Long-Term Safety and Efficacy Outcomes Following Previously Administered Short-Term Treatment With SHP607 in Extremely Premature Infants
Conditions: Retinopathy of Prematurity (ROP), Intraventricular Hemorrhage, Bronchopulmonary Dysplasia, Chronic Lung Disease of Prematurity
Sponsor: Oak Hill Bio Ltd

PROTOCOL: SHP607-203
TITLE:
Long-Term Safety and Efficacy Outcomes Following Previously 
Administered Short-Term Treatment with SHP607 in Extremely 
Premature Infants
DRUG:
SHP607 (mecasermin rinfabate)
IND:
133,076
EUDRACT NO.:
TBD
SPONSOR:
Premacure AB, A Member of the Shire Group of Companies
SPONSOR 
CONTACT:
300 Shire Way, Lexington, MA 02421 USA
+1-617-349-0200
PRINCIPAL/
COORDINATING
INVESTIGATOR:
TBD
PROTOCOL 
HISTORY:
Original Protocol: 18 November 2019
Amendment 1: 08 Apr 2020
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.

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SHP607-203 Protocol Amendment 1
HGT-ROP001 (mecasermin rinfabate)
08 Apr 2020
PROTOCOL SIGNATURE PAGE 
Signature: 
Date: 
Linda Han, MD, MPH 
Global Clinical Lead 
I have read this protocol for Study SHP607-203. 
Title: Long-Term Safety and Efficacy Outcomes Following Previously Administered 
Short-Term Treatment with SHP607 in Extremely Premature Infants 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
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 of Technical Requirements for 
Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice and with 
the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 

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SHP607-203 Protocol Amendment 1
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08 Apr 2020
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (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. The fax 
number and e-mail address are provided on the form (sent under separate cover). A copy of this 
form must also be sent to the contract research organization (CRO)/Shire medical monitor using 
the details below.
E-mail: drugsafety@shire.com
Fax:
+1-866 557 4473 (North America)
+44(0) 1256 89 4715 (Global)
For protocol- or safety-related questions or concerns at any time, the investigator must 
contact the PPD medical monitor:

North America: Anusha Streubel, MD, MPH, Medical Director, PPD, 
Pharmacovigilance 

Europe: Roxana Ruta, MD, Medical Director, PPD, Pharmacovigilance 

Asia Pacific (APAC): Amran Saifulanwar, MBBS, Medical Director, Medical Affairs 
and Pharmacovigilance 
Hotline numbers (24 hours a day/7 days a week):
North America: +1-888-483-7729
Europe, Middle East, Africa (EMEA)/Asia-Pacific (APAC): +44-1223-374-240
Fax numbers:
North America: +1-888-529-3580 and +1-919-654-3836
EMEA/APAC: +44-1223-374-102
Email:
North America: rtpsafety@ppdi.com 
EMEA/APAC: emeaasiasafetycentral.sm@ppdi.com

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SHP607-203 Protocol Amendment 1
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08 Apr 2020
SUMMARY OF CHANGES FROM PREVIOUS VERSION
An overview of the updates incorporated into Amendment 1 is provided in the table below.
Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Updated Signatory.
Protocol Signature 
Page
Updated Emergency Contact Information to match current template.
Emergency Contact 
Information
Updated Product Quality Complaints information to match current 
template.
Product Quality 
Complaints
Decreased the approximate number of subjects in 
Study SHP607-202, from 600 to 477; decreased the approximate 
number of subjects expected to complete Study SHP607-202 from 
160 to 127 per arm; decreased the approximate number of subjects 
in Study SHP607-203 from 480 to 382.
Study Synopsis
Section 1.3
Section 3.1
Figure 1
Section 9.5
Decreased the approximate number of sites in Study SHP607-203 
from 70 to 60.
Study Synopsis
Section 3.3
Added exploratory objective and endpoint of evaluation of cognitive 
impairment with an exploratory interactive electronic tablet 
application (BabyScreen)
Study Synopsis
Table 1
Section 2.1.3
Section 7.1.2.2
Section 9.7.3
Clarified that concomitant medications, procedures, and therapies 
will be collected only in the context of SAEs. In addition, 
respiratory medications (and medications that may be associated 
with respiratory conditions) will be captured in the pulmonary 
morbidity assessment, along with respiratory therapies.
Section 5.2
Clarified that the pulmonary morbidity assessment consists of the 
respiratory conditions assessment and the respiratory risk factors 
assessment.
Section 7.2.5.1
Clarified that the EQ-5D-5L is a measure of the health of the 
subject’s parent(s)
Section 7.2.5.6
Added section heading and description of the BabyScreen 
exploratory interactive electronic tablet application.
Section 7.2.5.7
Clarified that AEs will only be collected for specified targeted 
medical events, AEs related to investigational product, AEs leading 
to withdrawal from the study, and serious AEs that occur during the 
study period or were previously present and worsened during the 
study period.
Section 8.1

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SHP607-203 Protocol Amendment 1
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Summary of Change(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected 
by Change
Revised reporting procedures to provide actual contact information
Section 8.2.2
Added section heading and description of documentation and 
retention of electronic clinical outcome assessments records.
Section 10.2.3.2
AE=adverse event; EQ-5D-5L=EuroQol 5-dimensional 5-level descriptive system; IP=investigational product; 
SAE=serious adverse event.

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SHP607-203 Protocol Amendment 1
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08 Apr 2020
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that the product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following:
Unit issues

Bottle/vial fill shortage or overage

Vial cracked/broken

Missing components

Product discoloration
Labeling

Label missing

Leaflet or Instructions For Use 
missing 

Label illegible

Incomplete, inaccurate, or 
misleading labeling

Lot number or serial number missing
Packaging

Damaged packaging (eg, secondary, 
primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Product Quality Complaint Data 
Collection Form” via the email address:
PQC@shire.com
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
+1-800-828-2088

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08 Apr 2020
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE ....................................................................................................................17
1.
BACKGROUND INFORMATION.......................................................................................19
1.1
Indication and Current Treatment Options...............................................................19
1.1.1
Bronchopulmonary Dysplasia and Long-Term Respiratory Complications .........19
1.1.2
Intraventricular Hemorrhage..................................................................................20
1.1.3
Retinopathy of Prematurity....................................................................................21
1.1.4
Other Complications of Prematurity......................................................................22
1.2
Product Background and Clinical Information ........................................................23
1.2.1
Nonclinical Information.........................................................................................24
1.2.2
Clinical Experience with SHP607 .........................................................................25
1.3
Study Rationale ........................................................................................................26
1.4
Benefit/Risk Assessment..........................................................................................27
1.5
Compliance Statement..............................................................................................27
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................28
2.1
Study Objectives ......................................................................................................28
2.1.1
Primary Objectives.................................................................................................28
2.1.2
Secondary Objectives.............................................................................................28
2.1.3
Exploratory Objectives ..........................................................................................28
3.
STUDY DESIGN ...................................................................................................................30
3.1
Study Design and Flow Chart ..................................................................................30
3.2
Duration and Study Completion Definition .............................................................32
3.3
Sites and Regions .....................................................................................................32
4.
STUDY POPULATION.........................................................................................................33
4.1
Inclusion Criteria......................................................................................................33

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4.2
Exclusion Criterion ..................................................................................................33
4.3
Discontinuation of Subjects .....................................................................................33
4.3.1
Reasons for Discontinuation..................................................................................33
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................34
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................35
5.1
Prior Treatment ........................................................................................................35
5.2
Concomitant Treatment and Medications ................................................................35
6.
INVESTIGATIONAL PRODUCT ........................................................................................36
6.1
Identity of Investigational Product...........................................................................36
6.2
Administration of Investigational Product ...............................................................36
6.3
Labeling, Packaging, Storage, and Handling ...........................................................36
7.
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Initial Study Visit (12 Months CA) .......................................................................37
7.1.2
Study Visits............................................................................................................38
7.1.2.1
Assessments Conducted by Telephone ..................................................38
7.1.2.2
Assessments Conducted at Clinical Site Visits......................................38
7.1.3
Additional Care of Subjects after the Study ..........................................................40
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Informed Consent...................................................................................................40
7.2.2
Study Entrance Criteria..........................................................................................40
7.2.3
Study Enrollment ...................................................................................................40
7.2.4
Demographic and Other Baseline Characteristics .................................................41
7.2.5
Efficacy..................................................................................................................41
7.2.5.1
Pulmonary Morbidity Assessment .........................................................41
7.2.5.2
Growth Parameters.................................................................................41
7.2.5.3
Visual Acuity..........................................................................................42
7.2.5.4
Vision and Hearing Assessment History................................................42
7.2.5.5
Cognitive and Behavioral Assessments .................................................42
7.2.5.6
Health Economic Outcome Research Assessments ...............................44
7.2.5.7
BabyScreen Assessment (Optional).......................................................46
7.2.5.8
Spirometry (Optional) ............................................................................46
7.2.6
Cerebral Magnetic Resonance Imaging (Optional) ...............................................46
7.2.7
Safety .....................................................................................................................47
7.2.7.1
Medical History......................................................................................47
7.2.7.2
Physical Examination.............................................................................47
7.2.7.3
Blood Pressure, Heart Rate, and Respiratory Rate.................................47
7.2.7.4
Adverse Event Collection.......................................................................47

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7.2.8
Medication Assessment .........................................................................................47
7.2.9
Participation in Other Clinical Studies ..................................................................47
7.2.10 Appropriateness of Measurements.........................................................................48
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................49
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................49
8.1.1
Severity Categorization..........................................................................................49
8.1.2
Relationship Categorization...................................................................................50
8.1.3
Outcome Categorization ........................................................................................50
8.1.4
Targeted Medical Events .......................................................................................51
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................51
8.1.6
Abuse, Misuse, Overdose, and Medication Errors ................................................51
8.2
Serious Adverse Event Procedures ..........................................................................51
8.2.1
Reference Safety Information................................................................................51
8.2.2
Reporting Procedures.............................................................................................51
8.2.3
Serious Adverse Event Definition .........................................................................52
8.2.4
Serious Adverse Event Collection Time Frame.....................................................53
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................53
8.2.6
Fatal Outcome........................................................................................................53
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................53
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................54
9.1
Data Collection.........................................................................................................54
9.2
Clinical Data Management.......................................................................................54
9.3
Statistical Analysis Process......................................................................................54
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......54
9.5
Sample Size Calculation and Power Considerations................................................55
9.6
Study Population ......................................................................................................55
9.7
General Statistical Methodology..............................................................................55
9.7.1
Primary Efficacy Endpoint ....................................................................................55
9.7.2
Secondary Endpoints .............................................................................................56
9.7.3
Exploratory Endpoints ...........................................................................................56
9.7.4
Health Economics and Outcomes Research Analyses...........................................57
9.8
Safety Analyses........................................................................................................57
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................58
10.1
Sponsor’s Responsibilities .......................................................................................58
10.1.1 Good Clinical Practice Compliance.......................................................................58
10.1.2 Indemnity/Liability and Insurance.........................................................................58

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10.1.3 Public Posting of Study Information......................................................................58
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................59
10.1.5 Study Suspension, Termination, and Completion..................................................59
10.2
Investigator’s Responsibilities .................................................................................59
10.2.1 Good Clinical Practice Compliance.......................................................................59
10.2.2 Protocol Adherence and Investigator Agreement..................................................60
10.2.3 Documentation and Retention of Records.............................................................60
10.2.3.1
Case Report Forms.................................................................................60
10.2.3.2
Electronic Clinical Outcome Assessments.............................................60
10.2.3.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................61
10.2.3.4
Audit/Inspection.....................................................................................61
10.2.3.5
Financial Disclosure...............................................................................61
10.3
Ethical Considerations..............................................................................................62
10.3.1 Informed Consent...................................................................................................62
10.3.2 Institutional Review Board or Ethics Committee..................................................62
10.4
Privacy and Confidentiality......................................................................................63
10.5
Study Results/Publication Policy .............................................................................63
11. REFERENCES .......................................................................................................................65

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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................17
Table 2
Assessments for Physical Examinations .......................................................47
LIST OF FIGURES
Figure 1
Study Design Flow Diagram .........................................................................31
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................73

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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS
Attention-Deficit/Hyperactivity Disorder Rating Scale
AE
adverse event
ALS
acid-labile subunit
APAC
Asia Pacific
ASD
Autism Spectrum Disorder
BPD
bronchopulmonary dysplasia
BSID
Bayley Scales of Infant and Toddler Development
CA
age (in months) after expected date of full-term delivery
CI
confidence interval
CIQ
Caregiver Impact Questionnaire
CPAP
continuous positive airway pressure
CRA
clinical research associate
CRF
case report form
CRM
chronic respiratory morbidity
CRO
contract research organization
D
days
DMC
data monitoring committee
EC
ethics committee
EMEA
Europe, Middle East, Africa
EQ-5D-5L
EuroQol 5-dimensional 5-level descriptive system
EU
European Union
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GA
gestational age (time elapsed between first day of last menstrual period and day of birth)
GCP
Good Clinical Practice
GH
growth hormone
GMFM
Gross Motor Function Measure
HCRU
health care resource use
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
health-related quality of life
HUI
Health Utilities Index
HUI2/3
Health Utilities Index Mark 2 and Mark 3
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee

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IGF-1
insulin-like growth factor-1
IGFBP-3
insulin-like growth factor binding protein-3
IRB
institutional review board
IV
intravenous(ly)
IVH
intraventricular hemorrhage
KSPD
Kyoto Scale of Psychological Development
MRI
magnetic resonance imaging
NICHD
National Institute of Child Health and Human Development
NICU
Neonatal Intensive Care Unit
PedsQLTM
Pediatric Quality of Life Inventory
PK
pharmacokinetic
PMA
postmenstrual age
PROP
Prematurity and Respiratory Outcomes Program
ROP
retinopathy of prematurity
RTS
respiratory technology support
SAE
serious adverse event
SAP
statistical analysis plan 
SC
subcutaneous(ly)
SCQ
Social Communication Questionnaire
SEM
standard error of the mean
SOC
system organ class
t1/2
terminal elimination half-life
US
United States
VABS
Vineland Adaptive Behavior Scales
W
weeks
WPPSI
Wechsler Preschool and Primary Scale of Intelligence

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STUDY SYNOPSIS
Protocol number: SHP607-203
Drug: SHP607 (mecasermin rinfabate)
Title of the study: Long-Term Safety and Efficacy Outcomes Following Previously Administered Short-Term 
Treatment with SHP607 in Extremely Premature Infants
Number of subjects (total and for each treatment arm):
Approximately 477 subjects who previously received SHP607 or standard neonatal care in Study SHP607-202 are 
planned to be enrolled in Study SHP607-203. Although all subjects randomized into the primary Study SHP607-202 
(approximately 477) are eligible to enroll in Study SHP607-203, the actual number of subjects enrolled will more 
closely approximate the number of subjects who complete Study SHP607-202. A total of approximately 
382 subjects (approximately 127 subjects randomized to SHP607 250 μg/kg/24 hours, approximately 127 subjects 
randomized to SHP607 400 μg/kg/24 hours, and approximately 127 subjects randomized to standard neonatal care) 
are expected to complete Study SHP607-202.
Investigator(s): Multicenter
Site(s) and Region(s): 
Approximately 60 sites including, but not limited to, countries in the following regions: North America, Europe, and 
Asia Pacific (APAC).
Study period (planned):
2020-2026
Clinical phase:
2b
Objectives:
Primary: 

To evaluate long-term efficacy outcomes following previously administered short-term exposure to SHP607, as 
compared to a standard neonatal care group, as assessed by chronic respiratory morbidity (CRM) outcomes.

To evaluate the long-term safety outcomes following previously administered short-term exposure to SHP607, 
as compared to a standard neonatal care group.
Secondary: To evaluate long-term effects following previously administered short-term exposure to SHP607 on 
growth, cognitive and motor development, behavior, and resource utilization, as compared to a standard neonatal 
care group, by assessing:

Growth parameters

Physical development

Cognitive development

Gross motor function

Child behavior

Health-related quality of life (HRQoL)

Health utility

Health care resource use
Exploratory: 

To evaluate caregiver burden as assessed by the Caregiver Impact Questionnaire (CIQ).

To evaluate caregiver health status using EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L).

To evaluate cognitive impairment with an exploratory interactive electronic tablet application (BabyScreen)
used by children at 24 months corrected age (CA).

To evaluate pulmonary function following previously administered short-term exposure to SHP607, as 
compared to a standard neonatal care group.

To evaluate brain volume and cerebral neuroanatomic abnormalities following previously administered 
short-term exposure to SHP607, as compared to a standard neonatal care group. 

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Rationale:
Low levels of insulin-like growth factor-1 (IGF-1) in extremely preterm infants (gestational age [GA] of 23 weeks 
+0 days to 27 weeks +6 days) are a risk factor for CRM and other complications of extreme prematurity. Short-term 
administration of SHP607 may have long-lasting effects on safety and outcomes related to complications of 
prematurity. This non-interventional study will evaluate the long-term safety and efficacy outcomes of previously 
administered treatment with SHP607.
Investigational product, dose, and mode of administration:
No investigational product will be administered in this study.
Methodology:
This is a multicenter, long-term outcomes study of subjects who were randomized in Study SHP607-202 to either 
treatment (received SHP607) or control (received standard neonatal care) groups. Subjects will be followed from 
12 months CA through 5 years CA. Subjects will not be excluded from participating in other clinical studies.
Inclusion and exclusion criteria:
Inclusion Criteria:
Subjects must meet all of the criteria below:
1.
Subject was randomized into Study SHP607-202. Subjects who were randomized, but did not complete 
Study SHP607-202 must be at least 12 months CA.
2.
Written informed consents (and assents, if applicable) must be signed and dated by the subject's 
parent(s)/legally authorized representative(s) prior to any study-related procedures. The informed consent and 
any assents for underage parents must be approved by the institutional review board (IRB)/independent ethics 
committee (IEC). 
Exclusion Criterion: Subjects are excluded from the study if the subject or subject’s parent(s)/legally authorized 
representative(s) is/are unable to comply with the protocol or is/are unlikely to be available for long-term follow-up 
as determined by the investigator.
Maximum duration of subject involvement in the study:
Duration for an individual subject’s participation in this study is approximately 4 years.
Endpoints and statistical analysis:
Primary Efficacy Endpoints: Incidence of the following indicators of chronic respiratory morbidity through 
5 years CA:
1)
Emergency room visit or hospitalization associated with a respiratory diagnosis.
2)
Presence of coughing/wheezing.
3)
Use of respiratory medications (eg, bronchodilators, steroids, leukotriene inhibitors, diuretics). 
4)
Home respiratory technology use (eg, home oxygen, continuous positive airway pressure [CPAP], 
tracheostomy).
Primary Safety Endpoint:
The primary safety analysis will be based on:

AEs reported during the study period of SHP607-203
Secondary Endpoints:

Growth parameters including body weight, body length (or height), and head circumference.

Physical development as assessed by standardized, age appropriate tools including physical exam, neurological 
examination for assessment of cerebral palsy, and vision assessment. Reports of past vision and hearing 
assessments will also be collected

Cognitive development as assessed by the following standardized, age-appropriate tools:
-
Bayley Scales of Infant and Toddler Development (BSID) (or Kyoto Scale of Psychological Development 
[KSPD])
-
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)

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
Gross motor function as assessed by the Gross Motor Function Measure-88 (GMFM-88)

Child behavior as assessed by the following:
-
Vineland Adaptive Behavior Scales (VABS)
-
Attention-Deficit/Hyperactivity Disorder Rating Scale-fifth edition (ADHD RS-V) for the assessment of 
symptoms of attention-deficit/hyperactivity disorder (ADHD)
-
Social Communication Questionnaire (SCQ) for screening of Autism Spectrum Disorder (ASD)

Health-related quality of life will be assessed by the Pediatric Quality of Life Inventory (PedsQL™) Scales 
appropriate for the child's age of development with the Total Scale Score and 5 domains within Physical Health 
(Physical Functioning and Physical Symptoms) and Psychosocial Health Scores (Emotional, Social, and
Cognitive Functioning).

Health status (eg, health utility) will be measured by the Health Utilities Index Mark 2 (HUI2) and Mark 3 
(HUI3).

Health care resource use associated with inpatient visits, outpatient visits, emergency room visits, and visits to 
specialists will be assessed.
Secondary Safety Endpoints: 
The secondary safety analysis will be based on:

Targeted medical events occurring during the period of Study SHP607-203.

Fatal SAEs.
Exploratory Endpoints: 

Caregiver Impact Questionnaire (CIQ): Descriptive statistics of the CIQ item responses at baseline, 24 months 
CA, and 5 years CA.

EuroQol 5-dimensional 5-level descriptive system (EQ-5D-5L): Mean overall score on the EQ-5D-5L at 
24 months CA, 3 years CA, 4 years CA, and change from 24 months CA.

BabyScreen interactive electronic tablet application: Participation in the BabyScreen substudy is optional and 
has no impact on participation in the main study. The tool, used by children at 24 months CA to evaluate 
cognitive impairment, will be used for validation purposes only. 

Spirometry: Participation in the spirometry substudy is optional and has no impact on participation in the main 
study. Standard measures will be collected, including forced expiratory volume over 1 second (FEV1) and 
forced vital capacity (FVC).

Cerebral MRI: Participation in the cerebral MRI substudy is optional and has no impact on participation in the 
main study. Brain volume and neuroanatomic abnormalities will be assessed utilizing cerebral MRI at specific 
sites with MRI capabilities.
Statistical Analyses:
Continuous variables will be summarized using descriptive statistics including the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum values.
Categorical variables will be summarized using frequencies and percentages.
As referred to in descriptions of summary statistics, treatment groups refer to the antecedent SHP607 dose groups 
(SHP607 at 250 µg/kg/day and SHP607 at 400 µg/kg/day), combined SHP607 dose groups, and standard neonatal 
care group.
For analysis purposes, baseline is defined as the first assessment in this study (Study SHP607-203). 
Interim Analysis:
After the last subject in the primary Study SHP607-202 has completed the last study visit, an interim analysis for 
Study SHP607-203 will be performed for all enrolled subjects who have either completed the 24 months CA visit 
assessments or prematurely withdrawn from Study SHP607-203, and after all associated data have been entered into 
the database with queries and discrepancies resolved.

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STUDY SCHEDULE
Table 1
Schedule of Assessments
Proceduresa
Initial 
Study 
Visit
Months (CA)
Years (CA)
12 mo
+2 wkb
18 mo
±6 wk
24 mo
±6 wk
30 mo
±6 wk
3 yr
±6 wk
3.5 yr
±6 wk
4 yr
±6 wk
4.5 yr
±6 wk
5 yr
±6 wk 
/ET
Clinic
Phone
Clinic
Phone
Phone
Phone
Phone
Phone
Clinic
Informed consent
•
Eligibility criteria
•
Demographics
•
Medical historyc
•
Visual acuityd
•
Length
•
•
Height
•
Body weight
•
•
•
Head circumference
•
•
BSID (or KSPD)
•
BabyScreen
•
WPPSI
•
GMFM-88
•
•e
VABS
•
•
ADHD-RS
•
SCQ
•
CIQ
•
•
•
Physical examinationf
•
•
•
Blood pressure, heart rate, 
respiratory rate
•
•
•
Vision and hearing assessment 
historyg
•
•
•
•
•
•
•
•
Pulmonary morbidity 
assessment (in clinic or by 
phone interview)
•h
•
•
•
•
•
•
•
•
Cerebral MRI (optional)
•
Spirometry (optional)
•
EQ-5D-5L
•
•
•
PedsQL™
•i
•
•
•j
HCRU
•i
•
•i
•
•
•
•
•
•j
HUI2/3
•
Assessment of participation in 
other clinical studies
•
•
•
•
•
•
•
•
•

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Table 1
Schedule of Assessments
Proceduresa
Initial 
Study 
Visit
Months (CA)
Years (CA)
12 mo
+2 wkb
18 mo
±6 wk
24 mo
±6 wk
30 mo
±6 wk
3 yr
±6 wk
3.5 yr
±6 wk
4 yr
±6 wk
4.5 yr
±6 wk
5 yr
±6 wk 
/ET
Clinic
Phone
Clinic
Phone
Phone
Phone
Phone
Phone
Clinic
Medications, procedures, 
therapies
•
•
•
•
•
•
•
•
•
Adverse eventsj
•
•
•
•
•
•
•
•
•
ADHD-RS=Attention-Deficit/Hyperactivity Disorder Rating Scale; BSID=Bayley Scales of Infant and Toddler 
Development; CA=corrected age; CIQ=Caregiver Impact Questionnaire; EQ-5D-5L=EuroQol 5-dimensional 5-level 
descriptive system; GMFM=Gross Motor Function Measure; ET=early termination; HCRU=health care resource
use; HUI2/HUI3=Health Utilities Index Mark 2 and Mark 3; KSPD=Kyoto Scale of Psychological Development;
mo=months; MRI=magnetic resonance imaging; PedsQL™=Pediatric Quality of Life Inventory; SCQ=Social
Communication Questionnaire; VABS=Vineland Adaptive Behavior Scales; wk=weeks; WPPSI=Wechsler
Preschool and Primary Scale of Intelligence
a
Visits at 12 months, 24 months, and 5 years CA will be conducted in clinic; all other visits can be conducted by 
telephone. Assessments at 24 months and 5 years CA may be completed over more than one visit, if needed.
b
The initial visit in Study SHP607-203 should coincide with the final visit of the primary Study SHP607-202 at 
12 months CA +2 weeks. If the initial visit in Study SHP607-203 does not occur at the 12-month CA visit, the 
subject may still be enrolled until 24 months CA +6 weeks. Subjects enrolling between the 12 months CA 
visit and the 24 months CA visit should complete all 12-month CA assessments, and vision and hearing 
assessment history. Subjects enrolling at the 24 months CA visit should complete informed consent, eligibility 
criteria, demographics, medical history, and all 24 months CA assessments. Subjects are no longer eligible to 
enroll in this study after 24 months CA +6 weeks. Completion of Study SHP607-202 is not required for 
enrollment into Study SHP607-203.
c
Medical events or conditions should only be captured as medical history if they occur after the end of the 
subject’s participation in the primary Study SHP607-202 and before informed consent in the current 
Study SHP607-203.
d
Visual acuity will be assessed by eye chart only.
e
GMFM-88 Sections D (Standing) and E (Walking, Running, and Jumping) only will be administered at 5 years 
CA.
f
The physical examination should include tonsil assessment at all visits and should include cerebral palsy 
assessment at 24 months CA visit only.
g
Results of previously completed vision and hearing assessments, if performed, may be recorded at any time 
during the study up to the 5-year CA visit.
h
Only subjects who did not complete Study SHP607-202 should have pulmonary morbidity assessments 
performed at the 12-month visit.
i
The PedsQL™, EQ-5D-5L, and HCRU assessments for the 12-month, 24-month and 5-year CA visits may be 
performed by telephone by clinical site staff if there are time constraints during the on-site visit. At the 3-year 
and 4-year CA visits, these assessments will be performed by clinical site staff and may be performed at any 
time within the visit window.
j
Adverse event collection will include assessment of specified targeted medical events.

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1.
BACKGROUND INFORMATION
SHP607 (mecasermin rinfabate, rhIGF-1/rhIGFBP-3) is the recombinant human version of the 
naturally occurring protein complex of insulin-like growth factor-1 (IGF-1) and its most 
abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP-3). 
rhIGF-1/rhIGFBP-3 was approved by the United States (US) Food and Drug Administration 
(FDA) in December 2005 for the treatment of growth failure in children with severe primary
IGF-1 deficiency. This product, IPLEX™, has since been removed from the market following a 
patent dispute settlement, not safety concerns. SHP607 is currently being evaluated as a 
continuous intravenous (IV) infusion for prevention of chronic lung disease, including 
bronchopulmonary dysplasia (BPD), and other complications of premature birth.
Please refer to the current edition of the investigator’s brochure (IB) for further information 
concerning the safety and clinical development of SHP607.
1.1
Indication and Current Treatment Options 
Extremely premature infants are at very high risk for developing morbidities such as BPD, 
intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP), often resulting in 
delayed mortality or long-term disabilities. In fact, a simple count of the number of comorbidities 
in preterm infants with extremely low birth weight (BPD, IVH, and ROP) has been shown to 
strongly predict the risk of later death or neurocognitive impairment (Farooqi et al., 2011;
Schmidt et al., 2003; Schmidt et al., 2015; Koo et al., 2010). In a retrospective analysis of 
12,050 extremely preterm infants in the US, the frequent co-occurrence of these 3 morbidities is 
associated with an incremental increase in mortality, readmissions, length of hospital stay and 
costs (Mowitz et al., 2017). Although the survival rates have greatly improved in recent years for 
infants of borderline viability, these infants remain at risk of developing a wide array of neonatal 
and long-term complications (Saigal and Doyle, 2008). 
When preterm infants are deprived of their natural intrauterine environment they lose important 
factors normally found in utero, such as proteins, growth factors, and cytokines. It has been 
demonstrated that IGF-1 is one such factor that is introduced through placental absorption or 
ingestion from amniotic fluid. Thus, agents such as IGF-1 that promote organ development and 
drive growth in extremely preterm infants have the potential to address multiple complications of 
prematurity (Hellstrom et al., 2016).
1.1.1
Bronchopulmonary Dysplasia and Long-Term Respiratory Complications
Bronchopulmonary dysplasia is a chronic lung disorder that is among the most common
morbidities of preterm birth with an increased incidence with lower gestational age (GA) and 
birth weight, affecting at least one-quarter of infants born with weights <1500 g (Van Marter, 
2009; Stoll et al., 2015). Although the definition of BPD has evolved over time, it is generally 
classified based on the requirement of oxygen, continuous positive airway pressure, and 
mechanical ventilation according to criteria established by the National Institute of Child Health 
and Human Development (NICHD) (Ehrenkranz et al., 2005; Walsh et al., 2003; Walsh et al., 
2004; Pryhuber et al., 2015). Poor postnatal growth in preterm infants contributes to the 
multifactorial etiology of BPD (Lofqvist et al., 2012). 

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With advances in neonatal management, the current form of BPD is typically seen in neonates 
surviving at the threshold of viability and is characterized primarily by arrest of alveolar and 
vascular development (Iyengar and Davis, 2015). 
Studies have been published demonstrating a critical role for IGF-1 in the regulation of 
prenatal lung development. Bronchopulmonary dysplasia in preterm infants, which is 
characterized by pulmonary immaturity, undifferentiated alveoli with the presence of hyaline 
membrane and atelectasis, dilated capillaries immersed in the mesenchyme, and a distorted 
deposition of the extracellular matrix is correspondingly modeled by the prenatal lung phenotype 
of IGF-1 knockout mice (IGF-1 -/-) (Pais et al., 2013). Treatment of IGF-1 -/- prenatal lung 
explants with recombinant IGF-1 induced alveolar morphogenesis, further supporting the idea 
that IGF-1 induces prenatal lung maturation. Furthermore, IGF-1 levels were found to be 
significantly lower in the first weeks after birth of preterm infants who develop BPD compared 
with infants without BPD (Lofqvist et al., 2012; Beardsall et al., 2014).
A number of therapies such as corticosteroids and diuretics are used in the management of BPD 
in clinical practice; however, there is insufficient evidence supporting the use of many of these 
agents and no single therapy has been shown to have a significant impact on the incidence or 
severity of BPD (Iyengar and Davis, 2015). The majority of the drugs studied in randomized, 
controlled studies failed to reduce the incidence of BPD. No pharmacologic therapies are 
currently indicated for the prevention or treatment of BPD. IGF-1 was recognized as one of the 
potential novel therapies for BPD during the recent NICHD Workshop on BPD (Higgins et al., 
2018).
Chronic respiratory morbidity (CRM) after discharge from the Neonatal Intensive Care Unit 
(NICU) is a common adverse outcome of premature birth resulting in recurrent respiratory 
symptoms requiring treatment with pulmonary medications such as bronchodilators, need for 
supplementary home oxygen, frequent emergency room visits or hospital readmissions, 
especially during the first 2 years of life (Ali and Greenough, 2012). However, there is currently 
insufficient or conflicting evidence that the use of oxygen at term equivalence consistently 
predicts the later development of CLD in children born extremely premature. Extremely preterm 
infants diagnosed with BPD often continue to live with impaired lung or respiratory function 
after discharge from neonatal intensive care and put additional burden on health care systems 
with increased use of direct and indirect medical care that persists into infancy, school-age, 
adolescence, and possibly adulthood (Bhandari and McGrath-Morrow, 2013). The Prematurity 
and Respiratory Outcomes Program (PROP) study showed that 46-69% of extremely preterm 
infants had persistent respiratory morbidity, based on assessment of factors such as 
hospitalization, home support, and medications (Keller et al., 2017). Their lung function 
abnormalities may further increase their susceptibility for chronic obstructive pulmonary disease 
as they age (Filippone et al., 2009; Fakhoury et al., 2010; Fawke et al., 2010; Bhandari and 
McGrath-Morrow, 2013).
1.1.2
Intraventricular Hemorrhage
Intraventricular hemorrhage is estimated to occur in 20-25% of preterm infants with very low 
birth weight (<1500 g) in the US and is characterized initially by hemorrhage into the germinal 
matrix tissues of the developing brain (McCrea and Ment, 2008). 

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In the US between 1993 and 2012, 29,883 infants born at GA 22 through 28 weeks were 
diagnosed with severe intracranial hemorrhage, a mean of 1,494 infants per year (Stoll et al., 
2015). Intraventricular hemorrhage has been attributed to fluctuations in cerebral blood flow 
to the immature germinal matrix microvasculature and secondary periventricular venous 
infarction. Approximately 80% of cases of IVH in preterm infants occur by 72 hours after 
birth with a considerable proportion occurring within a few hours of birth (Levene et al., 1982;
Al-Abdi and Al-Aamri, 2014). The most common short-term outcomes associated with 
IVH are hydrocephalus and periventricular leukomalacia (McCrea and Ment, 2008). 
Intraventricular hemorrhage is associated with substantial mortality and morbidity and may 
result in long-term neurodevelopmental impairments (McCrea and Ment, 2008; Bolisetty et al., 
2014; Klebermass-Schrehof et al., 2012; Horsch et al., 2005; Mukerji et al., 2015). 
Studies have been published demonstrating a critical role for IGF-1 in prenatal neural 
development. IGF-1 is known to stimulate proliferation of progenitors that become neurons, 
oligodendrocytes, and astroglia (D'Ercole et al., 2002). In addition, IGF-1 augments neuron and 
oligodendrocyte survival and promotes differentiation, synaptogenesis, and myelination (Bondy 
and Cheng, 2004). Gene expression of IGF-1 in the prenatal rat brain displays distinct 
developmental patterns in different regions of the brain, supporting the idea that IGF-1 has a 
clear role in prenatal brain development (Bach et al., 1991). The phenotype of IGF-1 gene defect 
is characterized by low cranial circumference and the presence of microcephaly and 
developmental delay (Netchine et al., 2011). Increased levels of circulating IGF-1 in preterm 
infants are also correlated with increased brain volume and a decreased risk for subnormal 
developmental outcomes by 2 years of age (Hansen-Pupp et al., 2013). IGF-1 has important 
trophic effects and enhances barrier function by increasing expression of tight junction proteins 
in various organs, including the gut and lung, and may have a similar effect on the germinal 
matrix vascular bed (Dong et al., 2014; Drucker et al., 1997; Sabnis et al., 2015; Tian et al., 
2010; Yan et al., 2016). Taken together, these observations demonstrate that the integrity of 
IGF-1 signaling is important for proper growth and development of the brain.
Ongoing preclinical studies utilize a rabbit pup model of IVH (Georgiadis et al., 2008; Gram et 
al., 2013) to assess the role of the IGF-1 system in the development of rabbit brain vasculature 
and whether exogenous IGF-1 can decrease the incidence of IVH. 
Currently, the most effective option for prevention of IVH is antenatal glucocorticoids (Ballabh, 
2014). Upon detection of IVH, treatment is generally focused on managing sequelae and other 
systemic factors that may influence further progression (McCrea and Ment, 2008; Ballabh, 
2014). There is currently no approved treatment for IVH in extremely premature infants.Despite 
advances in neonatal care, the incidence of IVH among extremely preterm infants remains 
substantial, with limited treatment options once IVH is detected. Thus, there is a significant need 
for more effective preventive therapies.
1.1.3
Retinopathy of Prematurity
Retinopathy of prematurity is a major cause of blindness in children in the developed and 
developing world, despite current treatment of late-stage ROP (Silverman, 1980). As developing 
countries provide more neonatal and maternal intensive care, the incidence of ROP has 
increased. 

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Although ablation treatment, such as laser photocoagulation or cryotherapy of the retina reduces 
the incidence of blindness in those with late-stage disease, the visual outcomes after treatment 
are often poor (Good et al., 2010). 
Retinal blood vessel development begins during the fourth month of gestation and is not 
completed until term (Foos and Kopelow, 1973; Roth, 1977). Therefore, infants born 
prematurely have incompletely vascularized retinas, with a peripheral avascular zone, the area of 
which depends on the GA. With maturation of the infant, the resulting nonvascularized retina 
becomes increasingly metabolically active and hypoxic. The hypoxia-induced retinal 
neovascularization phase of ROP is similar to other proliferative retinopathies, such as diabetic 
retinopathy.
IGF-1 is critical for the normal development of retinal vessels (Hellstrom et al., 2001). After 
preterm delivery, IGF-1 levels rapidly fall below in utero levels. IGF-1 is critical to normal 
retinal vascular development and lack of IGF-1 in the early neonatal period is associated with 
lack of vascular growth and with subsequent proliferative ROP. In IGF-1 -/- mice, normal retinal 
vascular development was examined to determine whether IGF-1 is critical to normal blood 
vessel growth. Retinal blood vessels grow more slowly in IGF-1 -/- mice than in normal mice, a 
pattern very similar to that seen in preterm infants with ROP. These observations were confirmed 
in patients with ROP (Hellstrom et al., 2001; Hellstrom et al., 2003). 
In a prospective, longitudinal study measuring serum IGF-1 concentrations weekly in 
84 premature infants, the mean serum IGF-1 ±standard error of the mean (SEM) level during 
postmenstrual age (PMA) 30 to 33 weeks was lowest in those with severe ROP (25 ±2.41 μg/L), 
higher in those with moderate ROP (29 ±1.76 μg/L), and highest in those with no ROP 
(33 ±1.72 μg/L). The duration of low IGF-1 also correlated strongly with the severity of ROP. 
The interval from birth until serum IGF-1 levels reached >33 μg/L was 52 ±7.5 days for severe 
ROP, 44 ±4.8 days for moderate ROP, and 23 ±2.6 days for no ROP. Each adjusted stepwise 
increase of 5 μg/L in mean IGF-1 during PMA 30 to 33 weeks decreased the risk of proliferative 
ROP by 45% (Hellstrom et al., 2003). These findings suggest the possibility that replacement 
therapy with rhIGF-1 to restore IGF-1 to intrauterine levels might prevent morbidity by allowing 
normal vascular and neural development (Hellstrom et al., 2016).
1.1.4
Other Complications of Prematurity
Extremely premature infants have recognized instability in glycemic control that includes both 
hypoglycemia (Lubchenco and Bard, 1971; Wybregt et al., 1964) and hyperglycemia (Dweck 
and Cassady, 1974) events throughout their clinical course.
In addition, extremely premature infants experience extrauterine growth restriction as assessed 
by body weight, body length, and head circumference (Laron et al., 1992). These infants are at 
higher risk of later growth failure in their early childhood and long-term consequences (Farooqi 
et al., 2011).

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1.2
Product Background and Clinical Information
SHP607 is the recombinant protein complex of IGF-1 and its most abundant binding protein, 
IGFBP-3. In animal studies, SHP607 displays metabolic activities similar to those observed with 
rhIGF-1. 
In healthy individuals, IGF-1 is constantly present in the bloodstream. In the circulation, IGF-1 is 
generally bound to one of several IGF binding proteins. The predominant circulating IGF 
binding protein is IGFBP-3. The binary complex of IGF-1/IGFBP-3 commonly forms a 150 kD 
ternary complex with a third circulating protein, acid-labile subunit (ALS). The vast majority of 
circulating IGF-1 exists in the form of this ternary complex. The estimated terminal elimination 
half-life (t1/2) of the ternary complex is >12 hours compared with <15 minutes for free IGF-1. 
Because of its molecular size, the ternary complex is restricted to the circulation by the capillary 
endothelium and therefore serves as a circulating reservoir of IGF-1 with a long t1/2. However, in 
preterm infants, ALS is not produced or is produced in very low quantities; thus, the ternary 
complex is not formed in preterm infants. As a result of this lack of ternary complex formation, a 
different pharmacokinetic (PK) profile of SHP607 has been shown in preterm infants than that 
seen in children and adults (Lofqvist et al., 2009); t1/2 is markedly shortened to <1 hour. 
IGF-1 elicits many of the physiological effects of insulin, which are mediated through specific 
cell surface receptors (Massague and Czech, 1982). IGF-1 is a small polypeptide with structural 
and functional homology to proinsulin. In addition to inducing insulin-like effects, IGF-1 also 
promotes cell division, growth and differentiation in most tissues.
Unlike many other growth factors, IGF-1 is relatively abundant in the bloodstream and exists in 
the serum largely in an inactive state, bound to specific carrier proteins, which serve to regulate 
its distribution and biological activity. Circulating levels of IGF-1 can be influenced by a number 
of factors, including growth hormone (GH), insulin, and nutritional status (Frystyk et al., 1999). 
Although the liver is considered the major site of synthesis of circulating IGF-1, virtually all 
tissues produce some IGF-1.
To date, 2 main classes of carrier proteins have been identified. Six variants of the IGF binding 
proteins (IGFBP-1-6) comprise the first class. ALS constitutes the second class. IGFBP-3 is the 
most abundant binding protein in the circulation and sequentially binds both IGF-1 and ALS to 
form a large ternary complex (Rosenfeld et al., 1990). All 3 components of the ternary complex 
are largely GH dependent. Unlike free IGF-1, which can readily cross the vascular endothelium, 
the molecular size of the ternary complex restricts IGF-1 to the circulation and increases 
IGF-1 t1/2 from <15 minutes to >12 hours. IGFBP-3 influences the availability of IGF-1 by 
allowing IGF-1 to be slowly released for receptor interactions thus protecting receptors from 
down regulation by high IGF-1 exposure (Grimberg, 2000). The circulating reservoir of 
IGF-1 can facilitate endocrine actions and minimize the potential risk of acute, serious 
insulin-like effects that can be associated with supraphysiological exposure to free 
IGF-1 (Rosenfeld et al., 1990; Binoux and Hossenlopp, 1988; Martin and Baxter, 1992; Baxter 
and Martin, 1989; Zapf et al., 1995; Boisclair et al., 2001). 

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Many different effects have been observed upon administration of rhIGF-1 in animals and 
humans. These include promotion of linear growth (Laron et al., 1992), anabolic effects 
including enhanced wound healing (Froesch et al., 1985; Sommer et al., 1991), promotion of 
bone formation (Bagi et al., 1995), changes in body composition and muscle function 
(Vlachopapadopoulou et al., 1995), stimulation of lymphopoiesis (Clark et al., 1996), modified 
glucose metabolism and improved insulin sensitivity (Vlachopapadopoulou et al., 1995; Guler et 
al., 1987; Thrailkill et al., 1999), motor neuron survival and sprouting (Caroni and Grandes, 
1990; Lewis et al., 1993), increased creatinine clearance (Guler et al., 1989), and recovery of 
renal function following ischemic injury (Ding et al., 1993). 
In published clinical studies using rhIGF-1 administered without rhIGFBP-3, reported side 
effects have included hypoglycemia (Wilton, 1992); syncopal reactions in the absence of 
hypoglycemia, dizziness, seizure-like activity, bradycardia and asystole, and hypotension 
(Vlachopapadopoulou et al., 1995; Malozowski et al., 1994); intracranial hypertension and 
papilledema (Malozowski et al., 1993); cranial nerve palsy, and acute symptomatic 
hypophosphatemia (Usala et al., 1994); edema, parotid discomfort, jaw pain, arthralgia, myalgia, 
fatigue, tachycardia, flushing, orthostatic hypotension, headache, and dyspnea 
(Vlachopapadopoulou et al., 1995; Jabri et al., 1994; Bondy et al., 1994). In addition, injection 
site reactions, tonsillar and adenoid hypertrophy sometimes resulting in 
tonsillectomy/adenoidectomy, middle ear effusion, and hearing loss have occasionally been 
reported with administration of rhIGF-1 (Ranke et al., 1999; Ranke et al., 1995; Ehrnebo, 1998, 
Chernausek et al., 2004). Laboratory measurement abnormalities included hypoglycemia, 
anemia, hypokalemia, IGF-1 antibodies, and abnormal liver function tests (Ehrnebo, 1998; 
Guevara-Aguirre et al., 1995). Although most of the above adverse events (AEs) have not yet 
been observed in studies of SHP607, it is possible that these events might occur with 
SHP607 therapy.
1.2.1
Nonclinical Information
Appropriate PK, toxicokinetic, biodistribution, and toxicology studies have been performed in 
rats and monkeys, the 2 species used for nonclinical toxicology testing. In rats and monkeys, PK 
studies with SHP607, as compared to those with either rhIGF-1 or rhIGFBP-3 administered as 
single agents, demonstrated increased exposure to IGF-1 with the complex when compared to 
exposure obtained with either of the single proteins and were correspondingly associated with 
reduced clearance rate with the complex. These findings can be attributed to the ability of the 
SHP607 complex to bind to ALS in the circulation, as evidenced by size exclusion 
chromatography results (Baxter, 1990). SHP607 is well absorbed following subcutaneous (SC) 
administration as noted in both rats and monkeys. Though distribution studies with SHP607 have 
not been conducted, studies using radiolabeled rhIGF-1 in mice have shown wide distribution of 
radioactivity to highly vascularized tissues including lung and cerebrospinal fluid. 
The potential acute toxic effects of single-dose IV administration of SHP607 have been 
characterized in rats and monkeys. In the rat, doses up to 200 mg/kg were well tolerated, except 
for the expected pharmacologic decrease in serum glucose (200 mg/kg), and produced no signs 
of systemic toxicity. In monkeys, except for hypoglycemia, doses of 100 mg/kg were well 
tolerated. No other clinically significant adverse effects were noted.

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Fourteen consecutive days of IV dosing in rats (up to 100 mg/kg/day) and monkeys (up to 
25 mg/kg/day) were well tolerated and produced no signs of toxicity. Daily SC administration of 
SHP607 for 3 months to rats (up to 30 mg/kg/day) and monkeys (up to 10 mg/kg/day) was 
well tolerated and produced no signs of systemic toxicity. Expected pharmacologic effects of 
IGF-1 were noted in both species. An increase in the T-cell component of the thymus, spleen, 
and possible lymph nodes was observed in the rats and trace to mild lymphoid hyperplasia was 
observed in the monkeys. In a local tolerance study of SHP607, daily SC dosing of SHP607 for 
14 days to rats produced a mild to moderate inflammatory reaction in the SC tissue, which was 
reversed upon cessation of dosing.
1.2.2
Clinical Experience with SHP607
Two clinical studies, ROPP-2005-01 and ROPP-2008-01, have been conducted with SHP607 in 
premature infants. A third study, SHP607-201, is being conducted to assess the long-term 
efficacy and safety outcomes of SHP607 versus standard neonatal care (no investigational 
product is being administered) in subjects randomized in Study ROPP-2008-01, Section D. A fourth 
study, Study SHP607-202, is described in the section below. Subjects enrolled in this study are 
eligible for participation in Study SHP607-203.
In the Phase 1 Study ROPP-2005-01 in preterm infants, administration of SHP607 during a 
3-hour infusion increased the serum concentrations of IGF-1 at the postnatal age of 3 days and 
no safety concerns were seen in the study. At postnatal age of 3 days (mean weight [range]: 
973 g [760-1220 g]), 5 subjects were each administered an IV infusion of SHP607 in a dose of 6, 
24, 33, 33, or 59 µg/kg/3 hours, containing 21% IGF-1 by weight. The doses were calculated 
based on the birth weight, but were administered on Day 3, the day the PK samples were drawn, 
and thus are expressed as the dose/kg based on the infant weight at Day 3. In this Phase 1 study, 
the calculated t1/2 was 0.86 hours for a typical subject of 1 kg. The doses provided to these 
preterm infants were considerably lower than those studied in other SHP607 studies where the 
SHP607 was administered by the IV and SC routes to healthy human volunteers at doses up to 
6 mg/kg/day without serious adverse events (SAEs). In these other Phase 1 studies, the 
maximum tolerated single IV dose administered intravenously was determined to be 3.0 mg/kg. 
SHP607 was well-tolerated at doses up to 2.0 mg/kg/day by SC injection.
The Phase 2 Study ROPP-2008-01 in preterm infants was designed in 4 sections (Sections A, B, 
C, and D). In Sections A, B and C, the dosing of SHP607 was highly individualized based upon 
an algorithm and required both a significant level of investigator oversight and frequent serum 
IGF-1 measures. Subjects in Study Section A received infusion of SHP607 for 7 days and 
subjects in Study Sections B and C were randomly assigned to treatment with SHP607 or to 
receive standard neonatal care. After a thorough review of the data from Study ROPP-2005-01, 
Study ROPP -2008-01 (Sections A, B and C), population PK modeling, and from the literature, a 
standardized dose was selected for use in Section D. Subjects in Study ROPP-2008-01 Section D 
received a continuous infusion of 250 µg/kg of SHP607 administered over 24 hours to keep the 
levels of IGF-1 within the normal intrauterine range for corresponding GA from Study Day 0 up 
to and including maximum PMA 29 weeks +6 days. Clinical activities for all 4 sections are 
complete and safety, dosing, and PK results have been reviewed (see the IB). 

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Study ROPP-2008-01 did not meet the primary endpoint in reducing severity of ROP; however, 
positive trends were observed in secondary endpoints related to BPD and IVH. For BPD, a 
nominally statistically significant shift was observed in the distribution of severity of BPD. This 
was most evident in the difference between the groups in the percentage of subjects with severe 
BPD: 10 subjects (21.28%) in the SHP607 group and 22 subjects (44.90%) in the Standard of 
Care group. 
Although there were no statistically significant differences in IVH between the 2 groups, 
numerically the results favored the SHP607 group (13.1% in the treated vs 23.3% in the Standard 
of Care group with Grade 3 or 4). Upon review of data from the Safety Analysis Set of subjects 
treated with SHP607 in Sections A, B, and C (n=14) and in Section D (n=61), there were no 
newly identified risks and no important changes to the previous knowledge of safety for 
SHP607 that would impact the risk-benefit profile. Overall, the results of ROPP-2008-01 support 
the continued evaluation of SHP607 for the treatment of complications of premature birth at both 
the current dose and a higher dose, 400 µg/kg/24 hours. The high dose of 400 µg/kg/24 hours 
was chosen following modeling and simulation of IGF-1 levels in pre-term infants and is 
expected to result in concentrations within the upper bound of the 28-109 µg/L target range over 
the infusion duration.
SHP607-201 is a Phase 2, multicenter, long-term developmental outcome study enrolling 
subjects who were randomized in Section D of Study ROPP-2008-01 to receive either 
SHP607 (treated) or standard neonatal care (control). Enrolled subjects in this study will be 
followed through age 5 years corrected age (CA), with assessments that include measures of 
pulmonary morbidity and neurocognitive development. 
Always refer to the latest version of the SHP607 IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, PK, efficacy, and 
safety of SHP607.
1.3
Study Rationale
Despite significant advances in care over the past 20 years, extremely premature infants remain 
at very high risk for developing morbidities that affect multiple organ systems and often result in 
delayed mortality or long-term disabilities. Additional therapeutic and preventive options are 
very much needed to continue progress in the care of extremely preterm infants. Therapeutic 
agents such as SHP607 that activate pathways with positive impact on organ development and 
drive growth in extremely preterm infants have the potential to address multiple complications of 
prematurity such as BPD, ultimately translating into healthier infants with fewer or less severe 
morbidities and improved outcomes. 
Analysis of the Phase 2 Section D data showed that higher IGF-1 levels may have the 
potential to be associated with greater efficacy and scaled PK simulation models showed the 
exposure can be further improved by elevating the dose. Subjects with severe BPD were 
found to have significantly lower serum IGF-1 levels than subjects with no BPD. Similar trends 
were observed when comparing those with more severe stages of ROP to those without ROP. 
For IVH, there was an indication that the impact of IGF-1 may occur early in the course of 
the illness. 

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For safety reasons, the previously studied dose of 250 μg/kg/24 hours targeted the lower bound 
of the physiologic range. The PK model predicted that administration of this dose would result in 
a small proportion of subjects with serum IGF-1 that was below target level (<28 μg/L). This 
prediction was borne out in the observed study results. The updated PK model, which 
incorporated the Phase 2 Section D data, projects that at a dose of 400 μg/kg/24 hours, the 
resulting serum IGF-1 level should remain within the upper bound of the 28-109 µg/L target 
range, while the potential for under-dosing or overdosing will be minimal.
Study SHP607-202 is a Phase 2b, multicenter, randomized, open-label, controlled, 3-arm study 
that is being initiated to evaluate the clinical efficacy and safety of SHP607 in preventing chronic 
lung disease through 12 months CA compared to standard neonatal care in extremely premature 
infants. Approximately 477 subjects with GA of 23 weeks +0 days to 27 weeks +6 days will be 
randomized in a 1:1:1 ratio to receive either SHP607 at 250 µg/kg/24 hours, SHP607 at 
400 µg/kg/24 hours, or standard neonatal care alone. Subjects randomly assigned to treatment 
will receive continuous IV infusion of study drug commencing within 24 hours of birth, once all 
baseline assessments have been completed. The infusion of study drug will continue to PMA 
29 weeks +6 days. The primary objective of the study is to assess the effect of SHP607 on 
reducing the burden of CLD, as indicated by a reduction in time to final weaning off respiratory 
technology support (RTS) through 12 months CA, as compared to a standard neonatal care 
group.
Study SHP607-202 will evaluate the clinical efficacy and safety of SHP607 in preventing 
chronic lung disease through 12 months CA compared to standard neonatal care in extremely 
premature infants. Although treatment with SHP607 in Study SHP607-202 represents a 
short-term exposure (<2 months for each subject), SHP607 may have long-lasting effects on 
respiratory outcomes as well as other potential outcomes related to complications of prematurity 
such as neurodevelopment, vision, and growth impairments. In addition, it is critical to 
understand any long-term safety effects from short-term exposure to SHP607. The purpose of 
Study SHP607-203 is to evaluate the long-term safety and efficacy outcomes in subjects who 
received short-term treatment with SHP607 in Study SHP607-202.
The assessment tools used in this study will be different from those used in Study SHP607-202, 
given the changes in physical and cognitive development that will occur in the subjects as they 
age during their participation in this study. 
1.4
Benefit/Risk Assessment
Always refer to the latest version of the SHP607 IB for the overall benefit/risk assessment and 
the most accurate and current information regarding drug metabolism, pharmacokinetics, 
efficacy, and safety of SHP607. 
1.5
Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in Section 10.

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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Study Objectives
2.1.1
Primary Objectives
The primary objectives of this study are:

To evaluate long-term efficacy outcomes following previously administered short-term 
exposure to SHP607, as compared to a standard neonatal care group, as assessed by CRM 
outcomes.

To evaluate the long-term safety outcomes following previously administered short-term 
exposure to SHP607, as compared to a standard neonatal care group.
2.1.2
Secondary Objectives
The secondary objectives of this study are to evaluate long-term effects following previously 
administered short-term exposure to SHP607 on growth, cognitive and motor development, 
behavior, and resource utilization, as compared to a standard neonatal care group, by assessing:

Growth parameters

Physical development

Cognitive development

Gross motor function

Child behavior

Health-related quality of life (HRQoL)

Health utility

Health care resource use
2.1.3
Exploratory Objectives
The exploratory objectives of this study are:

To evaluate caregiver burden as assessed by the Caregiver Impact Questionnaire (CIQ).

To evaluate caregiver health status using EuroQol 5-dimensional 5-level descriptive 
system (EQ-5D-5L).

To evaluate cognitive impairment with an exploratory interactive electronic tablet 
application (BabyScreen) used by children at 24 months corrected age.

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
To evaluate pulmonary function following previously administered short-term exposure 
to SHP607, as compared to a standard neonatal care group.

To evaluate brain volume and cerebral neuroanatomic abnormalities following previously 
administered short-term exposure to SHP607, as compared to a standard neonatal care 
group.

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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 2b, multicenter, long-term outcomes study of subjects who were randomized in 
Study SHP607-202 to either treatment (received SHP607) or control (received standard neonatal 
care) groups. Subjects will be followed from 12 months CA through 5 years CA. Subjects will
not be excluded from participating in other clinical studies. No investigational product will be 
administered in this study.
Approximately 477 subjects who previously received SHP607 or standard neonatal care in 
Study SHP607-202 are planned to be enrolled in Study SHP607-203. Although all subjects 
randomized into the primary Study SHP607-202 (approximately 477) are eligible to enroll in 
Study SHP607 203, the actual number of subjects enrolled will more closely approximate the 
number of subjects who complete Study SHP607-202. No investigational product will be 
administered in Study SHP607-203. A total of approximately 382 subjects (approximately 
127 subjects randomized to SHP607 250 μg/kg/24 hours, approximately 127 subjects 
randomized to SHP607 400 μg/kg/24 hours, and approximately 127 subjects randomized to 
standard neonatal care) are expected to complete Study SHP607-202. At 12 months CA, subjects 
will be eligible to enroll into the long-term outcome Study SHP607-203.
For subjects who complete the primary Study SHP607-202, the initial visit in Study SHP607-203 
should coincide with the final visit of Study SHP607-202 at 12 months CA +2 weeks. If the 
initial visit in Study SHP607-203 does not occur at the 12-month CA visit, the subject may still 
be enrolled until 24 months CA +6 weeks. Subjects enrolling between the 12 months CA visit 
and the 24 months CA visit should complete all 12-month CA assessments, and vision and 
hearing assessment history. Subjects enrolling at the 24 months CA visit should complete 
informed consent, eligibility criteria, demographics, medical history, and all 24 months CA 
assessments. Subjects are no longer eligible to enroll in this study after 24 months CA +6 weeks. 
Completion of Study SHP607-202 is not required for enrollment into Study SHP607-203.
CRM will be assessed using pulmonary questionnaires, which will be administered to the parents 
or legally authorized representative(s) at regularly scheduled clinical site visits and telephone 
interviews through 5 years CA. Physical examinations (including tonsil examinations) will be 
performed at 12 months, 24 months, and 5 years CA. Additionally, AEs will be assessed to 
evaluate the long-term safety of SHP607.
Time points for assessments have been chosen to represent important developmental ages for 
premature infant follow-up. Both telephone and clinical site visits are included to minimize 
burden on families while maintaining contact with subjects throughout the 5-year duration of the 
study.
The study designs are presented in Figure 1 and the Schedule of Assessments is presented in 
Table 1.

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Figure 1
Study Design Flow Diagram
CA=corrected age; D=days; GA=gestational age; IV=intravenous; M=months; PMA=postmenstrual age; W=weeks
Visits conducted at the study site are indicated in blue. Visits conducted by telephone are indicated in red. Visit 
windows are provided in the Schedule of Events (Table 1). After the last subject in the primary Study SHP607-202 
has completed the last study visit, an interim analysis for Study SHP607-203 will be performed for all enrolled 
subjects who have either completed the 24 months CA visit assessments or prematurely withdrawn from 
Study SHP607-203, and after all associated data has been entered into the database with queries and discrepancies 
resolved

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3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 4 years. The 
study will be completed in approximately 8 years.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, 
whichever is later (refer to Section 7.1.2 for the defined follow-up period for this protocol).
3.3
Sites and Regions
The study will be conducted at approximately 60 sites including, but not limited to, countries in 
the following regions: North America, Europe, and Asia Pacific (APAC).

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4.
STUDY POPULATION
Subjects who previously received SHP607 or standard neonatal care in Study SHP607-202 are 
planned to be enrolled in Study SHP607-203. Subjects in Study SHP607-202 are premature 
infants (GA of 23 weeks +0 days to 27 weeks +6 days) who are randomized to receive either 
treatment with SHP607 at 250 ug/kg/day or 400 ug/kg/day, or standard neonatal care. 
Each subject's parent(s) or legally authorized representative(s) must participate in the informed 
consent process and provide written informed consent and/or assent before any procedures 
specified in the protocol are performed.
4.1
Inclusion Criteria
Subjects must meet all of the criteria below.
1. Subject was randomized into Study SHP607-202. Subjects who were randomized, but did not 
complete Study SHP607-202 must be at least 12 months CA.
2. Written informed consents (and assents, if applicable) must be signed and dated by the 
subject's parent(s)/legally authorized representative(s) prior to any study-related procedures. 
The informed consent and any assents for underage parents must be approved by the 
institutional review board (IRB)/independent ethics committee (IEC). 
4.2
Exclusion Criterion
Subjects are excluded from the study if the subject or subject’s parent(s)/legally authorized 
representative(s) is/are unable to comply with the protocol or is/are unlikely to be available for 
long-term follow-up as determined by the investigator.
4.3
Discontinuation of Subjects
A parent or legally authorized representative may withdraw the subject 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 with the 
medical monitor when possible.
4.3.1
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the case report form (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. 

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Reasons for discontinuation include, but are not limited to:

Adverse event

Protocol deviation

Lost to follow-up

Withdrawal by parent/legally authorized representative

Physician decision

Other 
Discontinuations due to AEs and protocol deviations should be reviewed in advance with the 
medical monitor, if possible.
Subjects withdrawn from the study for an SAE should be followed until the SAE has resolved. 
Appropriate supportive and/or definitive therapy should be administered as required.
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/legally authorized 
representative(s) of 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.

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5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Not applicable as no investigational product will be administered in this study.
5.2
Concomitant Treatment and Medications
Medications, procedures, and therapies administered to study subjects from the time of informed 
consent through the 5 year CA visit (or until the subject is withdrawn or discontinued) will be 
collected, only in the context of SAEs. In addition, respiratory medications (and medications 
that may be associated with respiratory conditions) will be captured in the pulmonary morbidity 
assessment (Section 7.2.5.1), along with respiratory therapies. Any investigational products, 
procedures, and therapies received by subjects in other clinical studies will be recorded 
separately as part of an assessment of subjects’ participation in other clinical studies 
(Section 7.2.9).

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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
Not applicable as no investigational product will be administered in this study.
6.2
Administration of Investigational Product
Not applicable.
6.3
Labeling, Packaging, Storage, and Handling
Not applicable.

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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1 for study procedures. The timing of all study visits is based on subjects’ CA. 
Although Study SHP607-202 is open-label, measures will be instituted in Study SHP607-203 to 
blind selected site personnel who are involved in efficacy assessments in order to minimize bias 
in study outcomes. Site personnel who administer the following study assessments will be 
blinded to the treatment status of each subject: BSID, KSPD, WPPSI, GMFM-88, spirometry,
and MRI. Families will be instructed not to discuss treatment assignment with the assessors. The 
assessors will not be part of the study team or participate in study team meetings. The Sponsor 
will work with each site to clarify the process for blinding and each site will document the 
manner in which blinding will be maintained at the site.
7.1.1
Initial Study Visit (12 Months CA)
In general, the initial visit in Study SHP607-203 should coincide with the final visit of the 
primary Study SHP607-202 at 12 months CA +2 weeks.
At the initial visit, informed consent will be obtained followed by an assessment of study 
eligibility criteria and collection of demographic data. Additionally, the following assessments 
will be conducted:

Medical history

Body weight and length

Head circumference

Physical examination

Blood pressure, heart rate, and respiratory rate

Caregiver Impact Questionnaire (CIQ)

Pulmonary morbidity assessment (only for subjects who did not complete Study 
SHP607-202)

Health care resource use

Assessment of participation in other clinical studies 

Medications, procedures, and therapies

Adverse events, including targeted medical events (refer to Section 8.1).
Results of previously completed vision and hearing assessments, if performed, may be recorded 
at any time during the study up to the 5-year CA visit.

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7.1.2
Study Visits 
Study visits will take place at the following time points in CA:

18 months (±6 weeks); conducted by telephone

24 months (±6 weeks); clinical site visit

30 months (±6 weeks); conducted by telephone

3 years (±6 weeks); conducted by telephone

3.5 years (±6 weeks); conducted by telephone

4 years (±6 weeks); conducted by telephone

4.5 years (±6 weeks); conducted by telephone

5 years (±6 weeks); clinical site visit
The activities at the study visits are described in Section 7.1.2.1 and Section 7.1.2.2.
7.1.2.1
Assessments Conducted by Telephone
Visits at 18 months, 30 months, 3 years, 3.5 years, 4 years, and 4.5 years CA will be conducted 
by telephone. The following assessments will be conducted at each of these 6 visits, unless 
otherwise indicated:

Pulmonary morbidity assessment 

Pediatric Quality of Life Inventory (PedsQL™) (3-year and 4-year visits) 

EQ-5D-5L (3-year and 4-year visits)

Health care resource use 

Assessment of participation in other clinical studies 

Medications, procedures, and therapies

Adverse events, including targeted medical events 
Results of previously completed vision and hearing assessments, if performed, may be recorded 
at any time during the study up to the 5-year CA visit.
7.1.2.2
Assessments Conducted at Clinical Site Visits
Visits at 24 months and 5 years CA will be conducted at clinical site visits. The following 
assessments will occur at these visits:

24 months (±6 weeks)
-
Body weight and height/length
-
Head circumference

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-
Bayley Scales of Infant and Toddler Development (BSID) (or Kyoto Scale of 
Psychological Development [KSPD])
-
Gross Motor Function Measure (GMFM-88)
-
Vineland Adaptive Behavior Scales (VABS)
-
Physical examination
-
Blood pressure, heart rate, and respiratory rate
-
Vision and hearing assessment history
-
Pulmonary morbidity assessment 
-
PedsQL
-
Health care resource use
-
CIQ
-
EQ-5D-5L
-
Assessment of participation in other clinical studies
-
Medications, procedures, and therapies
-
Adverse events, including targeted medical events
-
BabyScreen (optional)

5 years (±6 weeks)
-
Visual acuity
-
Body weight and height
-
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)
-
Gross Motor Function Measure (GMFM-88) Section D (Standing) and Section E 
(Walking, Running and Jumping) 
-
Vineland Adaptive Behavior Scales (VABS)
-
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS)
-
Social Communication Questionnaire (SCQ)
-
Physical examination
-
Blood pressure, heart rate, and respiratory rate
-
Vision and hearing assessment history
-
Pulmonary morbidity assessment 
-
PedsQL
-
Health care resource use
-
Health Utilities Index Mark 2 and Mark 3 (HUI2/3)

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-
Caregiver Impact Questionnaire (CIQ)
-
Assessment of participation in other clinical studies
-
Medications, procedures, and therapies
-
Adverse events, including targeted medical events
-
Spirometry (optional)
-
Cerebral magnetic resonance imaging (optional)
If a subject discontinues participation in the study or the subject is discontinued by the 
investigator, reasonable efforts will be made to perform any end of study examinations if deemed 
clinically relevant in the opinion of the investigator.
7.1.3
Additional Care of Subjects after the Study
No aftercare is planned for this study.
7.2
Study Evaluations and Procedures
7.2.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the subject’s parent(s) or legally authorized representative(s). Since the subjects cannot 
provide any information and decide for themselves, the parents or legally authorized 
representatives of the subjects will take full responsibility of information and any decisions on 
behalf of subjects.
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the subject, the subject’s parent(s), or the subject’s legally authorized representative 
by the investigator or designee in accordance with the guidelines described in Section 10.3.1. 
Documentation and filing of informed consent documents should be completed according to 
Section 10.3.1.
7.2.2
Study Entrance Criteria
At the initial visit, each subject will be reviewed for eligibility against the study entrance criteria. 
Subjects who do not meet the study entrance criteria will not be allowed to participate in the 
study. The reason(s) for the subject’s ineligibility for the study will be documented. No 
exemptions will be allowed.
If the initial visit in Study SHP607-203 does not occur at the 12 month CA visit, the subject may 
still be enrolled until 24 months CA +6 weeks. Subjects are no longer eligible to participate in 
this study after 24 months CA +6 weeks.
7.2.3
Study Enrollment
At the initial visit, subjects meeting study entrance criteria will be enrolled.

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7.2.4
Demographic and Other Baseline Characteristics
Subject demographic information including sex, date of birth, and ethnicity will be recorded at 
the initial visit. 
7.2.5
Efficacy
7.2.5.1
Pulmonary Morbidity Assessment
Pulmonary morbidity will be assessed through an interviewer-administered questionnaire at the 
clinical site at 12 months (only for subjects who did not complete Study SHP607-202), 
24 months and 5 years CA and by telephone visits at 18 months, 30 months, 3 years, 3.5 years, 
4 years, and 4.5 years CA. 
The questionnaire will be administered to the subject's parent(s) or legally authorized 
representative(s), and includes 2 components:
1) Respiratory Conditions Assessment: Data collected includes emergency room visits and 
hospitalizations for respiratory diagnoses, medications required for respiratory diagnoses, 
respiratory-related home technology use, and wheezing/coughing episodes. This is 
completed every 6 months through 5 years CA.
2) Respiratory Risk Factors Assessment: Data collected include second-hand smoke 
exposure, pets, and vaccinations/prophylaxis. This is completed annually through 5 years 
CA.
7.2.5.2
Growth Parameters
Body Length and Height
Body length (supine measurement) will be collected at the 12 months and 24 months CA visit. 
For the length measurement, the subject will be placed on his or her back so that the subject is 
lying straight and the shoulders and buttocks are flat against the measuring surface. The subject's 
eyes should be looking straight up and care should be taken that the head is in a neutral position 
(neither being flexed nor extended at the neck). Both legs should be fully extended and the toes 
should be pointing upward with feet perpendicular to the measuring surface.
Height (standing measure) will be collected at the 5 years CA visit. A stadiometer should be 
utilized for measurement of height. The subject should remove shoes.
For the measurement of standing height, the child is instructed to stand erect (stand up straight 
and look straight ahead) with the child’s head positioned in a horizontal plane. The moveable 
headpiece is brought onto the upper most (superior) point on the head with sufficient pressure to 
compress the hair. 
For height and length, 2 measures should take place and both will be recorded. If the 2 measures 
are discrepant by >2 cm, the measures should be repeated. All measures should be recorded in 
metric units and measurement should be recorded to the nearest tenth centimeter (0.1 cm).

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Body Weight
Body weight will be collected. Calibrated scales should be utilized for body weight measures. 
Care should be taken to remove any extraneous clothing prior to measures and shoes should be 
removed. Body weight should be recorded to the nearest 0.2 lb/0.1 kg.
Head Circumference
Head circumference will be measured for all subjects. An accurate head circumference 
measurement is obtained with a “lasso”-type, non-stretchable measuring tape such as the Lasso-o 
tape. Head circumference or occipital frontal circumference is measured over the occiput and just 
above the supraorbital ridge, which is the largest circumference of the head.
7.2.5.3
Visual Acuity
Visual acuity is a measure of how well a subject sees at different distances. Measurements will 
be recorded for the left (OS), right (OD), and both eyes (OU). Visual acuity will be attempted at 
5 years CA by the LEA Symbols Chart.
7.2.5.4
Vision and Hearing Assessment History
Results of previously completed vision and hearing assessments, if performed, may be recorded 
at any time during the study up to the 5 year CA visit. Visual acuity will be measured at 5 years 
CA (see Section 7.2.5.3), but hearing tests are not being performed as part of this study. 
7.2.5.5
Cognitive and Behavioral Assessments
Bayley Scales of Infant and Toddler Development (BSID)
The BSID will be used to assess cognitive, motor, and language skills at the 24 months CA visit.
The BSID is an assessment tool designed to measure a young child's skills in the 5 domains of 
development: cognitive, language, motor, social emotional and adaptive behavior. The 
2 language subscales (expressive and receptive) combine to make a total language score and the 
2 motor subtests (fine and gross motor) form a combined motor scale.
The tool is engaging, with colorful props and visual stimuli that capture the attention of the child. 
The individual test items are short, limiting the amount of attention required for each item. The 
test administration is flexible in that items can be administered out of order, provided the
assessor adheres to the specific guidelines in the Study Operations Manual.
The BSID will be administered to the subject, with participation of the subject’s parent(s) or 
legally authorized representative(s), by a trained professional. Scores to be recorded are detailed 
in the Study Operations Manual.
Kyoto Scale of Psychological Development (KSPD)
As an alternative to the BSID, the KSPD may be used to assess cognitive, motor, and language 
skills at the 24 months CA visit. 

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The KSPD is a validated neurodevelopmental outcome assessment that is standardized for 
Japanese children (Kono et al., 2016; Tatsuta et al., 2013), and has been evaluated in comparison 
to BSID in the assessment of developmental characteristics of very low birth weight Japanese 
infants. 
The KSPD is designed to measure a young child's skills in three domains of development: 
Cognitive-Adaptive (non-verbal reasoning or visuospatial perception), Language-Social 
(interpersonal relationships, socialization, verbal abilities), and Postural-Motor (fine and gross 
motor functions). Scores are converted into a developmental quotient that measures attainment of 
developmental age for the corrected age of the child. 
The KSPD will be administered to the subject, with participation of the subject’s parent(s) or 
legally authorized representative(s), by a trained professional. Scores to be recorded are detailed 
in the Study Operations Manual.
Wechsler Preschool and Primary Scale of Intelligence (WPPSI)
The WPPSI is a measure of general cognitive development in children that has components of 
both verbal and nonverbal tasks. It is applicable to preschoolers and young children aged 2 years 
+6 months to 7 years +7 months.
It is composed of the following 5 scales:

Verbal

Performance

Processing Speed

Full Scale

Language
It not only applies to healthy children, but in the course of the scale’s standardization special 
group validity studies were performed, including, but not limited to, groups of children with 
developmental risk factors, autistic disorder, and intellectual disability. Scores may be 
interpreted in the context of provided norms, which reflect inclusion of the special groups.
The WPPSI will be administered to the subject by a trained professional at 5 years CA. Scores to 
be recorded are detailed in the Study Operations Manual.
Gross Motor Function Measure-88 (GMFM)
The GMFM-88 will be used to measure motor function while lying and rolling, sitting, crawling 
and kneeling, standing, and walking, running and jumping. The test is considered to be 
appropriate for children whose motor skills are at or below those of a 5-year-old child without 
any motor disability (Russell et al., 1989).

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The GMFM-88 will be administered to the subject by a trained professional at 24 months CA. 
GMFM-88 Section D (Standing) and Section E (Walking, Running and Jumping) only will be 
administered at 5 years CA. Scores to be recorded are detailed in the Study Operations Manual.
Vineland Adaptive Behavior Scales (VABS)
The VABS Expanded Interview Form will be used to measure the personal and social skills. 
These scales are organized into domains, including Communication, Daily Living, Socialization, 
and Motor Skills.
The VABS Expanded Interview Form will be completed by the subject’s parent(s) or legally 
authorized representative(s) at 24 months CA and at 5 years CA/end of study. Scores to be 
recorded are detailed in the Study Operations Manual.
Attention-Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS)
The ADHD-RS was developed to measure the behaviors of children with attention-deficit 
hyperactivity disorder (ADHD). The ADHD-RS consists of 18 items designed to reflect 
current symptomatology of ADHD based on DSM-V criteria. Each item is scored from a 
range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging 
from 0-54. 
The 18 items are grouped into 2 subscales: hyperactivity impulsivity (even numbered items 2-18) 
and inattention (“inattentiveness”) (odd numbered items 1-17).
The ADHD-RS (DuPaul et al., 1998) will be completed by the subject’s parent(s) or legally 
authorized representative(s) at 5 years CA. The investigator or designee should review the 
assessment for completeness and to confirm all responses. Scores to be recorded are detailed in 
the Study Operations Manual.
Social Communication Questionnaire – Lifetime Form
The SCQ is a brief instrument that helps evaluate communication skills and social functioning in 
children (Rutter et al., 2003) that can be used for screening for autism or autism spectrum 
disorders in the general population (Chandler et al., 2007).
The SCQ will be completed by the subject’s parent(s) or legally authorized representative(s) at 
5 years CA. The investigator or designee should review the assessment for completeness and to 
confirm all responses. Scores to be recorded are detailed in the Study Operations Manual.
7.2.5.6
Health Economic Outcome Research Assessments
Health-related quality of life (HRQoL) is an important measure of health status or well-being and
can be influenced by clinical interventions. It is an important concept used in determining the 
value of health care services and can serve as a screening tool for identifying physical and 
psychosocial health concerns from the perspectives of both the child and parent (Matza et al., 
2004; Varni et al., 2005). HRQoL is a multidimensional construct; minimally it includes 
physical, psychological (including emotional and cognitive), and social health dimensions. 

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Pediatric Quality of Life Inventory (PedsQL) Infant Scales
In this study, HRQoL will be assessed via the validated Pediatric Quality of Life Inventory 
(PedsQL) Infant Scales appropriate for the child’s age of development (Varni and Limbers, 
2009; Varni et al., 2011; Varni et al., 2001).
The following scales will be used in this study:

Infant Scale for ages 13-24 months (45 Items)

Toddler Scale for 2-4 years of age (21 Items)s

Young Child Scale for 5-7 years of age (23 Items)
The PedsQL will be administered to the subject’s parent(s) or legally authorized representative(s) 
and may be conducted via telephone by clinical site staff at the time points specified in the 
Schedule of Assessments (Table 1). The scale(s) to be administered at each visit will be specified 
in the Study Operations Manual.
EQ-5D-5L
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
(EuroQol, 1990; Orgeta et al., 2015; Nolan et al., 2016). The EQ-5D-5L 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 the health of the subject’s parent(s), including 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is 
represented by a single item with 5 levels of responses.
The EQ-5D-5L will be administered to the subject’s parent(s) or legally authorized 
representative(s) by site personnel at 24 months CA, 3 years CA, and 4 years CA. Details about 
the use and administration of the EQ-5D-5L instrument will be provided in the Study Operations 
Manual.
Health Care Resource Use (HCRU)
To understand the value of the investigational product administered in Study SHP607-202, 
inpatient and outpatient visits, including visits to specialists, will be recorded at the time points 
specified in the Schedule of Assessments (Table 1). Learning support needs and impairment of 
caregiver productivity will also be assessed.
This assessment may be conducted in person at clinic visits or via telephone by clinical site staff.
Health Utilities Index (HUI)
The Health Utilities Index (HUI) is a family of generic health profiles and preference-based 
systems used for measuring health status, reporting HRQoL, and producing utility scores. 

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The HUI2/3 each include a generic comprehensive health status classification system and a 
generic HRQoL utility scoring system (Horsman et al., 2003). The HUI2/3 will be administered 
to the subject’s parent(s) or legally authorized representative(s) and may be conducted in person 
at clinic visits or via telephone by clinical site staff at 5 years CA as specified in the Schedule of 
Assessments (Table 1).
Caregiver Impact Questionnaire (CIQ)
Caregiver burden will be assessed by the CIQ. The CIQ includes 30 items in total and covers the 
key areas of impact for caregivers, including: 1) impact on relationships, family, social life, and 
leisure activities; 2) impact on personal time and daily activities; 3) psychological impacts; 
4) impact on physical health; and 5) impact on finances and productivity. Data will be collected 
and summarized descriptively. Results may also contribute to the recommended scoring for 
studies. The CIQ will be administered to the subject’s parent(s) or legally authorized 
representative(s) and may be conducted via telephone by clinical site staff at the time points 
specified in the Schedule of Assessments (Table 1).
7.2.5.7
BabyScreen Assessment (Optional)
BabyScreen is an interactive electronic tablet application to evaluate cognitive impairment, used 
by preterm children at approximately 24 months CA. The tool is engaging, with colorful screens 
and visual prompts that capture the attention of the child and promote engagement and 
interaction. Instructions for the site are minimal. The child is encouraged to play with the tablet; 
no or minimal prompting is needed. This exploratory, optional assessment will be used for 
validation purposes only, benchmarked against BSID for future use. Participation is limited to 
selected sites.
7.2.5.8
Spirometry (Optional)
Spirometry will be performed at the 5-year visit. Standard measures will be collected, including 
forced expiratory volume over 1 second (FEV1) and forced vital capacity (FVC). Participation is 
optional and has no impact on participating in the main study. Participation is limited to selected 
sites that have access to personnel with expertise in performing pediatric spirometry.
7.2.6
Cerebral Magnetic Resonance Imaging (Optional)
Participation in the MRI assessment is optional, limited to sites that participated in the MRI 
assessment in Study SHP607-202, and has no impact on participating in the main study. If 
consented to, MRI of the brain will be performed. 
Volumetric analyses of the cortical gray matter, cortical white matter, corpus callosum, frontal 
lobes, cerebellum, and total volume will be analyzed for the purposes of this study. 
The nature, scope, risks, benefits, and potential sedation associated with the procedure will be 
explained to the subject and subject’s parent(s) or legally authorized representative(s) by the 
investigator or a designated trained study personnel. Subject’s parent(s) or legally authorized 
representative(s) will be asked to separately opt in or decline participation in this part of the 
study in the informed consent document.

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7.2.7
Safety
7.2.7.1
Medical History
Medical events or conditions should only be captured as medical history if they occur after the 
end of the subject’s participation in the primary Study SHP607-202 and before informed consent 
in the current Study SHP607-203.
7.2.7.2
Physical Examination 
Physical examinations will include a general examination (including assessment of tonsillar 
hypertrophy) and a neurological examination (Table 2). Examinations will be performed at the 
time points specified in the Schedule of Assessments (Table 1).
Table 2
Assessments for Physical Examinations
General appearance
Cardiovascular
Head and neck
Abdomen
Eyes
Genitourinary
Ears
Skin
Nose
Musculoskeletal
Throat
Neurological
Tonsils
Cerebral palsy (24 months CA only)
Chest and lungs
7.2.7.3
Blood Pressure, Heart Rate, and Respiratory Rate
Blood pressure, heart rate, and respiratory rate will be measured at the 12-month, 24-month, and 
5-year CA visits.
7.2.7.4
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?”). 
Please refer to Section 8, Adverse and Serious Adverse Events Assessment.
7.2.8
Medication Assessment
All medications received by study subjects will be collected from the time of enrollment through 
the 5-year CA visit (or upon discontinuation). Any investigational product received by subjects 
will be recorded separately as part of an assessment of subjects’ participation in other clinical 
studies (Section 7.2.9).
7.2.9
Participation in Other Clinical Studies
Following enrollment, subjects in this study will not be restricted from enrolling in other clinical 
studies that involve the use of investigational product. The status of a subject’s participation in 
such studies will be recorded (ie, yes/no). If a subject is enrolled in such a study, additional 
parameters will be recorded, including the masking status of the study, the identity of the 
investigational product or treatment being evaluated in the study, and the subject’s treatment 
assignment in the study (if possible). 

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7.2.10
Appropriateness of Measurements
Overall, the primary and secondary efficacy and safety measures being employed in this study 
are considered appropriate for the follow-up of preterm infants. The validated tools being used to 
assess neurodevelopment, physical development, and health economic research outcomes in this 
pediatric population are widely used and recognized.
In some cases, tools were designed specifically for use in this study, namely, the pulmonary 
morbidity questionnaire. In this case, the assessment is based on published research in a similar 
pediatric population (Pryhuber et al., 2015). 

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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
According to the International Conference on Harmonization (ICH), an AE is "any untoward 
medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with 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 E6 [R2] 2016). 
In this long-term outcome study in follow-up to Study SHP607-202, no investigational product is 
being administered; it is therefore a non-interventional study. However, it seeks information on 
whether prior administration of IMP in Study SHP607-202 impacts long-term outcomes. 
For the purposes of this study only the following AEs will be collected:

Specified targeted medical events (Section 8.1.4) 

AEs related to investigational product

AEs leading to withdrawal from the study

Serious AEs that occur during the study period or were previously present and worsen during 
the study period.
All AEs described above are collected from the time the informed consent is signed until the 
defined follow-up period stated in Section 3.2. 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 described above should be captured on the appropriate AE pages in 
the CRF and in source documents. 
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. 

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The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to prior 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”. The causality assessment 
must be documented in the source.
The following additional guidance may be helpful:
Related
The temporal relationship between the event and the administration of the investigational 
product is compelling enough and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other 
therapies, or accident.
Not related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or biologic 
relationship exists between the investigational product and the event.
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

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
Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown
8.1.4
Targeted Medical Events
If it is determined that any of the following targeted medical events have been experienced by a 
subject, they will be recorded as AEs or SAEs (refer to Section 8.2.3), as appropriate, regardless 
of relationship to prior investigational product (SHP607 as administered in Study SHP607-202):

Intracranial hypertension

Any abnormality of glucose metabolism (eg, hypoglycemia, hyperglycemia, and diabetes)

Tonsillar hypertrophy (based on tonsil examination [part of the physical examination])

Increased cardiac size
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. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If there are abnormal clinical laboratory values or vital signs which were not present at the start 
of the study, and which are relevant to AEs collected in this study, 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 is clinically significant and 
therefore represents an AE.
8.1.6
Abuse, Misuse, Overdose, and Medication Errors
Not applicable.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
Investigators should refer to the most current version of the SHP607 IB for reference safety 
information, which is found in IB Section 6, Summary of Data and Guidance for the Investigator.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to Shire Global Drug 
Safety within 24 hours of the first awareness of the event. 

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The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form 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 SAE form to Shire Global Drug Safety
(drugsafety@shire.com). A copy of this form must also be sent to the CRO/Shire medical 
monitor by fax or e-mail using the details provided below:
NA Safety Fax number:
1-888-529-3580
EMEA and APAC Safety Fax: 
  +44 122 337 4102
E-mail:
drugsafety@shire.com 
8.2.3
Serious Adverse Event Definition
An SAE is any untoward clinical manifestation of signs, symptoms or outcomes (whether 
considered related to investigational product or not and 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 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:

Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization.

Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E 
virus (HEV), or parvovirus B19 (B19V)

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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study drug) are collected from the time the subject signs 
the informed consent until the defined follow-up period stated in Section 7.1.2 and must be 
reported to Shire Global Drug Safety within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product (SHP607 as 
administered in Study SHP607-202) and discovered by the investigator at any interval after the 
study has completed must be reported to the Shire Global Drug Safety 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 
date 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, or 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 assessed 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 not resolved, without a resolution date recorded.
For all fatal SAEs, all autopsy reports, pathology reports, death certificates, and other medical 
records should be provided to the sponsor. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and clinical contract research organization (CRO) are responsible for notifying the 
relevant regulatory authorities and US central IRBs/European Union (EU) central ethics 
committees (ECs) of related, unexpected SAEs.
In addition, the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP607 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.

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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. 
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
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
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. The SAP will also include a description of how missing, unused and spurious 
data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. All statistical analyses will be performed using SAS(SAS 
Institute, Cary, NC 27513).
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
After the last subject in the primary Study SHP607-202 has completed the last study visit, an 
interim analysis for Study SHP607-203 will be performed for all enrolled subjects who have 
either completed the 24 months CA visit assessments or prematurely withdrawn from 
Study SHP607-203, and after all associated data has been entered into the database with queries 
and discrepancies resolved.

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9.5
Sample Size Calculation and Power Considerations
No formal sample size calculation was performed for this study because this is a follow-up study 
to Study SHP607-202. Any subjects enrolled in Study SHP607-202 are eligible to enroll in this 
study. Although all subjects randomized into the primary Study SHP607-202 (approximately 
477) are eligible to enroll in Study SHP607-203 (completion of Study SHP607-202 is not 
required), the actual number of subjects enrolled will more closely approximate the number of 
subjects who complete Study SHP607-202. A total of approximately 382 subjects are expected to 
complete Study SHP607-202.
9.6
Study Population
The Enrolled Population will consist of all subjects for whom written informed consent has 
been provided for this study.
The Safety Population will consist of the subjects in the Enrolled Population who have safety 
follow-up data (including absence of AEs) in this long-term outcome study. 
9.7
General Statistical Methodology
For variables following a continuous distribution, tabular summaries will consist of number of 
subjects, mean, standard deviation, minimum, maximum, and median. For categorical variables, 
tabular summaries will include the frequency and the percentage in each category by treatment 
group. For analysis purposes, baseline is defined as the first assessment in this study 
(Study SHP607-203). Treatment groups refer to the antecedent SHP607 dose groups (SHP607 at 
250 µg/kg/day and SHP607 at 400 µg/kg/day), combined SHP607 dose groups, and standard 
neonatal care group. 
All efficacy analyses will be performed using the Enrolled Population.
9.7.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the incidence of the following indicators of CRM:
1)
Emergency room visit or hospitalization associated with a respiratory diagnosis.
2)
Presence of coughing/wheezing. 
3)
Use of respiratory medications (eg, bronchodilators, steroids, leukotriene inhibitors, 
diuretics). 
4)
Home respiratory technology use (eg, home oxygen, continuous positive airway pressure 
[CPAP], tracheostomy).
The frequency and proportion of each component of CRM at 5 years CA for each treatment 
group (as administered in Study SHP607-202) will be summarized and their respective 
95% confidence interval (CI) will be reported. The difference in the proportion between each of 
the SHP607 dose groups (individual dose and combined doses) and the standard neonatal care 
group and the corresponding 95% CI will also be summarized.

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9.7.2
Secondary Endpoints
The secondary endpoints are defined as:

Growth parameters including body weight, body length (or height), and head 
circumference.

Physical development as assessed by standardized, age appropriate tools including physical 
exam, neurological examination for assessment of cerebral palsy, and vision assessment. 
Reports of past vision and hearing assessments will also be collected

Cognitive development as assessed by the following standardized, age-appropriate tools:
-
BSID (or KSPD)
-
WPPSI 

Gross motor function as assessed by GMFM-88.

Child behavior as assessed by the following:
-
VABS
-
Attention-Deficit/Hyperactivity Disorder Rating Scale-fifth edition (ADHD RS-V) for 
the assessment of symptoms of ADHD
-
SCQ for screening of Autism Spectrum Disorder (ASD)

HRQoL will be assessed by the PedsQL Infant Scales appropriate for the child's age of 
development with the Total Scale Score and 5 domains within Physical Health (Physical 
Functioning and Physical Symptoms) and Psychosocial Health Scores (Emotional, Social, 
and Cognitive Functioning).

Health status (eg, health utility) will be measured by the HUI2/3.

Health care resource use associated with inpatient visits, outpatient visits, emergency room 
visits, and visits to specialists will be assessed. 
Continuous endpoints will be summarized by number of subjects, minimum, maximum, median, 
mean, standard deviation, two sided 95% CI by treatment groups. Binary and categorical 
endpoints will be summarized by number of subjects, frequency, proportion and two-sided
95% CI by treatment groups.
9.7.3
Exploratory Endpoints
Caregiver Impact Questionnaire (CIQ): Descriptive statistics of the CIQ item responses at 
baseline, 24 months CA, and 5 years CA.
EQ-5D-5L: Mean overall score on the EQ-5D-5L at 24 months CA, 3 years CA, 4 years CA, and 
change from 24 months CA.
BabyScreen interactive electronic tablet application: Participation in the BabyScreen substudy is 
optional and has no impact on participation in the main study. The tool, used by children at 
24 months CA to evaluate cognitive impairment, will be used for validation purposes only. 

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Spirometry: Participation in the spirometry substudy is optional and has no impact on 
participation in the main study. Standard measures will be collected, including forced expiratory 
volume over 1 second (FEV1) and forced vital capacity (FVC).
Cerebral MRI: Participation in the cerebral MRI substudy is optional and has no impact on 
participation in the main study. Brain volume and neuroanatomic abnormalities will be assessed 
utilizing cerebral MRI at specific sites with MRI capabilities.
9.7.4
Health Economics and Outcomes Research Analyses
For PedsQL, CIQ, and EQ-5D-5L, descriptive statistics will be provided for summary scores by 
treatment group (as administered in Study SHP607-202) and at each time point.
The HUI 2/3 system contains a number of attributes/domains to classify the level of health status. 
Each attribute or domain (eg, mobility, cognition, emotion or pain) is rated on a 5-point ordinal 
scale to indicate the severity level, ranging from 1 to 5 (higher numbers indicating a more severe 
level). Summary statistics will be provided by treatment group.
For HCRU the utilization for each resource-item (eg, hospital days, physician visits) reported at 
each time point will be reported descriptively by treatment group.
9.8
Safety Analyses
Safety data will be analyzed for the Safety Population. 
For safety analyses, baseline is defined as the first assessment in this study (Study SHP607-203). 
Treatment groups refer to the antecedent SHP607 dose groups (SHP607 at 250 µg/kg/day and 
SHP607 at 400 µg/kg/day), combined SHP607 dose groups, and standard neonatal care group.
The primary safety analysis will be based on:

AEs reported during the study period of SHP607-203
The secondary safety analysis will be based on:

Targeted medical events occurring during the period of Study SHP607-203.

Fatal SAEs
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of AEs will be calculated overall, by system organ 
class (SOC), by preferred term, and by treatment group. Adverse events will be further 
summarized by severity and relationship to prior investigational product. Adverse events related 
to investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.

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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements. 
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
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, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.

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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
The sponsor will provide the ECs with a copy of the same summary.
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.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
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 
(R2) (2016), 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 coordinating principal investigator, in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH GCP Guideline E6 (R2) (2016). 
The coordinating principal investigator will be chosen by the sponsor.

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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
Case report forms 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.
10.2.3.2
Electronic Clinical Outcome Assessments
Assessment data collected electronically are maintained in a secure database with access controls 
in place to ensure only approved users have the ability to review the data. The data are 
maintained by a third-party vendor and may change during the course of the project and through 
an established data management process. Following database lock, the electronic clinical 
outcome assessments (eCOA) vendor will produce a study archive on electronic media to both 
sites and the sponsor. Site archive media will include information pertinent to their study 
patients, but the sponsor is provided with content for the entire study. 

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Archive media consists of the following: trial documentation, metadata directory, XML data 
director, final data transfer file, and electronic case report forms that are generated from the 
eCOA system.
10.2.3.3
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 and original clinical laboratory 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 to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/IEC 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/IEC, 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.
10.2.3.4
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.
10.2.3.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).

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10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent (or assent) from all 
study subjects prior to any study-related procedures including screening assessments. All consent 
and assent 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 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 and assent 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.
The principal investigator provides the sponsor with a copy of the consent form and assent form 
that was reviewed by the IRB/IEC and received their favorable opinion/approval. A copy of the 
IRB/IEC’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/IEC 
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.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation.

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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 at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; 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 as 
required by IRB/EC procedures.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO.
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 SHP607; 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 purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. 

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The site agrees not to publish or present the site’s study results until such time as either the 
aggregate multi-site study results are published in a cooperative publication or for a period of 
one (1) year after termination or completion of the study at all participating sites, whichever shall 
first occur. After that time, the site may publish the site’s study results in scientific journals or 
present the study results at symposia or other professional meetings in accordance with the 
following provisions:
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.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Shire is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Shire-supported research. Therefore, after January 1, 2018, Shire 
will require the submission of all Shire-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and 
self-archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
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 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.

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11.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
18 Nov 2019
Global
Protocol Amendment 1
08 April 2020
Global