed for all female subjects at the screening visit (Visit -1) and final treatment evaluation 
(Visit 4). Urine pregnancy tests will be performed at all other visits.
k
Blood samples for pharmacokinetic analysis will be taken from adult subjects (aged ≥18 years). Subjects who do not participate in 
pharmacokinetic sampling will not be discontinued from the study and lack of participation will not be a considered protocol 
deviation. Blood samples for pharmacokinetic analysis can be obtained one time on any day starting 7 days after Visit 1 (Week 5) 
and through Visit 4 (Week 16). PK samples should be drawn, ideally, at pre-dose, 0.5 and 1 hour post-dose, and at additional post-
dose time points, if feasible (2, 3, 4, 6, 8, and 12 hours post-dose).
l
The baseline DXA scan may be performed any time during the placebo lead-in period after the subject has met all screening 
criteria and prior to blinded-treatment randomization. Baseline and post-treatment DXA scans should be performed using the 
same machine and software. Post-treatment DXA scan should occur at or within (±) 7 days of the scheduled visit.
m
Randomization will occur via IWRS at the baseline visit (Visit 1) once the subject’s eligibility for study entry is confirmed. 
n
Investigational product will be dispensed at Visit 4 to subjects who consent to enroll in the treatment extension study.
o
Subjects will receive oral administration of 10 mL of investigational product twice daily (qAM, pc, and hs), with no ingestion of 
food or liquids permitted for 30 minutes after study drug administration.
p
AE assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (eg, 
moon facies, acne, hirsutism, mood swings, insomnia, and depression).
q
If subject discontinues study prematurely, the evaluations listed for Visit 4 are to be performed as completely as possible.
r
For subjects who withdraw from the study or do not continue into treatment extension study, a safety follow-up contact by phone 
will be performed 4 weeks following the last dose of investigational product.


Shire
CONFIDENTIAL
Page 28
Protocol Amendment 2
SHP621-301
26 Jan 2018
1.
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Eosinophilic esophagitis (EoE) is defined as “a chronic, immune/antigen-mediated esophageal 
disease characterized clinically by symptoms related to esophageal dysfunction and 
histologically by eosinophil-predominant inflammation” (Liacouras et al., 2011). Clinical 
symptoms of EoE often vary by age: Infants and toddlers present with feeding difficulties; 
school-aged children are more likely to present with vomiting or pain; and adolescents and adults 
present with dysphagia and food impaction. When these symptoms are present, the diagnosis is 
confirmed by finding eosinophilic inflammation of ≥15 eosinophils/high-powered field (HPF) on 
at least 1 esophageal biopsy and when other causes such as proton pump inhibitor (PPI)-
responsive esophageal eosinophilia are excluded (Dellon et al., 2014a; Furuta et al., 2007). The 
standards of care are diet therapies and off-label use of glucocorticosteroids. Esophageal dilation 
is used to temporarily relieve symptoms but does not address underlying inflammation. Given 
the clinical outcomes associated with EoE, including severe dysphagia, esophageal stricture, 
food impaction, and esophageal perforation (Hirano and Aceves, 2014; Liacouras et al., 2011) 
and the fact that there are currently no FDA-approved treatments, there is a clear unmet medical 
need for a novel treatment for this disease.
1.2
Product Background and Clinical Information
Oral budesonide suspension (OBS) consists of budesonide formulated in a viscous suspension 
that is designed to increase the residence time of budesonide on the surface of the esophagus 
after swallowing compared to a non-viscous suspension. Shire is developing OBS as a first-line 
therapy for EoE in adolescents and adults. 
The nonclinical pharmacology, pharmacokinetics, and toxicity and the clinical pharmacology, 
pharmacokinetics, and safety of budesonide are well studied because budesonide is present in 
several US FDA-approved drug products. Budesonide is currently marketed for the management 
of Crohn’s disease, for asthma maintenance, for the treatment of allergic rhinitis, and for 
induction of remission in patients with active, mild to moderate ulcerative colitis. Budesonide 
has strong glucocorticoid receptor affinity and is subject to considerable first pass metabolism by 
the liver with a short half-life. These attributes permit budesonide to act rapidly and locally in the 
gut mucosa for treatment of inflammatory disorders such as Crohn’s disease and ulcerative 
colitis. Once absorbed into the systemic circulation, budesonide is rapidly metabolized in the 
liver and inactivated (FDA, 2011).
The efficacy of OBS for the treatment of EoE has been demonstrated in two Phase 2 studies in 
the OBS clinical development program. Studies MPI 101-01 and MPI 101-06 evaluated the 
efficacy of OBS in the treatment of EoE in children and adolescents aged 2-18 years and in 
adolescents and adults aged 11-40 years, respectively, by measuring histological response 
(defined as mean peak eosinophil count ≤6/HPF after treatment). Study MPI 101-06 also 
evaluated symptom response as measured by the Dysphagia Symptom Questionnaire (DSQ). The 
DSQ contains 4 questions related to consumption of solid food, the presence of dysphagia and its 
severity, as well as pain. The DSQ score is calculated only from responses to the questions 


Shire
CONFIDENTIAL
Page 29
Protocol Amendment 2
SHP621-301
26 Jan 2018
related to dysphagia, and this clinical outcome assessment was considered to be fit for purpose as 
a result of the MPI 101-06 study. Results from Study MPI 101-01 demonstrated a statistically 
significant histologic response (eosinophil count ≤6/HPF) and remission (eosinophil count 
≤1/HPF) in the medium-dose (1.4-2.0 mg daily) and high-dose (2.8-4.0 mg daily) OBS groups 
compared to placebo following 12 weeks of treatment. 
In Study MPI 101-06, a significant treatment effect for OBS vs placebo was shown for both the 
co-primary efficacy endpoints of histologic response and change from baseline in dysphagia 
symptoms. Following 12 weeks of twice daily treatment (every morning after meals [qAM, pc] 
and at bedtime [hs]), OBS-treated subjects demonstrated a highly consistent reduction from 
baseline values for cellular (mean peak eosinophil count and histopathology features), organ 
(endoscopy score), and holistic measures (Physician Global Assessment and DSQ scores); these 
results were independent of the type of rater/reviewer (central pathologist, physician at the study 
site, or subject). 
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. 


Shire
CONFIDENTIAL
Page 30
Protocol Amendment 2
SHP621-301
26 Jan 2018
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Currently there is no approved medication for the treatment of EoE. This study is being 
conducted in order to provide safety and efficacy data demonstrating histologic response (as 
measured by eosinophilic count ≤6/HPF) and improvement in dysphagia symptoms (as measured 
by the DSQ) following 12 weeks of treatment with OBS in adolescent and adult subjects with 
EoE.
2.2
Study Objectives
2.2.1
Primary Objectives
The co-primary objectives of the study are to demonstrate in a placebo-controlled trial that:

OBS induces a histologic response (eosinophilic count ≤6/HPF) in adolescent and adult 
subjects with EoE over a 12-week course of therapy. 

OBS reduces dysphagia, as measured by the DSQ, by at least 30% from baseline in 
adolescent and adult subjects with EoE over a 12-week course of therapy.
2.2.2
Secondary Objectives
The key secondary objective of this study is:

OBS reduces dysphagia, as measured by the DSQ score from baseline to the final treatment 
period evaluation (Visit 4). 
Additional secondary objectives of the study are:

To assess the response of endoscopically identified esophageal features to OBS as compared 
to placebo as measured by the EoE Endoscopic Reference Score (EREFS) 

To explore other responding criteria based on histology and DSQ

To assess the impact of OBS on pain, as measured by the DSQ pain score

To evaluate the safety and tolerability of OBS over a 12-week course of therapy 

To obtain OBS pharmacokinetic data in adult subjects with EoE
2.2.3
Exploratory Objective
The exploratory objective of this study is:


Shire
CONFIDENTIAL
Page 31
Protocol Amendment 2
SHP621-301
26 Jan 2018
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of OBS treatment administered twice daily (qAM, pc, 
and hs) for 12 weeks. The study will be conducted in adolescents and adults, aged 11-55 years, 
inclusive, with EoE and dysphagia. 
The original protocol (dated 31 Aug 2015) planned for approximately 300 subjects to be enrolled 
in the placebo lead-in period to allow for approximately 228 subjects to be randomized into the 
double-blind treatment period. Under this protocol amendment, up to approximately 420 subjects 
will be enrolled in the placebo lead-in period to allow for approximately 306 subjects to be 
randomized into the double blind period, in order to provide for at least 200 subjects who 
complete this study and enroll in the successive treatment extension study (SHP621-302). A 
minimum of 40 randomized subjects will be aged 11-17 years, inclusive. Subjects will be 
randomized 2:1 (approximately 204 and 102 per OBS and placebo treatment group, respectively) 
to receive either OBS 2 mg twice daily (qAM, pc, and hs) or placebo twice daily (qAM, pc, and 
hs).
This study will consist of 3 periods: a 3- to 6-week screening period, 4-week single-blind 
placebo lead-in period, and a 12-week double-blind treatment period (see Figure 1). 
Figure 1:
Study Design Flow Chart
BID=twice daily; EGD=esophagogastroduodenoscopy; ET=end of treatment; OBS=oral budesonide suspension
The upper limit of 55 years, inclusive, was selected for this study population based on the low 
prevalence of EoE in older patients (Dellon et al., 2014a) and the fact that the type of EoE that 
develops in older patients is not amenable to anti-inflammatory treatment alone (Dellon et al., 
2014b). A natural history study demonstrated that for every decade of life, the odds of 


Shire
CONFIDENTIAL
Page 32
Protocol Amendment 2
SHP621-301
26 Jan 2018
developing the fibrostenotic phenotype of EoE more than doubles (Dellon et al., 2014b). By age 
55, fibrostenotic EoE occurs in approximately 80% of patients. Fibrostenotic disease is treated 
with dilatation and is not amenable to anti-inflammatory treatment alone. Therefore, budesonide 
is not expected to be an effective treatment for the majority of patients above age 55.
Subjects will be required to visit the site up to 6 times over up to a 22-week period. Following 
completion of the screening and placebo lead-in visits, subjects will be evaluated for eligibility 
and safety at Week 4 (Visit 1). Subjects who are eligible and randomized will be evaluated for 
efficacy and safety at Weeks 8, 12, and 16 (Visits 2-4) and additionally for safety at follow-up at 
Week 20 (Visit 5; telephone contact). Subjects who fail to meet all eligibility criteria at Visits -1, 
0, or 1 will be considered screen failures. Subjects cannot be rescreened once it is confirmed they 
do not meet inclusion/exclusion criteria unless the screen failure was due to a temporary 
condition or incomplete information at the time of consent (Visit -1) that would make 
rescreening at a later date appropriate (eg, concomitant medication that can be discontinued prior 
to rescreening, review of subject medical records provides new information with respect to the 
date of a prior esophageal dilation or diet change, or subject has a minor illness such as an upper 
respiratory or urinary tract infection). All reasons for rescreening (ie, reasons unrelated to 
inclusion/exclusion criteria) must be discussed and approved prospectively with the medical 
monitor. Subjects who discontinue will not be replaced. 
The screening period will start when subjects sign informed consent (or assent as applicable for 
subjects <18 years of age; screening visit [Visit -1]) and will be approximately 3-6 weeks in 
duration. During the screening period, all subjects will receive an upper endoscopy with 
histologic analysis of biopsy specimens to confirm the diagnosis of EoE (eosinophil count of 
≥15/HPF from 2 of 3 [proximal, mid-, and/or distal] levels of the esophagus). In addition, 
subjects must complete the DSQ daily during the screening period (3-6 weeks) and have at least 
4 reported days with symptoms of dysphagia and completed the DSQ on ≥70% of days in any 2 
consecutive weeks. At the screening visit (Visit -1), subjects who are on a PPI must remain on 
the same dose of the PPI throughout the study; if they are not taking a PPI, they must remain off 
of a PPI for the remainder of the study. After the screening period, eligible subjects will enter a 
4-week single-blind placebo lead-in period and will receive 10 mL of OBS placebo twice daily 
(every morning after meals/breakfast [qAM, pc] and at bedtime [hs]). The placebo lead-in period 
will enable assessment of the subject’s ability to comply with twice daily medication 
administration and assess whether the subject experiences a placebo response. 
At the end of the placebo lead-in period, subjects will return for the baseline visit (Visit 1) to 
confirm eligibility. Subjects who continue to meet all eligibility criteria (those with at least 4 
reported dysphagia days and who completed the DSQ on ≥70% of days in the 2 weeks prior to 
randomization per daily DSQ completion) will be randomized to receive either OBS or placebo 
during the 12-week double-blind treatment period. 
OBS will be administered in 10 mL at a concentration of 0.2 mg/mL (2 mg dose), twice daily. 
The 0.2 mg/mL concentration of OBS and dosing regimens were selected for use in this Phase 3 
study based on the results of Study MPI 101-06, a Phase 2 study in 93 adolescent and adult 
subjects with EoE and symptoms of dysphagia. Subjects were treated in Study MPI 101-06 with 


Shire
CONFIDENTIAL
Page 33
Protocol Amendment 2
SHP621-301
26 Jan 2018
2 mg OBS twice daily to investigate the co-primary endpoints of histologic response (defined as 
≤6 eosinophils/HPF) and reduction in DSQ score from baseline to Week 12 of treatment. 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, or 0.00 mg/mL (matching placebo).
At the end of the 12-week double-blind treatment period (Visit 4, Week 16), subjects who 
complete the study will have the opportunity to enroll in the treatment extension study. These 
subjects will continue on the blinded assigned treatment for 2-4 weeks as part of the screening 
prior to enrolling into the treatment extension study. Subjects who do not enroll in the treatment 
extension study or who discontinue at any time during the SHP621-301 (Induction) study will 
receive a follow-up phone call 4 weeks post last dose of investigational product (Visit 5).
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 26 weeks, 
depending on the 3- to 6-week screening period.
The study will be completed in approximately 32 months.
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
A completer is a subject who completes all procedures and assessments up to and including Visit 
4 (Week 16), inclusive of the final treatment evaluation esophagogastroduodenoscopy (EGD). 
Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the SHP621-301 (Induction) study will receive a follow-up phone call 4 weeks 
post last dose of the investigational product to which they were randomized.
3.3
Sites and Regions
Approximately 70 sites in North America will participate.


Shire
CONFIDENTIAL
Page 34
Protocol Amendment 2
SHP621-301
26 Jan 2018
4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject 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.
2. Subject is male or female aged 11-55 years, inclusive, at time of consent. 
3. Subject has histologic evidence of EoE with a peak eosinophil count of ≥15/HPF, from 2 of 3 
(proximal, mid-, and/or distal) levels of the esophagus at the screening endoscopy.
4. Subject has a history of clinical symptoms of esophageal dysfunction (eg, eating problems, 
abdominal pain, heartburn, dysphagia, vomiting, food impaction, weight loss) intermittently 
or continuously at screening (Visit -1).
5. Subject must have experienced dysphagia (response of “yes” to question 2 on DSQ) on a 
minimum of 4 days and completed the DSQ on ≥70% of days in any 2 consecutive weeks of 
the screening period and in the last 2 weeks prior to the baseline visit (Visit 1).
6. Subject must not have PPI-responsive EoE based on esophageal biopsies performed after the 
patient has been on at least 8 weeks of high-dose PPI therapy (high-dose therapy refers to the 
total daily dose, which may have been administered as a once or twice daily dosing regimen). 
This may occur at the time of the qualifying EGD (in which case the same PPI regimen must 
be continued), or this may have been done previously (in which case PPI therapy may have 
been stopped if there was no response to therapy based on esophageal biopsy results). If PPI 
responsiveness was excluded by a previous EGD and biopsy, the historical EGD and biopsy 
must have been performed after the patient had been on a minimum of 6 weeks of high-dose 
PPI therapy.
7. Subject will be on a stable (no changes) diet ≥3 months prior to the screening visit 
(Visit -1).
8. Subject is willing and able to continue any dietary therapy, environmental therapy, and/or 
medical regimens (including gastric acid suppression; see exclusions below) in effect at the 
screening visit (Visit -1). There should be no change to these regimens during study 
participation.
9. All female subjects must have a negative serum pregnancy test (beta-human chorionic 
gonadotropin [β-hCG]) prior to enrollment into the study. Females of childbearing potential 
must agree to continue acceptable birth control measures (eg, abstinence, stable oral 
contraceptives, or double-barrier methods) throughout study participation.


Shire
CONFIDENTIAL
Page 35
Protocol Amendment 2
SHP621-301
26 Jan 2018
10. 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 any condition or abnormality (including laboratory abnormalities), current or 
past, that, in the opinion of the principal investigator or medical monitor, would compromise 
the safety of the subject or interfere with or complicate the assessment of signs or symptoms 
of EoE. Such conditions may include psychiatric problems; neurologic deficits or disease; 
developmental delay; cardiovascular, metabolic, or pulmonary disease; or previous 
gastroesophageal surgery. These should be discussed with the medical monitor.
2. Subject has used immunomodulatory therapy within 8 weeks prior to the qualifying EGD or 
between the qualifying EGD and baseline visit (Visit 1) or anticipates using 
immunomodulatory therapy during the treatment period (except for any ongoing regimen of 
allergy shots). Use of long-acting immunomodulatory therapy (eg, Rituxan) within 3 months 
of the qualifying EGD should be reviewed with the medical monitor.
3. Subject has been using swallowed topical corticosteroid for EoE or systemic corticosteroid 
for any condition within the 4 weeks prior to the qualifying EGD, between the qualifying 
EGD and baseline visit (Visit 1), or anticipates use during the treatment period; any 
temporary use (≤7 days) or initiation of new steroid treatment during the study should be 
documented and discussed with the medical monitor prospectively but cannot occur within 4 
weeks of the final EGD. 
4. Subject has been on inhaled steroids and has not been on stable treatment for ≥3 months prior 
to screening visit (Visit -1). Subjects on inhaled steroids need to stay on a stable treatment 
during study participation. Subject has been on intranasal steroids and has not been on stable 
treatment for a minimum of 4 weeks prior to the qualifying EGD. After the qualifying EGD, 
subjects with seasonal allergic rhinitis may resume (or discontinue) intranasal corticosteroids 
based on the subject's usual treatment regimen for allergy season.
5. Subject has initiated, discontinued, or changed dosage regimen of PPIs, H2 antagonists, 
antacids, or leukotriene inhibitors for any condition (such as gastroesophageal reflux disease, 
asthma or allergic rhinitis) within the 4 weeks prior to the qualifying EGD, between the 
qualifying EGD and baseline visit (Visit 1), or anticipates changes in the use of such 
medications during the treatment period.
6. Subject has been using cytochrome P450 3A4 (CYP450 3A4) inhibitors (eg, ketoconazole, 
grapefruit juice) within the 2 weeks prior to the baseline visit (Visit 1) or within 5 half-lives 
(whichever is greater) or anticipates using such medications during the treatment period.
7. Subject has an appearance on qualifying EGD of an esophageal stricture (high-grade), as 
defined by the presence of a lesion that does not allow passage of a diagnostic adult upper 
endoscope (eg, with an insertion tube diameter of >9 mm). 
8. Subject is on a pure liquid diet or the 6-food elimination diet.


Shire
CONFIDENTIAL
Page 36
Protocol Amendment 2
SHP621-301
26 Jan 2018
9. Subject has had an esophageal dilation within the 3 months prior to screening (Visit -1).
10. Subject has presence of esophageal varices at the screening endoscopy.
11. 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. 
12. Subject has other diseases causing or associated with EoE, including hypereosinophilic 
syndrome, collagen vascular disease, vasculitis, achalasia, or parasitic infection.
13. Subject has current evidence of oropharyngeal or esophageal candidiasis.
14. Subject has a potentially serious acute or chronic viral infection or immunodeficiency 
condition, including tuberculosis, fungal, bacterial, viral/parasite infection, ocular herpes 
simplex, herpes esophagitis, or chicken pox/measles.
15. Subject has upper gastrointestinal bleeding within 4 weeks prior to the screening visit (Visit -
1) or between the screening visit and baseline visit (Visit 1).
16. Subject has evidence of active infection with Helicobacter pylori.
17. Subject has evidence of unstable asthma within 4 weeks prior to the screening visit (Visit -1) 
and between the screening visit and baseline visit (Visit 1).
18. Subject is female and pregnant or nursing.
19. Subject has a history of intolerance, hypersensitivity, or idiosyncratic reaction to budesonide 
(or any other corticosteroids) or to any other ingredients of the investigational product.
20. Subject has taken part and received intervention in an interventional study related to EoE 
(except for an interventional study for a topical swallowed steroid) within 6 months prior to 
the screening visit (Visit -1), or any investigational study within 30 days prior to the 
screening visit (Visit -1). An investigational topical swallowed steroid must have been 
discontinued at least 30 days prior to the screening visit (Visit -1).
21. Subject has a history or high risk of noncompliance with treatment or regular clinic visits.
22. Subject has previously completed, discontinued, or withdrawn from this study.
23. Subject has participated in a previous clinical study involving OBS (SHP621).
24. Subject anticipates using sucralfate during the study.
4.3
Restrictions
Subjects must adhere to the following restrictions for the duration of the study:

No change in exercise (other than seasonal changes in sports or activities). Intense exercise 
should be avoided unless part of an established exercise routine. 

No change in diet (liquid diet for 3 days or less is acceptable).

Short course of systemic steroids (≤7 days) are permitted to treat, for example, exacerbation 
of asthma but cannot be used 4 weeks prior to the final EGD.


Shire
CONFIDENTIAL
Page 37
Protocol Amendment 2
SHP621-301
26 Jan 2018

Stable treatment with intranasal or inhaled corticosteroids. For subjects with perennial 
allergic rhinitis and stable asthma, the topical corticosteroid must be maintained at the same 
dose throughout the study. For subjects with seasonal allergic rhinitis, it is permissible after 
the qualifying EGD to resume (or discontinue) intranasal corticosteroids based on the 
subject's usual treatment regimen for allergy season. All topical corticosteroid dosing 
changes, including those for seasonal allergic rhinitis, should be avoided within 4 weeks 
prior to the Week 16 EGD. Subjects who require a change in inhaled corticosteroid treatment 
for an asthma exacerbation should be discussed with the medical monitor.

No change in PPI use

No use of CYP450 3A4 inhibitors

No use of sucralfate during the study as this may interfere with the adherence of OBS

An esophageal dilatation during the trial (Dilatation is considered a treatment failure, and the 
subject should be withdrawn from the study)
4.4
Reproductive Potential
4.4.1
Female Contraception
All females must have a negative pregnancy test at the screening visit (Visit -1), placebo lead-in 
visit (Visit 0), baseline visit (Visit 1), and Visits 1-4. A serum pregnancy test will be performed 
at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine pregnancy tests 
will be performed at all other visits.
Female subjects should be either:

Premenarchal and Tanner Stage 1, or

Post-menopausal (24 consecutive months of spontaneous amenorrhea and age 51 years or 
older).

Be surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential must agree to abstain from sexual activity that could result 
in pregnancy or agree to use acceptable methods of contraception throughout the study 
period and for 30 days following the last dose of investigational product.

Acceptable methods of contraception are:

Abstinence

Surgically sterile male partner

Stable oral contraceptives

Intrauterine devices plus condoms


Shire
CONFIDENTIAL
Page 38
Protocol Amendment 2
SHP621-301
26 Jan 2018

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 -1), 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 one of the other acceptable methods noted above in addition to the 
hormonal contraceptive until it has been stabilized for 30 days.
4.5
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, leading to subject discontinuation from the study, 
regardless of the reason, the evaluations listed for Visit 4 are to be performed as completely as 
possible. If investigational product is discontinued due to an adverse event (AE), the subject may 
remain on study to allow for completion of study procedures.
Whenever possible, all discontinued subjects should also undergo the protocol-specified follow-
up. Comments (spontaneous or elicited) or complaints made by the subject must be recorded in 
the source documents. The reason for termination, date of stopping investigational product, and 
total amount of investigational product taken must be recorded in the case report form (CRF) and 
source documents.
Subjects who discontinue will not be replaced. 
4.5.1
Subject Withdrawal Criteria
Medically important events that in the opinion of the investigator or medical monitor would 
compromise the subject’s ability to safely continue in the study, including but not limited to 
severe signs and symptoms of EoE, such as an esophageal stricture requiring dilation, weight 
loss due to severe dysphagia, and/or upper GI bleed would be considered a treatment failure and 
result in withdrawal of the subject 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:


Shire
CONFIDENTIAL
Page 39
Protocol Amendment 2
SHP621-301
26 Jan 2018

Completed

Death

AE

Noncompliance with study drug

Noncompliance with study procedure

Withdrawal by subject

Withdrawal by parent/guardian

Physician decision

Study terminated by sponsor

Site terminated by sponsor

Lost to follow-up

Pregnancy

Trial screen failure

Protocol deviation

Other 
4.5.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.
4.5.4
Safety-related Stopping Rules
An urgent safety review will be conducted within 7 days by the sponsor if one or more of the 
following criteria are met:

Death that is considered related to the study drug

Two serious adverse events (SAEs) of similar type (defined as same or similar Medical 
Dictionary for Regulatory Activities [MedDRA] higher level group code) and considered 
related to the study drug
The urgent review will be performed by a sponsor safety review group, which will include the 
study Global Drug Safety (GDS) physician and the GDS Therapeutic Area Head. The GDS
Therapeutic Area Head, not the GDS physician involved in the study, may be unblinded as part 
of this urgent safety review, if required. Following the sponsor’s review of safety data, one of the 
following actions will be taken with respect to study status:


Shire
CONFIDENTIAL
Page 40
Protocol Amendment 2
SHP621-301
26 Jan 2018

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.


Shire
CONFIDENTIAL
Page 41
Protocol Amendment 2
SHP621-301
26 Jan 2018
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 
within 3 months prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half-
lives, whichever is longer) 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 within 
3 months of the screening visit (Visit -1). Prior treatment information must be recorded on the 
appropriate CRF page.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded on the appropriate CRF page.
The investigator may prescribe additional medications during the study, as long as the prescribed 
medication is not prohibited by the protocol. In the event of an emergency, any needed 
medications may be prescribed without prior approval, but the medical monitor must be notified 
of the use of any prohibited medications immediately thereafter.
5.2.1
Permitted Treatment
The following medications are allowed during the course of the study if the subject has been on a 
stable dosing regimen (ie, same dose and frequency in the previous 4 weeks prior to the 
endoscopy required for entrance to this study) and will continue this dosing regimen throughout 
study participation. The investigator must contact the medical monitor to discuss any changes to 
concomitant steroid regimens or for any medications not listed here that could impact the 
outcome of the study.
1. Inhaled or intranasal steroids for conditions other than EoE; subject must be on stable 
treatment for ≥3 months prior to screening visit (Visit -1), except for seasonal allergic 
rhinitis, see Section 4.3.
2. PPIs
3. H2 antagonists
4. Antacids
5. Antihistamines or anti-leukotrienes
6. Maintenance immunotherapy (allergy shots or sublingual immunotherapy)


Shire
CONFIDENTIAL
Page 42
Protocol Amendment 2
SHP621-301
26 Jan 2018
Influenza 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. Immunomodulatory therapy within 8 weeks prior to the qualifying EGD or between the 
qualifying EGD and baseline visit (Visit 1) or anticipated use of immunomodulatory therapy 
during the treatment period (except for any ongoing regimen of allergy shots). Use of long-
acting immunomodulatory therapy (eg, Rituxan) within 3 months of the qualifying EGD 
should be reviewed with the medical monitor. 
2. Swallowed topical corticosteroid for EoE or systemic corticosteroid for any condition within 
the 4 weeks prior to the qualifying EGD, between the qualifying EGD and baseline visit 
(Visit 1) or anticipated use during the treatment period; any temporary use (≤7 days) or 
initiation of new steroid treatment during study should be documented and discussed with the 
medical monitor prospectively but cannot occur within the 4 weeks of the final EGD.
3. Inhaled steroids if initiated or changed in dose <3 months prior to screening visit 
(Visit -1). (Seasonal nasal corticosteroid use for seasonal allergic rhinitis is permitted; 
changes within 4 weeks of scheduled EGD should be avoided).
4. Initiation or change in dosing frequency of PPIs, H2 antagonists, antacids, or leukotriene 
inhibitors for any condition (such as gastroesophageal reflux disease, asthma, or allergic 
rhinitis) within the 4 weeks prior to the qualifying EGD, between the qualifying EGD and 
baseline visit 1, or anticipated changes in the use of such medications during the treatment 
period.
5. CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) within the 2 weeks prior to the 
baseline visit (Visit 1) or within 5 half-lives (whichever is greater) 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 (FDA 
Guidance 2012) and use their clinical judgment with respect to specific medications.
6. Esophageal dilation within the 3 months prior to screening (Visit -1)
7. Investigational study treatment within 6 months prior to the screening visit (Visit -1)
8. Sucralfate use during the treatment period


Shire
CONFIDENTIAL
Page 43
Protocol Amendment 2
SHP621-301
26 Jan 2018
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is OBS (oral budesonide suspension, 0.2 mg/mL), which will be provided in 
multi-dose amber glass bottles, each containing approximately 210 mL. Additional information 
is provided in the current SHP621 investigator’s brochure.
The reference/comparator product is placebo, which will be provided in amber glass bottle form 
with the same volume.
6.1.1
Blinding the Treatment Assignment
Investigational product will be supplied in amber glass, multi-dose bottles with child-resistant 
caps and refrigerated throughout the study (in the clinic and subject’s home). Each bottle 
contains approximately 210 mL of suspension with a budesonide concentration of 0.2 mg/mL. 
Inactive ingredients in OBS include dextrose, disodium edetate, citric acid, sodium citrate, 
potassium sorbate, polysorbate 80, glycerin, sodium benzoate, cherry flavor, Magnasweet 110, 
acesulfame potassium, and water.
The placebo solution will also be supplied in amber glass multi-dose bottles with child-resistant 
caps. Placebo consists of all components of the investigational product solution with the 
exception of budesonide.
6.2
Administration of Investigational Product(s) 
All investigational product and supplies (eg, dosing spoons) will be provided by Shire or its 
designee. At each visit, subjects will be supplied with enough investigational product to last until 
the subsequent visit. The first dose of investigational product (placebo) for each subject will be 
administered in the clinic at the placebo lead-in visit (Visit 0). The subject will continue with the 
evening dosing regimen at home.
OBS and placebo will be supplied in amber glass bottles and must be shaken well prior to 
administration. OBS and placebo should be refrigerated at 2-8ºC (36-46ºF) throughout the study 
(in the clinic and subject’s home). The appropriate dose will be dispensed using the graduated 
dosing spoon provided. For subjects who are minors (<18 years), a parent/guardian will be 
responsible for ensuring that the subjects take their investigational product appropriately.
Subjects will be instructed not to eat or drink for 30 minutes after taking the investigational 
product. Activities such as brushing teeth or rinsing the mouth should also be avoided during this 
time interval. After 30 minutes, subjects will be instructed to rinse with water and spit, 
particularly after the bedtime dose.
Please refer to the Investigational Product Administration Manual for additional details.


Shire
CONFIDENTIAL
Page 44
Protocol Amendment 2
SHP621-301
26 Jan 2018
6.2.1
Interactive Response Technology for Investigational Product Management 
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, randomization, investigational product supply dispensation and 
management, inventory management and supply ordering, investigational product expiration 
tracking and management, return of investigational product, and emergency unmasking. Please 
refer to the Study Manual for additional details regarding the IWRS. 
The investigator or designee will access the IWRS at the screening visit (Visit -1) to record 
subject-specific information (ie, unique subject number, date of birth, etc.). Subjects will be 
entered as screen failures or as entering the placebo lead-in period. Subjects cannot be rescreened 
once it is confirmed they do not meet inclusion/exclusion criteria unless the screen failure was 
due to a concomitant medication that can be discontinued prior to rescreening; those subjects 
may be rescreened. Other reasons for rescreening (ie, reasons unrelated to inclusion/exclusion 
criteria) must be discussed prospectively with the medical monitor. For subjects who enter the 
placebo lead-in period, IWRS will provide the assignment of placebo lead-in period medication 
to dispense. 
At the baseline visit (Visit 1), the investigator or designee will again access the IWRS to either 
document a screen failure or, if the subject has met all entry criteria, to randomize the subject.
Sites will enter eligibility criteria information prior to randomization. For randomized subjects, 
the IWRS will provide a medication identification (Med ID) number (ie, kit number to dispense 
for treatment).
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site and site personnel will receive training.
The IWRS provider will provide a user manual and training to each site, with detailed 
instructions on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This study consists of a single-blind lead-in period followed by a double-blind placebo-
controlled study period. The actual treatment given to individual subjects during the double-blind 
period is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject once eligibility has been determined following the placebo lead-in period.
Individual subject treatment is automatically assigned by the IWRS.


Shire
CONFIDENTIAL
Page 45
Protocol Amendment 2
SHP621-301
26 Jan 2018
Subjects will be randomized after confirmation of study eligibility in a ratio of 2:1 via a 
computer-generated randomization schedule to receive OBS 2 mg twice daily (qAM, pc, and hs) 
or placebo. The randomization will be performed centrally and stratified by age group (2 strata 
total: <18 years or ≥18 years) and diet restriction for EoE or other health-related conditions (no 
diet restriction or any diet restriction). The stratification by age will ensure a minimum of 
40 subjects in the pediatric group (11-17 years, inclusive). The stratification by age and diet 
restriction will ensure balance between treatment groups for the respective stratification factors. 
Fixed block randomization will be used to ensure that approximately equal numbers of patients 
are assigned each treatment within strata. 
 
6.2.3
Dosing
During the 4-week single-blind placebo lead-in period, all subjects will receive 10 mL of placebo 
twice daily (qAM, pc, and hs). During the 12-week double-blind treatment period, oral 
administration of 10 mL of investigational product will occur twice daily (qAM, pc, and hs), 
with no ingestion of food or liquids permitted for 30 minutes after study drug administration. 
Subjects randomized to OBS will receive 10 mL of 0.2 mg/mL of OBS (2 mg) twice daily for a 
total daily dose of 4 mg.
Investigational product doses that are required to be administered at the clinic include the first 
dose of placebo administered at the placebo lead-in visit (Visit 0), the first dose of randomized 
investigational product (OBS or placebo) administered at the baseline visit (Visit 1) and all 
morning doses of investigational product administered at Visits 2-4. Subjects will be required to 
eat breakfast at the clinic prior to self-administering these doses. Subjects can self-administer all 
other doses of placebo and investigational product at home.
During the day where the pharmacokinetic blood samples are collected, subjects will be required 
to eat a moderate-fat breakfast onsite and will be instructed to take their morning dose at a set 
time to establish the schedule for post-dose sample collection.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor and the sponsor as soon as possible 
after the investigator has been unblinded. 
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded in the IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes. Any code breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code-break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.


Shire
CONFIDENTIAL
Page 46
Protocol Amendment 2
SHP621-301
26 Jan 2018
There will be a provision for unblinding to ensure adequate treatment of the subject in the case of 
an emergency.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product is labeled with a minimum of the protocol number, Med ID, dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statements “For clinical 
trial use only” and/or “CAUTION: New Drug - Limited by Federal (or US) Law to 
Investigational Use,” “Keep out of reach of children,” and the sponsor’s name and address. Any 
additional labeling requirements for participating countries and/or controlled substances will also 
be included on the label.
Space is allocated on the label so that the site representative can record subject information. 
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
The sponsor will supply the following medication to the study sites in a blinded manner: OBS 
0.2 mg/mL or placebo in an 8-ounce amber glass bottle for multiple use. Three bottles will be 
packaged in an appropriately labeled carton.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.


Shire
CONFIDENTIAL
Page 47
Protocol Amendment 2
SHP621-301
26 Jan 2018
OBS and placebo must be stored at 2-8ºC (36-46ºF), protected from light.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an in-
house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
The investigational product should be stored under refrigeration at 2-8°C/36-46°F at all times. 
The investigational product should be protected from light and shaken well immediately prior to 
each dose.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon number of subjects. The investigator or designee will 
acknowledge receipt of the investigational product, documenting shipment content and 
condition. Accurate records of all investigational product dispensed, used, returned, and/or 
destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 


Shire
CONFIDENTIAL
Page 48
Protocol Amendment 2
SHP621-301
26 Jan 2018
in this study following the procedures set out in the study protocol. Each subject will be given 
only the investigational product carrying his/her treatment assignment. All dispensed medication 
will be documented on the CRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects. The investigator or 
his/her designee will enter the unique subject identifier and initials on the investigational product 
kit labels as they are assigned and dispensed.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken, and the labeled 
amount is to be documented in lieu of counting. Shipment return forms, when used, must be 
signed prior to shipment from the site. Validated electronic return systems (ie, IWRS) do not 
require a shipment form. Returned investigational product must be packed in a tamper-evident 
manner to ensure product integrity. Contact the sponsor for authorization to return any 
investigational product prior to shipment. Shipment of all returned investigational product must 
comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
Compliance with investigational product will be assessed at each study visit. Subjects must be 
instructed to bring their unused investigational product and empty/used investigational product 
packaging to every visit. Drug accountability must be assessed at the container/packaging level 
for unused investigational product that is contained within the original tamper-evident sealed 
container (eg, bottles) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
Visit to visit compliance of investigational product dosing will be assessed by site personnel. Site 
personnel must review the returned investigational product to assess compliance at every visit 
prior to dispensing additional investigational product. Any discrepancies should be reconciled 


Shire
CONFIDENTIAL
Page 49
Protocol Amendment 2
SHP621-301
26 Jan 2018
with the subject immediately. Subjects who do not return their used and unused investigational 
product should be reminded to bring all used and unused investigational product at their next 
visit. 
Subjects who have taken 70-130% of the investigational product will be assessed as being 
compliant with the study protocol. Compliance will be assessed at each treatment visit. 


Shire
CONFIDENTIAL
Page 50
Protocol Amendment 2
SHP621-301
26 Jan 2018
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 (see Table 1-1) and must be referred to in conjunction with the 
instructions provided in this section. 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject (as per 
local requirements). There must be documentation of consent (as per local requirements) 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions, prior to performing any study-related procedures.
7.1.1
Screening Period (Weeks -6 to 0)
The screening period starts when subjects sign informed consent. The screening period will 
comprise 3-6 weeks, during which all procedures listed for the screening visit (Visit -1) in Table 
1-1 shall be completed. The screening period will allow for the determination of eligibility of 
each subject’s inclusion into the study. A subject should not be instructed to discontinue use of 
any medication or treatment to participate in this study until informed consent has been obtained. 
Subjects should not stop permitted medications or treatments that are effective and well tolerated 
to participate in this study (see Section 5.2.1).
Screening assessments may take place across several days to allow an appropriate time frame in 
which to complete all procedures and confirm study eligibility.
After the screening period, subjects who meet eligibility criteria at the end of the screening visit 
(Visit -1) will enter the 4-week single-blind, placebo lead-in period. The placebo lead-in period 
should not commence until all screening assessments required to confirm initial eligibility have 
been completed. If the subject does not meet eligibility criteria following completion of 
screening assessments, the investigator or designee will document the subject as a screen failure 
in the IWRS.
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered randomized investigational product. Screen failures can occur at the screening, 
placebo lead-in, or baseline visits. Subjects cannot be rescreened once it is confirmed they do not 
meet inclusion/exclusion criteria unless the screen failure was due to temporary condition or 
incomplete information at the time of consent (Visit -1) that would make rescreening at a later 
date appropriate (eg, a concomitant medication that can be discontinued prior to rescreening, 
review of subject medical records provides new information with respect to the date of a prior 
esophageal dilation or diet change, or subject has a minor illness such as an upper respiratory or 
urinary tract infection). All reasons for rescreening (ie, reasons unrelated to inclusion/exclusion 
criteria) must be discussed and approved prospectively with the medical monitor.


Shire
CONFIDENTIAL
Page 51
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.1.1.1
Screening Visit (Visit -1) 
The screening visit (Visit -1) assessments and procedures, beginning with informed consent, will 
be performed as outlined in Table 1-1.
The following procedures should be performed first:

Obtain subject consent (or assent as applicable for subjects <18 years).

Review eligibility criteria.

Review medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height, and weight. Perform stadiometry in subjects aged 11-17 years, 
inclusive.

Review current use of concomitant medications, including medications taken and procedures 
completed within 3 months prior to the biopsy required for entrance to this study. Note: 
Subjects who are on a PPI must remain on the same dose of the PPI throughout the study, 
and if they are not taking a PPI, they must remain off of a PPI for the remainder of the study.

Clinical chemistry, hematology, and urinalysis laboratory tests will be performed on all 
subjects; all subjects must fast overnight prior to collection.
The following order is recommended for the remaining procedures that will be performed at this 
visit or within the 6-week screening period:

Dispense the DSQ electronic patient-reported outcome (ePRO) device for nightly completion 
and train the subject on its use. In order to qualify for study entry, subjects must have 
experienced dysphagia (response of “yes” to question 2 on DSQ) on a minimum of 4 days 
and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the screening 
period. 

Perform a physical examination on all subjects. Adolescents (subjects ≤17 years) will also 
undergo Tanner Staging Assessment.

Serum pregnancy test will be performed on all female subjects.

Perform EGD and biopsy; both must be performed within the 6 weeks prior to the Placebo 
Lead-in Visit either at the investigative site or by a referring physician. Biopsy specimens 
must be available to be sent to the central pathology lab at least 2 weeks prior to the Placebo 
Lead-in Visit to allow sufficient time for processing and central review and determination of 
eligibility.
7.1.2
Placebo Lead-in Period (Weeks 0 to 4)
The placebo lead-in period will comprise 4 weeks, during which all procedures listed for the 
placebo visit (Visit 0) in Table 1-1 shall be completed.


Shire
CONFIDENTIAL
Page 52
Protocol Amendment 2
SHP621-301
26 Jan 2018
During the 4-week single-blind placebo lead-in, all eligible subjects will self-administer 10 mL 
of placebo twice daily (qAM, pc, and hs). 
At the end of the placebo lead-in period, eligible subjects (those with at least 4 reported 
dysphagia days and completion of DSQ on ≥70% of days in the 2 weeks prior to baseline [Visit 
1]) will be randomized and enter the 12-week double-blind treatment period (baseline visit). 
Subjects must be administrated placebo during the placebo lead-in period for 4 weeks (±3 days) 
prior to Visit 1 (baseline) to be eligible for randomization into the 12-week double-blind 
treatment period.
7.1.2.1
Placebo Lead-in Visit (Visit 0) 
The placebo lead-in visit (Visit 0) assessments and procedures will be performed as outlined in 
Table 1-1. 
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight.

Perform AE assessments.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Confirm DSQ dysphagia episodes and compliance by completing screening eligibility report 
on DSQ device; re-dispense DSQ device to subject with instruction to continue completion 
of the DSQ nightly.

Perform a physical examination and assess any changes since screening.

Urine pregnancy test for female subjects.

Perform dual-energy X-ray absorptiometry (DXA) scan for bone mineral density (BMD) and 
body composition in subjects aged 11-17 years, inclusive; the DXA scan may be performed 
any time during the placebo lead-in period, after the subject has met all screening criteria and 
prior to blinded-treatment randomization. Baseline and post-treatment DXA scans should be 
performed using the same machine and software.

Dispense placebo study medication and review administration instructions. Subjects will self-
administer the first dose of placebo in the clinic after eating breakfast. Site personnel will 
record the date and time of the first placebo dose in the source documents. Beginning on the 
evening of Visit 0, the subject will take their second dose at home and continue with the 
twice daily (qAM, pc, and hs) dosing regimen.


Shire
CONFIDENTIAL
Page 53
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.1.3
Double-blind Treatment Period (Visits 1-4): Weeks 4, 8, 12, and 16 (or Early 
Termination)
The double-blind treatment period will comprise 12 weeks, during which all assessments and 
procedures listed for Visits 1-4 in Table 1-1 shall be completed.
During this period, a 3-day visit window will be permitted, unless otherwise specified. Visit 
windows are calculated based upon the date of the placebo lead-in visit (Visit 0).
Subjects who continue to meet all eligibility criteria will be randomized 2:1 to receive either 
OBS twice daily (qAM, pc, and hs) or placebo twice daily (qAM, pc, and hs). The investigator or 
assigned site staff will access the IWRS to randomize the subject and dispense the investigational 
product. Subjects who fail to meet eligibility criteria at the baseline visit (Visit 1) will be 
documented as screen failures in the IWRS.
Subjects who complete the 12-week double-blind treatment period will have the opportunity to 
enroll in the treatment extension study. These subjects will continue on the blinded assigned 
treatment for 2-4 weeks as part of the screening prior to enrolling into the treatment extension 
study. Subjects who do not enroll in the treatment extension study or who discontinue 
prematurely at any time during the SHP621-301 (Induction) study will receive a follow-up phone 
call 4-weeks post last dose of investigational product.
7.1.3.1
Baseline Visit (Visit 1): Week 4
Subjects will return to the site for the baseline visit (Visit 1) to confirm eligibility. The baseline 
visit (Visit 1) assessments and procedures will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Reassess eligibility according to the inclusion/exclusion criteria and medical history.

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight.

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 treatment 
emergent adverse event (TEAE).

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed. 

Administer adrenocorticotropic hormone (ACTH) stimulation testing; the type of synthetic 
and route of administration will be per local lab discretion. Additional cortisol samples will 


Shire
CONFIDENTIAL
Page 54
Protocol Amendment 2
SHP621-301
26 Jan 2018
be drawn at 30 and 60 minutes following stimulation testing.
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review study medication dosing compliance.

Confirm DSQ dysphagia episodes and compliance by completing baseline eligibility report 
on DSQ device; re-dispense DSQ device to subject with instruction to continue completion 
of the DSQ nightly.

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 PGI-S of disease assessment. 

Perform a physical examination and assess any changes since screening.

Re-administer urine pregnancy test for female subjects.

Dispense investigational product (OBS or placebo) according to IWRS randomization and 
review administration instructions. Subjects will self-administer the first dose of 
investigational product in the clinic during this visit after breakfast. Site personnel will record 
the date and time of the first randomized dose in the source documents. Beginning on the 
evening of Visit 1, the subject will take their first dose at home and continue with the twice 
daily (morning and evening) dosing regimen. For subjects who are minors (<18 years), a 
parent/guardian will be responsible for ensuring subject takes their investigational product 
appropriately.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.2
Visits 2 and 3 (Weeks 8 and 12)
Subjects will return to the site for Visit 2 (Week 8) and Visit 3 (Week 12). Assessments at these 
visits will be performed as outlined in Table 1-1.
The following procedures should be performed first:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature) and weight.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 


Shire
CONFIDENTIAL
Page 55
Protocol Amendment 2
SHP621-301
26 Jan 2018
to take the morning dose of study medication until after the morning cortisol test has been 
performed. 

Collect blood samples for pharmacokinetic analysis for adult subjects. Samples may be 
obtained one time on any day between 7 days after Visit 1 (Week 5) and through Visit 4 
(Week 16). PK samples should be drawn, ideally, at pre-dose, 0.5 and 1 hours post-dose and 
at additional time points, if feasible (2, 3, 4, 6, 8, and 12 hours post-dose). Subjects will be 
instructed to take their morning dose at a set time to establish the schedule for post-dose 
sample collection.
The following order is recommended for the remaining procedures that will be performed at this 
visit:

Review DSQ compliance and complete visit confirmation on the DSQ device; re-dispense 
DSQ device to subject with instruction to continue completion of the DSQ nightly.

Administer PGI-S assessment. 

Perform a physical examination and assess any changes since screening.

Re-administer urine pregnancy test for female subjects.

Dispense investigational product (OBS or placebo) and review investigational product dosing 
compliance.
Following all blood draws, subjects can eat breakfast and take their morning dose of 
investigational product.
7.1.3.3
Visit 4 (Week 16)
Subjects will return to the site for Visit 4 (Week 16). Assessments at this visit will be performed 
as outlined in Table 1-1.
The following order is recommended for the procedures that will be performed at this visit:

Record vital signs (including blood pressure [systolic and diastolic], heart rate, respirations, 
and temperature), height, and weight. Perform stadiometry in subjects aged 11-17 years, 
inclusive.

Perform AE assessments, including specific assessments for signs of glucocorticoid excess. 
Any AE that occurs during this visit will be recorded in the CRF and considered a TEAE.

Review concomitant medications and procedures.

Clinical chemistry, hematology, and urinalysis laboratory tests; all subjects must fast 
overnight prior to collection.

Morning cortisol (performed between 6:00 and 9:00 AM). Subjects should be instructed not 
to take the morning dose of investigational product until after the morning cortisol test has 
been performed.

Administer ACTH stimulation testing; the type of synthetic and route of administration will 


Shire
CONFIDENTIAL
Page 56
Protocol Amendment 2
SHP621-301
26 Jan 2018
be per local lab discretion. Additional cortisol samples will be drawn at 30 and 60 minutes
following stimulation testing.

Collect blood samples for pharmacokinetic analysis for adult subjects. Samples may be 
obtained one time on any day between 7 days after Visit 1 (Week 5) and through Visit 4 
(Week 16). PK samples should be drawn, ideally, at pre-dose, 0.5 and 1 hours post-dose and 
at additional time points, if feasible (2, 3, 4, 6, 8, and 12 hours post-dose).

Retrieve DSQ handset, review DSQ compliance, and complete visit confirmation on DSQ 
device.

Administer HRQoL assessments including the EQ-5D, PedsQL-EoE, and EoE-QoL-A as 
age-appropriate.

Administer PGI-S assessment. 

Perform a physical examination and assess any changes since screening. Adolescents 
(subjects ≤17 years) will also undergo Tanner Staging Assessment.

Re-administer serum pregnancy test for female subjects.

Perform DXA scan for BMD and body composition in subjects aged 11-17 years, inclusive. 
DXA scan should be completed at or within (±) 7 days of this visit. Baseline and post-
treatment DXA scans should be performed using the same machine and software.

Perform EGD and biopsy. EGD should be completed at or within (±) 7 days of the scheduled 
visit. If an esophageal dilatation is performed at Visit 4 (treatment failure), subjects will not 
be eligible to participate in the treatment extension study.

For eligible subjects continuing into the treatment extension study, obtain informed consent 
for the treatment extension study, dispense investigational product (OBS or placebo) 
according to IWRS randomization and review investigational product dosing compliance.
Following all safety blood draws, subjects can eat breakfast and take their morning dose of 
investigational product if they are continuing in the treatment extension study or staying in clinic 
for PK sampling (to be performed as described in Section 7.1.3.2 above).
7.1.4
Follow-up Period
The follow-up period for this protocol is 4 weeks from the last dose of investigational product. 
Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the study will receive a follow-up 4 phone call at Visit 5 (Week 20) to query for 
SAEs, AEs, and concomitant treatments (Section 7.1.4.1).
7.1.4.1
Safety Follow-up Contact (Visit 5): Week 20
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 


Shire
CONFIDENTIAL
Page 57
Protocol Amendment 2
SHP621-301
26 Jan 2018
AEs and SAEs that are not resolved at the time of this contact will be followed to closure.
7.1.5
Additional Care of Subjects after the Study
No after care is planned for this study for those subjects who do not enroll in the treatment 
extension study.
7.2
Study Evaluations and Procedures
The full title and details about who completes the scales used in this study is included in 
Appendix 1.
All assessments listed below will be performed by the subject and/or a qualified/trained site staff 
as indicated in the assessment description. For subject-completed assessments, trained site staff 
should not assist the subject in completing assessments in such a manner that it would influence 
their responses. Site staff should review the completed assessment to ensure completeness.
If an answer is marked in error, the subject may correct it by drawing a single line through the 
error and initialing and dating the change; however, corrections can only be made to scales by 
the subject during a study visit and changes must not be made to subject-completed scales after 
the visit has been completed. Assessments are to be performed according to the schedule shown 
in Table 1-1.
7.2.1
Efficacy
7.2.1.1
Esophagogastroduodenoscopy with Esophageal Biopsy and 
Histopathologic Evaluation
The EGD with endoscopy score and biopsy will be performed during the study as outlined in 
Table 1-1. 
An EGD with esophageal, gastric and duodenal biopsies will be required for study participation; 
the peak eosinophil count per HPF from each esophageal level will be used as a primary measure 
of efficacy. The qualifying/baseline EGD with biopsies must be performed by a physician at the 
investigative site within the 6 weeks prior to placebo lead-in visit (Visit 1). Biopsy specimens 
must be available to be sent to the central pathology lab by at least 2 weeks prior to the placebo 
lead-in visit to allow sufficient time for processing and central review and determination of 
eligibility.
Multiple specimens (at least 2 biopsies from each of 3 levels, 6 specimens total) will be obtained 
from the proximal (3 cm below the cricopharyngeus muscle), mid-esophagus (midpoint between 
the cricopharyngeus muscle and the gastroesophageal junction), and distal (3 cm above the 
gastroesophageal junction). Biopsy tissue will be placed in 3 separate vials (1 vial for each of the 
levels) and sent to the central pathology laboratory for processing of tissue into slides. A central 
pathologist will determine histologic eligibility for study entry. Peak eosinophil counts of 
≥15/HPF in specimens from 2 or more levels of the esophagus will be a requirement for study 
entry, as determined by a central pathologist. Eosinophil counts, histopathologic features, and 


Shire
CONFIDENTIAL
Page 58
Protocol Amendment 2
SHP621-301
26 Jan 2018
gross endoscopic findings will be evaluated and scored for each EGD. Eight histopathologic 
epithelial features (basal layer hyperplasia, eosinophil density, eosinophil micro-abscesses, 
eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic 
epithelial cells, lamina propria fibrosis) will be scored on a 4-point scale (0=normal, 3=worst) for 
both the severity of the abnormality (ie, grade) and the amount of tissue affected by the 
abnormality (ie, stage). 
Endoscopic findings with separate evaluations of the proximal and distal esophagus will be 
recorded with respect to 5 categories by the endoscopist: 1) exudates or plaques (grade 0–2); 2) 
fixed esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) 
strictures (grade 0–1). An endoscopy score for each category will be calculated and summed for 
each anatomic location (proximal and distal). The maximum endoscopy score is 10 points for 
each location, and a Total Endoscopy Score is the sum of the scores for the proximal and distal 
locations.
In addition, the general appearance of the stomach and duodenum will be assessed by the 
endoscopist. Biopsies will be taken from the stomach and duodenum for the screening EGD as 
follows: gastric body (greater curvature): 2 specimens, gastric antrum: 2 specimens, and 
duodenum (third part or distal): 2 specimens. Biopsies from the stomach should be submitted in 
one vial; biopsies from the duodenum should be submitted in a separate vial to the central 
pathology laboratory for processing of tissue into slides. If the pre-treatment biopsy identifies 
eosinophilia in the stomach and/or duodenum, the subject will be excluded from the study. 
At the Week 16 visit (Visit 4) or at early termination (ET), and EGD with esophageal biopsies (at 
least 2 biopsies from each of 3 levels [proximal, mid-, and distal]) is required. Endoscopic 
findings will be recorded by the endoscopist. Biopsies will be sent to the central laboratory for 
processing. A central pathologist will evaluate the slides. Gastric and duodenal biopsies may be 
repeated at the discretion of the investigator, but are not required.
7.2.1.2
Dysphagia Symptom Questionnaire
Subjects’ dysphagia symptoms will be evaluated using a DSQ ePRO device (Appendix 3). 
The questionnaire will be completed by subjects daily for a minimum of 3 weeks during the 
screening period, during the 4-week placebo lead-in period, and during the 12-week treatment 
period. Each evening before bedtime, subjects will be asked to indicate if they experienced 
dysphagia symptoms (eg, food passing slowly or food sticking) during that day. Subject must 
have experienced dysphagia (response of “yes” to question 2 on DSQ) on a minimum of 4 days 
total and completed the DSQ on ≥70% of days in any 2 consecutive weeks of the screening 
period and in the 2 weeks prior to the baseline visit (Visit 1). Subjects must fill out the DSQ at 
least 4 or more days during a given week in order to be compliant.
Visit to visit compliance of DSQ completion will also be assessed by site personnel. Protocol 
deviations will be documented for subjects who fail to complete the DSQ for 4 or more days in a 
given week.


Shire
CONFIDENTIAL
Page 59
Protocol Amendment 2
SHP621-301
26 Jan 2018
Calculations will be performed on daily ePRO entries during a 2-week interval prior to each 
study visit during the treatment periods. The DSQ score for the co-primary endpoint and 
secondary endpoints will be calculated by summing the scores of responses to questions 2 and 3 
only. Questions 1 and 4 will be excluded from the DSQ score:

DSQ score= (Sum of points from questions 2+3 in the daily DSQ)×14
Number of diaries reported with non-missing data
The DSQ + pain score for the secondary endpoints will be calculated by summing the scores of 
responses to questions 2, 3, and 4. Question 1 will be excluded from the DSQ + pain score.

DSQ + pain score= (Sum of points from questions 2+3+4 in the daily DSQ)×14
Number of diaries reported with non-missing data
The DSQ pain score for the secondary endpoint will be calculated by summing the scores of 
responses to Question 4 only.

DSQ pain score=(Sum of points from question 4 in the daily DSQ)×14
Number of diaries reported with non-missing data
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
7.2.2.1
Medical and Medication History
Medical History
The investigator must record all clinically or medically relevant information regardless of how 
much time has elapsed since the date of any diagnosis. Medical history will be classified as EoE 
or non-EoE by the investigator. The EoE medical history must include any prior history of 
esophageal strictures and esophageal dilations.
Medication History
Refer to Section 5.1 for full details on collection of prior treatment.
Prior treatment information, including any prior treatments for EoE (eg, dietary, medication, or 
other), must be recorded on the appropriate CRF page.


Shire
CONFIDENTIAL
Page 60
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.2.2.2
Physical Examination (Including Height and Weight)
Abnormalities identified at the screening visit (Visit -1) will be documented in the subject’s 
source documents and on the medical history CRF. Changes after the screening visit (Visit -1) 
will be captured as AEs on the AE CRF page, as deemed by the investigator.
Physical examination assessments at each visit should also include specific assessments for signs 
of glucocorticoid excess (eg, moon faces, acne, hirsutism, mood swings, insomnia, and 
depression). Physical examination at the screening visit (Visit -1) will also include Tanner 
Staging Assessments for subjects <18 years of age until investigator confirms subject is post-
puberty. 
Height will be collected at the screening visit (Visit -1) and Visit 4 for all subjects. Stadiometers 
will be used to measure height at Visit -1 and Visit 4 for subjects aged 11-17 years, inclusive. 
Statural height will be measured by trained site staff using a stabilized stadiometer. The same 
stadiometer should be used for the baseline and post-treatment measurements. Standard 
measuring procedures should be followed (eg, removal of socks, shoes, and hats). The 
stadiometer must be calibrated at least once daily, and as feasible, within 4 hours of 
measurement. All measurements should be recorded to the nearest 10th of a centimeter (1 mm);
measurements for adolescent subjects (11-17 years of age, inclusive), should be measured in 
triplicate. Please refer to the study manual for additional details.
Weight measurements for adolescent subjects (11-17 years, inclusive) should be measured in 
duplicate.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
AEs are collected from the time informed consent is signed. (Please refer to Section 8, Adverse 
and Serious Adverse Events Assessment.)
AE assessments at each visit should also include specific assessments for signs of glucocorticoid 
excess (eg, moon facies, acne, hirsutism, mood swings, insomnia, and depression).
7.2.2.4
Vital Signs
Vital signs will be conducted after the subject has been supine for at least 5 minutes immediately 
prior to the assessment and will include blood pressure (systolic and diastolic), heart rate, 
respirations, and temperature. Blood pressure should be determined by cuff (using the same 
method, the same arm, and in the same position throughout the study). Any clinically significant 
deviations from baseline (Visit 1) vital signs that are deemed clinically significant in the opinion 
of the investigator are to be recorded as an AE.


Shire
CONFIDENTIAL
Page 61
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.2.2.5
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
All subjects must fast overnight prior to collection of clinical laboratory tests.
Reference ranges are to be supplied by the laboratory and will be used to assess the clinical 
laboratory data for clinical significance and out-of-range pathological changes. The investigator 
should assess out-of-range clinical laboratory values for clinical significance, indicating if the
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which are unexpected or not explained by the subject’s clinical condition, may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved.
The following clinical laboratory assessments will be performed: 
Biochemistry

alkaline phosphatase

aspartate aminotransferase

alanine aminotransferase

total bilirubin

total protein

albumin

glucose

blood urea nitrogen

creatinine

sodium

potassium

chloride

calcium

carbon dioxide
Hematology

hemoglobin

hematocrit

mean corpuscular hemoglobin

mean corpuscular hemoglobin concentration

mean corpuscular volume

erythrocyte count

leukocyte count

neutrophils

lymphocytes

monocytes

eosinophils

basophils

platelet count
Urinalysis

glucose

protein

specific gravity

pH

nitrite

bilirubin

ketones

hemoglobin

urobilinogen

leukocyte esterase


Shire
CONFIDENTIAL
Page 62
Protocol Amendment 2
SHP621-301
26 Jan 2018
Other tests

serum pregnancy

urine pregnancy

morning cortisol (6:00-9:00 AM collection)

ACTH stimulation testing
ACTH stimulation testing will be performed by measuring the levels of cortisol in the blood 
following the injection of a synthetic form of ACTH. The type of synthetic and route of 
administration will be per local lab discretion. Blood samples will be collected just prior to and 
approximately 30 and 60 minutes following the injection. 
In the event of clinically significant abnormal laboratory test results, follow-up laboratory tests 
may be conducted. All subjects with an abnormal ACTH stimulation test or urinary or serum 
glucose level must be followed closely until resolution. For subjects who discontinue from the 
treatment period at any time and have an abnormal ACTH stimulation test at the ET visit, 
subjects will be scheduled for repeat testing approximately 6 weeks post last dose of 
investigational product to ensure that ACTH levels have normalized. Any clinically significant 
abnormalities noted in the laboratory tests will be discussed with the medical monitor.
7.2.2.6
Pregnancy Test 
A serum β-hCG pregnancy test is performed on all female subjects at the screening visit (Visit -
1) and the final treatment evaluation visit (Visit 4) or ET visit. A urine pregnancy test is 
performed on all female subjects at the placebo lead-in visit (Visit 0), baseline visit 
(Visit 1), Visit 2, and Visit 3 or if pregnancy is suspected.
7.2.2.7
Dual-energy X-ray Absorptiometry for Bone Mineral Density
Dual-energy X-ray absorptiometry (also referred to as DEXA) scans for determination of BMD 
and body composition will be performed in subjects aged 11-17 years, inclusive, as outlined in 
Table 1-1.
The sites for DXA measurement will be the lumber spine (L1-L4 preferred) and total body less 
head (Bachrach and Sills, 2011; Gordon et al., 2008; ISCD, 2014). The same DXA machine and 
software should be used for the baseline and post-treatment scans. The DXA manufacturer, 
model, and software version should be recorded in the CRF.
7.2.3
Other Assessments
7.2.3.1
Health-related Quality-of-life Assessment
EuroQol-5 Dimensions 3-level Questionnaire 
The EuroQol-5 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.


Shire
CONFIDENTIAL
Page 63
Protocol Amendment 2
SHP621-301
26 Jan 2018
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.
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; PROQOLID, 
2015). 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. 
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.


Shire
CONFIDENTIAL
Page 64
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.2.3.2
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 4) 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.
7.2.4
Clinical Pharmacology Assessments
Blood samples will be collected from adult subjects (≥18 years of age) as outlined in Table 1-1
to measure plasma concentrations of budesonide. Subjects who do not participate in 
pharmacokinetic sampling will not be discontinued from the study, and lack of participation will 
not be a considered protocol deviation. 
Actual pharmacokinetic blood sample collection times vs time of dosing will be monitored. The 
sponsor’s expectation is that the investigator will ensure that every effort will be made to collect 
all pharmacokinetic blood samples at the precise protocol scheduled time. Pharmacokinetic 
blood collection must not deviate from the nominal collection time set forth in the protocol by 
more than ± 5 minutes for samples drawn within 4 hours post-dose or by more than ± 15 minutes 
for samples drawn after 4 hours post-dose. Samples drawn outside these parameters will be 
considered a protocol deviation.
Blood samples (4 mL) for pharmacokinetic analysis will be drawn by direct venipuncture into 
K2EDTA tubes, capped and mixed by inversion (×3), and chilled immediately on crushed ice. 
The actual blood collection time will be recorded in the subject’s source documents and on the 
appropriate CRF page (24-hour format). After applying a tourniquet, venous blood will be drawn 
with a disposable needle. If a catheter is used, the first milliliter of blood on each sampling 
occasion will be discarded. Saline can be used to keep catheters patent.
Within 15 minutes following each sample collection, the blood tubes will be centrifuged at 
approximately 1500 g (15 minutes, 4°C). The separated plasma will be decanted into 
appropriately labeled primary and backup polypropylene tubes via a plastic pipette. All samples 
will be stored nominally at -20°C, and the freezer temperature will be controlled, monitored, and 
recorded during the storage period until the samples are shipped to the designated bioanalytical 
laboratory for analysis.
For additional information detailing sample handling, storage, and shipment, see Appendix 5.


Shire
CONFIDENTIAL
Page 65
Protocol Amendment 2
SHP621-301
26 Jan 2018
7.2.5
Volume of Blood to Be Drawn from Each Subject
Table 7-1: Approximate Volume of Blood to Be Drawn from Each Subject
Assessment
Sample Volume 
(mL)
Number of 
Samples
Approximate Total 
Volume (mL)
Pharmacokinetic samplesa
5
9
45
Safety
Biochemistry and -hCGb
6
6
36
ACTH
2
4
8
Cortisol
2
4
8
Hematology
2
6
12
Total mL
109
ACTH=adrenocorticotropic hormone; β-hCG=beta-human chorionic gonadotropin
a
If a catheter is used, the first mL is to be discarded; then take 4 mL into appropriate tube for pharmacokinetic 
sample. A total of 5 mL of blood drawn has been used in determination of sample volume.
b
-hCG testing is for females only.
During this study, it is expected that approximately 109 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 109 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined.


Shire
CONFIDENTIAL
Page 66
Protocol Amendment 2
SHP621-301
26 Jan 2018
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 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the CRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.


Shire
CONFIDENTIAL
Page 67
Protocol Amendment 2
SHP621-301
26 Jan 2018
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related.” Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related” based on the definitions in Table 8-1. The 
causality assessment must be documented in the source document.
Table 8-1: Adverse Event Relatedness
Term
Relationship Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of study drug, unlikely to be attributable to concurrent disease or other 
drugs and chemicals and which follows a clinically reasonable response on de-
challenge. The association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration of the study 
drug, follows a known or suspected response pattern to the study drug, is confirmed 
by improvement upon stopping the study drug (dechallenge), and reappears upon 
repeated exposure (rechallenge). Note that this is not to be construed as requiring re-
exposure of the patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown


Shire
CONFIDENTIAL
Page 68
Protocol Amendment 2
SHP621-301
26 Jan 2018
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 phase, 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 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global GDS Department using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire medical monitor 
using the details specified in the emergency contact information section of the protocol. The 
pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for SAEs and Non-serious AEs as Required by Protocol. Note: An elective abortion is not 
considered an SAE.


Shire
CONFIDENTIAL
Page 69
Protocol Amendment 2
SHP621-301
26 Jan 2018
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical 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 pre-specified 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 
parent/legally authorized representative/caregiver.


Shire
CONFIDENTIAL
Page 70
Protocol Amendment 2
SHP621-301
26 Jan 2018
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
GDS Department and the CRO medical monitor within 24 hours of the first awareness of the 
event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global GDS Department. A 
copy of the Shire Clinical Study Adverse Event Form for SAEs and Non-serious AEs as 
Required by Protocol (and any applicable follow-up reports) must also be sent to the CRO 
medical monitor using the details specified in the emergency contact information section of the 
protocol.
8.2.3
Serious Adverse Event Definition
A 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 
preexisting 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 


Shire
CONFIDENTIAL
Page 71
Protocol Amendment 2
SHP621-301
26 Jan 2018
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be reported 
to the Shire GDS Department and the medical monitor within 24 hours of the first awareness of 
the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire GDS
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, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
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.


Shire
CONFIDENTIAL
Page 72
Protocol Amendment 2
SHP621-301
26 Jan 2018
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.


Shire
CONFIDENTIAL
Page 73
Protocol Amendment 2
SHP621-301
26 Jan 2018
9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.1 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.


Shire
CONFIDENTIAL
Page 74
Protocol Amendment 2
SHP621-301
26 Jan 2018
In addition to a final SAP for the final analysis, a separate interim SAP for the interim analysis 
will be finalized prior to unblinding and performing the analysis. The SAP for the final analysis 
will be finalized prior to final database lock and performing analysis (ie, unblinding) to preserve 
the integrity of the statistical analysis and study conclusions.
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
A planned interim analysis for each of the co-primary endpoints will take place after 50% of all 
randomized subjects have either completed the study or prematurely withdrawn from the study, 
whichever comes first. The purpose of the unblinded interim analysis is to reassess the 
appropriateness of assumptions used for each of co-primary efficacy endpoints when the study 
was designed. The reassessment of the sample size will utilize the conditional power approach 
under certain conditions that do not inflate the type I error (Mehta and Pocock, 2011). The 
planned interim analysis will be conducted by an external independent statistical (EIS) group; the 
individuals involved in the day-to-day conduct of the trial will not be involved in the interim 
analysis or have access to the results of the interim analysis. The Sponsor will only be notified by 
the EIS group if any recommendation of increasing the sample size is needed from the 
conditional power; this will be detailed in the prespecified interim SAP including a potential 
maximum sample size to be increased if deemed necessary. 
A very minimal fraction of alpha (0.0001) will be spent at the interim analysis as the trial will 
not stop due to the interim results. The final analysis will use 4.99% for each of the co-primary
endpoints in order to preserve an overall type I error at 5% level.
9.6
Sample Size Calculation and Power Considerations
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected difference 
between treatment response proportions of 69% and 45% in the OBS 2 mg twice daily (qAM, pc, 
and hs) and placebo groups, respectively. The original protocol noted that a total of 228 subjects 
(152 subjects randomized to OBS and 76 subjects randomized to placebo) are required to achieve 
90% power at the significance level of 0.0499 (2-sided) using a 2-group chi-square test with 
unequal allocation 2:1 to treatment groups (OBS 2 mg twice daily and placebo). With the 
specified number of subjects per treatment group, the study will be powered at 99% assuming 
histological response proportions of 40% and 3% in the OBS 2 mg twice daily and placebo 
groups, respectively. The overall study power for the co-primary endpoints was estimated to be 
at least 85%. Therefore, approximately 228 (approximately 152:76 OBS and placebo subjects, 
respectively) were to be randomized in the study to allow for a loss of approximately 5% of 
subjects due to dropouts or invalid data. Expected response and dropout rates are based on 
observation from the Phase 2 study (MPI 101-06).
In this protocol amendment, in order to ensure that a sufficient number of subjects will complete 
this study and enroll in the treatment extension study, up to approximately 420 subjects will be 
enrolled in the placebo lead-in period to allow for approximately 306 subjects to be randomized 
into the double blind period of this study (approximately 204:102 OBS and placebo subjects, 
respectively). With a total of 306 randomized subjects in this study, using the same assumptions 


Shire
CONFIDENTIAL
Page 75
Protocol Amendment 2
SHP621-301
26 Jan 2018
for the co-primary endpoints and the dropout rate, the overall study power for the co-primary
endpoints is estimated to be at least 95%.
9.7
Study Population
The safety set will include all subjects who receive at least 1 dose of any double-blind 
investigational product.
The intent-to-treat (ITT) set will include all randomized subjects. Subjects will be analyzed 
according to their assigned treatment, regardless of the treatment actually received.
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of 
a double-blind investigational product and have both an evaluable post-baseline biopsy in the 
treatment period (ie, peak eosinophil count is reported for at least 2 esophageal levels) and a 
post-baseline DSQ score.
The per-protocol (PP) set will include all subjects in the FAS excluding subjects with protocol 
violations. The PP set will be identified prior to unblinding the treatment assignments by a team 
consisting of, at a minimum, a physician and a statistician from Shire.
The pharmacokinetic set will include all subjects in the safety set for whom the primary 
pharmacokinetic data are considered sufficient and interpretable.
9.8
Efficacy Analyses
The primary, key secondary and secondary efficacy analyses will be performed on the ITT set 
and presented by treatment group.
Data collected at the baseline visit (Visit 1) will be used as the baseline for all efficacy analyses.
9.8.1
Primary Efficacy Endpoints
The co-primary efficacy endpoints are the following:

Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation (Visit 4)

Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation (Visit 4)
The co-primary efficacy endpoints will be analyzed based on the ITT set. Each of the co-primary
efficacy endpoints is a binary response (ie, responders vs non-responders); the endpoint will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for age group (either 
<18 years or ≥18 years) and diet restriction for EoE or other health-related conditions (no diet 
restriction or any diet restriction). The adjusted odds ratio of being a responder on each of the co-
primary endpoints for the OBS 2 mg twice daily group vs placebo group and associated 95% 


Shire
CONFIDENTIAL
Page 76
Protocol Amendment 2
SHP621-301
26 Jan 2018
confidence interval (CI) will be provided. Subjects who withdraw without providing efficacy 
data at the final treatment period evaluation (Visit 4, Week 16) will be classified as non-
responders in the primary efficacy analysis.
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized, and their respective 95% CI will be reported. The 
difference in the proportion of responders between the 2 treatment groups and the corresponding 
95% CI will also be summarized.
The following sensitivity and supportive analyses will be performed for the co-primary to 
evaluate the robustness of the results from the primary analysis methods:

Each of the co-primary efficacy endpoints will be analyzed using a logistic regression 
with the effects of treatment group, age group (either <18 years or ≥18 years) and diet 
restriction for EoE or other health-related conditions (no diet restriction or any diet 
restriction). The odds ratio of being a responder on each of the co-primary endpoints for 
the OBS 2 mg twice daily group vs placebo group and associated 95% CI will be 
estimated from the final model. Subjects who withdraw without providing efficacy data 
at the final treatment period evaluation (Visit 4, Week 16) will be classified as non-
responders in the primary efficacy analysis.

Analyses will be repeated using the FAS and the PP set.

Analyses will be repeated by considering subjects who withdraw without providing 
efficacy data at the final treatment period evaluation (Visit 4) and will be classified as 
responders.
9.8.1.1
Missing Data Imputation
Method 1: Distribution-based Imputation
The subjects with missing co-primary efficacy endpoints will be assigned randomly according to 
the distribution of responders with available data for each of the co-primary endpoints (ie, those 
with non-missing data) across the 2 treatment groups by strata (see Table 9-1). 
Table 9-1: Percentage of Responders for All Available Data (ie, Non-missing Data) by 
Strata
Strata
No
Yes
<18 years
X0%
X1%
≥18 years
Y0%
Y1%
For instance, if there are N subjects with missing data in strata 1 (age <18 years), then X0%*N 
subjects will be randomly assigned as non-responders and X1%*N subjects will be randomly 
assigned as responders.


Shire
CONFIDENTIAL
Page 77
Protocol Amendment 2
SHP621-301
26 Jan 2018
Conversely, if there are M subjects with missing data in strata 2 (age ≥18 years), the Y0%*M 
subjects will be randomly assigned as non-responders and Y1%*M subjects will be randomly 
assigned as responders.
Method 2: Multiple Imputations
Multiple imputation (MI) methods will utilize the SAS procedures PROC MI and PROC 
MIANALYZE. The MI procedure will involve fitting a logistic regression model with the binary 
outcome (responders vs non-responders) as the dependent variable and the age group and the 
treatment group as the independent variables. The MI procedure will generate 10 version datasets 
with binary outcome imputed from the subjects with complete data. Once the missing values are 
imputed and each dataset is created, the results will be appropriately pooled across the multiply 
imputed estimated regression coefficients and their standard errors using PROC MIANALYZE.
Other sensitivity analyses will be explored, and details will be provided in the SAP.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is defined as the change in DSQ combined score (questions 
2+3) from baseline to the final treatment period evaluation (Visit 4). The change from baseline 
DSQ score at the final treatment period evaluation (Visit 4) will be analyzed using an analysis of 
covariance (ANCOVA) model with treatment group and age group as factors and the baseline 
DSQ score as a continuous covariate.
The additional secondary efficacy endpoints are the following:

Change in total endoscopy score, as measured by the EREFS classification, from baseline to 
the final treatment period evaluation (Visit 4)

Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment 
period evaluation (Visit 4)

Change from baseline in the peak eosinophil count to the final treatment period evaluation 
(Visit 4) for each available esophageal level (proximal, mid-, and distal)

Change from baseline in the histopathologic epithelial features combined total score (grade 
and stage) to the final treatment period evaluation (Visit 4)

Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation (Visit 
4)

Change from baseline in the DSQ combined score (questions 2+3) over time including post 
baseline visits


Shire
CONFIDENTIAL
Page 78
Protocol Amendment 2
SHP621-301
26 Jan 2018

Cumulative distribution function curves for the change and the percent change in the DSQ 
score from baseline to the final treatment period evaluation (Visit 4)

Overall binary response I, defined as a reduction in the DSQ score of ≥30% from baseline to 
the final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across 
all esophageal levels at the final treatment period evaluation (Visit 4)

Overall binary response II, defined as a reduction in the DSQ score of ≥50% from baseline to 
the final treatment period evaluation (Visit 4) and a peak eosinophil count of ≤6/HPF across 
all esophageal levels at the final treatment period evaluation (Visit 4)

Change in the DSQ + pain score (questions 2+3+4) from baseline to the final treatment 
period evaluation (Visit 4)

Change in the DSQ pain score (question 4) from baseline to the final treatment period 
evaluation (Visit 4)
The binary response endpoints will be analyzed using the same logistic model as the co-primary
efficacy endpoints.
Continuous endpoints will be analyzed as a change from baseline using an ANCOVA model that 
includes treatment group and age group as factors and baseline score as a covariate.
The analyses for all secondary efficacy endpoints (including the key secondary efficacy 
endpoint) will be carried out using 2-sided tests at the 5% level of significance. For each of the 
secondary efficacy endpoints, the treatment difference, corresponding 95% CI for the difference 
and treatment comparison p-value for testing the null hypothesis of zero treatment effect based 
on the final statistical model (ie, either logistic regression model or ANCOVA model) will be 
provided.
9.8.3
Exploratory Efficacy Endpoint
The exploratory endpoint that will be explored is the following:
9.9
Safety Analyses
Safety data will be presented for the safety set by treatment group.
The safety data collected at the baseline visit (Visit 1) or the last preceding visit if not collected 
at Visit 1 will be used as the baseline value for safety analyses.
TEAEs are defined as AEs that start or deteriorate on or after the first dose of investigational 
product (Visit 1) and no later than 3 days following the last dose of investigational product. 
However, for any subjects who die during the study (ie, the date of death is between the date of 
first dose of investigational product and the date of study discontinuation entered by the site, 


Shire
CONFIDENTIAL
Page 79
Protocol Amendment 2
SHP621-301
26 Jan 2018
inclusive), all AEs (including those resulting in death) that occur during the study will be 
considered as TEAEs irrespective of the last dose and will be included in the TEAE summaries.
AEs will be coded using MedDRA. The number of events, incidence, and percentage of TEAEs 
will be calculated overall by system organ class (SOC), preferred term (PT), and treatment 
group. TEAEs will be further summarized by severity and relationship to investigational product. 
AEs related to investigational product, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized/listed.
Safety parameters will include monitoring of AEs, physical examinations, stadiometry, vital 
signs (temperature, systolic and diastolic blood pressure, pulse, and respiratory rate), weight and 
height assessments, DXA scans for BMD and body composition measurements (for adolescents 
aged 11-17 years, inclusive), clinical laboratory tests (hematology, chemistry, urinalysis; serum 
pregnancy test, if appropriate), and ACTH stimulation tests. To account for the effects of puberty 
in adolescent subjects (11-17 years of age, inclusive), BMD z-scores will be adjusted for height 
z-scores using the Bone Mineral Density in Childhood Study calculator (BMDCS 2015) 
(http://www.bmdcspublic.com). Safety parameters will be descriptively summarized by 
treatment group at baseline and for each post-baseline visit.
9.10
Other Analyses
9.10.1
Health-related Quality-of-life Analyses 
The health economics and outcomes research endpoints that will be explored are the following:

EoE-QoL-A Questionnaire (Taft et al., 2011)

EQ-5D (EQ-5D-3L or EQ-5D-Y, according to subject’s age)

PedsQL-EoE
The submodules of the EoE-QoL-A and PedsQL-EoE will be assessed in addition to the overall 
score with a focus on emotional and physical elements. For all HRQoL analyses, change from 
baseline to the final treatment period evaluation (Visit 4) will be assessed.
9.10.2
Pharmacokinetic Analyses
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis for subjects who provide sufficient numbers of 
intensive PK samples. For all subjects who provide PK samples (ie, limited or intensive samples) 
population PK analysis will be conducted. A report for the population PK analysis will be 
provided separately from the clinical study report (CSR). 
The pharmacokinetic endpoints will include but not be limited to those listed in Table 9-2.


Shire
CONFIDENTIAL
Page 80
Protocol Amendment 2
SHP621-301
26 Jan 2018
Table 9-2: Pharmacokinetic Parameters
Parameter
Definition
AUC0-tau
Area under the curve for the defined interval between doses
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing interval
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters by overall and by week. Plasma concentrations at each nominal sampling time will 
also be summarized using descriptive statistics.


Shire
CONFIDENTIAL
Page 81
Protocol Amendment 2
SHP621-301
26 Jan 2018
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current good clinical practice (GCP) and the 
respective local and (inter)national government regulations and guidelines. Records and data 
may additionally be reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites.
Information included in clinical study registries may include participating investigators’ names 
and contact information.


Shire
CONFIDENTIAL
Page 82
Protocol Amendment 2
SHP621-301
26 Jan 2018
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric 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 sub-investigators 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).


Shire
CONFIDENTIAL
Page 83
Protocol Amendment 2
SHP621-301
26 Jan 2018
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic CRFs are supplied by the CRO and should be handled in accordance with instructions 
from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data from the investigator will have separate source documentation; no data will be recorded 
directly onto the CRF.
All data sent to the sponsor must be endorsed by the investigator.
The data from the central pathologist will be recorded directly onto paper CRFs.
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.


Shire
CONFIDENTIAL
Page 84
Protocol Amendment 2
SHP621-301
26 Jan 2018
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 to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC, or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.).
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
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.
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 


Shire
CONFIDENTIAL
Page 85
Protocol Amendment 2
SHP621-301
26 Jan 2018
ongoing consultation, or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (or assent as 
applicable for subjects <18 years of age) from all study subjects prior to any study-related 
procedures including screening assessments. All consent documentation must be in accordance 
with applicable regulations and GCP. Each subject or the subject’s legally authorized 
representative, as applicable, is requested to sign and date the subject’s informed consent form or 
a certified translation, if applicable, after the subject has received and read (or been read) the 
written subject information and received an explanation of what the study involves, including but 
not limited to the objectives, potential benefits and risk, inconveniences, and the subject’s rights 
and responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form consent (or 
assent as applicable for subjects <18 years of age) that was reviewed by the IRB/EC and received 
their favorable opinion/approval. A copy of the IRB’s/EC’s written favorable opinion/approval 
of these documents must be provided to the sponsor, prior to the start of the study unless it is 
agreed to and documented (abiding by regulatory guidelines and national provisions) prior to 
study start that another party (ie, sponsor or coordinating principal investigator) is responsible for 
this action. Additionally, if the IRB/EC requires modification of the sample subject information 
and consent document provided by the sponsor, the documentation supporting this requirement 
must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information, and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor or the investigator or, 
for multicenter studies, the coordinating principal investigator or sponsor, according to national 
provisions.


Shire
CONFIDENTIAL
Page 86
Protocol Amendment 2
SHP621-301
26 Jan 2018
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent (or assent as applicable for subjects <18 years of age) 
documents and amendments to the protocol unless there is a subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor or the investigator or, for 
multicenter studies, the coordinating principal investigator, according to national provisions. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the CRO/sponsor.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives’
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP621; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to 
and used in other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purposes of any such transfer would include 
supporting regulatory submissions, conducting new data analyses to publish or present the study 
results, or answering questions asked by regulatory or health authorities.


Shire
CONFIDENTIAL
Page 87
Protocol Amendment 2
SHP621-301
26 Jan 2018
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty-
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral, or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.


Shire
CONFIDENTIAL
Page 88
Protocol Amendment 2
SHP621-301
26 Jan 2018
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.


Shire
CONFIDENTIAL
Page 89
Protocol Amendment 2
SHP621-301
26 Jan 2018
11.
REFERENCES
Bone 
Mineral 
Density 
in 
Childhood 
Study 
(BMDCS) 
2015.
Available 
at: 
http://www.bmdcspublic.com. Accessed August 5, 2015.
Bachrach, L. K. & Sills, I. N. 2011. Clinical report-bone densitometry in children and 
adolescents. Pediatrics, 127, 189-94.
Dellon, E. S., Jensen, E. T., Martin, C. F., Shaheen, N. J. & Kappelman, M. D. 2014a. 
Prevalence of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol,
12, 589-96.e1.
Dellon, E. S., Kim, H. P., Sperry, S. L., Rybnicek, D. A., Woosley, J. T. & Shaheen, N. J. 2014b. 
A phenotypic analysis shows that eosinophilic esophagitis is a progressive fibrostenotic 
disease. Gastrointest Endosc, 79, 577-85.e4.
EuroQol 1990. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy, 16, 199-208.
FDA 2011. Uceris pharmacology review. NDA 203-634.
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., 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.
ISCD 2014. International Society for Clinical Densitometry 2013 Official Positions—Adult & 
Pediatric. 1-20.
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.
Mehta, C. R. & Pocock, S. J. 2011. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30, 3267-84.
PROQOLID 2015. Patient-Reported Outcome and Quality of Life Instruments Database 
(PROQOLID). Available at: http://www.proqolid.org. Accessed August 24, 2015.


Shire
CONFIDENTIAL
Page 90
Protocol Amendment 2
SHP621-301
26 Jan 2018
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.


Shire
CONFIDENTIAL
Page 91
Protocol Amendment 2
SHP621-301
26 Jan 2018
12.
APPENDICES


Shire
CONFIDENTIAL
Page 92
Protocol Amendment 2
SHP621-301
26 Jan 2018
Appendix 1
Protocol History 
Document
Date
Global/Country/Site Specific
Protocol Amendment 2
26 Jan 2018
Global
Protocol Amendment 1
16 Dec 2015
Global
Original Protocol
31 Aug 2015
Global


Shire
CONFIDENTIAL
Page 93
Protocol Amendment 2
SHP621-301
26 Jan 2018
Appendix 2
Scales and Assessments
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Completed By
DSQ
Subject
EQ-5D-3L (for subjects ≥18 years)
EQ-5D-Y (for subjects 11-17 years of age, inclusive)
Subject
PedsQL-EoE (subjects 11-17 years of age, inclusive)
Subject and parent or legal 
guardian
EoE-QoL-A (subjects ≥18 years of age)
Subject
PGI-S
Subject
Tanner Staging Assessment (for subjects 11-17 years of age, inclusive)
Site
EREFS
Site
DSQ=Dysphagia Symptom Questionnaire; EoE-QoL-A=Adult Eosinophilic Esophagitis Quality of Life; EQ-
5D=EuroQol; EREFS=EoE Endoscopic Reference Score; PedsQL-EoE=Pediatric Quality of Life Inventory – EoE; 
PGI-S=Patient Global Impression of Severity
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.


Shire
CONFIDENTIAL
Page 94
Protocol Amendment 2
SHP621-301
26 Jan 2018
Appendix 3
Dysphagia Symptom Questionnaire ePRO for EoE 


Shire
CONFIDENTIAL
Page 95
Protocol Amendment 2
SHP621-301
26 Jan 2018
Appendix 4
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


Shire
CONFIDENTIAL
Page 96
Protocol Amendment 2
SHP621-301
26 Jan 2018
Appendix 5
Biosciences Generic Clinical Protocol Insert
Blood Sample Collection
Blood samples will be collected at the times specified in Table 1-1 to measure plasma 
concentrations of budesonide. Potential metabolites may also be determined as appropriate.
Blood samples 4 mL for pharmacokinetic analysis will be drawn by in-dwelling catheters or 
direct venipuncture into K2EDTA tubes, capped and mixed by inversion (x3), and chilled 
immediately on crushed ice. The actual time that the sample was obtained will be recorded in the 
subject’s source document and on the appropriate CRF page. After applying a tourniquet, venous 
blood will be drawn with a disposable needle. If a catheter is used, the first milliliter of blood on 
each sampling occasion will be discarded. Saline can be used to keep catheters patent.
Blood/Plasma Sample Handling
Samples should be kept on crushed ice until plasma is separated as soon as possible after 
collection within <15 minutes, unless advised otherwise by refrigerated centrifugation (4C, 
1500 rpm 15 minutes). The separated plasma will be decanted into appropriately labeled 
polypropylene tubes via a plastic pipette. All samples will be stored at approximately -20C or 
colder and the freezer temperature will be controlled, monitored, and recorded during the storage 
period until they are transferred in the frozen state to a designated bioanalytical contract 
laboratory. Samples will remain frozen at -20C or colder until analysis.
Plasma sample tubes for bioanalysis must be freezer-safe and identified with freezer-safe labels 
provided by the central laboratory. The labels will contain the following information:

Study number

Subject identifier (randomization number)

Matrix identifier (plasma)

Visit

Nominal time
Shipment of Plasma Samples
Plasma samples should be double-bagged to contain leaks and packed with a sufficient quantity 
of dry ice to ensure that they remain frozen for at least 72 hours to allow for delays in shipment. 
All applicable shipping regulations must be followed. Shipments should be scheduled so that no 
samples arrive on the weekend and should be shipped Monday to Wednesday only.


Shire
CONFIDENTIAL
Page 97
Protocol Amendment 2
SHP621-301
26 Jan 2018
Plasma samples, along with the corresponding documentation, will be shipped to:
PPD
2 Tesseneer Drive
Highland Heights, KY 41076, USA
Email: 
Phone:
 or 
, 
Fax:
Plasma samples will be stored nominally at -20C prior to and after analysis at Quest 
Pharmaceutical Services (QPS) until their disposal is authorized by Shire.
Assay Methodology
Drug analysis will be performed at QPS under the guidance of the NCE group at Shire. Plasma 
sample analysis will be performed according to the bioanalytical study plans prepared for the 
study. 
Plasma samples will be analyzed at QPS for budesonide using the most current validated 
bioanalytical method. 
In addition, selected plasma samples may be used to investigate incurred sample reproducibility 
(full details will be described in the bioanalytical study plan). The presence of other metabolites 
or artifacts may be monitored or quantified as appropriate.
Raw data will be stored in the archives at QPS.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP621-301 
Protocol Title: 
Oral Budesonide Suspension (OBS) in Adolescent and 
Adult Subjects (11 to 5 5 Years of Age, Inclusive) with 
Eosinophilic Esophagitis: A Phase 3 Randomized, 
Double-blind, Placebo-controlled Study 
Drug: 
SHP621, oral budesonide suspension (OBS), budesonide 
oral suspension (BOS) 
Sponsor: 
Shire ViroPharma, Incorporated (Shire) 
300 Shire Way, Lexincton, MA 02421 USA 
Version No. and Date 
Final Version 1.0, Date ll-March-2019 
Issued by: 
PREPARED BY 
PPD,Inc. 
3900 Paramount Pkwy 
Morrisville, NC, 27560 
BIOS) 
neut 
ll Mnr201923:1J9:27 -04:00 
 
, Biostatistics 
PPD 
Date: .fil_/_ll_/2019 
!2 Mnr 2(}19 08:07:05 -04:00 
Reviewed by: 
Date:_/_/_ 
, Biostatistics 
PPD 
Upon review of this document, including table, listing, and figure shells, the undersigned 
approves the statistical analysis plan. The analysis methods and data presentation are acceptable, 
and the table, listing, and figure production can begin. 


ApproMJ 
 
, Global Clinical 
Development 
Shire 
, Global Clinical 
Development 
Shire 
Date 
D
Shire  
CONFIDENTIAL 
Page 2 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 


Shire  
CONFIDENTIAL 
Page 3 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ....................................................................................................................9 
2. 
STUDY DESIGN ...................................................................................................................10 
2.1 
General Study Design ...............................................................................................10 
2.2 
Randomization .........................................................................................................11 
2.3 
Blinding ....................................................................................................................11 
2.3.1 Blinding of Investigational Product .......................................................................11 
2.3.2 Blinding of Study Data ..........................................................................................12 
2.3.2.1 
SHP621-301 Study Conduct ..................................................................12 
2.3.2.2 
SHP621-302 Study Conduct ..................................................................12 
2.3.2.3 
SHP621-301 Study Results Reporting ...................................................12 
2.4 
Schedule of Assessments .........................................................................................13 
2.5 
Determination of Sample Size ..................................................................................17 
2.6 
Multiplicity Adjustments for Type I Error Control ..................................................17 
3. 
OBJECTIVES .........................................................................................................................19 
3.1 
Primary Objectives ...................................................................................................19 
3.2 
Secondary Objectives ...............................................................................................19 
3.3 
Exploratory Objectives .............................................................................................19 
4. 
SUBJECT POPULATION SETS ...........................................................................................20 
4.1 
Screened Set .............................................................................................................20 
4.2 
Full Analysis Set ......................................................................................................20 
4.3 
Safety Analysis Set ...................................................................................................20 
4.4 
Randomized Set ........................................................................................................20 
4.5 
Per-protocol Set ........................................................................................................20 
4.6 
Pharmacokinetic Set and Pharmacokinetic Parameter Set .......................................21 
5. 
SUBJECT DISPOSITION ......................................................................................................22 
6. 
PROTOCOL DEVIATIONS ..................................................................................................23 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................24 
7.1 
General Medical History ..........................................................................................24 
7.2 
EoE Medical History ................................................................................................24 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................26 
8.1 
Exposure to Investigational product .........................................................................26 
8.2 
Measurement of Treatment Compliance ..................................................................26 


Shire  
CONFIDENTIAL 
Page 4 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
9. 
PRIOR AND CONCOMITANT MEDICATION ..................................................................28 
10. EFFICACY ANALYSES .......................................................................................................29 
10.1 
Primary Efficacy Endpoint(s) and Analysis .............................................................29 
10.1.1 Definition of Co-primary Efficacy Endpoints .......................................................29 
10.1.2 Primary Analysis of Co-primary Efficacy Endpoints ............................................30 
10.1.3 Sensitivity and Other Analyses of Co-primary Efficacy Endpoints ......................30 
10.1.4 Subgroup Analyses of Co-primary Efficacy Endpoints.........................................34 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis .................................................34 
10.2.1 Definition of Key Secondary Efficacy Endpoint ...................................................34 
10.2.2 Primary Analysis of Key Secondary Efficacy Endpoint........................................34 
10.2.3 Sensitivity Analyses of Key Secondary Efficacy Endpoint ...................................35 
10.2.4 Subgroup Analysis of Key Secondary Efficacy Endpoint .....................................35 
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis ...............................................35 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses ......................................................37 
11. SAFETY ANALYSES ...........................................................................................................39 
11.1 
Adverse Events .........................................................................................................39 
11.2 
Clinical Laboratory Variables ..................................................................................40 
11.3 
Vital Signs ................................................................................................................41 
11.4 
Electrocardiogram (ECG).........................................................................................41 
11.5 
Other Safety Variables .............................................................................................41 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ............43 
12.1 
Pharmacokinetic Methods ........................................................................................43 
12.1.1 Concentration Data ................................................................................................43 
12.1.2 Handling BLQ Values............................................................................................43 
12.1.3 Pharmacokinetic Parameters ..................................................................................44 
12.2 
Pharmacodynamic Methods .....................................................................................45 
12.3 
Statistical Analysis of Pharmacodynamic Data........................................................45 
13. OTHER ANALYSES .............................................................................................................46 
13.1 
Quality of Life Analyses ..........................................................................................46 
14. INTERIM ANALYSIS ...........................................................................................................48 
15. DATA MONITORING/REVIEW COMMITTEE .................................................................49 
16. COMPUTER METHODS ......................................................................................................50 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .................................................51 
18. DATA HANDLING CONVENTIONS ..................................................................................53 
18.1 
General Data Reporting Conventions ......................................................................53 
18.2 
Derived Efficay Endpoints .......................................................................................53 
18.3 
Derived Safety Endpoints .........................................................................................53 
18.4 
Missing Date of Investigational Product ..................................................................54 


Shire  
CONFIDENTIAL 
Page 5 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
18.5 
Missing Date Information for Prior or Concomitant Medications ...........................54 
18.5.1 Incomplete Start Date ............................................................................................54 
18.5.2 Incomplete Stop Date .............................................................................................55 
18.6 
Missing Date Information for Adverse Events ........................................................55 
18.6.1 Incomplete Start Date ............................................................................................56 
18.6.2 Incomplete Stop Date .............................................................................................56 
18.7 
Missing Severity Assessment for Adverse Events ...................................................56 
18.8 
Missing Relationship to Investigation Product for Adverse Events ........................56 
18.9 
Character Values of Clinical Laboratory Variables .................................................56 
19. REFERENCES .......................................................................................................................57 
20. APPENDICES ........................................................................................................................58 
APPENDIX 1 
The Daily Dysphagia Symptom Questionnaire ......................................59 
APPENDIX 2 
Calculation of Adult Eosinophilic Esophagitis Quality of Life 
(EoE-QOL-A) Total Score .....................................................................................61 
APPENDIX 3 
Calculation of Pediatric Quality of Life – EoE (PedsQL-EoE, 
subjects 11-17 years of age) Total Score ...............................................................62 
APPENDIX 4 
Calculation of the EQ-5D Score .............................................................64 
APPENDIX 5 
Histopathologic Epithelial Features Combined Total Score (Grade 
and Stage)...............................................................................................................65 


Shire  
CONFIDENTIAL 
Page 6 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ...............................................................................13 
Table 2 
Percentage of Responders for All Available Data (i.e., Non-missing 
Data) by Strata ...............................................................................................33 
Table 3 
Pharmacokinetic Parameters .........................................................................44 
Table 4 
Examples for Coding of Special Character Values for Clinical 
Laboratory Variables .....................................................................................56 
LIST OF FIGURES 
Figure 1 
Study Design Flow Chart ..............................................................................11 
 


Shire  
CONFIDENTIAL 
Page 7 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
ABBREVIATIONS 
λz 
first order rate constant associated with the terminal (log-linear) portion of 
the curve 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA  
analysis of covariance 
AST 
aspartate aminotransferase 
AUCtau  
area under the curve for the defined interval between doses 
BID  
twice daily 
BMD 
bone mineral density 
BMI 
body mass index 
BSA 
Body surface area 
CI 
confidence interval 
CL/F 
apparent oral clearance 
Cmax  
maximum concentration occurring at tmax 
CMH 
Cochran-Mantel-Haenszel 
DSQ  
Dysphagia Symptom Questionnaire 
DXA  
(DEXA) dual-energy X-ray absorptiometry 
eCRF 
electronic case report form 
EGD 
esophagogastroduodenoscopy 
EoE 
eosinophilic esophagitis 
EoE-QoL-A 
Adult Eosinophilic Esophagitis Quality of Life 
EQ-5D 
EuroQol 
EQ-5D-3L  
EuroQol-5 Dimensions 3-level 
EQ-5D-Y  
EuroQol 5 Dimensions Youth 
ET 
early termination 
EREFS  
EoE Endoscopic Reference Score 
FAS 
Full Analysis Set 
HPF 
high-powered field 
HRQoL 
health-related quality of life 
hs 
at bedtime 
IWRS 
Interactive web-based response system 
MedDRA  
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 


Shire  
CONFIDENTIAL 
Page 8 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
OBS 
oral budesonide suspension 
BOS 
budesonide oral suspension 
PD 
Pharmacodynamics 
PedsQL-EoE  
Pediatric Quality of Life Inventory – EoE 
PGI-S  
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PP  
per-protocol 
pc 
after meals 
qAM 
every morning 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS®  
statistical analysis system 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
t½ 
terminal half-life 
VAS 
Visual Analogue Scale 
Vz/F 
apparent volume of distribution associated with the terminal slope 
WHO 
World Health Organization 
 
 
 
 
 
 


Shire  
CONFIDENTIAL 
Page 9 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
SHP621-301 statistical analyses of efficacy, safety/tolerability, health related quality of life 
(HRQoL) and pharmacokinetic (PK) data as described in study Protocol Amendment 2, dated 
26 January 2018 and SHP621-301 Protocol Amendment 2 – Administrative Change, dated 
20 February 2019. Specifications for tables, figures, and listings are contained in a separate 
document. 
 


Shire  
CONFIDENTIAL 
Page 10 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
2. 
STUDY DESIGN  
2.1 
General Study Design 
This is a Phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of Oral Budesonide Suspension (OBS, also named 
BOS: Budesonide Oral Suspension) treatment administered twice daily (qAM, pc, and hs) for 
12 weeks. The study will be conducted in adolescents and adults, aged 11-55 years, inclusive, 
with eosinophilic esophagitis (EoE) and dysphagia. 
This study will consist of 3 periods: a 3- to 6-week screening period, 4-week single-blind 
placebo lead-in period, and a 12-week double-blind treatment period (see Figure 1). 
Approximately 420 subjects will be enrolled into the placebo lead-in period to allow for 
approximately 306 subjects to be randomized in a 2:1 ratio (approximately 204 and 102 per BOS 
and placebo treatment group, respectively) into the double-blind treatment period  to receive 
either BOS 2 mg twice daily (qAM, pc, and hs) or placebo twice daily (qAM, pc, and hs). The 
randomization will be performed centrally and stratified by age group (2 strata total: <18 years or 
≥18 years) and diet restriction for EoE or other health-related conditions (no diet restriction or 
any diet restriction). The stratification by age will ensure a minimum of 40 subjects in the 
adolescent group (11-17 years, inclusive). The stratification by age and diet will ensure balance 
between treatment groups for the respective stratification factors. 
Subjects who sign informed consent (or assent as applicable for subjects <18 years) will be 
screened (Visit -1). Subjects who meet eligibility criteria at the screening visit (Visit -1) and at 
the placebo lead-in visit (Visit 0) will enter the 4-week placebo lead-in period to assess their 
ability to comply with twice daily medication administration and assess whether there is a 
placebo response. Upon completion of the placebo lead-in period, subjects will return for the 
baseline visit (Visit 1) to confirm eligibility. Eligible subjects will be randomized 2:1 into the 
double-blind treatment period and will be evaluated for efficacy and safety at Weeks 8, 12, and 
16 (Visits 2-4). Subjects who fail to meet all eligibility criteria at Visits -1, 0, or 1 will be 
considered screen failures. Subjects cannot be rescreened once it is confirmed they do not meet 
inclusion/exclusion criteria unless the screen failure was due to a temporary condition or 
incomplete information at the time of consent (Visit -1) that would make rescreening at a later 
date appropriate (eg, concomitant medication that can be discontinued prior to rescreening; 
review of subject medical records provides new information with respect to the date of a prior 
esophageal dilation or diet change, or subject has a minor illness such as an upper respiratory or 
urinary tract infection). All reasons for rescreening (ie, reasons unrelated to inclusion/exclusion 
criteria) must be discussed and approved prospectively with the medical monitor. Subjects who 
discontinue will not be replaced. 
At the end of the 12-week double-blind treatment period (Visit 4), subjects who complete the 
study will have the opportunity to enroll in the treatment extension study. These subjects will 
continue on the blinded assigned treatment for 2-4 weeks as part of the screening prior to 
enrolling into the treatment extension study. 


Shire  
CONFIDENTIAL 
Page 11 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Subjects will be required to visit the site up to 6 times over up to a 22-week period. A safety 
follow-up phone call will occur 4 weeks following the last dose of investigational product for 
subjects who discontinue prematurely during the double-blind treatment period or who do not 
enroll in the treatment extension study. 
Figure 1 
Study Design Flow Chart 
 
Abbreviations: BID=twice daily; EGD=esophagogastroduodenoscopy; ET=end of treatment; OBS=oral budesonide 
suspension 
2.2 
Randomization 
Subjects will be randomized after confirmation of study eligibility in a ratio of 2:1 via a 
computer-generated randomization schedule to receive BOS 2 mg twice daily (qAM, pc, and hs) 
or placebo twice daily (qAM,pc, and hs). The randomization will be performed centrally via 
Interactive Web-based Response System (IWRS) and stratified by age group (2 strata total: 
<18 years or ≥18 years) and diet restriction for EoE or other health-related conditions (no diet 
restriction or any diet restriction). The stratification by age will ensure a minimum of 40 subjects 
in the adolescent group (11-17 years, inclusive). The stratification by age and diet restriction will 
ensure balance between treatment groups for the respective stratification factors. Fixed block 
randomization will be used to ensure subjects are assigned to BOS or placebo in a ratio of 
2:1 within strata.  
2.3 
Blinding  
2.3.1 
Blinding of Investigational Product 
This is a double-blind study. Blinding was achieved by means of identical appearance for BOS 
and placebo. Placebo consists of all components of the investigational product solution with the 
exception of budesonide. 


Shire  
CONFIDENTIAL 
Page 12 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
2.3.2 
Blinding of Study Data 
2.3.2.1 
SHP621-301 Study Conduct 
To protect the integrity of the study blind in both the SHP621-301 and SHP621-302 (treatment 
extension study of SHP621-301) studies, the post-randomization central histology and 
Dysphagia Symptom Questionnaire (DSQ) subject level data are segregated in separate case 
report forms that are not available to the blinded study team, study sites, and subjects until the 
final database lock of SHP621-302. Although treatment assignment will remain blinded to the 
blinded study team, study sites, and subjects, these subject level data could potentially identify 
which treatment a subject is randomized to (e.g., in individual subjects with substantial decreases 
in esophageal eosinophils from screening). An Unblinded Data Team (UBDT) was established to 
handle the processing, review, and validation of all histology and DSQ data to ensure 
consistency in the conduct of these activities and collection of data in electronic case report 
forms. The UBDT has restricted access to post-randomization histology and DSQ data during the 
conduct of the SHP621-301 and SHP621-302 studies, and the UBDT operates independently 
from the blinded study team, who are involved in study oversight or day-to-day conduct, and 
investigators at study sites. 
2.3.2.2 
SHP621-302 Study Conduct 
The SHP621-302 study entitled “A Phase 3, Multicenter, Double-blind Extension Study to 
Evaluate Maintenance of Efficacy of Oral Budesonide Suspension (BOS) and Long-term 
Treatment Effect of BOS in Adolescent and Adult Subjects (11 to 55 Years of Age, Inclusive) 
with Eosinophilic Esophagitis (EoE)” is limited to subjects who complete the induction study 
and meet additional eligibility criteria. As the extension study will be ongoing at the time of the 
final SHP621-301 database lock, Shire will ensure that the blinded SHP621-302 study team, 
study sites, and subjectss remain blinded to treatment assignment and subject level central 
histology and DSQ data collected in both the SHP621-301 and SHP621-302 studies through the 
final database lock in the SHP621-302 study.   
2.3.2.3 
SHP621-301 Study Results Reporting 
After the final SHP621-301 database lock, select team members will have restricted access to 
individual patient treatment assignment, and patient-level efficacy, safety and PK data from the 
SHP621-301 study for purposes of study reporting. A separate charter will be completed prior to 
the final database lock for the SHP621-301 study to define processes for communicating 
SHP621-301 aggregate treatment-level efficacy, safety and PK results and for restricting access 
to subject-level data to ensure that the SHP621-302 blinded clinical trial team (CTT) remains 
blinded through the final database lock for the SHP621-302 study.   


CONFIDENTIAL 
Page 13 
Shire 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
2.4 
Schedule of Assessments 
Table 1 below presents the schematic of the study design. 
Table 1 
Schedule of Assessments 
Procedures 
Screening 
Placebo 
Lead-in 
Treatment Phase 
Safety 
Follow-up 
Telephone 
Contactr 
Visit -1 
Visit 0 
Randomization 
Baseline/Visit 1 
Visit 2 
Visit 3 
Visit 4 or 
ETq 
Visit 5 
Week 
 -6 
0 
4 
8 
12 
16 
20 
Window 
≤6 weeks 
-- 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
Informed consent/assent 
X 
Medical history review 
X 
Inclusion/exclusion criteria review 
X 
X 
X 
Vital signsa; heightb and weightc assessment 
X 
X 
X 
X 
X 
X 
EGD with endoscopy score (EREFS) and 
biopsyd
X 
X 
DSQ training and issue of handset 
X
Retrieval of DSQ handset 
X 
DSQ completion 
Once daily completion 
DSQ compliance assessmente
X 
X 
X 
X 
X 
EQ-5Df 
X 
X 
PedsQL-EoE (subjects 11-17 years of age, 
inclusive) 
X 
X 
EoE-QoL-A (subjects ≥18 years of age) 
X 
X 
PGI-S 
X 
X 
X 
X 
Physical examination
X 
X 
X 
X 
X 
X 
Tanner Staging Assessmentg 
X 
X 


CONFIDENTIAL 
Page 14 
Shire 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
Table 1 
Schedule of Assessments 
Procedures 
Screening 
Placebo 
Lead-in 
Treatment Phase 
Safety 
Follow-up 
Telephone 
Contactr 
Visit -1 
Visit 0 
Randomization 
Baseline/Visit 1 
Visit 2 
Visit 3 
Visit 4 or 
ETq 
Visit 5 
Week 
 -6 
0 
4 
8 
12 
16 
20 
Window 
≤6 weeks 
-- 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
Clinical laboratory testsh
X
X 
X 
X 
X 
X 
Urinalysisi 
X 
X 
X 
X 
X 
X 
Pregnancy testj 
X 
X 
X 
X 
X 
X 
Morning cortisol (target 6:00-9:00 AM) 
X 
X 
X 
X 
ACTH stimulation testing 
X 
X 
Blood pharmacokinetic sampling (subjects 
≥18 years of age)k 
X 
X 
X 
DXA Scan  
(subjects 11-17 years of age, inclusive)l 
X 
X 
Randomizationm 
X
Investigational product supplied 
X 
X 
X 
X 
Xl 
Investigational product administrationo 
Twice-daily administration of investigational product 
Investigational product compliance assessment 
X 
X 
X 
X 
Concomitant medications and procedures 
recorded  
X 
X 
X 
X 
X 
X 
X 
Review of adverse eventsp 
X 
X 
X 
X 
X 
X 
ACTH=adrenocorticotropic hormone; DSQ=Dysphagia Symptom Questionnaire; 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; EREFS=EoE 
Endoscopic Reference Score; 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 
Vital signs will be assessed after the subject has been in a supine position for at least 5 minutes immediately prior to the assessment and will include blood pressure (systolic 
and diastolic), heart rate, respirations, and temperature. 


CONFIDENTIAL 
Page 15 
Shire 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
Table 1 
Schedule of Assessments 
Procedures 
Screening 
Placebo 
Lead-in 
Treatment Phase 
Safety 
Follow-up 
Telephone 
Contactr 
Visit -1 
Visit 0 
Randomization 
Baseline/Visit 1 
Visit 2 
Visit 3 
Visit 4 or 
ETq 
Visit 5 
Week 
 -6 
0 
4 
8 
12 
16 
20 
Window 
≤6 weeks 
-- 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
b 
Height to be collected at screening visit (Visit -1) and Visit 4 for all subjects. Stadiometers are required for subjects 11-17 years of age, inclusive, and will be used at Visit -1 
and 4. Height measurements for adolescent subjects (11-17 years of age, inclusive) should be measured in triplicate. 
c 
Weight measurements for adolescent subjects (11-17 years, inclusive) should be measured in duplicate. 
d 
Pretreatment endoscopy will be performed during the screening period (at least 2 weeks prior to placebo lead-in visit [Visit 0] to allow adequate time for processing and 
central review). Endoscopy should include esophageal (proximal, mid-, and/or distal), gastric, and duodenal biopsies. Final treatment evaluation EGD must include 
esophageal biopsies; gastric and duodenal biopsies may be done at the discretion of the investigator. Final treatment evaluation EGD should occur at or within (±) 7 days of 
the scheduled visit.  
e 
DSQ assessment includes completion of reports on DSQ handset (ie, eligibility reports and visit confirmations). 
f
Subjects 11-17 years of age, inclusive, will complete the EQ-5D-Y; subjects ≥18 years of age will complete the EQ-5D-3L. 
g 
Tanner staging assessments will be performed for all subjects aged ≥11 years until investigator confirms subject is post-puberty. 
h 
Clinical laboratory tests will include the following: alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total protein, albumin, glucose, 
blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, carbon dioxide, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, mean corpuscular volume, erythrocyte count, leukocyte count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet count. All subjects 
must fast overnight prior to collection. 
i
Urinalysis parameters will include glucose, protein, specific gravity, pH, nitrite, bilirubin, ketones, hemoglobin, urobilinogen, and leukocyte esterase. 
j
The serum pregnancy test will be performed for all female subjects at the screening visit (Visit -1) and final treatment evaluation (Visit 4). Urine pregnancy tests will be 
performed at all other visits. 
k 
Blood samples for pharmacokinetic analysis will be taken from adult subjects (aged ≥18 years). Subjects who do not participate in pharmacokinetic sampling will not be 
discontinued from the study and lack of participation will not be a considered protocol deviation. Blood samples for pharmacokinetic analysis can be obtained one time on any 
day starting 7 days after Visit 1 (Week 5) and through Visit 4 (Week 16). PK samples should be drawn, ideally, at pre-dose, 0.5 and 1 hour post-dose, and at additional post-
dose time points, if feasible (2, 3, 4, 6, 8, and 12 hours post-dose). 
l 
The baseline DXA scan may be performed any time during the placebo lead-in period after the subject has met all screening criteria and prior to blinded-treatment 
randomization. Baseline and post-treatment DXA scans should be performed using the same machine and software. Post-treatment DXA scan should occur at or within (±) 7 
days of the scheduled visit. 
m 
Randomization will occur via IWRS at the baseline visit (Visit 1) once the subject’s eligibility for study entry is confirmed. 
n 
Investigational product will be dispensed at Visit 4 to subjects who consent to enroll in the treatment extension study. 
o
Subjects will receive oral administration of 10 mL of investigational product twice daily (qAM, pc, and hs), with no ingestion of food or liquids permitted for 30 minutes after
study drug administration.
p 
AE assessments at each visit and physical examination must include specific assessments for signs of glucocorticoid excess (e.g., moon facies, acne, hirsutism, mood swings, 


CONFIDENTIAL 
Page 16 
Shire 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
Table 1 
Schedule of Assessments 
Procedures 
Screening 
Placebo 
Lead-in 
Treatment Phase 
Safety 
Follow-up 
Telephone 
Contactr 
Visit -1 
Visit 0 
Randomization 
Baseline/Visit 1 
Visit 2 
Visit 3 
Visit 4 or 
ETq 
Visit 5 
Week 
 -6 
0 
4 
8 
12 
16 
20 
Window 
≤6 weeks 
-- 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
insomnia, and depression). 
q 
If subject discontinues study prematurely, the evaluations listed for Visit 4 are to be performed as completely as possible. 
r
For subjects who withdraw from the study or do not continue into treatment extension study, a safety follow-up contact by phone will be performed 4 weeks following the last 
dose of investigational product. 


Shire  
CONFIDENTIAL 
Page 17 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
2.5 
Determination of Sample Size 
The co-primary efficacy endpoints are the following: 
•
Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available
esophageal levels at the final treatment period evaluation Visit 4 (Week 16)
•
Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score
(questions 2+3) from baseline to the final treatment period evaluation Visit 4 (Week 16)
Based on at least a 30-percentage-point reduction in DSQ score, there is an expected difference 
between treatment response proportions of 69% and 45% in the BOS 2 mg twice daily (qAM, pc, 
and hs) and placebo groups, respectively. The original protocol noted that a total of 228 subjects 
(152 subjects randomized to BOS and 76 subjects randomized to placebo) were required to 
achieve 90% power at the significance level of 0.0499 (2-sided) using a 2-group chi-square test 
with unequal allocation 2:1 to treatment groups (BOS 2 mg twice daily and placebo). With the 
specified number of subjects per treatment group, the study was originally powered at 99% 
assuming histological response proportions of 40% and 3% in the BOS 2 mg twice daily and 
placebo groups, respectively. The overall study power for the co-primary endpoints was 
estimated to be at least 85%. Therefore, approximately 228 (approximately 152:76 BOS and 
placebo subjects, respectively) were to be randomized in the study to allow for a loss of 
approximately 5% of subjects due to dropouts or invalid data. 
In Protocol Amendment 2, in order to ensure that a sufficient number of subjects complete this 
study and enroll in the treatment extension study SHP621-302, up to approximately 420 subjects 
will be enrolled in the placebo lead-in period to allow for approximately 306 subjects to be 
randomized into the double blind period of this study (approximately 204:102 BOS and placebo 
subjects, respectively). With a total of 306 randomized subjects in this study, using the same 
assumptions for the co-primary endpoints and the dropout rate, the overall study power for the 
coprimary endpoints is estimated to be at least 95%.  
The key secondary endpoint is the change in DSQ combined score (questions 2+3) from baseline 
to the final treatment period evaluation Week 16. Based on data from the Phase 2 study  MPI 
101-06 , the common standard deviation for change in DSQ combined score among similar EoE 
subjects following 12 week treatment of BOS is 13 points. Assuming a 5% dropout rate in each 
group and a common standard deviation (SD) of 13 points, a total sample size of 306 
(approximately 204:102 BOS and placebo subjects, respectively) will have at least 90% power to 
detect a treatment difference of 5.3 points in the change of DSQ combined score from baseline to 
the final treatment period evaluation between treatment groups, using a 2-sided t-test at a 
significance level of 0.049. 
2.6 
Multiplicity Adjustments for Type I Error Control 
The study will be deemed successful if each of the co-primary efficacy endpoints are achieved. A 
very minimal fraction of alpha (0.0001) was spent at the interim analysis (refer to Section 14 for 
interim analysis) as the study was not stopped due to the interim results. The final analysis will 
use 4.99% for each of the co-primary endpoints in order to preserve an overall type I error at 
5% level. 


Shire  
CONFIDENTIAL 
Page 18 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
A hierarchical testing procedure will be used to control the Type I error for the multiple 
endpoints tested at α =0.049. For a test to be considered statistically significant within the testing 
hierarchy, it must be statistically significant at the 0.0499 level, and all previous tests within the 
testing hierarchy must be statistically significant at the 0.0499 level. The testing hierarchy is as 
follows: 
1. Histologic response and dysphagia symptom response (co-primary endpoints)
2. Change in DSQ combined score (questions 2+3) from baseline to the final treatment period
evaluation Week 16 (key secondary endpoint)


Shire  
CONFIDENTIAL 
Page 19 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
3.
OBJECTIVES
3.1 
Primary Objectives 
The co-primary objectives of the study are to demonstrate in a placebo-controlled study that: 
•
BOS induces a histologic response (eosinophilic count ≤6/HPF) in adolescent and adult
subjects with EoE over a 12-week course of therapy.
•
BOS reduces dysphagia, as measured by the DSQ, by at least 30% from baseline in
adolescent and adult subjects with EoE over a 12-week course of therapy.
3.2 
Secondary Objectives 
The key secondary objective of this study is: 
•
BOS reduces dysphagia, as measured by the DSQ score from baseline to the final
treatment period evaluation at Visit 4 (Week 16).
Additional secondary objectives of the study are: 
•
To assess the response of endoscopically identified esophageal features to BOS as
compared to placebo as measured by the EoE Endoscopic Reference Score (EREFS)
•
To explore other responding criteria based on histology and DSQ
•
To assess the impact of BOS on pain, as measured by the DSQ pain score
•
To evaluate the safety and tolerability of BOS over a 12-week course of therapy
•
To obtain BOS pharmacokinetic data in adult subjects with EoE
3.3 
Exploratory Objectives 


Shire  
CONFIDENTIAL 
Page 20 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
4.
SUBJECT POPULATION SETS
4.1 
Screened Set 
The Screened Set will consist of all subjects who have signed informed consent, and have 
conducted screening assessments. 
4.2 
Full Analysis Set 
The full analysis set (FAS) will include all randomized subjects who received at least 1 dose of a 
double-blind investigational product. The FAS is to be used in efficacy data analyses in which 
subjects will be analyzed according to their assigned randomized treatment, regardless of the 
treatment actually received. 
4.3 
Safety Analysis Set 
The safety analysis set will consist of all subjects who have taken at least 1 dose of any double 
blind investigational product. The Safety Set is to be used for all safety analyses in which 
subjects will be analyzed according to the treatment they received. 
4.4 
Randomized Set  
The randomized set will include all subjects who was randomized into the double-blind 
treatment period. 
4.5 
Per-protocol Set 
The per-protocol set (PP) will include all subjects in the FAS excluding subjects with major 
protocol deviations. The PP set will be identified prior to unbinding the treatment assignments by 
a team consisting of, at a minimum, a physician and a statistician from Shire. 
Major protocol deviations that may lead to exclusion from the Per-protocol Set, are as follows, 
but not limited to: 
1. Violations of inclusion and/or exclusion criteria
2. Compliance with study medication
A subject, who has less than 70% or greater than 130% overall compliance during the
double-blind treatment period with his/her assigned treatment
3. Study Treatment Administration/Dispensing
A subject who had incorrect IP treatment kit ID assigned/dispensed or was administered/
dispensed “damaged” IP (e.g., IP with unapproved temperature excursion)
4. Prohibited concomitant medications
• Significant use of CYP450 3A4 inhibitors (eg, ketoconazole, grapefruit juice) during
the treatment period
• Significant use of excluded medication while participating in the study


Shire  
CONFIDENTIAL 
Page 21 
SHP621-301 Statistical Analysis Plan 
Budesonide oral suspension 
11 March 2019 
• Initiation of swallowed topical corticosteroid for EoE or systemic corticosteroid for
any condition within 4 weeks of the final EGD
• Significant changes in uses of PPIs, H2 antagonists, antacids, or leukotriene inhibitors
for any condition during the treatment period
5. Accidental Unblinding
Subject unblinding occurs when a subject’s randomization drug code is broken
(accidentally or not per protocol) or their post-randomization pathology or DSQ results
are unblinded prior to completion of double-blind treatment period
4.6 
Pharmacokinetic Set and Pharmacokinetic Parameter Set 
The pharmacokinetic (PK) Set will include all subjects in the safety set who received BOS 
treatment and provided at least one quantifiable plasma concentration of budesonide. The PK 
Parameter Set will include all subjects in the PK set for whom budesonide PK parameter(s) can 
be estimated using noncompartmenal methods.  


Shire  
CONFIDENTIAL 
Page 22 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
5. 
SUBJECT DISPOSITION 
Listing of Screen Failures (subjects who were screened in screening period, and subjects who 
were in placebo lead-in period but not randomized, separately) will be presented along with 
reasons for screen failure during screening period and placebo lead-in period. 
The number of subjects included in each subject set (i.e., Screened, FAS, Safety, PP and PK) will 
be summarized by treatment group.  
The number and percentage of subjects who completed and prematurely discontinued during the 
12-week Double-blind Treatment Phase will be presented for each treatment group and overall 
for the FAS. Reasons for premature discontinuation from the Double-blind Treatment Phase as 
recorded on the study completion page of the eCRF will also be summarized (number and 
percentage) by treatment group. The number of subjects who consented to enroll into the 
extension study SHP621-302 will also be reported in the disposition summary. All subjects who 
prematurely discontinued during the Double-blind Treatment Phase will be listed by 
discontinuation reason for FAS Subjects. 
Number of and percentage of subjects who prematurely discontinued during the screening and 
placebo lead-in period will be summarized. 
Supporting listings of the discontinuation data from each study period (screening, placebo 
lead-in and double-blind treatment period) will be provided along with the information on 
adverse events (AE) that caused discontinuation (if subjects discontinued due to AE). 
The number of subjects screened, entered placebo lead-in, randomized and completed will be 
tabulated by site.  In addition, the duration of enrollment, in days, will be summarized for each 
site, and overall.  Duration of 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). 


Shire  
CONFIDENTIAL 
Page 23 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
6. 
PROTOCOL DEVIATIONS 
The number and percentage of subjects reporting any protocol deviations and the incidence of 
each deviation type will be summarized by treatment group and overall for the  FAS and 
individual responses will be presented in a data listing for all enrolled subjects. Protocol 
deviations will be summarized by deviation level (major or minor) and by type (ICH/GCP or 
Protocol Deviation) within each deviation level. Full list of deviations will be documented in a 
separate file. 


Shire  
CONFIDENTIAL 
Page 24 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Baseline characteristics for endpoints assessed by EGD with endoscopy biopsy will be 
determined using assessments at the Screening Visit (Visit -1). Other demographic and baseline 
characteristics will be determined using assessments at the Baseline Visit 1 (Week 4) or the last 
observation prior to the first dose of investigational product during double-blind treatment phase, 
whichever is later. Descriptive summaries of demographic and baseline characteristics will be 
presented by treatment group for the FAS and Safety Set.  
Subject demographic and baseline characteristics including age, age group (<18 years, 
>=18years), sex, race, ethnicity, weight, height, BMI,  Tanner stage, diet stratification (no diet 
restriction or any diet restriction), peak eosinophil count at three esophageal levels and overall,  
DSQ score, histopathologic epithelial features combined total score ratio for grade and stage, and  
total endoscopic reference score, will be summarized by treatment group for the FAS. If there are 
multiple measurements of weight and height collected on the same date (eg adolescent subjects), 
then the average of multiple measurements will be used as baseline. 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 number of subjects in each category and the percentage of subjects out of the total in the 
respective analysis set. 
Height and weight will be used to calculate BMI and BSA using the formula below: 
 
 
 
BMI = weight [kg]/(height [m])2                        
A listing will be created to show all the demographics and baseline characteristics for all subjects 
in the FAS. 
7.1 
General Medical History 
The investigator will record all clinically or medically relevant information regardless of how 
much time has elapsed since the date of any diagnosis into the CRF. General medical history 
data will be summarized by treatment group for the FAS. General medical history findings will 
also be listed for all subjects in FAS. Medical history will be coded using MedDRA Version 
18.0. 
7.2 
EoE Medical History 
The following information associated with EoE history will be recorded in the eCRF at the 
screening visit: 
• Prior EoE Procedures (each with yes/no answer): 
– Endoscopy with Biopsy 
– Endoscopy with dilation 


Shire  
CONFIDENTIAL 
Page 25 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
– Gastrointestinal Tube Placement 
– Nasogastric Tube Placement 
– Diet Restriction 
• Foods being eliminated from diet (yes – food is eliminated, no – food is not eliminated): 
– Egg, milk products, soy, peanuts/tree nuts, seafood, wheat, other. 
• Was subject on liquid diet in last 3 months? (yes/no) 
• Symptoms Related to EoE (each with yes/no answer): 
– Heartburn, chest pain, regurgitation, abdominal pain, nausea, eating problems, 
food impaction, weight loss, vomiting. 
• Prior EoE Therapies (each with yes/no answer): 
– Diet therapy 
o Histologic Response (< 15 eos/hpf) to Diet Therapy (yes/no/not 
assessed) 
– Systemic (oral) corticosteroids 
o Histologic Response (< 15 eos/hpf) to Systemic (oral) corticosteroids 
Therapy (yes/no/not assessed) 
– Budesonide suspension 
o Histologic Response (< 15 eos/hpf) to Budesonide suspension 
(yes/no/not assessed) 
– Fluticasone aerosol 
o Histologic Response (< 15 eos/hpf) to Fluticasone aerosol (yes/no/not 
assessed) 
– Other Medication 
o Histologic Response (< 15 eos/hpf) to Other Medication (yes/no/not 
assessed) 
EoE history will be summarized by treatment group for the FAS, and will also be listed for all 
the subjects in the FAS. 


Shire  
CONFIDENTIAL 
Page 26 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
For all treated subjects, including those who terminated early, treatment exposure is the duration 
between the first dose date and last dose date: 
Duration of exposure (days) = (Last dose date – First dose date +1). 
In addition, total dose administered (mg) and average daily dose will be calculated and 
summarized by treatment group: 
Actual Average Daily Dose (mg) = Sum of the doses (mg)/Duration of exposure (days). 
Descriptive statistics (n, mean, SD, Q1, Q3, minimum, median, and maximum) will be presented 
by treatment group for duration of exposure and average daily dose. 
A listing will be created by subject and treatment group and will provide exposure for the Safety 
Set. 
8.2 
Measurement of Treatment Compliance 
Compliance with study medication will be assessed overall across all study visits. Subjects will 
be instructed to bring any remaining study medication and empty bottles to each study visit. 
Designated site staff will evaluate compliance by questioning the subject and evaluating the 
amount of study medication remaining.  The subject will be questioned regarding any 
discrepancies. 
When a bottle is returned, the site will measure the amount of investigational product remaining 
in the bottle in centimeters. The volume taken in mL for each bottle can be determined in 
centimeters based on the equation below: 
Volume in mL=210 cm3 – [22.4 cm2 x height 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 ). 
Subjects will be considered compliant with study medication if they received no less than 
70% and no more than 130% of the intended dosing as assessed at the final Treatment Period 
Visit. 


Shire  
CONFIDENTIAL 
Page 27 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Study drug exposure and compliance will be summarized, separately and combined, by treatment 
for the FAS during double blind period. In addition, study drug exposure and compliance will be 
summarized, separately and combined, by treatment for the Safety Set beginning with subject 
randomization. The overall approximate compliance rates, and total dose taken (mg) will be 
summarized using descriptive statistics. The total dose taken will be the approximate amount of 
investigational product taken (mL) as collected from eCRF data during the corresponding 
analysis period for FAS and the Safety Set. The n and percentage of subjects whose compliance 
is <70%, ≥70% and ≤130% (with sub categories of ≥70% and ≤100%,  and >100% and ≤130%),  
or >130% will be summarized. 


Shire  
CONFIDENTIAL 
Page 28 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
9. 
PRIOR AND CONCOMITANT MEDICATION  
World Health Organization-Drug Dictionary (WHODRUG) as of March 2015 will be used to 
classify prior and concomitant medications by therapeutic class. 
Prior medication is defined as any medication with the start and stop date prior to the date of the 
first dose of investigational product (Visit 1). Concomitant medication is defined as any 
medication with a start date prior to the date of the first dose of investigational product (Visit 1) 
and continuing after the first dose of investigational product (Visit 1) or with a start date between 
the dates of the first dose of investigational product (Visit 1) and the Safety Follow-up Contact, 
or with a start date between the dates of the first dose of investigational product and 31 days after 
last dose of SHP621-301 investigational product for subjects who do not have a Safety 
Follow-up Contact. Medication that starts after the first dose of SHP621-302 investigational 
product (i.e., Visit 1 in the SHP621-302 study) will be collected in SHP621-302 database and 
will not be considered as concomitant medication in SHP621-301. The definition of concomitant 
medication is similar to the TEAE definition in Section 11.1.  
Medical/surgical procedures performed prior and during the treatment will be recorded on the 
eCRF, along with the date, and reason for the procedure.  
Both prior/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 Full Analysis Set.  Medications/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/concomitant medication and medical/surgical procedures will be listed. 


Shire  
CONFIDENTIAL 
Page 29 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
10. EFFICACY ANALYSES 
The primary, key secondary, and secondary efficacy analyses will be performed on the FAS and 
presented by treatment group. The most recent non-missing measurement (scheduled or  
unscheduled) collected prior to first dose of study drug administered in double-blind phase will 
be used as the baseline for all efficacy analyses. 
10.1 
Primary Efficacy Endpoint(s) and Analysis  
10.1.1 
Definition of Co-primary Efficacy Endpoints 
The co-primary efficacy endpoints are the following: 
• Histologic response, defined as a peak eosinophil count of ≤6/HPF across all available 
esophageal levels at the final treatment period evaluation at Visit 4 (Week 16). 
• Dysphagia symptom response, defined as ≥30% reduction in the DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation at Visit 4 
(Week 16). 
The derivation of co-primary endpoints is specified at below: 
Histology Response: 
An EGD with endoscopy biopsy will be performed during the study at the screening period and 
final treatment period evaluation Visit 4 (Week 16) or Early Termination (ET) Visit; the peak 
eosinophil count per high power field across all available esophageal levels at the final treatment 
period evaluation will be used as a primary measure of efficacy. If subject has peak eosinophil 
count of ≤6/HPF across all available levels then histology response variable will be set to 1 and 
subject will be considered as a histology responder. Otherwise, histology response will be set to 
0 and subject will be treated as a non-responder. Subjects that discontinue the Double-blind 
Treatment Phase early and who do not have a  peak eosinophil count available at Visit 4 
(Week 16) will be classified as histology non-responders. 
Dysphagia Symptom Response:  
Subject’s dysphagia symptoms will be evaluated using a DSQ ePRO device. The questionnaire 
will be completed each evening by subjects during the Screening Period, during the 4-week 
Baseline Period, and during the 12-week Treatment Period. Appendix 1 shows the daily DSQ 
consisting of four questions with corresponding potential point scoring in parentheses. Subjects 
are prompted to respond to Questions 1 first, if subjects respond positively to Question 1, then 
they are prompted to respond to Question  2, if subjects respond positively to Question 2, they 
are prompted to respond to Questions 3 and 4. 
Calculations of DSQ combined score at each scheduled visit will be based on daily ePRO entries 
during a 2-week interval prior to each study visit. The DSQ combined score will be calculated by 
summing the scores of responses to questions 2 and 3 only. Responses to Questions 1 and 4 will 
not be included to DSQ combined score calculation. 


Shire  
CONFIDENTIAL 
Page 30 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Percent change from baseline to Visit 4 (Week 16) in DSQ combined score will be calculated as 
(DSQ combined score at Week 16 – DSQ combined Score at Baseline)/ DSQ combined score at 
Baseline*100. 
Dysphagia Symptom Response (co-primary efficacy variable) will be set to 1 (responder) if 
subject achieved a minimum of 30% reduction in DSQ combined score between baseline and 
Week 16, i.e. percent change from baseline from above calculation is <=-30. Otherwise, if 
percent change from baseline is >-30 or subject discontinue Double-blind Treatment Phase early 
and DSQ combined score at Visit 4 (Week 16) is incalculable, a subject will be classified as 
non-responder. 
10.1.2 
Primary Analysis of Co-primary Efficacy Endpoints 
The co-primary efficacy endpoints will be analyzed based on the FAS. DSQ combined score 
derivation, which defines dysphagia symptom response, will be based on the missing DSQ daily 
diary data handling method described in Appendix 1. Each of the co-primary efficacy endpoints 
is a binary response (i.e., responders vs non-responders); the co-primary endpoints will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusting for age group (either 
<18 years or ≥18 years) and diet restriction for EoE or other health-related conditions (no diet 
restriction or any diet restriction). The adjusted odds ratio of being a responder on each of the 
co-primary endpoints for the BOS 2 mg twice daily group vs placebo group, associated 95% 
confidence interval (CI), and p-values based on CMH test will be provided. Subjects who 
withdraw without providing efficacy data at the final treatment period evaluation (Visit 4, 
Week 16) will be classified as non-responders in the primary efficacy analysis. 
Additionally, the proportion of responders based on each of the co-primary endpoints for each 
treatment group will be summarized, and their respective 95% CI will be reported. The CMH 
adjusted difference in the proportion of responders between the 2 treatment groups and the 
corresponding 95% Newcombe CI will also be summarized. If the Newcombe CI is not available 
due to low response rate in either treatment group the Mantel-Haenszel confidence interval will 
be used. DSQ responder frequencies and percentages will be summarized for each treatment 
group at the final treatment period evaluation by baseline DSQ severity level subgroups 
(i.e., 0-21, 22-42, 43-63, 64-84).  
10.1.3 
Sensitivity and Other Analyses of Co-primary Efficacy Endpoints 
The following sensitivity and supportive analyses will be performed for the co-primary endpoints 
to evaluate the robustness of the results from the primary analysis methods: 
I. 
Each of the co-primary efficacy endpoints will be analyzed based on FAS using a logistic 
regression with the effects of treatment group, age group (either <18 years or ≥18 years) 
and diet restriction for EoE or other health-related conditions (no diet restriction or any 
diet restriction). The odds ratio of being a responder on each of the co-primary endpoints 
for the BOS 2 mg twice daily group vs placebo group and associated 95% confidence 
interval (CI) will be estimated from the final model. Subjects who withdraw without 
providing efficacy data at the final treatment period evaluation (Visit 4, Week 16) will be 
classified as non-responders in the primary efficacy analysis. If there are convergence 
problems with logistic regression, Firth logistic regression will be used. 


Shire  
CONFIDENTIAL 
Page 31 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
II. 
CMH analyses will be repeated using the  PP set. 
III. 
CMH analyses will be repeated by considering subjects who withdraw without providing 
efficacy data at the final treatment period evaluation Visit 4 (Week 16) to be classified as 
responders. 
IV. 
CMH analysis will be repeated based on FAS using four different missing data handling 
methods to assess the impact of missing DSQ daily diary data on dysphagia symptom 
response as follows: 
Missing data handling method 1 for Dysphagia Symptom Response: Subjects who are 
missing 4 days or more of DSQ daily diary data in either week or 7 days in the last 2 weeks 
at a post-baseline visit, are treated as non-responders without applying the window shifting 
rule. 
In the case of missing DSQ daily diary data, DSQ data for a given day will be considered 
missing if the diary is not reported or if the diary is reported but the answer to Question 1 is 
“No”. If fewer than 8 reported diaries are available within the 14-day period prior to the Baseline 
Visit 1, the window shift rule for baseline DSQ calculation for the primary analysis will be 
performed: the most recent 8 reported diaries in a consecutive 14-day period will be used to 
calculate the baseline DSQ combined score. Such 14-day periods cannot be shifted for more than 
7 days (not including the study visit day) when calculating DSQ combined score at Baseline 
Visit 1. For the 14-day period used to calculate the DSQ combined score at the post-baseline 
visits Visit 2 (Week 8), Visit 3 (Week 12), and Visit 4 (Week 16)/Termination Visit, 4 out of 
7 days in each of the last 2 weeks are needed to calculate a DSQ combined score. The window 
shift rule for post-baseline data, which is described in Appendix 1 for the primary analysis will 
not be applied for this sensitivity analysis. Subjects who have missing data for at least 4 days in 
either of the last 2 weeks, or have missing data for at least 7 days in the last 2 weeks (ie, the 
14-day period), will be treated as non-responder of Dysphagia Symptom Response, and the 
corresponding DSQ combined score at the visit will be incalculable. 
Missing data handling method 2 for Dysphagia Symptom Response: Window shift rule is 
applied for post-baseline data (14-day periods cannot be shifted for more than 7 days at 
every visit). 
In the case of missing DSQ daily diary data, DSQ data for a given day will be considered 
missing if the diary is not reported or if the diary is reported but the answer to Question 1 is 
“No”. If fewer than 8 reported diaries are available within the 14-day period prior to the Baseline 
Visit 1, Visit 2 (Week 8), Visit 3 (Week 12) or Visit 4 (Week 16), the window shift rule for 
baseline or Week 16 DSQ calculation in the primary analysis will be performed (see 
Appendix 1), the most recent 8 reported diaries in a consecutive 14-day period would be used to 
calculate the DSQ combined score. Such 14-day periods cannot be shifted for more than 7 days 
(not including the study visit day) when calculating the DSQ combined score at Baseline Visit 1 
or Visit 4 (Week 16). If the DSQ combined score at Visit 1 or Visit 4 (Week 16) is incalculable, 
a subject will be classified as a non-responder. 


Shire  
CONFIDENTIAL 
Page 32 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Missing data handling method 3 for Dysphagia Symptom Response: Worst case imputation 
for DSQ combined score when the answer to Question 1 is “No”. 
For days the response to diary Question 1 is “No” during the 14-day period prior to the Baseline 
Visit 1 and the Final Treatment Period Evaluation Visit 4, the missing sum of points from 
question 2+3 for those days will be imputed with the worst (maximum) value of the sum of 
points from questions 2+3 from non-missing days during that 14-day period, After imputing the 
sum of points from questions 2+3  with the worst scores when the answer to Question 1 is “No”, 
the above missing data handling method 1 will be applied to post-baseline data, for subjects 
with missing data for at least 4 days in either of last 2 weeks prior to Visit 2 (Week 8), Visit 3 
(Week 12) or Visit 4 (Week 16), or for subjects with missing data for at least 7 days in the last 
2 weeks (ie, the 14-day period) before these visits being treated as non-responders. In such cases, 
the corresponding DSQ combined score at Week 16 will be incalculable.  
For the 14-day period used to calculate the DSQ score at the Baseline Visit 1, the window shift 
rule for baseline DSQ calculation in the primary analysis will be performed: if fewer than 
8 reported diaries are available within the 14-day period prior to the Baseline Visit 1, the window 
shift rule for baseline DSQ calculation in the primary analysis will be performed to calculate 
baseline DSQ score, and such 14-day periods cannot be shifted for more than 7 days. No 
imputation will be performed when calculating DSQ score at Baseline Visit 1. 
Missing data handling method 4 for Dysphagia Symptom Response: Best case imputation for 
DSQ combined score when answer to Question 1 is “No”. 
For days the response to diary Question 1 is “No” during the 14-day period prior to the Baseline 
Visit 1 and the Final Treatment Period Evaluation Visit 4, the missing sum of points from 
question 2+3 for those days will be imputed with the best (minimum) value of the sum of points 
from questions 2+3 from non-missing days during that 14-day period, After imputing the sum of 
points from questions 2+3  with the best scores when the answer to Question 1 is “No”, the 
above missing data handling method 1 will be applied to post-baseline data, for subjects with 
missing data for at least 4 days in either of last 2 weeks prior to Visit 2 (Week 8), Visit 3 
(Week 12) or Visit 4 (Week 16), or for subjects with missing data for at least 7 days in the last 
2 weeks (ie, the 14-day period) before these visits being treated as non-responders. In such cases, 
the corresponding DSQ combined score at Week 16 will be incalculable. 
For the 14-day period used to calculate the DSQ score at the Baseline Visit 1, the window shift 
rule for baseline DSQ calculation in the primary analysis will be performed: if fewer than 
8 reported diaries are available within the 14-day period prior to the Baseline Visit 1, the window 
shift rule for baseline DSQ calculation in the primary analysis will be performed to calculate 
baseline DSQ score, and such 14-day periods cannot be shifted for more than 7 days. No 
imputation will be performed when calculating DSQ score at Baseline Visit 1. 
V. 
Distribution-based imputation. 
If at least 5% subjects or more have missing responses for either of the co-primary efficacy 
endpoints in either treatment group, the missing responses for co-primary efficacy endpoints will 
be imputed using distribution-based method. 


Shire  
CONFIDENTIAL 
Page 33 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
The subjects with missing responses of co-primary efficacy endpoints will be assigned 
randomly according to the distribution of responders with available data for each of the 
co-primary endpoints (i.e., those with non-missing data) across the 2 treatment groups by strata 
(see Table 2). 
Table 2 
Percentage of Responders for All Available Data (i.e., Non-missing Data) by 
Strata 
Strata 1 
Strata 2 
No 
Yes 
Diet 
<18 years 
X00% 
X01% 
Diet 
≥18 years 
Y00% 
Y01% 
No Diet 
<18 years 
X10% 
X11% 
No Diet 
≥18 years 
Y10% 
Y11% 
 
 
For instance, if there are N subjects with missing data in strata (age <18 years and Diet), then 
X00%*N subjects will be randomly assigned as non-responders and X01%*N subjects will be 
randomly assigned as responders. 
Conversely, if there are M subjects with missing data in strata (age ≥18 years and diet), the 
Y00%*M subjects will be randomly assigned as non-responders and Y01%*M subjects will be 
randomly assigned as responders. Once the missing data are imputed a logistic regression model 
will be fitted with the binary outcome (responders vs non-responders) as the dependent variable 
and the age group, diet group, and the treatment group as independent variables. The odds ratio 
of being a responder on each of the co-primary endpoints for the BOS 2 mg twice daily group vs 
placebo group and associated 95% confidence interval (CI) will be estimated from the final 
model. 
VI. 
CMH analysis based on multiple imputations (MIs). 
If at least 5% subjects or more have missing responses for either of the co-primary efficacy 
endpoints in either treatment group, the missing responses for co-primary efficacy endpoints will 
be imputed with multiple imputations (MIs) by using SAS procedures PROC MI and PROC 
MIANALYZE. Multiple imputations (MIs) wiht the CMH analysis will be handled as follows: 
• Impute missing values using the logistic regression model from effects of treatment 
group, age group (either <18 years or ≥18 years) and diet restriction for EoE or other 
health-related conditions (no diet restriction or any diet restriction). 
• Repeated the process K (K=50) times, using the procedure described above to form K 
imputed completed datasets. 


Shire  
CONFIDENTIAL 
Page 34 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
• CMH analysis will be conducted to each imputed dataset adjusting for age group (either 
<18 years or ≥18 years) and diet restriction for EoE or other health-related conditions (no 
diet restriction or any diet restriction). The values of the general association test statistic 
from the CMH analysis will be transformed using the Wilson-Hilferty transformation to 
create a normally-distributed Z scale statistic. 
𝑍=
(𝐶𝑀𝐻)
1
3 −7
9
(2
9)
1
2
 
• Mean of the estimated co-primary endpoints from K imputations, and the resulting 
transformed  Z values will be combined using PROC MIANALYZE in SAS to yield the 
corresponding p-values. 
10.1.4 
Subgroup Analyses of Co-primary Efficacy Endpoints 
For the FAS, subgroup analyses of the co-primary efficacy endpoints will be performed in a 
manner similar to that of the primary analysis within each of the following subgroups: 
• Age as stratification factor (<18, and ≥18 years) 
• Diet restriction for EoE or other health-related conditions as stratification factor (no diet 
restriction or any diet restriction) 
For the subgroup analysis on age, co-primary endpoints will be analyzed using the CMH test 
adjusting for diet restriction for EoE or other health-related conditions (no diet restriction or any 
diet restriction). For the subgroup analysis on diet restriction for EoE or other health-related 
conditions, co-primary endpoints will be analyzed using the CMH test adjusting for age group 
(either <18 years or ≥18 years).  
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis  
10.2.1 
Definition of Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is defined as the change in DSQ combined score (questions 
2+3) from baseline to the final treatment period evaluation Week 16. The key secondary efficacy 
endpoints will be analyzed based on the FAS. 
10.2.2 
Primary Analysis of Key Secondary Efficacy Endpoint   
The same missing data approach described in Appendix 1 for the primary analysis of dysphagia 
symptom response (one of the co-primary endpoints) will be applied to the  primary analysis of 
key secondary efficacy endpoint. The change from baseline DSQ combined score at the final 
treatment period evaluation Week 16 will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment group (BOS vs Placebo) and age group (<18, ≥18 years of 
age) as factors and the baseline DSQ score as a continuous covariate. In addition, descriptive 
summary statistics, frequency distribution table and histogram will be reported for DSQ 
combined score at baseline, DSQ combined score at final treatment period evaluation Week 16, 
and  the change of DSQ combined scores from baseline to Week 16. 


Shire  
CONFIDENTIAL 
Page 35 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
If the DSQ combined score at Week 16 for a subject is incalculable after missing data handling, 
the change of DSQ score for this subject will be considered as missing in ANCOVA analyses. 
10.2.3 
Sensitivity Analyses of Key Secondary Efficacy Endpoint 
To assess the impact of missing DSQ daily diary data on the change in DSQ combined score 
(questions 2+3) from baseline to the final treatment period evaluation Week 16, ANCOVA 
model analysis for the primary analysis of key secondary efficacy endpoint will be repeated 
based on FAS using four missing data handling methods described in sensitivity analyses IV of 
Section 10.1.3, if the DSQ combined score at Week 16 for a subject is incalculable after missing 
data handling method 1 or method 2, the change of DSQ combined score for this subject will be 
considered as missing in ANCOVA analyses. 
If at least 10% subjects or more are missing DSQ combined score at Week 16 in either treatment 
group, the effect of missing patterns on treatment effect (i.e., missing due to no solid food taken 
or reasons to drop out early) will be assessed and identified,  and an overall treatment effect will 
be obtained from the pattern mixture analysis. 
10.2.4 
Subgroup Analysis of Key Secondary Efficacy Endpoint   
For the FAS, subgroup analysis of the key secondary efficacy endpoints will be performed in a 
manner similar to that of the primary analysis within the following age subgroups: 
• Age as stratification factor (<18, and ≥18 years) 
Key secondary efficacy endpoint will be analyzed using the ANCOVA model analysis with 
treatment group as factors and the baseline DSQ combined score as a continuous covariate.   
10.3 
Other Secondary Efficacy Endpoint(s) and Analysis 
The additional secondary efficacy endpoints are the following: 
• Change in total endoscopy score, as measured by the EREFS classification, from baseline to 
the final treatment period evaluation Week 16 (continuous) 
• Peak eosinophil count <15/HPF across all available esophagus levels at the final treatment 
period evaluation Week 16 (binary) 
• Peak eosinophil count ≤1/HPF across all available esophagus levels at the final treatment 
period evaluation Week 16 (binary) 
• Change from baseline in the peak eosinophil count to the final treatment period evaluation 
Week 16 for each available esophageal level (proximal, mid-, and distal) (continuous) 
• Change from baseline in the histopathologic epithelial features combined total score (grade 
and stage) to the final treatment period evaluation Week 16 (continuous) 
• Dysphagia symptom response (binary response), defined as a ≥50% reduction in the DSQ 
combined score (questions 2+3), from baseline to the final treatment period evaluation 
Week 16 (binary) 
• Change from baseline in the DSQ combined score (questions 2+3) over time including post 
baseline visits (continuous) 


Shire  
CONFIDENTIAL 
Page 36 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
• Cumulative distribution function curves for the change and the percent change in the DSQ 
combined score from baseline to the final treatment period evaluation Week 16 (continuous) 
• Overall binary response I, defined as a reduction in the DSQ combined score of ≥30% from 
baseline to the final treatment period evaluation Week 16 and a peak eosinophil count of 
≤6/HPF across all esophageal levels at the final treatment period evaluation Week 16 (binary) 
• Overall binary response II, defined as a reduction in the DSQ combined score of ≥50% from 
baseline to the final treatment period evaluation Week 16 and a peak eosinophil count of 
≤6/HPF across all esophageal levels at the final treatment period evaluation Week 16 (binary) 
• Change in the DSQ + pain score (questions 2+3+4) from baseline to the final treatment 
period evaluation Week 16 (continuous) 
• Change in the DSQ pain score (question 4) from baseline to the final treatment period 
evaluation Week 16 (continuous) 
The binary response endpoints will be analyzed using the same logistic model as the co-primary 
efficacy endpoints. Subjects who prematurely discontinued without efficacy evaluations at final 
treatment visit will be considered as non-responders for the analysis. If there are convergence 
problems with logistic regression, Firth logistic regression will be used. 
Refer to Appendix 5 for the analysis for histopathologic epithelial features. Other continuous 
endpoints will be analyzed as a change from baseline using an ANCOVA model that includes 
treatment group and age group as factors and baseline score as a covariate. In addition, 
descriptive summary statistics will be reported for DSQ combined score at baseline, at each post 
baseline assessment visit, and change from baseline at post baseline assessment visit. 
The analyses for all secondary efficacy endpoints (including the key secondary efficacy 
endpoint) will be carried out on FAS using 2-sided tests at the 5% level of significance. For each 
of the secondary efficacy endpoints, the treatment difference, corresponding 95% CI for the 
difference, and treatment comparison p-value for testing the null hypothesis of zero treatment 
effect based on the final statistical model (i.e., either logistic regression model or ANCOVA 
model) will be provided. 
Refer to Appendix 1 to derive the DSQ combined score, DSQ + pain score, DSQ pain score, 
DSQ question 2 score and  DSQ question 3 score at each scheduled visit using the same rules 
applied for the primary analysis of DSQ response. Descriptive summary statistics for each score 
at baseline and every post-baseline visit will be reported. Descriptive summary statistics, 
frequency distribution table and histogram for  the percent change of DSQ combined score, 
change of DSQ + pain score, change of DSQ pain score, change of DSQ question 2 score and  
change of DSQ question 3 score from baseline to the final treatment period Week 16. 
Change from baseline in the DSQ combined score (questions 2+3) overtime will be summarized 
descriptively for each treatment group by baseline DSQ severity level subgroups (i.e., 0-21, 
22-42, 43-63, 64-84). 


Shire  
CONFIDENTIAL 
Page 37 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
The total endoscopy score is the sum of endoscopy scores of proximal and distal locations from 
the following 5 major feature categories: 1) exudates or plaques (grade 0–2); 2) fixed 
esophageal rings (grade 0–3); 3) edema (grade 0–2); 4) furrows (grade 0–2); and 5) strictures 
(grade 0–1).The 10th, the 25th, the 50th (Median), the 75th,  and the 90th percentile change scores 
and sample sizes will be included in the cumulative distribution function curves. Besides the 
cumulative distribution curves specified above, the following additional secondary efficacy 
figures will be plotted, 95% Confidence interval band will also be plotted for all cumulative 
distribution curves: 
• The proportion of subjects who have a histology response as a peak eosinophil count of 
≤6/HPF, <15/HPF and  ≤1/HPF across all available esophageal levels at the final treatment 
period evaluation at Week 16 will be plotted by treatment group. 
• The proportion of subjects who have a reduction of ≥30% and 50% of DSQ combined score 
from baseline will be plotted across visits  (Week 4 (baseline), Weeks 8, 12, and 16) for each 
treatment group. 
• The proportion of subjects who have an overall response, defined as histology response as a 
peak eosinophil count of ≤6/HPF across all available esophageal levels at the final treatment 
period evaluation at Week 16, and a reduction in the DSQ combined score of ≥30% from 
baseline to the final treatment period of Week 16, will be plotted by treatment group. 
• The proportion of subjects who have an overall response, defined as histology response as a 
peak eosinophil count of ≤6/HPF across all available esophageal levels at the final treatment 
period evaluation at Week 16, and a reduction in the DSQ combined score of ≥50% from 
baseline to the final treatment period of Week 16, will be plotted by treatment group. 
• The mean DSQ combined score for each treatment group and standard deviations by visit 
(Week 4 (baseline), Weeks 8, 12, and 16) will be plotted.  
• A scatter plot with the maximum overall peak eosinophil count from the esophageal biopsies 
(x-axis) vs. DSQ combined score at the final treatment period evaluation Week 16. Different 
symbols will be used for each treatment group. 
• A scatter plot with the change from baseline in maximum overall peak eosinophil count from 
the esophageal biopsies (x-axis) vs. change from baseline in DSQ combined score at the final 
treatment period evaluation Week 16. Different symbols will be used for each treatment 
group. 
• A scatter plot with the percent change from baseline in maximum overall peak eosinophil 
count from the esophageal biopsies (x-axis) vs. the percent change from baseline in DSQ 
combined score at the final treatment period evaluation Week 16. Different symbols will be 
used for each treatment group. 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses  


Shire  
CONFIDENTIAL 
Page 38 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 


Shire  
CONFIDENTIAL 
Page 39 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
11. SAFETY ANALYSES 
Safety analyses will be performed by treatment group using the Safety Set.  Safety variables 
include AEs, physical examinations, stadiometry, vital signs (temperature, systolic and diastolic 
blood pressure, heart rate, and respiratory rate), weight and height assessments, DXA scans for 
BMD and body composition measurements (for adolescents aged 11-17 years, inclusive), clinical 
laboratory tests (hematology, chemistry, urinalysis; serum pregnancy test, if appropriate), and 
ACTH stimulation tests. To account for the effects of puberty in adolescent subjects (11-17 years 
of age, inclusive), BMD z-scores will be adjusted for height z-score. Continuous safety 
parameters will be descriptively summarized by treatment group at baseline and for each 
post-baseline visit. The last assessment prior to the first dose of investigational product will be 
used as baseline for all safety analyses. 
11.1 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 18.0 or newer.  
All AEs will be collected from the time of the informed consent through the completion of 
SHP621-301 post-treatment follow-up as described below. For subjects who do not consent to 
participate in the SHP621-302 study, AEs will be collected through the Safety Follow-up 
Contact. For eligible subjects who consent to participate in the SHP621-302 extension study, 
AEs will be collected in the SHP621-301 clinical database up to the date of the first dose of 
SHP621-302 investigational product (i.e., enrollment Visit 1 in the SHP621-302 study) or the 
Safety Follow-up Contact for subjects who screen fail prior to enrolling in extension study 
SHP621-302. AEs that have a start date after the first dose of SHP621-302 investigational 
product will be collected in SHP621-302 database.   
TEAEs are defined as AEs that start or deteriorate on or after the first dose of double-blind 
investigational product (Visit 1) and through the Safety Follow-up Contact, or 31 days after the 
last dose of SHP621-301 investigational product for subjects who do not have a Safety 
Follow-up Contact. This TEAE definition is a rule for programming TEAEs and will be applied 
only to the SHP621-301 database; and thus, events that occur after the first dose of SHP621-302 
investigational product (i.e., Visit 1 in the SHP621-302 study) will not be considered as TEAEs 
in SHP621-301.    
However, for any subjects who die 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 subjects with TEAEs will be presented, including  number 
and percentage of subjects with 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. 


Shire  
CONFIDENTIAL 
Page 40 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term, by SOC, preferred term, and 
maximum severity. Serious TEAEs, TEAEs considered 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, then 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. 
The incidence of common TEAEs (≥2% of subjects in any treatment group) will be summarized 
by preferred term.  Serious TEAEs, TEAEs leading to discontinuation of investigational product 
and TEAEs leading to discontinuation from the study will be summarized by SOC, preferred 
term and treatment group. Deaths will be summarized by preferred term and treatment group. 
11.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in US conventional units) and changes from 
baseline at each assessment time point as well as shift tables from baseline to each visit for 
quantitative variables will be presented by treatment group 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, mean platelet volume, 
erythrocyte count, erythrocyte distribution width, 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 
serum pregnancy, 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). 
Pregnancy test results will only be listed. A serum β-hCG pregnancy test is performed on all 
female subjects at the screening visit (Visit -1) and the final treatment evaluation visit (Visit 4) or 
ET visit. A urine pregnancy test is performed on all female subjects at the placebo lead-in visit 
(Visit 0), baseline visit (Visit 1), Visit 2, and Visit 3 or if pregnancy is suspected. 
ACTH stimulation testing will be performed by measuring the levels of cortisol in the blood 
following the injection of a synthetic form of ACTH. The type of synthetic and route of 
administration will be per local lab discretion. Blood samples will be collected just prior to and 
approximately 30 and 60 minutes following the injection at Baseline Visit 1 (Week 4) and 
Week 16. 


Shire  
CONFIDENTIAL 
Page 41 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Morning unstimulated cortisol testing results will be descriptively summarized by treatment 
group and visit. For ACTH stimulation testing results, the number and percentage of subjects 
with the highest of the two cortisol values at the 30 and 60 minute time points that meet a 
threshold criterion event of ≤18 mcg/dL will be summarized by treatment group at Baseline 
Visit 1 (Week 4) and Week 16, and worsening of the shift from Baseline Visit 1 to Week 16 will 
be presented.  ACTH stimulation testing results will also be presented with a higher threshold 
criterion of ≤ 20 mcg/dL, i.e., the number and percentage of subjects with the highest of the 
2 cortisol values at the 30 and 60 minutes time points of ≤ 20 mcg/dL. 
11.3 
Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, heart rate, respirations, 
temperature and weight) and their changes from baseline at each post-baseline visit and at the 
end of study will be presented by treatment group. Weight is collected at every visit for all 
subjects. For adolescent subjects 11-17 years of age, inclusive, two weight measurements per 
visit will be recorded. The average weight per visit will be used in summary tables for these 
subjects. 
A separate summary of height will be provided by visit and treatment group. Height will be 
collected at screening visit (Visit -1) and Visit 4 for all subjects. For adolescent subjects 
11-17 years of age, inclusive, stadiometers will be used to measure height, and three height 
measurements per visit will be recorded. The average height per visit will be used in summary 
tables for these subjects.  
All vital signs data will also be listed. 
11.4 
Electrocardiogram (ECG) 
Not applicable since ECG assessments are not planned for this study. 
11.5 
Other Safety Variables 
Physical Examination 
Physical examination assessments at each visit will include specific assessments for signs of 
glucocorticoid excess (e.g., moon faces, acne, hirsutism, mood swings, insomnia, and 
depression). Physical examination at the screening visit (Visit -1) will also include Tanner 
Staging Assessments for subjects <18 years of age. The number and percentage of subjects 
reporting symptoms described above will be presented by visit and treatment group. 
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 baseline and during last treatment Visit 4 
(Week 16). The sites for DXA measurement will be the lumber 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 z-scores. 


Shire  
CONFIDENTIAL 
Page 42 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Mean Z-scores at scheduled assessments and mean  within-subjects changes from baseline at 
Visit 4 (Week 16) will be calculated for the DXA Z-scores; corresponding two-sided 95% 
confidence intervals will be provided. 


Shire  
CONFIDENTIAL 
Page 43 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Pharmacokinetic analysis will be performed by PPD (Richmond, VA) under the supervision of 
Shire.  
12.1 
Pharmacokinetic Methods 
The following sections only pertain to the noncompartmental PK analysis of data collected in the 
SHP621-301 study. A population PK analysis will be performed separately using the pooled PK 
data from this study as well as historical studies; the population PK report will be prepared 
separately.  
All PK concentrations of budesonide will be presented using the PK set; summaries and analyses 
of the PK parameter data will be based on the PK Parameter set. 
12.1.1 
Concentration Data 
Blood samples will be drawn from adult subjecs (≥18 years of age) during this study for the 
determination of plasma concentrations of budesonide. Serial blood samples will be collected 
once during the treatment phase for PK analysis at predose, and at 0.5, and 1 hour post-dose in 
all subjects. Additional blood samples will be collected at 2, 3, 4, 6, 8, and 12 hours post-dose in 
subjects with intensive PK sampling. Actual sampling times post-dose will be considered 
protocol deviations where the sample deviated from nominal collection time by more than 
±5 minutes within the first 4 hours and ±15 minutes after 4 hours post-dose. Samples collected 
outside these windows will be flagged in data listings. Plasma concentrations of budesonide will 
be determined using a validated bioanalytical method. 
Individual budesonide plasma concentrations will be listed for all subjects by subject, visit, and 
time based on the PK set and summarized by time (overall and by visit [week]) based on the PK 
set with the following descriptive statistics: number of observations (n), arithmetic mean, 
standard deviation (SD), coefficient of variation (CV%), median, minimum, maximum, 
geometric mean, and geometric CV.  
Budesonide plasma concentrations will also be summarized based on the PK Parameter set. The 
mean and individual budesonide plasma concentration versus time profiles will be presented in 
figures on both linear and semi-logarithmic scales based on PK Parameter set. Mean (±SD) 
budesonide plasma concentration versus time profiles will be presented for the PK Parameter set 
using nominal time and all sampling times considered to be protocol deviations will be excluded 
from summaries and mean plots. Individual budesonide plasma concentration versus time 
profiles will be presented using actual time based on the PK Parameter set. 
12.1.2 
Handling BLQ Values 
The following procedures will be used for plasma concentrations that are below the lower limit 
of quantification (LLOQ): 
• Plasma samples that are below the limit of quantification (BLQ) will be reported as zero in 
the data listings. 


Shire  
CONFIDENTIAL 
Page 44 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
• Samples that are BLQ will be treated as zero in the calculation of summary statistics (e.g., 
mean, SD, etc.) for the plasma concentrations at individual time points. Geometric mean will 
be set to missing where zero values exist. 
• Mean concentrations will be reported as zero if all values are BLQ, and no descriptive 
statistics will be reported. If the calculated mean (± SD) concentration is less than the 
LLOQ, the value will be reported as calculated. The mean values derived using these 
conventions will be used to create the mean plasma concentration versus time plots. 
• For calculation of area under the plasma concentration curve (AUC), BLQ values will be set 
equal to zero in the dataset loaded into Phoenix® WinNonlin® (Certara USA, Inc, 
Princeton, NJ) for PK analysis. WinNonlin® uses the zero values that occur before the first 
time point with a concentration greater than LLOQ. Values that are BLQ after the first 
measurable concentration will be set to “missing” in the dataset loaded into WinNonlin®. 
• Missing values will not be imputed. 
12.1.3 
Pharmacokinetic Parameters 
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
budesonide by non-compartmental analysis using Phoenix® WinNonlin® (Certara, Princeton, NJ) 
Version 6.4 or higher for all subjects included in the PK Parameter set (i.e. subjects who provide 
at least 4 post-dose PK samples). All calculations will be based on actual sampling times, and all 
PK samples will be included in the PK analysis (including those with actual times outside the 
predefined collection interval and considered to be protocol deviations). 
The pharmacokinetic parameters will include, but may not be limited to, those listed in Table 3, 
subject to the quality of the PK data.  
Table 3 
Pharmacokinetic Parameters 
Parameter 
Definition 
AUC0-tau 
Area under the curve for the defined interval between doses (12 hours), 
calculated using the linear-up/log-down trapezoidal rule 
In this method, the linear trapezoidal method of calculation is used for 
each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid 
Cmax 
Maximum concentration 
tmax 
Time of maximum observed concentration sampled during a dosing 
interval 
λz 
First order rate constant associated with the terminal (log-linear) portion 
of the curve 
t½ 
Terminal half-life 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent volume of distribution associated with the terminal slope 
 


Shire  
CONFIDENTIAL 
Page 45 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
PK parameters will be summarized based on the PK Parameter set. The PK parameters for 
budesonide will be summarized with descriptive statistics (n, arithmetic mean, SD, CV%, 
median, maximum, minimum, geometric mean, CV% of geometric mean, and 95% CI of 
geometric mean) will be determined for all pharmacokinetic parameters overall and by visit 
(week). 
Population PK analysis will be performed for all subjects who provide PK samples (limited or 
intensive samples). Full details of the population PK analysis are documented separately. 
12.2 
Pharmacodynamic Methods 
Not applicable 
12.3 
Statistical Analysis of Pharmacodynamic Data 
Not applicable 


Shire  
CONFIDENTIAL 
Page 46 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
13. OTHER ANALYSES 
13.1 
Quality of Life Analyses 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire 
The EoE-QoL-A will be administered in subjects ≥18 years of age at baseline Visit 1 and final 
Visit 4. The EoE-QoL-A is a disease-specific measure of HRQoL in adult subjects (≥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. For 
each of the 30 questions subjects will be asked to provide a response on a 5-point scale: not at 
all, slightly, moderately, quite a bit and extremely.  
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 by treatment group 
and visit. 
Summary of change from baseline to the final treatment period evaluation Visit 4 (Week 16) in 
EoE-QoL-A total score and each of subscales will also be presented. Refer to Appendix 2 for 
derivation of EoE-QoL-A total score. 
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 baseline Visit 1 (Week 4) and final Visit 4 (Week 16). 
The PedsQL-EoE is a modular, disease-specific instrument designed to measure quality of life in 
children and adolescents (2-18 years of age) with EoE (Franciosi, 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 
by treatment group and visit. 
Summary of change from baseline to the final treatment period evaluation Visit 4 (Week 16) in 
PedsQL-EoE total score (adolescents and parents separately) and each of subscales will also be 
presented. Refer to Appendix 3 for derivation of PedsQL-EoE total score. 
EuroQol-5 Dimensions 3-level Questionnaire 
The EuroQol-5D Dimensions 3-level (EQ-5D-3L) will be for subjects ≥18 years (EuroQol, 1990; 
Brooks, 1996). 


Shire  
CONFIDENTIAL 
Page 47 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
The EuroQol-5 Dimensions Youth (EQ-5D-Y) will be for subjects 11-17 years of age, inclusive 
(Willie et al., 2010). The EQ-5D-3L and EQ-5D-Y will be administered during the study at 
baseline Visit 1 (Week 4) and final Visit 4 (Week 16). 
EQ-5D-3L consists of 2 pages – the EQ-5D descriptive system and the EQ visual analogue scale 
(EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression, each of which can take 1 of 
3 responses. The responses record 3 levels of severity within a particular dimension – (1) no 
problems, (2) some problems, (3) extreme problems. The EQ VAS records the respondent’s 
self-rated health on a vertical, visual analogue scale where the endpoints are labelled ‘Best 
imaginable health state’ (100) and ‘Worst imaginable health state’ (0). 
The EQ-5D-Y was developed to assess quality of life in children. As this version was intended to 
be comparable with the adult version EQ-5D-3L, the wording and layout of the EQ-5D-3L was 
modified to ensure relevance and clarity for the cognitive developmental stage of children. The 
measure requires children to self-report on five dimensions of health, namely; mobility (walking 
around), taking care of myself, doing usual activities, having pain or discomfort and feeling 
worried, sad or unhappy. The child can choose between three levels of severity (1) no, (2) some 
or (3) a lot of problems, which result in a health profile. Additionally, a Visual Analogue Scale 
(VAS) allows the child to subjectively rate their overall quality of life on a graduated scale, with 
0 indicating worst health state imaginable and 100 indicating best health.  
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 by treatment 
group and visit. VAS at baseline and final treatment period evaluation Visit 4 (Week 16), and 
change from baseline to the final treatment period 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 baseline and final treatment period 
evaluation Visit 4 (Week 16), and change from baseline to the final treatment period evaluation 
Visit 4 (Week 16) will also be presented. Refer to Appendix 4 for derivation of EQ-5D-3L 
composite index score. 


Shire  
CONFIDENTIAL 
Page 48 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
14. INTERIM ANALYSIS 
An unblinded interim analyses of the co-primary efficacy endpoints was performed by external 
independent unblinded statisticians and programmers at the Contract Research Organization, 
PPD, after 114 randomized subjects had either completed the study or withdrew prematurely 
from the study. The total of 114 randomized subjects represents 50% of the projected total 
randomization of 228 subjects based on protocol amendment 1 (i.e. information time t=0.5). No 
consideration was given to stop the study early at the time of interim analyses. A very minimal 
fraction of alpha (0.0001) was spent at the interim analysis because the study would not stop due 
to the interim results, and the sole purpose of the planned interim analyses was to adjust the 
sample size by using the conditional power approach under certain conditions that do not inflate 
the type I error (Mehta and Pocock 2011). 
The sample size re-estimation process was based on the 2-sided, 2-group chi-square tests, 
allowing for the control of the type I error to remain at 0.05 and using a conditional power 
approach to retain an 85% unconditional overall study power (using methods described by Mehta 
and Pocock 2011). The sample size was allowed to exceed 456, which is 100% more than the 
planned sample size. The external independent statisticians and programmers used pre-specified 
decision rules, and based on observed conditional power at the interim analyses. Refer to 
Interim Analyses SAP for further details. 
The  interim analysis was performed with the data collected through 29-Nov-2017 according to 
the interim analysis SAP, Version 2.0 dated on 21-Nov-2017.  The recommendation based on 
interim analysis results was that the sample size was to remain as planned without an increase. 
No unblinded data or results were disclosed to Shire, the PPD blinded study team, study sites, or 
subjects. 


Shire  
CONFIDENTIAL 
Page 49 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
15. DATA MONITORING/REVIEW COMMITTEE 
Not applicable 


Shire  
CONFIDENTIAL 
Page 50 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
16. COMPUTER METHODS  
All statistical analyses will be performed using SAS Version 9.2 or higher (SAS Institute, Cary, 
NC 27513) on a suitably qualified environment 


Shire  
CONFIDENTIAL 
Page 51 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
In the Memorandum of SHP621-301 Protocol Amendment 2 – Administrative Change (dated 
20 February 2019), the following changes related to statistical analysis were made to 
SHP621-301 Protocol Amendment 2 (dated 26 January 2018). 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
9.7 Study Population 
The intent-to-treat (ITT) set will include all 
randomized subjects. Subjects will be 
analyzed according to their assigned 
treatment, regardless of the treatment actually 
received. 
 
The full analysis set (FAS) will include all 
randomized subjects who received at least 1 
dose of a double-blind investigational product 
and have both an evaluable post-baseline 
biopsy in the treatment period (ie, peak 
eosinophil count is reported for at least 2 
esophageal levels) and a post-baseline DSQ 
score. 
 
The intent-to-treat (ITT) set will 
include all randomized subjects. Subjects 
will be analyzed according to their 
assigned treatment, regardless of the 
treatment actually received. 
 
The full analysis set (FAS) will include 
all randomized subjects who received at 
least 1 dose of a double-blind 
investigational product and have both an 
evaluable post-baseline biopsy in the 
treatment period (ie, peak eosinophil 
count is reported for at least 2 
esophageal levels) and a post-baseline 
DSQ score. 
9.8 Efficacy 
Analyses 
The primary, key secondary and secondary 
efficacy analyses will be performed on the 
ITT set and presented by treatment group. 
 
Data collected at the baseline visit (Visit 1) 
will be used as the baseline for all efficacy 
analyses. 
The primary, key secondary and 
secondary efficacy analyses will be 
performed on the ITT FAS set and 
presented by treatment group. 
 
Data collected at the baseline visit (Visit 
1) or the last observation prior to the first 
dose of investigational product during 
double-blind treatment phase, whichever 
is later, will be used as the baseline for 
all efficacy analyses. 
9.8.1 Primary 
Efficacy Endpoints 
The co-primary efficacy endpoints will be 
analyzed based on the ITT set. 
 
Analyses will be repeated using the FAS and 
the PP set. 
The co-primary efficacy endpoints will 
be analyzed based on the ITT FAS set. 
 
Analyses will be repeated using the FAS 
and the PP set. 
 
Analysis will be repeated based on FAS 
using different missing data handling 
methods to assess the impact of missing 
DSQ daily diary data on dysphagia 
symptom response.  
9.8.1.1 Missing Data 
Imputation 
The MI procedure will generate 10 version 
datasets with binary outcome imputed from 
the subjects with complete data. Once the 
missing values are imputed and each dataset is 
created, the results will be appropriately 
pooled across the multiply imputed estimated 
regression coefficients and their standard 
The MI procedure will generate 10 
50 version datasets with binary outcome 
imputed from the subjects with complete 
data. Once the missing values are 
imputed and each dataset is created, the 
results will be appropriately pooled 
across the multiply imputed estimated 


Shire  
CONFIDENTIAL 
Page 52 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
Protocol Section 
Protocol Amendment 2 Text 
Clarification 
errors using PROC MIANALYZE. 
 
regression coefficients estimates and 
their standard errors using PROC 
MIANALYZE. 
9.9  Safety Analyses 
TEAEs are defined as AEs that start or 
deteriorate on or after the first dose of 
investigational product (Visit 1) and no later 
than 3 days following the last dose of 
investigational product. 
TEAEs are defined as AEs that start or 
deteriorate on or after the first dose of 
investigational product (Visit 1) and no 
later than 3 days following through the 
Safety Follow-up Contact, or 31 days 
after the last dose of investigational 
product for subjects who do not have a 
Safety Follow-up Contact.  
 


Shire  
CONFIDENTIAL 
Page 53 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
18. DATA HANDLING CONVENTIONS 
18.1 
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 places 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 lab and vital sign results e.g. diastolic/systolic blood pressure and pulse (when taken in 
triplicate) should be rounded to 1 decimal place for reporting. 
In addition, p-values will generally be presented to 3 decimal places; values less than 0.001 will 
be presented as <0.001.  
18.2 
Derived Efficay Endpoints 
Refer to Section 10 for derivation instructions of histology response and DSQ scores by visit. 
DSQ scores including DSQ combined score and other DSQ scores will be calculated at study 
visits (Week 0, Week 4,  Week 8, Week 12 and Week 16) using the daily diary data in the 
selected 14-day period prior to the actual clinical visit date. For subjects who prematurely 
discontinue during the Double-blind Treatment Phase, the available daily DSQ diary data 
collected after the actual last visit and before early termination will be included in the calculation 
of  the diary data for the 14-day period for the next visit that was planned after ET. The target 
date of the next planned visit will be determined by the number of days since randomization, the 
next planned visit date =  the randomized date + 7*[the next planned visit week number-4] + 1 
(eg, for a subject who discontinued at week 15, the next planned visit week would be Week 16, 
and the calculated planned date for Week 16 would be determined as: [1+12 weeks*7] days after 
the date of randomization [Week 4 visit]. In this example, the subject who discontinued at 
Week 15 would have diary data included in the calculation of Week 16 DSQ scores that was 
within 14 days of the calculated planned date of Week 16.).   
18.3 
Derived Safety Endpoints 
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 
of completers and early termination visits.  Repeated or Unscheduled Assessments of Safety 
Parameters will be handled as follows: 


Shire  
CONFIDENTIAL 
Page 54 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
If a subject has repeated assessments before the start of investigational product in the 
double-blind treatment period, 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 double-blind treatment period and the end of study visit, the 
assessments of unscheduled visits will be excluded in the table summary, but all the records will 
be included in the listings. 
18.4 
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the Saety 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. 
18.5 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, 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. 
18.5.1 
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. 
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 


Shire  
CONFIDENTIAL 
Page 55 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
• 
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.  
18.5.2 
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, then replace it 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 
• 
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. 
18.6 
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, then the start date will be imputed first. 


Shire  
CONFIDENTIAL 
Page 56 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
18.6.1 
Incomplete Start Date  
Rulls will be followed as described in in Section 18.5.1. 
18.6.2 
Incomplete Stop Date  
When required per the protocol, follow the same rules as in Section 18.5.2.  
18.7 
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 the actual values will be used in data listings. 
18.8 
Missing Relationship to Investigation 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 double-blind investigational product will be used for incidence 
summaries, while the actual values will be presented in data listings. 
18.9 
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, that a character string is 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. 
Table 4 
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables 
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 


Shire  
CONFIDENTIAL 
Page 57 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
19. REFERENCES 
Brooks R. 1996. EuroQol: the current state of play. Health Policy. 37(1):53-72. 
EuroQol 1990. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy. 16, 199-208. 
Franciosi JP, Hommel KA, Bendo CB. 2013. PedsQL eosinophilic esophagitis module: 
feasibility,reliability, and validity. J Pediatr Gastroenterol Nutr. 57(1):57-66.  
Mehta, C.R., Pocock S.J.. 2011. Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine. 30:3267-3284. 
Taft TH,, Kern E., Kwiatek MA., Hirano I., Gonsalves N., Keefer L. 2011. The adult 
eosinophilic oesophagitis quality of life questionnaire: a new measure of health-related 
quality of life. Taft et al, Aliment Pharmacol Ther. 34: 790–798. 
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. 


Shire  
CONFIDENTIAL 
Page 58 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
20. APPENDICES 


Shire  
CONFIDENTIAL 
Page 59 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
APPENDIX 1 
 The Daily Dysphagia Symptom Questionnaire 
1. Since you woke up this morning, did you eat solid food? Possible responses=yes , no . 
2. Since you woke up this morning, has food gone down slowly or been stuck in your throat? 
Possible responses=yes (2), no (0). 
3. For the most difficult time you had while swallowing food today, did you have to do anything 
to make the food go down or to get relief? Possible responses: 
• No, it got better or cleared up on its own (0) 
• Yes, I had to drink liquid to get relief (1) 
• Yes, I had to cough and/or gag to get relief (2) 
• Yes, I had to vomit to get relief (3) 
• Yes, I had to seek medical attention to get relief (4) 
4. The following question concerns the amount of pain you have experienced when swallowing 
food. What was the worst pain you had while swallowing food today? Possible responses: 
• None, I had no pain (0) 
• Mild (1) 
• Moderate (2) 
• Severe (3) 
• Very Severe (4) 
DSQ combined score = (Sum of points from questions 2+3 in the daily DSQ)×14 days/(Number 
of diaries reported with nonmissing* data). 
DSQ + pain score = (Sum of points from questions 2+3+4 in the daily DSQ)×14 days/(Number 
of diaries reported with nonmissing* data). 
DSQ pain score = (Sum of points from questions 4 in the daily DSQ)×14 days/(Number of 
diaries reported with nonmissing* data). 
DSQ question 2 score=(Sum of points from questions 2 in the daily DSQ)×14 days/(Number of 
diaries reported with nonmissing* data). 
DSQ question 3 score=(Sum of points from questions 3 in the daily DSQ)×14 days/(Number of 
diaries reported with nonmissing* data). 
If answer for Question 1 is “Yes” and answer for Question 2 is “No”, then scores for Question 3 
and  Question 4 are set to each 0 before calculating the above scores for any analysis method 
proposed in the efficacy analyses.  


Shire  
CONFIDENTIAL 
Page 60 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
*Data for a given day will be considered missing if the diary is not reported or if the diary is 
reported but the answer to Question 1 is “No”. The number of diaries reported with non-missing 
data is also referred to as “reported diaries” in the following discussion. 
The DSQ combined score will be calculated summing the points from Questions 2 and 3 from 
each reported daily diary with non-missing data, and dividing this by the number of reported 
daily diaries with non-missing data in the selected 14-day period. This quotient will then be 
multiplied by 14. If subjects respond “No” to Question 2 the DSQ combined score will be set to 
zero for that day. 
The DSQ combined score calculated during the 14-day period prior to Baseline Visit 1 will be 
the Baseline DSQ Score. The DSQ combined score calculated during the 14-day period prior to 
the Final Treatment Period Evaluation will be the Final Treatment DSQ combined score. 
For each 14-day period, at least 8 reported diaries are needed to calculate a DSQ combined score. 
If fewer than 8 reported diaries are available within the 14-day period, then the most recent 8 
reported diaries in a consecutive 14-day period would be used to calculate the DSQ combined 
score. In order to determine the most recent 14-day period with the minimum number of reported 
diaries, it may be necessary to make adjustments in some cases by shifting to earlier diary 
entries. Such 14-day periods cannot be shifted for more than 7 days (not including the study visit 
day) when calculating DSQ combined score at Baseline Visit 1 (Week 4), Visit 2 (Week 8) and 
Visit 3 (Week 12), and cannot be shifted for more than 14 days prior to the Visit 4 (Week 16) 
(not including the visit day of Visit 4) for the DSQ combined score at the Final Treatment Period 
Evaluation. 


Shire  
CONFIDENTIAL 
Page 61 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
APPENDIX 2 
 Calculation of Adult Eosinophilic Esophagitis Quality of Life (EoE-QOL-
A) Total Score 
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. 
Overall score is a sum of the responses for all 30 questions (Q1-Q30) and it will have a score 
range from 0-120. 
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 0-4. 
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. 


Shire  
CONFIDENTIAL 
Page 62 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
APPENDIX 3 
 Calculation of Pediatric Quality of Life – EoE (PedsQL-EoE, subjects 11-
17 years of age) Total Score 
 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. 
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. 


Shire  
CONFIDENTIAL 
Page 63 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
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. 


Shire  
CONFIDENTIAL 
Page 64 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
APPENDIX 4 
 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 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 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 


Shire  
CONFIDENTIAL 
Page 65 
SHP621-301 Statistical Analysis Plan 
 
 
Budesonide oral suspension 
 
11 March 2019 
 
APPENDIX 5 
 Histopathologic Epithelial Features Combined Total Score (Grade and 
Stage) 
At each of the esophageal levels (proximal, mid and distal), histopathologic features are scored 
for both Grade and Stage. The histopathologic epithelial features consist of eosinophil peak, 
basal layer hyperplasia, eosinophil abcesses. surface layering, dilated intercellular spaces, surface 
alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Each of the 8 Histopathologic 
features at each eosophageal level has a possible score 0-3 points for both Grade (severity of 
abnormal histologic feature) and Stage (extend of abnormal histologic feature). Combined total 
scores include the following parameters for grade and stage respectively: 1, combined total score 
ratio (TSR) =(proximal TSR + mid TSR + distal TSR)/N, where N is the number of non missing 
sections for TSR; 2, combined score for each individual histopathologic feature 
(proximal+mid+distal)/N, where N is the number of non-missing sections for each individual 
feature.